Division of Cardiovascular Medicine

Overview

The goal of our research since its inception has been translation of cardiovascular pathophysiology from bench to bedside, with a focus on cardiac arrhythmias, a major public health problem.  Atrial Fibrillation (AF) affects 2-5 million Americans and continues to be a major cause of morbidity and mortality.  Although AF is the commonest arrhythmia requiring therapy, response in an individual patient is highly variable.  Studies at multiple centers, including our own, have identified both common and rare genetic variants contributing to AF susceptibility, and although the underlying mechanisms have not been entirely worked out, this line of investigation clearly suggests that the final common phenotype of AF arises through multiple pathways.

We have developed a research program that addresses both clinical management as well as underlying genetic issues in AF.  We established the Vanderbilt AF Registry, the key enabling resource for studying the genetic basis for AF and evaluating if variability to drug response is genetically modulated. Over 1,500 patients with ECG confirmation of AF have been enrolled;  304 have "lone" AF, i.e.,  AF in the absence of  detectable underlying heart disease, a subset enriched for genetic risk in AF.  This clinical-DNA Registry has already proven to be an important source for not only phenotyping large AF pedigrees but also analyzing genomic factors modulating drug response in patients with AF.

We have shown that common variation in the angiotensin-converting enzyme (ACE) gene may contribute to variability in drug response in AF.  The Registry was also the key resource in our discovery that mutations in the cardiac sodium channel - a key determinant of conduction in the heart - are unexpectedly quite common, almost 10%, in AF; this funding lends support to the idea of rare variants in common genes and pathways as modulators of risk for common phenotypes like AF.  We have recently used this resource to demonostrate that common AF-associated variants on chromosome 4q25 modify the clinical expression of latent cardiac ion channel and other gene mutations associated with familial AF.  These findings support the idea that the genetic architecture of common human phenotypes like AF includes both rare and common variants.  In summary, we have used the Vanderbilt AF Registry to identify genetic, molecular and clinical subtypes of  AF,  laying the basis for rational mechanism-based and directed treatments for this common and morbid condition.

Selected Publications