One fifth of us will die suddenly. The field has learned much in the last 20 years: we know that Sudden Cardiac Death (SCD) is often the result of ventricular tachycardia [VT] or fibrillation [VF]; we recognize that structural heart disease and/or coronary artery disease is found in most (>90%) individuals that die suddenly; we have identified new genetic pathways, loci, and specific variants that modulate arrhythmia susceptibility; and we have improved approaches to identify patients at risk. All that said, we have not come very far predicting or preventing SCD due to arrhythmia ' with the exception of treatment of VT/VF by the Implanted Cardioverter Defibrillator. Through this SFRN, the AHA has recognized the clinical challenges that this problem presents, and thus the opportunity presented by developing new knowledge around underlying mechanisms with the goal of 'building healthier lives, free of cardiovascular diseases and stroke'. The development of a new mechanism-based therapeutic strategy and the identification of underlying mechanisms in the human heart represent the major opportunities that our SCD SFRN proposal addresses. Genetic studies have established abnormal intracellular calcium release due to cardiac ryanodine receptor (RyR2) channel hyperactivity as one key arrhythmia mechanism in structurally normal hearts. RyR2 hyperactivity (due to oxidation and/or other posttranslational modification) causing Ca leak has been widely documented in animal models and humans with heart failure. However, its mechanistic role in patients with structural heart disease continues to be debated and has not been tested in clinical trials. This proposal builds on extensive interdisciplinary science at three different institutions (Vanderbilt, George Washington, Lipscomb) to test two interrelated hypotheses examining the role of RyR2 in SCD. We present an extensive body of published and preliminary work that supports hypothesis (1) that specifically targeting RyR2 mediated calcium leak inhibits VT/VF in animal models and humans. Further, we exploit the expertise we have developed over the last decades in studying animal arrhythmia models (Knollmann, Vanderbilt), the ex vivo human heart (Efimov, George Washington) and human inducible VT in the clinical electrophysiology laboratory (Stevenson, Vanderbilt) to test the mechanistic hypothesis (2) that RyR2 block prevents arrhythmogenic triggers and normalizes the pro-arrhythmic substrate in structural heart disease.
|Program type||Strategically Focused Research Network|
|Effective start/end date||07/01/2019 → 06/30/2023|