Different Mechanisms Linking Different Mechanisms Linking Heart Failure to ArrhythmiasHeart Failure to Arrhythmias

Wojciech Zareba, MD, PhD

Professor of Medicine/CardiologyUniversity of Rochester Medical Center

Rochester, NY

Disclosures: Research Grants from Boston Scientific and Medtronic

MADIT-IIMADIT-II

36% cumulative probability of 36% cumulative probability of appropriate ICD therapy at 3 appropriate ICD therapy at 3

yearsyears

36%36%

31%31%

31% cumulative probability of 31% cumulative probability of mortality in the conventional arm at 3 mortality in the conventional arm at 3

yearsyears

SCD-HeFTSCD-HeFT

2-year 2-year mortality mortality

= 15%= 15%

Number Needed to Treat To Save A LifeNumber Needed to Treat To Save A Life

3 4

119

20

2628

37

0

5

10

15

20

25

30

35

40

45

50

MUSTT MADIT MADIT II AVID SAVE Merit-HF 4S AmiodaroneMeta-

analysis (5 Yr) (2.4 Yr) (3 Yr) (3 Yr) (3.5 Yr) (1 Yr) (6 Yr) (2 Yr)

NNTx years = 100 / (% Mortality in Control Group – % Mortality in Treatment Group)

ICD Therapysimvastatin

captopril

metoprololsuccinate

amiodarone

Drug Therapy

ICD Therapy: ICD Therapy: Is It Really Expensive?Is It Really Expensive?

Annual CostAnnual Cost

Camm A et al.. Eur Heart J 2007;28:392

ICD Therapy: ICD Therapy: Is It Really Expensive?Is It Really Expensive?

Cost Effectiveness of Device Therapy (2003)

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.

Underutilization of ICDs in Preventing Mortality

Clinical Implementation of ICD Clinical Implementation of ICD Guidelines – The Netherlands ExperienceGuidelines – The Netherlands Experience

1886 patients in- and out-patients in November 1886 patients in- and out-patients in November 20052005

135 had indications for ICD135 had indications for ICD 19 had/received ICD (14%)19 had/received ICD (14%)

9/124 (7%) with primary and 10/11 (91%) with 9/124 (7%) with primary and 10/11 (91%) with secondary preventionsecondary prevention 116 patients included 14 new patients116 patients included 14 new patients

102 “old” patients had 466 cardiologist contacts 102 “old” patients had 466 cardiologist contacts over prior year (4.57/pt)over prior year (4.57/pt)

Botleffs et al. Neth Heart J 2007

Risk FactorRisk Factor HRHR CICI PP

NYHA functional class >IINYHA functional class >II 1.871.87 1.23–2.861.23–2.86 0.0040.004

Atrial fibrillation Atrial fibrillation 1.871.87 1.05–3.221.05–3.22 0.0340.034

QRS >120 msQRS >120 ms 1.651.65 1.08–2.511.08–2.51 0.0200.020

Age >70 yrsAge >70 yrs 1.571.57 1.02–2.411.02–2.41 0.0420.042

BUN >26 and <50 mg/dlBUN >26 and <50 mg/dl 1.561.56 1.00–2.421.00–2.42 0.0480.048

Bedside Risk Stratification for Risk of Mortality in MADIT II Patients

Risk Scoring and Risk of Mortality Risk Scoring and Risk of Mortality in MADIT II in MADIT II

Goldenberg, I. et al. J Am Coll Cardiol 2008;51:288-296

U-Shaped Curve for ICD Efficacy

Risk score= number of risk factors from Risk score= number of risk factors from multivariate analysismultivariate analysis

Low risk =0 pointsmedium risk =1-2 pointsHigh risk =>3 points

Cygankiewicz et al. Heart Rhytm 2009 April

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

the ICD Treatment Arm the ICD Treatment Arm

Severity of Heart Failure and Severity of Heart Failure and Modes of Death Modes of Death

MERIT-HF Study Group. LANCET. 1999;353:2001-2007.

NYHA Class III n = 103NYHA Class II n = 103

NYHA Class IV n = 27

64%

12%

24%

11%

56%

33%

59%

15%

26%

CARDIAC DEATHS: MADIT-II

SCD 61%

NSCD 26%

SCD 35%

NSCD 54%

CONVENTIONAL GROUP ICD GROUP Mortality: 19.8% 14.2%

MADIT-II: SCD

Hazard Ratio = 0.33Adjusted P<0.0001

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

MADIT II MADIT II

Zareba at al. Am J Cardiol 2005Zareba at al. Am J Cardiol 2005

MortalityMortality ICD TherapyICD Therapy

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

Zareba at al. Am J Cardiol 2005Zareba at al. Am J Cardiol 2005

ICD Group: Probability of DeathICD Group: Probability of Death

Patients At RiskPatients At RiskNone or Pre-CHFNone or Pre-CHF 736736 666666 414414 315315 213213 164164 9292 3838Post-CHFPost-CHF 00 9393 9090 7979 6868 4747 3434 2323

1 .0

0 .8

0 .6

0 .4

0 .2

0 .00 .0 0 .5 1 .0 1 .5 2 .0 2 .5 3 .0 3 .5 Years

Pro

bab

ility

of

De

ath

U nad justed P <0 .001

P ost-C H F

N one o r P re -C H F

1 .0

0 .8

0 .6

0 .4

0 .2

0 .00 .0 0 .5 1 .0 1 .5 2 .0 2 .5 3 .0 3 .5 Years

Pro

bab

ility

of

De

ath

U nad justed P <0 .001

P ost-C H F

N one o r P re -C H F

Prognosis of Heart Failure Patients with Preserved Prognosis of Heart Failure Patients with Preserved Ejection FractionEjection Fraction

Tribouilloy C et al. Tribouilloy C et al. Eur Heart J 2008;29:339-347 Eur Heart J 2008;29:339-347

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

Schematic summary of arrhythmia mechanisms in congestive heart failure (CHF)

Michael, G. et al. Cardiovasc Res 2008 0:cvn266v2-9;

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

Shah, M. et al. Circulation 2005;112:2517-2529

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

Genetic Background of LQTSGenetic Background of LQTS

LQT1LQT1 11p15.511p15.5 KCNQ1 KCNQ1 I IKsKs

LQT2LQT2 7q35-367q35-36 KCNH2KCNH2 I IKrKr

LQT3LQT3 3p21-243p21-24 SCN5ASCN5A I INaNa

LQT4LQT4 4q25-274q25-27 ANKB ANKB Na/CaNa/Ca

LQT5LQT5 21q2221q22 KCNE1KCNE1 I IKsKs

LQT6LQT6 21q2221q22 KCNE2KCNE2 I IKrKr

LQT7 LQT7 17q2317q23 KCNJ2KCNJ2 I IK1 K1 (Kir 2.1)(Kir 2.1)

LQT8LQT8 6q8A6q8A CACNA1CCACNA1C I ICa-LCa-L

LQT9LQT9 CAV-3CAV-3 Na Nav v 1.51.5

LQT10LQT10 SCN4BSCN4B I INaNa

LQTS TypeLQTS Type Chromosomal Gene Chromosomal Gene Ionic Ionic ChannelChannel Loci Loci Mutation Abnormality Mutation Abnormality

Kaab, S. et al. Circ Res 1996;78:262-273

Differences in the action potential shape and duration in control and failing

myocytes

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

Mechanisms of Increased Action Mechanisms of Increased Action Potential Duration in HFPotential Duration in HF

Repolarization ReserveRepolarization Reserve

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

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

Repolarization Reserve

Aiba, T. et al. Circulation 2009;119:1220-1230

IK and its underlying subunit mRNA and protein expression in control, DHF, and

CRT hearts

Antzelevitch C and Shimizu W. Curr Opin Cardiol Antzelevitch C and Shimizu W. Curr Opin Cardiol 2002;17:43-512002;17:43-51

Transmural Heterogeneity of RepolarizationTransmural Heterogeneity of Repolarization

Akar, F. G. et al. Circ Res 2003;93:638-645

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 HF

wedge (right)

Repolarization ParametersRepolarization ParametersEigenvector 1-2Eigenvector 1-2

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

PatientsPatients

ParameterParameter HRHR 95% CI95% CI p valuep value

LRD30 LRD30 1.030 1.030 1.015-1.040 1.015-1.040 <0.001 <0.001

L_tangentL_tangent 1.0451.045 1.000-1.0921.000-1.092 0.0480.048

After adjustment for: age, NYHA, EF, BUNAfter adjustment for: age, NYHA, EF, BUN

Haigney, et al.JACC,1998;31:701-6

Unstable AP

Stable AP

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

QT Variability in MADIT II QT Variability in MADIT II

Haigney et al. JACC 2004; 44: 1481-1487

HR = 2.18; p=0.002;

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

Mechanisms of Increased Action Mechanisms of Increased Action Potential Duration in HFPotential Duration in HF

Alteration in intracellular calcium handling

L-type Ca does not seem to be affected to much L-type Ca does not seem to be affected to much in HFin HFIncrease in Na/Ca exchanger – modulates DAD-Increase in Na/Ca exchanger – modulates DAD-mediated ventricular arrhythmiasmediated ventricular arrhythmiasAbnormal restitution of APD (subtle changes in Abnormal restitution of APD (subtle changes in diagnostic interval duration cause significant diagnostic interval duration cause significant chnages in action potential durationchnages in action potential durationIncreased lability/variability of repolarizationIncreased lability/variability of repolarization

Michael, G. et al. Cardiovasc Res 2008 0:cvn266v2-9;

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

Bloomfield JACC 2006;47:456-63

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

11

MMA -TWA as a Risk Marker MMA -TWA as a Risk Marker

StudyStudy PopulationPopulation MethodsMethods endpointendpoint cutoffcutoff

Verrier et al. Verrier et al. (ATRAMI)(ATRAMI)

20032003

Post MI, av Post MI, av EF 42%EF 42%

44 pts44 pts

Case control Case control

AECG AECG monitoringmonitoring

Cardiac arrest due to Cardiac arrest due to VF or arrhythmic VF or arrhythmic deathdeath

43-74µV43-74µV

Nieminen et al Nieminen et al

(FINCAVAS)(FINCAVAS)

20082008

Clinically Clinically indicated indicated TETTET

1037 pts1037 pts

ECG from ECG from exercise exercise testtest

All-cause deathAll-cause death

Cardiovascular deathCardiovascular death

Sudden deathSudden death

>=67µV>=67µV

Stein et al Stein et al

(EPHESUS)(EPHESUS)

20082008

postMI; postMI; EF<40%+HF EF<40%+HF and/or DMand/or DM

493 pts493 pts

Case controlCase control

AECGAECG Sudden cardiac deathSudden cardiac death >=43 or >=43 or 47µV47µV

Transmural Alternans of Repolarization

Chinushi et al. JCE 2002;13:599-604

Walker et al. Cardiovasc Res 2003;57:599-614

Calcium Handling and T wave Alternans

Cleland et al.

EHJ 2006

CARE-HF

Extension phase

CHF death

SCD

Fish, J. M. et al. Circulation 2004;109:2136-2142

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

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 not

endocardial stimulation

Aiba, T. et al. Circulation 2009;119:1220-1230

IK and its underlying subunit mRNA and protein expression in control, DHF, and

CRT hearts

Aiba, T. et al. Circulation 2009;119:1220-1230

IK1 and Kir2.1 mRNA 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

Autonomic Nervous SystemAutonomic Nervous SystemHeart Rate VariabilityHeart Rate Variability

Heart Rate TurbulenceHeart Rate Turbulence

Myocardial Myocardial SubstrateSubstrate

EF,EF,QRS, LP, QTc,QRS, LP, QTc,

T waveT wave

Myocardial Myocardial Vulnerability Vulnerability

NSVT, EP Inducibility, NSVT, EP Inducibility, TWA, QTVTWA, QTVIschemiaIschemia

Cardiac Cardiac DeathDeath

Tomaselli, G. F. et al. Circ Res 2004;95:754-763

Multi-hit hypothesis of the development of SCD