Advances in our understanding of the molecular mechanisms underlying various genetic arrhythmia syndromes bring the promise of many new and better treatments. Despite this promise, current treatment is based on empiric observations, retrospective data, and small case series. The research we propose addresses this disparity by translating discovery in cellular and animal models to prospective trials in genetic arrhythmia syndromes. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic syndrome characterized by frequent ventricular tachycardia and risk for sudden death. Although the genetic and molecular basis of the disease is now understood, current drug treatment strategies remain essentially unchanged since the initial description of the syndrome >30 years ago. We recently discovered that the antiarrhythmic drug flecainide directly targets the molecular defect in CPVT. We tested flecainide in our mouse model of CPVT and found that it completely eliminated VT. We then performed an international multicenter trial of flecainide in CPVT patients with persistent exercise-induced VT despite maximally-tolerated standard therapy. Flecainide significantly reduced or eliminated VT in the majority of these patients. Thus, flecainide is a promising candidate to translate basic discovery into better treatments for genetic arrhythmia syndromes. To date, the effectiveness of flecainide in improving the clinical outcome of CPVT patients has not been tested. This is a critical issue, as flecainide increases mortality in patients after myocardial infarction despite a strong suppression of ventricular ectopy. In this proposal, we will test the hypothesis that flecainide will reduce cardiac events in patients with CPVT. We will also seek to identify novel genetic causes and genetic modifiers of CPVT with next-generation sequencing of candidate genes in subjects enrolled in the trial. Accomplishing these specific aims will result in a radical shift in genetic arrhythmia syndrome research including mechanism- based and personalized treatments and prospective trials with hard endpoints.

Public Health Relevance

The proposed research will study a promising new treatment for a deadly heart rhythm disease, while studying how a person's genes affect that disease. This research has potential to identify new life-saving treatments for this disease, help scientists learn more about the disease, and provides a new model to do this in many other diseases, thereby significantly impacting public health.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL108173-04
Application #
8644871
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Boineau, Robin
Project Start
2011-06-20
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
4
Fiscal Year
2014
Total Cost
$542,270
Indirect Cost
$187,857
Name
Vanderbilt University Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Gomez-Hurtado, Nieves; Blackwell, Daniel Jesse; Knollmann, Bjorn Christian (2017) Modelling human calmodulinopathies with induced pluripotent stem cells: progress and challenges. Cardiovasc Res 113:437-439
Kannankeril, Prince J; Moore, Jeremy P; Cerrone, Marina et al. (2017) Efficacy of Flecainide in the Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia: A Randomized Clinical Trial. JAMA Cardiol 2:759-766
Gomez-Hurtado, Nieves; Boczek, Nicole J; Kryshtal, Dmytro O et al. (2016) Novel CPVT-Associated Calmodulin Mutation in CALM3 (CALM3-A103V) Activates Arrhythmogenic Ca Waves and Sparks. Circ Arrhythm Electrophysiol 9:
Roston, Thomas M; Vinocur, Jeffrey M; Maginot, Kathleen R et al. (2015) Catecholaminergic polymorphic ventricular tachycardia in children: analysis of therapeutic strategies and outcomes from an international multicenter registry. Circ Arrhythm Electrophysiol 8:633-42
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Faggioni, Michela; van der Werf, Christian; Knollmann, Bjorn C (2014) Sinus node dysfunction in catecholaminergic polymorphic ventricular tachycardia: risk factor and potential therapeutic target? Trends Cardiovasc Med 24:273-8
Faggioni, Michela; Savio-Galimberti, Eleonora; Venkataraman, Raghav et al. (2014) Suppression of spontaneous ca elevations prevents atrial fibrillation in calsequestrin 2-null hearts. Circ Arrhythm Electrophysiol 7:313-20

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