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

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.

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 (0.52-0.84) Echocardiographic outcome

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

Methods

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

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

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

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

Results

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

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

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

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

Multivariate analysis: Risk of ventricular tachyarrhythmic events Adjusted HR 95% CI P value High responders vs. ICD-only 0.45 0.31-0.66 <0.001 Low responders vs. ICD-only 1.26 0.88-1.82 0.21 High- vs. low- responders 0.36 0.23-0.56 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.

Multivariate analysis: Secondary endpoints Adjusted HR 95% CI P value VT High responders vs. ICD-only 0.47 0.31-0.70 <0.001 Low responders vs. ICD-only 1.40 0.97-2.04 0.07 High- vs. low- responders 0.33 0.21-0.53 VF/Vflutter 0.28 0.11-0.73 0.009 1.21 0.55-2.64 0.64 0.23 0.08-0.70 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.

Effect of 10% reduction in LVESV among CRT-D patients Adjusted HR 95% CI P value VTA 0.80 0.71-0.91 <0.001 VTA or death 0.79 0.71-0.88 VF/Vflutter 0.75 0.57-0.99 0.045 VT 0.70-0.90 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.

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

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.

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