Cardiac ryanodine receptor (RyR2) gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia, a condition characterized by prominent ventricular ectopy in response to catecholamine stress, which can be reproduced on exercise stress testing (EST). However, reports of sudden cardiac death (SCD) have emerged in EST-negative individuals who have loss-of-function (LOF) RyR2 mutations. The clinical relevance of RyR2 LOF mutations including their pathogenic mechanism, diagnosis, and treatment are all unknowns. Here, we performed clinical and genetic evaluations of individuals who suffered from SCD and harbored an LOF RyR2 mutation. We carried out electrophysiological studies using a programed electrical stimulation protocol consisting of a long-burst, long-pause, and short-coupled (LBLPS) ventricular extra-stimulus. Linkage analysis of RyR2 LOF mutations in six families revealed a combined logarithm of the odds ratio for linkage score of 11.479 for a condition associated with SCD with negative EST. A RyR2 LOF mouse model exhibited no catecholamine-provoked ventricular arrhythmias as in humans but did have substantial cardiac electrophysiological remodeling and an increased propensity for early afterdepolarizations. The LBLPS pacing protocol reliably induced ventricular arrhythmias in mice and humans having RyR2 LOF mutations, whose phenotype is otherwise concealed before SCD. Furthermore, treatment with quinidine and flecainide abolished LBLPS-induced ventricular arrhythmias in model mice. Thus, RyR2 LOF mutations underlie a previously unknown disease entity characterized by SCD with normal EST that we have termed RyR2 Ca2+ release deficiency syndrome (CRDS). Our study provides insights into the mechanism of CRDS, reports a specific CRDS diagnostic test, and identifies potentially efficacious anti-CRDS therapies.

ET in resynchronized CHF patients is feasible and further enhances exercise tolerance. Patients with severe CHF should be prescribed an exercise training programme after implantation in order to maximize the expected benefit.

In this Belgian national screening programme, prevalence of AF was 1.4%. The use of an ECG handheld machine is feasible to identify a significant number of new AF cases, most with a high thrombo-embolic risk. Given the low OAC use recorded, greater efforts in AF detection and treatment are urgently needed to reduce the burden of stroke associated with this common arrhythmia.

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Aims Overall, 40% of patients with atrial fibrillation are asymptomatic. The usefulness and cost-effectiveness of atrial fibrillation screening programmes are debated. We evaluated whether an atrial fibrillation screening programme with a handheld electrocardiogram (ECG) machine in a population-wide cohort has a high screening yield and is cost-effective. Methods We used a Markov-model based modelling analysis on 1000 hypothetical individuals who matched the Belgian Heart Rhythm Week screening programme. Subgroup analyses of subjects ≥65 and ≥75 years old were performed. Screening was performed with one-lead ECG handheld machine Omron® HeartScan HCG-801. Results In both overall population and subgroups, the use of the screening procedure diagnosed a consistently higher number of diagnosed atrial fibrillation than not screening. In the base-case scenario, the screening procedure resulted in 106.6 more atrial fibrillation patient-years, resulting in three fewer strokes, 10 more life years and five more quality-adjusted life years (QALYs). The number needed-to-screen (NNS) to avoid one stroke was 361. In subjects ≥65 years old, we found 80.8 more atrial fibrillation patient-years, resulting in three fewer strokes, four more life-years and five more QALYs. The NNS to avoid one stroke was 354. Similar results were obtained in subjects ≥75 years old, with a NNS to avoid one stroke of 371. In the overall population, the incremental cost-effectiveness ratio for any gained QALY showed that the screening procedure was cost-effective in all groups. Conclusions In a population-wide screening cohort, the use of a handheld ECG machine to identify subjects with newly diagnosed atrial fibrillation was cost-effective in the general population, as well as in subjects ≥65 and subjects ≥75 years old.