Research Highlights - Nashville Center, United States
Studies dating back to the 1970s at the Vanderbilt focused on mechanisms underlying variability in response drug therapy, including therapies directed at arrhythmias. These studies helped define the role of genetics of drug metabolism and the role of active drug metabolites in modulating variable drug actions. An area of special interest has been drug-induced arrhythmias, including those related to the long QT syndrome.
Vanderbilt has evolved into a leading center in the application of new genetic, molecular, and cellular information to understanding the electrophysiologic behavior of the heart and its response to drug therapy. The Clinical Arrhythmia Service at Vanderbilt has participated in multiple landmark multicenter trials, including the Cardiac Arrhythmia Suppression Trial (CAST), Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM), Antiarrhythmics Versus Implanted Devices (AVID), and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT).
Basic and clinical research at the Vanderbilt site continues to focus on molecular mechanisms in arrhythmias, and the use of contemporary genetic and genomic principles to approach the problem of variable drug responses in humans. Projects include studies in molecular medicine and genetics, incorporating in vitro electrophysiologic methods, mouse models, and studies in individual patients, families, and large human populations; examples are
- The functional consequences of coding and non-coding variants in ion channel and other genes;
- Evaluation of mechanisms of arrhythmia susceptibility and drug responses in mouse models of ion channel diseases;
- Studies of structure-function relations of wild-type and variant ion channels;
- Definition of the functional consequences of sodium channel deletion in zebrafish;
- The clinical genomics of SCD, atrial fibrillation and other human arrhythmias.