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Area Of Expertise And Primary Interest
My work involves basic and clinical research aimed at understanding the basis for the development of cardiac arrhythmias secondary to genetic mutations involving ion channels within the cells of the heart. Genetic errors in the genes that encode cardiac ion channels can lead to electrical disturbances that can cause lethal arrhythmias such as ventricular fibrillation or less life-threatening arrhythmias such as atrial fibrillation. After finding gene mutations associated with various arrhythmic syndromes such as Brugada and Long QT syndromes, I use heterologous expression of the mutated genes and voltage clamp techniques to study the nature of the dysfunction of the ion channel. When the electrical defect observed is consistent with the phenotype of the patient in the clinic, we gain confidence that the genetic variation uncovered is responsible for the disease. Using these same techniques we are able to begin a search for drug therapies that may be used to correct the abnormality in these patients. In a recent study, we demonstrated for the first time that a mutation in SCN5A, the gene that encodes the a subunit, may be responsible for the development of repeated episodes of ventricular fibrillation, referred to as an electrical storm, in some patients experiencing a heart attack. In other studies, we uncovered a mutation that sensitizes the heart to the antiarrhythmic drug lidocaine, causing it to unmask the Brugada syndrome, an inherited arrhythmias syndrome that leads to sudden death of young adults. In yet another study, we demonstrated the basis for the more sever clinical phenotype of family members with compound mutations responsible for the Brugada syndrome. We also recently demonstrated that a mutation in SCN5A is responsible for conduction disease. The mutation caused a trafficking-defect, meaning that the ion channel protein produced was not properly transported to the membrane of the cardiac cell. The results provide support for the hypothesis that, in addition to the Brugada syndrome, loss of proper transport and functional expression of the hNav1.5 protein in the plasma membrane can result in cardiac conduction defects. In another exciting study, we have attempted to delineate the molecular basis for the different characteristics of sodium channels in cells form the upper (atrial) and lower (ventricular) chambers of the heart. We provide evidence in support of the hypothesis that differences in the stochiometry of a/b subunits may contribute to difference in inactivation characteristics of atrial and ventricular sodium channels. This distinction is the basis for our efforts to identify atrial-selective sodium channel blockers for the management of atrial fibrillation. Selected PublicationsExpression, purification and functional characterization of a recombinant scorpion venom peptide BmTXK?. Effects of BmkTXK? on electrophysiological properties of rabbit atrial myocytes. Inhibitory Effect of BmkTXK? on Transient Outward Potassium Current in Rabbit Atrial Myocytes. Compound heterozygous mutations P336L and I1660V in the human cardiac sodium channel associated with the Brugada Syndrome. Novel mutation in the SCN5A gene associated with arrhythmic storm development during acute myocardial infarction. Genetic predisposition and cellular basis for ischemia-induced ST segment changes and arrhythmias. |
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Medical Research Saves Lives Cardiac Arrhythmias - Cardiovascular Diseases - Sudden Cardiac Arrest  |
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