Sudden cardiac death (SCD) accounts for up to 20% of deaths in the U.S. and ventricular tachycardia (VT) and ventricular fibrillation (VF) from structural heart disease are major causes. Fortunately, implantable defibrillators can terminate VT/VF, but they do not prevent it. Unfortunately, the occurrence of VT/VF increases the risk of heart failure hospitalizations and death, and once VT occurs, it is likely to recur. For decades antiarrhythmic drugs (AADs) have been the major therapy to prevent VT/VF, but they have been limited by poor efficacy and toxicity. A major unmet need is the development of a new class of AADs to prevent VT/VF in structural heart disease. We present here strong evidence implicating intracellular Ca leak as a mechanism contributing to VT/VF triggers and proarrhythmic changes in the ventricular substrate, and reduced Ca cycling leading to hemodynamic deterioration. For over a decade, Vanderbilt has been a leader in research focused on inhibiting RyR2-mediated Ca leak to treat VT/VF. Our early work resulted in flecainide (a combined Na channel plus RyR2 inhibitor) being adopted into clinical practice to prevent VT in patients with the rare genetic syndrome catecholaminergic polymorphic VT. Now, with the recognition that structural heart disease results in RyR2 hyperactivity, we and others have used experimental probe drugs to demonstrate the potential of selective RyR2 inhibition (without Na blockade) to treat VT from common causes such as structural heart disease. These drugs include dantrolene, an RyR1/RyR2 inhibitor which emerging data suggest reduces the susceptibility to VT/VF in experimental models of VF, heart failure, and myocardial infarction. Accordingly, we will conduct a randomized controlled trial of dantrolene versus placebo in patients with structural heart disease referred for VT ablation to test the hypotheses that RyR2 inhibition reverses proarrhythmic changes in ventricular conduction and refractoriness (Aim 1), improves cardiac hemodynamic performance (Aim 2), and reduces susceptibility to VT/VF (Aim 3). We have experience conducting clinical trials of investigational AADs in the EP lab and will accomplish the proposed Aims by performing an EP study with programmed ventricular stimulation and invasive hemodynamic assessment before and after administration of I.V. dantrolene, thereby generating in-vivo human data to advance the development of RyR2 modulators as a novel AAD class for the treatment of VT/VF.
|Program type||Strategically Focused Research Network|
|Effective start/end date||07/01/2019 → 06/30/2023|