Exercise Training Stabilizes RyR2-Dependent Ca2+ Release in Post-infarction Heart Failure.

Aim: Dysfunction of the cardiac ryanodine receptor (RyR2) is an almost ubiquitous finding in animal models of heart failure (HF) and results in abnormal Ca2+ release in cardiomyocytes that contributes to contractile impairment and arrhythmias. We tested whether exercise training (ET), as recommended by current guidelines, had the potential to stabilize RyR2-dependent Ca2+ release in rats with post-myocardial infarction HF. Materials and Methods: We subjected male Wistar rats to left coronary artery ligation or sham operations. After 1 week, animals were characterized by echocardiography and randomized to high-intensity interval ET on treadmills or to sedentary behavior (SED). Running speed was adjusted based on a weekly VO2max test. We repeated echocardiography after 5 weeks of ET and harvested left ventricular cardiomyocytes for analysis of RyR2-dependent systolic and spontaneous Ca2+ release. Phosphoproteins were analyzed by Western blotting, and beta-adrenoceptor density was quantified by radioligand binding. Results: ET increased VO2max in HF-ET rats to 127% of HF-SED (P < 0.05). This coincided with attenuated spontaneous SR Ca2+ release in left ventricular cardiomyocytes from HF-ET but also reduced Ca2+ transient amplitude and slowed Ca2+ reuptake during adrenoceptor activation. However, ventricular diameter and fractional shortening were unaffected by ET. Analysis of Ca2+ homeostasis and major proteins involved in the regulation of SR Ca2+ release and reuptake could not explain the attenuated spontaneous SR Ca2+ release or reduced Ca2+ transient amplitude. Importantly, measurements of beta-adrenoceptors showed a normalization of beta1-adrenoceptor density and beta1:beta2-adrenoceptor ratio in HF-ET. Conclusion: ET increased aerobic capacity in post-myocardial infarction HF rats and stabilized RyR2-dependent Ca2+ release. Our data show that these effects of ET can be gained without major alterations in SR Ca2+ regulatory proteins and indicate that future studies should include upstream parts of the sympathetic signaling pathway.

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.

Risk factors for exertional rhabdomyolysis with renal stress.

BACKGROUND: Exercise-induced rhabdomyolysis denotes the exertional damage of myocytes with leakage of sarcoplasmic content into the circulation. The purpose of this study was to determine important risk factors for the development of exertional rhabdomyolysis in a temperate climate and to study the renal effects of myoglobinuria. METHODS: A cluster of eight military recruits was admitted to hospital due to exertional rhabdomyolysis with myoglobinuria. The patients were treated according to current guidelines with isotonic saline and alkalinisation of the urine. The eight patients were compared with a randomly selected control group of 26 healthy fellow recruits. All subjects responded to a standardised questionnaire. RESULTS: There were little differences in baseline characteristics between patients and controls. In the present study, exercise intensity, duration and type were all significant determinants of exertional rhabdomyolysis in univariate models. However, in a multivariate model, high exercise intensity on day -1 was the only significant predictor of rhabdomyolysis (p=0.02). All patients had a stable serum creatinine and cystatin C. There was a significant increase in serum neutrophil gelatinase-associated lipocalin (NGAL) in the patients, suggesting renal stress. CONCLUSIONS: Sustained maximal intensity exercise is a crucial risk factor for rhabdomyolysis with gross pigmenturia. Elevated serum NGAL concentrations indicate the presence of renal stress. It appears to be possible to quantify the risk of rhabdomyolysis by means of a simple questionnaire. In the future, this may be used as a tool to prevent rhabdomyolysis.

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.

Beta-Adrenoceptor Stimulation Reveals Ca2+ Waves and Sarcoplasmic Reticulum Ca2+ Depletion in Left Ventricular Cardiomyocytes from Post-Infarction Rats with and without Heart Failure.

Abnormal cellular Ca2+ handling contributes to both contractile dysfunction and arrhythmias in heart failure. Reduced Ca2+ transient amplitude due to decreased sarcoplasmic reticulum Ca2+ content is a common finding in heart failure models. However, heart failure models also show increased propensity for diastolic Ca2+ release events which occur when sarcoplasmic reticulum Ca2+ content exceeds a certain threshold level. Such Ca2+ release events can initiate arrhythmias. In this study we aimed to investigate if both of these aspects of altered Ca2+ homeostasis could be found in left ventricular cardiomyocytes from rats with different states of cardiac function six weeks after myocardial infarction when compared to sham-operated controls. Video edge-detection, whole-cell Ca2+ imaging and confocal line-scan imaging were used to investigate cardiomyocyte contractile properties, Ca2+ transients and Ca2+ waves. In baseline conditions, i.e. without beta-adrenoceptor stimulation, cardiomyocytes from rats with large myocardial infarction, but without heart failure, did not differ from sham-operated animals in any of these aspects of cellular function. However, when exposed to beta-adrenoceptor stimulation, cardiomyocytes from both non-failing and failing rat hearts showed decreased sarcoplasmic reticulum Ca2+ content, decreased Ca2+ transient amplitude, and increased frequency of Ca2+ waves. These results are in line with a decreased threshold for diastolic Ca2+ release established by other studies. In the present study, factors that might contribute to a lower threshold for diastolic Ca2+ release were increased THR286 phosphorylation of Ca2+/calmodulin-dependent protein kinase II and increased protein phosphatase 1 abundance. In conclusion, this study demonstrates both decreased sarcoplasmic reticulum Ca2+ content and increased propensity for diastolic Ca2+ release events in ventricular cardiomyocytes from rats with heart failure after myocardial infarction, and that these phenomena are also found in rats with large myocardial infarctions without heart failure development. Importantly, beta-adrenoceptor stimulation is necessary to reveal these perturbations in Ca2+ handling after a myocardial infarction.

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.

The epidemiology of herpes zoster in 226 children with acute lymphoblastic leukemia.

BACKGROUND: Herpes zoster (HZ) is rare in healthy children, but may occur frequently and take a complicated course in children receiving chemotherapy. We determined the morbidity related to HZ in children with acute lymphoblastic leukaemia (ALL). PROCEDURE: Medical records of 226 children diagnosed with ALL were reviewed. Of these, 160 were seropositive at the time of diagnosis. HZ eruptions during primary chemotherapy, during therapy for relapse and following bone marrow transplantation (BMT) were registered. RESULTS: A total of 90 eruptions were recorded: 63 first-time attacks and 27 recurrent episodes among 14 children. All eruptions were treated with acyclovir (ACV) and in 60% it was given intravenously. Cutaneous dissemination occurred in 11 cases, post herpetic neuralgia in five, visceral dissemination in none. During primary chemotherapy 47 children (29%) had HZ. The eruption rate was significantly higher in children on high risk protocols compared to children on standard/intermediate risk protocols (0.36 vs. 0.07/0.09 per year) and was related to intensity of chemotherapy. During therapy for relapse 7 of 29 (24%) had a total of 13 eruptions. Following BMT 9 of 26 (35%) had a total of 10 eruptions. CONCLUSION: Almost one third of the seropositive children had HZ during primary chemotherapy. Of those treated on high risk protocols more than half had one or more eruptions during the course of treatment. The risk of complicated HZ is small, but prolonged intensive chemotherapy can lead to considerable morbidity from repeated eruptions. Attempts to improve immunity by vaccination after attaining remission seem warranted.