This is a new application to fund research designed to elucidate molecular mechanisms in the pathogenesis of arrhythmogenic right ventricular cardiomyopathy (ARVC). Although it is a relatively rare disease, ARVC should be studied for several reasons: it has an unusually dramatic arrhythmogenic phenotype (it is the most arrhythmogenic heart disease known);the monogenic causes implicate important disease mechanisms that are likely to apply to more common forms of heart disease;and it's highly variable genetic penetrance indicates the presence of powerful modifiers of the risk of sudden death. Future studies to define these modifiers could identify new targets for mechanism-based therapies to prevent lethal arrhythmias (something we sorely lack). A cardinal feature of ARVC is a very high incidence of ventricular arrhythmias which occur early in the natural history of the disease and often precede the development of significant ventricular remodeling or contractile dysfunction. While there has been important progress in identifying mutations in desmosomal genes that lead to ARVC, much less is known about how the mutant proteins cause the disease. One leading hypothesis is that abnormal cell-cell adhesion injures cardiac myocytes and promotes cell death and subsequent replacement by fibro-fatty tissue. Such a mechanism almost certainly plays a role. However, desmosomal proteins may fulfill dual roles as structural proteins in adhesion junctions and as signaling molecules which can inhibit Wnt signaling and, thereby, modulate pathological gene expression, promote cardiac myocyte apoptosis and perhaps mediate expression of a fibrogenic and/or adipogenic phenotype. Either or both mechanisms could lead to gap junction remodeling as an early manifestation in ARVC, but little is actually known about the responsible mechanism(s). We have discovered that redistribution of the desmosomal protein plakoglobin (aka 3-catenin) from junctional to intracellular pools occurs in virtually all cases of ARVC regardless of the specific mutation involved or even when no mutation can be identified. This strongly suggests that plakoglobin plays a fundamental role, via a final common pathway, in disease pathogenesis. Accordingly, the proposed research is focused specifically on two different disease-related mutations in the gene encoding plakoglobin (2057del2 and S39_K40insS) and how they cause ARVC. Using state-of-the-art in vitro approaches and new animal models, we will test the hypothesis that ARVC results from both compromised cell biomechanical properties and pathological perturbations in Wnt signaling via a common final pathway in which subcellular re-distribution of plakoglobin plays a pivotal role. This unifying hypothesis provides a novel, testable explanation for the clinical observation that ARVC patients often experience acute exacerbations following intense exercise. Thus, we will test the hypothesis that mechanical stress, such as might occur following strenuous or prolonged exercise, destabilizes desmosomes in the heart (especially in the right ventricle) which leads to increased cytoplasmic concentrations of plakoglobin and, then, to pathological signaling responses.

Public Health Relevance

This project is designed to advance our understanding of sudden cardiac death, a major public health plague, by defining fundamental mechanisms responsible for arrhythmogenic right ventricular cardiomyopathy (ARVC). Although ARVC is a relatively uncommon disease, it carries the greatest risk of sudden death of any human heart disease. We have made a major discovery about the underlying molecular pathway responsible for sudden death in ARVC. Through studies proposed in this application, we expect to gain a greater understanding of sudden death, not only in ARVC but in more common forms of heart disease as well. Our ultimate goal is to help develop mechanism-based therapies to prevent sudden death.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
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Lathrop, David A
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Beth Israel Deaconess Medical Center
United States
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Asimaki, Angeliki; Kléber, André G; MacRae, Calum A et al. (2014) Arrhythmogenic Cardiomyopathy - New Insights into Disease Mechanisms and Drug Discovery. Prog Pediatr Cardiol 37:3-7
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