different mechanisms linking heart failure to arrhythmias wojciech zareba, md, phd professor of...
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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
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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
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SCD-HeFTSCD-HeFT
2-year 2-year mortality mortality
= 15%= 15%
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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
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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
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ICD Therapy: ICD Therapy: Is It Really Expensive?Is It Really Expensive?
Cost Effectiveness of Device Therapy (2003)
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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
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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
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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
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Risk Scoring and Risk of Mortality Risk Scoring and Risk of Mortality in MADIT II in MADIT II
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Goldenberg, I. et al. J Am Coll Cardiol 2008;51:288-296
U-Shaped Curve for ICD Efficacy
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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
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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%
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CARDIAC DEATHS: MADIT-II
SCD 61%
NSCD 26%
SCD 35%
NSCD 54%
CONVENTIONAL GROUP ICD GROUP Mortality: 19.8% 14.2%
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MADIT-II: SCD
Hazard Ratio = 0.33Adjusted P<0.0001
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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
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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
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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
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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
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Nattel, S. et al. Physiol. Rev.2007; 87: 425-456
Schematic summary of arrhythmia mechanisms in congestive heart failure (CHF)
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Michael, G. et al. Cardiovasc Res 2008 0:cvn266v2-9;
Schematic cardiac action potential (AP) with phases and principal corresponding ion currents indicated
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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
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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
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Kaab, S. et al. Circ Res 1996;78:262-273
Differences in the action potential shape and duration in control and failing
myocytes
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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
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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
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Nattel, S. et al. Physiol. Rev. 2007; 87: 425-456
Repolarization Reserve
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Aiba, T. et al. Circulation 2009;119:1220-1230
IK and its underlying subunit mRNA and protein expression in control, DHF, and
CRT hearts
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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
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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%)
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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)
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Repolarization ParametersRepolarization ParametersEigenvector 1-2Eigenvector 1-2
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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
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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
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QT Variability in MADIT II QT Variability in MADIT II
Haigney et al. JACC 2004; 44: 1481-1487
HR = 2.18; p=0.002;
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MADIT II –T Wave Variability and MADIT II –T Wave Variability and Probability of Appropriate ICD TherapyProbability of Appropriate ICD Therapy
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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
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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
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Bloomfield JACC 2006;47:456-63
Mortality in Ischemic and Nonischemic Cardiomyopathy Patients with EF<40% by TWA Results
11
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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
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Transmural Alternans of Repolarization
Chinushi et al. JCE 2002;13:599-604
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Walker et al. Cardiovasc Res 2003;57:599-614
Calcium Handling and T wave Alternans
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Cleland et al.
EHJ 2006
CARE-HF
Extension phase
CHF death
SCD
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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
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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)
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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
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Aiba, T. et al. Circulation 2009;119:1220-1230
IK and its underlying subunit mRNA and protein expression in control, DHF, and
CRT hearts
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Aiba, T. et al. Circulation 2009;119:1220-1230
IK1 and Kir2.1 mRNA and protein levels in control, DHF, and CRT
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Aiba, T. et al. Circulation 2009;119:1220-1230
EADs in myocytes from control, DHF, and CRT hearts
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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
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Tomaselli, G. F. et al. Circ Res 2004;95:754-763
Multi-hit hypothesis of the development of SCD