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Different Mechanisms Linking Heart Failure to Arrhythmias

Explore connections between heart failure and arrhythmias, including risk factors, treatment outcomes, and prognostic implications. Gain insights into the mechanisms underlying these conditions for better patient care.

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Different Mechanisms Linking Heart Failure to Arrhythmias

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  1. Different Mechanisms Linking Heart Failure to Arrhythmias Wojciech Zareba, MD, PhD Professor of Medicine/Cardiology University of Rochester Medical CenterRochester, NY Disclosures: Research Grants from Boston Scientific and Medtronic

  2. MADIT-II 36% 31% 36% cumulative probability of appropriate ICD therapy at 3 years 31% cumulative probability of mortality in the conventional arm at 3 years

  3. SCD-HeFT 2-year mortality = 15%

  4. Number Needed to Treat To Save A Life NNTx years = 100 / (% Mortality in Control Group – % Mortality in Treatment Group) Drug Therapy amiodarone ICD Therapy simvastatin metoprolol succinate captopril (5 Yr) (2.4 Yr) (3 Yr) (3 Yr) (3.5 Yr) (1 Yr) (6 Yr) (2 Yr)

  5. ICD Therapy: Is It Really Expensive?Annual Cost Camm A et al.. Eur Heart J 2007;28:392

  6. ICD Therapy: Is It Really Expensive? Cost Effectiveness of Device Therapy (2003)

  7. Underutilization of ICDs in Preventing Mortality In 49,517 patients admitted with the primary diagnosis of cardiac arrest who survived to hospital discharge, only 31% received an ICD before discharge. Voigt A et al. J Am Coll Cardiol 2004;44:855-8. In 13,034 discharges at 217 hospitals, <40% of potentially eligible congestive heart failure (CHF) patients had an ICD at discharge or plans for ICD implantation after discharge. Hernandez AF et al. JAMA 2007;298:1525-1532.

  8. Clinical Implementation of ICD Guidelines – The Netherlands Experience • 1886 patients in- and out-patients in November 2005 • 135 had indications for ICD • 19 had/received ICD (14%) • 9/124 (7%) with primary and 10/11 (91%) with secondary prevention • 116 patients included 14 new patients • 102 “old” patients had 466 cardiologist contacts over prior year (4.57/pt) Botleffs et al. Neth Heart J 2007

  9. Bedside Risk Stratification for Risk of Mortality in MADIT II Patients

  10. Risk Scoring and Risk of Mortality in MADIT II

  11. U-Shaped Curve for ICD Efficacy Goldenberg, I. et al. J Am Coll Cardiol 2008;51:288-296

  12. Risk Factors Predicting Mortality During Long-Term Follow-up of MADIT II Patients Randomized to the ICD Treatment Arm • Risk score= number of risk factors from multivariate analysis Low risk =0 points medium risk =1-2 points High risk =>3 points Cygankiewicz et al. Heart Rhytm 2009 April

  13. Severity of Heart Failure and Modes of Death 12% 26% 24% 59% 64% 15% 33% NYHA Class III n = 103 NYHA Class II n = 103 56% 11% NYHA Class IV n = 27 MERIT-HF Study Group. LANCET. 1999;353:2001-2007.

  14. CARDIAC DEATHS: MADIT-II SCD 35% NSCD 26% SCD 61% NSCD 54% CONVENTIONAL GROUP ICD GROUP Mortality: 19.8% 14.2%

  15. MADIT-II: SCD Hazard Ratio = 0.33 Adjusted P<0.0001

  16. Probability of Appropriate ICD Therapy for VT/VF in Relationship to Ejection Fraction in MADIT II Zareba at al. Am J Cardiol 2005

  17. Mortality and ICD Therapy in MADIT II Patients by NYHA Class ICD Therapy Mortality Zareba at al. Am J Cardiol 2005

  18. ICD Group: Probability of Death Patients At Risk None or Pre-CHF 736 666 414 315 213 164 92 38 Post-CHF 0 93 90 79 68 47 34 23

  19. Prognosis of Heart Failure Patients with Preserved Ejection Fraction Tribouilloy C et al. Eur Heart J 2008;29:339-347

  20. Schematic summary of arrhythmia mechanisms in congestive heart failure (CHF) Nattel, S. et al. Physiol. Rev.2007; 87: 425-456

  21. Schematic cardiac action potential (AP) with phases and principal corresponding ion currents indicated Michael, G. et al. Cardiovasc Res 2008 0:cvn266v2-9;

  22. Depolarizing and repolarizing ionic currents that underlie ventricular and atrial action potentials (AP) in human heart Shah, M. et al. Circulation 2005;112:2517-2529

  23. Genetic Background of LQTS LQTS Type Chromosomal Gene Ionic Channel Loci Mutation Abnormality LQT1 11p15.5 KCNQ1 IKs LQT2 7q35-36 KCNH2 IKr LQT3 3p21-24 SCN5A INa LQT4 4q25-27 ANKB Na/Ca LQT5 21q22 KCNE1 IKs LQT6 21q22 KCNE2 IKr LQT7 17q23 KCNJ2 IK1 (Kir 2.1) LQT8 6q8A CACNA1C ICa-L LQT9 CAV-3 Nav 1.5 LQT10 SCN4B INa

  24. Differences in the action potential shape and duration in control and failing myocytes Kaab, S. et al. Circ Res 1996;78:262-273

  25. Mechanisms of Increased Action Potential Duration in HF Downregulation of K+ currents • Reduction in repolarization reserve => increased susceptibility to EADs => increased dispersion of repolarization => reentry • Ito – impaired adaptation of action potential duration to changingg heart rate => increases heterogeneity of repolarization after PVCs, irregular heart rate • IKs and IKr => prolongation of repolarization, increased dispersion of repolarization • IK1 => enhanced automacity

  26. Repolarization Reserve Ability of cardiomyocytes to compensate for the lose of repolarizing current by recruiting other outward currents in order to minimize the repolarization deficit

  27. Repolarization Reserve Nattel, S. et al. Physiol. Rev. 2007; 87: 425-456

  28. IK and its underlying subunit mRNA and protein expression in control, DHF, and CRT hearts Aiba, T. et al. Circulation 2009;119:1220-1230

  29. Transmural Heterogeneity of Repolarization Antzelevitch C and Shimizu W. Curr Opin Cardiol 2002;17:43-51

  30. HF-induced change in APD in cell layers spanning the ventricular wall from the epicardial border (defined as 0% of the wall thickness) to endocardium (100%) Akar, F. G. et al. Circ Res 2003;93:638-645

  31. Representative APD contour maps recorded from the transmural surfaces of a control (left) and HF wedge (right) Akar, F. G. et al. Circ Res 2003;93:638-645

  32. Repolarization ParametersEigenvector 1-2

  33. ECG Parameters Predicting Sudden Death or ICD Therapy in 719 MADIT-II Patients Parameter HR 95% CI p value LRD30 1.030 1.015-1.040 <0.001 L_tangent 1.045 1.000-1.092 0.048 After adjustment for: age, NYHA, EF, BUN

  34. Unstable AP Stable AP Severe LV dysfunction causes unstable beat-to-beat repolarization of the action potential Haigney, et al. JACC,1998;31:701-6

  35. QT Variability in MADIT II HR = 2.18; p=0.002; Haigney et al. JACC 2004; 44: 1481-1487

  36. MADIT II –T Wave Variability and Probability of Appropriate ICD Therapy

  37. Mechanisms of Increased Action Potential Duration in HF • Alteration in intracellular calcium handling • L-type Ca does not seem to be affected to much in HF • Increase in Na/Ca exchanger – modulates DAD-mediated ventricular arrhythmias • Abnormal restitution of APD (subtle changes in diagnostic interval duration cause significant chnages in action potential duration • Increased lability/variability of repolarization

  38. A schematic diagram showing the changes in Ca2+ handling and contractility and the potential compensatory function of ion-channel remodelling that causes action potential (AP) duration (APD) prolongation in congestive heart failure Michael, G. et al. Cardiovasc Res 2008 0:cvn266v2-9;

  39. Mortality in Ischemic and Nonischemic Cardiomyopathy Patients with EF<40% by TWA Results Bloomfield JACC 2006;47:456-63 11

  40. MMA -TWA as a Risk Marker

  41. Transmural Alternans of Repolarization Chinushi et al. JCE 2002;13:599-604

  42. Calcium Handling and T wave Alternans Walker et al. Cardiovasc Res 2003;57:599-614

  43. CHF death CARE-HF Extension phase SCD Cleland et al. EHJ 2006

  44. Effect of epicardial (Epi) vs endocardial (Endo) pacing on TDR, Tp-Te (T p-e), and APD90 Fish, J. M. et al. Circulation 2004;109:2136-2142

  45. Effect of reversal of transmural sequence of activation in a canine LV wedge preparation pretreated with an IKr blocker (5 {micro}mol/L E-4031) Fish, J. M. et al. Circulation 2004;109:2136-2142

  46. Cisapride (0.2 {micro}mol/L) permits induction of torsade de pointes during epicardial (Epi) but not endocardial stimulation Fish, J. M. et al. Circulation 2004;109:2136-2142

  47. IK and its underlying subunit mRNA and protein expression in control, DHF, and CRT hearts Aiba, T. et al. Circulation 2009;119:1220-1230

  48. IK1 and Kir2.1 mRNA and protein levels in control, DHF, and CRT Aiba, T. et al. Circulation 2009;119:1220-1230

  49. EADs in myocytes from control, DHF, and CRT hearts Aiba, T. et al. Circulation 2009;119:1220-1230

  50. Autonomic Nervous SystemHeart Rate VariabilityHeart Rate Turbulence Cardiac Death Myocardial SubstrateEF,QRS, LP, QTc,T wave Myocardial Vulnerability NSVT, EP Inducibility, TWA, QTVIschemia

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