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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
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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
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Key concepts
1) Epidemiology of AMI and heart failure complicating AMI
2) Pathophysiology of post-AMI cardiac remodeling
3) Treatment for AMI survivors
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Key concepts
1) Epidemiology of AMI and heart failure complicating AMI
2) Pathophysiology of post-AMI cardiac remodeling
3) Treatment for AMI survivors
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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
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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
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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
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“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 …”
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“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 …”
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“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
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Key concepts
1) Epidemiology of AMI and heart failure complicating AMI
2) Pathophysiology of post-AMI cardiac remodeling
3) Treatment for AMI survivors
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ACUTE MYOCARDIAL INFARCTION
Acute thrombosis of an epicardial coronary artery
Ischemic damage to the myocardium
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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
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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
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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
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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
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Therapeutic goals1) Prompt reperfusion of the
infarct-related artery (within 60-90 min), PCI preferred
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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
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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
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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
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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
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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
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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
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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
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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
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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%)
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No-reflow phenomenon
Epicardial revascularization = myocardial tissue reperfusion ?
The No-reflow is a dissociation between epicardial artery patency and myocardial perfusion.
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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)
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No ReflowA patient with anterior STEMI s/p
primary PCI with angiographic no-reflowMAY 2003 JULY 2004
EDV and EF%
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No ReflowA patient with anterior STEMI s/p
primary PCI with angiographic no-reflowMAY 2003 JULY 2004
Full-thickness scarNo Reflow
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No ReflowMAY 2003 JULY 2004
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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
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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
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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
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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)
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“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
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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
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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]
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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
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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
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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
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Therapeutic goals6) Prevention of cardiac sudden
death in AMI survivors with AICDs
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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
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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
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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
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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
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CELL DEATH in ACUTE MYOCARDIAL INFARCTION
Time 3h
NECROSIS
Accidental Death Chest Pain
APOPTOSIS
Programmed Death Silent
Time 7d
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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
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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
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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.)*
*
#
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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
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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’
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For further slides on these topics please feel free to visit the
metcardio.org website:
http://www.metcardio.org/slides.html