The -p.Glu401Asp mutation causes predominant inherited left ventricular arrhythmogenic cardiomyopathy/dysplasia with a high incidence of adverse clinical events in the absence of skeletal myopathy or conduction system disorders. The pathogenic mechanism probably corresponds to an alteration in desmin dimer and oligomer assembly and its connection with membrane proteins within the intercalated disc.

Restrictive cardiomyopathy (RCM) is a rare heart disease characterized by diastolic dysfunction and atrial enlargement. The genetic etiology of RCM is not completely known. We identified by a next-generation sequencing panel the novel CRYAB missense mutation c.326A>G, p.D109G in a small family with RCM in combination with skeletal myopathy with an early onset of the disease. CRYAB encodes αB-crystallin, a member of the small heat shock protein family, which is highly expressed in cardiac and skeletal muscle. In addition to in silico prediction analysis, our structural analysis of explanted myocardial tissue of a mutation carrier as well as in vitro cell transfection experiments revealed abnormal protein aggregation of mutant αB-crystallin and desmin, supporting the deleterious effect of this novel mutation. In conclusion, CRYAB appears to be a novel RCM gene, which might have relevance for the molecular diagnosis and the genetic counseling of further affected families in the future.

Atrial fibrillation (AF) is the most common cardiac arrhythmia with a substantial impact on morbidity and mortality. Antiarrhythmic drugs play a major role in rhythm-control therapy of AF. However, currently available agents exhibit limited efficacy and pronounced adverse effects, notably drug-induced proarrhythmia. Recent experimental studies have identified that Ca handling abnormalities are critical elements in AF pathophysiology with central roles in atrial ectopic activity, reentry, and atrial remodeling suggesting that Ca handling abnormalities could be promising targets for novel AF therapeutics. Here, we summarize key aspects of AF-related Ca-handling abnormalities, describe currently available compounds targeting atrial Ca handling, and highlight potential novel targets and experimental drugs currently under investigation. Finally, we assess how close AF therapeutics based on Ca-handling abnormalities are to clinical implementation.