Saverio Iacopino, FACC, Saverio Iacopino, FACC, FESCFESC
SantSant’’Anna HospitalAnna Hospital CatanzaroCatanzaro
Prognostic Indicators and Cardiac Remodeling
After CRT
Indications of CRT
Symptoms (Class I, level A)Hospitalizations (Class I, level A)Mortality (Class I, level B)
CRT using BIV pacing can be considered in patients with reduced EF and ventricular dyssynchrony (QRS widht > 120 msec), who remain symptomatic (NYHA III-IV) despite optimal medical therapy to improve:
ESC Guidelines
Prevalence and Prognosis of Ventricular Dysynchrony
Ventricular dysynchrony impairs diastolic and systolic function 4-6:Reduced LV filling time; Increased mitral regurgitation; Depressed dP/dt
4. Grines, et al. Circulation 1989;79:845-53 5. Xiao, et al. Br Heart J 1991;66:443-7 6. Xiao et al. Br Heart J 1992;68:403-7
Increased All-Cause Mortality with Wide QRS at 45 Months (3)
34%
49%
QRS < 120 ms
QRS >120 ms
3. Iuliano et al. AHJ 2002;143:1085-91
P < 0.001
LBBB More Prevalent with Impaired LV Systolic Function
38%
24%
8%
Mod/SevHF (2)
ImpairedLVSF (1)
PreservedLVSF (1)
1. Masoudi, et al. JACC 2003;41:217-232. Aaronson, et al. Circ 1997;95:2660-7
Limitations of ECG in the Evaluation of Asynchrony
It does not have enough sensitivity to detect the presence of electromechanical delay in each region of the left ventricle
Some patients have mechanical asynchrony without delay electric (hypertrophy, fibrosis, collagen-ultrastructural changes of myocytes)
CRT: how many can benefit?Clinical response (NYHA, QoL) : 60%-75% of patients
Objective response (e.g., ventricular reverse remodeling): 50%-60% of patients
Birnie et al. Curr Opin Cardiol 2006
Reduction of LVESV in Defining
“Prognostic Responder” to CRTReduction in LVESV ≥10% at 3-6
months post-implantation predictsall cause mortality (p = 0.0003)
Discriminatory ability was quite modest:
sensitivity and specificity 70%
Yu CM Yu CM et al. – et al. – CirculationCirculation 2005;112:1580-6 2005;112:1580-6
Surv
ival
All-cause mortality
ESV≥10%
ESV<10%
Reverse Remodeling After CRT
Relates Linearly to Prognosis
Ypenburg C Ypenburg C et al. – et al. – JACCJACC 2009;53:483-90 2009;53:483-90
More extensive reverse remodeling resulted in
lower mortality and hospitalization
37%37%
22%22%
12%12%
3%3%
Death, heart transplantation and hospitalization for HF
Necrotic tissueHealthy cells
Interstitial fibrotic tissue
New Criteria for Patient Selection?
extent of scar area and quantity of the interstizial
fibrotic tissue
presence and density of the myocardial beta-receptors
Is contractility assessment the key for success?
A model of impulse conduction in impaired tissue ...
Electrical impulse
Slow conducti
on
A reverse remodelling was significantly related to Contractile Reserve (r=0.63; p<0.00001)
At Multivariate logistic regression (including QRS duration):Contractile Reserve (OR: 11.2; CI: 6.2-19.8; p<0.001)
LODO-CRT Trial - Preliminary Experience
CRT response
DSE testresponse
R NR
R 25 2
NR 0 15
Sensitivity: 100%Specificity: 88%
Tuccillo B, Muto C et al., J Interv Card Electrophysiol. 2008 Nov;23(2):121-6
The nonresponse rate to CRT, evaluated by means of a remodeling end point, ranges from 40% to 50% of patients. Thus, assumed responder rate is estimated at 60% in this patient population
The DSE responder-nonresponder ratio is estimated to be 3:1
It is estimated that demonstration of LVCR using DSE (DSE-positive) will increase CRT responder rate by 20% compared to the absence of DSE-assessed LVCR
15% lost-to-follow-up rate
LODO-CRT - Methods
270 patients followed-up for 12 months
DSE test cut-offA patient is considered responder to DSE test if the increase of LVEF at
peak stress is at least 5 points with respect to the value at rest
Sample size justification
Muto C. et al., Am H J. 2008
Low-dose Dobutamine Stress-echocardiography to Predict Cardiac Resynchronization Therapy Response
(LODO-CRT) Trial - Baseline Characteristics of the Study PopulationSaverio Iacopino, MD; Maurizio Gasparini, MD; Francesco Zanon, MD; Cosimo
Dicandia, MD; Giuseppe Distefano, MD; Antonio Curnis, MD; Roberto Donati, MD; Valeria Calvi, MD; Carlo Peraldo Neja, MD; Mario Davinelli, PhD; Vanessa Novelli, BA;
Carmine Muto, MD
Iacopino S. et al., CHF 2010
297 patients enrolled
290 patients implanted
271 patients considered for the
analysis
19 incomplete baseline measures
- 8 LVESV not measured- 11 echo not completed- inadequate or missing
data
CRT implant success rate: 96%
EF assessment at rest
EF assessmentCut-off reached?
No
Yes
EF assessmentCut-off reached?
EF assessmentCut-off reached?
No
No
Yes
Yes
Final EF assessment
End test
End test
End test
Cut-off: increase of at least 5% in EF
value with respect to rest conditions
LODO-CRT – DSE Test
10 μg/Kg/min Dobutamine infusion
for 5 min
15 μg/Kg/min Dobutamine infusion
for 5 min
20 μg/Kg/min Dobutamine infusion
for 5 min
5 μg/Kg/min Dobutamine infusion
for 5 min
Iacopino S. et al., CHF 2010
LVEF at rest (%) 26± 6LVEF at peak-stress (%) 35±9
CR+ n (%)198 (73)
Test was interrupted in 3 patients due to ventricular arrhythmias onset
The test was feasible in 99% of the patients w/out complications
About 3 out of 4 patients showed presence of CRThis confirms preliminary experiences
LODO-CRT – Acute DSE Results
Iacopino S. et al., CHF 2010
DSE Test CR - (62) CR + (206) p value
LVEF at rest (%) 26±5 26 ±6 0,184
LVEF at peak stress (%) 28 ±6 38 ±8
<0,001
LODO-CRT – Acute DSE Results
Iacopino S. et al., CHF 2010
ECHO measures CR - 62
(23%) CR + 206
(77%)p
value
LVEDD (mm) 71±9 66±8 0,001
LVESD (mm) 59±10 55±9 0,005
LVEDV (ml) 237±91 197±72 0,001
LVESV (ml) 178±74 145±59 0,001
LVEF (%) 26±5 27±6 0,433
IVMD (ms) 30±49 28±51 0,586
Inter-Ventricular delay presence n (%) 36 (58) 89 (43) 0,040
Q - Lateral wall delay (ms) 358±135 377±147 0,399
Q - E wave delay (ms) 493±106 522±96 0,052
Delayed Lateral Contraction n (%) 8 (11) 24 (12) 0,878
E-A duration (ms) 405±159 381±133 0,336
E/A 1,6± 1,6 1,1±0,9 0,030
E wave deceleration time (ms) 126±56 174±83 0,002
Presence of restrictive pattern n (%) 31 (44) 45 (23)
<0,001
Mitral regurgitation 23 (38) 44 (22) 0,012
LODO-CRT – Acute DSE Results
Iacopino S. et al., CHF 2010
DSE test Ischemi
cNonischemi
c p
value
LVEF at rest (%) 26±5 26±6 0,600
LVEF at peak stress (%) 36 ±9 35±9 0,394
CR + (%) 76% 70% 0,270
106 (39%) patients have HF of ischemic origin
LODO-CRT – Etiology
Iacopino S. et al., CHF 2010
Presence of Left Ventricular Contractile Reserve Predicts Mid-term Response to Cardiac
Resynchronization Therapy Results from the LODO-CRT trial
Carmine Muto, Maurizio Gasparini, Carlo Peraldo Neja, Saverio Iacopino, Mario Davinelli, Francesco Zanon, Cosimo Dicandia, Giuseppe Distefano, Roberto
Donati, Valeria Calvi, Alessandra Denaro, Bernardino Tuccillo
Muto C. et al., Heart Rhythm 2010
CRT responders in patients with LVCR: 145/185 (78%)
Distribution of CRT Response in the
Groups with and without LVCR
Muto C. et al., Heart Rhythm 2010
LVEF increase under DSE is significantly associated with CRT response (OR:1.35, c.i. 1.08-1.68, p=0.008 for each 5-point increase of LVEF) (Univariable Logistic Regression)LVCR presence at baseline is an independent predictor of response to CRT(OR=5.59; c.i. 2.25-13.90; p<0.001) (Multivariable Logistic Regression)
Logistic Regression Analysis for Identification of Independent
Predictors to Response to CRT
Clinical Response
ECHO Response
Gasparini M. et al., JAMA submitted
Assessment of Survival Over Time to MCE in Patients with and without
LVCR
Gasparini M. et al., JAMA submitted
Positive Predictive Value of LVCR and inter-V Dyssynchrony Tests
Combined
Gasparini M. et al., JAMA submitted
Study LimitationsThe LODO-CRT is an observational trial
Results of this experience should in any case be confirmed by a randomized study, before considering the inclusion of the DSE test in the guidelines for CRT patient selection
The cut-off used for the definition of response to CRT is obviously arbitrary, although an association between this cut-off value and the long-term prognosis of these patients has been shown
The interaction between AF and HF means
that neither can be treated optimally without treating
both
HFAF
promotes
aggravates
Implantable CRT Device Diagnostics Identify
Patients with Increased Risk for Heart Failure
Hospitalization.
ICD Diagnostics quantify HF Hospitalization
Risk
Giovanni B. Perego, MD; Maurizio Landolina, MD; Giuseppe Vergara, MD;
Maurizio Lunati, MD; Gabriele Zanotto, MD; Alessia Pappone, MD; Gabriele
Lonardi, MD; Giancarlo Speca, MD; Saverio Iacopino, MD; Annamaria Varbaro,
MS; Shantanu Sarkar, PhD; Doug A. Hettrick, PhD; Alessandra Denaro, MS;
on behalf of the physicians of the Optivol-CRT Clinical Service
Observational Group.
To determine the association between device-determined diagnostic indices, including
intrathoracic impedance, and heart failure (HF) hospitalization
Journal of Interventional Cardiac Electrophysiology 2008
558 HF patients indicated for CRT-D were prospectively collected from 34 centers.
Device-recorded intrathoracic impedance fluid index threshold crossing event (TCE), mean activity counts, tachyarrhythmia events, night heart rate (NHR) and heart rate variability (HRV) were compared within patients with vs. without documented HF hospitalization.
Journal of Interventional Cardiac Electrophysiology 2008
Patient Characteristics (N=490)Variable Responders
(n = 263)Non-responders
(n = 227)p-value
Age (years) 65 ± 10 66 ± 11 0.392
Gender M/F 202/61 190/37 0.070
Ischemic etiology (n) 129 (49%) 164 (72%) <0.001
QRS duration (ms) 159 ± 33 154 ± 31 0.130
Serum creatinine (µmol/l) 104 ± 30 127 ± 51 <0.001
eGFR (ml/min/1.73m2) 74 ± 26 64 ± 28 <0.001
LVEDV (ml)
Baseline 234 ± 86 219 ± 79 0.055
follow-up 179 ± 71* 223 ± 75 <0.001
LVESV (ml)
Baseline 176 ± 77 167 ± 70 0.181
follow-up 116 ± 58‡ 167 ± 66 <0.001
LVEF (%)
Baseline 26 ± 8 25 ± 8 0.293
follow-up 37 ± 9* 26 ± 8 <0.001
J Am Coll Cardiol 2011;57:549-555
eGFR subgroupsVariable eGFR <60
ml/min/1.73m2
N = 193
eGFR 60-90 ml/min/1.73m2
N = 204
eGFR ≥ 90 ml/min/1.73m2
N = 93
p-value
Age (years) 71 ± 8 65 ± 8 56 ± 11 <0.001
Gender M/F 152/41 165/39 75/18 0.856
Ischemic etiology (n) 123 (64%) 121 (59%) 49 (53%) 0.200
QRS duration (ms) 161 ± 30 159 ± 33 147 ± 35 0.001
NYHA class 3.1 ± 0.3 3.1 ± 0.3 3.0 ± 0.2 0.160
6 MWT (m) 266 ± 99 308 ± 105 352 ± 98 <0.001
QoL score 37 ± 16 38 ± 18 33 ± 18 0.091
LVEDV (ml) 218 ± 77 235 ± 92 229 ± 72 0.127
LVESV (ml) 168 ± 71 177 ± 80 170 ± 64 0.423
LVEF (%) 24 ± 8 26 ± 8 27 ± 8 0.022
MR grade 1.7 ± 1.1 1.5 ± 1.1 1.1 ± 0.8 <0.001
J Am Coll Cardiol 2011;57:549-555
Differences in Response to CRT Between the 3 eGFR sub-
groups
<60 (n = 193) 60-90 (n = 204) 90 (n = 93)0%
20%
40%
60%
80%RespondersNon-responders
eGFR (ml/min)
**
RJ Van Bommel et al. J Am Coll Cardiol 2011;57:549-555
All-cause Mortality in the 3 eGFR subgroups
0 12 24 36 48 600%
20%
40%
60%
80%
100%
Follow-up (months)
Even
t-fr
ee s
urv
ival
eGFR <60
eGFR ≥90
p<0.001
eGFR 60-90
RJ Van Bommel et al. J Am Coll Cardiol 2011;57:549-555
Changes in eGFR from Baseline to 6 Months Follow-up, Responders vs. Non-
responders (N=133)
Responders Non-responders-8
-6
-4
-2
0
Ch
an
ge in
eG
FR (
ml/m
in)
p<0.05
RJ Van Bommel et al. J Am Coll Cardiol 2011;57:549-555