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Department of Internal Medicine – VCU Grand Rounds November 20, 2008

Department of Internal Medicine – VCU Grand Rounds November 20, 2008. Cardiac remodeling following acute myocardial infarction. Antonio Abbate , MD Assistant Professor of Medicine Virginia Commonwealth University Division of Cardiology Department of Internal Medicine Richmond, VA, USA.

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Department of Internal Medicine – VCU Grand Rounds November 20, 2008

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  1. Department of Internal Medicine – VCU Grand Rounds November 20, 2008 Cardiac remodeling following acute myocardial infarction Antonio Abbate, MD Assistant Professor of Medicine Virginia Commonwealth University Division of Cardiology Department of Internal Medicine Richmond, VA, USA

  2. 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

  3. Key concepts • Epidemiology of AMI and heart failure complicating AMI • Pathophysiology of post-AMI cardiac remodeling • Treatment for AMI survivors

  4. Key concepts • Epidemiology of AMI and heart failure complicating AMI • Pathophysiology of post-AMI cardiac remodeling • Treatment for AMI survivors

  5. Epidemiology 1.73 million hospital discharges for ACS UA/NSTEMI1.4 million discharges/yr STEMI 0.33 million discharges/yr 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.

  6. Spectrum of Acute Coronary Syndromes (ACS) Ischemic discomfort at rest Presentation ECG NSTE-ACS STEMI ED Cardiac markers + – + + In-hospital 6–24 hr Unstable Angina Non–Q-wave MI (NSTEMI) Q-wave MI (STEMI) Adapted from Braunwald E, et al. Available at: http://www.acc.org/clinical/guidelines/unstable/unstable.pdf. Accessed December 5, 2005.

  7. Braunwald’s lecture in 1997 * “Triumphs, concerns and opportunities” “Triumphs…” FRAMINGHAM STUDY * ECG monitoring Defibrillators Hemodynamics 30 15 20 10 Reperfusion Aspirin Beta-blockers 30-day Mortality 30-day Mortality 10 5 % % Pre-CCU (before 1962) Reperfusion (after 1984) 1970-79 1990-99 1980-89 CCU * Braunwald E – Shattuck Lecture – N Engl J Med 1997 * Velagaleti RS, Circulation 2008

  8. “Triumphs, concerns and opportunities” “… concerns …” FRAMINGHAM STUDY ** Death CHF 20 15 10 Incidence at 30 days 5 % 1970-79 1980-89 1990-99 * Braunwald E – Shattuck Lecture – N Engl J Med 1997 ** Velagaleti RS, Circulation 2008

  9. “Triumphs, concerns and opportunities” “… concerns …” WORCESTER HEART ATTACK STUDY ** Death CHF 1.5 1.0 Adjusted OR 0.5 % 1975-78 1981-91 1993-2001 * Braunwald E – Shattuck Lecture – N Engl J Med 1997 * * Goldberg RJ, Am J Cardiol 2004

  10. “Triumphs, concerns and opportunities” “… opportunities” New goals: To reduce AMI-related mortality and To prevent post-AMI heart failure * Braunwald E – Shattuck Lecture – N Engl J Med 1997

  11. Key concepts • Epidemiology of AMI and heart failure complicating AMI • Pathophysiology of post-AMI cardiac remodeling • Treatment for AMI survivors

  12. Acute thrombosis of an epicardial coronary artery Ischemic damage to the myocardium ACUTE MYOCARDIAL INFARCTION

  13. Post-infarction cardiac remodeling left ventricle 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 right ventricle INFARCT AREA UNCOMPLICATED AMI Clinical scenario: Mr. XY presents few months after reperfused acute lateral STEMI, LV is normal in size and function. LEFT VENTRICULAR DILATATION BIVENTRICULAR ENLARGEMENT

  14. 3 MONTHS 6 MONTHS No reperfusion Influence of IRA patency Modified from Pizzetti et al. J Am Coll Cardiol 1996 LV end-systolic volume index (ml/m2) TCO – total coronary occlusion NTCO – non TCO TCO NTCO Hosp Admission 7 days

  15. Early reperfusion and the ‘golden hour’ Paradigm: Time is muscle RR is  by 8% for each 5 min delay (P=0.04) Modified from DeLuca et al. Circulation 2004 12 9 1-year mortality (%) 6 3 60 120 180 240 360 300 Symptoms-Balloon Inflation (min)

  16. Early reperfusion and the ‘golden hour’ Paradigm: Time is muscle Short-term Mortality Aspirin (vs placebo) 19% RRR / 2.5% ARR 10.7% vs 13.7% Fibrinolysis (vs placebo) 18% RRR / 1.9% ARR PCI (vs fibronolysis) 35% RRR / 2.9% ARR 9.6% vs 11.5% 5.5% vs 8.4% PCI (vs placebo) hypothetical 52% RRR / 6.0% ARR 5.5% vs 11.5% 0.1 0.5 1.0 1.5 2.0 Repefusion better Alternative better

  17. Therapeutic goals • Prompt reperfusion of the infarct-related artery (within 60-90 min), PCI preferred

  18. failed PTCA * P<0.05 ? successful PTCA 3 MONTHS 6 MONTHS Late presentation / No reperfusion Influence of IRA patency Modified from Pizzetti et al. J Am Coll Cardiol 1996 LV end-systolic volume index (ml/m2) TCO – total coronary occlusion NTCO – non TCO TCO NTCO Hosp Admission 7 days

  19. Late presentation / No reperfusion GUSTO – I angiographic substudy Modified from Puma et al. Am J Cardiol 1999 Occluded IRA P<0.001 Open IRA 10 8 P<0.001 mortality (%) 6 P<0.001 * 4 * Independent of infarct size and ejection fraction 2 days 1-30 days 31-365 overall

  20. Late presentation / No reperfusion Better late than never ? Modified from Abbate et al. J Am Coll Cardiol 2008 • 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

  21. Late presentation / No reperfusion Better late than never ? Maybe not Modified from Hochman et al. N Engl J Med 2006 2,166 patients with total IRA occlusion 3-21 days after AMI

  22. Late presentation / No reperfusion Better late than never ? Or is it better? Modified from Abbate et al. J Am Coll Cardiol 2008 Meta-analysis of 3,560 patients from 10 different RCTs Study PCI Medical Rx OR (random) OR (random) or sub-category n/N n/N 95% CI 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 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% Outcome: Death Test for overall effect: Z = 2.15 (P = 0.03) 0.01 0.1 1 10 100 Favours PCI Favours medical Rx

  23. Late presentation / No reperfusion O Better late than never ? Or is it better? Modified by Abbate et al. J Am Coll Cardiol 2008 OR (random) 95% CI Meta-analysis of 3,560 patients from 10 different RCTs OAT Study PCI Medical Rx OR (random) OR (random) or sub-category n/N n/N 95% CI 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] 0.49 [0.26, 0.94] TOPS 0/42 0/45 Not estimable Total (95% CI) 1779 1781 0.49 [0.26, 0.94] Outcome: Death (NNT 48) Total events: 112 (PCI), 149 (Medical Rx) Test for heterogeneity: Chi² = 19.36, df = 8 (P = 0.01), I² = 58.7% Outcome: Death Test for overall effect: Z = 2.15 (P = 0.03) 0.01 0.1 1 10 100 0.01 0.1 1 10 100 Favours PCI Favours medical Rx Favours PCI Favours medical Rx

  24. Late presentation / No reperfusion Why such a difference in outcome? Longer follow up  greater benefit O OR (random) 95% CI Review: Late percutaneous coronary intervention for infarct-related artery occlusion OAT Comparison: Late percutaneous coronary intervention vs best medical therapy for infarct-related artery occlusion Outcome: Death Study PCI Medical Rx OR (random) OR (random) PCI Medical Rx or sub-category n/N n/N 95% CI 95% CI n/N n/N ALKK 6/149 17/151 0.33 [0.13, 0.86] 6/149 17/151 BRAVE-2 4/18 8/183 0.49 [0.15, 1.66] 4/18 8/183 DECOPI 8/109 9/103 0.83 [0.31, 2.23] 8/109 9/103 Horie et al 1/44 5/39 0.16 [0.02, 1.42] 1/44 5/39 OAT 87/1 84/1084 1.04 [0.76, 1.42] 87/1082 84/1084 Silva et al 0/1 2/18 0.18 [0.01, 3.99] 0/1 2/18 SWISSI II 3/ 22/105 0.12 [0.04, 0.42] 3/ 22/105 TOAT 2/32 1/34 2.20 [0.19, 25.52] 2/32 1/34 TOMIIS 1/2 1/19 0.75 [0.04, 12.82] 1/2 1/19 0.49 [0.26, 0.94] TOPS 0/42 0/45 Not estimable 0/42 0/45 Total (95% CI) 1779 1781 0.49 [0.26, 0.94] 1779 1781 Outcome: Death (NNT 48) 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 0.01 0.1 1 10 100 Favours PCI Favours medical Rx Favours PCI Favours medical Rx

  25. Late presentation / No reperfusion Why such a difference in outcome? Presence of ischemia  greater benefit O OR (random) 95% CI Review: Late percutaneous coronary intervention for infarct-related artery occlusion OAT Comparison: Late percutaneous coronary intervention vs best medical therapy for infarct-related artery occlusion Outcome: Death Study PCI Medical Rx OR (random) OR (random) PCI Medical Rx or sub-category n/N n/N 95% CI 95% CI n/N n/N ALKK 6/149 17/151 0.33 [0.13, 0.86] 6/149 17/151 BRAVE-2 4/18 8/183 0.49 [0.15, 1.66] 4/18 8/183 DECOPI 8/109 9/103 0.83 [0.31, 2.23] 8/109 9/103 Horie et al 1/44 5/39 0.16 [0.02, 1.42] 1/44 5/39 OAT 87/1 84/1084 1.04 [0.76, 1.42] 87/1082 84/1084 Silva et al 0/1 2/18 0.18 [0.01, 3.99] 0/1 2/18 SWISSI II 3/ 22/105 0.12 [0.04, 0.42] 3/ 22/105 TOAT 2/32 1/34 2.20 [0.19, 25.52] 2/32 1/34 TOMIIS 1/2 1/19 0.75 [0.04, 12.82] 1/2 1/19 0.49 [0.26, 0.94] TOPS 0/42 0/45 Not estimable 0/42 0/45 Total (95% CI) 1779 1781 0.49 [0.26, 0.94] 1779 1781 Outcome: Death (NNT 48) 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 0.01 0.1 1 10 100 Favours PCI Favours medical Rx Favours PCI Favours medical Rx

  26. Therapeutic goals • Prompt reperfusion of the infarct-related artery (within 60-90 min), PCI preferred • Late revascularization in selected patients (younger, [+]ischemia, low EF%)

  27. Epicardial revascularization = myocardial tissue reperfusion ? No-reflow phenomenon The No-reflow is a dissociation between epicardial artery patency and myocardial perfusion.

  28. Epicardial revascularization = myocardial tissue reperfusion ? Estimates of myocardial tissue reperfusion 1) • Patency of the epicardial coronary tree • 2) TIMI coronary flow grade • 3) Myocardial blush grade • 4) Myocardial perfusion at • contrast echo/ • cardiac MR 2) 3,4)

  29. No Reflow A patient with anterior STEMI s/p primary PCI with angiographic no-reflow MAY 2003 JULY 2004 EDV and  EF%

  30. No Reflow A patient with anterior STEMI s/p primary PCI with angiographic no-reflow MAY 2003 JULY 2004 No Reflow Full-thickness scar

  31. No Reflow MAY 2003 JULY 2004

  32. No-Reflow phenomenon Patients with no-reflow are denied the benefit of reperfusion Modified from van t’Hof et al. Circulation 1998 * All patients with successful PCI ** Independent of TIMI coronary flow No-Reflow

  33. No-Reflow phenomenon Original paradigm Expanded paradigm • Potential targets • for intervention • 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 CORONARY OCCLUSION PLATELET/ENDOTHELIAL ACTIVATION VASOCONSTRICTION (PARADOXICAL) INFLAMMATORY RESPONSE MYOCARDIAL EDEMA OXYGEN-DERIVED FREE RADICALS CALCIUM OVERLOAD PROLONGED ISCHEMIA MICROVASCULAR DAMAGE DISTAL EMBOLIZATION DURING PCI NO-REFLOW

  34. Therapeutic goals • Prompt reperfusion of the infarct-related artery (within 60-90 min), PCI preferred • Late revascularization in selected patients (younger, [+]ischemia, low EF%) • Prevent (or treat) No-Reflow

  35. Baseline Acute MI Compensatory hypertrophy Angiotensin II Beta-adrenergic stimulation Aldosterone Stretch stress Cytokines (IL-1) Angiotensin II Beta-adrenergic stimulation Aldosterone Stretch stress Cytokines (i.e. IL-1) APOPTOSIS NECROSIS APOPTOSIS APOPTOSIS ischemia APOPTOSIS coronary occlusion Infarct expansion Progressive dilatation  End-stage HF hours days weeks months years * Abbate et al. Int J Biochem Cell Biol 2006

  36. “Dilatation begets further dilatation” Modified from LeJemtel/Frishman/Sonnenblick – Hurst – The Heart manual Left Ventricular Dysfunction  Dilatation Neuro-hormonal activation Stretch-induced hypertrophy Inflammatory response Angiotensin II Norepinephrine Aldosterone BNP/ANP Wall stress Dyssinchrony Hypertension Interleukin-1 Toll-like receptor response Tumor Necrosis Factor

  37. 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

  38. Neuro-hormonal activation From bench to bedside ACE-inhibitors (see ISIS-4 and GISSI-3 studies)* Aldosterone-blockers (see EPHESUS study) Beta-blockers (see ISIS-1, MIAMI, COMMIT studies)# Angiotensin II, Aldosterone, and Norepinephrine Intravenous ACE-inhibitor and Beta-blockers should be used cautiously in patients with STEMI – oral administration is preferred [CONSENSUS and COMMIT trials] Prevent Adverse Remodeling and Heart Failure Cardiac Apoptosis, Inflammation, and Fibrosis 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) Heart Failure

  39. Therapeutic goals • Prompt reperfusion of the infarct-related artery (within 60-90 min), PCI preferred • Late revascularization in selected patients (younger, [+]ischemia, low EF%) • Prevent (or treat) No-Reflow • Neuro-hormonal blockade with ACE-inhibitors, Beta-blockers and Aldosterone blockers

  40. Stretch-induced hypertrophy From bench to bedside Limited clinical data in AMI, however Amelioration of volume/pressure overload due to valvular heart disease Cardiac Resynchronization therapy Aggressive treatment of hypertension Stretch-induced hypertrophy May Prevent Adverse Remodeling and Heart Failure Cardiac Apoptosis, Inflammation, and Fibrosis Likely Reduce Mortality Heart Failure

  41. Therapeutic goals • Prompt reperfusion of the infarct-related artery (within 60-90 min), PCI preferred • Late revascularization in selected patients (younger, [+]ischemia, low EF%) • Prevent (or treat) No-Reflow • Neuro-hormonal blockade with ACE-inhibitors, Beta-blockers and Aldosterone blockers • Correction of severe valvular disease and cardiac resynchronization tx

  42. Therapeutic goals 6) Prevention of cardiac sudden death in AMI survivors with AICDs

  43. Therapeutic goals 6) 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

  44. Therapeutic goals 6) 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

  45. CELL THERAPY FOR ACUTE MYOCARDIAL INFARCTION “the dogma has been abated” REGENERATING CARDIOMYOCYTES DERIVING FROM MOBILIZED BONE MARROW STEM CELLS Regenerating myocardium provides significant survival benefits Orlic et al. PNAS 2001

  46. CELL THERAPY FOR ACUTE MYOCARDIAL INFARCTION Modified from Lipinski et al. J Am Coll Cardiol 2007 Meta-analysis of 10 RCTs Study EF change % (SE) EF change % (random) EF change % (random) Year -1.40 [-2.81, 0.01] 2005 -1.4000 (0.7200) ASTAMI 2005 -3.10 [-9.14, 2.94] -3.1000 (3.0800) Bartunek et al 2004 -2.80 [-5.00, -0.60] -2.8000 (1.1200) BOOST -1.10 [-2.65, 0.45] 2006 -1.1000 (0.7900) Jannsens et al 2006 -5.20 [-7.18, -3.22] -5.2000 (1.0100) MAGIC-3 -2.00 [-2.96, -1.04] 2006 -2.0000 (0.4900) Meluzin et al -2.50 [-3.56, -1.44] 2006 -2.5000 (0.5400) REPAIR-AMI 2002 -1.00 [-4.06, 2.06] -1.0000 (1.5600) Strauer et al -6.70 [-9.89, -3.51] 2006 -6.7000 (1.6300) TCT-STAMI -5.50 [-7.17, -3.83] 2006 -5.5000 (0.8500) Zhan-Quan et al -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 A small yet consistently greater improvement in LVEF (+3%) is found with bone-marrow derived stem cell therapy

  47. Time 7d NECROSIS APOPTOSIS Accidental Death  Chest Pain Programmed Death  Silent CELL DEATH in ACUTE MYOCARDIAL INFARCTION Time 3h

  48. NOVEL ANTIAPOPTOTIC TREATMENTS INTERLEUKIN-1 RECEPTOR ANTAGONIST Anakinra1 mg/Kg for 7 days after AMI REDUCES APOPTOSIS BY 75% IN A MODEL OF PERMANENT ARTERY OCCLUSION IN MICE INFARCT SIZE APOPTOSIS at 7 days 100 5 P=NS P<0.001 80 4 60 3 40 2 20 1 % % treated untreated treated untreated Modified from Abbate et al. Circulation 2008

  49. NOVEL ANTIAPOPTOTIC TREATMENTS INTERLEUKIN-1 RECEPTOR ANTAGONIST Anakinra1 mg/Kg for 7 days after AMI REDUCES APOPTOSIS BY 75% IN A MODEL OF PERMANENT ARTERY OCCLUSION IN MICE LVESD and FS at 7 days SURVIVAL at 7 days P=0.001 50 5 100 P=0.040 40 4 80 * P=0.020 30 3 60 20 2 40 10 1 20 % mm % 2 4 6 days LVESD FS Modified from Abbate et al. Circulation 2008

  50. Virginia Commonwealth University Anakinra Remodeling Trial (VCU-ART)

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