Malignant hyperthermia (MH) is a life-threatening disorder characterized by skeletal muscle rigidity and elevated body temperature in response to halogenated anesthetics such as isoflurane or halothane. Mutation of tyrosine 522 of RyR1 (the predominant skeletal muscle calcium release channel) to serine has been associated with human malignant hyperthermia. In the present study, mice created harboring this mutation were found to represent the first murine model of human malignant hyperthermia. Mice homozygous for the Y522S mutation exhibit skeletal defects and die during embryonic development or soon after birth. Heterozygous mice, which correspond to the human occurrence of this mutation, are MH susceptible, experiencing whole body contractions and elevated core temperatures in response to isoflurane exposure or heat stress. Skeletal muscles from heterozygous mice exhibit increased susceptibility to caffeine- and heat-induced contractures in vitro. In addition, the heterozygous expression of the mutation results in enhanced RyR1 sensitivity to activation by temperature, caffeine, and voltage but not uncompensated sarcoplasmic reticulum calcium leak or store depletion. We conclude that the heterozygous expression of the Y522S mutation confers susceptibility to both heat- and anesthetic-induced MH responses.

Atrial fibrillation (AF), the most common human cardiac arrhythmia, is associated with abnormal intracellular Ca 2+ handling. Diastolic Ca 2+ release from the sarcoplasmic reticulum via "leaky" ryanodine receptors (RyR2s) is hypothesized to contribute to arrhythmogenesis in AF, but the molecular mechanisms are incompletely understood. Here, we have shown that mice with a genetic gain-of-function defect in Ryr2 (which we termed Ryr2 R176Q/+ mice) did not exhibit spontaneous AF but that rapid atrial pacing unmasked an increased vulnerability to AF in these mice compared with wild-type mice.

Mutations in the cardiac ryanodine receptor 2 (RyR2) have been associated with catecholaminergic polymorphic ventricular tachycardia and a form of arrhythmogenic right ventricular dysplasia. To study the relationship between RyR2 function and these phenotypes, we developed knockin mice with the human disease-associated RyR2 mutation R176Q. Histologic analysis of hearts from RyR2 R176Q/؉ mice revealed no evidence of fibrofatty infiltration or structural abnormalities characteristic of arrhythmogenic right ventricular dysplasia, but right ventricular end-diastolic volume was decreased in RyR2 R176Q/؉ mice compared with controls, indicating subtle functional impairment due to the presence of a single mutant allele. Ventricular tachycardia (VT) was observed after caffeine and epinephrine injection in RyR2 R176Q/؉ , but not in WT, mice. Intracardiac electrophysiology studies with programmed stimulation also elicited VT in RyR2 R176Q/؉ mice. Isoproterenol administration during programmed stimulation increased both the number and duration of VT episodes in RyR2 R176Q/؉ mice, but not in controls. Isolated cardiomyocytes from RyR2 R176Q/؉ mice exhibited a higher incidence of spontaneous Ca 2؉ oscillations in the absence and presence of isoproterenol compared with controls. Our results suggest that the R176Q mutation in RyR2 predisposes the heart to catecholamine-induced oscillatory calcium-release events that trigger a calcium-dependent ventricular arrhythmia.arrhythmogenic right ventricular dysplasia ͉ catecholaminergic polymorphic ventricular tachycardia ͉ calcium-release channel T he cardiac ryanodine receptor 2 (RyR2) regulates calcium release from the sarcoplasmic reticulum in cardiomyocytes (1). Two inherited arrhythmogenic syndromes have been linked to mutations in RyR2, arrhythmogenic right ventricular dysplasia (ARVD) and catecholaminergic polymorphic ventricular tachycardia (CPVT) (2, 3). ARVD and CPVT are both characterized by ventricular arrhythmias and a high rate of juvenile sudden death. Patients with CPVT exhibit catecholamine-induced bidirectional ventricular tachycardia (VT) in the setting of a structurally normal heart, whereas patients with ARVD exhibit progressive fibrofatty replacement of the right ventricular myocardium in addition to polymorphic VT. ARVD arising from RyR2 mutations (ARVD2) is typically associated with exercise-induced ventricular arrhythmias and relatively mild structural abnormalities compared with other forms of ARVD and, in some ways, mimics the CPVT phenotype. In fact, the diagnosis of ARVD2 in patients with RyR2 mutations is controversial because of the differences in degree of cardiac structural abnormalities between ARVD2 and other forms of ARVD (4).Disease-causing mutations in RyR2 and the skeletal muscle isoform RyR1 cluster in three highly conserved regions: a cytosolic N-terminal region, a cytosolic central region, and a C-terminal portion containing the transmembrane and pore regions of the channel (5, 6). Multiple mutations in RyR2 have been reported in patients with ...

This retrospective analysis demonstrated that more severe LA LGE is associated with increased MACCE risk, driven primarily by increased risk of stroke or TIA.

BACKGROUND-Although defective Ca 2+ homeostasis may contribute to arrhythmogenesis in atrial fibrillation (AF), the underlying molecular mechanisms remain poorly understood. Studies in patients with AF revealed that impaired diastolic closure of SR Ca 2+ -release channels (ryanodine receptors, RyR2) is associated with reduced levels of the RyR2-inhibitory subunit FKBP12.6.

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Background Late gadolinium enhancement magnetic resonance imaging is an effective tool for assessment of atrial fibrosis. The degree of left atrial fibrosis is a good predictor of atrial fibrillation ( AF ) ablation success at 1 year, but the association between left atrial fibrosis and long‐term ablation success has not been studied. Methods and Results Late gadolinium enhancement magnetic resonance images of sufficient quality to quantify atrial fibrosis were obtained before the first AF ablation in 308 consecutive patients. Left atrial fibrosis was classified in 4 Utah stages (I, 0–10%; II , 10–20%; III , 20–30%; and IV , >30%). Patients were followed up for up to 5 years until the time of first arrhythmia recurrence or second ablation. A total of 308 patients were included; the mean age was 64.5±12.1 years, and 63.4% were men. During follow‐up, 157 patients experienced an arrhythmia recurrence and 106 patients underwent a repeated ablation. A graded effect was observed in which patients with more advanced atrial fibrosis were more likely to experience recurrent AF (hazard ratio for stage IV versus stage I, 2.73; 95% confidence interval, 1.57–4.75) and undergo a repeated ablation (proportional odds ratio for stage IV versus stage I, 5.19; 95% confidence interval, 2.12–12.69). Conclusions The degree of left atrial fibrosis predicts the success of AF ablation at up to 5 years follow‐up. In patients with advanced atrial fibrosis, AF ablation is associated with a high procedural failure rate.

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