Store-Operated Ca(2+) Entry as a Putative Target of Flecainide for the Treatment of Arrhythmogenic Cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder that may lead patients to sudden cell death through the occurrence of ventricular arrhythmias. ACM is characterised by the progressive substitution of cardiomyocytes with fibrofatty scar tissue that predisposes the heart to life-threatening arrhythmic events. Cardiac mesenchymal stromal cells (C-MSCs) contribute to the ACM by differentiating into fibroblasts and adipocytes, thereby supporting aberrant remodelling of the cardiac structure. Flecainide is an I(c) antiarrhythmic drug that can be administered in combination with β-adrenergic blockers to treat ACM due to its ability to target both Na(v)1.5 and type 2 ryanodine receptors (RyR2). However, a recent study showed that flecainide may also prevent fibro-adipogenic differentiation by inhibiting store-operated Ca(2+) entry (SOCE) and thereby suppressing spontaneous Ca(2+) oscillations in C-MSCs isolated from human ACM patients (ACM C-hMSCs). Herein, we briefly survey ACM pathogenesis and therapies and then recapitulate the main molecular mechanisms targeted by flecainide to mitigate arrhythmic events, including Na(v)1.5 and RyR2. Subsequently, we describe the role of spontaneous Ca(2+) oscillations in determining MSC fate. Next, we discuss recent work showing that spontaneous Ca(2+) oscillations in ACM C-hMSCs are accelerated to stimulate their fibro-adipogenic differentiation. Finally, we describe the evidence that flecainide suppresses spontaneous Ca(2+) oscillations and fibro-adipogenic differentiation in ACM C-hMSCs by inhibiting constitutive SOCE.