1. Reverse Remodeling and the Risk of Ventricular Tachyarrhythmias in MADIT-CRT
Alon Barsheshet, MD1, Paul J. Wang, MD2, Arthur J. Moss, MD1, Scott D. Solomon, MD3, Amin Al-Ahmad, MD2, Scott McNitt, MS1, Elyse Foster, MD4,
David T. Huang, MD1, Helmut U. Klein, MD1, Wojciech Zareba, MD, PhD1,
Michael Eldar, MD5, Ilan Goldenberg, MD1
1Cardiology Division, University of Rochester Medical Center, Rochester, NY; 2Cardiology Division, Stanford University, Stanford, CA; 3Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; 4Department of Medicine, University of California at San Francisco, San Francisco, CA; 5Heart Institute, Sheba Medical Center, Tel Hashomer, Israel

2. Background
The effect of CRT on the risk of ventricular tachyarrhythmias (VTA) is controversial
Reverse remodeling
LV epicardial pacing
VTA and ICD shocks are associated with reduction in quality of life and with poor prognosis
LQT1 is the most common type of hereditary LQTS
making up about 30 to 35 percent of all LQTS patients and more than 50 percent of genotyped patients
LQT1 arises from a decrease in repolarizing potassium current due to mutations
arises from mutations in the KCNQ1 gene encoding the α subunit of the slowly acting potassium channel IKs
Exercise is the main trigger for cardiac arrhythmic events in patients with LQT1.
β1-AR activation leads to activation of protein kinase A (PKA), which directly phosphorylates the KCNQ1 subunit, increasing IKs function.
increase in IKs is thought to suppress the premature beats and afterdepolarization induced by increased Ca2+ currents during β-adrenergic stimulation.

3. MADIT CRT 1820 patients CRT-D or ICD (3:2 ratio) Mean FU 2.4 years
NYHA class I/II
LVEF <0.30
QRS > 130 msec
CRT-D or ICD (3:2 ratio)
Mean FU 2.4 years
Clinical outcome
Death or HF event
HR (95% CI) = 0.66 ( )
Echocardiographic outcome

4. Objective
To explore the association between the magnitude of echocardiographic response to CRT and subsequent risk for VTA in MADIT-CRT

5. Methods

6. Study Population 1372 patients Patients were categorized into 3 groups
CRT-D high echo responders (≥ 25% reduction in LVESV at 1-year)
CRT-D low echo responders
ICD-only patients

7. Definitions ΔVolume/ baseline volume = VT: ≤ 250 bpm
(1 year volume- baseline volume)/ baseline volume
VT: ≤ 250 bpm
VF: > 250 bpm with disorganized EGMs
Vflutter: > 250 bpm and monomorphic

8. Outcome measures Primary end point Secondary endpoints
Appropriate ICD therapy for VTA after the assessment of echocardiographic response
Secondary endpoints
Appropriate ICD therapy for
VTA or death VT VF
Vflutter

9. Statistical analysis
Effect of echocardiographic response to CRT-D on outcome
Categorical variable
Continuous measure
Cox proportional hazards model and a landmark analysis

10. Results

11. Clinical characteristics
ICD
CRT-D
(n=623)
Low Responders
(n=220)
High Responders
(n=529)
Age
65 (57-72)
65 (58-72)
66 (57-73)
Female
25%
16%
28%*†
Diabetes mellitus
29%
Non-ischemic cardiomyopathy
46%
31%
51%*†
QRS>= 150 msec
66%
57%
69%*†
LBBB
71%
77%*†
Beta blockers
93%
and had a significantly higher frequency of cardiac events of any type, including, syncope, ACA, and LQTS death, as compared with the other mutation subgroups. Notably, the frequency of cardiac events that were associated with sympathetic activation (defined as arousal or exercise triggers) was significantly higher among patients with C-loop-missense mutations (84 percent) than among patients in the other 3 mutation subgroups
* p<0.05 for comparison among the 3 groups.
† p<0.05 for comparison between low and high responders

12. Echocardiographic characteristics
ICD
CRT-D
Baseline Measurements
(n=623)
Low Responders
(n=220)
High Responders
(n=529)
LVESV/BSA, ml/m2 85 84
LVEDV/BSA, ml/m2
120
119
LVEF
29 %
30 %
% Volume Change at 1-Year
and had a significantly higher frequency of cardiac events of any type, including, syncope, ACA, and LQTS death, as compared with the other mutation subgroups. Notably, the frequency of cardiac events that were associated with sympathetic activation (defined as arousal or exercise triggers) was significantly higher among patients with C-loop-missense mutations (84 percent) than among patients in the other 3 mutation subgroups
Data are presented as median values

13. Probability of ventricular tachyarrhythmia by treatment and echocardiographic response
Kaplan Meier curves showed a significantly higher event rate in the C-loop-missense subgroup as compared with the other 3 subgroups
At age 40 years the cumulative event rate was 33 percent in patients with C-loop-missense mutations as compared with ≤16 percent in patients with other mutations

14. Secondary endpoints
p<0.001
p<0.001
With regard to beta blocker therapy, the event rate was lowest among patients with C-loop-missense mutations who were treated with b-blockers and highest among patients with C-loop-missense mutations who were not treated with b-blockers
whereas patients with other mutations exhibited intermediate and similar event rates with- and without b-blocker therapy
p<0.001

15. Multivariate analysis: Risk of ventricular tachyarrhythmic events
Adjusted HR
95% CI
P value
High responders vs. ICD-only
0.45
<0.001
Low responders vs. ICD-only
1.26
0.21
High- vs. low- responders
0.36
Consistently, Multivariate analysis showed a significant differential effect of ß-blocker therapy on the outcome of patients)
. ß-blocker therapy was associated with a significant 88% reduction in the risk of life threatening events among patients with C-loop-missense mutations, whereas the benefit of ß-blocker therapy was attenuated among patients with other mutations.
Adjusted for age, gender, ischemic etiology, QRS≥150 msec, LBBB, left ventricular end systolic volume indexed to body surface area, and blood urea nitrogen >25 mg/dl.

16. Multivariate analysis: Secondary endpoints
Adjusted HR
95% CI
P value VT
High responders vs. ICD-only
0.47
<0.001
Low responders vs. ICD-only
1.40
0.07
High- vs. low- responders
0.33
VF/Vflutter
0.28
0.009
1.21
0.64
0.23
Consistently, Multivariate analysis showed a significant differential effect of ß-blocker therapy on the outcome of patients)
. ß-blocker therapy was associated with a significant 88% reduction in the risk of life threatening events among patients with C-loop-missense mutations, whereas the benefit of ß-blocker therapy was attenuated among patients with other mutations.
Adjusted for age, gender, ischemic etiology, QRS≥150 msec, LBBB, left ventricular end systolic volume indexed to body surface area, and blood urea nitrogen >25 mg/dl.

17. Effect of 10% reduction in LVESV among CRT-D patients
Adjusted HR
95% CI
P value
VTA
0.80
<0.001
VTA or death
0.79
VF/Vflutter
0.75
0.045 VT
Consistently, Multivariate analysis showed a significant differential effect of ß-blocker therapy on the outcome of patients)
. ß-blocker therapy was associated with a significant 88% reduction in the risk of life threatening events among patients with C-loop-missense mutations, whereas the benefit of ß-blocker therapy was attenuated among patients with other mutations.
Adjusted for age, gender, ischemic etiology, QRS≥150 msec, LBBB, left ventricular end systolic volume indexed to body surface area, and blood urea nitrogen >25 mg/dl.

18. Incidence of VTA by deciles of LVESV change among CRT-D patients
In order to understand the mechanism underlying the increase in risk associated with C-loop mutations we measured channel basal function and regulation in four mutant channels associated with LQT1, two in the membrane spanning domains and two located in C-loops.
Channel current decreased significantly for all four mutations studied when compared to wild type subunits

19. Conclusions
Patients with high echocardiographic response to CRT-D (≥25% reduction in LVESV) exhibit a significant reduction in the risk of VTA events.
The magnitude of reverse remodeling is inversely related to VTA risk:
10% reduction in LVESV → 20 % reduction in the risk of VTA.

20. Conclusions
The process of reverse remodeling induced by CRT leads to a lower risk of both HF and arrhythmic events.