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E. Gronda, MD, FESC Cardiology Division Cardiovascular Department

Eleventh International Symposium Heart Failure & Co. Reggia di Caserta 29-30 April 2011. Session V APPROACHES to the PREVENTION of SUDDEN DEATH. “Can Neurohormonal Antagonists Help?”. E. Gronda, MD, FESC Cardiology Division Cardiovascular Department

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E. Gronda, MD, FESC Cardiology Division Cardiovascular Department

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  1. Eleventh International Symposium Heart Failure & Co. Reggia di Caserta 29-30 April 2011 Session V APPROACHES to the PREVENTION of SUDDEN DEATH “Can Neurohormonal Antagonists Help?” E. Gronda, MD, FESC Cardiology Division Cardiovascular Department IRCCS, H S. Giuseppe, MultiMedica, Group S.S. Giovanni - Milano

  2. SCD istheleadingcauseof CV death(mortalitybycause in controlgroupsof 39 selected HF trials) Other CV death SuddenCardiacDeath 44% HF progression38% P. Kress, PhD Medtronic 2004

  3. Why Left Ventricular Remodelling is an Independent Predictor of Malignant Ventricular Arrhythmia? Activation of SNS Activation of the RAAS • LV Dilation • Myocardial • stretch AldosteroneSynthesis in the Myocardium • Ionic Channels Function Mutations: • Na+ = prolonged depolarization, K+ = QT dispersion, Ca++ ,Mg++= Increased Authomaticity • Impact on ACTION Potential • Decreased refractoriness time, Increased vulnerable time Disruption of Myocytes Syncitial Integrity Fibrosis Pathologic Remodeling = Electrical Remodeling

  4. Electrical Instability in the Failing Heart QT interval dispersion Pye M Br Heart J 1994;71:511-514 Zaidi M European Heart Journal (1997) 18, 1129-1134

  5. ACE Inhibition Prevents Remodelling:SOLVD – EchocardiographicSubstudy P = 0. 025 P = 0.019 220 160 0.40 155 210 0.30 150 End-diastolic Volume (cc) End-systolic Volume (cc) Ejection Fraction 200 0.20 145 140 190 0.10 0 0 4 12 0 4 12 0 4 12 Month Month Month Placebo n = 130 130 142 Enalapril n = 128 127 137 Greenberg B et al. Circulation 1995

  6. IN SAVE STUDY LV DILATATION IN DIASTOLE (LEFT) AND SYSTOLE (RIGHT) INCREASED SIGNIFICANTLY FROM 1 TO 2 YEARS AFTER MI A CLEAR RELATION WAS PRESENT BETWEEN LV SIZE AND VT Sutton St J Circulation. 1997;96:3294-3299

  7. ACE-Ireduce mortality due to SCD by 13% P. Kress, PhD Medtronic 2004

  8. b-blockers ACEIs  12 month mortality by 17%  mortality by 32% (cumulative  by 44%) The Biomechanical Model of Heart Failure:Therapy that favorably affects the natural history of CHF prevents or partially reverses either of the two DCM pathophysiological processes Remodeling/ Pathological HTY Systolic Dysfunction < > Adapted from Mann DL, Bristow MR Circulation, 2005

  9. Pharmacogenetic Interaction Between the ACE Deletion Polymorphism and Beta-blocker Therapy in CHF Patients not on beta-blockers (n=208) Patients on beta-blockers (n=120) 1,00 1,00 0,80 0,80 0,60 0,60 Transplant-free survival 0,40 0,40 P=0.073 P=0.005 0,20 0,20 ACE II ACE ID ACE DD ACE II ACE ID ACE DD 0,00 0,00 0 6 12 18 24 30 0 6 12 18 24 30 Months of follow up Months of follow up McNamara et al., Circulation 2001; 103:1644

  10. Biological/Physiological Responses Mediated by Postjunctional Adrenergic Receptors in the Human Heart BiologicalResponseAdrenergicReceptor Beneficialeffects     Positive inotropicresponse ß1, ß2 >>1C     Positive chronotropicresponse ß1, ß2 Vasodilation ß1 (epicardial), ß2 (small vessel) Harmfuleffects Cardiacmyocytegrowth ß1> ß2 >>1C Fibroblasthyperplasia ß2 Myocytedamage/myopathy ß1> ß2, 1C Fetal gene induction ß1 Myocyteapoptosis ß1 Proarrhythmia ß1, ß2, 1C Vasoconstrictionß1C Mann, Bristow Circulation 2005;111;2837-2849

  11. MYOCARDIAL GENE EXPRESSION IN DILATED CARDIOMYOPATHY TREATED WITH BETA-BLOCKING AGENTS , Adult Phenotype Fetal Phenotype BRIAN D.Let al. N Engl J Med 2002;346:1357-65 (modified)

  12. 8 7 6 5 4 3 2 1 0 Effect of Carvedilol on LVEF MOCHA* † P<.001 † † LVEF (EF units) Placebo (n=81) 12.5 mg bid 25 mg bid 6.25 mg bid Carvedilol (n=261) Patients receiving diuretics, ACE inhibitors, ± digoxin; follow-up 6 months *Multicenter Oral Carvedilol Heart Failure Assessment. Adapted from Bristow et al. Circulation. 1996;94:2807-2816.

  13. Carvedilol trials: MOCHA Six-month crude mortality deaths/randomized pt X 100 16 - 14 - 12 - 10 - 8 - 6 - 4 - 2 - 0 - * p <.05 ** p <.07 *** p <.001 15.5 ** % * 6.7 6.0 *** 1.1 Placebo 6.25 mg 12.5 mg 25 mg bid bid bid Bristow et al. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation 1996;94:2807-2816

  14. Influence of Ejection Fraction on Cardiovascular Outcomesin a Broad Spectrum of Heart Failure Patients Salomon SD Circulation 2005;112:3738-3744

  15. Benefit on SCD of Beta - Adrenergic Blocking Agents MERIT-HF 37 % SCD - Treated pts MERIT-HF 3.6% CIBIS II 4% US Carvedilol 1.7% MOCHA 2.3% LV EF 28 % • AVERAGE SD decrease 33% Lancet 1999; 353: 2001-7

  16. Neurohormonal Interventions in Heart Failure 1 Pacifico A, Henry P. J Cardiovasc Electrophysiol, Vol. 14, pp. 764-775, July 2003. 11% on βBlocker Total Death RiskReduction52%

  17. EPHESUS: New subgroup analysis N = 6632 with post-MI LVSD, mean follow-up 16 months P 0.001 0.002 0.022 0.127 0.03 0.641 0.012 0.001 0.01 Eplerenone better Placebo better History of hypertension All-cause mortality CV mortality/hospitalization Sudden cardiac death History of diabetes All-cause mortality CV mortality/hospitalization Sudden cardiac death LVEF ≤30% All-cause mortality CV mortality/hospitalization Sudden cardiac death 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 Odds ratio (95% Cl) Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Pitt B et al. Am J Cardiol. 2006;97(suppl):26F-33F.

  18. EPHESUS Study N Eng J Med 2003; 348:1309-1321 ACE I / ARB and Beta Blockers • None • ACE I /ARB or Beta Blockers p-value for treatment interaction • Boths P=0.04 0.6 0.8 1.0 1.2 1.4 Eplerenone better Hazard ratio placebo better

  19. Ivabradine in heart failure: no paradigm SHIFT…yet NYHA Class III 95%: bisoprolol 304 (95%) pcb 305 (95%) mean age 68 y, IHD 56%, Mean LVEF% 25 17.3% of pts received 1.25 mg/d, 29.5% received 2.5 mg, 2% received 3.75 mg, and 51% received 5 mg NYHA Class II 52%: ivabradine 1605 (50%) pcb 1618 (50%), mean age 60 y, IHD 67% Mean LVEF% 29 More than 70% of pts were not in optimaizedβ – blockertherapy Teerlink JR. Lancet August 29, 2010 DOI:10.1016/S0140-6736(10)61314-1

  20. “… the dose of a β-blocker should be individualized in clinical practice.” “ in MERIT II study.. there were no significant predictors differentiating the high-dose and low dose groups. …. …An uptitration schedule for β-blocker dosing is therefore essential, as tolerated, to achieve the positive β-blocker mortality benefits observed in the completed mortality trials in patients with HF.” Bristow MR et al Journal of Cardiac Failure Vol. 9 No. 6 2003

  21. Mortality in the placebo arm of Val-HeFT by treatment group: 23-month mean follow-up Courtesy Prof. JN Cohn

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