Our laboratory is interested in understanding the basic mechanisms of cardiac arrhythmias with a focus on ventricular arrhythmias and sudden cardiac death. Cardiovascular disease remains the leading cause of death in the United States and other developed countries with a large proportion occurring suddenly. Ventricular arrhythmias account for a substantial portion of these deaths and the basic underlying mechanisms remain to be fully elucidated. The specialized cells of the cardiac conduction system (CCS) play a prominent role in the initiation of such arrhythmias and our aim is to understand the underlying cellular mechanisms. Using genetically engineered mouse models, we have discovered a number of molecular elements specific to conduction system cells that engender unique cellular identity and electrophysiology.
The first area of our research effort relates to the unique cellular behavior of CCS cells that predispose them to arrhythmogenesis. First described over 100 years ago, CCS cells remain poorly understood from a molecular and genetic standpoint due to their scarcity (comprising less than one percent of all cells in the heart) and the lack of cell culture model systems. However, in numerous inherited and acquired conditions such as hypertrophic cardiomyopathy and ischemic heart disease, these cells have been shown to be important for the initiation of ventricular arrhythmias. CCS cells have unique electrophysiologic and intracellular calcium cycling characteristics that make them particularly pro-arrhythmic. Investigation into the nature of this pro-arrhythmic behavior through gene expression analysis and single cell physiology has uncovered unique pathways and potential therapeutic targets. For instance, the regulation of intracellular calcium and calcium-calmodulin dependent kinase 2 (CamKII) within CCS cells through the small IQ motif protein Purkinje cell protein 4 (Pcp4) was first discovered in our lab and is a novel mechanism regulating both ionic currents as well as excitation-contraction coupling that is specific to this cardiomyocyte subtype.
The second area of interest for our lab is in the transcriptional circuitry that underlies CCS development and cell fate specification. While elements of this transcriptional network have been described, recent advances in deep sequencing, chromatin state assessment, and single cell transcriptomics have allowed unprecedented resolution into these processes. Leveraging these techniques has allowed for the discovery of novel transcription factors critical for proper CCS development and elucidated the genetic and molecular mechanisms that govern this process.
