Department of Internal Medicine – VCUDepartment of Internal Medicine – VCUGrand Rounds November 20, 2008Grand Rounds November 20, 2008

Cardiac remodeling following Cardiac remodeling following acute myocardial infarctionacute myocardial infarction

Antonio Abbate, MDAntonio Abbate, MDAssistant Professor of MedicineVirginia Commonwealth UniversityDivision of CardiologyDepartment of Internal MedicineRichmond, VA, USA

Definitions

Cardiac (or ventricular) remodeling following acute myocardial infarction refers to changes in size, shape, and thickness of the left and right ventricle involving both the infarcted and noninfarcted segments

Key concepts

1) Epidemiology of AMI and heart failure complicating AMI

2) Pathophysiology of post-AMI cardiac remodeling

3) Treatment for AMI survivors

Key concepts

1) Epidemiology of AMI and heart failure complicating AMI

2) Pathophysiology of post-AMI cardiac remodeling

3) Treatment for AMI survivors

CAD = coronary artery disease; ACS = acute coronary syndrome; UA = unstable angina; MI = myocardial infarction; NSTEMI = non–ST-segment elevation MI; STEMI = ST-segment elevation MI.

American Heart Association. Heart Disease and Stroke Statistics—2005 Update; 2005. Estimates for STEMI and NSTEMI proportions of MI extrapolated from statistics in Wiviott S, et al. J Am Coll Cardiol. 2003;41(suppl 2):365A-366A.

UA/NSTEMI1.4 million

discharges/yr

STEMI0.33 million

discharges/yr

1.73 millionhospital discharges for ACS

Epidemiology

STEMI

Spectrum of Acute Coronary Syndromes (ACS)

Ischemic discomfort at rest

Unstable Angina

Non–Q-wave MI

(NSTEMI)

Q-wave MI(STEMI)

NSTE-ACS

– + + +Cardiac markers

Presentation

ED

In-hospital6–24 hr

Adapted from Braunwald E, et al. Available at: http://www.acc.org/clinical/guidelines/unstable/unstable.pdf. Accessed December 5, 2005.

ECG

Braunwald’s lecture in 1997 *

“Triumphs, concerns and opportunities”

* Braunwald E – Shattuck Lecture – N Engl J Med 1997

“Triumphs…”

30

20

10

%

30-d

ay M

orta

lity

Pre-CCU(before 1962) CCU

Reperfusion(after 1984)

ECG monitoringDefibrillatorsHemodynamics

ReperfusionAspirinBeta-blockers

15

10

5

%

30-d

ay M

orta

lity

1970-79 1980-89

1990-99

FRAMINGHAM STUDY *

* Velagaleti RS, Circulation 2008

“Triumphs, concerns and opportunities”

* Braunwald E – Shattuck Lecture – N Engl J Med 1997

15

10

5

%Inci

denc

e at

30

days

1970-79 1980-89 1990-99

FRAMINGHAM STUDY **

** Velagaleti RS, Circulation 2008

20

Death CHF

“… concerns …”

“Triumphs, concerns and opportunities”

* Braunwald E – Shattuck Lecture – N Engl J Med 1997

1.0

0.5

%

Adj

uste

d O

R

1975-78 1981-91 1993-2001

WORCESTER HEART ATTACK STUDY **

* * Goldberg RJ, Am J Cardiol 2004

1.5

Death CHF

“… concerns …”

“Triumphs, concerns and opportunities”

* Braunwald E – Shattuck Lecture – N Engl J Med 1997

“… opportunities”

New goals: To reduce AMI-related mortality and To prevent post-AMI heart failure

Key concepts

1) Epidemiology of AMI and heart failure complicating AMI

2) Pathophysiology of post-AMI cardiac remodeling

3) Treatment for AMI survivors

ACUTE MYOCARDIAL INFARCTION

Acute thrombosis of an epicardial coronary artery

Ischemic damage to the myocardium

UNCOMPLICATEDAMI

left ventricle

right ventricle

INFARCTAREA

Post-infarction cardiac remodeling

Clinical scenario:Mr. XY presents few months after reperfusedacute lateral STEMI,LV is normal in size and function.

LEFT VENTRICULARDILATATION

BIVENTRICULARENLARGEMENT

Clinical scenario (2):Mr. XY presents several months after acute non-reperfused lateral STEMI, with symptoms of CHF. LV (and RV) enlargement and dysfunction is present

LV e

nd

-syst

olic

volu

me ind

ex (

ml/m

2)

Hosp Admission

TCO

NTCO

TCO – totalcoronary occlusionNTCO – non TCO

3 MONTHS

6 MONTHS

Influence of IRA patencyModified from Pizzetti et al. J Am Coll Cardiol 1996

No reperfusion

7 days

Early reperfusion and the ‘golden hour’

Paradigm: Time is muscle

1-y

ear

mort

alit

y (

%)

60 360120 300240180

3

12

6

9

Symptoms-Balloon Inflation (min)

RR is by 8%for each 5 mindelay (P=0.04)

Modified from DeLuca et al.

Circulation 2004

Early reperfusion and the ‘golden hour’

Paradigm: Time is muscle

0.1 0.5 2.01.51.0

Repefusionbetter

18% RRR / 1.9% ARRFibrinolysis (vs placebo)9.6% vs 11.5%

35% RRR / 2.9% ARRPCI (vs fibronolysis)5.5% vs 8.4%

52% RRR / 6.0% ARRPCI (vs placebo) hypothetical

5.5% vs 11.5%

Alternativebetter

19% RRR / 2.5% ARRAspirin (vs placebo)

10.7% vs 13.7%

Short-term Mortality

Therapeutic goals1) Prompt reperfusion of the

infarct-related artery (within 60-90 min), PCI preferred

LV e

nd

-syst

olic

volu

me ind

ex (

ml/m

2)

?failed PTCA * P<0.05

successful PTCA

Hosp Admission

TCO

NTCO

TCO – totalcoronary occlusionNTCO – non TCO

3 MONTHS

6 MONTHS

Influence of IRA patencyModified from Pizzetti et al. J Am Coll Cardiol 1996

Late presentation / No reperfusion

7 days

GUSTO – I angiographic substudyModified from Puma et al. Am J Cardiol 1999

Late presentation / No reperfusionm

ort

alit

y (

%)

4

10

6

8

overall

2

days1-30

days 31-365

P<0.001

P<0.001

P<0.001 ** Independent of infarct size and ejection fraction

Occluded IRA

Open IRA

Better late than never ?Modified from Abbate et al. J Am Coll Cardiol 2008

Late presentation / No reperfusion

10 studies 3,560 patients late PCI of the infarct-related artery >12h of AMI median 12 days (range 1-26 days) after AMI

10 studies over more than 15 years variable inclusion and exclusion criteria variable interventional and non-interventional tx

the Occluded Artery Trial (OAT) is the largest, most recent, and better known of the 10 studies

Better late than never ? Maybe notModified from Hochman et al. N Engl J Med 2006

Late presentation / No reperfusion

2,166 patients with total IRA occlusion 3-21 days after AMI

Study PCI Medical Rx OR (random)or sub-category n/N n/N 95% CI

ALKK 6/149 17/151 0.33 [0.13, 0.86] BRAVE-2 4/18 8/183 0.49 [0.15, 1.66] DECOPI 8/109 9/103 0.83 [0.31, 2.23] Horie et al 1/44 5/39 0.16 [0.02, 1.42] OAT 87/1082 84/1084 1.04 [0.76, 1.42] Silva et al 0/1 2/18 0.18 [0.01, 3.99] SWISSI II 3/ 22/105 0.12 [0.04, 0.42] TOAT 2/32 1/34 2.20 [0.19, 25.52] TOMIIS 1/2 1/19 0.75 [0.04, 12.82] TOPS 0/42 0/45 Not estimable

Total (95% CI) 1779 1781Total events: 112 (PCI), 149 (Medical Rx)Test for heterogeneity: Chi² = 19.36, df = 8 (P = 0.01), I² = 58.7%Test for overall effect: Z = 2.15 (P = 0.03)

Outcome: Death

OR (random) 95% CI

0.49 [0.26, 0.94]

0.01 0.1 1 10 100 Favours PCI Favours medical Rx

Better late than never ? Or is it better?

Modified from Abbate et al. J Am Coll Cardiol 2008

Late presentation / No reperfusion

Meta-analysis of 3,560 patients from 10 different RCTs

Study OR (random)or sub-category 95% CI

ALKK 0.33 [0.13, 0.86] BRAVE-2 0.49 [0.15, 1.66] DECOPI 0.83 [0.31, 2.23] Horie et al 0.16 [0.02, 1.42] OAT 1.04 [0.76, 1.42] Silva et al 0.18 [0.01, 3.99] SWISSI II 0.12 [0.04, 0.42] TOAT 2.20 [0.19, 25.52] TOMIIS 0.75 [0.04, 12.82] TOPS Not estimable

Total (95% CI)Total events: 112 (PCI), 149 (Medical Rx)Test for heterogeneity: Chi² = 19.36, df = 8 (P = 0.01), I² = 58.7%Test for overall effect: Z = 2.15 (P = 0.03)

Outcome: Death

OR (random) 95% CI

0.49 [0.26, 0.94]

0.01 0.1 1 10 100 Favours PCI Favours medical Rx

Better late than never ? Or is it better?

Modified by Abbate et al. J Am Coll Cardiol 2008

Late presentation / No reperfusion

Meta-analysis of 3,560 patients from 10 different RCTs

PCI Medical Rx n/N n/N

6/149 17/151 4/18 8/183 8/109 9/103 1/44 5/39 87/1082 84/1084 0/1 2/18 3/ 22/105 2/32 1/34 1/2 1/19 0/42 0/45

1779 1781

O

Outcome:Death (NNT 48)

OR (random) 95% CI

0.49 [0.26, 0.94]

0.01 0.1 1 10 100

Favours PCI Favours medical Rx

OAT

Review: Late percutaneous coronary intervention for infarct-related artery occlusionComparison: Late percutaneous coronary intervention vs best medical therapy for infarct-related artery occlusion Outcome: Death

Study PCI Medical Rx OR (random) OR (random)or sub-category n/N n/N 95% CI 95% CI

ALKK ALKK 6/149 17/151 0.33 [0.13, 0.86] BRAVE-2 4/18 8/183 0.49 [0.15, 1.66] DECOPI 8/109 9/103 0.83 [0.31, 2.23] Horie et al Horie et al 1/44 5/39 0.16 [0.02, 1.42] OAT 87/1 84/1084 1.04 [0.76, 1.42] Silva et al 0/1 2/18 0.18 [0.01, 3.99] SWISSI II SWISSI II 3/ 22/105 0.12 [0.04, 0.42] TOAT 2/32 1/34 2.20 [0.19, 25.52] TOMIIS 1/2 1/19 0.75 [0.04, 12.82] TOPS 0/42 0/45 Not estimable

Total (95% CI) 1779 1781 0.49 [0.26, 0.94]Total events: 112 (PCI), 149 (Medical Rx)Test for heterogeneity: Chi² = 19.36, df = 8 (P = 0.01), I² = 58.7%Test for overall effect: Z = 2.15 (P = 0.03)

0.01 0.1 1 10 100 Favours PCI Favours medical Rx

Why such a difference in outcome?Longer follow up greater benefit

Late presentation / No reperfusion

PCI Medical Rx n/N n/N

6/149 17/151 4/18 8/183 8/109 9/103 1/44 5/39 87/1082 84/1084 0/1 2/18 3/ 22/105 2/32 1/34 1/2 1/19 0/42 0/45

1779 1781

O

Outcome:Death (NNT 48)

OR (random) 95% CI

0.49 [0.26, 0.94]

0.01 0.1 1 10 100

Favours PCI Favours medical Rx

OAT

Review: Late percutaneous coronary intervention for infarct-related artery occlusionComparison: Late percutaneous coronary intervention vs best medical therapy for infarct-related artery occlusion Outcome: Death

Study PCI Medical Rx OR (random) OR (random)or sub-category n/N n/N 95% CI 95% CI

ALKK ALKK 6/149 17/151 0.33 [0.13, 0.86] BRAVE-2 4/18 8/183 0.49 [0.15, 1.66] DECOPI 8/109 9/103 0.83 [0.31, 2.23] Horie et al 1/44 5/39 0.16 [0.02, 1.42] OAT 87/1 84/1084 1.04 [0.76, 1.42] Silva et al 0/1 2/18 0.18 [0.01, 3.99] SWISSI II SWISSI II 3/ 22/105 0.12 [0.04, 0.42] TOAT 2/32 1/34 2.20 [0.19, 25.52] TOMIIS 1/2 1/19 0.75 [0.04, 12.82] TOPS 0/42 0/45 Not estimable

Total (95% CI) 1779 1781 0.49 [0.26, 0.94]Total events: 112 (PCI), 149 (Medical Rx)Test for heterogeneity: Chi² = 19.36, df = 8 (P = 0.01), I² = 58.7%Test for overall effect: Z = 2.15 (P = 0.03)

0.01 0.1 1 10 100 Favours PCI Favours medical Rx

Why such a difference in outcome?Presence of ischemia greater benefit

Late presentation / No reperfusion

PCI Medical Rx n/N n/N

6/149 17/151 4/18 8/183 8/109 9/103 1/44 5/39 87/1082 84/1084 0/1 2/18 3/ 22/105 2/32 1/34 1/2 1/19 0/42 0/45

1779 1781

O

Outcome:Death (NNT 48)

OR (random) 95% CI

0.49 [0.26, 0.94]

0.01 0.1 1 10 100

Favours PCI Favours medical Rx

OAT

Therapeutic goals1) Prompt reperfusion of the

infarct-related artery (within 60-90 min), PCI preferred

2) Late revascularization in selected patients (younger, [+]ischemia, low EF%)

No-reflow phenomenon

Epicardial revascularization = myocardial tissue reperfusion ?

The No-reflow is a dissociation between epicardial artery patency and myocardial perfusion.

Estimates of myocardial tissue reperfusion

Epicardial revascularization = myocardial tissue reperfusion ?

1) Patency of the epicardial coronary tree

2) TIMI coronary flow grade

3) Myocardial blush grade4) Myocardial perfusion at

contrast echo/cardiac MR

1)

2)

3,4)

No ReflowA patient with anterior STEMI s/p

primary PCI with angiographic no-reflowMAY 2003 JULY 2004

EDV and EF%

No ReflowA patient with anterior STEMI s/p

primary PCI with angiographic no-reflowMAY 2003 JULY 2004

Full-thickness scarNo Reflow

No ReflowMAY 2003 JULY 2004

Patients with no-reflow are denied the benefit of reperfusion

Modified from van t’Hof et al. Circulation 1998

No-Reflow phenomenon

No-Reflow

* All patients with successful PCI** Independent of TIMI coronary flow

CORONARY OCCLUSION

NO-REFLOW

PROLONGED ISCHEMIA

MICROVASCULAR DAMAGE

PLATELET/ENDOTHELIAL ACTIVATION

VASOCONSTRICTION (PARADOXICAL)INFLAMMATORY RESPONSE MYOCARDIAL EDEMA OXYGEN-DERIVED FREE

RADICALSCALCIUM OVERLOAD

DISTAL EMBOLIZATION DURING PCI

Potential targets for intervention

1) Reduced ischemic time

2) Platelet inhibitors (ASA, clopidogrel, Abciximab)

3) Vasodilators (adenosine, nitroprusside,

verapamil)

4) Anti-inflammatory agents (statins)

5)Anti-thrombotic agents [+2)]

(heparins,bivalirudin)

6) Thrombectomy/ Thrombus aspiration

Expanded paradigmOriginal paradigm

No-Reflow phenomenon

Therapeutic goals1) Prompt reperfusion of the

infarct-related artery (within 60-90 min), PCI preferred

2) Late revascularization in selected patients (younger, [+]ischemia, low EF%)

3) Prevent (or treat) No-Reflow

Baseline Acute MI

Infarct expansion

Compensatory hypertrophy

Progressive dilatation End-stage HF

hours days weeks months years

coronaryocclusion

* Abbate et al. Int J Biochem Cell Biol 2006

ischemia

APOPTOSIS

APOPTOSIS

NECROSIS APOPTOSIS

APOPTOSIS

Angiotensin IIBeta-adrenergic stimulationAldosteroneStretch stressCytokines (IL-1)Angiotensin II

Beta-adrenergic stimulationAldosteroneStretch stressCytokines (i.e. IL-1)

“Dilatation begets further dilatation”Modified from LeJemtel/Frishman/Sonnenblick – Hurst – The Heart manual

Left Ventricular Dysfunction Dilatation

Neuro-hormonalactivation

Stretch-inducedhypertrophy

Inflammatoryresponse

Angiotensin IINorepinephrineAldosteroneBNP/ANP

Wall stressDyssinchronyHypertension

Interleukin-1Toll-like receptor

responseTumor Necrosis

Factor

Neuro-hormonal activation

In the past decades we have witnessed a shift in paradigm:

• from the effects of AT2 and Aldo on the kidney and vessels

• to the direct effects of AT2 and Aldo on the heart

Neuro-hormonal activation

From bench to bedside

Angiotensin II,Aldosterone, andNorepinephrine

Cardiac Apoptosis,Inflammation, and Fibrosis

Heart Failure

ACE-inhibitors (see ISIS-4 and GISSI-3 studies)*

Aldosterone-blockers (see EPHESUS study)

Beta-blockers (see ISIS-1, MIAMI, COMMIT studies)#

Prevent Adverse Remodeling and Heart Failure

Reduce Early and Late Mortality(approx 0.5% ARR at 30 days within 30 days with ACE-inh and Beta-block; 1.2% ARR [high risk pts] for eplerenone)

Intravenous ACE-inhibitor and Beta-blockers should be used cautiously in patients with STEMI – oral administration is preferred [CONSENSUS and COMMIT trials]

Therapeutic goals1) Prompt reperfusion of the

infarct-related artery (within 60-90 min), PCI preferred

2) Late revascularization in selected patients (younger, [+]ischemia, low EF%)

3) Prevent (or treat) No-Reflow4) Neuro-hormonal blockade with

ACE-inhibitors, Beta-blockers and Aldosterone blockers

Stretch-induced hypertrophy

From bench to bedside

Stretch-induced hypertrophy

Cardiac Apoptosis,Inflammation, and Fibrosis

Heart Failure

Limited clinical data in AMI, howeverAmelioration of volume/pressure overload

due to valvular heart diseaseCardiac Resynchronization therapyAggressive treatment of hypertensionMay Prevent Adverse Remodeling and Heart Failure

Likely Reduce Mortality

Therapeutic goals1) Prompt reperfusion of the

infarct-related artery (within 60-90 min), PCI preferred

2) Late revascularization in selected patients (younger, [+]ischemia, low EF%)

3) Prevent (or treat) No-Reflow4) Neuro-hormonal blockade with

ACE-inhibitors, Beta-blockers and Aldosterone blockers

5) Correction of severe valvular disease and cardiac resynchronization tx

Therapeutic goals6) Prevention of cardiac sudden

death in AMI survivors with AICDs

Therapeutic goals6) Prevention of cardiac sudden

death in AMI survivors with AICDs

7) Hemodynamic support for patients with cardiogenic shock as a bridge to recovery or a bridge to transplant

Therapeutic goals6) Prevention of cardiac sudden

death in AMI survivors with AICDs

7) Hemodynamic support for patients with cardiogenic shock as a bridge to recovery or a bridge to transplant

8) Experimental therapy for patients at high risk for heart failure after AMI cell therapy cytokine therapy

CELL THERAPY FOR ACUTE MYOCARDIAL INFARCTION

“the dogma has been abated”

REGENERATING CARDIOMYOCYTES DERIVING FROM MOBILIZED BONE MARROW STEM CELLS

Orlic et al. PNAS 2001

Regenerating myocardium provides significant survival benefits

CELL THERAPY FOR ACUTE MYOCARDIAL INFARCTION

Modified from Lipinski et al. J Am Coll Cardiol 2007Meta-analysis of 10 RCTs

A small yet consistently greater improvement in LVEF (+3%) is found with bone-marrow derived stem cell

therapy

-1.40 [-2.81, 0.01] -3.10 [-9.14, 2.94] -2.80 [-5.00, -0.60] -1.10 [-2.65, 0.45] -5.20 [-7.18, -3.22] -2.00 [-2.96, -1.04] -2.50 [-3.56, -1.44] -1.00 [-4.06, 2.06] -6.70 [-9.89, -3.51] -5.50 [-7.17, -3.83]

Study EF change % (random) EF change % (random) EF change % (SE) Year

ASTAMI -1.4000 (0.7200) 2005

Bartunek et al -3.1000 (3.0800) 2005

BOOST -2.8000 (1.1200) 2004

Jannsens et al -1.1000 (0.7900) 2006

MAGIC-3 -5.2000 (1.0100) 2006

Meluzin et al -2.0000 (0.4900) 2006

REPAIR-AMI -2.5000 (0.5400) 2006

Strauer et al -1.0000 (1.5600) 2002

TCT-STAMI -6.7000 (1.6300) 2006

Zhan-Quan et al -5.5000 (0.8500) 2006

-2.97 [-4.06, -1.88]Test for heterogeneity: Chi² = 33.62, df = 9 (P = 0.0001), I² = 73.2%

Test for overall effect: Z = 5.35 (P < 0.00001)

-10 -5 0 5 10

Favours cell therapy Favours control

CELL DEATH in ACUTE MYOCARDIAL INFARCTION

Time 3h

NECROSIS

Accidental Death Chest Pain

APOPTOSIS

Programmed Death Silent

Time 7d

NOVEL ANTIAPOPTOTIC TREATMENTS

INTERLEUKIN-1 RECEPTOR ANTAGONIST

%

1

2

3

4

5

treated untreated

P<0.001

Anakinra 1 mg/Kg for 7 days after AMIREDUCES APOPTOSIS BY 75% IN A MODEL OF

PERMANENT ARTERY OCCLUSION IN MICE

APOPTOSIS at 7 days

Modified from Abbate et al. Circulation 2008

%

20

40

60

80

100

treated untreated

P=NS

INFARCT SIZE

NOVEL ANTIAPOPTOTIC TREATMENTS

%

20

40

60

80

100

2

* P=0.020

SURVIVAL at 7 days

4 daysmm

1

2

3

4

5

LVESD FS

P=0.001

LVESD and FS at 7 days

%

10

20

30

40

50

P=0.040

6

Modified from Abbate et al. Circulation 2008

INTERLEUKIN-1 RECEPTOR ANTAGONIST

Anakinra 1 mg/Kg for 7 days after AMIREDUCES APOPTOSIS BY 75% IN A MODEL OF

PERMANENT ARTERY OCCLUSION IN MICE

Virginia Commonwealth University Anakinra Remodeling Trial (VCU-ART)

24-96 h

Figure 3. Study design.Abbreviations: BNP: brain natriuretic peptide; cardiac MRI: cardiac magnetic resonance imaging study; CBC: complete

blood cell count; cECG: continuous electrocardiographic monitoring; EPC: endothelial progenitor cells; STEMI: ST segment elevation acute myocardial infarction; SQ: subcutaneously

Double blind placebo-controlled randomized controlled trial

STEMIreperfusion

Cardiac MRI, Doppler Echocardiography, BNP and EPC determination

Complete history and physical

1:1 randomization

10-14 weeks

Anakinra 100 mg orequivalent matching placebo

given SQ every 24 hoursfor 14 days

# cECGmonitoring

IL-1RN genotyping

* * blood sampling(CBC with diff.)*

*

#24-96 h

Figure 3. Study design.Abbreviations: BNP: brain natriuretic peptide; cardiac MRI: cardiac magnetic resonance imaging study; CBC: complete

blood cell count; cECG: continuous electrocardiographic monitoring; EPC: endothelial progenitor cells; STEMI: ST segment elevation acute myocardial infarction; SQ: subcutaneously

Double blind placebo-controlled randomized controlled trial

STEMIreperfusion

Cardiac MRI, Doppler Echocardiography, BNP and EPC determination

Complete history and physical

1:1 randomization

10-14 weeks

Anakinra 100 mg orequivalent matching placebo

given SQ every 24 hoursfor 14 days

# cECGmonitoring

IL-1RN genotyping

* * blood sampling(CBC with diff.)*blood sampling(CBC with diff.)*

*

#

Conclusions

1) AMI remains a common cause of

death

2) AMI survivors are at high risk for delayed death due to heart failure

3) The aging of the population and the greater survival rates in AMI will lead to an increase in post-AMI heart failure cases

Conclusions

4) The ‘healing’ after an AMI is a highly dynamic process, and adverse cardiac remodeling and heart failure can be, at least in part, prevented

5) A strategy including established treatment options and novel therapeutic approach is necessary to limit the ‘heart failure epidemics’

For further slides on these topics please feel free to visit the

metcardio.org website:

http://www.metcardio.org/slides.html