Arrhythmia initiation in catecholaminergic polymorphic ventricular tachycardia type 1 depends on both heart rate and sympathetic stimulation.

AIMS: Catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) predisposes to ventricular tachyarrhythmias (VTs) during high heart rates due to physical or psychological stress. The essential role of catecholaminergic effects on ventricular cardiomyocytes in this situation is well documented, but the importance of heart rate per se for arrhythmia initiation in CPVT1 is largely unexplored. METHODS AND RESULTS: Sixteen CPVT1 patients performed a bicycle stress-test. Occurrence of VT triggers, i.e. premature ventricular complexes (PVC), depended on high heart rate, with individual thresholds. Atrial pacing above the individual PVC threshold in three patients did not induce PVCs. The underlying mechanism for the clinical observation was explored using cardiomyocytes from mice with the RyR2-R2474S (RyR2-RS) mutation, which exhibit exercise-induced VTs. While rapid pacing increased the number of Ca2+ waves in both RyR2-RS and wild-type (p<0.05), ß-adrenoceptor (ßAR) stimulation induced more Ca2+ waves in RyR2-RS (p<0.05). Notably, Ca2+ waves occurred despite decreased sarcoplasmic reticulum (SR) Ca2+ content in RyR2-RS (p<0.05), suggesting increased cytosolic RyR2 Ca2+ sensitivity. A computational model of mouse ventricular cardiomyocyte electrophysiology reproduced the cellular CPVT1 phenotype when RyR2 Ca2+ sensitivity was increased. Importantly, diastolic fluctuations in phosphorylation of RyR2 and SR Ca2+ content determined Ca2+ wave initiation. These factors were modulated towards increased propensity for arrhythmia initiation by increased pacing rates, but even more by ßAR stimulation. CONCLUSION: In CPVT1, VT propensity depends on individual heart rate thresholds for PVCs. Through converging data from clinical exercise stress-testing, cellular studies and computational modelling, we confirm the heart rate-independent pro-arrhythmic effects of ßAR stimulation in CPVT1, but also identify an independent and synergistic contribution from effects of high heart rate.

Exercise training prevents ventricular tachycardia in CPVT1 due to reduced CaMKII-dependent arrhythmogenic Ca2+ release.

AIMS: Catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) is caused by mutations in the cardiac ryanodine receptor (RyR2) that lead to disrupted Ca(2+) handling in cardiomyocytes and ventricular tachycardia. The aim of this study was to test whether exercise training could reduce the propensity for arrhythmias in mice with the CPVT1-causative missense mutation Ryr2-R2474S by restoring normal Ca(2+) handling. METHODS AND RESULTS: Ryr2-R2474S mice (RyR-RS) performed a 2 week interval treadmill exercise training protocol. Each exercise session comprised five 8 min intervals at 80-90% of the running speed at maximal oxygen uptake (VO2max) and 2 min active rest periods at 60%. VO2max increased by 10 ± 2% in exercise trained RyR-RS (ET), while no changes were found in sedentary controls (SED). RyR-RS ET showed fewer episodes of ventricular tachycardia compared with RyR-RS SED, coinciding with fewer Ca(2+) sparks and waves, less diastolic Ca(2+) leak from the sarcoplasmic reticulum, and lower phosphorylation levels at RyR2 sites associated with Ca(2) (+)-calmodulin-dependent kinase type II (CaMKII) compared with RyR-RS SED. The CaMKII inhibitor autocamtide-2-related inhibitory peptide and also the antioxidant N-acetyl-l-cysteine reduced Ca(2+) wave frequency in RyR-RS equally to exercise training. Protein analysis as well as functional data indicated a mechanism depending on reduced levels of oxidized CaMKII after exercise training. Two weeks of detraining reversed the beneficial effects of the interval treadmill exercise training protocol in RyR-RS ET. CONCLUSION: Long-term effects of interval treadmill exercise training reduce ventricular tachycardia episodes in mice with a CPVT1-causative Ryr2 mutation through lower CaMKII-dependent phosphorylation of RyR2.

Effects of individualized exercise training in patients with catecholaminergic polymorphic ventricular tachycardia type 1.

Ventricular arrhythmias (VAs) in patients with catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) are triggered at an individual and reproducible heart rate (HR) during exercise. Long-term effects of exercise on arrhythmia threshold in CPVT1 are not known. To investigate whether exercise training (ET) is feasible in patients with CPVT1, 13 patients with CPVT1 and confirmed genetic mutations performed bicycle exercise testing with maximal oxygen uptake (VO2max) measurements at baseline and after 13 weeks. The threshold HR for VA was defined as the HR when bigeminal ventricular extrasystoles or more severe VAs occurred. Six patients were enrolled in a 12-week high-intensity ergometer bicycle ET program (ET patients) with 60 min exercise sessions 3 times per week. The remaining 7 patients with CPVT1 were included as "sedentary" control (SED) patients complying with current recommendations to restrain from high-intensity physical activity. ET patients completed 28 ± 3 exercise sessions (78 ± 8% program completion) with 13 ± 3% increase in VO2max versus baseline (20.2 ± 1.6 vs 17.9 ± 1.3 ml/kg/min, p <0.05). No adverse events occurred. Baseline threshold for VA was 100 ± 6 beats/min in ET patients and 135 ± 4 beats/min in SED patients. After the training period, threshold HR for VA was 111 ± 10 beats/min in ET patients and 123 ± 6 beats/min in SED patients. The threshold for VA increased in ET compared with SED patients (+11 vs -12 beats/min, p <0.05). In conclusion, patients with CPVT1 benefitted from individualized ET with improved aerobic capacity and increased threshold HR for VA compared with SED patients.