Grant: Project Grant

Abnormal enlargement of the heart main chambers is associated with a disease called dilated cardiomyopathy or DCM and is the most common cause of failing hearts. DCM is associated with abnormal heart beats called arrhythmias and sudden cardiac death in addition to abnormal heart structure that results in abnormal heart contraction. Typically, DCM is diagnosed either when affected individuals present with abnormal heart beats and/or during screening for cardiac pump weakness in individuals considered at risk, such as in family members of DCM patients. Early symptoms are mild and nonspecific and include easy fatigue, shortness of breath, intermittent chest pain, palpitations, fainting, and/or syncope. For over a decade, an ion channel termed sodium channel encoded by SCN5A gene has been associated exclusively to cardiac electrical abnormalities in diseases like Brugada and Long QT syndromes. Recently, we identified a new SCN5A variant where an amino-acid, histidine replaces the arginine (R219H) in a family with complex and irregular heart beats and associated with DCM. The question that remains unanswered is whether abnormal myocardial contractility seen in DCM patients is caused directly by abnormal heart beats, or as we often think that abnormal myocardial contractility (structural defects) is the diver of abnormal heart beats. In this application, we intend to address this new paradigm and answer this question. We developed, for the first time, a mouse model of DCM carrying the R219H mutation using gene targeting technique. Interestingly, these mice also showed the clinical features of DCM seen in patients including abnormal heart beats and abnormal contractility. The objective of the application is to develop and exploit combinations of state-of-the-art approaches and techniques, including our unique mouse model and patient specific stem cell, as well as steps towards developing new drugs that reverses and prevent abnormal heart beats and DCM in these patients.