Transcript Folia Cardiologica 2006

Different Mechanisms Linking
Heart Failure to Arrhythmias
Wojciech Zareba, MD, PhD
Professor of Medicine/Cardiology
University of Rochester Medical Center
Rochester, NY
Disclosures: Research Grants from Boston Scientific and Medtronic
MADIT-II
36%
31%
31% cumulative probability of
mortality in the conventional arm at 3
36% cumulative probability of
appropriate ICD therapy at 3
SCD-HeFT
2-year
mortality
= 15%
Number Needed to Treat To Save A Life
NNTx years = 100 / (% Mortality in Control Group – % Mortality in Treatment Group)
50
Drug Therapy
45
37
40
35
26
30
amiodarone
25
20
ICD Therapy
20
simvastatin
11
15
10
28
9
metoprolol
succinate
3
4
MUSTT
MADIT
MADIT II
AVID
SAVE
Merit-HF
(2.4 Yr)
(3 Yr)
(3 Yr)
(3.5 Yr)
(1 Yr)
captopril
5
0
(5 Yr)
4S
(6 Yr)
Amiodarone
Metaanalysis
(2 Yr)
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)
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 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
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
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 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%
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.
CHF
Other
Sudden Death
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
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
Mortality
ICD Therapy
Zareba at al. Am J Cardiol 2005
ICD Group: Probability of Death
1.0
Probability of Death
0.8
0.6
Unadjusted P<0.001
Post-CHF
0.4
0.2
None or Pre-CHF
0.0
0.0
Patients At Risk
None or Pre-CHF
Post-CHF
736
0
0.5
1.0
666
93
1.5
414
90
2.0
315
79
2.5
213
68
3.0
164
47
3.5 Years
92
34
38
23
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. Physiol. Rev.2007; 87: 425-456
Schematic cardiac action potential (AP) with phases and principal
corresponding ion currents indicated
Michael, G. et al. Cardiovasc Res 2008 0:cvn266v2-9;
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
LQTS Type
Channel
Chromosomal
Gene
Ionic
Loci
Mutation Abnormality
LQT1
LQT2
LQT3
LQT4
LQT5
11p15.5
7q35-36
3p21-24
4q25-27
21q22
KCNQ1
KCNH2
SCN5A
ANKB
KCNE1
IKs
IKr
INa
Na/Ca
IKs
LQT6
LQT7
LQT8
LQT9
LQT10
21q22
17q23
6q8A
KCNE2
IKr
KCNJ2
IK1 (Kir 2.1)
CACNA1C
ICa-L
CAV-3 Nav 1.5
SCN4B
INa
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 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
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
IK and its underlying subunit mRNA 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;17:43-51
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)
Akar, F. G. et al. Circ Res 2003;93:638-645
Repolarization Parameters
Eigenvector 1-2
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
Unstable AP
Severe LV dysfunction
causes unstable beatto-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. JACC 2004; 44: 1481-1487
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 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 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;
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
Post MI, av
AECG
EF 42%
monitoring
44 pts
Case control
Nieminen et al Clinically
indicated
(FINCAVAS)
TET
2008
1037 pts
Stein et al
(EPHESUS)
2008
Methods
ECG from
exercise
test
postMI;
AECG
EF<40%+HF
and/or DM
493 pts
Case control
endpoint
cutoff
Cardiac arrest due to
VF or arrhythmic
death
43-74µV
All-cause death
Cardiovascular death
Sudden death
>=67µV
Sudden cardiac death
>=43 or
47µV
Transmural Alternans of Repolarization
Chinushi et al. JCE 2002;13:599-604
Calcium Handling and
T wave Alternans
Walker et al. Cardiovasc Res 2003;57:599-614
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
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
Fish, J. M. et al. Circulation 2004;109:2136-2142
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
Aiba, T. et al. Circulation 2009;119:1220-1230
Autonomic Nervous System
Heart Rate Variability
Heart Rate Turbulence
Cardiac
Death
Myocardial
Substrate
Myocardial
Vulnerability
EF,
QRS, LP, QTc,
T wave
NSVT, EP Inducibility,
TWA, QTV
Ischemia
Multi-hit hypothesis of the development of SCD
Tomaselli, G. F. et al. Circ Res 2004;95:754-763