Division of Cardiovascular Diseases Strategic Plan

Goals in Cardiovascular Clinical Problems or Disease States

2.3a. Develop means to predict and prevent sudden cardiac arrest and subsequent death

Table of Contents

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Overview

There are 250,000-400,000 sudden cardiac arrests and subsequent deaths (SCA/D) in the U.S. each year, accounting for up to 20 percent of all deaths in adults. For patients with CAD, most of these deaths are due to ventricular fibrillation and other tachyarrhythmias. Despite dramatic advances in arrhythmia therapy, contemporary treatment approaches to SCA/D continue to be limited. Use of implantable cardioverter defibrillator (ICDs) in primary prevention of SCA/D is life-saving, but inefficient and costly, as currently applied. Traditional antiarrhythmic drugs have not reduced mortality and in some cases, are proarrhythmic. Failed pharmacotherapy may be due to the gathering of preclinical data from inappropriate animal models, and to the clinical dissociation between prevention of premature ventricular depolarizations and SCA/D. Evidence indicates that arrhythmias result from the dynamic interplay among genes, a susceptible substrate, proximal triggers, upstream modulators, and perpetuators. The integration of molecular, cellular, physiological, and clinical approaches to improve understanding of fundamental mechanisms, as well as the translational testing of already identified mechanisms, are needed to delineate risk factors to predict and prevent SCA/D.

Strategies to Accomplish this Goal May Entail:

Basic Research:

  • Elucidate fundamental mechanisms responsible for SCA/D.
  • Identify risk stratifiers that include electrocardiographic changes, biomolecules, genetic and environmental factors to improve SCA/D diagnosis, treatment, and prevention.
  • Investigate mechanisms through which abnormalities in ion channel function, structural remodeling, ischemia/reperfusion injury, and neurohormonal alterations contribute to the development of lethal ventricular arrhythmias.
  • Develop an integrative understanding of factors resulting in arrhythmia-induced SCA/D and identify new, effective and as yet unrecognized diagnostic and therapeutic targets.
  • Develop new approaches to arrhythmia treatment, including noninvasive or leadless defibrillators.
  • Create the infrastructure to obtain, in a standardized manner, diseased and healthy human cardiac tissue obtained at surgery for immediate electromechanical studies to further the fundamental understanding of cardiac rhythm and contractility.

Translational Research:

  • Develop ways to accurately foretell SCA/D by utilizing electrical, imaging, genetic, and other techniques as predictive risk stratifiers.
  • Investigate promising pharmacologic and other interventions designed to reduce the incidence of arrhythmia and SCA/D using well-justified endpoints in appropriate animal models prone to spontaneous lethal arrhythmia development.
  • Create and support an infrastructure for a repository of clinically obtained, human cardiac tissue that is well phenotyped, and made available for histologic, immunohistochemical, and genetic analyses to be integrated with the results of cellular electrophysiology studies and available clinical data.

Clinical Research:

  • Develop non-invasive means, by using imaging, and electrical, functional, genetic, and biological markers, to clinically identify patients at high risk of SCA/D.
  • Develop and validate rapid cost-effective tools for screening athletes, and eventually the general population, to identify SCA/D risk.
  • Develop evidence-based screening protocols for diagnosing genetic conditions and environmental factors in both children and adults at increased risk of SCA/D.
  • Examine the impact of novel pharmacologic and other therapeutic interventions designed to prevent and terminate life-threatening arrhythmias and reduce SCA/D incidence.
  • Develop and validate a risk stratification tool to reliably predict the occurrence of spontaneous “shockable” ventricular arrhythmias after MI, and efficiently identify very high-risk participants for whom an ICD would be most cost-effective, as well as very low-risk participants for whom an ICD is not needed.

Contributing Sources:

September 2008

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