My laboratory studies the molecular and genetic basis of sudden cardiac death in animal models, human families with inherited rhythm disorders, and populations at increased risk for sudden death. Pioneering studies in my laboratory engineered the first mouse models of long QT syndrome. Using these mouse models of arrhythmias and heart failure, we helped to define the ion channels important for cardiac repolarization, developed technologies for studying arrhythmias, and identified some of the basic mechanisms involved in the initiation and propagation of arrhythmias through collaborations with Dr. Guy Salama using optical mapping at the University of Pittsburgh.
Expanding into human studies, we used positional cloning in a large family to identify a novel oxidation-reduction gene (GPD1-L; Glycerol-3-Phosphate Dehydrogenase 1-Like) that modifies trafficking of the cardiac Na+ channel (SCN5A, Nav1.5) and causes both the rare inherited arrhythmia syndrome (Brugada syndrome) and Sudden Infant Death Syndrome (SIDS). Followup mechanistic studies done in collaboration with Dr. Irani, at the University of Iowa, have shown that SIRT1-mediated deacetylation is a novel post-translational modification of Nav1.5. We also studied SERCA2a gene therapy in heart failure using dog models. In addition, we received an NIH Pioneer Award to develop novel tools to noninvasively image electrical activity in the heart. In addition, we will use clinical and genetic data from GRADE to help to identify the genetic causes of dilated cardiomyopathy in African Americans.
Specific Research Focuses
Mouse Models of Arrhythmia
Many K+ channels are expressed in the heart. The role of individual ion channels and their contributions to cardiac repolarization and arrhythmia susceptibility were not known. My laboratory generated a series of transgenic and gene targeted mice to study the roles of individual K+ channels in the cardiac action potential. The first mouse model, a dominant negative transgenic mouse that targeted the Kv1.x family of channels, was begun as a postdoctoral fellow in the laboratory of Dr. Nadal-Ginard [insert link to website] and completed in collaboration with Dr. Gideon Koren. My laboratory then generated and analyzed a number of K+ channel knockout mice (Kv1.4, Merg1) and the first K+ channel knock-in mouse (Kv1.5). These studies produced the first mouse models of inherited arrhythmias, and helped define which ion channels contribute to repolarization and arrhythmias in the mouse.
Novel Tools for Imaging Electrical Activity and Arrhythmias
The development of mouse models with mutant ion channels required the development of equipment and protocols to study murine physiology and electrophysiology. We characterized the mouse electrocardiogram, developed optical mapping of voltage and calcium in collaboration with Dr. Guy Salama, studied heart rate variability and T-wave alternans in collaboration with Dr. Vladimir Shusterman. We translated some of these analyses to the identification of arrhythmias in large animals and humans, and are currently continuing work on noninvasive imaging of electrical activity in the heart (by MRI) started under an NIH Pioneer Award.
Identifying Novel Brugada Syndrome Genes
We began to study families with inherited forms of sudden cardiac death, including Brugada syndrome, with the goal of identifying new genes that would shed insight into cardiac electrophysiology. We identified a cardiac Na+ channel trafficking mutation, and then used positional cloning to identify mutations in a novel gene, GPD1-L, that also affected Na+ channel trafficking and caused Brugada syndrome and SIDS. Ongoing studies are examining the mechanisms by which this redox gene affects trafficking.
Ongoing Research Projects
Regulation of the Cardiac Sodium Channel by SIRTUIN1
Project aims to identify the role of acetylation in sodium channel function and arrhythmias, in collaboration with Dr. Kaiko Irani.
Mitigation of Radiation Induced Damage to the Cardiac Conduction System by Mitochondrial Superoxide Scavengers
GENETIC-AF: A Genotype-Directed Comparative Effectiveness Trial of Bucindolol and Toprol-XL for Prevention of Symptomatic Atrial Fibrillation/Atrial Flutter in Patients with Heart Failure.
Randomized trial of Bisoprolol vs. Toprol XL for the prevention of recurrent AFib in a genotype-guided study
A SIRTUIN-5 Mutation as a Potential Cause of Brugada Syndrome
Project to test whether SIRT5 variants identified by whole exome screening cause Brugada syndrome.