Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease that is characterized by right ventricular (RV) dysfunction and sudden death due to ventricular arrhythmias. It often affects young athletic men and is an important cause of sudden death during sport activities. Right ventricular failure in this condition is progressive resulting in shortness of breath and fatigue, and ultimately need for cardiac transplantation..Currently, patients with ARVC receive defibrillators to prevent sudden death;however no therapies exist to alter the progress of RV dysfunction. RV failure in ARVC is also associated with the development of conduction delays, particularly a right bundle branch block (RBBB). This makes the heart contract in a discoordinate manner. Recent studies have highlighted the role of dyssynchrohous electrical activation in left ventricular dysfunction associated with LBBB, and for this disorder, bi-ventricular pacing or cardiac resynchronization therapy has been used to restore electrical synchrony. This improves function, symptoms, and survival in these patients. We believe a similar mechanism exists in ARVC related RV dysfunction and the current proposal is designed to explore this association of RBBB and RV dysfunction in an attempt to investigate novel pacing strategies to acutely improve RV function in ARVC. We have designed our specific aims to study the interaction between electrical activation and mechanical function.
The specific aims of this proposal are 1) To test the hypothesis that the electrical delay in septal to RV free wall activation time is tightly correlated with RV regional and global function in patients with ARVC;2) To study a potential mechanism that underlies activation delay in the RV, namely the localization and expression of the key conduction protein connexin-43 at the gap junctions, and its relation to electrical propagation;and 3). To test the hypothesis that resynchronization of the RV by simultaneous pacing of RV free wall and septum will improve RV function in ARVC. In addition a key component of this proposal is a carefully planned career development plan that will allow me to develop my research and clinical skills to achieve my long term objective to be a leader in diagnosis and management of genetic cardiomyopathies. The studies proposed in this grant will greatly expand our understanding of ARVC, and potential pave the way for a new therapeutic approach to treating this often tragic disease. The results may prove applicable to other disorders, such as forms of congenital heart disease and pulmonary hypertension, where right ventricular function is often affected. Finally, insights gained from gap junctional protein expression in ARVC may stimulate research in the role of gap junctional proteins in arrhythmogenesis in other inherited cardiomyopathies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZHL1-CSR-R (M1))
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Scott, Jane
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Johns Hopkins University
Internal Medicine/Medicine
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Philips, Binu; Madhavan, Srinivasa; James, Cynthia A et al. (2014) Arrhythmogenic right ventricular dysplasia/cardiomyopathy and cardiac sarcoidosis: distinguishing features when the diagnosis is unclear. Circ Arrhythm Electrophysiol 7:230-6
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Ling, Zhiyu; Hari, Adithya; Tandri, Harikrishna (2014) VT ablation: New Developments and Approaches. Curr Treat Options Cardiovasc Med 16:297
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Philips, Binu; Madhavan, Srinivasa; James, Cynthia et al. (2013) High prevalence of catecholamine-facilitated focal ventricular tachycardia in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Arrhythm Electrophysiol 6:160-6
James, Cynthia A; Bhonsale, Aditya; Tichnell, Crystal et al. (2013) Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers. J Am Coll Cardiol 62:1290-1297

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