Pathophysiological mechanism of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) caused by Phospholamban R14 delet

  • Stillitano, Francesca (PI)

Project Details


Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a heritable disease that bridges the gap between the cardiomyopathies and the inherited arrhythmia syndromes. In its early 'concealed' phase, ARVC promotes the incidence of ventricular arrhythmias in the absence of overt structural or mechanical remodeling. As the disease progresses, myocyte loss, inflammation, and fibrofatty infiltration emerge, first in the right and ultimately left ventricles. The pathophysiological significance of the disease, and in particular its early concealed form, is underscored by the fact that ARVC is a leading cause of sudden cardiac death in individuals under the age of 35, and a common trigger appears to be exercise or adrenergic stimulation. Although classically considered to be a disease of the desmosome, there is growing recognition of the importance of mutations in non-desmosomal proteins in ARVC pathophysiology. In particular, a mutation in the Phospholamban gene (PLN R14del) was recently identified in patients diagnosed with ARVC. Using patient-specific induced pluripotent stem cell derived cardiomyocytes (hiPS-CMs), we recently generated an in vitro model for studying cardiac dysfunction caused by the PLN-R14del mutation. In these studies, we observed defective calcium handling and abnormal cytoplasmic distribution of mutated PLN. Furthermore, using either a TALEN-mediated gene correction strategy or a combinatorial gene therapy approach, we successfully rescued the disease phenotype in both hiPS-CMs and human engineered cardiac tissues (hECT). More recently, we developed mouse models with knock-in of the human wild type (hPLN WT) and R14del mutation (hPLN R14del). These mice exhibited selective right-sided prolongation of action potentials and impairment of excitability, increased inter-ventricular repolarization gradients driven by abnormal right-to-left action potential duration (APD) gradients, impaired adaptation of APD to isoproterenol, and a marked increase in adrenergic-mediated ventricular arrhythmias caused by right ventricular reentrant circuits. Based on these data, our central hypothesis is that the hPLN-R14del mutation plays a central role in ARVC related cardiac dysfunction with its overlapping phenotype of early-onset arrhythmias and late-onset heart failure. (AHA Program: Transformational Project Award)

Effective start/end date1/07/1830/06/21


  • American Heart Association: $300,000.00


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