Sudden cardiac death accounts for more than 300,000 deaths in the United States alone. Arrhythmias due to primary structural diseases such as dilated cardiomyopathy (DCM) followed by other non-structural cardiac diseases, such as long QT syndrome (LQTS) and Brugada syndrome (BS) must be considered as likely causes of sudden cardiac death. Cytoskeletal proteins such as dystrophin, the major link between the sarcomere and the sarcolemma in cardiac cells, have been involved in sudden cardiac death. Other dystrophin associated proteins, such as alpha1-syntrophin, when altered, could fail to provide correct anchorage and localization for ion channels on the plasma membrane. We hypothesize that alpha1-syntrophin mutations can cause both ventricular dysfunction and arrhythmias. In particular our aims are: 1) to evaluate for genetic abnormalities in alpha1-syntrophin as causing DCM, LQTS and BS. We hypothesize that alpha1-syntrophin mutations cause DCM, LQTS and BS.
Specific Aim #1 : To evaluate for genetic abnormalities in alpha1-syntrophin as determinants of ventricular arrhythmias with or without structural damage.
Specific Aim #2 : To perform functional analysis in alpha1-syntrophin mutant models of cardiomyopathy and ventricular arrhythmias. Specific #3: To evaluate the effect of mechanical unloading on cardiac reverse remodeling in alpha1-syntrophin mutant models. We will screen alpha1-syntrophin gene for mutations in 200 DCM, LQTS and 100 BS probands. We expect to identify mutations in alpha1-syntrophin as the cause of DCM, LQTS and BS; 2) to perform functional analysis in alpha1-syntrophin mutant models of DCM, LQTS or BS. We hypothesize that alpha1-syntrophin mutations cause protein structural changes leading to cytoskeletal network disruption and ion channels displacement. Identifying cytoskeletal mecahnisms involved in malignant arrhythmias, could lead to the design of novel drugs and the employment of therapeutic means, resulting in a better patients management.
