university of groningen left ventricular function after

University of Groningen

Left ventricular function after STEMIVleuten Pieter Adriaan van der

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Left ventricular function after STEMI

Developments in diagnostics and cell therapy

Pieter A van der Vleuten

Financial support by the Netherlands Heart Foundation and the UMCG for the publication of

this thesis is gratefully acknowledged

Van der Vleuten Pieter A

Left ventricular function after STEMI Developments in diagnostics and cell therapy

Proefschrift Groningen

ISBN 978-90-367-3906-1

ISBN (Digitaal) 978-90-367-3907-8

copy Copyright 2009 PA van der Vleuten

All rights are reserved No part of this publication may be reproduced stored in a retrieval

system or transmitted in any form or by any means mechanically by photocopying

recording or otherwise without the written permission of the author

Cover Gonda de Jonge

Lay-out and printed by Gildeprint Drukkerijen - Enschede The Netherlands

RIJKSUNIVERSITEIT GRONINGEN



Proefschrift

ter verkrijging van het doctoraat in de

Medische Wetenschappen

aan de Rijksuniversiteit Groningen

op gezag van de

Rector Magnificus dr F Zwarts

in het openbaar te verdedigen op

woensdag 16 december 2009

om 1615 uur

door

Pieter Adriaan van der Vleuten

geboren op 25 augustus 1980

te Mook en Middelaar

Promotor Prof dr F Zijlstra

Copromotor Dr RA Tio

Beoordelingscommissie Prof dr ROB Gans

Prof dr JJ Piek

Prof dr DJ van Veldhuisen

Paranimfen Drs Niels van Minnen

Drs Michiel Kuijpers

The research presented in this thesis is supported by the Netherlands Heart Foundation

Additional contributions by the following sponsors are gratefully acknowledged

Pfizer Medtronic Bakken Research Center Sanofi-Aventis Nederland Biotronik Nederland

Interuniversitair Cardiologisch Instituut Nederland Novartis Bayer Healthcare Boehringer

Ingelheim NL Eli Lilly Nederland Astra Zeneca GUIDE Roche Diagnostics Nederland

Medtronic NL Servier Nederland Farma Siemens Stichting Edu Cardio Groningen University

of Groningen

Contents

Chapter 1 9

Introduction and scope of this thesis

Part 1 Developments in diagnostics Indicators of prognosis

Chapter 2 17

The importance of left ventricular function for long-term outcome after primary percutaneous

coronary intervention

BMC Cardiovasc Disord 2008 Feb 2384

Chapter 3 29

Prognostic value of Q-waves on the 12-lead electrocardiogram after primary percutaneous

coronary intervention for ST-elevation myocardial infarction Analysis of data from the

thrombus aspiration during primary percutaneous coronary intervention study (TAPAS)

J Electrocardiol 2009 Jul-Aug42(4)310-8

Chapter 4 51

Early assessment of ST-segment resolution residual ST-segment elevation and Q waves in

relation to left ventricular function size and extent of infarction and microvascular injury in

acute myocardial infarction

J Am Coll Cardiol Img 2009 Oct2(10)1187-94

Chapter 5 67

Value and limitations of Electromechanical Endocardial Mapping in the assessment of global

and regional left ventricular function and transmural extent of infarction A comparison with

Cardiovascular Magnetic Resonance

Submitted

Part 2 Cell therapy after STEMI

Chapter 6 87

Cell-therapy after reperfusion therapy for ST-elevation myocardial infarction

Chapter in ldquoMechanical Reperfusion For STEMI From Randomized Trial to Clinical Practicerdquo

Chapter 7 99

Intracoronary infusion of autologous mononuclear bone marrow cells in patients with acute

myocardial infarction treated with primary PCI pilot study of the multicenter HEBE trial

Catheter Cardiovasc Interv 2008 Feb 1571(3)273-81

Chapter 8 115

Intracoronary infusion of autologous mononuclear bone marrow cells or peripheral

mononuclear blood cells after primary PCI Rationale and design of the HEBE trial - a

prospective multicenter randomized trial

Am Heart J 2006 Sep152(3)434-41

Chapter 9 133

Intracoronary infusion of mononuclear bone marrow or peripheral blood cells after primary

percutaneous coronary intervention

Submitted

Chapter 10 155

Summary and conclusions

Summary in Dutch (Nederlandse samenvatting) 161

Dankwoord 167

Introducti on and scope of this thesis

1

Chap

ter

1

10

Intr

oduc

tion

and

scop

e of

this

thes

is

11


The management of patients with an acute ST-elevation myocardial infarction (STEMI) has

fundamentally changed over the last twenty years In the eighties thrombolytic agents were

introduced and more recently primary percutaneous coronary intervention (PCI) has been

shown to be even more effective(12) In patients surviving the first days after primary PCI

risk stratification is of great clinical relevance for the further (medical) management Among

others global left ventricular function has always been viewed as an important prognostic

factor after acute myocardial infarction Earlier trials in large cohorts of STEMI-patients

treated with either thrombolytic agents or supportive care (no reperfusion-therapy) have

confirmed this prognostic value for a period of six months after myocardial infarction(3-7)

Assessment of LVEF can be performed by a number of different imaging modalities

ranging from echocardiography to direct contrast ventriculography The current standard

of reference for global left ventricular function analysis is short-axis magnetic resonance

imaging (MRI) using Steady State Free Precession sequences(8-10) The main advantage of

MRI is its excellent temporal resolution without exposing the patient to ionising radiation

or iodine-based contrast-agents In addition MRI does not rely on geometrical assumptions

for assessment of LV function parameters However MRI is contra-indicated in a substantial

number of patients for various reasons eg non- MR compatible implants or claustrophobia

(11) Furthermore assessment of coronary artery anatomy using MRI is currently held to be

inferior to assessment by computed tomography (CT)(12) Although MRI remains the gold

standard for assessment of cardiac functional parameters CT is slowly gaining ground due

to several major extensive technological improvements(13-15)

In chapter 2 we sought to determine the long-term prognostic value of left ventricular

ejection fraction (LVEF) assessed by planar radionuclide ventriculography after STEMI

treated with primary PCI In chapter 3 we set out to assess the clinical and prognostic value

of Q-waves on the surface electrocardiogram after primary PCI for STEMI

In chapter 4 we analyze the relationship between diverse baseline and electrocardiographic

parameters and MRI In chapter 5 we assess the value of 3D electromechanical cardiac

mapping and compare it to MRI

Chap

ter

1

12

Part 2 Modulation of left ventricular function after STEMI by cell therapy

Although numerous studies have shown that prompt reperfusion of the coronary arteries

reduces early mortality and improves late clinical outcome in patients with acute myocardial

infarction an increasing number of patients suffers from symptoms of heart failure as a

result of post-infarct deterioration of left ventricular function In order to challenge these

ever-growing problems the concept of improving left ventricular function after reperfusion

therapy by bone marrow-derived progenitor cell infusion has been advocated extensively

and various trials have been conducted predominantly with positive results Several reports

have demonstrated that cell transplantation after acute myocardial infarction in humans is

safe and could lead to better preserved left ventricular function and improved myocardial

perfusion and coronary flow reserve(16-21)

Cell therapy in vivo

A detailed overview of available evidence for cell therapy is provided in chapter 6 In

chapter 7 we sought to evaluate whether intracoronary bone-marrow derived progenitor

cell infusion in patients with acute myocardial infarction is safe and feasible In order to

fully elucidate the potential effect of intra-coronary autologous progenitor cell infusion the

outline (chapter 8) and results of a randomized multicenter trial (chapter 9) are in presented

in this thesis

Intr

oduc

tion

and

scop

e of

this

thes

is

13

References

(1) Keeley EC Boura JA Grines CL Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction a quantitative review of 23 randomised trials Lancet 2003 Jan 4361(9351)13-20

(2) Zijlstra F de Boer MJ Hoorntje JC Reiffers S Reiber JH Suryapranata H A comparison of immediate coronary angioplasty with intravenous streptokinase in acute myocardial infarction N Engl J Med 1993 Mar 11328(10)680-4

(3) Jensen-Urstad M Samad BA Jensen-Urstad K Hulting J Ruiz H Bouvier F et al Risk assessment in patients with acute myocardial infarction treated with thrombolytic therapy J Intern Med 2001 Jun249(6)527-37

(4) Nicolosi GL Latini R Marino P Maggioni AP Barlera S Franzosi MG et al The prognostic value of predischarge quantitative two-dimensional echocardiographic measurements and the effects of early lisinopril treatment on left ventricular structure and function after acute myocardial infarction in the GISSI-3 Trial Gruppo Italiano per lo Studio della Sopravvivenza nellrsquoInfarto Miocardico Eur Heart J 1996 Nov17(11)1646-56

(5) Pfeffer MA Braunwald E Moye LA Basta L Brown EJ Jr Cuddy TE et al Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction Results of the survival and ventricular enlargement trial The SAVE Investigators N Engl J Med 1992 Sep 3327(10)669-77

(6) St John Sutton M Pfeffer MA Moye L Plappert T Rouleau JL Lamas G et al Cardiovascular death and left ventricular remodeling two years after myocardial infarction baseline predictors and impact of long-term use of captopril information from the Survival and Ventricular Enlargement (SAVE) trial Circulation 1997 Nov 1896(10)3294-9

(7) Volpi A De Vita C Franzosi MG Geraci E Maggioni AP Mauri F et al Determinants of 6-month mortality in survivors of myocardial infarction after thrombolysis Results of the GISSI-2 data base The Ad hoc Working Group of the Gruppo Italiano per lo Studio della Sopravvivenza nellrsquoInfarto Miocardico (GISSI)-2 Data Base Circulation 1993 Aug88(2)416-29

(8) Sechtem U Pflugfelder PW Gould RG Cassidy MM Higgins CB Measurement of right and left ventricular volumes in healthy individuals with cine MR imaging Radiology 1987 Jun163(3)697-702

(9) Rominger MB Bachmann GF Pabst W Ricken WW Dinkel HP Rau WS [Left ventricular heart volume determination with fast MRI in breath holding technique how different are quantitative heart catheter quantitative MRI and visual echocardiography] Rofo 2000 Jan172(1)23-32

(10) Thiele H Paetsch I Schnackenburg B Bornstedt A Grebe O Wellnhofer E et al Improved accuracy of quantitative assessment of left ventricular volume and ejection fraction by geometric models with steady-state free precession J Cardiovasc Magn Reson 20024(3)327-39

(11) Tornqvist E Mansson A Larsson EM Hallstrom I Itrsquos like being in another world--patientsrsquo lived experience of magnetic resonance imaging J Clin Nurs 2006 Aug15(8)954-61

(12) Schuijf JD Bax JJ Shaw LJ de Roos A Lamb HJ van der Wall EE et al Meta-analysis of comparative diagnostic performance of magnetic resonance imaging and multislice computed tomography for noninvasive coronary angiography Am Heart J 2006 Feb151(2)404-11

(13) Groen JM van der Vleuten PA Greuter MJ Zijlstra F Oudkerk M Comparison of MRI 64-slice MDCT and DSCT in assessing functional cardiac parameters of a moving heart phantom Eur Radiol 2008 Oct 25

(14) van der Vleuten PA Willems TP Gotte MJ Tio RA Greuter MJ Zijlstra F et al Quantification of global left ventricular function comparison of multidetector computed tomography and magnetic resonance imaging a meta-analysis and review of the current literature Acta Radiol 2006 Dec47(10)1049-57

Chap

ter

1

14

(15) van der Vleuten PA de Jonge GJ Lubbers DD Tio RA Willems TP Oudkerk M et al Evaluation of global left ventricular function assessment by dual-source computed tomography compared with MRI Eur Radiol 2008 Aug 15

(16) Lunde K Solheim S Forfang K Arnesen H Brinch L Bjornerheim R et al Anterior myocardial infarction with acute percutaneous coronary intervention and intracoronary injection of autologous mononuclear bone marrow cells safety clinical outcome and serial changes in left ventricular function during 12-monthsrsquo follow-up J Am Coll Cardiol 2008 Feb 1251(6)674-6

(17) Lunde K Solheim S Aakhus S Arnesen H Abdelnoor M Egeland T et al Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction N Engl J Med 2006 Sep 21355(12)1199-209

(18) Schachinger V Erbs S Elsasser A Haberbosch W Hambrecht R Holschermann H et al Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction final 1-year results of the REPAIR-AMI trial Eur Heart J 2006 Dec27(23)2775-83

(19) Schachinger V Erbs S Elsasser A Haberbosch W Hambrecht R Holschermann H et al Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction N Engl J Med 2006 Sep 21355(12)1210-21

(20) Assmus B Schachinger V Teupe C Britten M Lehmann R Dobert N et al Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) Circulation 2002 Dec 10106(24)3009-17

(21) Britten MB Abolmaali ND Assmus B Lehmann R Honold J Schmitt J et al Infarct remodeling after intracoronary progenitor cell treatment in patients with acute myocardial infarction (TOPCARE-AMI) mechanistic insights from serial contrast-enhanced magnetic resonance imaging Circulation 2003 Nov 4108(18)2212-8

PART 1

Developments in diagnostics

Indicators of prognosis

The importance of left ventricular functi on

for long-term outcome aft er primary percutaneous

coronary interventi on

Pieter A van der Vleuten1 Saman Rasoul2 Willem Huurnink3

Iwan CC van der Horst1 Riemer HJA Slart4

Stoff er Reiff ers3 Rudi A Dierckx4 Reneacute A Tio1

Jan Paul Ott ervanger2 Menko-Jan De Boer2 Felix Zijlstra1

1Thoraxcentre Department of Cardiology University Medical Centre Groningen

The Netherlands

2 Department of Cardiology Isala klinieken Zwolle The Netherlands

3 Department of Nuclear Medicine Isala klinieken Zwolle The Netherlands

4Department of Nuclear Medicine and molecular imaging University Medical

Centre Groningen The Netherlands

BMC Cardiovasc Disord 2008 Feb 23 8 4

2

Chap

ter

2

18

Abstract

Background

In the present study we sought to determine the long-term prognostic value of left

ventricular ejection fraction (LVEF) assessed by planar radionuclide ventriculography

(PRV) after ST-elevation myocardial infarction (STEMI) treated with primary percutaneous

coronary intervention (PPCI)

Methods

In total 925 patients underwent PRV for LVEF assessment after PPCI for myocardial infarction

before discharge from the hospital PRV was performed with a standard dose of 500 Mbq of 99mTc-pertechnetate Average follow-up time was 25 years

Results

Mean (plusmn SD) age was 60 plusmn 12 years Mean (plusmn SD) LVEF was 457 plusmn 122 1 year survival

was 973 and 3 year survival was 942 Killip class multi vessel-disease previous

cardiovascular events peak creatin kinase and its MB fraction age and LVEF proved to be

univariate predictors of mortality When entered in a forward conditional Cox regression

model age and LVEF were independent predictors of 1 and 3 year mortality

Conclusion

LVEF assessed by PRV is a powerful independent predictor of long term mortality after PPCI

for STEMI

LVEF

aft

er S

TEM

I

19

Background



introduced and more recently primary percutaneous coronary intervention (PPCI) has been

shown to be even more effective(12) In patients surviving the first days after PPCI risk

stratification is of great clinical relevance for the further (medical) management Among





Planar radionuclide ventriculography (PRV) is a well established and widely used technique

for the assessment of left ventricular function The technique is simple robust and easy to

perform(8-10) PRV assesses LVEF by measurement of photon-activity of the bloodpool in

the left ventricle in both the end-diastolic and end-systolic phase of the cardiac cycle The

aim of the present study was to evaluate the long term prognostic value of LVEF assessed by

routine PRV in a large cohort of patients treated with PPCI for STEMI

Methods

As part of two consecutive multicentre randomized controlled trials consecutive patients

treated with PPCI for STEMI in two large hospitals in the Netherlands were entered in a

registry(1112) The registry was opened in April 1998 and was closed in December 2004

The inclusion criteria differed in inclusion of all Killip classes in GIPS 1(11) versus only Killip

1 in GIPS 2(12) Baseline characteristics such as medical history cardiovascular risk factors

heart rate and blood pressure delay-times and procedural parameters were recorded For

the present study data from the registries of two large hospitals in The Netherlands were

used Average follow-up time was 25 years No patients were lost to follow-up The present

study was conducted in accordance with the declaration of Helsinki and was approved by

the institutional review boards of both cooperating hospitals

Chap

ter

2

20

PRV was performed in routine clinical practice before discharge from the hospital between

day 1 and day 11 after myocardial infarction Four patients with atrial fibrillation were

excluded Measurements were performed using the multiple-gated equilibrium method

with in vivo labelling of red blood cells with 99mTc pertechnetate after pre-treatment

with 1 mg of stannous chloride A γ-camera (General Electric Milwaukee WI USA) was

used The camera head was positioned in the best septal LAO projection typically with a

caudal tilt of 5-10 degrees R-wave triggering was performed in a 20 beat acceptance

window with 23 forward and 13 backward framing per cardiac cycle for 20 frames per R-R

interval for a total of 6 minutes LVEF was calculated using a Star View computer (General

Electric Wisconsin USA) using the fully automatic PAGE program (version 23) The standard

deviation of the difference between repeat measurements obtained by this technique is

1-2(13)

Statistical analyses

Analyses were performed with the commercially available package SPSS version 1201 (SPSS

inc Chicago IL USA) Continuous data of LVEF values were expressed as mean plusmn standard

deviation (SD) Mortality rates were calculated according to the product-limit method

Further estimation of risk was performed using Cox proportional hazards models Variables

considered as potential predictors for multivariable modelling were selected by univariate

analyses and were subsequently selected by stepwise forward selection with entry and

retention in the model set at a significance level of 05

Results

PRV was not performed in 14 patients because they were too hemodynamically unstable

Furthermore 10 patients died before PRV could be performed In total 925 patients

underwent routine PRV Clinical and angiographic characteristics are shown in table 1 All

patients underwent PPCI of the infarct related artery which was successful in 872 (defined

as TIMI 3 flow in combination with a myocardial blush grade ge 2) PRV was performed

at a median of 2 days after PPCI (range 1 day - 11 days) Mean LVEF was 457 plusmn 122

(interquartile-range 370 - 540 )

LVEF

aft

er S

TEM

I

21

Table 1 Baseline clinical and angiographic characteristics Age yrs (mean plusmn SD) 598 plusmn 120Male sex 778

Body mass index kgm2 (mean plusmn SD) 267 plusmn 38

History of MI 99History of PCI 51History of CABG 28History of stroke 28

Diabetes mellitus 97Hypertension 285Hyperlipidemia 221Current smoker 507Positive family history 423

Ischemia duration min (mean plusmn SD) 205 plusmn 212

Killip class 1 959Killip class 2 24Killip class 3 13Killip class 4 04

Anterior MI 486Multivessel disease 514TIMI 3 flow after PCI 969

Successful reperfusionDagger 872Intra-aortic balloon pump 50Mechanical ventilation 05Stent 576Glycoprotein IIbIIIa receptor blocker 212

Max CK Ul (mean plusmn SD) 2450 plusmn 2159Max CK-MB Ul (mean plusmn SD) 248 plusmn 198

Data are displayed as percentage unless otherwise indicated Ischemia duration denotes time between onset of symptoms and until PCI Daggersuccessful reperfusion denotes TIMI 3 flow and myocardial blush grade 2 or 3

CABG = coronary artery bypass graftingCK = creatin kinaseCK-MB = creatin kinase myoglobin bindingMI = myocardial infarctionPCI = percutaneous coronary interventionSD = standard deviationTIMI = thrombolysis in myocardial infarction

Chap

ter

2

22

Follow-up was obtained for all 925 patients All-cause mortality was 02 09 27

and 58 at 3 days 30 days 1 year and 3 years respectively Three day mortality in the

entire registry was 23 Kaplan Meier curves for all-cause mortality in the 925 patients

who underwent PRV before discharge are shown in figure 1 The unadjusted mortality rate

increased exponentially with decreasing LVEF (figure 2)

Figure 1 Kaplan-Meier curve of 925 patients who underwent planar radionuclide ventriculography

after primary percutaneous coronary intervention for ST-elevation myocardial infarction

LVEF = Left Ventricular Ejection Fraction

LVEF

aft

er S

TEM

I

23

Figure 2 Adjusted 3 year mortality rate for patients who underwent planar radionuclide ventriculography

after primary percutaneous coronary intervention for ST-elevation myocardial infarction grouped by

left ventricular ejection fraction

By univariate Cox proportional hazards analysis several baseline clinical characteristics and

infarct related parameters were shown to be significant predictors of death Significant

predictors of both 1 year and 3 year mortality were age history of MI history of PCI peak

CK peak CK-MB-fraction and LVEF Killip class multivessel disease and history of CABG were

only significant univariate predictors of 3 year mortality Details are shown in table 2 Sex

history of stroke diabetes hypertension hyperlipidemia smoking habit positive family

history infarct-duration infarct location TIMI flow after PPCI myocardial blush grade use

of G2b3a inhibitors use of intra-aortic balloon pump or mechanical ventilation were not

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䰀攀昀琀嘀攀渀琀爀椀挀甀氀愀爀䔀樀攀挀琀椀漀渀䘀爀愀挀琀椀漀渀

　

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氀椀琀礀

Chap

ter

2

24

significant predictors of mortality When a forward conditional Cox proportional hazard

model of only the factors age and LVEF was implemented none of the other variables

provided incremental prognostic value (table 3)

Table 2 Predictors of 1 and 3 year mortality by univariate Cox proportional hazard analysis1 year mortality

Characteristics Hazard ratio (95 CI) pAge per 10 years increase 200 (135 - 297) 0001Previous MI 291 (116 ndash 728) 0023Previous PCI 958 (413 ndash 2221) lt0001Max CK per 500 Ul increase 101 (100 ndash 102) 0050Max CK-MB per 50 Ul increase 109 (101 ndash 118) 0039LVEF per 5 decrease 147 (125 ndash 173) lt0001

3 year mortality

Characteristics Hazard ratio (95 CI) pAge per 10 years increase 163 (125 - 214) lt0001Previous MI 219 (106 - 452) 0035Previous PCI 516 (250 - 107) lt0001Previous CABG 327 (117 ndash 910) 0024Multi-vessel disease 150 (106 ndash 211) 0021Killip class per class increase 173 (108 ndash 275) 0022Max CK per 500 Ul increase 101 (100 ndash 102) 0040Max CK-MB per 50 Ul increase 107 (101 ndash 114) 0020LVEF per 5 decrease 129 (115 ndash 146) lt0001

CABG = coronary artery bypass graftingCK = creatin kinaseCK-MB = creatin kinase myoglobin bindingLVEF = left ventricular ejection fractionMI = myocardial infarctionPCI = percutaneous coronary intervention

Table 3 Predictors of 1 and 3 years mortality by forward conditional Cox proportional hazard

analysis1 year mortality

Characteristics Hazard ratio 95 CI Wald χ2 pAge per 10 years 201 133 ndash 303 111 0001LVEF per 5 decreasing 144 123 ndash 169 204 lt 0001

3 year mortality

Characteristics Hazard ratio 95 CI Wald χ2 pAge per 10 years 164 125 ndash 215 126 lt 0001LVEF per 5 decreasing 128 114 ndash 144 176 lt 0001

LVEF = left ventricular ejection fraction

LVEF

aft

er S

TEM

I

25

Discussion

The present study shows that LVEF assessed shortly after PPCI for STEMI is a powerful

predictor of long term survival Earlier studies most designed to establish the value of

various pharmacologic interventions after myocardial infarction have shown the prognostic

value of global left ventricular function measured as LVEF in terms of mortality and re-

admission rates for heart failure(14-17) However the follow-up duration and patient

selection differed from the present study

The event-rate was relatively low for a post-infarction cohort with a 3 year mortality of

only 58 The fact that this study looks at data from patients who underwent PRV on

average 2 days after PPCI in the routine of daily clinical practice in most cases just before

discharge or transfer to another hospital has systematically excluded patients who were

too hemodynamically unstable to undergo PRV For all analyses total mortality was used It

can be hypothesized that the relationship between LVEF and cause-specific mortality would

be even stronger The fact that the traditional risk-factors for coronary artery disease (sex

hypertension diabetes hyperlipidemia smoking and family history) were not significant

predictors of mortality may be explained by the fact that these risk-factors for the most

part contributed to the occurrence of the index-MI itself and have only limited effect on

the prognosis after the index-MI In addition a number of these risk-factors (hypertension

hyperlipidemia and smoking) is usually treated more aggressively after the index-MI The

fact that some infarct-treatment parameters such as use of mechanical ventilation and use

of IABP were not significant predictors of mortality is most likely explained by the relatively

low numbers in this cohort with a relatively low event-rate

Noteworthy is the relatively small difference in prognosis between the patient category with

LVEF between 35 and 55 and the patient category with LVEF above 55 which is

generally viewed as the lower limit of normal In contrast there was a large difference in

survival between the patient category with LVEF between 35 and 55 and the patient

category with LVEF below 35 which is the current cut-off point for implantable cardioverter

defibrillator implementation (figure 1)

The data in the present study suggest that markers of infarct size such as maximum creatin

kinase myoglobin binding level Killip class and previous myocardial damage from earlier

Chap

ter

2

26

events add up to a risk burden which is related to global left ventricular function LVEF can

therefore be viewed as a representative of the final common pathway of left ventricular

damage when predicting long-term prognosis after PPCI The fact that this LVEF-assessment

can be performed just a few days after the index myocardial infarction facilitates simple and

fast risk stratification after PPCI

Besides PRV LVEF can be measured by a number of techniques which all have their own

specific advantages and limitations For instance echocardiography can be performed easily

and at low cost However the diagnostic accuracy is limited(18) Nuclear techniques such

as positron emission tomography and single photon emission computed tomography have

better diagnostic accuracy but are more labour intensive and are not available in every

hospital Recently multi detector row computed tomography has been propagated as very

fast and accurate technique for LVEF assessment(19) However besides ionising radiation

this technique also requires the use of intravenous nephrotoxic contrast agents LVEF can

even be assessed directly after PPCI by contrast ventriculography Besides the obvious

advantage of almost instant LVEF-assessment the main drawbacks from this approach are

the relatively high volume of nephrotoxic contrast the limited accuracy and the fact that

LVEF can be severely underestimated by myocardial stunning shortly after STEMI Magnetic

resonance imaging is regarded by many to be the gold standard for LVEF measurement(20)

Unfortunately this technique is limited to patients without intra-corporal devices such as

pacemakers and is not generally available for routine clinical patients

Conclusion

In conclusion LVEF assessed by PRV before discharge from the hospital is a powerful

independent predictor of long term prognosis after PPCI for STEMI

Abbreviations

CABG = Coronary artery bypass grafting CK = Creatin kinase CK-MB = Creatin kinase

myocardial band LVEF = Left ventricular ejection fraction PCI = Percutaneous coronary

intervention PPCI = Primary percutaneous coronary intervention PRV = Planar radionuclide

ventriculography SD = Standard deviation STEMI = ST-elevation myocardial infarction TIMI

= Thrombolysis in myocardial infarction (study group)

LVEF

aft

er S

TEM

I

27

References








(8) Abrams DS Starling MR Crawford MH OrsquoRourke RA Value of noninvasive techniques for predicting early complications in patients with clinical class II acute myocardial infarction J Am Coll Cardiol 1983 Nov2(5)818-25

(9) Madanay LD Cerqueira MD Jacobson AF Matsuoka D Matsuda M Stratton JR Radionuclide ventriculographic quantitation of left ventricular dimensions Comparison to echocardiography Clin Nucl Med 1991 Aug16(8)588-92

(10) Rerych SK Scholz PM Newman GE Sabiston DC Jr Jones RH Cardiac function at rest and during exercise in normals and in patients with coronary heart disease evaluation by radionuclide angiocardiography Ann Surg 1978 May187(5)449-64

(11) van der Horst IC Zijlstra F vanrsquot Hof AW Doggen CJ de Boer MJ Suryapranata H et al Glucose-insulin-potassium infusion inpatients treated with primary angioplasty for acute myocardial infarction the glucose-insulin-potassium study a randomized trial J Am Coll Cardiol 2003 Sep 342(5)784-91

(12) Timmer JR Svilaas T Ottervanger JP Henriques JP Dambrink JH van den Broek SA et al Glucose-insulin-potassium infusion in patients with acute myocardial infarction without signs of heart failure the Glucose-Insulin-Potassium Study (GIPS)-II J Am Coll Cardiol 2006 Apr 1847(8)1730-1

(13) De Bondt P De Winter O Vandenberghe S Vandevijver F Segers P Bleukx A et al Accuracy of commercially available processing algorithms for planar radionuclide ventriculography using data for a dynamic left ventricular phantom Nucl Med Commun 2004 Dec25(12)1197-202

(14) Mehta RH Orsquoneill WW Harjai KJ Cox DA Brodie BR Boura J et al Prediction of one-year mortality among 30-day survivors after primary percutaneous coronary interventions Am J Cardiol 2006 Mar 1597(6)817-22

Chap

ter

2

28

(15) Ottervanger JP Ramdat Misier AR Dambrink JH de Boer MJ Hoorntje JC Gosselink AT et al Mortality in patients with left ventricular ejection fraction lt=30 after primary percutaneous coronary intervention for ST-elevation myocardial infarction Am J Cardiol 2007 Sep 1100(5)793-7

(16) Ndrepepa G Mehilli J Martinoff S Schwaiger M Schomig A Kastrati A Evolution of left ventricular ejection fraction and its relationship to infarct size after acute myocardial infarction J Am Coll Cardiol 2007 Jul 1050(2)149-56

(17) Dutcher JR Kahn J Grines C Franklin B Comparison of left ventricular ejection fraction and exercise capacity as predictors of two- and five-year mortality following acute myocardial infarction Am J Cardiol 2007 Feb 1599(4)436-41

(18) Chuang ML Danias PG Riley MF Hibberd MG Manning WJ Douglas PS Effect of increased body mass index on accuracy of two-dimensional echocardiography for measurement of left ventricular volume ejection fraction and mass Am J Cardiol 2001 Feb 187(3)371-4 A10

(19) Yamamuro M Tadamura E Kubo S Toyoda H Nishina T Ohba M et al Cardiac functional analysis with multi-detector row CT and segmental reconstruction algorithm comparison with echocardiography SPECT and MR imaging Radiology 2005 Feb234(2)381-90

(20) Pattynama PM De Roos A Van der Wall EE Van Voorthuisen AE Evaluation of cardiac function with magnetic resonance imaging Am Heart J 1994 Sep128(3)595-607

Predicti ve value of Q-waves on the 12-lead

electrocardiogram aft er reperfusion therapy for STEMI

Pieter A van der Vleuten MD Mathijs Vogelzang MD

Tone Svilaas MD Iwan CC van der Horst MD PhD

Reneacute A Tio MD PhD Felix Zijlstra MD PhD FESC FACC

Thoraxcenter Department of Cardiology University Medical Center Groningen University of

Groningen The Netherlands


3

Chap

ter

3

30

Abstract

Design

The data used for the present study were obtained as part of a clinical trial evaluating the

effect of thrombus aspiration after primary PCI

Setting

The study was conducted at a tertiary referral facility for primary PCI at a University Medical

Center in The Netherlands

Background

Prognosis after ST-elevation myocardial infarction (STEMI) is strongly related to infarct-size

Methods

As part of a randomized clinical trial the first ECG after primary PCI for STEMI was analyzed

for the incidence of Q-waves (gt 01 millivolt) on the 12-lead ECG Infarct-size was measured

as area under curve (AUC) of creatine-kinase (CK) and creatine-kinase myocardial band (CK-

MB)

Results

933 patients were included the median number of Q-waves on the post-procedural ECG

was 3 (interquartile-range 1ndash 4) The number of Q-waves on the post-procedural ECG was an

independent predictor of infarct-size measured either as AUC of CK (p lt 0001) or AUC of CK-

MB (p lt 0001) and was a significant predictor of mortality during follow-up of 14 months

Conclusion

The number of Q waves on the post-procedural 12-lead ECG after primary PCI for STEMI is a

strong predictor of infarct-size and long-term mortality

Q-w

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aft

er S

TEM

I

31

Introduction

In patients surviving an acute ST-elevation myocardial infarction (STEMI) risk stratification is

of great clinical relevance for the further medical management Prognosis after myocardial

infarction has been studied extensively and has been shown to be related to a number

of baseline and treatment variables Based on these observations the Thrombolysis In

Myocardial Infarction (TIMI) risk score (age 65-74 2 points age ge75 3 points systolic

blood-pressure lt 100 mm Hg 3 points heart rate gt 100min 2 points Killip class II-IV

2 points anterior ST-elevation or left bundle branch block 1 point diabetes or history of

hypertension or angina 1 point weight lt 67 kg 1 point time to treatment gt 4 hours 1

point) was introduced in 2000(1) and has been validated in different STEMI-cohorts(23)

Various baseline and procedural variables after primary percutaneous coronary intervention

(PCI) for STEMI are related to infarct-size Infarct-size has been proven to be a major

predictor of outcome after STEMI(45) Recently Stone et al performed a pooled analysis of

four contemporary trials of primary and rescue PCI(6) Using multivariate linear regression

analysis male gender anterior myocardial infarction (MI) location baseline TIMI-flow 01

post-procedural TIMI-flow lt3 previous MI rescue PCI and ischemic time were identified as

independent predictors of infarct-size

A 12-lead electrocardiogram (ECG) is obtained routinely in all patients after reperfusion

therapy and it is the most generally available diagnostic tool in clinical practice shortly

after primary PCI Previous research showed that ST-segment resolution is associated with

infarct-size and outcome(78) We hypothesized that a simple electrocardiographic variable

could have additional prognostic value to the above-mentioned independent predictors of

prognosis and infarct-size Q-waves on a 12-lead surface ECG are generally viewed as proof

of an earlier transmural MI since it represents reduced electric activity in the area of the

heart related to that specific ECG-lead Therefore in the present study we evaluated the

incidence of Q-waves immediately following primary PCI in relation to long-term prognosis

and infarct-size in a large STEMI cohort In addition we analysed if the number of Q-waves

could further improve the predictive value of the TIMI risk score

Chap

ter

3

32

Methods

The present study was performed as a prospective sub-study within the thrombus aspiration

during primary percutaneous coronary intervention study (TAPAS) a randomized controlled

trial evaluating the effect of thrombus aspiration during primary PCI for STEMI(9-11) In

short all 1161 consecutive patients presenting with STEMI for primary PCI at the University

Medical Center Groningen between January 2005 and December 2006 were assessed for

eligibility In total 1071 patients were randomly assigned to undergo either thrombus

aspiration or conventional PCI before coronary angiography Primary PCI was performed in

1005 patients

As part of this trial all available admission ECGrsquos and post-procedural ECGrsquos were collected

along with the baseline clinical and procedural data In case of bundle branch blocks or

accelerated ideoventricular rhythm (AIVR) on the first post-procedural ECG the patientrsquos

hospital records were consulted for the presence of a subsequent ECG without these

conduction abnormalities If an ECG without conduction abnormalities was present and

performed within 6 hours after primary PCI that ECG was used for analyses

Analysis of 12-lead surface ECG

All ECGrsquos were analysed by investigators who were blinded for all other clinical data or

outcome The initial STEMI ECG and the first ECG after primary PCI were analyzed as pairs

Q-waves were scored on the post-procedural 12-lead ECG Q-waves were defined as an

initial negative deflection of the QRS-complex of gt 01 millivolt in an ECG-lead with ST-

elevation gt 01 millivolt on the ECG at diagnosis The total number of Q-waves was recorded

per patient The degree of resolution of ST-segment elevation was categorized as complete

(gt70) partial (30 to 70) or none (lt30)

Angiographic data

All coronary angiograms were scored by a core-lab for anatomical parameters TIMI-flow

grades and myocardial blush grades were assessed as previously described(1213)

Q-w

aves

aft

er S

TEM

I

33

Follow-up

The present study was conducted in accordance with the declaration of Helsinki and was

approved by the institutional review board Follow-up was obtained as part of the study-

protocol(9-11) Follow-up was obtained through telephone-interviews and whenever

necessary through consultation of the municipal population registration or general

practitioner

Creatin kinase and creatin kinase myocardial band measurements

All serum creatin kinase (CK) and myocardial band of creatin kinase (CK-MB) measurements

were collected for all patients during admission Patients with who died within 24 hours

after primary PCI or patients who were transferred to a regional hospital within 24 hours

post primary PCI were excluded from the infarct-size analyses because in these patients a

representative CK or CK-MB curve could not be recorded In addition patients with less

than 4 measurements of CK or CK-MB were excluded from the infarct-size analyses since

analyses of area-under-curve (AUC) with 3 values or less were considered inadequate AUC

was calculated as previously described with the primary PCI procedure at t=0 and values

were linearly interpolated between measurements(1415)

TIMI risk score

The TIMI risk score was calculated for all patients as previously described(1)

Statistical analysis

Analyses were performed with the commercially available package SPSS version 1201

(SPSS inc Chicago IL USA) Continuous data with normal distribution were expressed as

mean plusmn standard deviation (SD) Continuous data not normally distributed were expressed

as median with corresponding interquartile-range Trends in baseline parameters between

groups were investigated using ANOVA and Kruskal-Wallis analysis when appropriate

Survival was calculated with Kaplan Meier curves Mortality rates were calculated according

to the product-limit method Further estimation of risk was performed using Cox proportional

hazards models Cox proportional hazards analysis with Wald χ2 assessment was used to

examine if the number of Q-waves could further strengthen the TIMI risk score(1) (age 65-

Chap

ter

3

34

74 2 points age ge75 3 points systolic blood-pressure lt 100 mm Hg 3 points heart rate

gt 100min 2 points Killip class II-IV 2 points anterior ST-elevation or left bundle branch

block 1 point diabetes or history of hypertension or angina 1 point weight lt 67 kg 1

point time to treatment gt 4 hours 1 point) Relation between Q-waves and enzymatic

infarct-size was assessed using univariate and multivariate linear regression with R-square

assessment Multivariate linear regression was corrected for the independent predictors

of infarct-size as described by Stone et al(6) (male gender anterior MI location baseline

TIMI-flow 01 post-procedural TIMI-flow lt3 previous MI and ischemic time) In the Cox

proportional harzard model variables with a p-value of lt 010 were included When patients

were lost to follow-up the date of last contact was used for survival-analyses

Results

A total of 1005 patients underwent primary PCI and were included in the analysis After

exclusion of patients with persistent conduction abnormalities on their post-procedural

ECG 933 patients were analysed for the incidence of Q-waves on their post-procedural

12- lead ECG (figure 1) Median number of Q-waves on the post-procedural ECG was 3

(interquartile-range 1ndash 4) Patients with more Q-waves on their post-primary PCI ECG were

older (p lt0001) had more often an anterior MI (p lt0001) and had more often need for

hemodynamic support by intra-aortic balloon counterpulsation (p lt0001) Furthermore

these patients had more often a total occlusion of the infarct-related coronary artery before

primary PCI (p lt0001) In addition the lower TIMI-flow-grade and myocardial blush grade

after primary PCI reflect that these patients had less optimal myocardial perfusion and

more extensive microvascular damage All baseline clinical and angiographic characteristics

of the study-cohort are shown in table I

Q-w

aves

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er S

TEM

I

35

Figure 1 Flowchart of included patients

Abbreviations TAPAS = thrombus aspiration during primary percutaneous coronary intervention trial

PCI = percutaneous coronary intervention AIVR = accelerated ideoventricular rhythm CK = creatine

kinase CK MB = creatine kinase myocardial band STEMI = ST-segment elevation myocardial infarction

Chap

ter

3

36

Tabl

e 1

Bas

elin

e cl

inic

al a

nd a

ngio

grap

hic

char

acte

risti

csTo

tal (

n =

933)

0-1

Q-w

aves

(n =

309

)2-

4 Q

-wav

es (n

= 4

98)

gt 4

Q-w

aves

(n =

126

)p

Age

yrs

mea

n (S

D)

627

(12

5)

601

(12

1)

633

(12

4)

665

(12

6)

lt 0

001

Mal

e se

x71

472

571

767

5n

s

His

tory

of M

I 9

77

210

712

0n

sH

isto

ry o

f PCI

71

62

79

64

ns

His

tory

of C

ABG

3

33

33

43

2n

sH

isto

ry o

f str

oke

38

27

41

57

ns

Dia

bete

s m

ellit

us

110

7

911

915

20

058

Hyp

erte

nsio

n35

631

035

945

50

018

Hyp

erlip

idem

ia25

426

524

426

8n

sCu

rren

t sm

oker

48

2

526

473

412

ns

Posi

tive

fam

ily h

isto

ry

464

53

544

536

90

004

Infa

rct l

ocati

onLM

08

06

04

24

ns

LAD

430

411

363

738

lt 0

001

CX16

621

615

75

50

002

RCA

385

361

464

167

lt 0

001

Gra

ft1

10

61

21

6n

s

Tota

l isc

hem

ic ti

me

in h

ours

(med

ian

+ IQ

R)3

1 [2

2 ndash

45

] 3

0 [2

1 ndash

42

] 3

5 [2

2 ndash

45

] 3

4 [2

3 ndash

61

] 0

050

Intr

a-ao

rtic

ballo

on p

ump

60

21

56

168

lt 0

001

Sten

t 92

795

291

292

4n

sG

lyco

prot

ein

IibI

IIa re

cept

or b

lock

er

926

93

591

489

7n

s

Q-w

aves

aft

er S

TEM

I

37

Tabl

e 1

Bas

elin

e cl

inic

al a

nd a

ngio

grap

hic

char

acte

risti

cs (c

ontin

ued)

TIM

I flow

bef

ore

prim

ary

PCI

049

931

557

066

7lt

000

11

104

89

100

159

ns

217

922

916

411

10

007

321

836

716

66

3lt

000

1

TIM

I flow

aft

er p

rim

ary

PCI

01

30

01

44

10

003

11

80

62

42

5n

s2

126

65

144

205

lt 0

001

384

392

981

872

9lt

000

1

Myo

card

ial b

lush

gra

de a

fter

pri

mar

y PC

I0

53

16

51

149

lt 0

001

116

010

917

324

00

002

239

841

838

838

8n

s3

389

457

388

223

lt 0

001

TIM

I ris

k sc

ore

28

24

28

39

lt 0

001

Max

CK

Ul

(med

ian

+ IQ

R)52

8 [2

32 ndash

13

20]

233

[89

ndash 45

5]65

8 [3

48 ndash

138

2]17

05 [1

022

ndash 28

79]

lt 0

001

Max

CK-

MB

Ul

(med

ian

+ IQ

R)57

[24

ndash 10

3]23

[8 ndash

51]

70 [3

8 ndash

115]

155

[85

ndash 26

3]lt

000

1

Dat

a ar

e di

spla

yed

as p

erce

ntag

e u

nles

s ot

herw

ise

indi

cate

d

Tota

l isc

hem

ic ti

me

deno

tes

time

betw

een

onse

t of s

ympt

oms

and

prim

ary

PCI

CABG

= c

oron

ary

arte

ry b

ypas

s gr

aftin

g LM

= le

ft m

ain

coro

nary

art

ery

CX =

circ

umfle

x co

rona

ry a

rter

y M

I = m

yoca

rdia

l inf

arcti

onCK

= c

reati

n ki

nase

PC

I = p

ercu

tane

ous

coro

nary

inte

rven

tion

CK-M

B =

crea

tin k

inas

e m

yoca

rdia

l ban

d RC

A =

rig

ht c

oron

ary

arte

ryIQ

R =

inte

rqua

rtile

-ran

ge

SD =

sta

ndar

d de

viati

onLA

D =

left

ant

erio

r de

scen

ding

cor

onar

y ar

tery

TI

MI =

thro

mbo

lysi

s in

myo

card

ial i

nfar

ction

Chap

ter

3

38

One-year follow-up was obtained for 923 patients (99) Ten patients were lost to follow-

up All-cause mortality was 19 32 and 64 at 3 days 30 days and 1 year respectively

A Kaplan-Meier curve for the number of Q-waves in relation to all-cause mortality is shown

in figure 2 In a Cox proportional hazards model the number of Q-waves remained related to

long term mortality in addition to age CK-AUC CK-MB AUC diabetes previous PCI previous

MI previous cerebrovascular event positive family history ventricular fibrillation before

primary PCI TIMI-flow post primary PCI myocardial blush grade post primary PCI use of

Glycoprotein IIbIIIa inhibitors ST-segment resolution and hemodynamic support 1 day

after primary PCI Details are shown in table II

Figure 2 Kaplan-Meier curve for categories of number of Q-waves on post-procedural electrocardio-

gram Straight line = 0 or 1 Q-wave (n = 309) Dotted line = 2 3 or 4 Q-waves (n = 498) Dash-dotted

line = 5 or more Q-waves (n = 126)

Q-w

aves

aft

er S

TEM

I

39

Table 2 Predictors of mortality by univariate and multivariate Cox proportional hazards

analysis

Univariate model

Characteristic Hazard ratio 90 CI Wald χ2 pAge (per 1 year increase) 108 106 ndash 110 325 lt 0001Diabetes 454 281 ndash 733 269 lt 0001History of PCI 245 130 ndash 460 54 0020History of MI 201 110 ndash 367 36 0057History of cerebrovascular event 346 169 ndash 706 82 0004Positive family history 061 037 ndash 099 28 0096VF before primary PCI 197 138 ndash 282 98 0002TIMI flow post primary PCI (per class) 061 045 ndash 084 68 0009Myocardial blush grade (per class) 060 047 ndash 077 117 0001Glycoprotein IibIIIa inhibitor use 037 022 ndash 073 72 0007Hemodynamic support 453 253 ndash 812 182 lt 0001Anterior MI 228 142 ndash 366 82 0003ST-segment resolution (per 1 category increase) 234 190 ndash 345 345 lt 0001Number of Q-waves (per 1 increase) 146 127 ndash 160 198 lt 0001

Multivariate model

Characteristic Hazard ratio 90 CI Wald χ2 pAge (per 1 year increase) 109 106 ndash 112 235 lt 0001Diabetes 461 275 ndash 770 239 lt 0001History of MI 271 146 ndash 505 70 0008Positive family history 194 109 ndash 345 36 0058VF before primary PCI 218 148 ndash 320 111 0001ST-segment resolution (per 1 category increase) 155 104 ndash 230 33 0069Number of Q-waves (per 1 increase) 118 101 ndash 138 30 0085

CK = creatin kinaseCK-MB = creatin kinase myocardial bandMI = myocardial infarctionPCI = percutaneous coronary interventionTIMI = Trombolysis in myocardial infarction

The TIMI risk score was significantly higher in patients with more Q-waves on their post-

procedural ECG (Table I p lt0001) Consequently the number of Q-waves was higher in

patients with a higher TIMI risk score (figure 3) The TIMI risk score was shown to be a

significant predictor of mortality by univariate Cox proportional hazards analysis The

number of Q-waves remained an independent predictor of mortality when this variable

was entered in a multivariate Cox model alongside the TIMI risk score When the number

of Q-waves was added to the TIMI risk score this variable yielded a larger Wald χ2 than the

TIMI-risk score alone (645 vs 562) Details are shown in Table III

Chap

ter

3

40

Figure 3 Bargraph showing the average number of Q-waves on the post-procedural electrocardiogram

per category of TIMI risk score (n = 933)

Abbreviations TIMI = thrombolysis in myocardial infarction


analysis

Univariate model

Characteristic Hazard ratio 95 CI Wald χ2 pTIMI risk score (per 1 increase) 156 139 ndash 176 562 lt 0001

Multivariate modelCharacteristic Hazard ratio 95 CI Wald χ2 pTIMI risk score (per 1 increase) 148 131 ndash 167 385 lt 0001Number of Q-waves (per 1 increase) 126 110 ndash 144 100 0002

Univariate model

Characteristic Hazard ratio 95 CI Wald χ2 pTIMI risk score + number of Q-waves (per 1 increase) 154 139 ndash 171 645 lt 0001

TIMI = Trombolysis in myocardial infarction

Q-w

aves

aft

er S

TEM

I

41

The number of Q-waves on the post-procedural ECG corresponded well with both the peak

values and the AUCrsquos of CK and CK-MB Boxplots for these variables are shown in figures 4

through 7

Figure 4 Boxplot for peak creatine kinase level per number of Q-waves on post-procedural

electrocardiogram (n = 699)

Abbreviations CK = creatine kinase

In addition within the categories of ST-segment resolution an increasing number of

Q-waves still corresponds with a larger enzymatic infarct-size (figures 8 and 9) Univariate

linear regression showed a statistically significant relationship between the number of

Q-waves and enzymatic infarct-size (p lt0001 for CK AUC p lt0001 for CK-MB AUC) This

effect was shown to be independent of other previously established risk-factors for infarct-

size (male gender previous MI anterior MI location TIMI-flow 01 before primary PCI TIMI-

flow lt 3 after primary PCI and ischemia duration) Results of univariate and multivariate

linear regression are shown in tables IV and V respectively Addition of age or ST-segment

resolution as variable to the multiple linear regression models did not alter the statistical

significance of either the number of Q-waves or any other variable

Chap

ter

3

42

Although the analyses were not specifically designed to single out a particular ECG lead

in which the incidence of a Q-wave is of more importance than in other ECG leads it was

noted that the incidence of a Q-wave in V4 is associated with both increased mortality (p lt

0001) and a larger enzymatic infarct-size (p lt 0001 for both CK AUC and CK-MB AUC) when

entered in a univariate Cox-proportional hazards and linear regression model respectively

In a large majority of these cases (917) the infarct-related artery was the LAD

Figure 5 Boxplot for peak creatine kinase myocardial band level per number of Q-waves on post-

procedural electrocardiogram (n =699)

Abbreviations CK MB = creatine kinase myocardial band

Q-w

aves

aft

er S

TEM

I

43

Figure 6 Boxplot of area under

curve for creatine kinase per

number of Q-waves on post-

procedural electrocardiogram

(n = 699)

Abbreviations AUC = area

under curve (in Ulhr) CK =

creatine kinase


curve for creatine kinase

myocardial band per number

of Q-waves on post-procedural



under curve (in Ulhr) CK MB

= creatine kinase myocardial

band

Chap

ter

3

44

Figure 8 Bargraph of area under curve for creatine kinase per category of Q-waves grouped by

category of ST-segment resolution on post-procedural electrocardiogram (n = 699)

Abbreviations AUC = area under curve (in Ulhr) CK = creatine kinase

Figure 9 Bargraph of area under curve for creatine kinase myocardial band per category of Q-waves

grouped by category of ST-segment resolution on post-procedural electrocardiogram (n = 699)

Abbreviations AUC = area under curve (in Ulhr) CK MB = creatine kinase myocardial band

Q-w

aves

aft

er S

TEM

I

45

Table 4 Predictors of enzymatic infarct-size by univariate linear regression

CK-area under curveCharacteristic B 95 CI pNumber of Q-waves (per 1 increase) 1963 1713 ndash 2213 lt0001

R-square for model 0254

CK-MB-area under curveCharacteristic B 95 CI pNumber of Q-waves (per 1 increase) 156 137 ndash 174 lt0001


CK = creatin kinaseCK-MB = creatin kinase myocardial band

Table 5 Predictors of enzymatic infarct-size by multivariate linear regression

CK-area under curveCharacteristics B 95 CI pMale gender 759 -250 ndash 1768 0140Previous MI -599 -2170 ndash 971 0454Anterior MI 1312 397 - 2227 0005TIMI 0-1 before primary PCI 3393 2414 ndash 4373 lt0001TIMI lt 3 after primary PCI 1056 -169 - 2281 0091Total ischemic time (per hour increase) 0003 -0001 ndash 0007 0209Number of Q-waves (per 1 increase) 1610 1348 - 1870 lt0001


CK-MB-area under curveCharacteristics B 95 CI pMale gender -21 -97 ndash 55 0591Previous MI -104 -222 - 14 0085Anterior MI 90 21 - 159 0010TIMI 0-1 before primary PCI 265 191 ndash 338 lt0001TIMI lt 3 after primary PCI 93 01 - 185 0047Total ischemic time (per hour increase) 0001 00 - 01 0006Number of Q-waves (per 1 increase) 129 109 - 148 lt0001


CK = creatin kinase PCI = percutaneous coronary interventionCK-MB = creatin kinase myocardial band TIMI = Trombolysis in myocardial infarctionMI = myocardial infarction

Chap

ter

3

46

Discussion

An increasing number of Q-waves on the first 12-lead ECG after primary PCI in this

contemporary patient-cohort is strongly associated with adverse long-term prognosis and

the extent of myocardial damage measured as CK and CK-MB AUC In addition an increasing

number of Q-waves is of additional value to the well validated TIMI risk score

To the best of our knowledge this is the first study assessing the value of the number of

Q-waves on the post-primary PCI 12-lead surface ECG in relation to prognosis and infarct-size

Earlier studies focused on the prognostic value of the pre-intervention ECG or ST-elevation

resolution(16-18) The presence or absence of Q-waves has been studied extensively to

assess the incidence of earlier undetected MI in the general population(19-22) In this

context a Q-wave is regarded as proof of a previous myocardial infarction when certain

additional criteria are met with regard to the duration and relation to the following R-wave

(typically a duration of gt 40 milliseconds andor a depth of gt 13 of the following R-wave)

However as a STEMI was the initial presentation in all our patients we defined a qualifying

Q-wave in our study as an initial negative deflection of the QRS-complex of gt 01 millivolt

in an ECG-lead related to the myocardial area involved in the STEMI This is a more liberal

definition than the classic Q-wave definition However since the question at hand was not

whether myocardial damage was present but rather what the extent of the damage was in

combination with the fact that the ECG-leads at risk can be undisputedly identified by the

ST-deviation on the STEMI ECG the use of the classic definition (with its known substantial

false-negative test-characteristic) was considered to be less appropriate than the definition

implemented in the present study

The rationale to investigate the predictive value of the post-procedural ECG is that the effect

of the reperfusion therapy is taken into account Furthermore the pre-intervention ECG

is often made in the pre-hospital setting nowadays and is sometimes not available after

primary PCI and coronary care unit admission making the ECG immediately following the

primary PCI an attractive and practical means for risk stratification and further clinical

decision-making

The present study was conducted using data from a well-documented patient-cohort

treated with primary PCI for STEMI The high rate of glycoprotein IIbIIIa receptor-blocker-

administration and frequent use of coronary stents in combination with the overall low

Q-w

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aft

er S

TEM

I

47

mortality in the study-cohort represent the developments in contemporary clinical practice

in Western Europe(23)

The TIMI risk score has been validated in large thrombolysis studies(23) In the present

study we observed an incremental prognostic value to the TIMI risk score when the number

of Q-waves was added to the score Although this finding needs to be confirmed in other

STEMI cohorts it seems likely that the ldquoQ-wave countrdquo will find its way into future risk

prediction models

For the present study we corrected the multivariate linear regression models for previously

established risk factors for infarct-size in order to assess the added value of post-procedural

Q-waves on the surface ECG However since the present study was conducted in a setting

where primary PCI is performed in all STEMI-patients and pre-hospital thrombolytics are

rarely administered rescue PCI was not used as variable in the multivariate models (rescue

PCI was one of the exclusion-criteria of the TAPAS-trial 11 patients were excluded for that

particular reason)

The incidence of prior MI in the present cohort was 97 Although Q-waves from a prior

MI could be expected to influence the relationship between the number of Q-waves after

the index event and enzymatic infarct-size Although it is contradictory to many previous

studies this effect was not observed in the present study (p = 0454 for CK AUC and p =

0085 for CK MB AUC) It could be speculated that even though the method of calculating

myocardial infarct-size in this manner is well-validated the fact that myocardial damage

was assessed by area-under-curve calculation of CK and CK-MB rather than by an imaging

modality such as positron emission tomography or magnetic resonance imaging this effect

could not be fully elucidated In addition exact infarct location or transmurality could also

not be taken into account

A potential pitfall of any Q-wave definition is a pronounced Q-wave in the lateral and inferior

ECG-leads caused by septal activation often seen in healthy young individuals However

since we only assessed the ECG-leads with ST-elevation at diagnosis in our cohort with an

average age of 627 plusmn 125 this effect has not negated the predictive value of the number of

Q-wave on prognosis or infarct-size

Patients who were transferred early to other regional hospitals and patients with less than

4 measurements of CK and CK-MB within 24 hours had to be excluded from the infarct-size

analyses This may have introduced selection-bias However it should be noted that the

Chap

ter

3

48

excluded patients were transferred early for geographic rather than clinical reasons and the

699 patients included in the infarct-size analyses form a cohort representative of a general

myocardial infarction population surviving the first day after primary PCI

Patients with complete bundle-branch blocks or persistent AIVR on their post-procedural

ECG were excluded Since the incidence of a complete bundle-branch block on the post-

procedural ECG may in itself represent additional prognostic risk the results of the present

study can only be extrapolated to patients without these conduction abnormalities on the

post-procedural ECG

Unfortunately LV functional parameters were not available for all patients and this is a

limitation of the present study Although it is known that LVEF is closely related to mortality

after primary PCI for STEMI(24) the relationship between the number of Q-waves on the

post-procedural ECG and LVEF was not assessed in the present study and remains to be fully

elucidated

It is tempting to speculate that this easy and low-cost method of clinical assessment

after primary PCI could lead to more focused use of advanced and expensive additional

therapeutic or diagnostic means such as magnetic resonance imaging for left ventricular

function and infarct-size analysis Since the ldquoQ-wave countrdquo can be obtained in a large

number of patients without the need for additional (radiological) measurements invasive

procedures or strict collection of blood-samples it is also a practical surrogate end-point

for clinical trials evaluating peri-primary PCI interventions aimed at further reduction of

myocardial damage As illustration of the potential value of the ldquoQ-wave countrdquo when

the ldquoQ-wave countrdquo was applied in our recently published TAPAS trial(9-11) the average

number of Q-wave in the thrombus-aspiration group was 225 (plusmn 184) versus 268 (plusmn 187)

in the control-group (plt 0001) confirming a clear benefit of thrombus aspiration prior to

stenting of the infarct related coronary artery in patients presenting with STEMI

Conclusion

The number of Q waves on the post-procedural surface ECG after primary PCI for STEMI is a

strong independent predictor of long-term mortality and enzymatic infarct-size In addition

the ldquoQ-wave countrdquo further improves the predictive value of the TIMI risk score

Q-w

aves

aft

er S

TEM

I

49

References

(1) Morrow DA Antman EM Charlesworth A Cairns R Murphy SA de Lemos JA et al TIMI risk score for ST-elevation myocardial infarction A convenient bedside clinical score for risk assessment at presentation An intravenous nPA for treatment of infarcting myocardium early II trial substudy Circulation 2000 Oct 24102(17)2031-7

(2) Morrow DA Antman EM Parsons L de Lemos JA Cannon CP Giugliano RP et al Application of the TIMI risk score for ST-elevation MI in the National Registry of Myocardial Infarction 3 JAMA 2001 Sep19286(11)1356-9

(3) Wiviott SD Morrow DA Frederick PD Giugliano RP Gibson CM McCabe CH et al Performance of the thrombolysis in myocardial infarction risk index in the National Registry of Myocardial Infarction-3 and -4 a simple index that predicts mortality in ST-segment elevation myocardial infarction J Am Coll Cardiol 2004 Aug 1844(4)783-9

(4) Miller TD Christian TF Hopfenspirger MR Hodge DO Gersh BJ Gibbons RJ Infarct size after acute myocardial infarction measured by quantitative tomographic 99mTc sestamibi imaging predicts subsequent mortality Circulation 1995 Aug 192(3)334-41

(5) Miller TD Hodge DO Sutton JM Grines CL OrsquoKeefe JH DeWood MA et al Usefulness of technetium-99m sestamibi infarct size in predicting posthospital mortality following acute myocardial infarction Am J Cardiol 1998 Jun 1581(12)1491-3

(6) Stone GW Dixon SR Grines CL Cox DA Webb JG Brodie BR et al Predictors of infarct size after primary coronary angioplasty in acute myocardial infarction from pooled analysis from four contemporary trials Am J Cardiol 2007 Nov 1100(9)1370-5

(7) Rakowski T Dziewierz A Siudak Z Mielecki W Brzozowska-Czarnek A Legutko J et al ST-segment resolution assessed immediately after primary percutaneous coronary intervention correlates with infarct size and left ventricular function in cardiac magnetic resonance at 1-year follow-up J Electrocardiol 2009 Jan 21

(8) Sciagra R Parodi G Migliorini A Valenti R Antoniucci D Sotgia B et al ST-segment analysis to predict infarct size and functional outcome in acute myocardial infarction treated with primary coronary intervention and adjunctive abciximab therapy Am J Cardiol 2006 Jan 197(1)48-54

(9) Svilaas T van der Horst IC Zijlstra F Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study (TAPAS)--study design Am Heart J 2006 Mar151(3)597

(10) Svilaas T Vlaar PJ van der Horst IC Diercks GF de Smet BJ van den Heuvel AF et al Thrombus aspiration during primary percutaneous coronary intervention N Engl J Med 2008 Feb 7358(6)557-67

(11) Vlaar PJ Svilaas T van der Horst IC Diercks GF Fokkema ML de Smet BJ et al Cardiac death and reinfarction after 1 year in the Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study (TAPAS) a 1-year follow-up study Lancet 2008 Jun 7371(9628)1915-20

(12) The Thrombolysis in Myocardial Infarction (TIMI) trial Phase I findings TIMI Study Group N Engl J Med 1985 Apr 4312(14)932-6

(13) van lsquot Hof AW Liem A Suryapranata H Hoorntje JC de Boer MJ Zijlstra F Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty for acute myocardial infarction myocardial blush grade Zwolle Myocardial Infarction Study Group Circulation 1998 Jun 1697(23)2302-6

(14) Simoons ML Serruys PW van den Brand M Res J Verheugt FW Krauss XH et al Early thrombolysis in acute myocardial infarction limitation of infarct size and improved survival J Am Coll Cardiol 1986 Apr7(4)717-28

(15) van der Laarse A Kerkhof PL Vermeer F Serruys PW Hermens WT Verheugt FW et al Relation between infarct size and left ventricular performance assessed in patients with first acute myocardial infarction randomized to intracoronary thrombolytic therapy or to conventional treatment Am J Cardiol 1988 Jan 161(1)1-7

Chap

ter

3

50

(16) van lsquot Hof AW Liem A de Boer MJ Zijlstra F Clinical value of 12-lead electrocardiogram after successful reperfusion therapy for acute myocardial infarction Zwolle Myocardial infarction Study Group Lancet 1997 Aug 30350(9078)615-9

(17) Wasserman AG Bren GB Ross AM Richardson DW Hutchinson RG Rios JC Prognostic implications of diagnostic Q waves after myocardial infarction Circulation 1982 Jun65(7)1451-5

(18) Wong CK Gao W Raffel OC French JK Stewart RA White HD Initial Q waves accompanying ST-segment elevation at presentation of acute myocardial infarction and 30-day mortality in patients given streptokinase therapy an analysis from HERO-2 Lancet 2006 Jun 24367(9528)2061-7

(19) Asch FM Shah S Rattin C Swaminathan S Fuisz A Lindsay J Lack of sensitivity of the electrocardiogram for detection of old myocardial infarction a cardiac magnetic resonance imaging study Am Heart J 2006 Oct152(4)742-8

(20) Pahlm O Haisty WK Jr Wagner NB Pope JE Wagner GS Specificity and sensitivity of QRS criteria for diagnosis of single and multiple myocardial infarcts Am J Cardiol 1991 Nov 1568(13)1300-4

(21) Uusitupa M Pyorala K Raunio H Rissanen V Lampainen E Sensitivity and specificity of Minnesota Code Q-QS abnormalities in the diagnosis of myocardial infarction verified at autopsy Am Heart J 1983 Oct106(4 Pt 1)753-7

(22) Wu E Judd RM Vargas JD Klocke FJ Bonow RO Kim RJ Visualisation of presence location and transmural extent of healed Q-wave and non-Q-wave myocardial infarction Lancet 2001 Jan 6357(9249)21-8

(23) Eagle KA Nallamothu BK Mehta RH Granger CB Steg PG Van de Werf F et al Trends in acute reperfusion therapy for ST-segment elevation myocardial infarction from 1999 to 2006 we are getting better but we have got a long way to go Eur Heart J 2008 Mar29(5)609-17

(24) van der Vleuten PA Rasoul S Huurnink W van der Horst IC Slart RH Reiffers S et al The importance of left ventricular function for long-term outcome after primary percutaneous coronary intervention BMC Cardiovasc Disord 2008 Feb 23844

Early assessment of ST-segment resoluti on residual

ST-segment elevati on and Q waves in relati on to left

ventricular functi on size and extent of infarcti on and

microvascular injury in acute myocardial infarcti on

Robin Nijveldt MD12 Pieter A van der Vleuten MD3 Alexander Hirsch MD24 Aernout M Beek

MD1 Reneacute A Tio MD PhD3 Jan GP Tijssen PhD4 Victor AWM Umans MD PhD5 Paul R Algra

MD PhD6 Jan J Piek MD PhD4 Albert C van Rossum MD PhD12 and Felix Zijlstra MD PhD3

1) Department of Cardiology VU University Medical Center Amsterdam 2) Interuniversity Cardiology

Insti tute of the Netherlands Utrecht 3) Department of Cardiology University Medical Center

Groningen Groningen 4) Academic Medical Center Amsterdam 5) Department of Cardiology

Medical Center Alkmaar Alkmaa r 6) Department of Radiology Medical Center Alkmaar

Alkmaar the Netherlands

) Both authors contributed equally to the manuscript


4

Chap

ter

4

52

Abstract

Objectives

We investigated early electrocardiographic findings in relation to left ventricular (LV)

function extent and size of infarction and microvascular injury in patients with acute

myocardial infarction (MI) treated with percutaneous coronary intervention (PCI)

Background

ST-segment resolution and residual ST-segment elevation have been used for prognosis in

acute MI whereas Q waves are related to outcome in chronic MI We hypothesized that the

combination of these electrocardiographic measures early after primary PCI would enhance

risk stratification

Methods

A 12-lead electrocardiogram (ECG) was analyzed in 180 patients with a first acute ST-

segment elevation MI to assess ST-segment resolution residual ST-segment elevation and

number of Q waves acquired on admission and 1 hour after successful PCI ECG findings

were related to left ventricular (LV) function infarction and microvascular injury as assessed

with cardiovascular magnetic resonance 4plusmn2 days after reperfusion

Results

Residual ST-segment elevation (b=-200 p=0004) and the number of Q waves (b=-146

p=001) were the strongest ECG predictors of LV ejection fraction While the number of

Q waves best predicted infarct size (b=197 plt0001) and transmural extent (b=059

plt0001) residual ST-segment elevation was the strongest predictor of microvascular injury

(OR 191 (24ndash154) p=0005) ST-segment resolution was not associated with LV function or

infarction indices in multivariable analysis

Conclusions

In patients after successful coronary intervention for acute MI residual ST-segment elevation

and the number of Q waves on the post-procedural ECG offer valuable complementary

information on prediction of myocardial function and necrosis

ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

53

Introduction

The electrocardiogram (ECG) is the most used and simple clinical method to evaluate the

risk for patients immediately after successful reperfusion therapy for acute myocardial

infarction (MI) In the early 1970s experimental and in vivo studies established the use of

ST-segment elevation as reflection of myocardial injury (12) and later the ECG has proven

to offer valuable prognostic information for patients treated with thrombolytic therapy or

primary angioplasty (34) Patients with acute MI are stratified to ST-segment elevation or

non-ST-segment elevation MI (5) and incomplete normalization of the ST-segment after

reperfusion is associated with more extensive myocardial damage microvascular injury and

a higher mortality rate (36-9) Similarly patients with old infarction are divided into Q wave

and non-Q wave MI (5) in which the presence of Q waves is related to larger infarcts and

an increased mortality (10-In current clinical practice an ECG is routinely obtained shortly

after percutaneous coronary intervention (PCI) for acute MI to evaluate the success of

reperfusion and for initial risk stratification Besides ST-segment resolution and residual ST-

segment elevation the ECG offers information on early Q waves Limited data is available on

the additional value of Q wave assessment compared to ST-segment resolution or residual

ST-segment elevation early after reperfusion with respect to myocardial function and

necrosis

The purpose of this study was therefore to prospectively explore the significance of

electrocardiographic findings early after primary PCI in relation to left ventricular function

extent and size of infarction and microvascular injury as assessed by cardiovascular magnetic

resonance (CMR)

Methods

Patient population

We screened consecutive patients presenting with a first ST-segment elevation acute MI

according to standard electrocardiographic and enzymatic criteria (5) All patients had

undergone primary PCI with stent implantation within 12 hours of symptom onset Exclusion

Chap

ter

4

54

criteria were unsuccessful PCI haemodynamic instability elevation of creatine kinase

myocardial-brain (CK-MB) less than 10 times the local upper limit of normal and (relative)

contraindications for CMR One-hundred eighty patients were prospectively enrolled

in the study in 4 Dutch angioplasty centers Patients were treated with aspirin heparin

abciximab clopidogrel statins beta-blocking agents and ACE-inhibitors according to ACC

AHA practice guidelines (13) All patients gave informed consent to the study protocol

which was approved by the local ethics committees of the participating centers

Electrocardiography

ST-segment resolution was evaluated on a 12-lead surface ECG acquired on admission and 1

hour after PCI The total degree of ST-segment resolution was determined 60 ms after the J

point and categorized as complete (ge70) partial (30 to lt70) or no (lt30) ST-segment

resolution (3) Residual ST-segment elevation and the presence of Q-waves were assessed

on the post-procedural ECG Residual ST-segment elevation was stratified as 0ndash2 3ndash5 6ndash10

and gt10 mV of persisting ST-segment elevation The presence of a Q wave was defined as

an initial negative deflection of the QRS complex of gt30 ms in duration and gt01 mV The

number of Q waves was categorized as 0ndash2 3 4 and ge5 Q waves ECG parameters were

assessed in all 12 standard leads


CMR examination was performed on a 15-T clinical MR scanner (Symphony SonataAvanto

Siemens Erlangen Germany) using a phased array cardiac receiver coil at 4plusmn2 days after

reperfusion ECG-gated images were acquired during repeated breath-holds Contiguous

short axis slices were acquired using a segmented steady state free precession pulse

sequence in multiple short axis views every 10 mm covering the entire left ventricle from

base to apex to examine global and segmental LV function Typical in plane resolution was

16x19 mm2 with slice thickness 50ndash60 mm (repetition timeecho time = 3216 ms flip

angle 60deg matrix 256x156 temporal resolution 35ndash50 ms) Late gadolinium enhancement

(LGE) was performed 10 to 15 minutes after administration of a gadolinium-based contrast

agent (Dotarem Guerbet Roissy France 02 mmolkg) with a 2D segmented inversion

recovery gradient-echo pulse sequence to examine infarct size and segmental transmural

ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

55

extent of infarction Typical in plane resolution was 14x17 mm2 with slice thickness 50ndash

60 mm (repetition timeecho time = 9644 ms flip angle 25deg triggering to every other

heart beat) The inversion time was set to null the signal of viable myocardium

CMR data were analyzed using a dedicated software package (Mass 2008beta Medis

Leiden the Netherlands) On short axis cine slices the endocardial and epicardial borders

were outlined manually in end-diastolic and end-systolic images From these left ventricular

end-systolic (LVESV) and end-diastolic (LVEDV) volumes ejection fraction (LVEF) and mass

were calculated The assessment of LGE images for infarct size and microvascular injury

(microvascular obstruction MVO) was done as previously described (8) Total infarct size was

expressed as percentage of LV mass MVO was defined as any region of hypoenhancement

within the hyperenhanced area and was included in the calculation of total infarct size

The standard 17-segment model was used for segmental analysis of myocardial function

and transmural extent of infarction (14) excluding segment 17 (apex) since segmental

evaluation in the short axis orientation is not considered reliable due to the partial volume

effect and longitudinal shortening of the heart Segmental wall thickening was calculated

by subtracting end-diastolic from end-systolic wall thickness Dysfunctional segments were

defined as segments with systolic wall thickening of less than 3 mm Transmural extent

of infarction was calculated by dividing the hyperenhanced area by the total area of the

predefined segment Segments with more than 50 hyperenhancement were considered

segments with transmural enhancement


Values are reported as mean plusmn standard deviation (SD) or median (25thndash75th percentile) for

continuous variables and as frequency with percentage for categorical variables Comparison

of symptom-to-balloon times between anterior and non-anterior infarcts was done by the

Mann-Whitney U test The independent samples t test was used to compare continuous

CMR parameters and comparison of MVO presence was done by the Chi-square test Chi-

square test for trend was used for the association between categorized ECG parameters and

the location of infarction (anterior versus non-anterior)

To identify independent predictors of global LV indices multivariable linear regression

analysis with a forward selection procedure was used Variables entered the model if plt010

Chap

ter

4

56

Similar analysis was performed using multivariable logistic regression for the relation with

the presence of MVO

All statistical tests were two-tailed and a p-value lt005 was considered statistically significant

Results

Patient characteristics and angiographic and ECG data are listed in table 1 Mean LVEDV

was 994plusmn183 mLm2 LVESV was 578plusmn169 mLm2 and LVEF was 427plusmn86 in the total

group of patients with a mean number of 84plusmn32 dysfunctional segments The mean total

size of gadolinium-enhanced infarction was 166plusmn89 of LV mass with a mean number

of 32plusmn24 transmural enhanced segments In 578 of the patients there was presence

of MVO on the LGE images Patients with anterior MI (n=114 63) had significantly worse

LVEF more dysfunctional segments larger infarct size and more segments with transmural

enhancement than patients with non-anterior MI (plt0001 for all data not shown) There

was no difference in median symptom-to-balloon time between patients with anterior or

non-anterior MI (26 (20ndash40) versus 35 (21ndash45) hours respectively p=010) or between

patients with or without MVO (29 (20ndash45) versus 29 (20ndash43) hours respectively p=080)

ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

57

Table 1 Patient characteristics and angiographic and electrocardiographic data Number of patients 180Age 55 (plusmn 10)Body mass index (kgm2) 263 (plusmn 31)Risk factors Men 156 (87) Diabetes mellitus 7 (4) Hyperlipidaemia 39 (22) Hypertension 45 (25) Current smoking 101 (56)Median maximum serum creatine kinase MB divided by local upper limit of normal

44 (24ndash69)

Median time to reperfusion (hr) 29 (20ndash45)Platelet glycoprotein IIbIIIa inhibitors 137 (76)Infarct related artery Left anterior descending artery 114 (63) Left circumflex artery 19 (11) Right coronary artery 47 (26)Multivessel disease 53 (29)TIMI flow post-PC I (n=180) TIMI 1 2 (1) TIMI 2 20 (11) TIMI 3 158 (88)Myocardial blush grade post-PCI (n=173) MBG 0ndash1 57 (33) MBG 2ndash3 116 67)ST-segment resolution (n=171) complete 102 (59) partial 49 (29) incomplete 20 (12)Residual ST-segment elevation (n=178) 0ndash2 mm 75 (42) 3ndash5 mm 56 (32) 6ndash10 mm 32 (18) gt10 mm 15 (8)Number of Q waves (n=180) 0 ndash2 Q waves 42 (23) 3 Q waves 50 (28) 4 Q waves 39 (22) gt5 Q waves 49 (27)

Values are presented as number () mean (plusmn standard deviation) or median (25thndash75th percentile) MBG = myocardial blush grade PCI = percutaneous coronary intervention TIMI = Thrombolysis In Myocardial Infarction

Chap

ter

4

58

ST-segment resolution

Twelve-lead ECGrsquos were available for assessment of ST-segment resolution in 171 of 180

patients (2 left bundle branch block 2 right bundle branch block and 5 pre procedural

ECGrsquos were missing or of poor technical quality) There was a moderate statistical relation

for ST-segment resolution with LVEF and the number of dysfunctional segments (plt005)

ST-segment resolution was also moderately associated with the number of transmural

enhanced segments (p=002) but not with either infarct size or the presence of MVO (figure

1)

Residual ST-segment elevation

There were 178 of the 180 ECGrsquos available for assessment of residual ST-segment elevation

(2 left bundle branch block) There was a statistical association between residual ST-segment

elevation and LVEDV LVESV LVEF and the number of dysfunctional segments (plt001) There

was a stronger relationship with total infarct size the number of segments with transmural

enhancement and the presence of MVO (plt0001 figure 1)

Number of Q waves

All ECGrsquos were available and interpretable for Q wave assessment The number of Q waves

related moderately with LVEDV (p=001) and there was a good correlation with LVESV LVEF

and the number of dysfunctional segments (plt0001) A significant association was found

with size and transmural extent of infarction (plt0001) but the number of Q waves did not

statistically correlate with the presence of MVO (p=009 figure 1)

ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

59Figure 1 Relation between electrocardiographic measures and left ventricular function transmurality

and microvascular obstruction (MVO)

Predictive value of Electrocardiographic measures

Table 2 shows the predictive value of each ECG parameter with respect to myocardial

function size and extent of infarction and microvascular injury The strongest predictors

of LVEF were residual ST-segment elevation and the number of Q waves in multivariable

analysis Additionally the number of Q waves independently predicted infarct size and

transmural extent whereas residual ST elevation was the single and best predictor of MVO

presence ST-segment resolution is no longer associated with LV function or transmurality

Chap

ter

4

60

after adjustment for residual ST-segment elevation and the number of Q waves Furthermore

anterior MI was a strong independent predictor of LVEF the number of dysfunctional

segments infarct size and the number of segments with transmural infarction

Table 2A Predictive value of electrocardiographic measures on myocardial function and

necrosis ndash Univariable and multivariable stepwise linear regression analysis of ST-segment

resolution residual ST-segment elevation number of Q waves and location of infarction

for prediction of myocardial function infarction and transmural extent of infarction in 171

patients with complete ECG data Univariable Multivariable

beta p-value beta p-value

LVEF

ST-segment resolution -247 0008Residual ST-segment elevation -309 lt0001 -200 0004Number of Q waves -244 lt0001 -146 001Anterior myocardial infarction -547 lt0001 -273 0048

Dys

func

t

segm

ents

ST-segment resolution 084 002

Residual ST-segment elevation 100 lt0001

Number of Q waves 097 lt0001 061 0004

Anterior myocardial infarction 297 lt0001 249 lt0001

Infa

rct

size

ST-segment resolution 185 0045Residual ST-segment elevation 246 lt0001Number of Q waves 276 lt0001 197 lt0001Anterior myocardial infarction 691 lt0001 536 lt0001

Tran

smur

al

segm

ents



Number of Q waves 087 lt0001 059 lt0001


LVEF = left ventricular ejection fraction electrocardiographic variables are categorized as in table 1

ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

61

Table 2B Predictive value of electrocardiographic measures on microvascular obstruction ndash

Univariable and multivariable stepwise logistic regression analysis of ST-segment resolution

residual ST-segment elevation number of Q waves and location of infarction for prediction

of the presence of microvascular obstruction (MVO) in 171 patients with complete ECG dataUnivariable Multivariable

OR (95CI) p-value OR (95CI) p-value

Pres

ence

of M

VO

ST-segment resolution 020 complete 1 partial 16 (08ndash32) incomplete 22 (08ndash61)Residual ST-segment elevation 0005 0005 0ndash2 mm 1 1 3ndash5 mm 23 (11ndash47) 23 (11ndash47) 6ndash10 mm 26 (12ndash87) 26 (12ndash87) gt10 mm 191 (24ndash154) 191 (24ndash154)Number of Q waves 009 0ndash2 Q waves 1 3 Q waves 14 (06 ndash33) 4 Q waves 23 (09ndash57) gt5 Q waves 29 (12ndash70)Anterior myocardial infarction 19 (10ndash35) 005

Electrocardiography in relation to Angiography and Infarct size

There was no relation between incomplete TIMI flow grade after primary PCI (defined as

TIMI flow 1ndash2) and LVEF (b=-237 p=022) the number of transmural enhanced segments

(b=-0005 p=099) or the presence of MVO (OR 17 (07ndash44) p=027) An impaired

myocardial blush grading (defined as MBG 0ndash1) correlated with LVEF (b=-406 p=0003)

and with transmurality (b=124 p=0001) Also impaired MBG was associated with the

presence of MVO (OR 36 (18ndash74) plt0001) Multivariable linear regression analysis of all

angiographic and electrocardiographic parameters revealed residual ST-segment elevation

and the number of Q waves as only independent variables for prediction of LVEF and the

number of Q waves for predicting transmurality For predicting the presence of MVO

impaired MBG was the strongest variable in multivariable logistic regression analysis (OR

27 (13ndash57) p=0009) Additionally residual ST-segment elevation of more than 10 mm

was independently associated with MVO presence (OR 105 (12ndash889) p=003)

There was a strong association between gadolinium-enhanced infarct size and LVEF (b=-058

plt0001) transmurality (b=024 plt0001) and MVO (b=004 plt0001) After adjustment for

Chap

ter

4

62

infarct size in multivariable analysis residual ST-segment resolution remained independently

associated with LVEF (b=-181 p=0002) and the presence of MVO (b=010 p=0006) and

the number of Q waves with transmurality (b=024 p=0007)

Discussion

The principal finding of this study in patients after successful PCI for acute ST-segment

elevation MI was that residual ST-segment elevation and the number of Q waves on the

post-procedural ECG are complementary in predicting myocardial function and necrosis

Residual ST-segment elevation the number of Q waves and anterior MI were the strongest

predictors of LV function Additionally residual elevation was the single and best predictor

of microvascular injury while Q wave count and anterior infarction best predicted infarct

size and transmural extent of infarction

The changes of the electrocardiographic ST-segment in patients with ST-segment elevation

MI have been associated with patency of the infarct related artery in multiple clinical studies

(1516) Although this is no misapprehension an important percentage of the patients fails

to demonstrate normalization of the ST-segment after successful revascularization despite

TIMI 3 flow grade (17) due to impaired reperfusion at the myocardial tissue level This is

caused by a multitude of processes including tissue edema platelet plugging neutrophil

adhesion myonecrosis and intracapillary red blood cell stasis resulting in MVO which

is also known as the lsquono-reflowrsquo phenomenon (18) Experimental and clinical studies

have shown that MVO is common and that it is associated with a higher incidence of LV

remodeling congestive heart failure and death (1920) Thus the ST-segment early after

PCI offers prognostic information by reflecting myocardial perfusion status rather than

epicardial flow and predicts clinical outcome in patients with reperfused MI (321) The

present study extends these findings by demonstrating that persisting elevation of the ST-

segment is strongly related to LV volumes and function and strongly correlated with the

presence of microvascular injury which is essential information during hospitalization

In line with previous studies residual ST-segment elevation performed better as predictive

measure than ST-segment resolution (722) ST-segment elevation in acute MI may have

already partially normalized on admission due to the drastically improved infarct treatment

ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

63

including heparin and aspirin during transfer to the tertiary center for primary PCI Thus

the ECG before reperfusion therapy may underestimate the true amount of ST-segment

elevation and consequently affect its prognostic power Residual ST-segment elevation may

therefore better express reperfusion injury at the myocardial tissue level than ST-segment

resolution

Early work has reported that there is a relation between the presence of Q waves on the

ECG and the transmural extent of infarction in chronic MI (23) Later human autopsy studies

suggested that this association was doubtful however many anatomic and clinical research

showed that the distinction of Q waves in patients with previous MI is useful for prognosis

since its presence predicts larger infarcts and higher mortality (111224) To our knowledge

the present study is the first to evaluate the significance of the number of Q waves early

after PCI with respect to myocardial function and necrosis in patients with acute MI The

number of Q waves strongly predicted LV end-systolic volume LVEF and the number of

dysfunctional segments and was the strongest independent predictor on the ECG of infarct

size and its transmural extent

Another important difference between the results of this study and those of earlier studies

assessing the predictive value of electrocardiographic measures in patients with acute MI

is that both residual ST-segment elevation and the number of Q waves offered incremental

information besides angiographic measures and infarct size with respect to LV function

transmurality and microvascular injury Previous reports have shown that incomplete TIMI

flow grade and impaired MBG predict worse clinical outcome and LV function (2526)

Although we found no statistical significant relation between incomplete TIMI flow grade

and LV function in our study impaired MBG correlated with LVEF transmurality and MVO In

multivariable analysis electrocardiographic measures remained stronger predictors of LVEF

and transmurality and MBG was only predictive for the presence of MVO

Methodological considerations

Assessment of ECG measures was done semi-quantitatively Continuous ST-segment

monitoring using automated analysis systems may have improved the evaluation of

myocardial reperfusion over time (16) In this study however we have evaluated a clinically

applicable and generally available approach Our findings cannot be generalized to all patients

with acute MI since only patients with ST-elevation MI were included in the study with

Chap

ter

4

64

relatively large infarcts (elevation of CK-MB gt10 times the upper limit of normal) Although

these data suggest an incremental role for the number of Q waves in relation to LV function

and infarction it is unknown whether these results can be extrapolated to patients with

acute MI without ST-segment elevation Additionally patients in whom revascularization

was not successful those treated conservatively or those who underwent coronary artery

bypass surgery for acute MI were not included in the study

Clinical implications

Since residual ST-segment elevation reflects myocardial function and no-reflow whereas

the number of Q waves relates to myocardial function and sizeextent of infarction both

parameters offer complementary information for patients after reperfused acute MI beyond

infarct size and angiography Therefore we believe that the readily available and simple ECG

shortly after PCI may help the physicianrsquos clinical decision making and risk stratification of

patients after acute MI Additionally our findings may be relevant for selecting patients that

may benefit from adjunctive therapeutic interventions (eg cell therapy) to limit functional

deterioration and promote the repair of infarcted myocardium

In conclusion we found that residual ST-segment elevation and the number of Q waves on

the ECG shortly after PCI for acute MI have complementary predictive value on myocardial

function size and extent of infarction and microvascular injury

Abbreviations and acronyms

MI = myocardial infarction

CMR = cardiovascular magnetic resonance

ECG = electrocardiography

LGE = late gadolinium enhancement

LV = left ventricular

LVEDV = left ventricular end-diastolic volume


LVESV = left ventricular end-systolic volume

PCI = percutaneous coronary intervention

TIMI = Thrombolyis In Myocardial Infarction

ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

65

References

(1) Muller JE Maroko PR Braunwald E Evaluation of precordial electrocardiographic mapping as a means of assessing changes in myocardial ischemic injury Circulation 1975 Jul52(1)16-27

(2) Muller JE Maroko PR Braunwald E Precordial electrocardiographic mapping A technique to assess the efficacy of interventions designed to limit infarct size Circulation 1978 Jan57(1)1-18

(3) Schroder R Dissmann R Bruggemann T Wegscheider K Linderer T Tebbe U et al Extent of early ST segment elevation resolution a simple but strong predictor of outcome in patients with acute myocardial infarction J Am Coll Cardiol 1994 Aug24(2)384-91

(4) lsquot Hof AW Liem A de Boer MJ Zijlstra F Clinical value of 12-lead electrocardiogram after successful reperfusion therapy for acute myocardial infarction Zwolle Myocardial infarction Study Group Lancet 1997 Aug 30350(9078)615-9

(5) Thygesen K Alpert JS White HD Jaffe AS Apple FS Galvani M et al Universal definition of myocardial infarction Circulation 2007 Nov 27116(22)2634-53


(7) De Luca G Maas AC Suryapranata H Ottervanger JP Hoorntje JC Gosselink AT et al Prognostic significance of residual cumulative ST-segment deviation after mechanical reperfusion in patients with ST-segment elevation myocardial infarction Am Heart J 2005 Dec150(6)1248-54

(8) Nijveldt R Beek AM Hirsch A Stoel MG Hofman MB Umans VA et al Functional recovery after acute myocardial infarction A comparison between angiography electrocardiography and cardiovascular magnetic resonance measures of microvascular injury J Am Coll Cardiol 2008Jul 1552(3)181-9

(9) Sorajja P Gersh BJ Costantini C McLaughlin MG Zimetbaum P Cox DA et al Combined prognostic utility of ST-segment recovery and myocardial blush after primary percutaneous coronary intervention in acute myocardial infarction Eur Heart J 2005 Apr26(7)667-74

(10) Goldberg RJ Gore JM Alpert JS Dalen JE Non-Q wave myocardial infarction recent changes in occurrence and prognosis--a community-wide perspective Am Heart J 1987 Feb113(2 Pt 1)273-9

(11) Nicod P Gilpin E Dittrich H Polikar R Hjalmarson A Blacky AR et al Short- and long-term clinical outcome after Q wave and non-Q wave myocardial infarction in a large patient population Circulation 1989 Mar79(3)528-36

(12) Aguirre FV Younis LT Chaitman BR Ross AM McMahon RP Kern MJ et al Early and 1-year clinical outcome of patientsrsquo evolving non-Q-wave versus Q-wave myocardial infarction after thrombolysis Results from The TIMI II Study Circulation 1995 May 1591(10)2541-8

(13) Ryan TJ Antman EM Brooks NH Califf RM Hillis LD Hiratzka LF et al 1999 update ACCAHA Guidelines for the Management of Patients With Acute Myocardial Infarction Executive Summary and Recommendations A report of the American College of CardiologyAmerican Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction) Circulation 1999 Aug 31100(9)1016-30

(14) Cerqueira MD Weissman NJ Dilsizian V Jacobs AK Kaul S Laskey WK et al Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart a statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association Circulation 2002 Jan 29105(4)539-42

(15) Clemmensen P Ohman EM Sevilla DC Peck S Wagner NB Quigley PS et al Changes in standard electrocardiographic ST-segment elevation predictive of successful reperfusion in acute myocardial infarction Am J Cardiol 1990 Dec 1566(20)1407-11

Chap

ter

4

66

(16) Klootwijk P Langer A Meij S Green C Veldkamp RF Ross AM et al Non-invasive prediction of reperfusion and coronary artery patency by continuous ST segment monitoring in the GUSTO-I trial Eur Heart J 1996 May17(5)689-98


(18) Kloner RA Ganote CE Jennings RB The ldquono-reflowrdquo phenomenon after temporary coronary occlusion in the dog J Clin Invest 1974 Dec54(6)1496-508

(19) Ito H Maruyama A Iwakura K Takiuchi S Masuyama T Hori M et al Clinical implications of the lsquono reflowrsquo phenomenon A predictor of complications and left ventricular remodeling in reperfused anterior wall myocardial infarction Circulation 1996 Jan 1593(2)223-8

(20) Wu KC Zerhouni EA Judd RM Lugo-Olivieri CH Barouch LA Schulman SP et al Prognostic significance of microvascular obstruction by magnetic resonance imaging in patients with acute myocardial infarction Circulation 1998 Mar 397(8)765-72


(22) McLaughlin MG Stone GW Aymong E Gardner G Mehran R Lansky AJ et al Prognostic utility of comparative methods for assessment of ST-segment resolution after primary angioplasty for acute myocardial infarction the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial J Am Coll Cardiol 2004 Sep 1544(6)1215-23

(23) Prinzemetal M SHAW CM Jr MAXWELL MH FLAMM EJ GOLDMAN A KIMURA N et al Studies on the mechanism of ventricular activity VI The depolarization complex in pure subendocardial infarction role of the subendocardial region in the normal electrocardiogram Am J Med 1954

(24) Moon JC De Arenaza DP Elkington AG Taneja AK John AS Wang D et al The pathologic basis of Q-wave and non-Q-wave myocardial infarction a cardiovascular magnetic resonance study J Am Coll Cardiol 2004 Aug 444(3)554-60

(25) Piana RN Paik GY Moscucci M Cohen DJ Gibson CM Kugelmass AD et al Incidence and treatment of lsquono-reflowrsquo after percutaneous coronary intervention Circulation 1994 Jun89(6)2514-8

(26) lsquot Hof AW Liem A Suryapranata H Hoorntje JC de Boer MJ Zijlstra F Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty for acute myocardial infarction myocardial blush grade Zwolle Myocardial Infarction Study Group Circulation 1998 Jun 1697(23)2302-6

Value and limitati ons of Electromechanical Endocardial

Mapping in the assessment of global and regional left

ventricular functi on and transmural extent of infarcti on

A comparison with Cardiovascular Magneti c Resonance

Pieter A van der Vleuten MD1 Robin Nijveldt MD23

Eng-Shiong Tan MD PhD1 Reneacute A Tio MD PhD1

Albert C van Rossum MD PhD23 Felix Zijlstra MD PhD FESC1

1) Department of Cardiology University Medical Center Groningen NL

2) Department of Cardiology VU University Medical Center NL

3)Interuniversity Cardiology Insti tute of the Netherlands Utrecht NL

) Both authors contributed equally

Submitt ed

5

Chap

ter

5

68

Abstract

Objective

To determine the relation between electromechanical endocardial mapping (EEM) and

cardiac magnetic resonance (CMR) derived functional and anatomical parameters

Patients

Forty-two patients treated for a large myocardial infarction

Interventions

All patients underwent EEM and CMR 4 months after myocardial infarction EEM was

performed to assess linear local shortening (LLS) unipolar voltage (UV) and bipolar voltage

(BV) CMR cine imaging was performed to determine global and regional left ventricular

function Late gadolinium enhancement (LGE) was used to assess total infarct size and

transmural extent of infarction per segment

Results

The average left ventricular ejection fraction (LVEF) measured by EEM was 97 -point

lower than LVEF measured by CMR (362 versus 459 plt0001) Average LLS UV and

BV differed significantly between normal and dysfunctional segments (98 vs 73 118 vs

98 and 33 vs 28 for LLS UV and BV respectively plt001) Also average LLS UV and BV

differed significantly between normal segments segments with subendocardial LGE and

segments with transmural LGE (105 vs 82 vs 50 119 vs 103 vs 95 and 34 vs 29 vs 23

for LLS UV and BV respectively plt0001)

Conclusions

Although there were relatively large differences in global left ventricular functional

parameters between EEM and CMR segmental analyses showed that EEM can be used to

determine both regional function and extent of infarction in patients with a large myocardial

infarction However exact pinpointing of myocardial areas benefiting from direct injection

of therapeutics remains difficult

5 N

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Introduction

The outcome of patients with ST-elevation myocardial infarction (STEMI) has improved

since the introduction of primary percutaneous coronary intervention (PPCI) (1) However

an increasing number of patients suffers from symptoms of heart failure as a result of post-

infarct deterioration of left ventricular function In order to challenge these ever-growing

problems the concept of improving left ventricular function after reperfusion therapy by

bone marrow-derived progenitor cell infusion has been advocated extensively and various

trials have been conducted predominantly with positive results (2-4)

Although there have been many encouraging reports so far there is still much debate about

the optimal timing of cell-therapy which cell-type is most suitable for transplantation and

the optimal route of delivery (5) Various routes and methods have been used for cell delivery

(eg intracoronary and retrograde coronary venous injection or direct intramyocardial

injection by surgical or percutaneous approaches) each with their own potential benefits

and disadvantages At the present time intracoronary cell administration is the most

commonly applied method because of its minimally invasive characteristics However

there are indications that intravascular cell injection (ie intracoronary) is associated with

low rates of cell retention (6) Since direct cell injection is only a reasonable option as

adjuvant to cardiac surgery the percutanous route is the logical option for intra-myocardial

cell injection for all other patients Direct injection with only fluoroscopic guidance would

require unacceptably high doses of radiation and would not lead to an even distribution

of cell injections Commercially available non-fluoroscopic electromechanical endocardial

mapping systems (EEM) that measure both wall motion and electrical activity could aid

the interventional cardiologist by providing online information regarding left ventricular (LV)

function and viability without excessive radiation exposure In addition these systems can

be fitted with dedicated (cell) injection catheters This technique has proved to be safe and

feasible both in the cell and gene delivery setting (27-9) It was hypothesized that besides

facilitating cell delivery the generated maps could provide information on both regional

and global LV function as well as on viability which can be used to monitor the potential

effects of the applied therapy Although previous studies have focused on the identification

of viable myocardium with EEM (10-14) only one study has validated the accuracy of

Chap

ter

5

70

EEM parameters to detect viable myocardium so far (15) but this study has not validated

functional EEM parameters

The purpose of this study was to evaluate the assessment of global and regional left

ventricular function and size and transmural extent of infarction by EEM validated against

cardiovascular magnetic resonance (CMR) which is considered the gold standard for

assessment of LV function(1617) and (extent of) infarction(16-19)

Methods

Patients

The present study was conducted at the University Medical Center Groningen As part of a

multi-center randomized controlled trial evaluating the effect of intracoronary infusion of

autologous bone marrow derived cells following PPCI for STEMI all patients underwent both

CMR and re-catheterization 4 months after PPCI (20) Due to the specific in- and exclusion-

criteria only patients with a relatively large myocardial infarction were enrolled in the study

All baseline clinical and procedural data were entered in a database All patients gave written

informed consent for participation in the trial

Electromechanical mapping procedure

EEM maps were obtained as previously described (9) In short the mapping NOGACARTO

system (Biosense Webster Diamond bar Ca USA) comprises a miniature passive magnetic

field sensor an external ultralow magnetic field emitter (location pad) and a processing

unit The catheter tip incorporates standard electrodes that allow recording of unipolar or

bipolar signals and the location sensor The mapping catheter was introduced through an 8F

or 9F femoral sheath and placed in the left ventricle Another reference catheter also with a

tip sensor was taped securely to the patientrsquos back The apex the inflow and outflow tract

were identified to form the first three dimensional image of the ventricle After that the

remaining points were measured without fluoroscopy The stability of the catheter-to-wall

contact was evaluated at every site in real time and points were deleted from the map if 1

of the following criteria was met (1) a premature beat or a beat after a premature beat (2)

5 N

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location stability defined as a difference of gt5 mm in end-diastolic location of the catheter at

2 sequential heartbeats (3) loop stability defined as an average distance of gt5 mm between

the location of the catheter at 2 consecutive beats at corresponding time intervals in the

cardiac cycle (4) cycle length that deviated gt10 from the median cycle length (5) different

morphologies of the local ECG at 2 consecutive beats (6) local activation time differences

of gt5 ms between 2 consecutive beats and (7) different QRS morphologies of the body

surface ECG On average around 100 points were measured evenly distributed throughout

the left ventricle in order to complete a representative 3D image Fluoroscopy is used for

approximately three minutes during the beginning of the procedure An example of an EEM

reconstruction is shown in figure 1

Figure 1 Example of cine (A diastole amp B systole) and late gadolinium enhanced (C) images and

corresponding bipolar voltage endocardial electromechanical map (D bullrsquos eye map amp E 3D

reconstruction) of a patient with a large anterior myocardial infarction Asterisk indicates akinetic

anterior wall on the cine images (A amp B) and transmural extent of infarction on the late gadolinium

enhanced image (C) The endocardial electromechanical 3D map displays a low amplitude (lt006 mV)

in the infarct region (E) which is also seen on the bullrsquos eye map (D) in the anterior segments 1 7 and

13

LA left atrium LV left ventricle

Chap

ter

5

72

Cardiovascular magnetic resonance

CMR was performed on a 15-T clinical scanner (Sonata Siemens Erlangen Germany) using

a phased array cardiac receiver coil at 4 months after primary PCI Electrocardiogram-

gated images were acquired during repeated breath-holds of approximately 10 seconds LV

function was determined with cine imaging using a segmented steady state free precession

pulse sequence in multiple short axis views every 10 mm covering the entire left ventricle

Typical in plane resolution was 16 x 19 mm2 with slice thickness of 60 mm (repetition

timeecho time = 3216 ms flip angle 60deg matrix 256 x 156 temporal resolution 35 -

50 ms) Late gadolinium-enhanced (LGE) images were acquired to determine infarct size

and transmural extent of infarction A 2D segmented inversion recovery gradient-echo

pulse sequence was used 15 minutes after administration of a gadolinium-based contrast

agent (Dotarem Guerbet Roissy France)(02 mmolkg) with slice locations identical to the

cine images Typical in plane resolution was 14 x 18 mm2 with slice thickness of 60 mm

(repetition timeecho time = 9644 ms flip angle 25deg matrix 256 x 166 triggering to every

other heart beat) The inversion time was set to null the signal of viable myocardium and

typically ranged from 260 to 350 ms

Data analysis and definitions

Extraction of the contractility data and conversion to a 17-segment bullrsquos-eye maps for EEM

parameters were performed off-line (figure 1) End-diastolic volumes end-systolic volumes

and the surface area for UV (with a transmurality threshold of 69 mV (15)) expressed as

percentage of total surface were calculated for each EEM map When an EEM segment had

less than four contact points within its boundaries that segment was excluded from regional

analysis One value per segment was calculated for all three variables

All CMR data were analyzed on a separate workstation using dedicated software (Mass

version 2006beta Medis Leiden the Netherlands) Cine and LGE images were acquired

during the same imaging session and therefore matched by using slice position On all short

axis cine slices the endocardial and epicardial borders were outlined manually on end-

diastolic and end-systolic images LV volumes and LVEF were calculated Segment location

was defined on cine and LGE images according to the 17-segment model Segmental wall

thickening was calculated by subtracting end-diastolic wall thickness from end-systolic wall

5 N

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thickness and expressed as percentage of end-diastolic wall thickness Segments were

considered dysfunctional if there was less than 33 percent wall thickening during systole

Total infarct size was calculated by summation of all slice volumes of hyperenhancement

using a standardized and predefined definition (signal intensity gt5 SD above the mean

signal intensity of remote myocardium) (21) and expressed as percentage of LV mass The

transmural extent of infarction was calculated by dividing the hyperenhanced area by the

total area of the predefined segment ()

To assess the agreement of the segmental data between EEM and CMR all data were first

converted to standard 17-segment bullrsquos-eye maps (22) Per individual segment three

EEM parameters (LLS UV and BV) and two CMR parameters were available (regional wall

thickening and transmural extent of infarction) For analysis of segmental function and

transmural extent of infarction the apex-segment (segment 17) was excluded due to the

partial volume effect of the short-axis oriented data-acquisition of CMR All EEM and CMR

images were analyzed by two observers who were blinded to patient data and clinical status



(SPSS inc Chicago IL USA) Continuous data were expressed as mean plusmn standard deviation

(SD) Categorical data were expressed as median with corresponding inter-quartile range

The method of Bland and Altman was used to display the average difference and limits of

agreement between the reference values of CMR and the functional parameters of EEM

(23) Pearsonrsquos correlation coefficient was calculated to assess the correlation between CMR

and EEM Mean LLS UV and BV values for normal segments segments with subendocardial

LGE and segments with transmural LGE were compared using ANOVA In addition Mean

LLS UV and BV values for normal segments and dysfunctional segments were compared

using ANOVA All statistical tests were two-sided with a significance level of ple005

Chap

ter

5

74

Results

Forty-two consecutive patients underwent EEM-mapping and CMR assessment of both

global and regional left ventricular function parameters Demographic and procedural

characteristics are provided in table I From the EEM-maps 557 from the 672 segments were

included in the analyses Global and regional functional CMR data were available from all 42

patients LGE CMR data were available from 41 patients

Figure 2 Bland-Altman plot of left ventricular ejection fraction derived from endocardial

electromechanical mapping and cardiovascular magnetic resonance

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Table 1 Baseline clinical characteristics at primary PCI (n=42)Age yrs (mean plusmn SD) 547 plusmn 102 Male sex (34) 810

History of MI (0) 0History of PCI (0) 0History of CABG (0) 0History of stroke (2) 48

Killip class I (38) 905Killip class II (3) 71Killip class III (1) 24Killip class IV (0) 0

Diabetes mellitus (2) 48 Hypertension (12) 286Hyperlipidemia (13) 310Current smoker (24) 571 Positive family history (19) 452

Infarct locationLAD (24) 571CX (7) 167RCA (11) 262

Number of diseased vessels1 (33) 7862 (6) 1433 (3) 71

Total ischemic time (median + interquartile range) 342 [233 ndash 450]Type B2C lesion (41) 976Stent (42) 100 Bare metal (42) 100Drug eluting (0) 0Stent diameter (mean plusmn SD) 33 plusmn 03Length of stented segment 231 plusmn 102Glycoprotein IIbIIIa receptor blocker (41) 976 Intra-aortic balloon pump (1) 24

TIMI flow before PPCI0 (31) 7381 (3) 712 (6) 1433 (2) 48

TIMI flow after PPCI0 (()) 01 (2) 482 (5) 1193 (35) 833

Chap

ter

5

76

Table I ContinuedMyocardial blush grade after PPCI0 (2) 481 (14) 3332 (21) 5003 (5) 119

Max CK Ul (median + interquartile range) 3314 [1546 ndash 5158]Max CK-MB Ul (median + interquartile range) 280 [161 ndash 541]

Data are displayed as percentage unless otherwise indicated Total ischemic time denotes time between onset of symptoms and until PPCI Daggersuccessful reperfusion denotes TIMI 3 flow and myocardial blush grade 2 or 3

CABG = coronary artery bypass graftingCX = circumflex coronary arteryCK = creatin kinaseCK-MB = creatin kinase myoglobin bindingLAD = left anterior descending coronary arteryMI = myocardial infarctionPCI = percutaneous coronary interventionPPCI = primary percutaneous coronary interventionRCA = right coronary arterySD = standard deviationTIMI = thrombolysis in myocardial infarction

Global parameters

The average LVEF measured by EEM was 362 (plusmn 87 -point) Compared to the average

LVEF measurement by CMR of 459 (plusmn 105 -point) there was an average underestimation

of 97 -point (plt0001) Figure 2 represents the Bland-Altman analysis of the differences

between both EEM and CMR measurements of LVEF The Pearsonrsquos correlation coefficient

for LVEF was 066 (plt0001) All functional global parameters are provided in table II

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Table 2 Global left ventricular function parametersEEM CMR Difference

End-diastolic volume (ml plusmn SD) 1486 (plusmn 546) 2270 (plusmn 616) -784 (plusmn 401)End-systolic volume (ml plusmn SD) 976 (plusmn 486) 1265 (plusmn 566) -289 (plusmn 270) Stroke volume (ml plusmn SD) 509 (plusmn 146) 1005 (plusmn 240) -496 (plusmn 250)LVEF ( plusmn SD) 362 (plusmn 87) 459 (plusmn 107) -97 (plusmn 80)

EEM = Electromechanical endocardial mappingLVEF = Left ventricular ejection fractionML = millilitreCMR = Cardiovascular magnetic resonance SD = Standard deviation

Average infarct-size measured by CMR was 118 plusmn 72 The EEM surface-area with a UV cut

off value of lt 69 mV expressed as percentage of the total surface-area correlated well with

LGE CMR infarct size (R=0578 plt0001) (figure 3)

Figure 3 Relation between infarct size assessment by EEM and CMR expressed as percentage of the

total left ventricular myocardial mass

Chap

ter

5

78

Regional parameters

All three EEM parameters LLS UV and BV differed significantly between normal

and dysfunctional segments (98 vs 73 118 vs 97 and 33 vs 28 for LLS UV and BV

respectively plt0001 for LLS and UV p=0006 for BV) Furthermore average LLS UV and

BV differed significantly between normal segments segments with subendocardial LGE and


for LLS UV and BV respectively plt0001 for all variables)

The receiver operator characteristic curves (ROC) for LLS UV and BV for the identification

of subendocardial infarction on CMR are shown in figure 4A The area under the curve for

LLS UV and BV was 0589 0619 and 0594 respectively The ROC-curves for LLS UV and

BV for the identification of transmural infarction on CMR are shown in figure 4B The area

under the curve for LLS UV and BV was 0725 0698 and 0713 respectively Although a

large inter-patient variability in terms of maximum and minimum values for all three EEM-

parameters was noted normalization of the segmental values (EEM-parameters expressed

as percentage of maximum average or minimum value of that particular map) did not

significantly alter the ROC-curves

Figure 4 Receiver operator characteristic analysis for the identification of (A) viable myocardium

defined as segmental transmural extent of lt50 and (B) non-viable myocardium defined as segmental

transmural extent of ge50 at late gadolinium enhancement CMR using endocardial electromechanical

mapping parameters

LLS linear local shortening UV unipolar voltage BV bipolar voltage

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Discussion

In the present study we evaluated the value and limitations of EEM in the assessment of

global and regional left ventricular function and size and transmural extent of infarction in

comparison with CMR Our results demonstrate that despite a significant underestimation

of LVEF assessment EEM can be used to determine both regional function and transmural

extent of infarction in patients with a large myocardial infarction However our data

indicate that exact pinpointing of myocardial arearsquos which could potentially benefit from

locally injected therapeutics remains difficult This makes the further development of this

diagnostic modality important because it could become a valuable tool in the rapidly

evolving field of myocardial cell therapy Numerous studies have compared EEM with

other imaging modalities and although electro-mechanical cardiac mapping measurements

are quantitative no generally accepted cut-off values for EEM-parameters have been

identified(1124-28) At the present time only one other study comparing EEM to CMR in

post-STEMI patients has been published (15) In this study 15 patients underwent both EEM

and CMR with LGE Perin et al found a cut-off value of 69 mV for differentiation between

normal and transmural myocardial infarction using ROC-analyses (area 094 sensitivity 93

specificity 88) Although the ROC analyses were less convincing in the present study it

was noted that there was a strong correlation between the percentage of the surface-area

of the EEM-maps with an UV lt 69 mV and the extent of LGE expressed as percentage

of the total myocardial mass When bearing in mind that myocardial damage from STEMI

originates from the endocardial surface with variable penetration to the epicardium the

Pearsonrsquos correlation coefficient of 0578 can be attributed to the nature of the physical

data-acquisition (endocardial detection for EEM vs whole-myocardium LGE in CMR) In

this light it is tempting to speculate that the trabecularisation of the left ventricle may be

responsible for the overall lower ventricular volumes measured by EEM in comparison with

CMR in which all trabecularisation and papillary muscle-mass are considered part of the

left ventricular cavity An earlier study comparing global LV function measured by EEM to

bi-plane LV angiography also showed a considerable underestimation of these parameters

by EEM(29)

Chap

ter

5

80

It was noted that there were large inter-patient differences in terms of maximal and minimal

values of the EEM parameters This was unexpected since the patient-population was rather

uniform due to the tight in- and exclusion criteria of the trial in which all patients were

enrolled However normalisation of the EEM-parameters for either minimal or maximal

values did not improve or weaken the discriminative power of EEM for extent of LGE or

regional function indicating that there may be another factor explaining these variations

It could be argued that additional local ischemia is responsible for this effect However the

present study was not designed to elucidate this effect

Although we found statistically significant differences between the infarcted and non-

infarcted myocardial tissue it remained uncertain in individual patients to establish the

exact location of the border-zone of the myocardial infarction which is arguably the area

benefiting most from direct injection of progenitor cells or other therapeutics Combining

the EEM-technique with other imaging modalities as CMR computed tomography or

nuclear imaging may overcome this problem by fusing the image on-line with the EEM-map

This technique is already implemented for electrophysiological interventions of the atria

Limitations

The present study was performed in a selected patient-cohort with a known large MI

Furthermore with the use of a 17-segment bullrsquos-eye maps for data-assessment there is

a risk of ldquosegmental shiftrdquo in which areas of myocardial tissue are projected in different

segments creating a mismatch This approach could also have caused some ldquosmearingrdquo of

the infarcted areas since multiple individual measurements were used to form one variable

per segment In this study two pairs of measurements were compared that have slightly

different biomechanical and physiological backgrounds This could have been responsible

for some mismatching Furthermore we excluded 17 of the EEM segments in the

segmental analyses It could be hypothesized this has negatively influenced the segmental

analyses However the majority of the excluded segments were excluded because there

were less than four contact-points within the segmental border and were mostly located in

non-infarcted myocardial areas

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In conclusion although relatively large differences in global left ventricular functional

parameters between EEM and CMR were found there was a good correlation between

the surface-area of the EEM-map with a UV below 69 mV and LGE infarct size Segmental

analyses showed that EEM can be used to determine both regional function and extent of

infarction in patients with a large myocardial infarction however convincing cut-off values

for EEM-parameters could not established Exact pinpointing of myocardial areas benefiting

from direct injection of therapeutics remains difficult

Chap

ter

5

82

References

(1) Zijlstra F Hoorntje JC de Boer MJ Reiffers S Miedema K Ottervanger JP et al Long-term benefit of primary angioplasty as compared with thrombolytic therapy for acute myocardial infarction N Engl J Med 1999 Nov 4341(19)1413-9

(2) Perin EC Dohmann HF Borojevic R Silva SA Sousa AL Mesquita CT et al Transendocardial autologous bone marrow cell transplantation for severe chronic ischemic heart failure Circulation 2003 May 13107(18)2294-302

(3) Beeres SL Bax JJ bbets-Schneider P Stokkel MP Fibbe WE van der Wall EE et al Intramyocardial injection of autologous bone marrow mononuclear cells in patients with chronic myocardial infarction and severe left ventricular dysfunction Am J Cardiol 2007 Oct 1100(7)1094-8


(5) Segers VF Lee RT Stem-cell therapy for cardiac disease Nature 2008 Feb 21451(7181)937-42

(6) Hofmann M Wollert KC Meyer GP Menke A Arseniev L Hertenstein B et al Monitoring of bone marrow cell homing into the infarcted human myocardium Circulation 2005 May 3111(17)2198-202

(7) Smits PC van Geuns RJ Poldermans D Bountioukos M Onderwater EE Lee CH et al Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure clinical experience with six-month follow-up J Am Coll Cardiol 2003 Dec 1742(12)2063-9

(8) Vale PR Losordo DW Milliken CE McDonald MC Gravelin LM Curry CM et al Randomized single-blind placebo-controlled pilot study of catheter-based myocardial gene transfer for therapeutic angiogenesis using left ventricular electromechanical mapping in patients with chronic myocardial ischemia Circulation 2001 May 1103(17)2138-43

(9) Tio RA Tkebuchava T Scheuermann TH Lebherz C Magner M Kearny M et al Intramyocardial gene therapy with naked DNA encoding vascular endothelial growth factor improves collateral flow to ischemic myocardium Hum Gene Ther 1999 Dec 1010(18)2953-60

(10) Gyongyosi M Khorsand A Sochor H Sperker W Strehblow C Graf S et al Characterization of hibernating myocardium with NOGA electroanatomic endocardial mapping Am J Cardiol 2005 Mar 1595(6)722-8

(11) Koch KC Vom Dahl J Wenderdel M Nowak B Schaefer WM Sasse A et al Myocardial viability assessment by endocardial electroanatomic mapping comparison with metabolic imaging and functional recovery after coronary revascularization J Am Coll Cardiol 2001 Jul38(1)91-8

(12) Koch KC Vom Dahl J Schaefer WM Nowak B Kapan S Hanrath P Prognostic value of endocardial electromechanical mapping in patients with left ventricular dysfunction undergoing percutaneous coronary intervention Am J Cardiol 2004 Nov 194(9)1129-33

(13) Poppas A Sheehan FH Reisman M Harms V Kornowski R Validation of viability assessment by electromechanical mapping by three-dimensional reconstruction with dobutamine stress echocardiography in patients with coronary artery disease Am J Cardiol 2004 May 193(9)1097-101

(14) Samady H Choi CJ Ragosta M Powers ER Beller GA Kramer CM Electromechanical mapping identifies improvement in function and retention of contractile reserve after revascularization in ischemic cardiomyopathy Circulation 2004 Oct19110(16)2410-6

(15) Perin EC Silva GV Sarmento-Leite R Sousa AL Howell M Muthupillai R et al Assessing myocardial viability and infarct transmurality with left ventricular electromechanical mapping in patients with stable coronary artery disease validation by delayed-enhancement magnetic resonance imaging Circulation 2002 Aug20106(8)957-61

5 N

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to M

RI

83



(18) Kim RJ Fieno DS Parrish TB Harris K Chen EL Simonetti O et al Relationship of MRI delayed contrast enhancement to irreversible injury infarct age and contractile function Circulation 1999 Nov 9100(19)1992-2002

(19) Kim RJ Judd RM Chen EL Fieno DS Parrish TB Lima JA Relationship of elevated 23Na magnetic resonance image intensity to infarct size after acute reperfused myocardial infarction Circulation 1999 Jul 13100(2)185-92

(20) Hirsch A Nijveldt R Van der Vleuten PA Biemond BJ Doevendans PA van Rossum AC et al Intracoronary infusion of autologous mononuclear bone marrow cells or peripheral mononuclear blood cells after primary percutaneous coronary intervention rationale and design of the HEBE trial--a prospective multicenter randomized trial Am Heart J 2006 Sep152(3)434-41

(21) Bondarenko O Beek AM Hofman MB Kuhl HP Twisk JW van Dockum WG et al Standardizing the definition of hyperenhancement in the quantitative assessment of infarct size and myocardial viability using delayed contrast-enhanced CMR J Cardiovasc Magn Reson 20057(2)481-5


(23) Bland JM Altman DG Statistical methods for assessing agreement between two methods of clinical measurement Lancet 1986 Feb 81(8476)307-10

(24) Fuchs S Hendel RC Baim DS Moses JW Pierre A Laham RJ et al Comparison of endocardial electromechanical mapping with radionuclide perfusion imaging to assess myocardial viability and severity of myocardial ischemia in angina pectoris Am J Cardiol 2001 Apr 187(7)874-80

(25) Graf S Gyongyosi M Khorsand A Nekolla SG Pirich C Kletter K et al Electromechanical properties of perfusionmetabolism mismatch comparison of nonfluoroscopic electroanatomic mapping with 18F-FDG PET J Nucl Med 2004 Oct45(10)1611-8

(26) Keck A Hertting K Schwartz Y Kitzing R Weber M Leisner B et al Electromechanical mapping for determination of myocardial contractility and viability A comparison with echocardiography myocardial single-photon emission computed tomography and positron emission tomography J Am Coll Cardiol 2002 Sep 1840(6)1067-74

(27) Kornowski R Hong MK Leon MB Comparison between left ventricular electromechanical mapping and radionuclide perfusion imaging for detection of myocardial viability Circulation 1998 Nov 398(18)1837-41

(28) Wiggers H Botker HE Sogaard P Kaltoft A Hermansen F Kim WY et al Electromechanical mapping versus positron emission tomography and single photon emission computed tomography for the detection of myocardial viability in patients with ischemic cardiomyopathy J Am Coll Cardiol 2003 Mar 541(5)843-8

(29) Van Langenhove G Hamburger JN Smits PC Albertal M Onderwater E Kay IP et al Evaluation of left ventricular volumes and ejection fraction with a nonfluoroscopic endoventricular three-dimensional mapping technique Am Heart J 2000 Oct140(4)596-602

Chap

ter

5

84

PART 2

Cell therapy after STEMI

Myocardial regenerati on

Cell-therapy aft er reperfusion in pati ents with ST-elevati on

myocardial infarcti on

Pieter A van der Vleuten MD Reneacute A Tio MD PhD

Felix Zijlstra MD PhD FESC FACC

Thoraxcenter Department of Cardiology University Medical Center Groningen

University of Groningen The Netherlands

Chapter in ldquoMechanical Reperfusion For STEMI From Randomized Trial to Clinical Practi cerdquo

6

Chap

ter

6

88

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Introduction

Myocardial infarction (MI) and the subsequent loss of left ventricular (LV) function are a

major cause of morbidity and mortality Until recently the main focus of the research-effort

in the MI-field has been on limitation of myocardial damage by primary percutaneous

coronary intervention (PCI) and preservation of left ventricular function by acute and

long-term pharmacological interventions To date however the dogma that the heart is a

terminally differentiated pot-mitotic organ with very limited ability for regeneration has

been abandoned after a number of landmark-publications has provided convincing in-

vitro evidence to support the contrary(12) These publications have inspired many active

research groups to further investigate this very appealing concept of cardiac repair through

cell-therapy

Potential mechanisms of (stem) cell-mediated myocardial repair

The observation that a male recipient of a female donor-heart displayed XY-genotype cardiac

cells after some time supported the idea that the heart has the ability to incorporate cells

from outside the heart(34) Although this innate mechanism is insufficient to compensate

for the gradual loss of cardiomyocytes during life let alone the large acute loss of myocytes

after MI it triggered the idea that this mechanism could be augmented by transplantation

of (stem) cells In 2001 Orlic et al showed in an animal model that labelled bone-marrow

derived cells grafted in damaged myocardium after coronary ligation and expressed

cardiomyocyte-characteristics(2) Although this finding was heavily debated after its initial

publication it was the start of the development of a new therapeutic option for post-MI

heart failure

There are several different cell-types under investigation which can be used for the purpose

of myocardial regeneration ranging from the pluripotent stem-cells such as the embryonic

stem cell capable of differentiating into any cell-type in the human body to the more

differentiated multipotent (stem) cell types such as mesenchymal stem cells (MSC) and

bone marrow derived hemotopoetic (stem) cells (BMC) which have limited differentiation

abilities but are more readily available and can be used for autologous transplantation

herewith eliminating the problem of rejection

Chap

ter

6

90

Cell types

Embryonic stem cells

In terms of regenerative properties embryonic stem cells are superior to any other type of

progenitor cells since this cell type still has the ability to differentiate and proliferate into

an entire organ or even a complete individual Although this makes the embryonic stem cell

the most appealing cell type for cell therapy research the risk of teratoma formation and

limited availability in humans are severe drawbacks In addition the use of this cell type

is topic of extensive ethical debates Implementation of this cell type in post MI clinical

practice in the near future is therefore unlikely

Cardiac stem cells

The heart was long considered to be one of the only organs that did not possess a resident

progenitor cell which would have the capacity to regenerate sections of the healthy or

injured myocardium In 2003 the discovery of this particular cell type in rats was reported

(5) As cardiac stem cells already reside in the myocardium it is tempting to speculate that

multiplication or activation of this cell type may be very likely to provide new cardiomyocytes

However in order to be able to implement these cells it should first be elucidated how many

cardiac stem cells are present in the adult human heart why these cells do not regenerate

the myocardium under normal circumstances and how they may be stimulated to do so So

far no human studies have been conducted with this cell type

Skeletal myoblasts

Skeletal muscle is able to regenerate after injury because it contains myoblasts which retain

the capacity to fuse with the surrounding myocytes and differentiate into functional skeletal

muscle Early cell therapy studies in animals implemented skeletal myoblasts However

detailed analysis later showed that these cells did not differentiate to cardiomyocytes

rather they were differentiating into skeletal muscle cell identity In addition these skeletal

myoblasts did not couple electrophysiologically with the host myocardium and subsequently

may cause a proarrhythmic substrate(6)

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91

Mesenchymal stem cells

MSCs reside in the stroma of the bone marrow which was originally believed to function

as a structural framework for the hematopoietic cells that also occupy the bone marrow

Closer examination showed that these cells express a variety of growth factors that enhance

hematopoiesis both in vivo and in vitro The in vitro capacity of mouse bone marrowndash

derived MSCs to differentiate into cardiomyocytes was first reported in 1999(7) One of

the advantages of this cell type is that is relatively easy accessible autologous cell source

with a documented ability to differentiate into cardiomyocyts However the time needed

for mesenchymal stem cells to proliferate in culture to a sufficient cell number is extensive

and exceeds the approximately 10 day period considered optimal timing for cell therapy

post MI A Phase I study with bone marrowndashderived mesenchymal stem cells is currently

conducted at the Johns Hopkins medical institution USA

Bone marrow derived mononuclear cells

Bone marrow derived mononuclear cells (BMMNC) are a mix of cells containing the

hemotopoetic stem cell (BMC) fraction Although the reported numbers vary unselected

BMMNCs contain on average approximately 3 percent BMCs This cell type is studied

extensively and its safety and feasibility in clinical practice has been established However it

is known from various in vitro studies that the stem cell plasticity of HSCS is limited

Paracrine effects

Although the theory of cardiomyocyte regeneration is plausible and supported by a large

body of in-vitro evidence as cell-therapy research progresses a discrepancy has been

noted between the measured beneficial effects and the actual degree of cardiomyogeneic

differentiation These observations have lead to the hypothesis that potential paracrine

effects may play an important role in stem cell therapy These paracrine influences may

include secretion of factors that either attenuate apoptosis of endogenous cardiomyocytes

or promote angiogenesis by local VEGF production(89) It has even been postulated that

the cells activate resident cardiac stem cells(10) Mesenchymal stem cells have been

shown secrete chemotactic factors including PGF and MCP-1 which recruit monocytes

and promote angiogenesis(11) However to date a large part of these paracrine effects

Chap

ter

6

92

continues to be unexplained and needs to be further elucidated in order to direct future

in-vivo trials

In-vivo experience with BMMNCs

Although the overall in-vivo experience with cell therapy is limited and for the larger part

derived from small single-centre studies two different approaches can be distinguished

There have been a number of clinical trials in patients with longer existing LV dysfunction

most of which comprised of cell-injection during or shortly after either cardiac surgery

(mostly coronary artery bypass grafting)(12) or percutaneous intracoronary procedures

(mostly PCI for stable coronary artery disease)(13) Although it may be concluded from

these trials that the procedures required for cell-delivery are safe and feasible the benefit

of cell-therapy in this patient category remains questionable

In contrast percutaneous intracoronary cell-therapy shortly after MI has been investigated

more extensively and a number of relatively large and well-conducted randomised clinical

trials (RCT) is available to assess its efficacy The mainstay of these trials implemented a

protocol of intracoronary delivery of unselected autologous BMMNCs to the MI-related

coronary artery 1 to 9 days after MI The mononuclear cell-fraction containing the HSC

fraction was isolated from the full bone marrow harvested from the patientrsquos iliac crest by

density gradient centrifugation

Cell delivery

There are several methods for cell delivery The first trials used direct injection into the

targeted myocardium either by direct injection by a cardiothoracic surgeon (in addition to

cardiac surgery) or percutaneous aided by fluoroscopy or 3D electromechanical LV mapping

Although direct injection ensures maximal retention of cells it has been largely abandoned

since it is locally invasive Moreover it has been speculated that local regeneration at an

injection site surrounded by transmurally infarcted tissue could lead to a proarrhythmic

substrate Nowadays most study protocols employ a percutaneous stop-flow technique This

is performed by advancing an over-the-wire balloon through the infarct related coronary

artery to the site of the stent implanted during primary PCI The guidewire is than removed

and the balloon is inflated to create an obstruction without obliterating the central lumen

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93

of the over-wire balloon catheter Through this lumen the cells can than be delivered distal

from the initial coronary occlusion Although it is inevitable that some cells will be flushed

out through the venous system this method ensures even delivery of cells to the border

zone of the infarcted myocardial tissue Coronary occlusion can be performed safely and

without myocardial damage for up to three minutes This procedure may even be repeated

several times waiting for ST segment normalisation after each balloon inflation

Overview of RCTs of intracoronary infusion of HSCs after acute MI

In order to provide an insight into the current experience with HSCs all currently available

RCTs were pooled to establish a quantitative overview Only randomised studies carried out

in patients shortly after MI employing a stop-flow coronary delivery strategy of autologous

bone marrow derived progenitor cells with a clear pre-specified control-group and well-

defined end-points were included in the analysis At the present time data from 6 studies

are available that meet these criteria(14-19) In total 542 patients were included A small

but statistically significant effect of 159 -point gain in LVEF over control was observed in

the pooled analysis (figure 1) However it should be noted that this effect did not translate

into a statistically significant reduction in remodelling measured as change in LV end-

diastolic volume (figure 2) or reduction in 4 to 6 months mortality (figure 3) Moreover

when grouping the studies by outcome-modality the three RCTs implementing magnetic

resonance imaging (MRI) as outcome parameter proved negative (figure 1)

Considerations

Some observations from RCTs have raised new questions regarding cardiac cell-therapy

A subanalysis of the study by Schaumlchinger et al(16) showed that there may be a time-

dependant relationship between the initial MI and the cell delivery favouring later cell

delivery (5-7 days after MI) Most RCTs report a positive effect of cell therapy in particular in

patients with more extensive MI This may suggest a dose-response relationship

Chap

ter

6

94

Figure 1 forest plot of improvement in left ventricular ejection fraction 4-6 months after randomisation

as outcome measure in 6 RCTs with autologous bone marrow derived mononuclear cells BMMNC =

Bone marrow derived mononuclear cell fraction Boost 2004 (ref 14) HEBE 2008 (data presented at

AHA Chicago 2008) Janssens 2006 (ref 15) ASTAMI (ref 17) Repair AMI (ref 16) TCT-STAMI (ref 18)

Figure 2 forest plot of reduction of end diastolic volume 4-6 months after randomisation as outcome

measure in 6 RCTs with autologous bone marrow derived mononuclear cells BMMNC = Bone marrow

derived mononuclear cell fraction Boost 2004 (ref 14) HEBE 2008 (data presented at AHA Chicago

2008) Janssens 2006 (ref 15) ASTAMI (ref 17) Repair AMI (ref 16) TCT-STAMI (ref 18)

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95

Figure 3 Pooled analysis of mortality 4-6 months after randomisation as outcome measure in 6

RCTs with autologous bone marrow derived mononuclear cells BMMNC = Bone marrow derived

mononuclear cell fraction Boost 2004 (ref 14) HEBE 2008 (data presented at AHA Chicago 2008)

Janssens 2006 (ref 15) ASTAMI (ref 17) Repair AMI (ref 16) TCT-STAMI (ref 18)

Limitations and risks of cell therapy

It should be noted that cell therapy in its present form is both time-consuming and expensive

Furthermore it requires uncomfortable procedures for patients such as large-volume bone

marrow aspiration and repeated coronary angiography In addition these procedures all

have there own risks and side-effects These aspects should be considered in present and

future cell therapy projects since there is as yet not enough evidence of clinically relevant LV

functional recovery or long term benefit in terms of mortality to disregard these important

issues

Conclusion

Although cell therapy remains a promising concept which harbours hope for a (partial)

solution to a very important clinical problem there is as yet not enough evidence for it to be

implemented on a large scale in daily clinical practice

Chap

ter

6

96

References

(1) Beltrami AP Urbanek K Kajstura J Yan SM Finato N Bussani R et al Evidence that human cardiac myocytes divide after myocardial infarction N Engl J Med 2001 Jun 7344(23)1750-7

(2) Orlic D Kajstura J Chimenti S Jakoniuk I Anderson SM Li B et al Bone marrow cells regenerate infarcted myocardium Nature 2001 Apr 5410(6829)701-5

(3) Quaini F Urbanek K Beltrami AP Finato N Beltrami CA Nadal-Ginard B et al Chimerism of the transplanted heart N Engl J Med 2002 Jan 3346(1)5-15

(4) Laflamme MA Myerson D Saffitz JE Murry CE Evidence for cardiomyocyte repopulation by extracardiac progenitors in transplanted human hearts Circ Res 2002 Apr 590(6)634-40

(5) Beltrami AP Barlucchi L Torella D Baker M Limana F Chimenti S et al Adult cardiac stem cells are multipotent and support myocardial regeneration Cell 2003 Sep114(6)763-76

(6) Reinecke H MacDonald GH Hauschka SD Murry CE Electromechanical coupling between skeletal and cardiac muscle Implications for infarct repair J Cell Biol 2000 May 1149(3)731-40

(7) Makino S Fukuda K Miyoshi S Konishi F Kodama H Pan J et al Cardiomyocytes can be generated from marrow stromal cells in vitro J Clin Invest 1999 Mar103(5)697-705

(8) Takahashi T Kalka C Masuda H Chen D Silver M Kearney M et al Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization Nat Med 1999 Apr5(4)434-8

(9) Fuchs S Baffour R Zhou YF Shou M Pierre A Tio FO et al Transendocardial delivery of autologous bone marrow enhances collateral perfusion and regional function in pigs with chronic experimental myocardial ischemia J Am Coll Cardiol 2001 May37(6)1726-32

(10) Misao Y Takemura G Arai M Ohno T Onogi H Takahashi T et al Importance of recruitment of bone marrow-derived CXCR4+ cells in post-infarct cardiac repair mediated by G-CSF Cardiovasc Res 2006 Aug 171(3)455-65

(11) Kinnaird T Stabile E Burnett MS Lee CW Barr S Fuchs S et al Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms Circ Res 2004 Mar 1994(5)678-85

(12) Stamm C Kleine HD Choi YH Dunkelmann S Lauffs JA Lorenzen B et al Intramyocardial delivery of CD133+ bone marrow cells and coronary artery bypass grafting for chronic ischemic heart disease safety and efficacy studies J Thorac Cardiovasc Surg 2007 Mar133(3)717-25

(13) Assmus B Honold J Schachinger V Britten MB Fischer-Rasokat U Lehmann R et al Transcoronary transplantation of progenitor cells after myocardial infarction N Engl J Med 2006 Sep 21355(12)1222-32

(14) Wollert KC Meyer GP Lotz J Ringes-Lichtenberg S Lippolt P Breidenbach C et al Intracoronary autologous bone-marrow cell transfer after myocardial infarction the BOOST randomised controlled clinical trial Lancet 2004 Jul 10364(9429)141-8

(15) Janssens S Dubois C Bogaert J Theunissen K Deroose C Desmet W et al Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction double-blind randomised controlled trial Lancet 2006 Jan 14367(9505)113-21



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(18) Ge J Li Y Qian J Shi J Wang Q Niu Y et al Efficacy of emergent transcatheter transplantation of stem cells for treatment of acute myocardial infarction (TCT-STAMI) Heart 2006 Dec92(12)1764-7

(19) Hirsch A Nijveldt R van der Vleuten PA Biemond BJ Doevendans PA van Rossum AC et al Intracoronary infusion of autologous mononuclear bone marrow cells or peripheral mononuclear blood cells after primary percutaneous coronary intervention rationale and design of the HEBE trial--a prospective multicenter randomized trial Am Heart J 2006 Sep152(3)434-41

Chap

ter

6

98

Intracoronary infusion of autologous mononuclear bone

marrow cells in pati ents with acute myocardial infarcti on

treated with primary PCI

pilot study of the multi center HEBE trial

Alexander Hirsch MD1 Robin Nijveldt MD2 Pieter A van der Vleuten MD3 Reneacute A Tio MD

PhD3 Willem J van der Giessen MD PhD4 Koen MJ Marques MD2 Pieter A Doevendans MD

PhD5 Johannes Waltenberger MD PhD6 Jurrien M ten Berg MD PhD7 Wim RM Aengevaeren

MD PhD8 Bart J Biemond MD PhD9 Jan GP Tijssen PhD1 Albert C van Rossum MD PhD2

Jan J Piek MD PhD1 Felix Zijlstra MD PhD3

1 Department of Cardiology Academic Medical Center Amsterdam The Netherlands

2 Department of Cardiology VU University Medical Center Amsterdam The Netherlands

3 Department of Cardiology University Medical Center Groningen Groningen The Netherlands

4 Department of Cardiology Erasmus Medical Center Rott erdam The Netherlands

5 Department of Cardiology University Medical Center Utrecht Utrecht The Netherlands

6 Department of Cardiology University Hospital Maastricht Maastricht The Netherlands

7 Department of Cardiology St Antonius Hospital Nieuwegein The Netherlands

8 Department of Cardiology University Medical Center St Radboud Nijmegen The Netherlands

9 Department of Haematology Academic Medical Center Amsterdam The Netherlands

First three authors contributed equally to the manuscript and their names are provided in

alphabeti cal order


7

Chap

ter

7

100

Abstract

Objective

This study was a pilot trial to determine safety and feasibility of intracoronary infusion of

mononuclear bone marrow cells (MBMC) in patients with acute myocardial infarction (MI)

Background

Studies reporting the effect of MBMC therapy on improvement of left ventricular (LV)

function have shown variable results The HEBE trial is a large multicenter randomized trial

that currently enrolls patients Prior to this trial we performed an uncontrolled pilot study

Methods

Twenty-six patients with a first acute MI were prospectively enrolled in 8 centers Bone

marrow aspiration was performed at a median of 6 days after primary PCI (interquartile

range 5 to 7 days) MBMC were isolated by gradient centrifugation and were infused

intracoronary the same day All patients underwent magnetic resonance imaging before cell

infusion and after 4 months Clinical events were assessed up to 12 months

Results

Within 10 hours after bone marrow aspiration 246plusmn133 x106 MBMC were infused of

which 39plusmn23 x106 cells were CD34+ In one patient this procedure was complicated by

local dissection LV ejection fraction significantly increased from 450plusmn63 to 472plusmn65

(p=003) Systolic wall thickening in dysfunctional segments at baseline improved with

09plusmn07 mm (plt0001) Infarct size decreased 37 from 178plusmn82 to 112plusmn42 gram (plt0001)

During 12 months follow-up 3 additional revascularizations were performed and an ICD was

implanted in one patient 3 weeks after PCI

Conclusion

In patients with acute MI intracoronary infusion of MBMC is safe in a multicenter setting At

4 months follow-up a modest increase in global and regional LV function was observed with

a concomitant decrease in infarct size

HEB

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101

Introduction

Survival and prognosis of patients with an acute myocardial infarction (MI) have improved

substantially by therapies aiming at prompt reperfusion of the infarct-related artery

Nonetheless myocardial necrosis starts rapidly after coronary occlusion Despite sustained

patency of the infarct-related artery left ventricular (LV) remodeling after successful primary

percutaneous coronary intervention (PCI) occurs in up to 30 of the patients leading to

chamber dilation and contractile dysfunction (12)

Cell therapy as an adjunctive therapy to promote myocardial function after an acute MI has

been widely studied in both experimental and clinical conditions Results from experimental

studies have shown that injection of (selected) bone marrow cells can improve myocardial

function by inducing angiogenesis inhibiting apoptosis enhancing scar tissue formation

and possible myocardial regeneration (3-6) However recent clinical randomized controlled

trials investigating the effect of intracoronary infusion of unselected bone marrow cells on

enhancement of functional recovery in patients with acute MI have shown equivocal results

(7-12) In addition the size of most trials was smaWe therefore designed the HEBE trial

and are currently enrolling 200 patients in this multicenter randomized controlled trial to

evaluate the effect of bone marrow cell therapy on LV function after acute MI treated with

primary PCI (13) Prior to the main trial we performed a non-randomized pilot trial in which

all patients were treated with mononuclear bone marrow cells (MBMC) to assess the safety

and feasibility of intracoronary cell infusion in a multicenter setting

Methods

Patients and study protocol

Between February and December 2005 26 patients with first ST-segment elevation MI

treated with primary PCI and stenting were prospectively enrolled in 8 Dutch centers

Patients between 30 to 75 years of age were included if they met the following inclusion

criteria successful primary PCI with stent placement within 12 hours after onset of symptoms

three or more hypokinetic or akinetic LV segments observed on resting echocardiogram

Chap

ter

7

102

performed at least 12 hours after PCI and an elevation of creatine kinase (CK) or CK-MB

more than 10 times the local upper limit of normal (ULN) Main exclusion criteria were

haemodynamic instability an anticipated PCI or CABG within the next 4 months severe

comorbidity and contraindications for Magnetic Resonance Imaging (MRI) Patients were

treated with aspirin heparin and clopidogrel according to Dutch practice guidelines

Figure 1 shows the study design All patients received intracoronary infusion of autologous

MBMC MRI was performed before cell infusion and at 4 months after inclusion Patients

were continuously monitored with telemetry after cell infusion until discharge and

underwent 24-hour ECG monitoring at 1 month after treatment Patients were seen at the

outpatient clinic at 1 4 and 12 months to assess their clinical status

This study complied with the principles set out in the Declaration of Helsinki All patients

gave informed consent to the study protocol which was approved by the local ethics

committees of all participating centers

Cell harvesting and intracoronary cell infusion

Within 8 days after PCI bone marrow aspiration and intracoronary cell infusion were

performed on the same day Bone marrow aspirate was collected in a sterile container

with heparin (concentration of 20 IEmL) from the posterior iliac crest (approximately 50

mL) and send to one of the six participating cell-processing laboratories All laboratories

are certified stem cell laboratories and are (or related to) a haematology laboratory

that is qualified to perform FACS analysis for cell counting Moreover they are all

engaged in programs for standardization of cell isolation procedures (by the ldquoWerkgroep

Stamcellaboratoria Nederlandrdquo working group of the Dutch haemato-oncology association

HOVON) and for standardization of diagnostics including multiple tests of the same sample

for CD34+ stem cell counting MBMC were isolated by density gradient centrifugation using

LymphoprepTM After 2 washing steps mononuclear cells were resuspended in 15 to 20

ml saline supplemented with 4 human serum albumine and 20 IEml sodium heparin

The number of nucleated blood cells was measured and the number of CD34+ cells and

CD14+ cells were determined in the final cell suspension by FACS analysis according to the

ISHAGE protocol (14) Bacterial and fungal cultures of the clinically used cell preparations

were performed afterwards and proved to be negative in all cell preparations The protocol

specified that cell infusion must take place within 4 hours after preparation

HEB

E pi

lot

103

Prior to cell infusion stent patency of the culprit lesion was visually assessed by coronary

angiography of the infarct-related artery Cell suspension was infused into the infarct-

related artery through the central lumen of an over-the-wire balloon catheter as previously

described (1516) In three sessions of coronary occlusion interrupted by three minutes of

coronary reflow a total of 15 to 20 ml of cell suspension was infused in the infarct territory

Magnetic Resonance Imaging

Patients were studied on a clinical 15 or 30 Tesla scanner using a four-element phased

array cardiac receiver coil MRI acquisition involved a standardized protocol of which the

details were published previously (13) In short ECG-gated images were acquired during

repeated breath-holds Contiguous short axis slices were acquired using a segmented steady

state free precession pulse sequence in multiple short axis views every 10 mm covering the

entire left ventricle from base to apex to examine regional and global LV function Late

gadolinium enhanced (LGE) images were acquired 10 to 15 minutes after administration of

a gadolinium-based contrast agent (Dotarem Guerbet 02 mmolkg) with a 2D segmented

inversion recovery gradient-echo pulse sequence All MRI images were sent to the core

laboratory at VU University Medical Center for quality control and central analysis

MRI data were analyzed using a dedicated software package (Mass Medis Leiden

the Netherlands) On short axis cine slices the endocardial and epicardial borders were

outlined manually in end-diastolic and end-systolic images excluding trabeculae and

papillary muscles From these left ventricular volumes ejection fraction (EF) and mass

were calculated For analysis of segmental myocardial function each short axis slice was

divided in 12 equi-angular segments starting at the posterior septal insertion of the right

ventricle Systolic wall thickening is expressed in absolute values (end-diastolic wall thickness

subtracted from end-systolic wall thickness mm) Dysfunctional segments were defined

as segments with systolic wall thickening of less than 3 mm For analysis of LGE images

areas of hyperenhancement were outlined including central dark zones of microvascular

obstruction allowing calculation of total infarct size Segmental extent of hyperenhancement

was calculated by dividing the infarct area by the total area of the predefined segment ()

The extent was then graded according to the following classification 0 to 25 26 to

75 and 76 to 100 hyperenhancement

Chap

ter

7

104


Continuous baseline variables with normal distribution are expressed as mean plusmn SD and

data with a non normal distribution are given as median value (25th to 75th percentile) The

paired samples t test was used to compare concentrations of cardiac enzymes before and

after cell infusion and differences in global and regional LV parameters between baseline and

follow-up Linear non-parametric correlation was calculated by the Spearman correlation

All statistical tests were two-tailed and statistical significance was set at plt005 Statistical

analysis was done with the Statistical Package for Social Sciences software (SPSS 120 for

Windows) Review Manager (RevMan 42 for Windows The Cochrane Collaboration http

wwwcc-imsnetRevMan) was used for the meta-analysis

Results

Baseline clinical and angiographic characteristics are shown in table I Mean age was 54

years 85 were men median time from symptom onset to PCI was 28 hours TIMI III flow

was documented in all patients after PCI and two thirds of the patients had an anterior

myocardial infarction During hospitalization patients received medication according to the

current guidelines for myocardial infarction At discharge all patients used clopidogrel and

statins 24 (92) patients used aspirin 3 (12) oral anticoagulation 21 (81) ACE inhibitors

or angiotensin-receptor antagonists and 24 (92) beta blockers

HEB

E pi

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105

Table 1 Baseline Clinical and Angiographic characteristics n=26Age years 54 plusmn 8Male gender 22 (85)Body mass index kgm2 27 6 3Diabetes mellitus 0 (0)Known hypertension 5 (19)Family history of ischemic heart disease 14 (56)Hypercholesterolemia 6 (23)Current cigarette smoking 12 (46)Median time from symptom onset to PCI hr 28 (20 - 45)Infarct-related arteryLeft anterior descending artery 16 (62)Left circumflex artery 4 (15)Right coronary artery 6 (23)Multivessel disease 6 (23)TIMI flow grade III after PCI 26 (100)Type of stentBare metal 23 (88)Drug eluting 3 (12)Median number of stents (range) 1 (1 2 4)Size of stent mm 33 plusmn 04Length of stent mm 24 plusmn 13Platelet glycoprotein IIbIIIa inhibitors 19 (73)Median maximum serum creatine kinaseMB divided by local upper limit of normal 24 (16 - 40)

Values are expressed as number () mean plusmn SD or median (25th-75th percentile) unless otherwise specified TIMI thrombolysis in myocardialinfarction PCI percutaneous coronary intervention MB myocardial band

Cell infusion

Bone marrow aspiration was performed 3 to 8 days after primary PCI (median 6 interquartile

range 5 to 7 days) The final cell suspension contained 246 plusmn 133 x 106 cells This consisted

of 39 plusmn 23 x 106 (17 plusmn 09 ) CD34+ cells and 205 plusmn 114 x 106 (88 plusmn 40 ) CD14+ cells The

total number of cells in the final cell suspension did not differ between laboratories (data

not shown) No complications of the bone marrow aspiration procedure were noted At the

same day intracoronary injection of MBMC into the infarct-related artery was performed

Median time from bone marrow harvest to cell infusion was 7 hours (range 5 to 10)

Concentration of CK or CK-MB divided by the local ULN was 066 plusmn 026 before cell infusion

080 plusmn 059 (p=021) at 12 hours after cell infusion and 080 plusmn 052 (p=015) at 24 hours after

cell infusion A CK or CK-MB elevation between 1 and 2 times the ULN was detected in 4

patients and between 2 and 3 times the ULN in 1 patient

Chap

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7

106

In one patient cell infusion procedure was complicated by local dissection of the infarct-

related artery which was successfully treated by immediate stent implantation and no peri-

procedural CK or CK-MB elevation occurred No sustained ventricular arrhythmias were

detected during in-hospital telemetric monitoring after cell infusion

Follow-up

At 4 months follow-up 22 patients (85) were in New York Heart Association (NYHA) class

I and 4 patients (15) were in class II Twenty-three (88) patients used aspirin 5 (19)

oral anticoagulation 15 (50) clopidogrel 24 (92) ACE inhibitors or angiotensin-receptor

antagonists 25 (96) beta blockers and 25 (96) statins

Table II summarizes the adverse clinical events during one year follow-up All patients

were alive at one year after MI and none had been lost to follow-up None of the patients

suffered a recurrent myocardial infarction and three patients underwent a second

percutaneous revascularization The reasons were one stent thrombosis in a bare metal

stent 11 weeks after inclusion and two de novo interventions One patient required an

implantable cardioverter-defibrillator 3 weeks after primary PCI because of non-sustained

ventricular tachycardia and a severely depressed LV function In the same patient a non-

sustained ventricular tachycardia was recorded during 24-hour ECG monitoring at 1 month

No episodes of sustained ventricular tachycardia or appropriate shocks were recorded

during follow-up In all other patients no ventricular arrhythmias occurred during 24-hour

ECG monitoring

Table 2 Clinical Events During 1-year Follow-Up n = 26

Death 0Recurrent myocardial infarction 0Revascularization 3Acute stent thrombosis 1Target vessel nontarget lesion revascularization 1Nontarget vessel revascularization 1Documented ventricular arrhythmia treated by ICD 1Hospitalization for heart failure 0Stroke 0Cancer 0

ICD implantable cardioverter-defibrillator

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Figure 1 Study design and trial profile

PCI = percutaneous coronary intervention MRI = magnetic resonance imaging


Paired cine MRI images for global and segmental function were available in 24 patients and

paired LGE images for infarct size in 19 Baseline MRI was performed at 4 plusmn 1 days after

PCI and at 136 plusmn 18 days of follow-up There was a significant increase in global LV EF from

450 plusmn 63 to 472 plusmn 65 (p=003) (table III) There was no significant correlation between

the change in EF and the total number of injected cells (r=-003 p=089) the number of

CD34+ cells (r=-019 p=038) or the time from PCI to cell infusion (r=-007 p=076) Infarct

size decreased 37 from 178 plusmn 82 to 112 plusmn 42 gram (plt0001) The mean percentage of

dysfunctional segments at baseline was 49 plusmn 15 Figure 2 shows the observed changes in

Chap

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systolic wall thickening during follow-up stratified by baseline function and by the extent of

hyperenhancement Systolic wall thickening in dysfunctional segments at baseline improved

with 09 plusmn 07 mm (from 13 plusmn 04 mm to 22 plusmn 08 mm plt0001)

Table 3 Quantitative data from magnetic resonance imaging (n = 24)

Baseline Follow-up Change P-valueLV ejection fraction () 450 plusmn63 472 plusmn 65 22 plusmn 46 003LV end-diastolic volume index (mLmsup2)

952 plusmn 154 1016 plusmn 160 64 plusmn 102 0005

LV end-systolic volume index (mLmsup2) 529 plusmn 140 543 plusmn 138 14 plusmn 76 039LV mass (gmsup2) 653 plusmn 140 592 plusmn 111 -61 plusmn 66 lt0001Late gadolinium enhancement (gram) n=19

178 plusmn 82 112 plusmn 42 -66 plusmn 57 lt0001

Late gadolinium enhancement( of LV) n=19


LV left ventricular

Figure 2 Change in systolic wall thickening after bone marrow cell injection in (A) dysfunctional

segments at baseline versus normal segments (n=24) and in (B) dysfunctional segments stratified by

extent of hyperenhancement (n=19) Improvement in systolic wall thickening was 10 plusmn 06 mm in

segments with 0-25 hyperenhancement 09 plusmn 12 mm in 26-75 and 10 plusmn 14 mm in 76-100

Base = baseline ES = end-systolic ED = end-diastolic FU = follow-up LGE = late gadolinium

enhancement

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Figure 3 Estimation of the effect of intracoronary injection of non-mobilized bone marrow cells on

left ventricular ejection fraction after acute myocardial infarction Meta-analysis including current

randomized controlled trials Test for heterogeneity p=068 and test for overall effect p=0002

Follow-up was 4 months in REPAIR-AMI trial and in the study by Janssens et al 6 months in ASTAMI

trial and in the study by Ge et al and 18 months in the BOOST Base = baseline EF = ejection fraction

Δ = change from baseline to follow-up WMD = weighted mean difference

Discussion

The findings of this study indicate that intracoronary infusion of autologous MBMC after

recent myocardial infarction is safe in a multicenter setting At 4 months follow-up a modest

but significant increase in global and regional LV function was observed with a concomitant

decrease in infarct size

Since the first preliminary clinical studies of cell therapy in patients after acute MI have

been published (1516) more than four hundred patients were treated with intracoronary

injection of (selected) bone marrow cells in several non-randomized and randomized

controlled trials (79-1215-23) In none of these studies complications of bone marrow

aspiration were reported In our pilot study one local dissection of the infarct-related artery

occurred during cell infusion This complication has been reported previously by others in

four patients using the same technique for cell infusion (2324) One patient in the study by

Meluzin et al developed a thrombus in the infarct-related artery in relation to cell infusion

procedure (23) We noted a mild elevation of CK or CK-MB concentration above the ULN

in five patients after cell infusion procedure corresponding to minor myocardial damageA

Chap

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potential arrhythmogenic effect of cell therapy has been described after autologous

transplantation of cultured skeletal myoblasts (25) After intracoronary bone marrow cell

infusion one patient developed ventricular fibrillation one day after cell infusion in the

ASTAMI trial (9) and a sustained ventricular arrhythmia occurred two days after infusion

in the study by Bartunek et al (17) In our trial one of the 26 treated patients had a non-

sustained ventricular tachycardia during follow-up We cannot exclude the possibility that

cell treatment contributed to the observed arrhythmias in the different trials However in

the randomized trials performed to date the occurrence of ventricular arrhythmias was

not different between the bone marrow and control group and the number of observed

arrhythmias in the non-randomized trials was not unexpectedly high

Concerns have been raised about safety of cell therapy on the long-term because of reports

of high rates of in-stent restenosis (172627) Kang et al reported in-stent restenosis in

7 of the 10 patients treated with granulocyte-colony stimulating factor with or without

additional intracoronary infusion (26) Bartunek et al also observed in a non-randomized

pilot trial a surprisingly high rate of 37 in-stent restenosis and 11 reocclusion in 19

patients treated with intracoronary injection of selected CD133+ bone marrow cells (17)

The injected CD133+ cells carry a high angiogenic potential and this might be an explanation

for the pro-atherogenic effect in that study (27) None of the other trials reported higher

rates of clinical or angiographic restenosis after injection of unselected bone marrow

cells In the double-blind REPAIR-AMI trial even a trend towards a reduction in target

vessel revascularization was observed at one year follow-up (28) In our study we did not

perform routine catheterization during follow-up but in only one patient a target lesion

revascularization was performed during one year follow-up In spite of these results the

possibility that specific types of cell therapy may induce progression of atherosclerosis has

been reported in preclinical studies (29) In conclusion the number of patients that have

been treated until now is only sufficient to derive preliminary data about the safety and

feasibility of intracoronary injection of bone marrow cells Large studies and long-term

follow-up are needed to definitely establish its safety profile

The treatment effect of bone marrow infusion after MI reported in the first non-randomized

trials was promising and suggested an improvement in global EF of approximately 6

However the results of the first randomized clinical trials are conflicting (79-11) Figure 3

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shows a summary of the change in LV EF between baseline and follow-up in the published

randomized controlled trials of intracoronary infusion of non-mobilized unselected bone

marrow cells The follow-up of these studies ranged from 4 to 18 months Compared with

control bone marrow cell therapy significantly improved global LV EF by 22 (95 CI 08 ndash

38 p=0002) None of the trials were powered to detect differences in clinical endpoints

However the REPAIR-AMI trial showed a significant reduction in the occurrence of major

adverse cardiovascular events This raises the possibility that clinical benefits may exceed

the modest improvement seen in ventricular function (28)

We observed a modest increase in LV EF of 22 This trial was not designed to test efficacy

and we did not include a control group Therefore we can not determine the role of the

additional treatment with bone marrow cells on the observed change in LV EF This modest

increase that we observed may be part of the natural course in patients treated by primary

PCI and optimized medical therapy However the change in EF in the control group in the

published randomized trials varied substantially and ranged from -19 to +70 (912)

This underscores the necessity of a randomized trial for an appropriate interpretation of the

effect of cell therapy

The most notable result of our analysis of regional function is that improvement of systolic

wall thickening in segments with 76-100 hyperenhancement is similar to segments with

less transmural infarction In the study by Janssens et al cell therapy did not augment

recovery of global LV EF however they observed enhanced recovery of regional function in

infarcted regions after cell transfer especially in the most severely injured segments (10)

When comparing trials investigating bone marrow cell infusion it is important to note

that there are differences in patient selection and study design For example there are

differences in timing of bone marrow aspiration and cell infusion (one day to few weeks

after reperfusion) cell types (nucleated cells mononuclear cells or selected bone marrow

cells) cell preparation protocol (overnight culture storage medium) and used techniques

to assess functional effects (echocardiography LV angiography gated SPECT MRI)

Although studies with intracoronary cell transplantation have used a similar technique to

infuse bone marrow cells the number of infused cells differs Remarkable is the difference

in recovery of MBMC by density gradient centrifugation from the same amount of bone

marrow (36 million cells from 40 ml bone marrow in the study by Ge et al to 236 million

Chap

ter

7

112

from 50 ml bone marrow in the REPAIR-AMI trial) As shown by Seeger et al isolation

protocols are important and can have impact on the number of isolated cells and the

functional activity of these cells (30) The number of injected MBMC and CD34+ cells in our

current study were comparable with the REPAIR-AMI trial 246 plusmn 133 x 106 versus 236 plusmn 174 x

106 and 39 plusmn 23 x 106 versus 36 plusmn 36 x 106 (11) On the other hand a recent meta-analysis

found no relation between the number of cells and functional recovery (31)

The major limitation of this pilot trial is the lack of a randomized control group which did

not receive intracoronary infusion of MBMC However this study was designed as a phase I

safety and feasibility trial Because multiple centers and stem cell laboratories are involved

this pilot study and the randomized HEBE trial allows a more general feasibility assessment

in contrast to all previous single-center studies

The aim of the HEBE trial is to include 200 patients divided over 3 treatment arms Patients

will be randomized to be treated with either intracoronary infusion MBMC mononuclear

blood cells derived from peripheral blood or standard therapy The primary end point is the

change in regional myocardial function in dysfunctional segments at 4 months relative to

baseline based on segmental analysis as measured by MRI (13)

In conclusion our results of this uncontrolled pilot study show that intracoronary infusion

of autologous MBMC in patients after acute myocardial infarction appears to be safe in

a multicenter setting At 4 months follow-up a modest increase in global and regional LV

function was observed with a concomitant decrease in infarct size

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References

(1) Bolognese L Neskovic AN Parodi G Cerisano G Buonamici P Santoro GM et al Left ventricular remodeling after primary coronary angioplasty patterns of left ventricular dilation and long-term prognostic implications Circulation 2002 Oct 29106(18)2351-7

(2) Cohn JN Ferrari R Sharpe N Cardiac remodeling--concepts and clinical implications a consensus paper from an international forum on cardiac remodeling Behalf of an International Forum on Cardiac Remodeling J Am Coll Cardiol 2000 Mar 135(3)569-82


(4) Kocher AA Schuster MD Szabolcs MJ Takuma S Burkhoff D Wang J et al Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis reduces remodeling and improves cardiac function Nat Med 2001 Apr7(4)430-6

(5) Murry CE Soonpaa MH Reinecke H Nakajima H Nakajima HO Rubart M et al Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts Nature 2004 Apr 8428(6983)664-8



(8) Meyer GP Wollert KC Lotz J Steffens J Lippolt P Fichtner S et al Intracoronary bone marrow cell transfer after myocardial infarction eighteen monthsrsquo follow-up data from the randomized controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial Circulation 2006 Mar 14113(10)1287-94






(14) Sutherland DR Anderson L Keeney M Nayar R Chin-Yee I The ISHAGE guidelines for CD34+ cell determination by flow cytometry International Society of Hematotherapy and Graft Engineering J Hematother 1996 Jun5(3)213-26


(16) Strauer BE Brehm M Zeus T Kostering M Hernandez A Sorg RV et al Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans Circulation 2002 Oct 8106(15)1913-8

Chap

ter

7

114

(17) Bartunek J Vanderheyden M Vandekerckhove B Mansour S De Bruyne B De Bondt P et al Intracoronary injection of CD133-positive enriched bone marrow progenitor cells promotes cardiac recovery after recent myocardial infarction - Feasibility and safety Circulation 2005 Aug 30112(9)I178-I183

(18) Chen SL Fang WW Ye F Liu YH Qian J Shan SJ et al Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction Am J Cardiol 2004 Jul 194(1)92-5

(19) Fernandez-Aviles F San Roman JA Garcia-Frade J Fernandez ME Penarrubia MJ de la FL et al Experimental and clinical regenerative capability of human bone marrow cells after myocardial infarction Circ Res 2004 Oct 195(7)742-8

(20) Katritsis DG Sotiropoulou PA Karvouni E Karabinos I Korovesis S Perez SA et al Transcoronary transplantation of autologous mesenchymal stem cells and endothelial progenitors into infarcted human myocardium Catheter Cardiovasc Interv 2005 Jul65(3)321-9

(21) Kuethe F Richartz BM Sayer HG Kasper C Werner GS Hoffken K et al Lack of regeneration of myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans with large anterior myocardial infarctions Int J Cardiol 2004 Oct97(1)123-7

(22) Schachinger V Assmus B Britten MB Honold J Lehmann R Teupe C et al Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction final one-year results of the TOPCARE-AMI Trial J Am Coll Cardiol 2004 Oct 1944(8)1690-9

(23) Meluzin J Mayer J Groch L Janousek S Hornacek I Hlinomaz O et al Autologous transplantation of mononuclear bone marrow cells in patients with acute myocardial infarction the effect of the dose of transplanted cells on myocardial function Am Heart J 2006 Nov152(5)975-15


(25) Menasche P Hagege AA Vilquin JT Desnos M Abergel E Pouzet B et al Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction J Am Coll Cardiol 2003 Apr 241(7)1078-83

(26) Kang HJ Kim HS Zhang SY Park KW Cho HJ Koo BK et al Effects of intracoronary infusion of peripheral blood stem-cells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction the MAGIC cell randomised clinical trial Lancet 2004 Mar 6363(9411)751-6

(27) Mansour S Vanderheyden M De BB Vandekerckhove B Delrue L Van H I et al Intracoronary delivery of hematopoietic bone marrow stem cells and luminal loss of the infarct-related artery in patients with recent myocardial infarction J Am Coll Cardiol 2006 Apr 1847(8)1727-30


(29) George J Afek A Abashidze A Shmilovich H Deutsch V Kopolovich J et al Transfer of endothelial progenitor and bone marrow cells influences atherosclerotic plaque size and composition in apolipoprotein E knockout mice Arterioscler Thromb Vasc Biol 2005 Dec25(12)2636-41

(30) Seeger FH Tonn T Krzossok N Zeiher AM Dimmeler S Cell isolation procedures matter a comparison of different isolation protocols of bone marrow mononuclear cells used for cell therapy in patients with acute myocardial infarction Eur Heart J 2007 Mar28(6)766-72

(31) Abdel-Latif A Bolli R Tleyjeh IM Montori VM Perin EC Hornung CA et al Adult Bone Marrow-Derived Cells for Cardiac Repair A Systematic Review and Meta-analysis Arch Intern Med 2007 May 28167(10)989-97

Autologous mononuclear bone marrow cells or peripheral

mononuclear blood cells aft er primary PCI

Rati onale and design of the HEBE trial ndash a prospecti ve

multi center randomized trial

Alexander Hirsch MD1 Robin Nijveldt MD2 Pieter A van der Vleuten MD3 Bart J Biemond MD

PhD4 Pieter A Doevendans MD PhD5 Albert C van Rossum MD PhD2 Jan GP Tijssen PhD1

Felix Zijlstra MD PhD3 amp Jan J Piek MD PhD1 on behalf of the HEBE investi gators


alphabeti cal order

1 Department of Cardiology Academic Medical Center Amsterdam the Netherlands

2 Department of Cardiology VU University Medical Center Amsterdam the Netherlands

3 Department of Cardiology University Medical Center Groningen Groningen the Netherlands

4 Department of Haematology Academic Medical Center Amsterdam the Netherlands

5 Department of Cardiology University Medical Center Utrecht Utrecht the Netherlands


Am Heart J 2006 Sep152(3)434-41

8

Chap

ter

8

116

Abstract

Background

Although mortality from acute myocardial infarction is decreasing heart failure as a result

of left ventricular remodelling remains a major cause of morbidity and mortality Recently

several preliminary reports have demonstrated that cell transplantation after acute

myocardial infarction in humans was safe and leads to better preserved left ventricular

function and improved myocardial perfusion and coronary flow reserve

Methods

This is a multicenter prospective randomized three-arm open trial with blinded evaluation

of end points Patients with acute large myocardial infarction treated with primary

PCI will undergo MRI and echocardiography A total of 200 patients are randomized to

treatment with (1) intracoronary infusion of autologous mononuclear bone marrow cells

(2) intracoronary infusion of peripheral mononuclear blood cells or (3) standard therapy

Mononuclear cells are isolated from bone marrow aspirate or venous blood by density

gradient centrifugation Within 7 days after PCI and within 24 hours after aspiration or

blood collection a catheterization for intracoronary infusion of the mononuclear cells in the

infarct-related artery is performed In all patients follow-up will be obtained at 1 4 and 12

months MRI and catheterization are repeated at 4 months The primary end point of the

study is the change of regional myocardial function based on a MRI-segmental analysis at 4

months relative to baseline

Implications

If intracoronary infusion of autologous mononuclear bone marrow cells or peripheral

mononuclear blood cells is proven to be beneficial after primary PCI it could be a valuable

tool in preventing heart failure-related morbidity and mortality after myocardial infarction

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Introduction

Numerous studies have shown that prompt reperfusion reduces early mortality and

improves late clinical outcome in patients with acute myocardial infarction However an

increasing number of patients suffers from symptoms of heart failure as a result of post-

infarct deterioration of left ventricular function

In order to challenge these ever-growing problems the concept of improving left ventricular

function after reperfusion therapy by bone marrow-derived progenitor cell infusion has

been advocated(1-4)

Background

Different mechanisms by which bone marrow-derived progenitor cells may induce a

beneficial effect have been suggested (1) enhanced neovascularization following release

of angiogenic and arteriogenic cytokines by the injected mononuclear cells (2) enhanced

scar tissue formation following the inflammatory response (3) decreased apoptosis and (4)

myocardial regeneration

Research on potential cardiac myocyte regeneration is currently ongoing and has reared

both positive(5) and negative(6-8) results However despite this ongoing dispute regarding

the regeneration hypothesis neovascularization is generally accepted to be an important

mechanism of the documented functional recovery of left ventricular function in various

in-vitro and in-vivo research(9)

Initial experience

Several preliminary reports in humans have demonstrated that local progenitor cell infusion

in patients with acute myocardial infarction is safe and may lead to better preserved left

ventricular function improved myocardial perfusion and coronary flow reserve(10-14)

In detail Schachinger et al reported that intracoronary infusion of adult progenitor cells

was associated with a significant increase in global left ventricular ejection fraction an

improvement in wall motion abnormalities in the infarct area and a significant reduction

in end systolic left ventricular volumes 4 months after acute myocardial infarction(11)

The improved left ventricular function was accompanied by complete normalization of

Chap

ter

8

118

coronary flow reserve in the infarct-related artery and by significant increases in myocardial

viability within the infarcted segments as assessed by F-18-fluorodeoxyglucose-positron

emission tomography (13) Likewise Strauer et al(10) have reported a beneficial effect on

myocardial perfusion following the infusion of bone marrow-derived progenitor cells into

the infarct-related artery of patients with an acute myocardial infarction These findings

were corroborated by the results of a small non-blinded randomized trial by Wollert(14)

A short overview of the currently available main studies in humans is provided in table 1

The principle limitation of most previously conducted studies is that these studies are small

andor non-controlled andor have not included an appropriate control group and all were

performed single center

Mononuclear cells

Progenitor cells characterized by expression of the CD 34 and CD 133 antigens are only a

small fraction of all mononuclear cells found in bone marrow Even after density gradient

centrifugation these cells remain a small fraction of the final cell suspension which is

infused Since all mononuclear cells are capable of releasing vast amounts of growth factors

and cytokines it has been suggested that the potential beneficial effects can be attributed

to the combined effects of all infused mononuclear cells rather than the progenitor cell

sub-population(15)

Current study design

These considerations constituted the rationale for a randomized controlled trial to determine

the effect of intracoronary infusion of mononuclear cells in patients with acute myocardial

infarction treated by percutaneous coronary intervention (PCI) in a multicenter design To

distinguish between the effect of progenitor cells and other mononuclear cells on cardiac

function patients will be randomized to be treated with either intracoronary infusion of

bone marrow derived mononuclear cells (including haematopoietic progenitor cells) or

mononuclear blood cells derived from peripheral blood or standard therapy

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119

Tabl

e 1

Ove

rvie

w o

f stu

dies

of i

ntra

-cor

onar

y in

fusi

on o

f aut

olog

ous

bone

mar

row

in p

atien

ts a

fter

acu

te m

yoca

rdia

l inf

arcti

on

Stud

yN

Des

ign

Day

s aft

er M

IFo

llow

-up

(mon

ths)

Stat

usRe

sults

Stau

er e

t al(

10)

20Se

quen

tial B

MC

(10)

than

co

ntro

l (10

) Si

ngle

cen

ter

83

Publ

ishe

dD

ecre

ased

infa

rct r

egio

n an

d ES

V on

LV-

angi

o In

crea

sed

regi

onal

con

trac

tility

on

LV-a

ngio

Impr

oved

per

fusi

on o

n sc

intig

raph

yIn

crea

sed

stro

ke v

olum

e in

dex

on R

V-ca

thet

eris

ation

Scha

chin

ger

et a

l ldquoT

OPC

ARE

-A

MIrdquo

(11)

59

Rand

omiz

ed

BMC

(29)

vs

CPC

(30)

O

pen-

labe

l Si

ngle

cen

ter

512

Publ

ishe

dD

ecre

ased

ESV

on

LV-a

ngio

In

crea

sed

LVEF

on

LV-a

ngio

and

MRI

Wol

lert

et a

l ldquoB

OO

STrdquo(

14)

60Ra

ndom

ized

BM

C (3

0) v

s C

ontr

ol (3

0)

Ope

n la

bel

Sing

le c

ente

r

56

Publ

ishe

dIn

crea

sed

LVEF

on

MRI

Fern

aacutende

z-Av

ileacutes

et a

l(16

)20

Non

-ran

dom

ized

Si

ngle

cen

ter

1411

Pu

blis

hed

Incr

ease

d LV

EF o

n M

RIIn

crea

sed

regi

onal

con

trac

tility

on

MRI

Jans

sens

et a

l66

Rand

omiz

ed

BMC

(32)

vs

con

trol

(34)

D

oubl

e bl

ind

Sin

gle

cent

er

14

Pres

ente

d at

co

ngre

ssD

ecre

ased

infa

rct s

ize

on L

CE im

ages

on

MRI

MI =

myo

card

ial i

nfar

ction

BM

C =

mon

onuc

lear

bon

e m

arro

w c

ells

ESV

= e

nd-s

ysto

lic v

olum

e L

V =

left

ven

tric

ular

RV

= ri

ght

vent

ricu

lar

CPC

= cu

ltiva

ted

circ

ulati

ng p

roge

nito

r ce

lls fr

om p

erip

hera

l blo

od L

VEF

= le

ft v

entr

icul

ar e

jecti

on fr

actio

n M

RI =

mag

netic

res

onan

ce im

agin

g L

CE =

late

co

ntra

st-e

nhan

ced

Chap

ter

8

120

Methods

Overview

The HEBE-trial is a multicenter prospective randomized open trial with blinded evaluation

of end points with participation of hospitals with coronary intervention facilities in the

Netherlands To be eligible for participation in the study patients have to meet the inclusion

and exclusion criteria listed in Tables 2 and 3 A total of 200 patients will be randomly

assigned to treatment with mononuclear bone marrow cells or peripheral mononuclear

blood cells or to standard therapy (ratio 111) A flow chart of the study design is shown

in Figure 1

Table 2 Inclusion criteriaPCI within 12 hours of onset of symptomsSuccessful treatment of a culprit lesion in the LAD RCA or RCX (segment 1 2 3 6 7 11 12 or 13

according to the CASS quantification)A stent diameter ge 30 mmAt least one CK and or CK-MB measurement 10 times higher than the local upper limit of normalHypokinesia or akinesia of ge 3 segments using a 16-segment model documented by routine resting

echocardiography at least 12 hours after primary PCI Clinically and haemodynamically stable over the previous 12 hours preceding informed consentCell infusion can be scheduled within 7 days after primary PCI

PCI = percutaneous coronary intervention LAD = left anterior descending coronary artery RCA = right coronary artery RCX = ramus circumflexus CASS = Coronary Artery Surgery Study CK = creatinin kinase

HEB

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121

Table 3 Exclusion criteriaAge lt30 or gt70 yearsCardiogenic shock or treatment with intra-aortic balloon pump in 12 hours preceding informed

consentThrombolytic therapy in the previous weekAdditional PCI in a vessel other than the vessel of primary PCI Anticipated percutaneous or surgical coronary intervention within the next 4 months Presence of supraventricular or ventricular arrhythmiasAn extended myocardial infarction as evidenced by a new episode of chest pain with new ST-

segment elevations and a new CK CK-MB peakHistory of myocardial infarction coronary artery bypass grafting heart failure moderate to severe

valve disease cardiomyopathy or congenital cardiac diseaseLeft ventricular ejection fraction lt 45 prior to current admission for myocardial infarctionBlood transfusion in 24 hours preceding informed consentStroke or transient ischemic attack within 24 hours preceding informed consentInability to schedule the intracoronary infusion of the mononuclear cell suspension within 24 hours

after bone marrow aspiration or venous blood collectionContraindication for MRIChronic use of anti-inflammatory medication except for the use of non-steroidal anti-inflammatory

drugsPositive test(s) for HIV HBV or HCV infectionKnown concomitant disease with a life expectancy of less than one yearEnrolment in any other study

PCI = percutaneous coronary intervention CK = creatinin kinase MRI = magnetic resonance imaging HBV = hepatitis B virus HCV = hepatitis C virus

Patients and enrolment

Patients with an acute large myocardial infarction treated by primary PCI of one of the

pre-defined coronary artery segments are potential candidates for the study All patients

are treated with aspirin heparin and clopidogrel according to Dutch practice guidelines

Concentrations of creatinine kinase and its MB isoenzyme are measured at hospital

admission and every 6 hours for 48 hours

Before randomization at least 12 hours after PCI resting echocardiography is performed

in five standard views (parasternal long and short views and apical four- two- and three-

chamber views) If there are three or more hypokinetic akinetic or dyskinetic segments using

a 16-segment model and all inclusion and exclusion criteria are met the patient is asked for

written informed consent as required by the Institutional Review Board in accordance with

the Declaration of Helsinki

Chap

ter

8

122

Figure 1 Study design CAG = coronary angiography ETT = exercise tolerance test MI = myocardial

infarction MRI = magnetic resonance imaging PCI = percutaneous coronary intervention =

haemodynamic measurements during re-CAG are optional re-CAG for haemodynamic measurements

is optional in the control group

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After written informed consent Magnetic Resonance Imaging (MRI) is performed in all

patients at least 48 hours after PCI Patients are studied on a clinical 15 or 30 Tesla scanner

using a four-element phased array cardiac receiver coil For functional imaging ECG-gated

cine steady state free precession MR images are obtained during repeated breath-holds in

the three standard long axis views (four- three- and two-chamber view) Contiguous short

axis slices are acquired covering the entire left ventricle from base to apex to examine

regional and global left ventricular function Late contrast-enhanced (LCE) images are

acquired 10 minutes after administration of a gadolinium-based contrast agent (Dotarem

Guerbet 02 mmolkg) with an inversion-recovery gradient-echo pulse sequence to identify

the location and extent of myocardial infarction The data are obtained with slice locations

identical to the functional images All MRI images are sent to a core laboratory for quality

control and blinded central analysis

The MRI data are analyzed using a dedicated software package (Mass Medis Leiden

the Netherlands) On the short axis cine slices the endocardial and epicardial borders

are outlined manually in end-diastolic and end-systolic images excluding trabeculae and

papillary muscles Assessment of global left ventricular function is obtained by calculating

left ventricular volumes mass and ejection fraction using the summation of slice method

multiplied by slice distance For analysis of segmental myocardial function each short axis

slice is divided in 12 equi-angular segments starting at the posterior septal insertion of the

right ventricle Segmental wall thickening is expressed in absolute values (end-diastolic wall

thickness subtracted from end-systolic wall thickness mm) and relative values (absolute

wall thickening divided by end-diastolic wall thickness ) Areas of hyperenhancement are

outlined including central dark zones of microvascular obstruction allowing to calculate total

infarct size by summation of all slice volumes of hyperenhancement The segmental extent

of hyperenhancement is calculated by dividing the hyperenhanced area by the total area

of the predefined segment () Since both cine and LCE image acquisitions are performed

using identical slice positions within one imaging session both data sets are matched per

slice to combine functional and LCE information per segment For analysis of segmental

function and segmental extent of hyperenhancement the two most basal and two most

distal slices are excluded as segmental evaluation at these levels is not reliable due to the

Chap

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left ventricular outflow tract and small diameter respectively Comparison of follow-up to

baseline images is achieved by consensus of two observers using anatomic landmarks

Echocardiography

Two-dimensional echocardiography with a phased array electronic ultrasound is also

performed at least 48 hours after PCI Standard parasternal long axis and short axis views

are acquired for the assessment of global and regional left ventricular function Regional

function is calculated using regional wall motion score (1 = normal 2 = hypokinetic 3 =

akinetic 4 = dyskinetic) and wall motion score index (sum of the segment scores number

of segments scored) in a 16-segment model Left ventricular volumes are assessed using the

method of discs (Simpsonrsquos Rule)

Randomization and treatment

When MRI and echocardiography are successfully performed the investigator contacts

the randomization service by telephone Patients are randomized following a computer-

generated list to (1) intracoronary infusion of autologues mononuclear bone marrow cells

(2) intracoronary infusion of peripheral mononuclear blood cells or (3) optimal medical

treatment without infusion of cells All treatment groups are treated with aspirin clopidogrel

beta-blockers angiotensin converting enzyme inhibitors or angiotensin II receptor blockers

and aggressive lipid lowering therapy

Cell material

Collection of cells for intracoronary infusion is performed within 24 hours of the anticipated

time of cell infusion and only when tests for HIV hepatitis B virus and hepatitis C virus

infection are known to be negative Either 60 ml of bone marrow is aspirated from the

iliac crest under local anaesthesia or 150 ml of venous blood is collected after which it is

transported to the local stem cell facility Mononuclear bone marrow cells or peripheral

mononuclear blood cells are isolated by density gradient centrifugation and 15 ml of

cell suspension is transported back for intracoronary infusion The local stem cell facility

forwards a small volume of the final cell suspension to a central laboratory for further

characterization and analysis

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Intracoronary cell infusion

Intracoronary cell infusion is performed within 7 days after PCI Prior to cell infusion the

patency of the stent in the culprit lesion of the primary PCI is visually assessed by coronary

angiography of the infarct-related artery Myocardial blush grade collateral filling according

to the Rentrop classification the TIMI frame count and TIMI flow are also evaluated before

cell infusion Coronary pressure and flow measurements are performed prior to cell infusion

in the centers where this technique is available

The cell suspension is infused into the infarct-related artery through the central lumen of an

over-the-wire balloon catheter During infusion the balloon is inflated in the stented lesion

with low pressure for three minutes to stimulate adhesion of the cells in the infarcted zone

In three sessions of coronary occlusion 15 ml of cell suspension is infused with interruptions

of three minutes of reflow by deflating the balloon

Follow-up

All patients are scheduled for follow-up visits at 1 4 and 12 months after primary PCI The

visits consist of clinical evaluation blood analysis and 12-leads electrocardiogram death

myocardial re-infarction coronary artery bypass grafting PCI major arrhythmias heart

failure coronary angiography stroke and hospital admission are documented To assess

whether treatment with intracoronary infusion of cells is associated with arrhythmia

24-hours Holter registration is obtained at 1 month after PCI At 4 months MRI is repeated

and all patients are scheduled to undergo coronary angiography to assess the patency of the

infarct-related artery Echocardiography and exercise tolerance tests are performed at 4 and

12 months follow-up

End points

The primary end point of the study is the change of regional myocardial function based on

segmental analysis at 4 months relative to baseline as measured by MRI All secondary end

points are displayed in Table 4 They include clinical angiographical echocardiographical

and MRI-related parameters

Chap

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Table 4 Secondary endpoints assessed at 4 and 12 monthsChange in global left ventricular ejection fraction at 4 months relative to baseline measured by MRIChange of LCE MRI infarct size at 4 months relative to baselineChange in left ventricular ejection fraction at 4 months and 12 months relative to baseline

measured by resting echocardiographyChange in global and regional wall motion score index measured by resting echocardiography at 4

months and 12 months relative to baselineOccurrence within 4 and 12 months of a major adverse cardiac event defined as cardiac death

myocardial infarction coronary bypass grafting or a repeat percutaneous intervention of the culprit lesion

Occurrence within 4 and 12 months of arrhythmiaPresence of clinically overt heart failure at 4 and 12 monthsFunctional class according to the NYHA- and CCS-Classification at 4 and 12 monthsChange of exercise capacity at 4 months relative to 12 months measured by exercise tolerance testChange in concentrations of NT-pro-BNP at 4 and 12 monthsOccurrence of clinical and angiographic binary in-stent restenosisLate luminal loss at 4 months Change in intracoronary haemodynamic parameters at 4 months

MRI = magnetic resonance imaging LCE = late contrast-enhanced NYHA = New York Heart Association CCS = Canadian Cardiovascular Society BNP = brain natriuretic peptide

Sample size and statistical analysis

The study is powered for the secondary endpoint of the change in global left ventricular

ejection fraction (LVEF) at 4 months relative to baseline measured by Magnetic Resonance

Imaging (MRI) Note this sample size calculation is based on the supposition that the power

of this study for the primary endpoint will at least match the power for the secondary

endpoint

With 60 patients in each study group the study has 90 power to detect a 6 difference

in change in ejection fraction between active treatment and control (assuming a two-sided

alpha of 005 and a standard deviation of 10 for the change in left ventricular ejection

fraction) Based on the experience in previous studies it is assumed that up to 10 of

patients will be unevaluable with respect to the ejection fraction measurements To maintain

90 power an increase to a total of 200 patients is required

The primary analysis of the study consists of separate comparisons of the change in

regional myocardial function between each of the active treatment groups and control The

comparison between the two active groups is a secondary analysis

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Analysis of secondary endpoints is performed using a similar strategy as outlined above

for the primary endpoint For the analysis of binary endpoints treatment comparisons will

be performed using Fisherrsquos exact probability test For continuous outcomes independent-

samples T-tests are used For clinical outcomes such as the incidence of MACE Kaplan-Meier

curves displaying the pattern of events over the 4- and 12-month follow-up period are

drawn

Study organization and monitoring

The HEBE-trial is supervised by an executive committee and coordinated by a study

coordination committee Members of both committees are listed in appendix I The steering

committee is responsible for design and conduct of the study An independent data and

safety monitoring committee monitors the patient safety as the study progresses and

reviews safety issues every three months

Prior to the start of the study an initiation visit is scheduled to ensure that all local

investigators are appropriately trained and all necessary arrangements have been made to

achieve a high degree of compliance with the study protocol Participating centers are also

required to perform at least 3 MRI scans of sufficient quality using the standardized and

uniform MRI protocol before patient enrolment can be started

Current status

The names of the 10 participating centers and their representatives are provided in the

appendix Recruitment will commence September 2005 and is expected to be completed

September 2006 Analysis and reporting is to be completed by August 2007

Discussion

The current study design as outlined above was drafted to investigate the effect of

intracoronary infusion of mononuclear cells in patients with an acute myocardial infarction

treated by PCI In previously conducted studies (Table 1) autologous mononuclear bone

marrow cells were infused intracoronary As mentioned earlier such a cell suspension consists

Chap

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128

of a heterogeneous cell population including only a small percentage of haematopoietic

progenitor cells Since it seems unlikely that the improved cardiac function can be totally

attributed to the formation of new cardiac myocytes or endothelial cells the positive effects

could also be a combined effect of all mononuclear cells through the release of growth

factors and cytokines In order to test this hypothesis the current study design includes

a separate arm in which patients are treated with peripheral mononuclear blood cells

following the same density gradient centrifugation and infusion protocols

In the field of cardiac cell treatment intracoronary infusion is generally accepted to

be the optimal mode of delivery since it ensures that the cells reach the infarcted area

without being locally invasive and thus avoiding the arrhytmogenic effects associated with

intracardiac injection In contrast the time window for cell delivery is widely disputed The

rationale for choosing the time window in the current study design was that infusion within

48 hours of the index myocardial infarction as performed in the study by Janssens et al (as

presented at the 2005 American College of Cardiology congress in Orlando) could lead to

a sub-optimal treatment effect since the inflammatory response peaks in the first 48 hours

after myocardial infarction This leads to increased debridement and formation of a fibrin-

based provisional matrix It was also contemplated that after 7 days scar tissue formation

would limit the effects of cell infusion However it needs to be stressed that the optimal

time of cell delivery is not elucidated

The study design incorporates a control group to verify that any measured effect can not

be attributed to the natural course of disease after optimal standard care for myocardial

infarction The design of the study is not double-blind because the impact of implementing

such a design is that all patients would have to undergo bone marrow aspiration peripheral

blood collection and repetitive coronary occlusion Since there is no evidence in the current

literature that suggests that either bone marrow aspiration infusion of the cell medium or

repetitive occlusion by balloon inflation 3 to 7 days after primary PCI has a positive effect on

left ventricular functional recovery the decision was made not to expose the participating

patients to more procedures than was considered necessary for both executing the

treatment to which the patient is randomized and obtaining a proper follow-up To avoid

bias in data analysis the blinded evaluation of the primary end point is performed by an

independent MRI core laboratory Additionally randomization is performed after baseline

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129

MRI assessment However the open-label study design compromises the validity of any

quality of life or other self-assessment questionnaires

The aim of the study in terms of inclusion is 200 patients divided over three treatment

arms This number of patients exceeds any current study on the subject To achieve these

patient numbers within the pre-defined time-constraints a multicenter study design is

implemented Since multiple centers and stem cell facilities are involved this study design

also allows a more general feasibility assessment in contrast to all previous single center

studies The results from the current study will either further strengthen or weaken the

growing body of evidence concerning intracoronary cell therapy

Implications




Appendix

Executive committee

JJ Piek MD PhD Academic Medical Center Amsterdam (principal investigator) F Zijlstra

MD PhD University Medical Center Groningen Groningen (principal investigator) BJ

Biemond MD PhD Academic Medical Center Amsterdam AC van Rossum MD PhD

VU University Medical Center Amsterdam JGP Tijssen PhD Academic Medical Center

Amsterdam PA Doevendans MD PhD University Medical Center Utrecht Utrecht

Participating centers

Academic Medical Center Amsterdam ndash JJ Piek MD PhD Catharina Hospital Eindhoven ndash

JJ Koolen MD PhD Erasmus Medical Center Rotterdam ndash WJ van der Giessen MD PhD

Medical Center Alkmaar Alkmaar ndash JOJ Peels MD St Antonius Hospital Nieuwegein ndash JM

ten Berg MD PhD University Hospital Maastricht Maastricht ndash J Waltenberger MD PhD

University Medical Center Groningen Groningen ndash RA Tio MD PhD University Medical

Center St Radboud Nijmegen ndash W Aengevaeren MD PhD University Medical Center

Utrecht Utrecht ndash PA Doevendans MD PhD VU University Medical Center Amsterdam ndash

K Marques MD All centres are in the Netherlands

Chap

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130

Study coordination committee

Clinical study A Hirsch MD Academic Medical Center Amsterdam R Nijveldt MD VU

University Medical Center Amsterdam PA van der Vleuten MD University Medical Center

Groningen Groningen In vitro studies on cell material JJ Zwaginga MD PhD Sanquin

Research at CLB Amsterdam

The HEBE-trial is initiated by the Interuniversity Institute of Cardiology of the Netherlands

(ICIN) Utrecht The Netherlands ndash WH van Gilst PhD University Medical Center Groningen

Groningen and CA Visser MD PhD VU University Medical Center Amsterdam

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References



(3) Orlic D Kajstura J Chimenti S Limana F Jakoniuk I Quaini F et al Mobilized bone marrow cells repair the infarcted heart improving function and survival Proc Natl Acad Sci U S A 2001 Aug 2898(18)10344-9

(4) Tomita S Mickle DA Weisel RD Jia ZQ Tumiati LC Allidina Y et al Improved heart function with myogenesis and angiogenesis after autologous porcine bone marrow stromal cell transplantation J Thorac Cardiovasc Surg 2002 Jun123(6)1132-40

(5) Kajstura J Rota M Whang B Cascapera S Hosoda T Bearzi C et al Bone marrow cells differentiate in cardiac cell lineages after infarction independently of cell fusion Circ Res 2005 Jan 796(1)127-37

(6) Balsam LB Wagers AJ Christensen JL Kofidis T Weissman IL Robbins RC Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium Nature 2004 Apr 8428(6983)668-73

(7) Bel A Messas E Agbulut O Richard P Samuel JL Bruneval P et al Transplantation of autologous fresh bone marrow into infarcted myocardium a word of caution Circulation 2003 Sep 9108 Suppl 1II247-II252


(9) Wollert KC Drexler H Clinical applications of stem cells for the heart Circ Res 2005 Feb 496(2)151-63






(15) Yoshioka T Ageyama N Shibata H Yasu T Misawa Y Takeuchi K et al Repair of infarcted myocardium mediated by transplanted bone marrow-derived CD34+ stem cells in a nonhuman primate model Stem Cells 2005 Mar23(3)355-64


Chap

ter

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132

Intracoronary infusion of mononuclear cells from bone

marrow or peripheral blood aft er primary percutaneous


Alexander Hirsch MD1 Robin Nijveldt MD PhD2 Pieter A van der Vleuten MD3 Jan GP Tijssen PhD1 Willem

J van der Giessen MD PhD4 Reneacute A Tio MD PhD3 Johannes Waltenberger MD PhD5 Jurrien M ten Berg MD

PhD6 Pieter A Doevendans MD PhD7 Wim RM Aengevaeren MD PhD8 Jaap Jan Zwaginga MD PhD9 Bart J

Biemond MD PhD10 Albert C van Rossum MD PhD2 Jan J Piek MD PhD1 Felix Zijlstra MD PhD3 on behalf of

the HEBE investi gatorsdagger

1 Department of Cardiology Academic Medical Center University of Amsterdam Amsterdam The Netherlands


3 Thorax Center University Medical Center Groningen Un iversity of Groningen The Netherlands

4 Thorax Center Department of Cardiology Erasmus University Medical Center Rott erdam The Netherlands





9 Department of Experimental Immunohaematology Sanquin Research Amsterdam and Department of

Immunohaematology and Blood transfusion Leiden University Medical Center The Netherlands

10 Department of Haematology Academic Medical Center University of Amsterdam Amsterdam The

Netherlands

Drs Hirsch Dr Nijveldt and Drs van der Vleuten contributed equally to this arti cle

dagger Investi gators of the HEBE trial are listed in the appendix

Submitt ed

9

Chap

ter

9

134

Abstract

Background

Previous randomized trials that investigated the effect of intracoronary infusion of bone

marrow cells after acute myocardial infarction (AMI) on myocardial function have shown

conflicting results

Methods

In a multicenter trial 200 patients with large first AMI treated with primary percutaneous

coronary intervention were randomly assigned to either intracoronary infusion of

mononuclear bone marrow cells (n=69) mononuclear peripheral blood cells (n=66) or

standard therapy (without placebo infusion)(n=65) Mononuclear cells were delivered

intracoronary between 3 and 8 days after AMI Regional and global left ventricular

myocardial function and volumes were assessed by magnetic resonance imaging before

randomization and at 4 months and clinical events were reported The primary endpoint

was the percentage of dysfunctional left ventricular segments at baseline with improved

segmental wall thickening at 4 months

Results

The percentage of dysfunctional left ventricular segments that improved during follow-up

did not differ significantly between either of the treatment groups and control 386plusmn247

in the bone marrow group 368plusmn209 in the peripheral blood group and 424plusmn187 in

the control group (P=033 and P=014) Improvement of left ventricular ejection fraction was

38plusmn74 in the bone marrow group 42plusmn62 in the peripheral blood group as compared

with 40plusmn58 in the control group (P=094 and P=090) Furthermore the 3 groups did

not differ significantly in changes in left ventricular volumes mass and infarct size and had

similar rates of clinical events

Conclusions

Intracoronary infusion of mononuclear cells from bone marrow or peripheral blood following

AMI does not improve regional or global systolic myocardial function (Netherlands Trial

Register number NTR166 and Current Controlled Trials number ISRCTN95796863)

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Introduction

Major advances in treatment for acute myocardial infarction over the past decades have

translated into a considerable decline in mortality(1) However an increasing number

of patients suffers from symptoms of heart failure as a result of post-infarct ventricular

remodeling(2) In an attempt to address these problems the use of cell therapy as an

adjunctive therapy has been advocated(34) Recent randomized trials that investigated the

effect of intracoronary infusion of (selected) bone marrow cells after primary percutaneous

coronary intervention (PCI) for acute myocardial infarction have shown conflicting results

(5-8) This may in part be explained by differences in cell isolation protocols timing of cell

infusion patient selection and the imaging modalities used to measure the treatment effect

(Although mononuclear bone marrow cells and in particular hematopoietic progenitor cells

have been suggested to improve cardiac function by myocardial and vascular regeneration

the positive effect could also be induced by other mononuclear cells capable of releasing

growth factors and cytokines(1213) We designed a randomized controlled trial to

determine the effect of intracoronary infusion of mononuclear cells in patients with large

acute myocardial infarction treated by primary PCI To distinguish between the effect of

progenitor cells and other mononuclear cells on cardiac function patients were randomized

to either intracoronary infusion of bone marrow-derived mononuclear cells (including

hematopoietic progenitor cells) or mononuclear cells derived from peripheral blood or no

intracoronary infusion

Methods

The HEBE trial was a multicenter randomized open trial with blinded evaluation of end

points Between August 2005 and April 2008 200 patients with first ST-segment elevation

myocardial infarction treated with primary PCI and stent implantation were enrolled in 8

hospitals in The Netherlands The design of the study has previously been published(14)

and prior to participation all centers had to participate in a pilot trial(15) In summary

patients 30 to 75 years of age were eligible for inclusion if they met the following inclusion

Chap

ter

9

136

criteria successful PCI within 12 hours after onset of symptoms three or more hypokinetic

or akinetic left ventricular (LV) segments observed on echocardiography performed at least

12 hours after PCI and an elevation of creatine kinase (CK) or CK-MB more than 10 times

the local upper limit of normal (ULN) Main exclusion criteria were hemodynamic instability

anticipated additional PCI or coronary-artery bypass grafting within the next 4 months

severe comorbidity and contraindications for magnetic resonance imaging (MRI)

The study complied with the principles set out in the Declaration of Helsinki All patients

gave informed consent The study protocol was approved by the Institutional Review Boards

of the participating centers


Baseline MRI was performed at least 2 days after PCI After MRI on day 2 to 7 patients

were randomly assigned in a 111 ratio to either intracoronary infusion of autologous

mononuclear bone marrow cells intracoronary infusion of mononuclear peripheral blood

cells or standard therapy (without placebo infusion) Permuted-block randomization was

performed with stratification according to site with the use of a computerized voice-

response system After randomization study processes were not blinded

In the bone marrow and peripheral blood group cell harvesting was performed within 8

days after primary PCI Either 60 ml of bone marrow was aspirated from the iliac crest under

local anesthesia or 150 to 200 ml of venous blood was taken Bone marrow or peripheral

blood was collected in a sterile container with heparin and send to one of the 6 participating

cell-processing laboratories In both groups mononuclear cells were isolated by density

gradient centrifugation using LymphoprepTM After two washing steps mononuclear cells

were resuspended in 15 to 20 ml saline supplemented with 4 human serum albumin and 20

IEml sodium heparin(1115) The number of nucleated blood cells was measured and the

number of CD34+ cells and CD14+ cells were determined according to the ISHAGE protocol

(16) All participating laboratories are accredited stem cell laboratories We validated our

isolation protocol with regard to the quantity and quality of isolated cells by comparing it

with processing protocols used in other clinical trials for cell therapy(11)

Cell infusion was performed at the same day of harvesting in all but one patient in whom

infusion was done the following day Cells were infused into the infarct-related artery

HEB

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through the central lumen of an over-the-wire balloon catheter in 3 sessions of 3 minutes of

coronary occlusion interrupted by 3 minutes of coronary flow The level of CK-MB andor CK

was measured at 6-hour intervals during the first 24 hours after cell infusion

Magnetic resonance imaging

MRI was performed at baseline and repeated after 4 months Patients were studied on

a clinical 15 or 30 Tesla scanner (193 and 7 patients respectively) MRI acquisition and

analyses involved a standardized protocol published previously(1415) MRI analyses were

performed by two blinded core laboratories Bio-Imaging Technologies BV (Leiden) for

functional analysis and VU University medical center (Amsterdam) for infarct size analysis

In short contiguous short axis slices were acquired every 10 mm covering the whole left

ventricle using a segmented steady state free precession pulse sequence Late gadolinium

enhancement (LGE) images were obtained 10 to 15 minutes after administration of a

gadolinium-based contrast agent (Dotarem Guerbet 02 mmolkg) using a 2D segmented

inversion recovery gradient-echo pulse sequence with slice position identical to the cine

images

LV volumes and mass were measured on the cine images and indexed for body-surface

area LV ejection fraction was calculated Infarct size was determined on the LGE images as

previously described using a standardized and predefined definition of hyperenhancement

(1417) For analysis of regional myocardial function each short axis slice was divided in 12

equi-angular segments to calculate wall thickening (in mm) of each segment by subtracting

end-diastolic from end-systolic wall thickness Myocardial segments were considered

dysfunctional if segmental wall thickening was lt3 mm(18) Improved wall thickening of a

segment at follow-up was defined as gt15 mm improvement in segmental wall thickening

between baseline and follow-up

End point measures

The primary end point was the change in regional myocardial function in dysfunctional

segments at baseline defined as the percentage of dysfunctional segments with improved

segmental wall thickening at 4 months Secondary end points included changes in absolute

segmental wall thickening in dysfunctional segments and changes in global LV ejection

Chap

ter

9

138

fraction volumes mass and infarct size To assess clinical status and adverse events patients

were seen at the outpatient clinic at 1 and 4 months after randomization Recurrent

myocardial infarction associated with cell delivery was defined as an increase of CK-MB

levels of at least 3 times the ULN within 24 hours after delivery A clinical event committee

independently adjudicated all potential clinical events


We estimated enrolment of 60 patients in each study group to achieve a power of 90

with a two-sided significance level of 005 to detect a 6 difference in change in global

LV ejection fraction between active treatment and control assuming a standard deviation

of 10 It was assumed that up to 10 of patients would not have paired MRI studies and

therefore a total of 200 patients was required The decision about the sample size was

based upon the consideration that the power of this study for the primary end point would

at least match the power for the secondary end point of the change in global LV ejection

fraction(14)

All analyses were performed on the basis of the intention-to-treat principle Categorical data

are presented as frequencies (percentage) and continuous data as meanplusmnSD (unless stated

otherwise) The prespecified primary analysis consisted of separate comparisons of the end

points between the two active treatment groups and control For the comparison of changes

in MRI variables between groups analysis of covariance was used including treatment group

as the main factor and each baseline variable as a covariate Paired Studentrsquos t test was used

to compare baseline and follow-up values within each study group Because the study was

not powered for clinical outcomes the event rates are presented for descriptive purposes

only and no statistical comparisons were done All P values are two-sided and statistical

significance was set at Plt005

HEB

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Results

Enrolment and baseline characteristics

A total of 200 patients were enrolled in the study and underwent baseline MRI at a median

time of 3 days after primary PCI (interquartile range 2 to 4) After MRI 69 patients were

assigned to the bone marrow group 66 to the peripheral blood group and 65 to the control

group Intracoronary infusion was not performed in 3 patients assigned to the bone marrow

group One patient withdrew consent in one the bone marrow aspiration was unsuccessful

and in one the infarct-related artery was occluded on control angiography prior to cell

delivery In the peripheral blood group intracoronary delivery was performed in all but one

patient who refused cell delivery (Figure 1) The 3 groups were well matched with respect

to baseline and procedural characteristics (Table 1) Overall the mean age was 56plusmn9 years

85 of the patients were men median time from onset of symptoms to reperfusion was

33 hours (interquartile range 23 to 45) and 90 had TIMI flow grade 3 after primary PCI

Cell harvesting and intracoronary infusion

Intracoronary cell infusion was performed between 3 and 8 days after PCI with a median

of 6 days in the bone marrow group and 5 days in the peripheral blood group The median

time from cell harvesting to cell infusion was 63 hours (interquartile range 57 to 69) in the

bone marrow group and 63 (interquartile range 58 to 70) in the peripheral blood group

The total number of cells was comparable in the bone marrow and peripheral blood group

(296plusmn164 x106 vs 287plusmn137 x106) see also Table 1 No complications of cell harvesting were

noted in either group

The adverse events related to the catheterization for cell delivery are summarized in Table

2 Three patients in the peripheral blood group developed a recurrent myocardial infarction

related to the cell delivery procedure in one patient this was due to coronary spasm after

cell infusion in one an occlusion of a small side branch occurred and in the third patient no

cause was identified

Chap

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140

Table 1 Baseline characteristicsCharacteristic Bone Marrow

Group

(N = 69)

Peripheral Blood Group

(N = 66)

Control Group

(N = 65)

Age ndash yr 56 plusmn 9 57 plusmn 9 55 plusmn 10Male gender ndash no () 58 (84) 56 (85) 56 (86)Body mass index dagger 26 plusmn 3 26 plusmn 4 27 plusmn 3Risk factors ndash no () Diabetes mellitus 3 (4) 7 (11) 2 (3) Known hypertension 27 (39) 13 (20) 17 (26) Family history of coronary heart disease 33 (48) 30 (45) 33 (51) Hypercholesterolemia 17 (25) 14 (21) 15 (23) Current cigarette smoking 37 (54) 31 (47) 37 (57)Angiography and infarct treatment Time from symptom onset to PCI ndash hours Median 35 30 34 Interquartile range 24ndash51 21ndash48 23ndash42 Infarct-related artery ndash no () Left anterior descending artery 42 (61) 46 (70) 40 (62) Left circumflex artery 14 (20) 5 (8) 5 (8) Right coronary artery 13 (19) 15 (23) 20 (31) Multivessel disease ndash no () 12 (17) 21 (32) 16 (25) TIMI flow grade post-PCI ndash no () Grade 1 1 (1) 1 (2) 0 Grade 2 8 (12) 5 (8) 6 (9) Grade 3 60 (87) 60 (91) 59 (91) Type of stent(s) used ndash no () Bare metal 62 (90) 60 (91) 57 (88) Drug eluting 7 (10) 6 (9) 8 (12) Number of stents Median 1 1 1 Range 1ndash2 1ndash3 1ndash4 Size of stent ndash mm 34 plusmn 04 34 plusmn 04 35 plusmn 04 Length of stent ndash mm Median 18 20 23 Interquartile range 15ndash28 18ndash28 18ndash28 Platelet glycoprotein IIbIIIa inhibitors ndash no () 49 (71) 47 (71) 43 (66) Intra-aortic balloon pump ndash no () 3 (4) 4 (6) 4 (6) Maximum serum creatine kinase MB or creatine kinase ndash xULN

Median 37 38 42 Interquartile range 22ndash63 26ndash64 24ndash67Cell infusion Dagger Days after primary PCI Median 6 5 ndash Interquartile range 4ndash7 4ndash6 ndash Number of injected cells ndash x106 296 plusmn 164 287 plusmn 137 ndash

HEB

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141

Table 1 continued CD34+ cells Absolute no ndash x106 48 plusmn 40 03 plusmn 02 ndash Percentage 16 plusmn 09 01 plusmn 007 ndash CD14+ cells Absolute no ndash x106 246 plusmn 142 613 plusmn 327 ndash Percentage 96 plusmn 61 221 plusmn 79 ndashMedication at discharge ndash no () int Aspirin 65 (96) 62 (94) 65 (100) Clopidogrel 68 (100) 66 (100) 65 (100) Coumarin derivate 6 (9) 15 (23) 11 (17) Beta-blockers 64 (94) 63 (95) 62 (95) ACE inhibitor or AT IIndashreceptor blocker 63 (93) 58 (88) 65 (100) Statins 68 (100) 65 (98) 65 (100)Medication at 4 months follow-up ndash no () para Aspirin 65 (96) 53 (82) 61 (94) Clopidogrel 58 (85) 52 (80) 62 (95) Coumarin derivate 7 (10) 19 (29) 10 (15) Beta-blockers 63 (93) 60 (92) 60 (92) ACE inhibitor or AT IIndashreceptor blocker 66 (97) 54 (83) 63 (97) Statins 67 (99) 63 (97) 63 (97)

Plus-minus values are means plusmn SD TIMI denotes thrombolysis in myocardial infarction PCI percutaneous coronary intervention MB myocardial band ULN upper limit of normal ACE angiotensin-converting-enzyme and AT angiotensin

dagger The body-mass index is the weight in kilograms divided by the square of the heights in meters

Dagger This analysis included only patients in whom cell infusion was performed 66 patients in the bone marrow group and 65 in the peripheral blood group There was no difference between the total number of injected cells between the bone marrow and peripheral blood group P=079 by nonparametric testing

int The analysis included 68 patients in the bone marrow group 66 in the peripheral blood group and 65 in the control group

para The analysis included 68 patients in the bone marrow group 65 in the peripheral blood group and 65 in the control group

Chap

ter

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142

Figure 1 Trial profile

STEMI denotes ST-segment elevation myocardial infarction and MRI magnetic resonance imaging

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Table 2 Adverse events and clinical outcome from randomization to 4 months follow-upEvent Bone Marrow

Group

(N = 69)


(N = 66)

Control Group

(N = 65)

No of patientsCatheterization for cell deliveryAdverse events during cell delivery Coronary spasm 1 3 ndash Transient bradycardia 1 0 ndash Thrombus in infarct-related artery dagger 1 0 ndash Occlusion of small side branch of infarct-related artery

0 1 ndash

Recurrent myocardial infarction Dagger 0 3 ndashAdditional revascularization int Target lesion revascularization 3 3 ndash Target vessel nontarget lesion revascularization

1 2 ndash

At 4 months follow-up (cumulative)Death 0 1 0Recurrent myocardial infarction 0 4 1 Related to cell infusion procedure 0 3 ndash Spontaneous 0 1 1Revascularization 4 6 6 Target lesion revascularization 3 3 4 Target vessel nontarget lesion revascularization

1 3 0

Nontarget vessel revascularization 0 0 3Documented ventricular arrhythmia treated by ICD 0 1 1Hospitalization for heart failure 0 1 1Stroke 0 0 0Cancer 0 1 0Composite of death recurrent myocardial infarction or target lesion revascularization

3 6 4

Composite of death recurrent myocardial infarction or any revascularization

4 9 6

Composite of death recurrent myocardial infarction or hospitalization for heart failure

0 5 2

ICD denotes implantable cardioverter-defibrillator

dagger The occlusion was treated with a glycoprotein IIbIIIa inhibitor thrombosuction and balloon inflation resulting in TIMI grade 3 flow This event did not result in a procedural related myocardial infarctionDagger Causes of myocardial infarctions related to cell delivery were an occlusion of a small side branch in one patient coronary spasm in another and in one patient no cause was identified

int This included an additional PCI in a patient in the bone marrow group who did not undergo cell delivery due to a total occlusion of the infarct-related artery The attempt to reopen the vessel failed In the peripheral blood group one patient was treated by stent implantation for a local dissection of the infarct-related artery caused by an intracoronary flow wire and one patient was treated by balloon inflation for a thrombus in the infarct-related artery during cell delivery as described above All other patients were treated before cell infusion without complications

Chap

ter

9

144

Left ventricular function volumes and infarct size

Paired cine MRI images for functional analysis were available for 67 patients in the bone

marrow group 62 in the peripheral blood group and 60 in the control group Paired images

for infarct analysis were available for 58 57 and 52 patients respectively (Figure 1) There

were no differences in MRI parameters between the three groups at baseline Among all

patients baseline LV end-diastolic volume was 984plusmn154 mlm2 and LV end-systolic volume

was 570plusmn151 mlm2 This resulted in a mean LV ejection fraction of 426plusmn88

The mean percentage of dysfunctional segments at baseline was 533plusmn196 in the bone

marrow group 575plusmn196 in the peripheral blood group and 562plusmn184 in the control

group At 4 months 386plusmn247 of the dysfunctional segments showed improved segmental

wall thickening in patients treated with mononuclear bone marrow cells compared with

368plusmn209 in the peripheral blood group and 424plusmn187 in the control group This

resulted in nonsignificant differences between either of the treatment groups and control

(P=033 and P=014 Table 3) Improvement of LV ejection fraction was 38plusmn74 in the bone

marrow group 42plusmn62 in the peripheral blood group as compared with 40plusmn58 in the

control group (p=094 and p=090 Figure 2) There were also no significant differences in the

changes in absolute segmental wall thickening in dysfunctional segments and changes in

LV volumes mass and infarct size between the bone marrow peripheral blood and control

group (Table 3)

Clinical outcome

During follow-up one patient assigned to the peripheral blood group died of ventricular

fibrillation at 18 days after randomization (13 days after cell delivery) Autopsy revealed

thrombus in the infarct-related artery Ventricular fibrillation occurred in another patient

in the peripheral blood group one day after randomization (within a few hours after cell

infusion) and in one patient in the control group 3 days after randomization Both patients

survived without sequelae after resuscitation and received an implantable cardioverter-

defibrillator Table 2 summarizes all clinical events from randomization to 4 months follow-

up With regard to clinical symptoms at 4 months 19 (1368) of the patients in the bone

marrow group were in New York Heart Association class II or higher compared to 20

(1365) and 18 (1265) in the peripheral blood and control group

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Figu

re 2

Esti

mati

on o

f the

effe

ct o

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raco

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on o

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one

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or

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In

the

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pan

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e lin

es re

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the

stan

dard

err

or

Chap

ter

9

146

Tabl

e 3

Qua

ntita

tive

mea

sure

s of

regi

onal

and

glo

bal l

eft v

entr

icul

ar fu

nctio

n v

olum

es m

ass

and

infa

rct s

ize

by m

agne

tic re

sona

nce

imag

ing

Bo

ne M

arro

w

Gro

upPe

riph

eral

Blo

od

Gro

upCo

ntro

l

Gro

upBo

ne M

arro

w v

s C

ontr

olPe

riph

eral

Blo

od v

s C

ontr

ol

(N =

67)

(N =

62)

(N =

60)

Trea

tmen

t eff

ect dagger

Estim

ate

(95

CI)

P va

lue

Trea

tmen

t eff

ect dagger

Estim

ate

(95

CI)

P va

lue

Prim

ary

end

poin

t ndash

D

ysfu

nctio

nal s

egm

ents

at

b

asel

ine

533

plusmn 1

96

575

plusmn 1

96

562

plusmn 1

84

D

ysfu

nctio

nal s

egm

ents

that

im

prov

ed d

urin

g fo

llow

-up

386

plusmn 2

47

368

plusmn 2

09

424

plusmn 1

87

ndash39

(ndash11

7 to

40

)0

33ndash5

3 (ndash

123

to 1

7)

014

Segm

enta

l wal

l thi

cken

ing

in

dysf

uncti

onal

seg

men

ts ndash

mm

B

asel

ine

119

plusmn 0

55

118

plusmn 0

49

114

plusmn 0

52

F

ollo

w-u

p2

31 plusmn

13

22

21 plusmn

12

12

31 plusmn

09

7

Cha

nge

112

plusmn 1

20

103

plusmn 0

99

118

plusmn 0

80

ndash00

6 (ndash

043

to 0

30)

073

ndash01

5 (ndash

048

to 0

17)

035

P

val

ue (b

asel

ine

vs 4

mon

ths)

lt00

01lt0

001

lt00

01LV

eje

ction

frac

tion

ndash

B

asel

ine

437

plusmn 9

041

7 plusmn

91

424

plusmn 8

3

Fol

low

-up

475

plusmn 9

946

0 plusmn

93

464

plusmn 9

2

Cha

nge

38

plusmn 7

44

2 plusmn

62

40

plusmn 5

80

1 (ndash

22

to 2

4)

094

01

(ndash2

0 to

22

)0

90

P v

alue

(bas

elin

e vs

4 m

onth

s)lt0

001

lt00

01lt0

001

LV e

nd-d

iast

olic

vol

ume

ndash m

lm

2

B

asel

ine

973

plusmn 1

40

980

plusmn 1

54

100

0 plusmn

169

F

ollo

w-u

p10

26

plusmn 19

110

34

plusmn 22

610

82

plusmn 24

6

Cha

nge

54

plusmn 13

45

3 plusmn

163

82

plusmn 13

5ndash2

5 (ndash

72

to 2

2)

029

ndash26

(ndash8

0 to

27

)0

33

P v

alue

(bas

elin

e vs

4 m

onth

s)0

002

001

lt00

01LV

end

-sys

tolic

vol

ume

ndash m

lm

2

B

asel

ine

554

plusmn 1

45

578

plusmn 1

59

581

plusmn 1

51

F

ollo

w-u

p54

9 plusmn

19

557

1 plusmn

21

659

3 plusmn

21

7

Cha

nge

ndash05

plusmn 1

34

ndash07

plusmn 1

44

12

plusmn 11

7ndash1

5 (ndash

59

to 3

0)

052

ndash19

(ndash6

6 to

28

)0

43

P v

alue

(bas

elin

e vs

4 m

onth

s)0

750

710

42

HEB

E st

udy

147

LV m

ass

ndash gr

m2

B

asel

ine

598

plusmn 1

22

596

plusmn 1

14

591

plusmn 1

19

F

ollo

w-u

p51

7 plusmn

10

551

3 plusmn

10

251

4 plusmn

10

6

Cha

nge

ndash80

plusmn 9

6ndash8

3 plusmn

79

ndash78

plusmn 7

6ndash0

03

(ndash2

6 to

26

)0

98ndash0

4 (ndash

28

to 2

0)

074

P

val

ue (b

asel

ine

vs 4

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ths)

lt00

01lt0

001

lt00

01In

farc

t siz

e ndash

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B

asel

ine

229

plusmn 1

26

211

plusmn 1

12

236

plusmn 1

38

F

ollo

w-u

p15

2 plusmn

82

132

plusmn 7

314

2 plusmn

89

C

hang

endash7

7 plusmn

85

ndash79

plusmn 6

5ndash9

4 plusmn

71

13

(ndash0

5 to

32

)0

160

4 (ndash

11

to 1

9)

062

P

val

ue (b

asel

ine

vs 4

mon

ths)

lt00

01lt0

001

lt00

01

Pl

us-m

inus

val

ues

are

mea

ns plusmn

SD

LV

deno

tes

left

ven

tric

ular

P v

alue

s fo

r th

e ch

ange

bet

wee

n ba

selin

e an

d fo

llow

-up

with

in e

ach

stud

y gr

oup

wer

e ca

lcul

ated

with

pai

red

Stud

entrsquos

t te

st

dagger Tr

eatm

ent e

ffect

and

P v

alue

s w

ere

dete

rmin

ed b

y an

alys

is o

f cov

aria

nce

Dagger Th

e an

alys

is in

clud

ed 5

8 pa

tient

s in

the

bone

mar

row

gro

up 5

7 in

the

peri

pher

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lood

gro

up a

nd 5

2 in

the

cont

rol g

roup

Chap

ter

9

148

Discussion

We evaluated the potential benefit of intracoronary infusion of mononuclear cells from

bone marrow or peripheral blood in the subacute phase after acute myocardial infarction

in patients treated with primary PCI There were no significant differences between the

treatment groups and standard therapy in the efficacy end points that were evaluated

including the primary end point of percentage of dysfunctional segments at baseline with

improved segmental wall thickening at 4 months and the secondary end points of change in

LV ejection fraction volumes mass and infarct size

To date intracoronary injection of bone marrow-derived cells as an adjunctive therapy in

patients with acute myocardial infarction has been tested in several small and medium-sized

trials with various results The results of the ASTAMI trial and the study by Janssens et al did

not indicate an improvement of LV function whereas the data from the BOOST and REPAIR-

AMI trial showed a significant 60 and 25 absolute increase in LV ejection fraction

respectively (56819) Our study differed from the aforementioned studies in several ways

MRI was used for assessment of the primary end point of change in regional myocardial

function patients with relatively large first myocardial infarctions and short total ischemic

time were included cell infusion was performed at the same day of cell harvesting and a

second treatment group with infusion of mononuclear peripheral blood cells was included

We have chosen the change in regional systolic myocardial function measured by MRI as our

primary end point based on the assumption that regional function is more sensitive than

global LV function for the evaluation of cell therapy(20) Several mechanisms of action by

which cell therapy may enhance functional cardiac recovery have been suggested including

cardiac and vascular regeneration Alternatively paracrine activities of the transplanted

mononuclear cells may responsible for the functional recovery(1221) Detailed MRI analysis

in the BOOST trial demonstrated enhanced recovery of regional systolic wall motion mostly

in the border zone of the infarct whereas Janssens et al noted improvement especially in the

most severely infarcted segments(519) Restoration of microvascular function determined

by intracoronary flow measurements in patients in the REPAIR-AMI trial provided first

clinical proof of concept of vascular repair by intracoronary cell therapy(22) However

these measurements were secondary end points and in part post-hoc analyses Our study is

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the largest study so far that used a highly accurate and quantitative imaging technique for

assessment of regional systolic function in a multicenter setting

Compared to other cell therapy studies after acute myocardial infarction we included

relatively large infarcts This resulted in a population with a markedly depressed LV ejection

fraction (426plusmn88) despite a relatively short symptom onset to PCI time and contemporary

post-infarct treatment(23) While subgroup analyses of the REPAIR-AMI trial demonstrated

an interaction between the baseline LV ejection fraction and the improvement seen after

bone marrow cell therapy with cell therapy being most effective in patients with a lower LV

ejection fraction (lt49) we observed no improvement in our study(8)

Most clinical studies have used the stop-flow technique with an over-the-wire balloon

catheter for cell infusion after acute myocardial infarction However isolation protocols

and numbers of injected cells have differed substantially As shown by Seeger et al the

isolation protocol and incubation period are important and can have a major impact on the

number of isolated cells and the functional activity of these cells(10) It has been suggested

that differences in cell isolation procedures between the REPAIR-AMI and ASTAMI trial

are responsible for the contrasting outcomes(6810) In agreement we have previously

demonstrated that particular composition of the washing medium and centrifugation speed

influence cell recovery and functional activity of the isolated cells(11) In this light we

showed that our choice of density gradient solution (LymphoprepTM) did not have an effect

on cell recovery as compared to Ficoll Moreover in this study cell infusion was performed at

the day of harvesting thus avoiding overnight storage a procedure that may have a negative

impact on functional activity of isolated cells(10) Finally our isolation method was shown

to result in a cell fraction with quantities at least comparable to the REPAIR-AMI trial

(11) In fact the number of isolated cells and CD34+ cell fraction in the present study was

comparable with the REPAIR-AMI trial 296plusmn164 x106 and 236plusmn174 x106 cells with 16plusmn09

and 15plusmn07 CD34+ cells respectively Considering these data we believe that the lack of

beneficial effect in our trial is not explained by the cell isolation protocol

Our trial has several limitations First for ethical reasons the HEBE trial was not a double-

blind placebo controlled study Bone marrow aspiration and venous blood collection was not

performed in all patients and the control group did not undergo sham infusion However

there was a blind evaluation of end points using a core laboratory for MRI analysis Second

Chap

ter

9

150

baseline MRI was not performed on a fixed time point after myocardial infarction and this

may influence the measured changes in LV parameters However in all patients MRI was

performed before randomization and no differences between the 3 groups were observed

Finally we performed follow-up MRI at 4 months after cell therapy Due to this relative short

follow-up period long-term effects on LV function and remodeling may have been missed

This should be further investigated and therefore repeat MRI will be performed at 2 years

In conclusion we did not show a beneficial effect of intracoronary delivery of mononuclear

cells from bone marrow or peripheral blood on regional and global systolic myocardial

function at 4 months follow-up in patients with a first acute myocardial infarction treated

with primary PCI

Funding

The HEBE trial has been initiated by the Interuniversity Cardiology Institute of The

Netherlands (ICIN) Utrecht The Netherlands (directors WH van Gilst University Medical

Center Groningen Groningen and EE van der Wall Leiden University Medical Center

Leiden) The study is financially supported by funds provided by the ICIN the Netherlands

Heart Foundation (grant 2005T101) and by unrestricted grants from Biotronik Boston

Scientific Guerbet Guidant Medtronic Novartis Pfizer and Sanofi-Aventis Dr Robin

Nijveldt was supported by the Netherlands Heart Foundation grant 2003B126

Appendix

In addition to the authors the following investigators and committee members all in The

Netherlands participated in the HEBE trial (numbers in parentheses are the numbers of

patients enrolled) University Medical Center Groningen Groningen (87) W Nieuwland

M Oudkerk LH Piers JT de Wolf Academic Medical Center Amsterdam (58) JD Haeck

MI Klees AM van der Laan AM Spijkerboer VU University Medical Center Amsterdam

(18) F Afsharzada AM Beek PC Huijgens KMJ Marques Erasmus University Medical

Center Rotterdam (16) PAW te Boekhorst E Braakman RJ van Geuns University

Medical Center Utrecht Utrecht (8) MJM Cramer ICM Slaper-Cortenbach EJVonken

University Hospital Maastricht Maastricht (6) M Grommeacute HC Schouten G Snoep St

Antonius Hospital Nieuwegein (5) D Biesma MAR Bosschaert B Rensing University

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151

Medical Center St Radboud Nijmegen (2) FWMB Preijers FWA Verheugt MJ van

der Vlugt Sanquin Research at CLB Amsterdam (core laboratory for in vitro studies on

cell material) RT van Beem S Dohmen IM Lommerse E van der Schoot C Voermans

Trial Management and Executive Committee JJ Piek (cochair) F Zijlstra (cochair) AC van

Rossum JGP Tijssen BJ Biemond PA Doevendans A Hirsch R Nijveldt PA van der

Vleuten Data and Safety Monitoring Committee M van den Brand H Wellens AW van

rsquot Hof Adjudication Committee AF van den Heuvel IC van der Horst Data Center and

Monitoring JL Hillege Trial Coordination Center University Medical Center Groningen

Groningen Core laboratories for MRI Bio-Imaging Technologies BV Leiden (for functional

analysis) and VU University medical center Amsterdam (for infarct size analysis)

Chap

ter

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152

References

(1) Van de Werf F Bax J Betriu A Blomstrom-Lundqvist C Crea F Falk V et al Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology Eur Heart J 2008 Dec29(23)2909-45

(2) Velagaleti RS Pencina MJ Murabito JM Wang TJ Parikh NI DrsquoAgostino RB et al Long-term trends in the incidence of heart failure after myocardial infarction Circulation 2008 Nov 11118(20)2057-62







(9) Arnesen H Lunde K Aakhus S Forfang K Cell therapy in myocardial infarction Lancet 2007 Jun 30369(9580)2142-3


(11) van Beem RT Hirsch A Lommerse IM Zwaginga JJ Noort WA Biemond BJ et al Recovery and functional activity of mononuclear bone marrow and peripheral blood cells after different cell isolation protocols used in clinical trials for cell therapy after acute myocardial infarction Eurointervention 2008 May4(1)133-8

(12) Gnecchi M Zhang Z Ni A Dzau VJ Paracrine mechanisms in adult stem cell signaling and therapy Circ Res 2008 Nov 21103(11)1204-19

(13) Kamihata H Matsubara H Nishiue T Fujiyama S Amano K Iba O et al Improvement of collateral perfusion and regional function by implantation of peripheral blood mononuclear cells into ischemic hibernating myocardium Arterioscler Thromb Vasc Biol 2002 Nov 122(11)1804-10


(15) Hirsch A Nijveldt R van der Vleuten PA Tio RA van der Giessen WJ Marques KM et al Intracoronary infusion of autologous mononuclear bone marrow cells in patients with acute myocardial infarction treated with primary PCI Pilot study of the multicenter HEBE trial Catheter Cardiovasc Interv 2008 Feb 1571(3)273-81

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(18) Nijveldt R Beek AM Hirsch A Stoel MG Hofman MB Umans VA et al Functional recovery after acute myocardial infarction comparison between angiography electrocardiography and cardiovascular magnetic resonance measures of microvascular injury J Am Coll Cardiol 2008 Jul 1552(3)181-9


(20) Herbots L Drsquohooge J Eroglu E Thijs D Ganame J Claus P et al Improved regional function after autologous bone marrow-derived stem cell transfer in patients with acute myocardial infarction a randomized double-blind strain rate imaging study Eur Heart J 2008 Dec 23doi101093eurheartjehn532

(21) Dimmeler S Zeiher AM Schneider MD Unchain my heart the scientific foundations of cardiac repair J Clin Invest 2005 Mar115(3)572-83

(22) Erbs S Linke A Schachinger V Assmus B Thiele H Diederich KW et al Restoration of microvascular function in the infarct-related artery by intracoronary transplantation of bone marrow progenitor cells in patients with acute myocardial infarction the Doppler Substudy of the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial Circulation 2007 Jul 24116(4)366-74

(23) Martin-Rendon E Brunskill SJ Hyde CJ Stanworth SJ Mathur A Watt SM Autologous bone marrow stem cells to treat acute myocardial infarction a systematic review Eur Heart J 2008 Aug29(15)1807-18

Chap

ter

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154

10Summary and conclusions

Chap

ter

10

156

Sum

mar

y an

d co

nclu

sion

s

157

Earlier studies mostly designed to establish the value of various pharmacologic interventions

after myocardial infarction have shown the prognostic value of global left ventricular function

measured as left ventricular ejection fraction (LVEF) in terms of mortality and re-admission

rates for heart failure(1-3) In chapter 2 we showed that LVEF assessed shortly after primary

percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) is a

powerful predictor of long term survival However the post-procedural ECG is available even

sooner In chapter 3 it was shown that an increasing number of Q-waves on the first 12-lead

ECG after PPCI is strongly associated with the extent of myocardial damage measured as

area under the curve of creatin kinase and its myocardial isoenzyme and adverse long-term

prognosis This easy and low-cost method of clinical assessment after PPCI could lead to

more focused use of advanced and expensive additional diagnostics or therapeutics

In chapter 4 the relationship between ST-segment resolution residual ST-segment elevation

and Q waves in relation to left ventricular function size and extent of infarction and

microvascular injury in acute myocardial infarction measured by MRI was explored

In chapter 5 we compared electromechanical endocardial mapping (EEM) with MRI

and we found that EEM-derived global left ventricular functional parameters showed a

significant underestimation compared to MRI However regional parameters appeared to

be useful indicators of dysfunctional myocardial segments Although there were substantial

differences in global left ventricular functional parameters between EEM and MRI a good

correlation was found between the surface-area of the EEM-map with a unipolar voltage

below 69 mV and MRI infarct-size(4) Segmental analyses showed that EEM can be used to


infarction Although regional data showed good correlation with MRI convincing cut-off

values for EEM-parameters could not be established Exact pinpointing of myocardial areas

benefiting from direct injection of therapeutics remains difficult

Since residual left ventricular function was shown to be one of the most powerful predictors

of prognosis after primary PCI for STEMI every effort should be made to conserve and

possibly even improve left ventricular function after STEMI Cell therapy has been a

promising new modality in the field of post-STEMI care which has rendered mixed results

so far(5-10) (chapter 6) In order to assess the full potential of cell therapy in a national

Chap

ter

10

158

multicenter trial a pilot-study was conducted to establish the safety and feasibility of all

study related procedures (chapter 7) This study indicated that intracoronary infusion of

autologous bone marrow derived mononuclear cells after recent myocardial infarction is

safe in a multicenter setting At 4 months follow-up a modest but significant increase in

global and regional LV function was observed with a concomitant decrease in infarct-size

After successfully completing the pilot-study the multicenter HEBE trial could be initiated

(chapter 8 and 9) The rationale behind the three arm-armed study design is to test the

hypothesis that the beneficial effects of cell-therapy on left ventricular function cannot be

completely attributed to the formation of new cardiac myocytes or endothelial cells but

that these positive effects could also be a combined effect of all mononuclear cells through

the release of growth factors and cytokines Intracoronary infusion was chosen as mode

of delivery since the benefits of avoiding local injection were considered to outweigh the

obvious drawback of decreased local cell-retention(11) The rationale behind the choice for

MRI as imaging modality for the primary end-point of the study is its ability to combine left

ventricular function analysis with infarct-size analyses

The HEBE trial showed no benefit of infusion of autologous bone marrow derived progenitor

cells after STEMI Research in this field will most likely continue since cell therapy remains

a very appealing concept In the future trials with other cell types or pre-treatment of cells

may be conducted However since the procedures involved in cell therapy are relatively

invasive and time-consuming great care should be taken to identify those patients in which

the potential of success is the highest and clearly outweighs the procedural risk costs and

patient discomfort

Sum

mar

y an

d co

nclu

sion

s

159

References











(11) Penicka M Lang O Widimsky P Kobylka P Kozak T Vanek T et al One-day kinetics of myocardial engraftment after intracoronary injection of bone marrow mononuclear cells in patients with acute and chronic myocardial infarction Heart 2007 Jul93(7)837-41

Chap

ter

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160

Summary in Dutch

(Nederlandse samenvatting)

Sam

enva

tting

162

Sam

enva

tting

163

Het acute ST-elevatie myocardinfarct (STEMI) gaat vrijwel altijd gepaard met schade aan

de hartspier Het is lastig gebleken om deze schade betrouwbaar in maat en getal weer te

geven Wat uiteindelijk voor de patieumlnt het belangrijkste is zijn de overlevingskansen en

het vermogen om zonder beperkende klachten deel te nemen aan het dagelijkse leven In

het eerste deel van dit proefschrift wordt in ingegaan op een aantal ontwikkelingen op het

gebied van het beoordelen van de schade na een infarct

Tegenwoordig wordt de schade bij veel patieumlnten voor een deel beperkt doordat het

afgesloten bloedvat dat het infarct veroorzaakt zo snel mogelijk wordt opengemaakt

door een directe percutane coronaire interventie (PCI ofwel dotterbehandeling) Bij

sommige patieumlnten ontstaat desondanks veel schade aan de hartspier Uit veelbelovend

dierexperimenteel onderzoek is naar voren gekomen dat een behandeling met uit beenmerg

of bloed afkomstige cellen kort na een hartinfarct zou kunnen bijdragen aan het herstel van

de schade van een hartinfarct Deel twee van dit proefschrift gaat dieper in op de toepassing

van deze therapie bij patieumlnten

In grote onderzoeken veelal verricht om het effect van verschillende medicijnen bij

patieumlnten met stabiel hartfalen te onderzoeken is al eerder het verband aangetoond

tussen de pompfunctie uitgedrukt in de linkerventrikelejectiefractie (LVEF) en overleving

In hoofdstuk 2 tonen wij aan dat er een duidelijk verband is tussen de LVEF gemeten in

de weken na het infarct en de overleving op lange termijn Opvallend is daarbij dat een

kleine achteruitgang in LVEF gepaard gaat met een beperkte toename in mortaliteit maar

een afname tot onder de 35 (normaalwaarde gt 55) grote gevolgen heeft wat betreft

overlevingskansen

Om de prognose kort na een PCI voor STEMI te kunnen schatten hebben we gekeken naar de

waarde van het tellen van Q-golven op het eerste beschikbare 12-kanaals elektrocardiogram

(ECG) na de PCI bij een groot aantal STEMI patieumlnten (hoofdstuk 3) Daarbij hebben we

gezien dat bij een toenemend aantal Q-golven op het ECG het infarct biochemisch groter is

en de 1-jaarsmortaliteit hoger Dit effect bleek nog aanwezig te zijn als er werd gecorrigeerd

voor andere bekende voorspellers van infarctgrootte en prognose

In hoofdstuk 4 tonen we aan dat het aantal Q-golven op het eerste ECG na de PCI en de

normalisatie van het ST-segment gerelateerd is aan linkerkamerfunctie en infarctgrootte

gemeten met magnetische resonantie (MRI)

Sam

enva

tting

164

Endocardiale elektromechanische mapping (ook wel NOGA genoemd naar de naam van

het hierbij gebruikte systeem) is een techniek om in het linker ventrikel van het hart de

regionale (en globale) wandbeweging en elektrische activiteit van de hartspier evenals de

mate van infarcering te beoordelen Deze techniek wordt tegenwoordig veel toegepast bij

elektrofysiologische interventies (bijvoorbeeld bij boezemfibrilleren) In het licht van de

mogelijke toepassing bij celtherapie (deel 2 van dit proefschrift) hebben wij de met NOGA

gemeten globale en regionale karakteristieken van het myocard vergeleken met de gegevens

van de MRI In hoofdstuk 5 beschrijven we dat er een goede overeenkomst is maar dat het

niettemin moeilijk blijft om exact de begrenzing van het door de STEMI aangetaste gedeelte

van het myocard te bepalen

Ondanks grote vooruitgang in het beperken van de schade van een hartinfarct is er

vooralsnog geen werkzame manier gevonden om de eenmaal ontstane schade aan

de hartspier te repareren Uit dierexpirimenteel onderzoek en enkele onderzoeken bij

patieumlnten is naar voren gekomen dat het gunstig zou kunnen zijn om kort na een hartinfarct

mononucleaire cellen uit het beenmerg (met daaronder de voorloper- of stamcellen) te

isoleren en in de kransslagader te infunderen In hoofdstuk 6 worden alle beschikbare data

uit gerandomiseerd klinisch onderzoek op een rij gezet Om de veiligheid van alle (deels

invasieve) procedures te waarborgen is eerst een veiligheidsonderzoek verricht (hoofdstuk

7)

In het multicenter gerandomiseerde onderzoek dat daarna is uitgevoerd onder auspicieumln

van het Interuniversitair Cardiologisch Instituut Nederland (ICIN) (hoofdstuk 8 en 9) is

onderzocht of het intracoronair infunderen van uit het beenmerg of uit perifeer bloed

afkomstige mononucleaire cellen kan bijdragen aan het herstel van linker ventrikel

functie na een STEMI Er werden 200 patieumlnten geiumlncludeerd die een primaire PCI hadden

ondergaan binnen 12 uur na het ontstaan van klachten Er werd geloot of deze mensen

in de ldquobeenmergrdquo-groep de ldquobloedrdquo-groep of de ldquocontrolerdquo-groep terecht kwamen Bij de

patieumlnten in de ldquobeenmergrdquo-groep werd 60 milliliter beenmerg uit de rand van het bekkenbot

geaspireerd Uit dit beenmerg werd vervolgens de mononucleaire celfractie geiumlsoleerd

Deze celsuspensie werd vervolgens via een procedure die lijkt op een PCI geiumlnfundeerd in de

bij het infarct betrokken coronairarterie Bij de patieumlnten in de ldquobloedrdquo-groep werd in plaats

Sam

enva

tting

165

van beenmerg 200 ml perifeer bloed gebruikt om de mononucleaire celfractie uit te isoleren

Ook deze celsuspensie werd toegediend in de bij het infarct betrokken coronairarterie

Bij de patieumlnten in de ldquocontrolerdquo-groep werd een dergelijke behandeling niet uitgevoerd

Daarnaast werden alle patieumlnten in het onderzoek behandeld zoals normaal gebruikelijk is

na een STEMI Bij alle patieumlnten werd binnen een week na de primaire PCI een MRI-scan van

het hart gemaakt

Na 4 maanden werd opnieuw een MRI verricht om het effect van de behandeling te

evalueren Hierbij bleek dat in alle drie de groepen de linkerventrikelfunctie zowel globaal

als regionaal licht was verbeterd ten opzichte van de situatie kort na het hartinfarct De

resultaten in de ldquobeenmergrdquo- en de ldquobloedrdquo-groep waren echter niet beter dan de resultaten

in de ldquocontrolerdquo-groep De behandelingen zoals die zijn uitgevoerd in ons onderzoek zijn dus

in de praktijk veilig toepasbaar maar leiden niet tot verbetering van de linkerventrikelfunctie

na een STEMI Nieuwe inzichten en aanvullend onderzoek zullen de brug moeten slaan van

het veelbelovende dierexperimenteel onderzoek naar de dagelijkse cardiologische praktijk

om na een infarct kamerfunctieherstel mogelijk te maken

Sam

enva

tting

166

Dankwoord

Dan

kwoo

rd

168

Dan

kwoo

rd

169

De totstandkoming van dit proefschrift zou nooit een feit zijn geworden zonder de directe

en indirecte hulp van een groot aantal mensen Hoewel ik me besef dat het onmogelijk is

om iedereen met naam en toenaam te noemen wil ik toch graag een aantal mensen in het

bijzonder bedanken

Allereerst mijn promotor prof dr F Zijlstra Beste Felix je weet in je rol als promotor op

onnavolgbare wijze twee uitersten te combineren Enerzijds houd je voldoende afstand

zodat je promovendi zelfstandig kunnen werken Anderzijds heb je een grote inhoudelijke

betrokkenheid bij alle projecten en ben je desgevraagd altijd bereid je handen uit de

mouwen te steken Daarnaast heb je een fascinerend vermogen om nooit lang stil te staan

bij een probleem maar direct te zoeken naar een oplossing Bedankt voor de kans om dit

proefschrift te schrijven en ik hoop dat we in de toekomst nog veel onderzoek blijven doen

op en rond de HC

Mijn co-promotor dr RA Tio Beste Reneacute op het moment van het verschijnen van dit

boekje kennen we elkaar alweer ruim 8 jaar Zonder jou was ik nooit aan dit proefschrift

begonnen en je onverstoorbare positiviteit hebben mij menig maal de dagelijkse obstakels

van het onderzoek doen relativeren

Mijn officieuze ldquotweede co-promotorrdquo dr Gillian Jessurun is slechts zijdelings betrokken

geweest bij de directe inhoud van dit proefschrift Echter je onorthodoxe persoonlijkheid

en enthousiasme voor een niet nader te noemen Duits automerk hebben mijn dagen als

onderzoeker absoluut opgefleurd

Ook met de overige interventiecardiologen (dr Yung Tan dr Bart de Smet dr Rutger

Anthonio en dr Ad van den Heuvel) was en is het erg prettig samenwerken

Uiteraard wil ik ook de beoordelingscommissie bestaande uit prof dr ROB Gans prof dr

JJ Piek en prof dr DJ van Veldhuisen danken voor het kritisch lezen en becommentarieumlren

van dit proefschrift

Dan

kwoo

rd

170

Daarnaast ben ik de opleiders van de afdeling cardiologie (dr MP van den Berg en prof

dr DJ van Veldhuisen) en de afdeling interne geneeskunde (prof dr ROB Gans dr CA

Stegeman en dr JTM van Leeuwen) zeer erkentelijk voor de mogelijkheid om mijn opleiding

tot cardioloog en mijn interne vooropleiding te doorlopen in het UMCG

Door de HEBE-studie heb ik naast de afdeling cardiologie ook veel te maken gehad met

andere afdelingen binnen en buiten het UMCG

De afdeling radiologie (in het bijzonder dr Tineke Willems Peter Kappert Danieumll Lubbers

en Gonda de Jonge) heeft mij de kans gegeven om mijn horizon te verbreden richting de

cardiale imaging

De afdeling hematologie (in het bijzonder dr Joost de Wolf Jenne Kits en Marchienus

Weggemans) heeft mij en een groot aantal patieumlnten ervan overtuigd dat een crista-

punctie mits technisch goed uitgevoerd lang niet zo belastend is als wordt verondersteld

door veel mensen binnen en buiten de gezondheidszorg

Daarnaast was de ondersteuning door Cardio Research (Margriet Couperus en Trienke

Steenhuis in het bijzonder) ldquode dames van C2rdquo (Anja en Trudie) en de verpleging van de

diverse afdelingen essentieel voor het slagen van de studie Tevens wil ik ook dr Wiebe

Nieuwland bedanken voor zijn continue waakzaamheid op de CCU

Buiten het UMCG heb ik zeer intensief samengewerkt met mijn ldquoHEBE-maatjesrdquo Robin

Nijveldt Alexander Hirsch Farshid Afsharzada en Anja van der Laan Ik verheug me op het

verder uitwerken van de studie en hoop dat dit zal leiden tot een aantal mooie publicaties

In dat kader wil ik ook Lieuwe Piers bedanken voor het waarnemen van de HEBE-taken

tijdens het begin van mijn vooropleiding Ik hoop van harte dat je in de Randstad letterlijk

en figuurlijk je plek vindt

Dan

kwoo

rd

171

Een goede werksfeer begint met gezellige collegarsquos Gelukkig heb ik met mijn collegarsquos (onder

andere Daan Kevin Mathijs Tone Jessica Marieke Pieter-Jan Christiane Yulan Marthe

Sheba Marcelle Sandra Hessel Ali Anne Jan-Pieter Tom Martin Michiel Pim Peter

Suzan Bart Willem-Peter Jardi Liza Jasper en Rik) zowel in als buiten ldquode Greenhouserdquo

een mooie tijd gehad Ik hoop dat we die lijn kunnen voortzetten in de kliniek

Niels van Minnen en Michiel Kuijpers wil hartelijk bedanken voor het feit dat zij de taak van

paranimf op zich hebben genomen Ik hoop met jullie beiden nog lang ldquoin het Noorden te

blijven plakkenrdquo

Als laatste bedank ik Saskia Tideman voor allerlei dingen die stuk voor stuk niets met

onderzoek te maken hebben



Pieter A van der Vleuten






ISBN 978-90-367-3906-1

ISBN (Digitaal) 978-90-367-3907-8










Proefschrift




op gezag van de




om 1615 uur

door







Prof dr JJ Piek










of Groningen

Contents

Chapter 1 9



Chapter 2 17




Chapter 3 29





Chapter 4 51





Chapter 5 67




Submitted


Chapter 6 87



Chapter 7 99




Chapter 8 115




Am Heart J 2006 Sep152(3)434-41

Chapter 9 133



Submitted

Chapter 10 155



Dankwoord 167


1

Chap

ter

1

10

Intr

oduc

tion

and

scop

e of

this

thes

is

11






























Chap

ter

1

12


















in this thesis

Intr

oduc

tion

and

scop

e of

this

thes

is

13

References















Chap

ter

1

14








PART 1











The Netherlands






2

Chap

ter

2

18

Abstract

Background





Methods



Results






Conclusion


for STEMI

LVEF

aft

er S

TEM

I

19

Background
















Methods











Chap

ter

2

20












1-2(13)









Results








LVEF

aft

er S

TEM

I

21












Chap

ter

2

22









LVEF

aft

er S

TEM

I

23














　

　Ⰰ　㔀

　Ⰰ

　Ⰰ㔀

　Ⰰ

　Ⰰ㔀

　Ⰰ䴀

攀愀渀

礀攀

愀爀洀

漀爀琀愀

氀椀琀礀

Chap

ter

2

24






3 year mortality






3 year mortality



LVEF

aft

er S

TEM

I

25

Discussion






























Chap

ter

2

26





















Conclusion



Abbreviations






LVEF

aft

er S

TEM

I

27

References















Chap

ter

2

28















3

Chap

ter

3

30

Abstract

Design



Setting



Background


Methods




MB)

Results





Conclusion



Q-w

aves

aft

er S

TEM

I

31

Introduction




























Chap

ter

3

32

Methods








1005 patients















Angiographic data



Q-w

aves

aft

er S

TEM

I

33

Follow-up





practitioner











TIMI risk score












Chap

ter

3

34











Results













Q-w

aves

aft

er S

TEM

I

35





Chap

ter

3

36

Tabl

e 1

Bas

elin

e cl

inic

al a

nd a

ngio

grap

hic

char

acte

risti

csTo

tal (

n =

933)

0-1

Q-w

aves

(n =

309

)2-

4 Q

-wav

es (n

= 4

98)

gt 4

Q-w

aves

(n =

126

)p

Age

yrs

mea

n (S

D)

627

(12

5)

601

(12

1)

633

(12

4)

665

(12

6)

lt 0

001

Mal

e se

x71

472

571

767

5n

s

His

tory

of M

I 9

77

210

712

0n

sH

isto

ry o

f PCI

71

62

79

64

ns

His

tory

of C

ABG

3

33

33

43

2n

sH

isto

ry o

f str

oke

38

27

41

57

ns

Dia

bete

s m

ellit

us

110

7

911

915

20

058

Hyp

erte

nsio

n35

631

035

945

50

018

Hyp

erlip

idem

ia25

426

524

426

8n

sCu

rren

t sm

oker

48

2

526

473

412

ns

Posi

tive

fam

ily h

isto

ry

464

53

544

536

90

004

Infa

rct l

ocati

onLM

08

06

04

24

ns

LAD

430

411

363

738

lt 0

001

CX16

621

615

75

50

002

RCA

385

361

464

167

lt 0

001

Gra

ft1

10

61

21

6n

s

Tota

l isc

hem

ic ti

me

in h

ours

(med

ian

+ IQ

R)3

1 [2

2 ndash

45

] 3

0 [2

1 ndash

42

] 3

5 [2

2 ndash

45

] 3

4 [2

3 ndash

61

] 0

050

Intr

a-ao

rtic

ballo

on p

ump

60

21

56

168

lt 0

001

Sten

t 92

795

291

292

4n

sG

lyco

prot

ein

IibI

IIa re

cept

or b

lock

er

926

93

591

489

7n

s

Q-w

aves

aft

er S

TEM

I

37

Tabl

e 1

Bas

elin

e cl

inic

al a

nd a

ngio

grap

hic

char

acte

risti

cs (c

ontin

ued)

TIM

I flow

bef

ore

prim

ary

PCI

049

931

557

066

7lt

000

11

104

89

100

159

ns

217

922

916

411

10

007

321

836

716

66

3lt

000

1

TIM

I flow

aft

er p

rim

ary

PCI

01

30

01

44

10

003

11

80

62

42

5n

s2

126

65

144

205

lt 0

001

384

392

981

872

9lt

000

1

Myo

card

ial b

lush

gra

de a

fter

pri

mar

y PC

I0

53

16

51

149

lt 0

001

116

010

917

324

00

002

239

841

838

838

8n

s3

389

457

388

223

lt 0

001

TIM

I ris

k sc

ore

28

24

28

39

lt 0

001

Max

CK

Ul

(med

ian

+ IQ

R)52

8 [2

32 ndash

13

20]

233

[89

ndash 45

5]65

8 [3

48 ndash

138

2]17

05 [1

022

ndash 28

79]

lt 0

001

Max

CK-

MB

Ul

(med

ian

+ IQ

R)57

[24

ndash 10

3]23

[8 ndash

51]

70 [3

8 ndash

115]

155

[85

ndash 26

3]lt

000

1

Dat

a ar

e di

spla

yed

as p

erce

ntag

e u

nles

s ot

herw

ise

indi

cate

d

Tota

l isc

hem

ic ti

me

deno

tes

time

betw

een

onse

t of s

ympt

oms

and

prim

ary

PCI

CABG

= c

oron

ary

arte

ry b

ypas

s gr

aftin

g LM

= le

ft m

ain

coro

nary

art

ery

CX =

circ

umfle

x co

rona

ry a

rter

y M

I = m

yoca

rdia

l inf

arcti

onCK

= c

reati

n ki

nase

PC

I = p

ercu

tane

ous

coro

nary

inte

rven

tion

CK-M

B =

crea

tin k

inas

e m

yoca

rdia

l ban

d RC

A =

rig

ht c

oron

ary

arte

ryIQ

R =

inte

rqua

rtile

-ran

ge

SD =

sta

ndar

d de

viati

onLA

D =

left

ant

erio

r de

scen

ding

cor

onar

y ar

tery

TI

MI =

thro

mbo

lysi

s in

myo

card

ial i

nfar

ction

Chap

ter

3

38













Q-w

aves

aft

er S

TEM

I

39


analysis

Univariate model


Multivariate model











Chap

ter

3

40





analysis

Univariate model



Univariate model



Q-w

aves

aft

er S

TEM

I

41



through 7














Chap

ter

3

42










Q-w

aves

aft

er S

TEM

I

43





(n = 699)



creatine kinase









band

Chap

ter

3

44







Q-w

aves

aft

er S

TEM

I

45













Chap

ter

3

46

Discussion



























decision-making




Q-w

aves

aft

er S

TEM

I

47







prediction models







particular reason)



















Chap

ter

3

48








post-procedural ECG





elucidated













Conclusion




Q-w

aves

aft

er S

TEM

I

49

References
















Chap

ter

3

50
























4

Chap

ter

4

52

Abstract

Objectives




Background




risk stratification

Methods






Results







Conclusions




ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

53

Introduction

















necrosis




resonance (CMR)

Methods

Patient population




Chap

ter

4

54








Electrocardiography






















ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

55































Chap

ter

4

56


the presence of MVO


Results












ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

57


44 (24ndash69)



Chap

ter

4

58








1)







Number of Q waves






ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI










Chap

ter

4

60










LVEF


Dys

func

t

segm

ents





Infa

rct

size


Tran

smur

al

segm

ents






ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

61






Pres

ence

of M

VO

















Chap

ter

4

62




Discussion


























ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

63





resolution



























Chap

ter

4

64






























ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

65

References
















Chap

ter

4

66























Submitt ed

5

Chap

ter

5

68

Abstract

Objective



Patients


Interventions






Results








Conclusions






5 N

OG

A c

ompa

red

to M

RI

69

Introduction






























Chap

ter

5

70







Methods

Patients




















5 N

OG

A c

ompa

red

to M

RI

71

















13


Chap

ter

5

72































5 N

OG

A c

ompa

red

to M

RI

73


























Chap

ter

5

74

Results








5 N

OG

A c

ompa

red

to M

RI

75










Chap

ter

5

76





Global parameters






5 N

OG

A c

ompa

red

to M

RI

77









Chap

ter

5

78

Regional parameters



















mapping parameters


5 N

OG

A c

ompa

red

to M

RI

79

Discussion




























by EEM(29)

Chap

ter

5

80
















Limitations













5 N

OG

A c

ompa

red

to M

RI

81








Chap

ter

5

82

References
















5 N

OG

A c

ompa

red

to M

RI

83















Chap

ter

5

84

PART 2










6

Chap

ter

6

88

Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

89

Introduction










cell-therapy











heart failure








Chap

ter

6

90

Cell types









Cardiac stem cells










Skeletal myoblasts








Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

91



















Paracrine effects











Chap

ter

6

92


in-vivo trials

















Cell delivery











Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

93




















Considerations






Chap

ter

6

94









Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

95












issues

Conclusion




Chap

ter

6

96

References


















Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

97



Chap

ter

6

98




















alphabeti cal order


7

Chap

ter

7

100

Abstract

Objective



Background




Methods






Results








Conclusion




HEB

E pi

lot

101

Introduction




















Methods







Chap

ter

7

102
































HEB

E pi

lot

103































Chap

ter

7

104











Results








HEB

E pi

lot

105



Cell infusion












Chap

ter

7

106





Follow-up















ECG monitoring




HEB

E pi

lot

107












Chap

ter

7

108











LV left ventricular






enhancement

HEB

E pi

lot

109







Discussion















Chap

ter

7

110
































HEB

E pi

lot

111
































Chap

ter

7

112





















HEB

E pi

lot

113

References

















Chap

ter

7

114
























alphabeti cal order







Am Heart J 2006 Sep152(3)434-41

8

Chap

ter

8

116

Abstract

Background






Methods













Implications




HEB

E pr

otoc

ol

117

Introduction







been advocated(1-4)

Background











Initial experience









Chap

ter

8

118











Mononuclear cells







sub-population(15)









HEB

E pr

otoc

ol

119

Tabl

e 1

Ove

rvie

w o

f stu

dies

of i

ntra

-cor

onar

y in

fusi

on o

f aut

olog

ous

bone

mar

row

in p

atien

ts a

fter

acu

te m

yoca

rdia

l inf

arcti

on

Stud

yN

Des

ign

Day

s aft

er M

IFo

llow

-up

(mon

ths)

Stat

usRe

sults

Stau

er e

t al(

10)

20Se

quen

tial B

MC

(10)

than

co

ntro

l (10

) Si

ngle

cen

ter

83

Publ

ishe

dD

ecre

ased

infa

rct r

egio

n an

d ES

V on

LV-

angi

o In

crea

sed

regi

onal

con

trac

tility

on

LV-a

ngio

Impr

oved

per

fusi

on o

n sc

intig

raph

yIn

crea

sed

stro

ke v

olum

e in

dex

on R

V-ca

thet

eris

ation

Scha

chin

ger

et a

l ldquoT

OPC

ARE

-A

MIrdquo

(11)

59

Rand

omiz

ed

BMC

(29)

vs

CPC

(30)

O

pen-

labe

l Si

ngle

cen

ter

512

Publ

ishe

dD

ecre

ased

ESV

on

LV-a

ngio

In

crea

sed

LVEF

on

LV-a

ngio

and

MRI

Wol

lert

et a

l ldquoB

OO

STrdquo(

14)

60Ra

ndom

ized

BM

C (3

0) v

s C

ontr

ol (3

0)

Ope

n la

bel

Sing

le c

ente

r

56

Publ

ishe

dIn

crea

sed

LVEF

on

MRI

Fern

aacutende

z-Av

ileacutes

et a

l(16

)20

Non

-ran

dom

ized

Si

ngle

cen

ter

1411

Pu

blis

hed

Incr

ease

d LV

EF o

n M

RIIn

crea

sed

regi

onal

con

trac

tility

on

MRI

Jans

sens

et a

l66

Rand

omiz

ed

BMC

(32)

vs

con

trol

(34)

D

oubl

e bl

ind

Sin

gle

cent

er

14

Pres

ente

d at

co

ngre

ssD

ecre

ased

infa

rct s

ize

on L

CE im

ages

on

MRI

MI =

myo

card

ial i

nfar

ction

BM

C =

mon

onuc

lear

bon

e m

arro

w c

ells

ESV

= e

nd-s

ysto

lic v

olum

e L

V =

left

ven

tric

ular

RV

= ri

ght

vent

ricu

lar

CPC

= cu

ltiva

ted

circ

ulati

ng p

roge

nito

r ce

lls fr

om p

erip

hera

l blo

od L

VEF

= le

ft v

entr

icul

ar e

jecti

on fr

actio

n M

RI =

mag

netic

res

onan

ce im

agin

g L

CE =

late

co

ntra

st-e

nhan

ced

Chap

ter

8

120

Methods

Overview







in Figure 1





HEB

E pr

otoc

ol

121




















Chap

ter

8

122





HEB

E pr

otoc

ol

123
































Chap

ter

8

124



Echocardiography
















Cell material










HEB

E pr

otoc

ol

125













Follow-up









12 months follow-up

End points





Chap

ter

8

126












endpoint










HEB

E pr

otoc

ol

127






drawn












Current status




Discussion





Chap

ter

8

128
































HEB

E pr

otoc

ol

129










Implications




Appendix

Executive committee















Chap

ter

8

130









HEB

E pr

otoc

ol

131

References

















Chap

ter

8

132




















Netherlands



Submitt ed

9

Chap

ter

9

134

Abstract

Background



conflicting results

Methods










Results









Conclusions




HEB

E st

udy

135

Introduction




















Methods







Chap

ter

9

136































HEB

E st

udy

137















images










End point measures





Chap

ter

9

138














fraction(14)











HEB

E st

udy

139

Results


























Chap

ter

9

140


Group

(N = 69)


(N = 66)

Control Group

(N = 65)



HEB

E st

udy

141







Chap

ter

9

142



HEB

E st

udy

143


Group

(N = 69)


(N = 66)

Control Group

(N = 65)


0 1 ndash


1 2 ndash


1 3 0


3 6 4


4 9 6


0 5 2




Chap

ter

9

144



















group (Table 3)

Clinical outcome











HEB

E st

udy

145

Figu

re 2

Esti

mati

on o

f the

effe

ct o

f int

raco

rona

ry in

jecti

on o

f mon

onuc

lear

cel

ls fr

om b

one

mar

row

or

peri

pher

al b

lood

on

left

ven

tric

ular

eje

ction

fr

actio

nLV

den

otes

left

ven

tric

ular

In

the

left

pan

el th

e lin

es re

pres

ent t

he c

hang

e ob

serv

ed in

indi

vidu

al p

atien

ts a

nd th

e sq

uare

s re

pres

ent t

he m

ean

with

th

e st

anda

rd d

evia

tion

In th

e ri

ght p

anel

the

mea

n ch

ange

bet

wee

n ba

selin

e an

d fo

llow

-up

at 4

mon

ths

is p

rese

nted

with

the

stan

dard

err

or

Chap

ter

9

146

Tabl

e 3

Qua

ntita

tive

mea

sure

s of

regi

onal

and

glo

bal l

eft v

entr

icul

ar fu

nctio

n v

olum

es m

ass

and

infa

rct s

ize

by m

agne

tic re

sona

nce

imag

ing

Bo

ne M

arro

w

Gro

upPe

riph

eral

Blo

od

Gro

upCo

ntro

l

Gro

upBo

ne M

arro

w v

s C

ontr

olPe

riph

eral

Blo

od v

s C

ontr

ol

(N =

67)

(N =

62)

(N =

60)

Trea

tmen

t eff

ect dagger

Estim

ate

(95

CI)

P va

lue

Trea

tmen

t eff

ect dagger

Estim

ate

(95

CI)

P va

lue

Prim

ary

end

poin

t ndash

D

ysfu

nctio

nal s

egm

ents

at

b

asel

ine

533

plusmn 1

96

575

plusmn 1

96

562

plusmn 1

84

D

ysfu

nctio

nal s

egm

ents

that

im

prov

ed d

urin

g fo

llow

-up

386

plusmn 2

47

368

plusmn 2

09

424

plusmn 1

87

ndash39

(ndash11

7 to

40

)0

33ndash5

3 (ndash

123

to 1

7)

014

Segm

enta

l wal

l thi

cken

ing

in

dysf

uncti

onal

seg

men

ts ndash

mm

B

asel

ine

119

plusmn 0

55

118

plusmn 0

49

114

plusmn 0

52

F

ollo

w-u

p2

31 plusmn

13

22

21 plusmn

12

12

31 plusmn

09

7

Cha

nge

112

plusmn 1

20

103

plusmn 0

99

118

plusmn 0

80

ndash00

6 (ndash

043

to 0

30)

073

ndash01

5 (ndash

048

to 0

17)

035

P

val

ue (b

asel

ine

vs 4

mon

ths)

lt00

01lt0

001

lt00

01LV

eje

ction

frac

tion

ndash

B

asel

ine

437

plusmn 9

041

7 plusmn

91

424

plusmn 8

3

Fol

low

-up

475

plusmn 9

946

0 plusmn

93

464

plusmn 9

2

Cha

nge

38

plusmn 7

44

2 plusmn

62

40

plusmn 5

80

1 (ndash

22

to 2

4)

094

01

(ndash2

0 to

22

)0

90

P v

alue

(bas

elin

e vs

4 m

onth

s)lt0

001

lt00

01lt0

001

LV e

nd-d

iast

olic

vol

ume

ndash m

lm

2

B

asel

ine

973

plusmn 1

40

980

plusmn 1

54

100

0 plusmn

169

F

ollo

w-u

p10

26

plusmn 19

110

34

plusmn 22

610

82

plusmn 24

6

Cha

nge

54

plusmn 13

45

3 plusmn

163

82

plusmn 13

5ndash2

5 (ndash

72

to 2

2)

029

ndash26

(ndash8

0 to

27

)0

33

P v

alue

(bas

elin

e vs

4 m

onth

s)0

002

001

lt00

01LV

end

-sys

tolic

vol

ume

ndash m

lm

2

B

asel

ine

554

plusmn 1

45

578

plusmn 1

59

581

plusmn 1

51

F

ollo

w-u

p54

9 plusmn

19

557

1 plusmn

21

659

3 plusmn

21

7

Cha

nge

ndash05

plusmn 1

34

ndash07

plusmn 1

44

12

plusmn 11

7ndash1

5 (ndash

59

to 3

0)

052

ndash19

(ndash6

6 to

28

)0

43

P v

alue

(bas

elin

e vs

4 m

onth

s)0

750

710

42

HEB

E st

udy

147

LV m

ass

ndash gr

m2

B

asel

ine

598

plusmn 1

22

596

plusmn 1

14

591

plusmn 1

19

F

ollo

w-u

p51

7 plusmn

10

551

3 plusmn

10

251

4 plusmn

10

6

Cha

nge

ndash80

plusmn 9

6ndash8

3 plusmn

79

ndash78

plusmn 7

6ndash0

03

(ndash2

6 to

26

)0

98ndash0

4 (ndash

28

to 2

0)

074

P

val

ue (b

asel

ine

vs 4

mon

ths)

lt00

01lt0

001

lt00

01In

farc

t siz

e ndash

gr Dagger

B

asel

ine

229

plusmn 1

26

211

plusmn 1

12

236

plusmn 1

38

F

ollo

w-u

p15

2 plusmn

82

132

plusmn 7

314

2 plusmn

89

C

hang

endash7

7 plusmn

85

ndash79

plusmn 6

5ndash9

4 plusmn

71

13

(ndash0

5 to

32

)0

160

4 (ndash

11

to 1

9)

062

P

val

ue (b

asel

ine

vs 4

mon

ths)

lt00

01lt0

001

lt00

01

Pl

us-m

inus

val

ues

are

mea

ns plusmn

SD

LV

deno

tes

left

ven

tric

ular

P v

alue

s fo

r th

e ch

ange

bet

wee

n ba

selin

e an

d fo

llow

-up

with

in e

ach

stud

y gr

oup

wer

e ca

lcul

ated

with

pai

red

Stud

entrsquos

t te

st

dagger Tr

eatm

ent e

ffect

and

P v

alue

s w

ere

dete

rmin

ed b

y an

alys

is o

f cov

aria

nce

Dagger Th

e an

alys

is in

clud

ed 5

8 pa

tient

s in

the

bone

mar

row

gro

up 5

7 in

the

peri

pher

al b

lood

gro

up a

nd 5

2 in

the

cont

rol g

roup

Chap

ter

9

148

Discussion






























HEB

E st

udy

149
































Chap

ter

9

150










with primary PCI

Funding








Appendix











HEB

E st

udy

151











Chap

ter

9

152

References
















HEB

E st

udy

153









Chap

ter

9

154


Chap

ter

10

156

Sum

mar

y an

d co

nclu

sion

s

157































Chap

ter

10

158






















patient discomfort

Sum

mar

y an

d co

nclu

sion

s

159

References












Chap

ter

10

160

Summary in Dutch


Sam

enva

tting

162

Sam

enva

tting

163






















overlevingskansen










Sam

enva

tting

164



















7)












Sam

enva

tting

165






het hart gemaakt










Sam

enva

tting

166

Dankwoord

Dan

kwoo

rd

168

Dan

kwoo

rd

169




bijzonder bedanken








op en rond de HC














Dan

kwoo

rd

170









cardiale imaging















Dan

kwoo

rd

171
















ISBN 978-90-367-3906-1

ISBN (Digitaal) 978-90-367-3907-8










Proefschrift




op gezag van de




om 1615 uur

door







Prof dr JJ Piek










of Groningen

Contents

Chapter 1 9



Chapter 2 17




Chapter 3 29





Chapter 4 51





Chapter 5 67




Submitted


Chapter 6 87



Chapter 7 99




Chapter 8 115




Am Heart J 2006 Sep152(3)434-41

Chapter 9 133



Submitted

Chapter 10 155



Dankwoord 167


1

Chap

ter

1

10

Intr

oduc

tion

and

scop

e of

this

thes

is

11






























Chap

ter

1

12


















in this thesis

Intr

oduc

tion

and

scop

e of

this

thes

is

13

References















Chap

ter

1

14








PART 1











The Netherlands






2

Chap

ter

2

18

Abstract

Background





Methods



Results






Conclusion


for STEMI

LVEF

aft

er S

TEM

I

19

Background
















Methods











Chap

ter

2

20












1-2(13)









Results








LVEF

aft

er S

TEM

I

21












Chap

ter

2

22









LVEF

aft

er S

TEM

I

23














　

　Ⰰ　㔀

　Ⰰ

　Ⰰ㔀

　Ⰰ

　Ⰰ㔀

　Ⰰ䴀

攀愀渀

礀攀

愀爀洀

漀爀琀愀

氀椀琀礀

Chap

ter

2

24






3 year mortality






3 year mortality



LVEF

aft

er S

TEM

I

25

Discussion






























Chap

ter

2

26





















Conclusion



Abbreviations






LVEF

aft

er S

TEM

I

27

References















Chap

ter

2

28















3

Chap

ter

3

30

Abstract

Design



Setting



Background


Methods




MB)

Results





Conclusion



Q-w

aves

aft

er S

TEM

I

31

Introduction




























Chap

ter

3

32

Methods








1005 patients















Angiographic data



Q-w

aves

aft

er S

TEM

I

33

Follow-up





practitioner











TIMI risk score












Chap

ter

3

34











Results













Q-w

aves

aft

er S

TEM

I

35





Chap

ter

3

36

Tabl

e 1

Bas

elin

e cl

inic

al a

nd a

ngio

grap

hic

char

acte

risti

csTo

tal (

n =

933)

0-1

Q-w

aves

(n =

309

)2-

4 Q

-wav

es (n

= 4

98)

gt 4

Q-w

aves

(n =

126

)p

Age

yrs

mea

n (S

D)

627

(12

5)

601

(12

1)

633

(12

4)

665

(12

6)

lt 0

001

Mal

e se

x71

472

571

767

5n

s

His

tory

of M

I 9

77

210

712

0n

sH

isto

ry o

f PCI

71

62

79

64

ns

His

tory

of C

ABG

3

33

33

43

2n

sH

isto

ry o

f str

oke

38

27

41

57

ns

Dia

bete

s m

ellit

us

110

7

911

915

20

058

Hyp

erte

nsio

n35

631

035

945

50

018

Hyp

erlip

idem

ia25

426

524

426

8n

sCu

rren

t sm

oker

48

2

526

473

412

ns

Posi

tive

fam

ily h

isto

ry

464

53

544

536

90

004

Infa

rct l

ocati

onLM

08

06

04

24

ns

LAD

430

411

363

738

lt 0

001

CX16

621

615

75

50

002

RCA

385

361

464

167

lt 0

001

Gra

ft1

10

61

21

6n

s

Tota

l isc

hem

ic ti

me

in h

ours

(med

ian

+ IQ

R)3

1 [2

2 ndash

45

] 3

0 [2

1 ndash

42

] 3

5 [2

2 ndash

45

] 3

4 [2

3 ndash

61

] 0

050

Intr

a-ao

rtic

ballo

on p

ump

60

21

56

168

lt 0

001

Sten

t 92

795

291

292

4n

sG

lyco

prot

ein

IibI

IIa re

cept

or b

lock

er

926

93

591

489

7n

s

Q-w

aves

aft

er S

TEM

I

37

Tabl

e 1

Bas

elin

e cl

inic

al a

nd a

ngio

grap

hic

char

acte

risti

cs (c

ontin

ued)

TIM

I flow

bef

ore

prim

ary

PCI

049

931

557

066

7lt

000

11

104

89

100

159

ns

217

922

916

411

10

007

321

836

716

66

3lt

000

1

TIM

I flow

aft

er p

rim

ary

PCI

01

30

01

44

10

003

11

80

62

42

5n

s2

126

65

144

205

lt 0

001

384

392

981

872

9lt

000

1

Myo

card

ial b

lush

gra

de a

fter

pri

mar

y PC

I0

53

16

51

149

lt 0

001

116

010

917

324

00

002

239

841

838

838

8n

s3

389

457

388

223

lt 0

001

TIM

I ris

k sc

ore

28

24

28

39

lt 0

001

Max

CK

Ul

(med

ian

+ IQ

R)52

8 [2

32 ndash

13

20]

233

[89

ndash 45

5]65

8 [3

48 ndash

138

2]17

05 [1

022

ndash 28

79]

lt 0

001

Max

CK-

MB

Ul

(med

ian

+ IQ

R)57

[24

ndash 10

3]23

[8 ndash

51]

70 [3

8 ndash

115]

155

[85

ndash 26

3]lt

000

1

Dat

a ar

e di

spla

yed

as p

erce

ntag

e u

nles

s ot

herw

ise

indi

cate

d

Tota

l isc

hem

ic ti

me

deno

tes

time

betw

een

onse

t of s

ympt

oms

and

prim

ary

PCI

CABG

= c

oron

ary

arte

ry b

ypas

s gr

aftin

g LM

= le

ft m

ain

coro

nary

art

ery

CX =

circ

umfle

x co

rona

ry a

rter

y M

I = m

yoca

rdia

l inf

arcti

onCK

= c

reati

n ki

nase

PC

I = p

ercu

tane

ous

coro

nary

inte

rven

tion

CK-M

B =

crea

tin k

inas

e m

yoca

rdia

l ban

d RC

A =

rig

ht c

oron

ary

arte

ryIQ

R =

inte

rqua

rtile

-ran

ge

SD =

sta

ndar

d de

viati

onLA

D =

left

ant

erio

r de

scen

ding

cor

onar

y ar

tery

TI

MI =

thro

mbo

lysi

s in

myo

card

ial i

nfar

ction

Chap

ter

3

38













Q-w

aves

aft

er S

TEM

I

39


analysis

Univariate model


Multivariate model











Chap

ter

3

40





analysis

Univariate model



Univariate model



Q-w

aves

aft

er S

TEM

I

41



through 7














Chap

ter

3

42










Q-w

aves

aft

er S

TEM

I

43





(n = 699)



creatine kinase









band

Chap

ter

3

44







Q-w

aves

aft

er S

TEM

I

45













Chap

ter

3

46

Discussion



























decision-making




Q-w

aves

aft

er S

TEM

I

47







prediction models







particular reason)



















Chap

ter

3

48








post-procedural ECG





elucidated













Conclusion




Q-w

aves

aft

er S

TEM

I

49

References
















Chap

ter

3

50
























4

Chap

ter

4

52

Abstract

Objectives




Background




risk stratification

Methods






Results







Conclusions




ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

53

Introduction

















necrosis




resonance (CMR)

Methods

Patient population




Chap

ter

4

54








Electrocardiography






















ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

55































Chap

ter

4

56


the presence of MVO


Results












ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

57


44 (24ndash69)



Chap

ter

4

58








1)







Number of Q waves






ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI










Chap

ter

4

60










LVEF


Dys

func

t

segm

ents





Infa

rct

size


Tran

smur

al

segm

ents






ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

61






Pres

ence

of M

VO

















Chap

ter

4

62




Discussion


























ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

63





resolution



























Chap

ter

4

64






























ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

65

References
















Chap

ter

4

66























Submitt ed

5

Chap

ter

5

68

Abstract

Objective



Patients


Interventions






Results








Conclusions






5 N

OG

A c

ompa

red

to M

RI

69

Introduction






























Chap

ter

5

70







Methods

Patients




















5 N

OG

A c

ompa

red

to M

RI

71

















13


Chap

ter

5

72































5 N

OG

A c

ompa

red

to M

RI

73


























Chap

ter

5

74

Results








5 N

OG

A c

ompa

red

to M

RI

75










Chap

ter

5

76





Global parameters






5 N

OG

A c

ompa

red

to M

RI

77









Chap

ter

5

78

Regional parameters



















mapping parameters


5 N

OG

A c

ompa

red

to M

RI

79

Discussion




























by EEM(29)

Chap

ter

5

80
















Limitations













5 N

OG

A c

ompa

red

to M

RI

81








Chap

ter

5

82

References
















5 N

OG

A c

ompa

red

to M

RI

83















Chap

ter

5

84

PART 2










6

Chap

ter

6

88

Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

89

Introduction










cell-therapy











heart failure








Chap

ter

6

90

Cell types









Cardiac stem cells










Skeletal myoblasts








Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

91



















Paracrine effects











Chap

ter

6

92


in-vivo trials

















Cell delivery











Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

93




















Considerations






Chap

ter

6

94









Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

95












issues

Conclusion




Chap

ter

6

96

References


















Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

97



Chap

ter

6

98




















alphabeti cal order


7

Chap

ter

7

100

Abstract

Objective



Background




Methods






Results








Conclusion




HEB

E pi

lot

101

Introduction




















Methods







Chap

ter

7

102
































HEB

E pi

lot

103































Chap

ter

7

104











Results








HEB

E pi

lot

105



Cell infusion












Chap

ter

7

106





Follow-up















ECG monitoring




HEB

E pi

lot

107












Chap

ter

7

108











LV left ventricular






enhancement

HEB

E pi

lot

109







Discussion















Chap

ter

7

110
































HEB

E pi

lot

111
































Chap

ter

7

112





















HEB

E pi

lot

113

References

















Chap

ter

7

114
























alphabeti cal order







Am Heart J 2006 Sep152(3)434-41

8

Chap

ter

8

116

Abstract

Background






Methods













Implications




HEB

E pr

otoc

ol

117

Introduction







been advocated(1-4)

Background











Initial experience









Chap

ter

8

118











Mononuclear cells







sub-population(15)









HEB

E pr

otoc

ol

119

Tabl

e 1

Ove

rvie

w o

f stu

dies

of i

ntra

-cor

onar

y in

fusi

on o

f aut

olog

ous

bone

mar

row

in p

atien

ts a

fter

acu

te m

yoca

rdia

l inf

arcti

on

Stud

yN

Des

ign

Day

s aft

er M

IFo

llow

-up

(mon

ths)

Stat

usRe

sults

Stau

er e

t al(

10)

20Se

quen

tial B

MC

(10)

than

co

ntro

l (10

) Si

ngle

cen

ter

83

Publ

ishe

dD

ecre

ased

infa

rct r

egio

n an

d ES

V on

LV-

angi

o In

crea

sed

regi

onal

con

trac

tility

on

LV-a

ngio

Impr

oved

per

fusi

on o

n sc

intig

raph

yIn

crea

sed

stro

ke v

olum

e in

dex

on R

V-ca

thet

eris

ation

Scha

chin

ger

et a

l ldquoT

OPC

ARE

-A

MIrdquo

(11)

59

Rand

omiz

ed

BMC

(29)

vs

CPC

(30)

O

pen-

labe

l Si

ngle

cen

ter

512

Publ

ishe

dD

ecre

ased

ESV

on

LV-a

ngio

In

crea

sed

LVEF

on

LV-a

ngio

and

MRI

Wol

lert

et a

l ldquoB

OO

STrdquo(

14)

60Ra

ndom

ized

BM

C (3

0) v

s C

ontr

ol (3

0)

Ope

n la

bel

Sing

le c

ente

r

56

Publ

ishe

dIn

crea

sed

LVEF

on

MRI

Fern

aacutende

z-Av

ileacutes

et a

l(16

)20

Non

-ran

dom

ized

Si

ngle

cen

ter

1411

Pu

blis

hed

Incr

ease

d LV

EF o

n M

RIIn

crea

sed

regi

onal

con

trac

tility

on

MRI

Jans

sens

et a

l66

Rand

omiz

ed

BMC

(32)

vs

con

trol

(34)

D

oubl

e bl

ind

Sin

gle

cent

er

14

Pres

ente

d at

co

ngre

ssD

ecre

ased

infa

rct s

ize

on L

CE im

ages

on

MRI

MI =

myo

card

ial i

nfar

ction

BM

C =

mon

onuc

lear

bon

e m

arro

w c

ells

ESV

= e

nd-s

ysto

lic v

olum

e L

V =

left

ven

tric

ular

RV

= ri

ght

vent

ricu

lar

CPC

= cu

ltiva

ted

circ

ulati

ng p

roge

nito

r ce

lls fr

om p

erip

hera

l blo

od L

VEF

= le

ft v

entr

icul

ar e

jecti

on fr

actio

n M

RI =

mag

netic

res

onan

ce im

agin

g L

CE =

late

co

ntra

st-e

nhan

ced

Chap

ter

8

120

Methods

Overview







in Figure 1





HEB

E pr

otoc

ol

121




















Chap

ter

8

122





HEB

E pr

otoc

ol

123
































Chap

ter

8

124



Echocardiography
















Cell material










HEB

E pr

otoc

ol

125













Follow-up









12 months follow-up

End points





Chap

ter

8

126












endpoint










HEB

E pr

otoc

ol

127






drawn












Current status




Discussion





Chap

ter

8

128
































HEB

E pr

otoc

ol

129










Implications




Appendix

Executive committee















Chap

ter

8

130









HEB

E pr

otoc

ol

131

References

















Chap

ter

8

132




















Netherlands



Submitt ed

9

Chap

ter

9

134

Abstract

Background



conflicting results

Methods










Results









Conclusions




HEB

E st

udy

135

Introduction




















Methods







Chap

ter

9

136































HEB

E st

udy

137















images










End point measures





Chap

ter

9

138














fraction(14)











HEB

E st

udy

139

Results


























Chap

ter

9

140


Group

(N = 69)


(N = 66)

Control Group

(N = 65)



HEB

E st

udy

141







Chap

ter

9

142



HEB

E st

udy

143


Group

(N = 69)


(N = 66)

Control Group

(N = 65)


0 1 ndash


1 2 ndash


1 3 0


3 6 4


4 9 6


0 5 2




Chap

ter

9

144



















group (Table 3)

Clinical outcome











HEB

E st

udy

145

Figu

re 2

Esti

mati

on o

f the

effe

ct o

f int

raco

rona

ry in

jecti

on o

f mon

onuc

lear

cel

ls fr

om b

one

mar

row

or

peri

pher

al b

lood

on

left

ven

tric

ular

eje

ction

fr

actio

nLV

den

otes

left

ven

tric

ular

In

the

left

pan

el th

e lin

es re

pres

ent t

he c

hang

e ob

serv

ed in

indi

vidu

al p

atien

ts a

nd th

e sq

uare

s re

pres

ent t

he m

ean

with

th

e st

anda

rd d

evia

tion

In th

e ri

ght p

anel

the

mea

n ch

ange

bet

wee

n ba

selin

e an

d fo

llow

-up

at 4

mon

ths

is p

rese

nted

with

the

stan

dard

err

or

Chap

ter

9

146

Tabl

e 3

Qua

ntita

tive

mea

sure

s of

regi

onal

and

glo

bal l

eft v

entr

icul

ar fu

nctio

n v

olum

es m

ass

and

infa

rct s

ize

by m

agne

tic re

sona

nce

imag

ing

Bo

ne M

arro

w

Gro

upPe

riph

eral

Blo

od

Gro

upCo

ntro

l

Gro

upBo

ne M

arro

w v

s C

ontr

olPe

riph

eral

Blo

od v

s C

ontr

ol

(N =

67)

(N =

62)

(N =

60)

Trea

tmen

t eff

ect dagger

Estim

ate

(95

CI)

P va

lue

Trea

tmen

t eff

ect dagger

Estim

ate

(95

CI)

P va

lue

Prim

ary

end

poin

t ndash

D

ysfu

nctio

nal s

egm

ents

at

b

asel

ine

533

plusmn 1

96

575

plusmn 1

96

562

plusmn 1

84

D

ysfu

nctio

nal s

egm

ents

that

im

prov

ed d

urin

g fo

llow

-up

386

plusmn 2

47

368

plusmn 2

09

424

plusmn 1

87

ndash39

(ndash11

7 to

40

)0

33ndash5

3 (ndash

123

to 1

7)

014

Segm

enta

l wal

l thi

cken

ing

in

dysf

uncti

onal

seg

men

ts ndash

mm

B

asel

ine

119

plusmn 0

55

118

plusmn 0

49

114

plusmn 0

52

F

ollo

w-u

p2

31 plusmn

13

22

21 plusmn

12

12

31 plusmn

09

7

Cha

nge

112

plusmn 1

20

103

plusmn 0

99

118

plusmn 0

80

ndash00

6 (ndash

043

to 0

30)

073

ndash01

5 (ndash

048

to 0

17)

035

P

val

ue (b

asel

ine

vs 4

mon

ths)

lt00

01lt0

001

lt00

01LV

eje

ction

frac

tion

ndash

B

asel

ine

437

plusmn 9

041

7 plusmn

91

424

plusmn 8

3

Fol

low

-up

475

plusmn 9

946

0 plusmn

93

464

plusmn 9

2

Cha

nge

38

plusmn 7

44

2 plusmn

62

40

plusmn 5

80

1 (ndash

22

to 2

4)

094

01

(ndash2

0 to

22

)0

90

P v

alue

(bas

elin

e vs

4 m

onth

s)lt0

001

lt00

01lt0

001

LV e

nd-d

iast

olic

vol

ume

ndash m

lm

2

B

asel

ine

973

plusmn 1

40

980

plusmn 1

54

100

0 plusmn

169

F

ollo

w-u

p10

26

plusmn 19

110

34

plusmn 22

610

82

plusmn 24

6

Cha

nge

54

plusmn 13

45

3 plusmn

163

82

plusmn 13

5ndash2

5 (ndash

72

to 2

2)

029

ndash26

(ndash8

0 to

27

)0

33

P v

alue

(bas

elin

e vs

4 m

onth

s)0

002

001

lt00

01LV

end

-sys

tolic

vol

ume

ndash m

lm

2

B

asel

ine

554

plusmn 1

45

578

plusmn 1

59

581

plusmn 1

51

F

ollo

w-u

p54

9 plusmn

19

557

1 plusmn

21

659

3 plusmn

21

7

Cha

nge

ndash05

plusmn 1

34

ndash07

plusmn 1

44

12

plusmn 11

7ndash1

5 (ndash

59

to 3

0)

052

ndash19

(ndash6

6 to

28

)0

43

P v

alue

(bas

elin

e vs

4 m

onth

s)0

750

710

42

HEB

E st

udy

147

LV m

ass

ndash gr

m2

B

asel

ine

598

plusmn 1

22

596

plusmn 1

14

591

plusmn 1

19

F

ollo

w-u

p51

7 plusmn

10

551

3 plusmn

10

251

4 plusmn

10

6

Cha

nge

ndash80

plusmn 9

6ndash8

3 plusmn

79

ndash78

plusmn 7

6ndash0

03

(ndash2

6 to

26

)0

98ndash0

4 (ndash

28

to 2

0)

074

P

val

ue (b

asel

ine

vs 4

mon

ths)

lt00

01lt0

001

lt00

01In

farc

t siz

e ndash

gr Dagger

B

asel

ine

229

plusmn 1

26

211

plusmn 1

12

236

plusmn 1

38

F

ollo

w-u

p15

2 plusmn

82

132

plusmn 7

314

2 plusmn

89

C

hang

endash7

7 plusmn

85

ndash79

plusmn 6

5ndash9

4 plusmn

71

13

(ndash0

5 to

32

)0

160

4 (ndash

11

to 1

9)

062

P

val

ue (b

asel

ine

vs 4

mon

ths)

lt00

01lt0

001

lt00

01

Pl

us-m

inus

val

ues

are

mea

ns plusmn

SD

LV

deno

tes

left

ven

tric

ular

P v

alue

s fo

r th

e ch

ange

bet

wee

n ba

selin

e an

d fo

llow

-up

with

in e

ach

stud

y gr

oup

wer

e ca

lcul

ated

with

pai

red

Stud

entrsquos

t te

st

dagger Tr

eatm

ent e

ffect

and

P v

alue

s w

ere

dete

rmin

ed b

y an

alys

is o

f cov

aria

nce

Dagger Th

e an

alys

is in

clud

ed 5

8 pa

tient

s in

the

bone

mar

row

gro

up 5

7 in

the

peri

pher

al b

lood

gro

up a

nd 5

2 in

the

cont

rol g

roup

Chap

ter

9

148

Discussion






























HEB

E st

udy

149
































Chap

ter

9

150










with primary PCI

Funding








Appendix











HEB

E st

udy

151











Chap

ter

9

152

References
















HEB

E st

udy

153









Chap

ter

9

154


Chap

ter

10

156

Sum

mar

y an

d co

nclu

sion

s

157































Chap

ter

10

158






















patient discomfort

Sum

mar

y an

d co

nclu

sion

s

159

References












Chap

ter

10

160

Summary in Dutch


Sam

enva

tting

162

Sam

enva

tting

163






















overlevingskansen










Sam

enva

tting

164



















7)












Sam

enva

tting

165






het hart gemaakt










Sam

enva

tting

166

Dankwoord

Dan

kwoo

rd

168

Dan

kwoo

rd

169




bijzonder bedanken








op en rond de HC














Dan

kwoo

rd

170









cardiale imaging















Dan

kwoo

rd

171














Proefschrift




op gezag van de




om 1615 uur

door







Prof dr JJ Piek










of Groningen

Contents

Chapter 1 9



Chapter 2 17




Chapter 3 29





Chapter 4 51





Chapter 5 67




Submitted


Chapter 6 87



Chapter 7 99




Chapter 8 115




Am Heart J 2006 Sep152(3)434-41

Chapter 9 133



Submitted

Chapter 10 155



Dankwoord 167


1

Chap

ter

1

10

Intr

oduc

tion

and

scop

e of

this

thes

is

11






























Chap

ter

1

12


















in this thesis

Intr

oduc

tion

and

scop

e of

this

thes

is

13

References















Chap

ter

1

14








PART 1











The Netherlands






2

Chap

ter

2

18

Abstract

Background





Methods



Results






Conclusion


for STEMI

LVEF

aft

er S

TEM

I

19

Background
















Methods











Chap

ter

2

20












1-2(13)









Results








LVEF

aft

er S

TEM

I

21












Chap

ter

2

22









LVEF

aft

er S

TEM

I

23














　

　Ⰰ　㔀

　Ⰰ

　Ⰰ㔀

　Ⰰ

　Ⰰ㔀

　Ⰰ䴀

攀愀渀

礀攀

愀爀洀

漀爀琀愀

氀椀琀礀

Chap

ter

2

24






3 year mortality






3 year mortality



LVEF

aft

er S

TEM

I

25

Discussion






























Chap

ter

2

26





















Conclusion



Abbreviations






LVEF

aft

er S

TEM

I

27

References















Chap

ter

2

28















3

Chap

ter

3

30

Abstract

Design



Setting



Background


Methods




MB)

Results





Conclusion



Q-w

aves

aft

er S

TEM

I

31

Introduction




























Chap

ter

3

32

Methods








1005 patients















Angiographic data



Q-w

aves

aft

er S

TEM

I

33

Follow-up





practitioner











TIMI risk score












Chap

ter

3

34











Results













Q-w

aves

aft

er S

TEM

I

35





Chap

ter

3

36

Tabl

e 1

Bas

elin

e cl

inic

al a

nd a

ngio

grap

hic

char

acte

risti

csTo

tal (

n =

933)

0-1

Q-w

aves

(n =

309

)2-

4 Q

-wav

es (n

= 4

98)

gt 4

Q-w

aves

(n =

126

)p

Age

yrs

mea

n (S

D)

627

(12

5)

601

(12

1)

633

(12

4)

665

(12

6)

lt 0

001

Mal

e se

x71

472

571

767

5n

s

His

tory

of M

I 9

77

210

712

0n

sH

isto

ry o

f PCI

71

62

79

64

ns

His

tory

of C

ABG

3

33

33

43

2n

sH

isto

ry o

f str

oke

38

27

41

57

ns

Dia

bete

s m

ellit

us

110

7

911

915

20

058

Hyp

erte

nsio

n35

631

035

945

50

018

Hyp

erlip

idem

ia25

426

524

426

8n

sCu

rren

t sm

oker

48

2

526

473

412

ns

Posi

tive

fam

ily h

isto

ry

464

53

544

536

90

004

Infa

rct l

ocati

onLM

08

06

04

24

ns

LAD

430

411

363

738

lt 0

001

CX16

621

615

75

50

002

RCA

385

361

464

167

lt 0

001

Gra

ft1

10

61

21

6n

s

Tota

l isc

hem

ic ti

me

in h

ours

(med

ian

+ IQ

R)3

1 [2

2 ndash

45

] 3

0 [2

1 ndash

42

] 3

5 [2

2 ndash

45

] 3

4 [2

3 ndash

61

] 0

050

Intr

a-ao

rtic

ballo

on p

ump

60

21

56

168

lt 0

001

Sten

t 92

795

291

292

4n

sG

lyco

prot

ein

IibI

IIa re

cept

or b

lock

er

926

93

591

489

7n

s

Q-w

aves

aft

er S

TEM

I

37

Tabl

e 1

Bas

elin

e cl

inic

al a

nd a

ngio

grap

hic

char

acte

risti

cs (c

ontin

ued)

TIM

I flow

bef

ore

prim

ary

PCI

049

931

557

066

7lt

000

11

104

89

100

159

ns

217

922

916

411

10

007

321

836

716

66

3lt

000

1

TIM

I flow

aft

er p

rim

ary

PCI

01

30

01

44

10

003

11

80

62

42

5n

s2

126

65

144

205

lt 0

001

384

392

981

872

9lt

000

1

Myo

card

ial b

lush

gra

de a

fter

pri

mar

y PC

I0

53

16

51

149

lt 0

001

116

010

917

324

00

002

239

841

838

838

8n

s3

389

457

388

223

lt 0

001

TIM

I ris

k sc

ore

28

24

28

39

lt 0

001

Max

CK

Ul

(med

ian

+ IQ

R)52

8 [2

32 ndash

13

20]

233

[89

ndash 45

5]65

8 [3

48 ndash

138

2]17

05 [1

022

ndash 28

79]

lt 0

001

Max

CK-

MB

Ul

(med

ian

+ IQ

R)57

[24

ndash 10

3]23

[8 ndash

51]

70 [3

8 ndash

115]

155

[85

ndash 26

3]lt

000

1

Dat

a ar

e di

spla

yed

as p

erce

ntag

e u

nles

s ot

herw

ise

indi

cate

d

Tota

l isc

hem

ic ti

me

deno

tes

time

betw

een

onse

t of s

ympt

oms

and

prim

ary

PCI

CABG

= c

oron

ary

arte

ry b

ypas

s gr

aftin

g LM

= le

ft m

ain

coro

nary

art

ery

CX =

circ

umfle

x co

rona

ry a

rter

y M

I = m

yoca

rdia

l inf

arcti

onCK

= c

reati

n ki

nase

PC

I = p

ercu

tane

ous

coro

nary

inte

rven

tion

CK-M

B =

crea

tin k

inas

e m

yoca

rdia

l ban

d RC

A =

rig

ht c

oron

ary

arte

ryIQ

R =

inte

rqua

rtile

-ran

ge

SD =

sta

ndar

d de

viati

onLA

D =

left

ant

erio

r de

scen

ding

cor

onar

y ar

tery

TI

MI =

thro

mbo

lysi

s in

myo

card

ial i

nfar

ction

Chap

ter

3

38













Q-w

aves

aft

er S

TEM

I

39


analysis

Univariate model


Multivariate model











Chap

ter

3

40





analysis

Univariate model



Univariate model



Q-w

aves

aft

er S

TEM

I

41



through 7














Chap

ter

3

42










Q-w

aves

aft

er S

TEM

I

43





(n = 699)



creatine kinase









band

Chap

ter

3

44







Q-w

aves

aft

er S

TEM

I

45













Chap

ter

3

46

Discussion



























decision-making




Q-w

aves

aft

er S

TEM

I

47







prediction models







particular reason)



















Chap

ter

3

48








post-procedural ECG





elucidated













Conclusion




Q-w

aves

aft

er S

TEM

I

49

References
















Chap

ter

3

50
























4

Chap

ter

4

52

Abstract

Objectives




Background




risk stratification

Methods






Results







Conclusions




ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

53

Introduction

















necrosis




resonance (CMR)

Methods

Patient population




Chap

ter

4

54








Electrocardiography






















ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

55































Chap

ter

4

56


the presence of MVO


Results












ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

57


44 (24ndash69)



Chap

ter

4

58








1)







Number of Q waves






ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI










Chap

ter

4

60










LVEF


Dys

func

t

segm

ents





Infa

rct

size


Tran

smur

al

segm

ents






ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

61






Pres

ence

of M

VO

















Chap

ter

4

62




Discussion


























ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

63





resolution



























Chap

ter

4

64






























ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

65

References
















Chap

ter

4

66























Submitt ed

5

Chap

ter

5

68

Abstract

Objective



Patients


Interventions






Results








Conclusions






5 N

OG

A c

ompa

red

to M

RI

69

Introduction






























Chap

ter

5

70







Methods

Patients




















5 N

OG

A c

ompa

red

to M

RI

71

















13


Chap

ter

5

72































5 N

OG

A c

ompa

red

to M

RI

73


























Chap

ter

5

74

Results








5 N

OG

A c

ompa

red

to M

RI

75










Chap

ter

5

76





Global parameters






5 N

OG

A c

ompa

red

to M

RI

77









Chap

ter

5

78

Regional parameters



















mapping parameters


5 N

OG

A c

ompa

red

to M

RI

79

Discussion




























by EEM(29)

Chap

ter

5

80
















Limitations













5 N

OG

A c

ompa

red

to M

RI

81








Chap

ter

5

82

References
















5 N

OG

A c

ompa

red

to M

RI

83















Chap

ter

5

84

PART 2










6

Chap

ter

6

88

Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

89

Introduction










cell-therapy











heart failure








Chap

ter

6

90

Cell types









Cardiac stem cells










Skeletal myoblasts








Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

91



















Paracrine effects











Chap

ter

6

92


in-vivo trials

















Cell delivery











Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

93




















Considerations






Chap

ter

6

94









Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

95












issues

Conclusion




Chap

ter

6

96

References


















Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

97



Chap

ter

6

98




















alphabeti cal order


7

Chap

ter

7

100

Abstract

Objective



Background




Methods






Results








Conclusion




HEB

E pi

lot

101

Introduction




















Methods







Chap

ter

7

102
































HEB

E pi

lot

103































Chap

ter

7

104











Results








HEB

E pi

lot

105



Cell infusion












Chap

ter

7

106





Follow-up















ECG monitoring




HEB

E pi

lot

107












Chap

ter

7

108











LV left ventricular






enhancement

HEB

E pi

lot

109







Discussion















Chap

ter

7

110
































HEB

E pi

lot

111
































Chap

ter

7

112





















HEB

E pi

lot

113

References

















Chap

ter

7

114
























alphabeti cal order







Am Heart J 2006 Sep152(3)434-41

8

Chap

ter

8

116

Abstract

Background






Methods













Implications




HEB

E pr

otoc

ol

117

Introduction







been advocated(1-4)

Background











Initial experience









Chap

ter

8

118











Mononuclear cells







sub-population(15)









HEB

E pr

otoc

ol

119

Tabl

e 1

Ove

rvie

w o

f stu

dies

of i

ntra

-cor

onar

y in

fusi

on o

f aut

olog

ous

bone

mar

row

in p

atien

ts a

fter

acu

te m

yoca

rdia

l inf

arcti

on

Stud

yN

Des

ign

Day

s aft

er M

IFo

llow

-up

(mon

ths)

Stat

usRe

sults

Stau

er e

t al(

10)

20Se

quen

tial B

MC

(10)

than

co

ntro

l (10

) Si

ngle

cen

ter

83

Publ

ishe

dD

ecre

ased

infa

rct r

egio

n an

d ES

V on

LV-

angi

o In

crea

sed

regi

onal

con

trac

tility

on

LV-a

ngio

Impr

oved

per

fusi

on o

n sc

intig

raph

yIn

crea

sed

stro

ke v

olum

e in

dex

on R

V-ca

thet

eris

ation

Scha

chin

ger

et a

l ldquoT

OPC

ARE

-A

MIrdquo

(11)

59

Rand

omiz

ed

BMC

(29)

vs

CPC

(30)

O

pen-

labe

l Si

ngle

cen

ter

512

Publ

ishe

dD

ecre

ased

ESV

on

LV-a

ngio

In

crea

sed

LVEF

on

LV-a

ngio

and

MRI

Wol

lert

et a

l ldquoB

OO

STrdquo(

14)

60Ra

ndom

ized

BM

C (3

0) v

s C

ontr

ol (3

0)

Ope

n la

bel

Sing

le c

ente

r

56

Publ

ishe

dIn

crea

sed

LVEF

on

MRI

Fern

aacutende

z-Av

ileacutes

et a

l(16

)20

Non

-ran

dom

ized

Si

ngle

cen

ter

1411

Pu

blis

hed

Incr

ease

d LV

EF o

n M

RIIn

crea

sed

regi

onal

con

trac

tility

on

MRI

Jans

sens

et a

l66

Rand

omiz

ed

BMC

(32)

vs

con

trol

(34)

D

oubl

e bl

ind

Sin

gle

cent

er

14

Pres

ente

d at

co

ngre

ssD

ecre

ased

infa

rct s

ize

on L

CE im

ages

on

MRI

MI =

myo

card

ial i

nfar

ction

BM

C =

mon

onuc

lear

bon

e m

arro

w c

ells

ESV

= e

nd-s

ysto

lic v

olum

e L

V =

left

ven

tric

ular

RV

= ri

ght

vent

ricu

lar

CPC

= cu

ltiva

ted

circ

ulati

ng p

roge

nito

r ce

lls fr

om p

erip

hera

l blo

od L

VEF

= le

ft v

entr

icul

ar e

jecti

on fr

actio

n M

RI =

mag

netic

res

onan

ce im

agin

g L

CE =

late

co

ntra

st-e

nhan

ced

Chap

ter

8

120

Methods

Overview







in Figure 1





HEB

E pr

otoc

ol

121




















Chap

ter

8

122





HEB

E pr

otoc

ol

123
































Chap

ter

8

124



Echocardiography
















Cell material










HEB

E pr

otoc

ol

125













Follow-up









12 months follow-up

End points





Chap

ter

8

126












endpoint










HEB

E pr

otoc

ol

127






drawn












Current status




Discussion





Chap

ter

8

128
































HEB

E pr

otoc

ol

129










Implications




Appendix

Executive committee















Chap

ter

8

130









HEB

E pr

otoc

ol

131

References

















Chap

ter

8

132




















Netherlands



Submitt ed

9

Chap

ter

9

134

Abstract

Background



conflicting results

Methods










Results









Conclusions




HEB

E st

udy

135

Introduction




















Methods







Chap

ter

9

136































HEB

E st

udy

137















images










End point measures





Chap

ter

9

138














fraction(14)











HEB

E st

udy

139

Results


























Chap

ter

9

140


Group

(N = 69)


(N = 66)

Control Group

(N = 65)



HEB

E st

udy

141







Chap

ter

9

142



HEB

E st

udy

143


Group

(N = 69)


(N = 66)

Control Group

(N = 65)


0 1 ndash


1 2 ndash


1 3 0


3 6 4


4 9 6


0 5 2




Chap

ter

9

144



















group (Table 3)

Clinical outcome











HEB

E st

udy

145

Figu

re 2

Esti

mati

on o

f the

effe

ct o

f int

raco

rona

ry in

jecti

on o

f mon

onuc

lear

cel

ls fr

om b

one

mar

row

or

peri

pher

al b

lood

on

left

ven

tric

ular

eje

ction

fr

actio

nLV

den

otes

left

ven

tric

ular

In

the

left

pan

el th

e lin

es re

pres

ent t

he c

hang

e ob

serv

ed in

indi

vidu

al p

atien

ts a

nd th

e sq

uare

s re

pres

ent t

he m

ean

with

th

e st

anda

rd d

evia

tion

In th

e ri

ght p

anel

the

mea

n ch

ange

bet

wee

n ba

selin

e an

d fo

llow

-up

at 4

mon

ths

is p

rese

nted

with

the

stan

dard

err

or

Chap

ter

9

146

Tabl

e 3

Qua

ntita

tive

mea

sure

s of

regi

onal

and

glo

bal l

eft v

entr

icul

ar fu

nctio

n v

olum

es m

ass

and

infa

rct s

ize

by m

agne

tic re

sona

nce

imag

ing

Bo

ne M

arro

w

Gro

upPe

riph

eral

Blo

od

Gro

upCo

ntro

l

Gro

upBo

ne M

arro

w v

s C

ontr

olPe

riph

eral

Blo

od v

s C

ontr

ol

(N =

67)

(N =

62)

(N =

60)

Trea

tmen

t eff

ect dagger

Estim

ate

(95

CI)

P va

lue

Trea

tmen

t eff

ect dagger

Estim

ate

(95

CI)

P va

lue

Prim

ary

end

poin

t ndash

D

ysfu

nctio

nal s

egm

ents

at

b

asel

ine

533

plusmn 1

96

575

plusmn 1

96

562

plusmn 1

84

D

ysfu

nctio

nal s

egm

ents

that

im

prov

ed d

urin

g fo

llow

-up

386

plusmn 2

47

368

plusmn 2

09

424

plusmn 1

87

ndash39

(ndash11

7 to

40

)0

33ndash5

3 (ndash

123

to 1

7)

014

Segm

enta

l wal

l thi

cken

ing

in

dysf

uncti

onal

seg

men

ts ndash

mm

B

asel

ine

119

plusmn 0

55

118

plusmn 0

49

114

plusmn 0

52

F

ollo

w-u

p2

31 plusmn

13

22

21 plusmn

12

12

31 plusmn

09

7

Cha

nge

112

plusmn 1

20

103

plusmn 0

99

118

plusmn 0

80

ndash00

6 (ndash

043

to 0

30)

073

ndash01

5 (ndash

048

to 0

17)

035

P

val

ue (b

asel

ine

vs 4

mon

ths)

lt00

01lt0

001

lt00

01LV

eje

ction

frac

tion

ndash

B

asel

ine

437

plusmn 9

041

7 plusmn

91

424

plusmn 8

3

Fol

low

-up

475

plusmn 9

946

0 plusmn

93

464

plusmn 9

2

Cha

nge

38

plusmn 7

44

2 plusmn

62

40

plusmn 5

80

1 (ndash

22

to 2

4)

094

01

(ndash2

0 to

22

)0

90

P v

alue

(bas

elin

e vs

4 m

onth

s)lt0

001

lt00

01lt0

001

LV e

nd-d

iast

olic

vol

ume

ndash m

lm

2

B

asel

ine

973

plusmn 1

40

980

plusmn 1

54

100

0 plusmn

169

F

ollo

w-u

p10

26

plusmn 19

110

34

plusmn 22

610

82

plusmn 24

6

Cha

nge

54

plusmn 13

45

3 plusmn

163

82

plusmn 13

5ndash2

5 (ndash

72

to 2

2)

029

ndash26

(ndash8

0 to

27

)0

33

P v

alue

(bas

elin

e vs

4 m

onth

s)0

002

001

lt00

01LV

end

-sys

tolic

vol

ume

ndash m

lm

2

B

asel

ine

554

plusmn 1

45

578

plusmn 1

59

581

plusmn 1

51

F

ollo

w-u

p54

9 plusmn

19

557

1 plusmn

21

659

3 plusmn

21

7

Cha

nge

ndash05

plusmn 1

34

ndash07

plusmn 1

44

12

plusmn 11

7ndash1

5 (ndash

59

to 3

0)

052

ndash19

(ndash6

6 to

28

)0

43

P v

alue

(bas

elin

e vs

4 m

onth

s)0

750

710

42

HEB

E st

udy

147

LV m

ass

ndash gr

m2

B

asel

ine

598

plusmn 1

22

596

plusmn 1

14

591

plusmn 1

19

F

ollo

w-u

p51

7 plusmn

10

551

3 plusmn

10

251

4 plusmn

10

6

Cha

nge

ndash80

plusmn 9

6ndash8

3 plusmn

79

ndash78

plusmn 7

6ndash0

03

(ndash2

6 to

26

)0

98ndash0

4 (ndash

28

to 2

0)

074

P

val

ue (b

asel

ine

vs 4

mon

ths)

lt00

01lt0

001

lt00

01In

farc

t siz

e ndash

gr Dagger

B

asel

ine

229

plusmn 1

26

211

plusmn 1

12

236

plusmn 1

38

F

ollo

w-u

p15

2 plusmn

82

132

plusmn 7

314

2 plusmn

89

C

hang

endash7

7 plusmn

85

ndash79

plusmn 6

5ndash9

4 plusmn

71

13

(ndash0

5 to

32

)0

160

4 (ndash

11

to 1

9)

062

P

val

ue (b

asel

ine

vs 4

mon

ths)

lt00

01lt0

001

lt00

01

Pl

us-m

inus

val

ues

are

mea

ns plusmn

SD

LV

deno

tes

left

ven

tric

ular

P v

alue

s fo

r th

e ch

ange

bet

wee

n ba

selin

e an

d fo

llow

-up

with

in e

ach

stud

y gr

oup

wer

e ca

lcul

ated

with

pai

red

Stud

entrsquos

t te

st

dagger Tr

eatm

ent e

ffect

and

P v

alue

s w

ere

dete

rmin

ed b

y an

alys

is o

f cov

aria

nce

Dagger Th

e an

alys

is in

clud

ed 5

8 pa

tient

s in

the

bone

mar

row

gro

up 5

7 in

the

peri

pher

al b

lood

gro

up a

nd 5

2 in

the

cont

rol g

roup

Chap

ter

9

148

Discussion






























HEB

E st

udy

149
































Chap

ter

9

150










with primary PCI

Funding








Appendix











HEB

E st

udy

151











Chap

ter

9

152

References
















HEB

E st

udy

153









Chap

ter

9

154


Chap

ter

10

156

Sum

mar

y an

d co

nclu

sion

s

157































Chap

ter

10

158






















patient discomfort

Sum

mar

y an

d co

nclu

sion

s

159

References












Chap

ter

10

160

Summary in Dutch


Sam

enva

tting

162

Sam

enva

tting

163






















overlevingskansen










Sam

enva

tting

164



















7)












Sam

enva

tting

165






het hart gemaakt










Sam

enva

tting

166

Dankwoord

Dan

kwoo

rd

168

Dan

kwoo

rd

169




bijzonder bedanken








op en rond de HC














Dan

kwoo

rd

170









cardiale imaging















Dan

kwoo

rd

171














Prof dr JJ Piek










of Groningen

Contents

Chapter 1 9



Chapter 2 17




Chapter 3 29





Chapter 4 51





Chapter 5 67




Submitted


Chapter 6 87



Chapter 7 99




Chapter 8 115




Am Heart J 2006 Sep152(3)434-41

Chapter 9 133



Submitted

Chapter 10 155



Dankwoord 167


1

Chap

ter

1

10

Intr

oduc

tion

and

scop

e of

this

thes

is

11






























Chap

ter

1

12


















in this thesis

Intr

oduc

tion

and

scop

e of

this

thes

is

13

References















Chap

ter

1

14








PART 1











The Netherlands






2

Chap

ter

2

18

Abstract

Background





Methods



Results






Conclusion


for STEMI

LVEF

aft

er S

TEM

I

19

Background
















Methods











Chap

ter

2

20












1-2(13)









Results








LVEF

aft

er S

TEM

I

21












Chap

ter

2

22









LVEF

aft

er S

TEM

I

23














　

　Ⰰ　㔀

　Ⰰ

　Ⰰ㔀

　Ⰰ

　Ⰰ㔀

　Ⰰ䴀

攀愀渀

礀攀

愀爀洀

漀爀琀愀

氀椀琀礀

Chap

ter

2

24






3 year mortality






3 year mortality



LVEF

aft

er S

TEM

I

25

Discussion






























Chap

ter

2

26





















Conclusion



Abbreviations






LVEF

aft

er S

TEM

I

27

References















Chap

ter

2

28















3

Chap

ter

3

30

Abstract

Design



Setting



Background


Methods




MB)

Results





Conclusion



Q-w

aves

aft

er S

TEM

I

31

Introduction




























Chap

ter

3

32

Methods








1005 patients















Angiographic data



Q-w

aves

aft

er S

TEM

I

33

Follow-up





practitioner











TIMI risk score












Chap

ter

3

34











Results













Q-w

aves

aft

er S

TEM

I

35





Chap

ter

3

36

Tabl

e 1

Bas

elin

e cl

inic

al a

nd a

ngio

grap

hic

char

acte

risti

csTo

tal (

n =

933)

0-1

Q-w

aves

(n =

309

)2-

4 Q

-wav

es (n

= 4

98)

gt 4

Q-w

aves

(n =

126

)p

Age

yrs

mea

n (S

D)

627

(12

5)

601

(12

1)

633

(12

4)

665

(12

6)

lt 0

001

Mal

e se

x71

472

571

767

5n

s

His

tory

of M

I 9

77

210

712

0n

sH

isto

ry o

f PCI

71

62

79

64

ns

His

tory

of C

ABG

3

33

33

43

2n

sH

isto

ry o

f str

oke

38

27

41

57

ns

Dia

bete

s m

ellit

us

110

7

911

915

20

058

Hyp

erte

nsio

n35

631

035

945

50

018

Hyp

erlip

idem

ia25

426

524

426

8n

sCu

rren

t sm

oker

48

2

526

473

412

ns

Posi

tive

fam

ily h

isto

ry

464

53

544

536

90

004

Infa

rct l

ocati

onLM

08

06

04

24

ns

LAD

430

411

363

738

lt 0

001

CX16

621

615

75

50

002

RCA

385

361

464

167

lt 0

001

Gra

ft1

10

61

21

6n

s

Tota

l isc

hem

ic ti

me

in h

ours

(med

ian

+ IQ

R)3

1 [2

2 ndash

45

] 3

0 [2

1 ndash

42

] 3

5 [2

2 ndash

45

] 3

4 [2

3 ndash

61

] 0

050

Intr

a-ao

rtic

ballo

on p

ump

60

21

56

168

lt 0

001

Sten

t 92

795

291

292

4n

sG

lyco

prot

ein

IibI

IIa re

cept

or b

lock

er

926

93

591

489

7n

s

Q-w

aves

aft

er S

TEM

I

37

Tabl

e 1

Bas

elin

e cl

inic

al a

nd a

ngio

grap

hic

char

acte

risti

cs (c

ontin

ued)

TIM

I flow

bef

ore

prim

ary

PCI

049

931

557

066

7lt

000

11

104

89

100

159

ns

217

922

916

411

10

007

321

836

716

66

3lt

000

1

TIM

I flow

aft

er p

rim

ary

PCI

01

30

01

44

10

003

11

80

62

42

5n

s2

126

65

144

205

lt 0

001

384

392

981

872

9lt

000

1

Myo

card

ial b

lush

gra

de a

fter

pri

mar

y PC

I0

53

16

51

149

lt 0

001

116

010

917

324

00

002

239

841

838

838

8n

s3

389

457

388

223

lt 0

001

TIM

I ris

k sc

ore

28

24

28

39

lt 0

001

Max

CK

Ul

(med

ian

+ IQ

R)52

8 [2

32 ndash

13

20]

233

[89

ndash 45

5]65

8 [3

48 ndash

138

2]17

05 [1

022

ndash 28

79]

lt 0

001

Max

CK-

MB

Ul

(med

ian

+ IQ

R)57

[24

ndash 10

3]23

[8 ndash

51]

70 [3

8 ndash

115]

155

[85

ndash 26

3]lt

000

1

Dat

a ar

e di

spla

yed

as p

erce

ntag

e u

nles

s ot

herw

ise

indi

cate

d

Tota

l isc

hem

ic ti

me

deno

tes

time

betw

een

onse

t of s

ympt

oms

and

prim

ary

PCI

CABG

= c

oron

ary

arte

ry b

ypas

s gr

aftin

g LM

= le

ft m

ain

coro

nary

art

ery

CX =

circ

umfle

x co

rona

ry a

rter

y M

I = m

yoca

rdia

l inf

arcti

onCK

= c

reati

n ki

nase

PC

I = p

ercu

tane

ous

coro

nary

inte

rven

tion

CK-M

B =

crea

tin k

inas

e m

yoca

rdia

l ban

d RC

A =

rig

ht c

oron

ary

arte

ryIQ

R =

inte

rqua

rtile

-ran

ge

SD =

sta

ndar

d de

viati

onLA

D =

left

ant

erio

r de

scen

ding

cor

onar

y ar

tery

TI

MI =

thro

mbo

lysi

s in

myo

card

ial i

nfar

ction

Chap

ter

3

38













Q-w

aves

aft

er S

TEM

I

39


analysis

Univariate model


Multivariate model











Chap

ter

3

40





analysis

Univariate model



Univariate model



Q-w

aves

aft

er S

TEM

I

41



through 7














Chap

ter

3

42










Q-w

aves

aft

er S

TEM

I

43





(n = 699)



creatine kinase









band

Chap

ter

3

44







Q-w

aves

aft

er S

TEM

I

45













Chap

ter

3

46

Discussion



























decision-making




Q-w

aves

aft

er S

TEM

I

47







prediction models







particular reason)



















Chap

ter

3

48








post-procedural ECG





elucidated













Conclusion




Q-w

aves

aft

er S

TEM

I

49

References
















Chap

ter

3

50
























4

Chap

ter

4

52

Abstract

Objectives




Background




risk stratification

Methods






Results







Conclusions




ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

53

Introduction

















necrosis




resonance (CMR)

Methods

Patient population




Chap

ter

4

54








Electrocardiography






















ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

55































Chap

ter

4

56


the presence of MVO


Results












ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

57


44 (24ndash69)



Chap

ter

4

58








1)







Number of Q waves






ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI










Chap

ter

4

60










LVEF


Dys

func

t

segm

ents





Infa

rct

size


Tran

smur

al

segm

ents






ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

61






Pres

ence

of M

VO

















Chap

ter

4

62




Discussion


























ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

63





resolution



























Chap

ter

4

64






























ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

65

References
















Chap

ter

4

66























Submitt ed

5

Chap

ter

5

68

Abstract

Objective



Patients


Interventions






Results








Conclusions






5 N

OG

A c

ompa

red

to M

RI

69

Introduction






























Chap

ter

5

70







Methods

Patients




















5 N

OG

A c

ompa

red

to M

RI

71

















13


Chap

ter

5

72































5 N

OG

A c

ompa

red

to M

RI

73


























Chap

ter

5

74

Results








5 N

OG

A c

ompa

red

to M

RI

75










Chap

ter

5

76





Global parameters






5 N

OG

A c

ompa

red

to M

RI

77









Chap

ter

5

78

Regional parameters



















mapping parameters


5 N

OG

A c

ompa

red

to M

RI

79

Discussion




























by EEM(29)

Chap

ter

5

80
















Limitations













5 N

OG

A c

ompa

red

to M

RI

81








Chap

ter

5

82

References
















5 N

OG

A c

ompa

red

to M

RI

83















Chap

ter

5

84

PART 2










6

Chap

ter

6

88

Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

89

Introduction










cell-therapy











heart failure








Chap

ter

6

90

Cell types









Cardiac stem cells










Skeletal myoblasts








Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

91



















Paracrine effects











Chap

ter

6

92


in-vivo trials

















Cell delivery











Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

93




















Considerations






Chap

ter

6

94









Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

95












issues

Conclusion




Chap

ter

6

96

References


















Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

97



Chap

ter

6

98




















alphabeti cal order


7

Chap

ter

7

100

Abstract

Objective



Background




Methods






Results








Conclusion




HEB

E pi

lot

101

Introduction




















Methods







Chap

ter

7

102
































HEB

E pi

lot

103































Chap

ter

7

104











Results








HEB

E pi

lot

105



Cell infusion












Chap

ter

7

106





Follow-up















ECG monitoring




HEB

E pi

lot

107












Chap

ter

7

108











LV left ventricular






enhancement

HEB

E pi

lot

109







Discussion















Chap

ter

7

110
































HEB

E pi

lot

111
































Chap

ter

7

112





















HEB

E pi

lot

113

References

















Chap

ter

7

114
























alphabeti cal order







Am Heart J 2006 Sep152(3)434-41

8

Chap

ter

8

116

Abstract

Background






Methods













Implications




HEB

E pr

otoc

ol

117

Introduction







been advocated(1-4)

Background











Initial experience









Chap

ter

8

118











Mononuclear cells







sub-population(15)









HEB

E pr

otoc

ol

119

Tabl

e 1

Ove

rvie

w o

f stu

dies

of i

ntra

-cor

onar

y in

fusi

on o

f aut

olog

ous

bone

mar

row

in p

atien

ts a

fter

acu

te m

yoca

rdia

l inf

arcti

on

Stud

yN

Des

ign

Day

s aft

er M

IFo

llow

-up

(mon

ths)

Stat

usRe

sults

Stau

er e

t al(

10)

20Se

quen

tial B

MC

(10)

than

co

ntro

l (10

) Si

ngle

cen

ter

83

Publ

ishe

dD

ecre

ased

infa

rct r

egio

n an

d ES

V on

LV-

angi

o In

crea

sed

regi

onal

con

trac

tility

on

LV-a

ngio

Impr

oved

per

fusi

on o

n sc

intig

raph

yIn

crea

sed

stro

ke v

olum

e in

dex

on R

V-ca

thet

eris

ation

Scha

chin

ger

et a

l ldquoT

OPC

ARE

-A

MIrdquo

(11)

59

Rand

omiz

ed

BMC

(29)

vs

CPC

(30)

O

pen-

labe

l Si

ngle

cen

ter

512

Publ

ishe

dD

ecre

ased

ESV

on

LV-a

ngio

In

crea

sed

LVEF

on

LV-a

ngio

and

MRI

Wol

lert

et a

l ldquoB

OO

STrdquo(

14)

60Ra

ndom

ized

BM

C (3

0) v

s C

ontr

ol (3

0)

Ope

n la

bel

Sing

le c

ente

r

56

Publ

ishe

dIn

crea

sed

LVEF

on

MRI

Fern

aacutende

z-Av

ileacutes

et a

l(16

)20

Non

-ran

dom

ized

Si

ngle

cen

ter

1411

Pu

blis

hed

Incr

ease

d LV

EF o

n M

RIIn

crea

sed

regi

onal

con

trac

tility

on

MRI

Jans

sens

et a

l66

Rand

omiz

ed

BMC

(32)

vs

con

trol

(34)

D

oubl

e bl

ind

Sin

gle

cent

er

14

Pres

ente

d at

co

ngre

ssD

ecre

ased

infa

rct s

ize

on L

CE im

ages

on

MRI

MI =

myo

card

ial i

nfar

ction

BM

C =

mon

onuc

lear

bon

e m

arro

w c

ells

ESV

= e

nd-s

ysto

lic v

olum

e L

V =

left

ven

tric

ular

RV

= ri

ght

vent

ricu

lar

CPC

= cu

ltiva

ted

circ

ulati

ng p

roge

nito

r ce

lls fr

om p

erip

hera

l blo

od L

VEF

= le

ft v

entr

icul

ar e

jecti

on fr

actio

n M

RI =

mag

netic

res

onan

ce im

agin

g L

CE =

late

co

ntra

st-e

nhan

ced

Chap

ter

8

120

Methods

Overview







in Figure 1





HEB

E pr

otoc

ol

121




















Chap

ter

8

122





HEB

E pr

otoc

ol

123
































Chap

ter

8

124



Echocardiography
















Cell material










HEB

E pr

otoc

ol

125













Follow-up









12 months follow-up

End points





Chap

ter

8

126












endpoint










HEB

E pr

otoc

ol

127






drawn












Current status




Discussion





Chap

ter

8

128
































HEB

E pr

otoc

ol

129










Implications




Appendix

Executive committee















Chap

ter

8

130









HEB

E pr

otoc

ol

131

References

















Chap

ter

8

132




















Netherlands



Submitt ed

9

Chap

ter

9

134

Abstract

Background



conflicting results

Methods










Results









Conclusions




HEB

E st

udy

135

Introduction




















Methods







Chap

ter

9

136































HEB

E st

udy

137















images










End point measures





Chap

ter

9

138














fraction(14)











HEB

E st

udy

139

Results


























Chap

ter

9

140


Group

(N = 69)


(N = 66)

Control Group

(N = 65)



HEB

E st

udy

141







Chap

ter

9

142



HEB

E st

udy

143


Group

(N = 69)


(N = 66)

Control Group

(N = 65)


0 1 ndash


1 2 ndash


1 3 0


3 6 4


4 9 6


0 5 2




Chap

ter

9

144



















group (Table 3)

Clinical outcome











HEB

E st

udy

145

Figu

re 2

Esti

mati

on o

f the

effe

ct o

f int

raco

rona

ry in

jecti

on o

f mon

onuc

lear

cel

ls fr

om b

one

mar

row

or

peri

pher

al b

lood

on

left

ven

tric

ular

eje

ction

fr

actio

nLV

den

otes

left

ven

tric

ular

In

the

left

pan

el th

e lin

es re

pres

ent t

he c

hang

e ob

serv

ed in

indi

vidu

al p

atien

ts a

nd th

e sq

uare

s re

pres

ent t

he m

ean

with

th

e st

anda

rd d

evia

tion

In th

e ri

ght p

anel

the

mea

n ch

ange

bet

wee

n ba

selin

e an

d fo

llow

-up

at 4

mon

ths

is p

rese

nted

with

the

stan

dard

err

or

Chap

ter

9

146

Tabl

e 3

Qua

ntita

tive

mea

sure

s of

regi

onal

and

glo

bal l

eft v

entr

icul

ar fu

nctio

n v

olum

es m

ass

and

infa

rct s

ize

by m

agne

tic re

sona

nce

imag

ing

Bo

ne M

arro

w

Gro

upPe

riph

eral

Blo

od

Gro

upCo

ntro

l

Gro

upBo

ne M

arro

w v

s C

ontr

olPe

riph

eral

Blo

od v

s C

ontr

ol

(N =

67)

(N =

62)

(N =

60)

Trea

tmen

t eff

ect dagger

Estim

ate

(95

CI)

P va

lue

Trea

tmen

t eff

ect dagger

Estim

ate

(95

CI)

P va

lue

Prim

ary

end

poin

t ndash

D

ysfu

nctio

nal s

egm

ents

at

b

asel

ine

533

plusmn 1

96

575

plusmn 1

96

562

plusmn 1

84

D

ysfu

nctio

nal s

egm

ents

that

im

prov

ed d

urin

g fo

llow

-up

386

plusmn 2

47

368

plusmn 2

09

424

plusmn 1

87

ndash39

(ndash11

7 to

40

)0

33ndash5

3 (ndash

123

to 1

7)

014

Segm

enta

l wal

l thi

cken

ing

in

dysf

uncti

onal

seg

men

ts ndash

mm

B

asel

ine

119

plusmn 0

55

118

plusmn 0

49

114

plusmn 0

52

F

ollo

w-u

p2

31 plusmn

13

22

21 plusmn

12

12

31 plusmn

09

7

Cha

nge

112

plusmn 1

20

103

plusmn 0

99

118

plusmn 0

80

ndash00

6 (ndash

043

to 0

30)

073

ndash01

5 (ndash

048

to 0

17)

035

P

val

ue (b

asel

ine

vs 4

mon

ths)

lt00

01lt0

001

lt00

01LV

eje

ction

frac

tion

ndash

B

asel

ine

437

plusmn 9

041

7 plusmn

91

424

plusmn 8

3

Fol

low

-up

475

plusmn 9

946

0 plusmn

93

464

plusmn 9

2

Cha

nge

38

plusmn 7

44

2 plusmn

62

40

plusmn 5

80

1 (ndash

22

to 2

4)

094

01

(ndash2

0 to

22

)0

90

P v

alue

(bas

elin

e vs

4 m

onth

s)lt0

001

lt00

01lt0

001

LV e

nd-d

iast

olic

vol

ume

ndash m

lm

2

B

asel

ine

973

plusmn 1

40

980

plusmn 1

54

100

0 plusmn

169

F

ollo

w-u

p10

26

plusmn 19

110

34

plusmn 22

610

82

plusmn 24

6

Cha

nge

54

plusmn 13

45

3 plusmn

163

82

plusmn 13

5ndash2

5 (ndash

72

to 2

2)

029

ndash26

(ndash8

0 to

27

)0

33

P v

alue

(bas

elin

e vs

4 m

onth

s)0

002

001

lt00

01LV

end

-sys

tolic

vol

ume

ndash m

lm

2

B

asel

ine

554

plusmn 1

45

578

plusmn 1

59

581

plusmn 1

51

F

ollo

w-u

p54

9 plusmn

19

557

1 plusmn

21

659

3 plusmn

21

7

Cha

nge

ndash05

plusmn 1

34

ndash07

plusmn 1

44

12

plusmn 11

7ndash1

5 (ndash

59

to 3

0)

052

ndash19

(ndash6

6 to

28

)0

43

P v

alue

(bas

elin

e vs

4 m

onth

s)0

750

710

42

HEB

E st

udy

147

LV m

ass

ndash gr

m2

B

asel

ine

598

plusmn 1

22

596

plusmn 1

14

591

plusmn 1

19

F

ollo

w-u

p51

7 plusmn

10

551

3 plusmn

10

251

4 plusmn

10

6

Cha

nge

ndash80

plusmn 9

6ndash8

3 plusmn

79

ndash78

plusmn 7

6ndash0

03

(ndash2

6 to

26

)0

98ndash0

4 (ndash

28

to 2

0)

074

P

val

ue (b

asel

ine

vs 4

mon

ths)

lt00

01lt0

001

lt00

01In

farc

t siz

e ndash

gr Dagger

B

asel

ine

229

plusmn 1

26

211

plusmn 1

12

236

plusmn 1

38

F

ollo

w-u

p15

2 plusmn

82

132

plusmn 7

314

2 plusmn

89

C

hang

endash7

7 plusmn

85

ndash79

plusmn 6

5ndash9

4 plusmn

71

13

(ndash0

5 to

32

)0

160

4 (ndash

11

to 1

9)

062

P

val

ue (b

asel

ine

vs 4

mon

ths)

lt00

01lt0

001

lt00

01

Pl

us-m

inus

val

ues

are

mea

ns plusmn

SD

LV

deno

tes

left

ven

tric

ular

P v

alue

s fo

r th

e ch

ange

bet

wee

n ba

selin

e an

d fo

llow

-up

with

in e

ach

stud

y gr

oup

wer

e ca

lcul

ated

with

pai

red

Stud

entrsquos

t te

st

dagger Tr

eatm

ent e

ffect

and

P v

alue

s w

ere

dete

rmin

ed b

y an

alys

is o

f cov

aria

nce

Dagger Th

e an

alys

is in

clud

ed 5

8 pa

tient

s in

the

bone

mar

row

gro

up 5

7 in

the

peri

pher

al b

lood

gro

up a

nd 5

2 in

the

cont

rol g

roup

Chap

ter

9

148

Discussion






























HEB

E st

udy

149
































Chap

ter

9

150










with primary PCI

Funding








Appendix











HEB

E st

udy

151











Chap

ter

9

152

References
















HEB

E st

udy

153









Chap

ter

9

154


Chap

ter

10

156

Sum

mar

y an

d co

nclu

sion

s

157































Chap

ter

10

158






















patient discomfort

Sum

mar

y an

d co

nclu

sion

s

159

References












Chap

ter

10

160

Summary in Dutch


Sam

enva

tting

162

Sam

enva

tting

163






















overlevingskansen










Sam

enva

tting

164



















7)












Sam

enva

tting

165






het hart gemaakt










Sam

enva

tting

166

Dankwoord

Dan

kwoo

rd

168

Dan

kwoo

rd

169




bijzonder bedanken








op en rond de HC














Dan

kwoo

rd

170









cardiale imaging















Dan

kwoo

rd

171



















of Groningen

Contents

Chapter 1 9



Chapter 2 17




Chapter 3 29





Chapter 4 51





Chapter 5 67




Submitted


Chapter 6 87



Chapter 7 99




Chapter 8 115




Am Heart J 2006 Sep152(3)434-41

Chapter 9 133



Submitted

Chapter 10 155



Dankwoord 167


1

Chap

ter

1

10

Intr

oduc

tion

and

scop

e of

this

thes

is

11






























Chap

ter

1

12


















in this thesis

Intr

oduc

tion

and

scop

e of

this

thes

is

13

References















Chap

ter

1

14








PART 1











The Netherlands






2

Chap

ter

2

18

Abstract

Background





Methods



Results






Conclusion


for STEMI

LVEF

aft

er S

TEM

I

19

Background
















Methods











Chap

ter

2

20












1-2(13)









Results








LVEF

aft

er S

TEM

I

21












Chap

ter

2

22









LVEF

aft

er S

TEM

I

23














　

　Ⰰ　㔀

　Ⰰ

　Ⰰ㔀

　Ⰰ

　Ⰰ㔀

　Ⰰ䴀

攀愀渀

礀攀

愀爀洀

漀爀琀愀

氀椀琀礀

Chap

ter

2

24






3 year mortality






3 year mortality



LVEF

aft

er S

TEM

I

25

Discussion






























Chap

ter

2

26





















Conclusion



Abbreviations






LVEF

aft

er S

TEM

I

27

References















Chap

ter

2

28















3

Chap

ter

3

30

Abstract

Design



Setting



Background


Methods




MB)

Results





Conclusion



Q-w

aves

aft

er S

TEM

I

31

Introduction




























Chap

ter

3

32

Methods








1005 patients















Angiographic data



Q-w

aves

aft

er S

TEM

I

33

Follow-up





practitioner











TIMI risk score












Chap

ter

3

34











Results













Q-w

aves

aft

er S

TEM

I

35





Chap

ter

3

36

Tabl

e 1

Bas

elin

e cl

inic

al a

nd a

ngio

grap

hic

char

acte

risti

csTo

tal (

n =

933)

0-1

Q-w

aves

(n =

309

)2-

4 Q

-wav

es (n

= 4

98)

gt 4

Q-w

aves

(n =

126

)p

Age

yrs

mea

n (S

D)

627

(12

5)

601

(12

1)

633

(12

4)

665

(12

6)

lt 0

001

Mal

e se

x71

472

571

767

5n

s

His

tory

of M

I 9

77

210

712

0n

sH

isto

ry o

f PCI

71

62

79

64

ns

His

tory

of C

ABG

3

33

33

43

2n

sH

isto

ry o

f str

oke

38

27

41

57

ns

Dia

bete

s m

ellit

us

110

7

911

915

20

058

Hyp

erte

nsio

n35

631

035

945

50

018

Hyp

erlip

idem

ia25

426

524

426

8n

sCu

rren

t sm

oker

48

2

526

473

412

ns

Posi

tive

fam

ily h

isto

ry

464

53

544

536

90

004

Infa

rct l

ocati

onLM

08

06

04

24

ns

LAD

430

411

363

738

lt 0

001

CX16

621

615

75

50

002

RCA

385

361

464

167

lt 0

001

Gra

ft1

10

61

21

6n

s

Tota

l isc

hem

ic ti

me

in h

ours

(med

ian

+ IQ

R)3

1 [2

2 ndash

45

] 3

0 [2

1 ndash

42

] 3

5 [2

2 ndash

45

] 3

4 [2

3 ndash

61

] 0

050

Intr

a-ao

rtic

ballo

on p

ump

60

21

56

168

lt 0

001

Sten

t 92

795

291

292

4n

sG

lyco

prot

ein

IibI

IIa re

cept

or b

lock

er

926

93

591

489

7n

s

Q-w

aves

aft

er S

TEM

I

37

Tabl

e 1

Bas

elin

e cl

inic

al a

nd a

ngio

grap

hic

char

acte

risti

cs (c

ontin

ued)

TIM

I flow

bef

ore

prim

ary

PCI

049

931

557

066

7lt

000

11

104

89

100

159

ns

217

922

916

411

10

007

321

836

716

66

3lt

000

1

TIM

I flow

aft

er p

rim

ary

PCI

01

30

01

44

10

003

11

80

62

42

5n

s2

126

65

144

205

lt 0

001

384

392

981

872

9lt

000

1

Myo

card

ial b

lush

gra

de a

fter

pri

mar

y PC

I0

53

16

51

149

lt 0

001

116

010

917

324

00

002

239

841

838

838

8n

s3

389

457

388

223

lt 0

001

TIM

I ris

k sc

ore

28

24

28

39

lt 0

001

Max

CK

Ul

(med

ian

+ IQ

R)52

8 [2

32 ndash

13

20]

233

[89

ndash 45

5]65

8 [3

48 ndash

138

2]17

05 [1

022

ndash 28

79]

lt 0

001

Max

CK-

MB

Ul

(med

ian

+ IQ

R)57

[24

ndash 10

3]23

[8 ndash

51]

70 [3

8 ndash

115]

155

[85

ndash 26

3]lt

000

1

Dat

a ar

e di

spla

yed

as p

erce

ntag

e u

nles

s ot

herw

ise

indi

cate

d

Tota

l isc

hem

ic ti

me

deno

tes

time

betw

een

onse

t of s

ympt

oms

and

prim

ary

PCI

CABG

= c

oron

ary

arte

ry b

ypas

s gr

aftin

g LM

= le

ft m

ain

coro

nary

art

ery

CX =

circ

umfle

x co

rona

ry a

rter

y M

I = m

yoca

rdia

l inf

arcti

onCK

= c

reati

n ki

nase

PC

I = p

ercu

tane

ous

coro

nary

inte

rven

tion

CK-M

B =

crea

tin k

inas

e m

yoca

rdia

l ban

d RC

A =

rig

ht c

oron

ary

arte

ryIQ

R =

inte

rqua

rtile

-ran

ge

SD =

sta

ndar

d de

viati

onLA

D =

left

ant

erio

r de

scen

ding

cor

onar

y ar

tery

TI

MI =

thro

mbo

lysi

s in

myo

card

ial i

nfar

ction

Chap

ter

3

38













Q-w

aves

aft

er S

TEM

I

39


analysis

Univariate model


Multivariate model











Chap

ter

3

40





analysis

Univariate model



Univariate model



Q-w

aves

aft

er S

TEM

I

41



through 7














Chap

ter

3

42










Q-w

aves

aft

er S

TEM

I

43





(n = 699)



creatine kinase









band

Chap

ter

3

44







Q-w

aves

aft

er S

TEM

I

45













Chap

ter

3

46

Discussion



























decision-making




Q-w

aves

aft

er S

TEM

I

47







prediction models







particular reason)



















Chap

ter

3

48








post-procedural ECG





elucidated













Conclusion




Q-w

aves

aft

er S

TEM

I

49

References
















Chap

ter

3

50
























4

Chap

ter

4

52

Abstract

Objectives




Background




risk stratification

Methods






Results







Conclusions




ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

53

Introduction

















necrosis




resonance (CMR)

Methods

Patient population




Chap

ter

4

54








Electrocardiography






















ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

55































Chap

ter

4

56


the presence of MVO


Results












ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

57


44 (24ndash69)



Chap

ter

4

58








1)







Number of Q waves






ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI










Chap

ter

4

60










LVEF


Dys

func

t

segm

ents





Infa

rct

size


Tran

smur

al

segm

ents






ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

61






Pres

ence

of M

VO

















Chap

ter

4

62




Discussion


























ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

63





resolution



























Chap

ter

4

64






























ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

65

References
















Chap

ter

4

66























Submitt ed

5

Chap

ter

5

68

Abstract

Objective



Patients


Interventions






Results








Conclusions






5 N

OG

A c

ompa

red

to M

RI

69

Introduction






























Chap

ter

5

70







Methods

Patients




















5 N

OG

A c

ompa

red

to M

RI

71

















13


Chap

ter

5

72































5 N

OG

A c

ompa

red

to M

RI

73


























Chap

ter

5

74

Results








5 N

OG

A c

ompa

red

to M

RI

75










Chap

ter

5

76





Global parameters






5 N

OG

A c

ompa

red

to M

RI

77









Chap

ter

5

78

Regional parameters



















mapping parameters


5 N

OG

A c

ompa

red

to M

RI

79

Discussion




























by EEM(29)

Chap

ter

5

80
















Limitations













5 N

OG

A c

ompa

red

to M

RI

81








Chap

ter

5

82

References
















5 N

OG

A c

ompa

red

to M

RI

83















Chap

ter

5

84

PART 2










6

Chap

ter

6

88

Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

89

Introduction










cell-therapy











heart failure








Chap

ter

6

90

Cell types









Cardiac stem cells










Skeletal myoblasts








Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

91



















Paracrine effects











Chap

ter

6

92


in-vivo trials

















Cell delivery











Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

93




















Considerations






Chap

ter

6

94









Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

95












issues

Conclusion




Chap

ter

6

96

References


















Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

97



Chap

ter

6

98




















alphabeti cal order


7

Chap

ter

7

100

Abstract

Objective



Background




Methods






Results








Conclusion




HEB

E pi

lot

101

Introduction




















Methods







Chap

ter

7

102
































HEB

E pi

lot

103































Chap

ter

7

104











Results








HEB

E pi

lot

105



Cell infusion












Chap

ter

7

106





Follow-up















ECG monitoring




HEB

E pi

lot

107












Chap

ter

7

108











LV left ventricular






enhancement

HEB

E pi

lot

109







Discussion















Chap

ter

7

110
































HEB

E pi

lot

111
































Chap

ter

7

112





















HEB

E pi

lot

113

References

















Chap

ter

7

114
























alphabeti cal order







Am Heart J 2006 Sep152(3)434-41

8

Chap

ter

8

116

Abstract

Background






Methods













Implications




HEB

E pr

otoc

ol

117

Introduction







been advocated(1-4)

Background











Initial experience









Chap

ter

8

118











Mononuclear cells







sub-population(15)









HEB

E pr

otoc

ol

119

Tabl

e 1

Ove

rvie

w o

f stu

dies

of i

ntra

-cor

onar

y in

fusi

on o

f aut

olog

ous

bone

mar

row

in p

atien

ts a

fter

acu

te m

yoca

rdia

l inf

arcti

on

Stud

yN

Des

ign

Day

s aft

er M

IFo

llow

-up

(mon

ths)

Stat

usRe

sults

Stau

er e

t al(

10)

20Se

quen

tial B

MC

(10)

than

co

ntro

l (10

) Si

ngle

cen

ter

83

Publ

ishe

dD

ecre

ased

infa

rct r

egio

n an

d ES

V on

LV-

angi

o In

crea

sed

regi

onal

con

trac

tility

on

LV-a

ngio

Impr

oved

per

fusi

on o

n sc

intig

raph

yIn

crea

sed

stro

ke v

olum

e in

dex

on R

V-ca

thet

eris

ation

Scha

chin

ger

et a

l ldquoT

OPC

ARE

-A

MIrdquo

(11)

59

Rand

omiz

ed

BMC

(29)

vs

CPC

(30)

O

pen-

labe

l Si

ngle

cen

ter

512

Publ

ishe

dD

ecre

ased

ESV

on

LV-a

ngio

In

crea

sed

LVEF

on

LV-a

ngio

and

MRI

Wol

lert

et a

l ldquoB

OO

STrdquo(

14)

60Ra

ndom

ized

BM

C (3

0) v

s C

ontr

ol (3

0)

Ope

n la

bel

Sing

le c

ente

r

56

Publ

ishe

dIn

crea

sed

LVEF

on

MRI

Fern

aacutende

z-Av

ileacutes

et a

l(16

)20

Non

-ran

dom

ized

Si

ngle

cen

ter

1411

Pu

blis

hed

Incr

ease

d LV

EF o

n M

RIIn

crea

sed

regi

onal

con

trac

tility

on

MRI

Jans

sens

et a

l66

Rand

omiz

ed

BMC

(32)

vs

con

trol

(34)

D

oubl

e bl

ind

Sin

gle

cent

er

14

Pres

ente

d at

co

ngre

ssD

ecre

ased

infa

rct s

ize

on L

CE im

ages

on

MRI

MI =

myo

card

ial i

nfar

ction

BM

C =

mon

onuc

lear

bon

e m

arro

w c

ells

ESV

= e

nd-s

ysto

lic v

olum

e L

V =

left

ven

tric

ular

RV

= ri

ght

vent

ricu

lar

CPC

= cu

ltiva

ted

circ

ulati

ng p

roge

nito

r ce

lls fr

om p

erip

hera

l blo

od L

VEF

= le

ft v

entr

icul

ar e

jecti

on fr

actio

n M

RI =

mag

netic

res

onan

ce im

agin

g L

CE =

late

co

ntra

st-e

nhan

ced

Chap

ter

8

120

Methods

Overview







in Figure 1





HEB

E pr

otoc

ol

121




















Chap

ter

8

122





HEB

E pr

otoc

ol

123
































Chap

ter

8

124



Echocardiography
















Cell material










HEB

E pr

otoc

ol

125













Follow-up









12 months follow-up

End points





Chap

ter

8

126












endpoint










HEB

E pr

otoc

ol

127






drawn












Current status




Discussion





Chap

ter

8

128
































HEB

E pr

otoc

ol

129










Implications




Appendix

Executive committee















Chap

ter

8

130









HEB

E pr

otoc

ol

131

References

















Chap

ter

8

132




















Netherlands



Submitt ed

9

Chap

ter

9

134

Abstract

Background



conflicting results

Methods










Results









Conclusions




HEB

E st

udy

135

Introduction




















Methods







Chap

ter

9

136































HEB

E st

udy

137















images










End point measures





Chap

ter

9

138














fraction(14)











HEB

E st

udy

139

Results


























Chap

ter

9

140


Group

(N = 69)


(N = 66)

Control Group

(N = 65)



HEB

E st

udy

141







Chap

ter

9

142



HEB

E st

udy

143


Group

(N = 69)


(N = 66)

Control Group

(N = 65)


0 1 ndash


1 2 ndash


1 3 0


3 6 4


4 9 6


0 5 2




Chap

ter

9

144



















group (Table 3)

Clinical outcome











HEB

E st

udy

145

Figu

re 2

Esti

mati

on o

f the

effe

ct o

f int

raco

rona

ry in

jecti

on o

f mon

onuc

lear

cel

ls fr

om b

one

mar

row

or

peri

pher

al b

lood

on

left

ven

tric

ular

eje

ction

fr

actio

nLV

den

otes

left

ven

tric

ular

In

the

left

pan

el th

e lin

es re

pres

ent t

he c

hang

e ob

serv

ed in

indi

vidu

al p

atien

ts a

nd th

e sq

uare

s re

pres

ent t

he m

ean

with

th

e st

anda

rd d

evia

tion

In th

e ri

ght p

anel

the

mea

n ch

ange

bet

wee

n ba

selin

e an

d fo

llow

-up

at 4

mon

ths

is p

rese

nted

with

the

stan

dard

err

or

Chap

ter

9

146

Tabl

e 3

Qua

ntita

tive

mea

sure

s of

regi

onal

and

glo

bal l

eft v

entr

icul

ar fu

nctio

n v

olum

es m

ass

and

infa

rct s

ize

by m

agne

tic re

sona

nce

imag

ing

Bo

ne M

arro

w

Gro

upPe

riph

eral

Blo

od

Gro

upCo

ntro

l

Gro

upBo

ne M

arro

w v

s C

ontr

olPe

riph

eral

Blo

od v

s C

ontr

ol

(N =

67)

(N =

62)

(N =

60)

Trea

tmen

t eff

ect dagger

Estim

ate

(95

CI)

P va

lue

Trea

tmen

t eff

ect dagger

Estim

ate

(95

CI)

P va

lue

Prim

ary

end

poin

t ndash

D

ysfu

nctio

nal s

egm

ents

at

b

asel

ine

533

plusmn 1

96

575

plusmn 1

96

562

plusmn 1

84

D

ysfu

nctio

nal s

egm

ents

that

im

prov

ed d

urin

g fo

llow

-up

386

plusmn 2

47

368

plusmn 2

09

424

plusmn 1

87

ndash39

(ndash11

7 to

40

)0

33ndash5

3 (ndash

123

to 1

7)

014

Segm

enta

l wal

l thi

cken

ing

in

dysf

uncti

onal

seg

men

ts ndash

mm

B

asel

ine

119

plusmn 0

55

118

plusmn 0

49

114

plusmn 0

52

F

ollo

w-u

p2

31 plusmn

13

22

21 plusmn

12

12

31 plusmn

09

7

Cha

nge

112

plusmn 1

20

103

plusmn 0

99

118

plusmn 0

80

ndash00

6 (ndash

043

to 0

30)

073

ndash01

5 (ndash

048

to 0

17)

035

P

val

ue (b

asel

ine

vs 4

mon

ths)

lt00

01lt0

001

lt00

01LV

eje

ction

frac

tion

ndash

B

asel

ine

437

plusmn 9

041

7 plusmn

91

424

plusmn 8

3

Fol

low

-up

475

plusmn 9

946

0 plusmn

93

464

plusmn 9

2

Cha

nge

38

plusmn 7

44

2 plusmn

62

40

plusmn 5

80

1 (ndash

22

to 2

4)

094

01

(ndash2

0 to

22

)0

90

P v

alue

(bas

elin

e vs

4 m

onth

s)lt0

001

lt00

01lt0

001

LV e

nd-d

iast

olic

vol

ume

ndash m

lm

2

B

asel

ine

973

plusmn 1

40

980

plusmn 1

54

100

0 plusmn

169

F

ollo

w-u

p10

26

plusmn 19

110

34

plusmn 22

610

82

plusmn 24

6

Cha

nge

54

plusmn 13

45

3 plusmn

163

82

plusmn 13

5ndash2

5 (ndash

72

to 2

2)

029

ndash26

(ndash8

0 to

27

)0

33

P v

alue

(bas

elin

e vs

4 m

onth

s)0

002

001

lt00

01LV

end

-sys

tolic

vol

ume

ndash m

lm

2

B

asel

ine

554

plusmn 1

45

578

plusmn 1

59

581

plusmn 1

51

F

ollo

w-u

p54

9 plusmn

19

557

1 plusmn

21

659

3 plusmn

21

7

Cha

nge

ndash05

plusmn 1

34

ndash07

plusmn 1

44

12

plusmn 11

7ndash1

5 (ndash

59

to 3

0)

052

ndash19

(ndash6

6 to

28

)0

43

P v

alue

(bas

elin

e vs

4 m

onth

s)0

750

710

42

HEB

E st

udy

147

LV m

ass

ndash gr

m2

B

asel

ine

598

plusmn 1

22

596

plusmn 1

14

591

plusmn 1

19

F

ollo

w-u

p51

7 plusmn

10

551

3 plusmn

10

251

4 plusmn

10

6

Cha

nge

ndash80

plusmn 9

6ndash8

3 plusmn

79

ndash78

plusmn 7

6ndash0

03

(ndash2

6 to

26

)0

98ndash0

4 (ndash

28

to 2

0)

074

P

val

ue (b

asel

ine

vs 4

mon

ths)

lt00

01lt0

001

lt00

01In

farc

t siz

e ndash

gr Dagger

B

asel

ine

229

plusmn 1

26

211

plusmn 1

12

236

plusmn 1

38

F

ollo

w-u

p15

2 plusmn

82

132

plusmn 7

314

2 plusmn

89

C

hang

endash7

7 plusmn

85

ndash79

plusmn 6

5ndash9

4 plusmn

71

13

(ndash0

5 to

32

)0

160

4 (ndash

11

to 1

9)

062

P

val

ue (b

asel

ine

vs 4

mon

ths)

lt00

01lt0

001

lt00

01

Pl

us-m

inus

val

ues

are

mea

ns plusmn

SD

LV

deno

tes

left

ven

tric

ular

P v

alue

s fo

r th

e ch

ange

bet

wee

n ba

selin

e an

d fo

llow

-up

with

in e

ach

stud

y gr

oup

wer

e ca

lcul

ated

with

pai

red

Stud

entrsquos

t te

st

dagger Tr

eatm

ent e

ffect

and

P v

alue

s w

ere

dete

rmin

ed b

y an

alys

is o

f cov

aria

nce

Dagger Th

e an

alys

is in

clud

ed 5

8 pa

tient

s in

the

bone

mar

row

gro

up 5

7 in

the

peri

pher

al b

lood

gro

up a

nd 5

2 in

the

cont

rol g

roup

Chap

ter

9

148

Discussion






























HEB

E st

udy

149
































Chap

ter

9

150










with primary PCI

Funding








Appendix











HEB

E st

udy

151











Chap

ter

9

152

References
















HEB

E st

udy

153









Chap

ter

9

154


Chap

ter

10

156

Sum

mar

y an

d co

nclu

sion

s

157































Chap

ter

10

158






















patient discomfort

Sum

mar

y an

d co

nclu

sion

s

159

References












Chap

ter

10

160

Summary in Dutch


Sam

enva

tting

162

Sam

enva

tting

163






















overlevingskansen










Sam

enva

tting

164



















7)












Sam

enva

tting

165






het hart gemaakt










Sam

enva

tting

166

Dankwoord

Dan

kwoo

rd

168

Dan

kwoo

rd

169




bijzonder bedanken








op en rond de HC














Dan

kwoo

rd

170









cardiale imaging















Dan

kwoo

rd

171











Contents

Chapter 1 9



Chapter 2 17




Chapter 3 29





Chapter 4 51





Chapter 5 67




Submitted


Chapter 6 87



Chapter 7 99




Chapter 8 115




Am Heart J 2006 Sep152(3)434-41

Chapter 9 133



Submitted

Chapter 10 155



Dankwoord 167


1

Chap

ter

1

10

Intr

oduc

tion

and

scop

e of

this

thes

is

11






























Chap

ter

1

12


















in this thesis

Intr

oduc

tion

and

scop

e of

this

thes

is

13

References















Chap

ter

1

14








PART 1











The Netherlands






2

Chap

ter

2

18

Abstract

Background





Methods



Results






Conclusion


for STEMI

LVEF

aft

er S

TEM

I

19

Background
















Methods











Chap

ter

2

20












1-2(13)









Results








LVEF

aft

er S

TEM

I

21












Chap

ter

2

22









LVEF

aft

er S

TEM

I

23














　

　Ⰰ　㔀

　Ⰰ

　Ⰰ㔀

　Ⰰ

　Ⰰ㔀

　Ⰰ䴀

攀愀渀

礀攀

愀爀洀

漀爀琀愀

氀椀琀礀

Chap

ter

2

24






3 year mortality






3 year mortality



LVEF

aft

er S

TEM

I

25

Discussion






























Chap

ter

2

26





















Conclusion



Abbreviations






LVEF

aft

er S

TEM

I

27

References















Chap

ter

2

28















3

Chap

ter

3

30

Abstract

Design



Setting



Background


Methods




MB)

Results





Conclusion



Q-w

aves

aft

er S

TEM

I

31

Introduction




























Chap

ter

3

32

Methods








1005 patients















Angiographic data



Q-w

aves

aft

er S

TEM

I

33

Follow-up





practitioner











TIMI risk score












Chap

ter

3

34











Results













Q-w

aves

aft

er S

TEM

I

35





Chap

ter

3

36

Tabl

e 1

Bas

elin

e cl

inic

al a

nd a

ngio

grap

hic

char

acte

risti

csTo

tal (

n =

933)

0-1

Q-w

aves

(n =

309

)2-

4 Q

-wav

es (n

= 4

98)

gt 4

Q-w

aves

(n =

126

)p

Age

yrs

mea

n (S

D)

627

(12

5)

601

(12

1)

633

(12

4)

665

(12

6)

lt 0

001

Mal

e se

x71

472

571

767

5n

s

His

tory

of M

I 9

77

210

712

0n

sH

isto

ry o

f PCI

71

62

79

64

ns

His

tory

of C

ABG

3

33

33

43

2n

sH

isto

ry o

f str

oke

38

27

41

57

ns

Dia

bete

s m

ellit

us

110

7

911

915

20

058

Hyp

erte

nsio

n35

631

035

945

50

018

Hyp

erlip

idem

ia25

426

524

426

8n

sCu

rren

t sm

oker

48

2

526

473

412

ns

Posi

tive

fam

ily h

isto

ry

464

53

544

536

90

004

Infa

rct l

ocati

onLM

08

06

04

24

ns

LAD

430

411

363

738

lt 0

001

CX16

621

615

75

50

002

RCA

385

361

464

167

lt 0

001

Gra

ft1

10

61

21

6n

s

Tota

l isc

hem

ic ti

me

in h

ours

(med

ian

+ IQ

R)3

1 [2

2 ndash

45

] 3

0 [2

1 ndash

42

] 3

5 [2

2 ndash

45

] 3

4 [2

3 ndash

61

] 0

050

Intr

a-ao

rtic

ballo

on p

ump

60

21

56

168

lt 0

001

Sten

t 92

795

291

292

4n

sG

lyco

prot

ein

IibI

IIa re

cept

or b

lock

er

926

93

591

489

7n

s

Q-w

aves

aft

er S

TEM

I

37

Tabl

e 1

Bas

elin

e cl

inic

al a

nd a

ngio

grap

hic

char

acte

risti

cs (c

ontin

ued)

TIM

I flow

bef

ore

prim

ary

PCI

049

931

557

066

7lt

000

11

104

89

100

159

ns

217

922

916

411

10

007

321

836

716

66

3lt

000

1

TIM

I flow

aft

er p

rim

ary

PCI

01

30

01

44

10

003

11

80

62

42

5n

s2

126

65

144

205

lt 0

001

384

392

981

872

9lt

000

1

Myo

card

ial b

lush

gra

de a

fter

pri

mar

y PC

I0

53

16

51

149

lt 0

001

116

010

917

324

00

002

239

841

838

838

8n

s3

389

457

388

223

lt 0

001

TIM

I ris

k sc

ore

28

24

28

39

lt 0

001

Max

CK

Ul

(med

ian

+ IQ

R)52

8 [2

32 ndash

13

20]

233

[89

ndash 45

5]65

8 [3

48 ndash

138

2]17

05 [1

022

ndash 28

79]

lt 0

001

Max

CK-

MB

Ul

(med

ian

+ IQ

R)57

[24

ndash 10

3]23

[8 ndash

51]

70 [3

8 ndash

115]

155

[85

ndash 26

3]lt

000

1

Dat

a ar

e di

spla

yed

as p

erce

ntag

e u

nles

s ot

herw

ise

indi

cate

d

Tota

l isc

hem

ic ti

me

deno

tes

time

betw

een

onse

t of s

ympt

oms

and

prim

ary

PCI

CABG

= c

oron

ary

arte

ry b

ypas

s gr

aftin

g LM

= le

ft m

ain

coro

nary

art

ery

CX =

circ

umfle

x co

rona

ry a

rter

y M

I = m

yoca

rdia

l inf

arcti

onCK

= c

reati

n ki

nase

PC

I = p

ercu

tane

ous

coro

nary

inte

rven

tion

CK-M

B =

crea

tin k

inas

e m

yoca

rdia

l ban

d RC

A =

rig

ht c

oron

ary

arte

ryIQ

R =

inte

rqua

rtile

-ran

ge

SD =

sta

ndar

d de

viati

onLA

D =

left

ant

erio

r de

scen

ding

cor

onar

y ar

tery

TI

MI =

thro

mbo

lysi

s in

myo

card

ial i

nfar

ction

Chap

ter

3

38













Q-w

aves

aft

er S

TEM

I

39


analysis

Univariate model


Multivariate model











Chap

ter

3

40





analysis

Univariate model



Univariate model



Q-w

aves

aft

er S

TEM

I

41



through 7














Chap

ter

3

42










Q-w

aves

aft

er S

TEM

I

43





(n = 699)



creatine kinase









band

Chap

ter

3

44







Q-w

aves

aft

er S

TEM

I

45













Chap

ter

3

46

Discussion



























decision-making




Q-w

aves

aft

er S

TEM

I

47







prediction models







particular reason)



















Chap

ter

3

48








post-procedural ECG





elucidated













Conclusion




Q-w

aves

aft

er S

TEM

I

49

References
















Chap

ter

3

50
























4

Chap

ter

4

52

Abstract

Objectives




Background




risk stratification

Methods






Results







Conclusions




ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

53

Introduction

















necrosis




resonance (CMR)

Methods

Patient population




Chap

ter

4

54








Electrocardiography






















ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

55































Chap

ter

4

56


the presence of MVO


Results












ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

57


44 (24ndash69)



Chap

ter

4

58








1)







Number of Q waves






ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI










Chap

ter

4

60










LVEF


Dys

func

t

segm

ents





Infa

rct

size


Tran

smur

al

segm

ents






ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

61






Pres

ence

of M

VO

















Chap

ter

4

62




Discussion


























ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

63





resolution



























Chap

ter

4

64






























ST-s

egm

ent c

hang

es a

nd Q

-wav

es a

fter

STE

MI

65

References
















Chap

ter

4

66























Submitt ed

5

Chap

ter

5

68

Abstract

Objective



Patients


Interventions






Results








Conclusions






5 N

OG

A c

ompa

red

to M

RI

69

Introduction






























Chap

ter

5

70







Methods

Patients




















5 N

OG

A c

ompa

red

to M

RI

71

















13


Chap

ter

5

72































5 N

OG

A c

ompa

red

to M

RI

73


























Chap

ter

5

74

Results








5 N

OG

A c

ompa

red

to M

RI

75










Chap

ter

5

76





Global parameters






5 N

OG

A c

ompa

red

to M

RI

77









Chap

ter

5

78

Regional parameters



















mapping parameters


5 N

OG

A c

ompa

red

to M

RI

79

Discussion




























by EEM(29)

Chap

ter

5

80
















Limitations













5 N

OG

A c

ompa

red

to M

RI

81








Chap

ter

5

82

References
















5 N

OG

A c

ompa

red

to M

RI

83















Chap

ter

5

84

PART 2










6

Chap

ter

6

88

Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

89

Introduction










cell-therapy











heart failure








Chap

ter

6

90

Cell types









Cardiac stem cells










Skeletal myoblasts








Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

91



















Paracrine effects











Chap

ter

6

92


in-vivo trials

















Cell delivery











Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

93




















Considerations






Chap

ter

6

94









Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

95












issues

Conclusion




Chap

ter

6

96

References


















Ove

rvie

w o

f cel

l the

rapy

aft

er S

TEM

I

97



Chap

ter

6

98




















alphabeti cal order


7

Chap

ter

7

100

Abstract

Objective



Background




Methods






Results








Conclusion




HEB

E pi

lot

101

Introduction




















Methods







Chap

ter

7

102
































HEB

E pi

lot

103































Chap

ter

7

104











Results








HEB

E pi

lot

105



Cell infusion












Chap

ter

7

106





Follow-up















ECG monitoring




HEB

E pi

lot

107












Chap

ter

7

108











LV left ventricular






enhancement

HEB

E pi

lot

109







Discussion















Chap

ter

7

110
































HEB

E pi

lot

111
































Chap

ter

7

112





















HEB

E pi

lot

113

References

















Chap

ter

7

114
























alphabeti cal order







Am Heart J 2006 Sep152(3)434-41

8

Chap

ter

8

116

Abstract

Background






Methods













Implications




HEB

E pr

otoc

ol

117

Introduction







been advocated(1-4)

Background











Initial experience









Chap

ter

8

118











Mononuclear cells







sub-population(15)









HEB

E pr

otoc

ol

119

Tabl

e 1

Ove

rvie

w o

f stu

dies

of i

ntra

-cor

onar

y in

fusi

on o

f aut

olog

ous

bone

mar

row

in p

atien

ts a

fter

acu

te m

yoca

rdia

l inf

arcti

on

Stud

yN

Des

ign

Day

s aft

er M

IFo

llow

-up

(mon

ths)

Stat

usRe

sults

Stau

er e

t al(

10)

20Se

quen

tial B

MC

(10)

than

co

ntro

l (10

) Si

ngle

cen

ter

83

Publ

ishe

dD

ecre

ased

infa

rct r

egio

n an

d ES

V on

LV-

angi

o In

crea

sed

regi

onal

con

trac

tility

on

LV-a

ngio

Impr

oved

per

fusi

on o

n sc

intig

raph

yIn

crea

sed

stro

ke v

olum

e in

dex

on R

V-ca

thet

eris

ation

Scha

chin

ger

et a

l ldquoT

OPC

ARE

-A

MIrdquo

(11)

59

Rand

omiz

ed

BMC

(29)

vs

CPC

(30)

O

pen-

labe

l Si

ngle

cen

ter

512

Publ

ishe

dD

ecre

ased

ESV

on

LV-a

ngio

In

crea

sed

LVEF

on

LV-a

ngio

and

MRI

Wol

lert

et a

l ldquoB

OO

STrdquo(

14)

60Ra

ndom

ized

BM

C (3

0) v

s C

ontr

ol (3

0)

Ope

n la

bel

Sing

le c

ente

r

56

Publ

ishe

dIn

crea

sed

LVEF

on

MRI

Fern

aacutende

z-Av

ileacutes

et a

l(16

)20

Non

-ran

dom

ized

Si

ngle

cen

ter

1411

Pu

blis

hed

Incr

ease

d LV

EF o

n M

RIIn

crea

sed

regi

onal

con

trac

tility

on

MRI

Jans

sens

et a

l66

Rand

omiz

ed

BMC

(32)

vs

con

trol

(34)

D

oubl

e bl

ind

Sin

gle

cent

er

14

Pres

ente

d at

co

ngre

ssD

ecre

ased

infa

rct s

ize

on L

CE im

ages

on

MRI

MI =

myo

card

ial i

nfar

ction

BM

C =

mon

onuc

lear

bon

e m

arro

w c

ells

ESV

= e

nd-s

ysto

lic v

olum

e L

V =

left

ven

tric

ular

RV

= ri

ght

vent

ricu

lar

CPC

= cu

ltiva

ted

circ

ulati

ng p

roge

nito

r ce

lls fr

om p

erip

hera

l blo

od L

VEF

= le

ft v

entr

icul

ar e

jecti

on fr

actio

n M

RI =

mag

netic

res

onan

ce im

agin

g L

CE =

late

co

ntra

st-e

nhan

ced

Chap

ter

8

120

Methods

Overview







in Figure 1





HEB

E pr

otoc

ol

121




















Chap

ter

8

122





HEB

E pr

otoc

ol

123
































Chap

ter

8

124



Echocardiography
















Cell material










HEB

E pr

otoc

ol

125













Follow-up









12 months follow-up

End points





Chap

ter

8

126












endpoint










HEB

E pr

otoc

ol

127






drawn












Current status




Discussion





Chap

ter

8

128
































HEB

E pr

otoc

ol

129










Implications




Appendix

Executive committee















Chap

ter

8

130









HEB

E pr

otoc

ol

131

References

















Chap

ter

8

132




















Netherlands



Submitt ed

9

Chap

ter

9

134

Abstract

Background



conflicting results

Methods










Results









Conclusions




HEB

E st

udy

135

Introduction




















Methods







Chap

ter

9

136































HEB

E st

udy

137















images










End point measures





Chap

ter

9

138














fraction(14)











HEB

E st

udy

139

Results


























Chap

ter

9

140


Group

(N = 69)


(N = 66)

Control Group

(N = 65)



HEB

E st

udy

141







Chap

ter

9

142



HEB

E st

udy

143


Group

(N = 69)


(N = 66)

Control Group

(N = 65)


0 1 ndash


1 2 ndash


1 3 0


3 6 4


4 9 6


0 5 2




Chap

ter

9

144



















group (Table 3)

Clinical outcome











HEB

E st

udy

145

Figu

re 2

Esti

mati

on o

f the

effe

ct o

f int

raco

rona

ry in

jecti

on o

f mon

onuc

lear

cel

ls fr

om b

one

mar

row

or

peri

pher

al b

lood

on

left

ven

tric

ular

eje

ction

fr

actio

nLV

den

otes

left

ven

tric

ular

In

the

left

pan

el th

e lin

es re

pres

ent t

he c

hang

e ob

serv

ed in

indi

vidu

al p

atien

ts a

nd th

e sq

uare

s re

pres

ent t

he m

ean

with

th

e st

anda

rd d

evia

tion

In th

e ri

ght p

anel

the

mea

n ch

ange

bet

wee

n ba

selin

e an

d fo

llow

-up

at 4

mon

ths

is p

rese

nted

with

the

stan

dard

err

or

Chap

ter

9

146

Tabl

e 3

Qua

ntita

tive

mea

sure

s of

regi

onal

and

glo

bal l

eft v

entr

icul

ar fu

nctio

n v

olum

es m

ass

and

infa

rct s

ize

by m

agne

tic re

sona

nce

imag

ing

Bo

ne M

arro

w

Gro

upPe

riph

eral

Blo

od

Gro

upCo

ntro

l

Gro

upBo

ne M

arro

w v

s C

ontr

olPe

riph

eral

Blo

od v

s C

ontr

ol

(N =

67)

(N =

62)

(N =

60)

Trea

tmen

t eff

ect dagger

Estim

ate

(95

CI)

P va

lue

Trea

tmen

t eff

ect dagger

Estim

ate

(95

CI)

P va

lue

Prim

ary

end

poin

t ndash

D

ysfu

nctio

nal s

egm

ents

at

b

asel

ine

533

plusmn 1

96

575

plusmn 1

96

562

plusmn 1

84

D

ysfu

nctio

nal s

egm

ents

that

im

prov

ed d

urin

g fo

llow

-up

386

plusmn 2

47

368

plusmn 2

09

424

plusmn 1

87

ndash39

(ndash11

7 to

40

)0

33ndash5

3 (ndash

123

to 1

7)

014

Segm

enta

l wal

l thi

cken

ing

in

dysf

uncti

onal

seg

men

ts ndash

mm

B

asel

ine

119

plusmn 0

55

118

plusmn 0

49

114

plusmn 0

52

F

ollo

w-u

p2

31 plusmn

13

22

21 plusmn

12

12

31 plusmn

09

7

Cha

nge

112

plusmn 1

20

103

plusmn 0

99

118

plusmn 0

80

ndash00

6 (ndash

043

to 0

30)

073

ndash01

5 (ndash

048

to 0

17)

035

P

val

ue (b

asel

ine

vs 4

mon

ths)

lt00

01lt0

001

lt00

01LV

eje

ction

frac

tion

ndash

B

asel

ine

437

plusmn 9

041

7 plusmn

91

424

plusmn 8

3

Fol

low

-up

475

plusmn 9

946

0 plusmn

93

464

plusmn 9

2

Cha

nge

38

plusmn 7

44

2 plusmn

62

40

plusmn 5

80

1 (ndash

22

to 2

4)

094

01

(ndash2

0 to

22

)0

90

P v

alue

(bas

elin

e vs

4 m

onth

s)lt0

001

lt00

01lt0

001

LV e

nd-d

iast

olic

vol

ume

ndash m

lm

2

B

asel

ine

973

plusmn 1

40

980

plusmn 1

54

100

0 plusmn

169

F

ollo

w-u

p10

26

plusmn 19

110

34

plusmn 22

610

82

plusmn 24

6

Cha

nge

54

plusmn 13

45

3 plusmn

163

82

plusmn 13

5ndash2

5 (ndash

72

to 2

2)

029

ndash26

(ndash8

0 to

27

)0

33

P v

alue

(bas

elin

e vs

4 m

onth

s)0

002

001

lt00

01LV

end

-sys

tolic

vol

ume

ndash m

lm

2

B

asel

ine

554

plusmn 1

45

578

plusmn 1

59

581

plusmn 1

51

F

ollo

w-u

p54

9 plusmn

19

557

1 plusmn

21

659

3 plusmn

21

7

Cha

nge

ndash05

plusmn 1

34

ndash07

plusmn 1

44

12

plusmn 11

7ndash1

5 (ndash

59

to 3

0)

052

ndash19

(ndash6

6 to

28

)0

43

P v

alue

(bas

elin

e vs

4 m

onth

s)0

750

710

42

HEB

E st

udy

147

LV m

ass

ndash gr

m2

B

asel

ine

598

plusmn 1

22

596

plusmn 1

14

591

plusmn 1

19

F

ollo

w-u

p51

7 plusmn

10

551

3 plusmn

10

251

4 plusmn

10

6

Cha

nge

ndash80

plusmn 9

6ndash8

3 plusmn

79

ndash78

plusmn 7

6ndash0

03

(ndash2

6 to

26

)0

98ndash0

4 (ndash

28

to 2

0)

074

P

val

ue (b

asel

ine

vs 4

mon

ths)

lt00

01lt0

001

lt00

01In

farc

t siz

e ndash

gr Dagger

B

asel

ine

229

plusmn 1

26

211

plusmn 1

12

236

plusmn 1

38

F

ollo

w-u

p15

2 plusmn

82

132

plusmn 7

314

2 plusmn

89

C

hang

endash7

7 plusmn

85

ndash79

plusmn 6

5ndash9

4 plusmn

71

13

(ndash0

5 to

32

)0

160

4 (ndash

11

to 1

9)

062

P

val

ue (b

asel

ine

vs 4

mon

ths)

lt00

01lt0

001

lt00

01

Pl

us-m

inus

val

ues

are

mea

ns plusmn

SD

LV

deno

tes

left

ven

tric

ular

P v

alue

s fo

r th

e ch

ange

bet

wee

n ba

selin

e an

d fo

llow

-up

with

in e

ach

stud

y gr

oup

wer

e ca

lcul

ated

with

pai

red

Stud

entrsquos

t te

st

dagger Tr

eatm

ent e

ffect

and

P v

alue

s w

ere

dete

rmin

ed b

y an

alys

is o

f cov

aria

nce

Dagger Th

e an

alys

is in

clud

ed 5

8 pa

tient

s in

the

bone

mar

row

gro

up 5

7 in

the

peri

pher

al b

lood

gro

up a

nd 5

2 in

the

cont

rol g

roup

Chap

ter

9

148

Discussion






























HEB

E st

udy

149
































Chap

ter

9

150










with primary PCI

Funding








Appendix











HEB

E st

udy

151











Chap

ter

9

152

References
















HEB

E st

udy

153









Chap

ter

9

154


Chap

ter

10

156

Sum

mar

y an

d co

nclu

sion

s

157































Chap

ter

10

158






















patient discomfort

Sum

mar

y an

d co

nclu

sion

s

159

References












Chap

ter

10

160

Summary in Dutch


Sam

enva

tting

162

Sam

enva

tting

163






















overlevingskansen










Sam

enva

tting

164



















7)












Sam

enva

tting

165






het hart gemaakt










Sam

enva

tting

166

Dankwoord

Dan

kwoo

rd

168

Dan

kwoo

rd

169




bijzonder bedanken








op en rond de HC














Dan

kwoo

rd

170









cardiale imaging















Dan

kwoo

rd

171











university of groningen left ventricular function after

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