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Background The recessive form of catecholaminergic polymorphic ventricular tachycardia 2 (CPVT2) is caused by mutations in cardiac calsequestrin (CASQ2), leading to protein deficiency. Objectives The aims of this study were to develop a viral-delivered gene therapy for CPVT2 and to determine the relationship between CASQ2 expression and antiarrhythmic efficacy in a murine model. Methods We used a murine model of CPVT2 caused by the D307H human mutation (CASQ2 D307H ) or CASQ2 knockout (CASQ2 Δ/Δ ). Adeno-associated virus (AAV) particles containing the CASQ2 gene (AAV CASQ2 ) were injected into the heart or intraperitoneally to 12-week-old mice. A telemetry device was implanted, and mice underwent provocation testing 7–8 weeks after gene therapy. Results CASQ2 Δ/Δ mice injected intracardiacally with AAV CASQ2 expressed 40% ± 25% of the normal CASQ2 protein level, which was increased compared to untreated CASQ2 Δ/Δ mice (n = 10; P D307H (n = 12) and CASQ2 Δ/Δ (n = 4) mice. All control mice with CPVT2 had nonsustained ventricular tachycardia (VT) and 8 of 13 had sustained VT on provocation. Expressing ≥33% of the normal CASQ2 level was needed to protect from nonsustained VT as well as stress-induced premature ventricular contractions. Lower levels of expression prevented sustained VT in AAV CASQ2 -treated mice (0 of 26; P Conclusion AAV CASQ2 displays a long-lasting capacity to attenuate and potentially cure CPVT2. Systemic delivery is feasible and convenient, reproducibly providing adequate levels of transgene expression. Antiarrhythmic efficacy depends on the CASQ2 level: ≥33% of the normal CASQ2 level is needed to prevent arrhythmia. However, even lower levels of protein protect from sustained VT, thereby potentially reducing the risk of sudden death.

Background Spontaneous calcium release evoking delayed afterdepolarization is believed to cause catecholaminergic polymorphic ventricular tachycardia (CPVT), a lethal human arrhythmia provoked by exercise or emotional stress. β-Adrenergic blockers are the drug of choice, but fail to achieve complete arrhythmia control in some patients. These individuals often require flecainide, device implantation, and/or sympathetic denervation. Objective To optimize the arrhythmia therapy by pharmacological inhibition of the sympathetic nervous system in the homozygous calsequestrin knockout (CASQ2 Δ/Δ ) mouse model of CPVT2. Methods A heart telemetry device was implanted for continuous electrocardiographic recording at rest and during provocation testing. Calcium transients and abnormal calcium release were studied in cardiomyocytes isolated from adult mice. Adrenergic receptor expression was determined by using Western blotting and confocal microscopy. Results Adult CASQ2 Δ/Δ mice suffer from complex ventricular arrhythmia at rest and ventricular tachycardia during treadmill exercise and after epinephrine injection. β-Adrenergic blockers, propranolol and metoprolol, attenuated arrhythmia at rest but not after stress. Reserpine had no efficacy in controlling arrhythmia. Agents with α-blocking activity, phentolamine or labetalol, abolished both exercise- and epinephrine-induced arrhythmia. In contrast, injection of α-adrenergic agonist phenylephrine reproducibly provoked ventricular tachycardia. Isolated cardiomyocytes from CASQ2 Δ/Δ mice had delayed calcium release waves upon exposure to sympathetic agonists, which were abolished by phentolamine. Hearts of calsequestrin-mutant mice expressed more α1-adrenergic receptor than did wild type control mice ( P Conclusion We identified a contribution of the α-adrenergic pathway to the pathogenesis of catecholamine-induced arrhythmia. α-Blockade emerges as an effective therapy in the murine model of CPVT2 and should be tried in humans resistant to β-blockers.

Background Coronary revascularization (CR) may confer electrical stability in patients with ischemic cardiomyopathy. However, data regarding the effect of CR on the development of ventricular tachyarrhythmias in this population are limited. Objective The purpose of this study was to evaluate the association between CR and arrhythmic risk in postmyocardial infarction (post-MI) patients with left ventricular dysfunction. Methods The risk for life-threatening ventricular tachyarrhythmias (defined as a first appropriate defibrillator therapy for ventricular tachycardia [VT]/ventricular fibrillation [VF] or death) was compared between post-MI patients with and those without prior CR (n = 612 and 147, respectively) enrolled in the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT). Results The 3-year cumulative rate of VT/VF or death was significantly higher among patients without prior CR (42%) than in patients who underwent prior CR (32%, P = .02). Multivariate analysis demonstrated that patients without prior CR had 48% increased risk ( P = .01) for VT/VF or death. Risk reduction associated with CR was related to elapsed time from CR, assessed both as a categorical variable (tertiles for time from CR: ≥7 years, hazard ratio [HR] = 1.93, P = .001; 1.5–7 years, HR=1.70, P = .01 vs P = .002, increased risk for VT/VF or death per 1-year increment of elapsed time from CR). The effect of CR on arrhythmic risk was similar in patients treated with a defibrillator alone or when combined with cardiac resynchronization therapy. Conclusion Post-MI patients with left ventricular dysfunction who undergo CR experience a time-dependent reduction in the risk for subsequent life-threatening ventricular tachyarrhythmias.

Purpose: in a previous randomized controlled study we showed the advantage of J-shaped over straight screw-in leads in the atrium. In the present study we compared J-shaped tined passive fixation (PF) to screw-in active fixation (AF) leads. Methods: two hundred consecutive patients (pts) were randomized to have either a Medtronic 5568 J-shaped screw-in atrial lead (AF group, n=97) or a Medtronic 5592 J-shaped tined lead (PF group, n=103) implanted in the atrium. We documented implant data and electrical measurements at implant, pre-discharge, 3 months and one year; echocardiography and chest X-ray were performed at one day post implantation. All implant and follow-up complications were documented. Results: two hundred pts were included (103 males), aged 75.44-10.4, EF = 53 4- 11, of whom 39 (19.5%) had previously undergone cardiac surgery. In 5 cases (4 with a PF and one with an AF lead, P = 0.39), there was crossover to the alternate lead at implant due to inability to achieve a satisfactory position. Fluoroscopy times were shorter with PF: 2.14-3.6 vs. 3.3 4- 4.5 min (P=0.04). Bipolar electrical measurements are listed in the table. Lead Implant Pre-discharge 3 months One year 5568 (AF) Pwave mVoks 4.2±2.1 3.1±1.5 3.0±1.5 3.0±1.4 Impedance Ohm 434±133 533±126 531±142 529±139 Threshold Voks 0.9±0.3* 0.8±0.4* 1.2±0.7" 1.3±0.9" 5592 (PF) P wave mVoks 4.8±2.2 3.3±1.4 3.3±1.4 3.2±1.4 Impedance Ohm 448±100 476±88 498±84 500±77 Threshold Voks 0.7±0.5* 0.6±0.3* 0.7±0.6* 0.8±0.6* *P