Desmoplakinopathies: Integrated Pathophysiology and Therapeutics

PROJECT SUMMARY
Arrhythmogenic Cardiomyopathy (ACM) is a heritable disease that bridges the gap between the
cardiomyopathies and the inherited arrhythmia syndromes. In its early “concealed” phase, ACM 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, culminating in biventricular failure and
further risk of sudden cardiac death (SCD). The pathophysiological significance of the disease is underscored
by the fact that ACM is a leading cause of SCD in young individuals < 35 years of age. Mutations in desmosomal
proteins account for the majority (approx. 60%) of ACM cases, and in this project we focus on a form of ACM
known as Desmoplakin (DSP) cardiomyopathy (DSP-CM). DSP-CM has recently emerged as a unique clinical
entity that engenders a severe left-dominant form of the disease. DSP-CM is now well recognized to be a
heritable disease that is transmitted in an autosomal dominant pattern, albeit with incomplete and highly variable
penetrance. Indeed, a major challenge in the field has been the lack of ability to distinguish whom amongst
carriers of pathogenic DSP variants are truly at risk of SCD and whom will go on to live healthy and symptom-
free lives. This issue takes on added urgency given that the prevention strategy for SCD in DSP-CM is exercise
restriction, a rather draconian measure for young healthy individuals, often athletes. The highly variable
penetrance associated with DSP-CM as well as the typical mode of SCD that these patients exhibit highlight the
importance of gene-environment interactions in unmasking disease pathogenicity. Our own recent work has
identified calpain-mediated desmoplakin degradation as a key factor linking DSP mutations with the development
of ACM and its exacerbation by exercise. Our central hypothesis is that: 1) calpain-mediated loss of myocyte
DSP protein is a key molecular event that is unmasked by exercise and β-adrenergic stimulation, and 2) the
pathogenic effects of DSP degradation at the intercalated disc (ID) are exacerbated by abnormal stretch-related
mechanotransduction leading to arrhythmias and heart failure. We will address this dual hypothesis using a multi-
scale approach encompassing complementary studies in human engineered heart tissues (hEHT) and
innovative genetic and surgical mouse models that are designed to address the complex interactions between
external stressors (increased preload) and genetic predisposition (DSP mutations) in the manifestation of DSP-
CM. Our studies will enable us to tease out contributions of separate aspects of endurance exercise to myocyte
dysfunction and expose pathophysiological mechanisms by which calpain vulnerability is unmasked by external
stressors to promote early onset arrhythmias and heart failure progression. Finally, we will test novel gene and
small molecule-based approaches to inhibit exercise-related calpain vulnerability while avoiding toxicity.

Grant Number: 5R01HL163092-04
NIH Institute/Center: NIH
Principal Investigator: STUART CAMPBELL