Different Mechanisms Linking Heart Failure to Arrhythmias Wojciech

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Different Mechanisms Linking Heart Failure to Arrhythmias Wojciech Zareba, MD, Ph. D Professor of

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

MADIT-II 36% 31% cumulative probability of mortality in the conventional arm at 3 36%

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

SCD-He. FT 2 -year mortality = 15%

SCD-He. FT 2 -year mortality = 15%

Number Needed to Treat To Save A Life NNTx years = 100 / (%

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. 5 Yr) (1 Yr) (6 Yr) (2 Yr)

ICD Therapy: Is It Really Expensive? Annual Cost Camm A et al. . Eur

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

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

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

Underutilization of ICDs in Preventing Mortality In 49, 517 patients admitted with the primary

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.

Clinical Implementation of ICD Guidelines – The Netherlands Experience 1886 patients in- and out-patients

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

Bedside Risk Stratification for Risk of Mortality in MADIT II Patients Risk Factor HR

Bedside Risk Stratification for Risk of Mortality in MADIT II Patients Risk Factor HR CI P NYHA functional class >II 1. 87 1. 23– 2. 86 0. 004 Atrial fibrillation 1. 87 1. 05– 3. 22 0. 034 QRS >120 ms 1. 65 1. 08– 2. 51 0. 020 Age >70 yrs 1. 57 1. 02– 2. 41 0. 042 BUN >26 and <50 mg/dl 1. 56 1. 00– 2. 42 0. 048

Risk Scoring and Risk of Mortality in MADIT II

Risk Scoring and Risk of Mortality in MADIT II

U-Shaped Curve for ICD Efficacy Goldenberg, I. et al. J Am Coll Cardiol 2008;

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

Risk Factors Predicting Mortality During Long-Term Follow-up of MADIT II Patients Randomized to the

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

Severity of Heart Failure and Modes of Death 12% 26% 64% 24% 59% 15%

Severity of Heart Failure and Modes of Death 12% 26% 64% 24% 59% 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.

CARDIAC DEATHS: MADIT-II NSCD 26% SCD 61% CONVENTIONAL GROUP Mortality: 19. 8% SCD 35%

CARDIAC DEATHS: MADIT-II NSCD 26% SCD 61% CONVENTIONAL GROUP Mortality: 19. 8% SCD 35% NSCD 54% ICD GROUP 14. 2%

MADIT-II: SCD Hazard Ratio = 0. 33 Adjusted P<0. 0001

MADIT-II: SCD Hazard Ratio = 0. 33 Adjusted P<0. 0001

Probability of Appropriate ICD Therapy for VT/VF in Relationship to Ejection Fraction in MADIT

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

Mortality and ICD Therapy in MADIT II Patients by NYHA Class ICD Therapy Mortality

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

ICD Group: Probability of Death Patients At Risk None or Pre-CHF Post-CHF 736 0

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

Prognosis of Heart Failure Patients with Preserved Ejection Fraction Tribouilloy C et al. Eur

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

Schematic summary of arrhythmia mechanisms in congestive heart failure (CHF) Nattel, S. et al.

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

Schematic cardiac action potential (AP) with phases and principal corresponding ion currents indicated Michael,

Schematic cardiac action potential (AP) with phases and principal corresponding ion currents indicated Michael, G. et al. Cardiovasc Res 2008 0: cvn 266 v 2 -9;

Depolarizing and repolarizing ionic currents that underlie ventricular and atrial action potentials (AP) in

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

Genetic Background of LQTS Type Channel Chromosomal Gene Ionic Loci Mutation Abnormality LQT 1

Genetic Background of LQTS Type Channel Chromosomal Gene Ionic Loci Mutation Abnormality LQT 1 LQT 2 LQT 3 LQT 4 LQT 5 11 p 15. 5 7 q 35 -36 3 p 21 -24 4 q 25 -27 21 q 22 KCNQ 1 KCNH 2 SCN 5 A ANKB KCNE 1 IKs IKr INa Na/Ca IKs LQT 6 LQT 7 LQT 8 LQT 9 LQT 10 21 q 22 17 q 23 6 q 8 A KCNE 2 IKr KCNJ 2 IK 1 (Kir 2. 1) CACNA 1 C ICa-L CAV-3 Nav 1. 5 SCN 4 B INa

Differences in the action potential shape and duration in control and failing myocytes Kaab,

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

Mechanisms of Increased Action Potential Duration in HF Downregulation of K+ currents Reduction in

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 IK 1 => enhanced automacity

Repolarization Reserve Ability of cardiomyocytes to compensate for the lose of repolarizing current by

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

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

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

IK and its underlying subunit m. RNA and protein expression in control, DHF, and

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

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

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

HF-induced change in APD in cell layers spanning the ventricular wall from the epicardial

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

Representative APD contour maps recorded from the transmural surfaces of a control (left) and

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

Repolarization Parameters Eigenvector 1 -2

Repolarization Parameters Eigenvector 1 -2

ECG Parameters Predicting Sudden Death or ICD Therapy in 719 MADIT-II Patients Parameter HR

ECG Parameters Predicting Sudden Death or ICD Therapy in 719 MADIT-II Patients Parameter HR 95% CI p value LRD 30 1. 015 -1. 040 <0. 001 L_tangent 1. 045 1. 000 -1. 092 0. 048 After adjustment for: age, NYHA, EF, BUN

Unstable AP Severe LV dysfunction causes unstable beat-to -beat repolarization of the action potential

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

QT Variability in MADIT II HR = 2. 18; p=0. 002; Haigney et al.

QT Variability in MADIT II HR = 2. 18; p=0. 002; Haigney et al. JACC 2004; 44: 1481 -1487

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

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

Mechanisms of Increased Action Potential Duration in HF Alteration in intracellular calcium handling L-type

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 DADmediated ventricular arrhythmias Abnormal restitution of APD (subtle changes in diagnostic interval duration cause significant chnages in action potential duration Increased lability/variability of repolarization

A schematic diagram showing the changes in Ca 2+ handling and contractility and the

A schematic diagram showing the changes in Ca 2+ 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: cvn 266 v 2 -9;

Mortality in Ischemic and Nonischemic Cardiomyopathy Patients with EF<40% by TWA Results Bloomfield JACC

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

MMA -TWA as a Risk Marker Study Population Verrier et al. (ATRAMI) 2003 Methods

MMA -TWA as a Risk Marker Study Population Verrier et al. (ATRAMI) 2003 Methods endpoint cutoff Post MI, av AECG EF 42% monitoring 44 pts Case control Cardiac arrest due to VF or arrhythmic death 43 -74µV Nieminen et al (FINCAVAS) 2008 Clinically indicated TET 1037 pts All-cause death Cardiovascular death Sudden death >=67µV Stein et al (EPHESUS) 2008 post. MI; AECG EF<40%+HF and/or DM 493 pts Case control ECG from exercise test Sudden cardiac death >=43 or 47µV

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

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

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

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

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

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

Effect of epicardial (Epi) vs endocardial (Endo) pacing on TDR, Tp-Te (T p-e), and

Effect of epicardial (Epi) vs endocardial (Endo) pacing on TDR, Tp-Te (T p-e), and APD 90 Fish, J. M. et al. Circulation 2004; 109: 2136 -2142

Effect of reversal of transmural sequence of activation in a canine LV wedge preparation

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

Cisapride (0. 2 {micro}mol/L) permits induction of torsade de pointes during epicardial (Epi) but

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

IK and its underlying subunit m. RNA and protein expression in control, DHF, and

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

IK 1 and Kir 2. 1 m. RNA and protein levels in control, DHF,

IK 1 and Kir 2. 1 m. RNA and protein levels in control, DHF, and CRT Aiba, T. et al. Circulation 2009; 119: 1220 -1230

EADs in myocytes from control, DHF, and CRT hearts Aiba, T. et al. Circulation

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

Autonomic Nervous System Heart Rate Variability Heart Rate Turbulence Cardiac Death Myocardial Substrate EF,

Autonomic Nervous System Heart Rate Variability Heart Rate Turbulence Cardiac Death Myocardial Substrate EF, QRS, LP, QTc, T wave Myocardial Vulnerability NSVT, EP Inducibility, TWA, QTV Ischemia

Multi-hit hypothesis of the development of SCD Tomaselli, G. F. et al. Circ Res

Multi-hit hypothesis of the development of SCD Tomaselli, G. F. et al. Circ Res 2004; 95: 754 -763