NHLBI Working Group
Modifiers of Arrhythmias: New Targets for Therapy and Prevention

Executive Summary

The National Heart, Lung, and Blood Institute convened a Working Group on September 14, 2005, in Bethesda, Maryland to: (1) evaluate gaps and barriers in basic research; (2) identify clinical settings where control of acute arrhythmia triggers and modulators might be effective; (3) identify basic science findings ready for translation into clinical research; and (4) provide recommendations to facilitate research to improve arrhythmia detection, treatment, and prevention.

Discussion:

Several major gaps in current knowledge were discussed, including the need for indicators to better identify individuals most susceptible for sudden cardiac death (SCD). The Working Group (WG) believed that identifying surrogate markers and presymptomatic predictors of arrhythmias would permit more appropriate targeting of complex therapeutic interventions, such as the use of automatic internal cardioverter defibrillators (AICDs). Previous studies have only broadly defined high-risk groups, resulting in AICD overuse. A majority of individuals receiving an AICD never need defibrillation, and several large clinical trials have shown no survival benefit in patients treated with an AICD until 18-24 months after implantation.

The WG speculated about the role of oxidant stress in modifying cardiac ion channel function and the influence of these possible effects on arrhythmia production. New insights into the genetic propensities for arrhythmias were also discussed, with a focus on the need for more tractable genomic systems, like fruit flies, zebrafish, mice, and dogs, where genome scans could be used to identify candidate genes involved in arrhythmogenesis. The WG also recognized the need for research into the fundamental relations between mechanical load and dysfunction, electrical remodeling, and arrhythmogenesis, as well as intracellular pathways triggered by the interaction between mechanical and electrical activity.

The WG stressed the need to focus more on effective antiarrhythmic interventions rather than on purely palliative therapy (like the use of AICDs). Opportunities for developing novel therapeutic interventions that might target gap junctions, ion channel expression modulation, and intracellular calcium regulation, as well as cell and gene therapies were explored. The WG believed that additional, new, therapeutic targets were likely to emerge from improved understanding of the interaction of ion channels with scaffold and integrated signaling proteins. They agreed that investigations of the role of microvascular flow, vascular remodeling, and energetic reserve on arrhythmogenesis are also important. In addition, the WG agreed that selective targeting of individual classes of ion channels was not likely to be an appropriate approach for reducing the burden of SCD, although targeting chamber-specific potassium channels may prove effective for atrial fibrillation. The lack of appropriate experimental arrhythmia models was lamented, particularly for SCD, and the group indicated the need for development and preclinical testing of novel antiarrhythmic interventions.

Recommendations:

• Develop improved markers/identifiers of arrhythmia phenotype and genotype. This includes the broad banking of patient phenotypes and DNA in large populations. A major goal is the early identification of susceptible patients to permit early intervention to modify development of therapy-resistant arrhythmias. An additional goal is to improve on the successful use of AICDs and to better identify those patients who require them.
• Develop animal models that mimic spontaneous human arrhythmias and underlying mechanisms similar to those in human arrhythmogenic disease.
• Establish and define new molecular targets that permit development of more specific and effective antiarrhythmic interventions. Broaden future investigations from the more traditional studies of the effects of an intervention on an individual class of ion channels to include the interplay of ion channels and cardiac function, as well as the effects of regulatory proteins and substances that may interact with several ion channel classes. Examples might be targets related to contractile dysfunction and arrhythmogenesis and cell-to-cell communication.
• Improve existing therapeutic paradigms and forge new approaches, such as cellular and gene therapy and new molecular targets. Develop new pharmacologic interventions directed at novel molecular targets. Optimize implantable defibrillator algorithms for arrhythmia prediction and appropriate intervention prior to inappropriate AICD discharge. Optimize current resynchronization therapies and novel device therapies, including nerve stimulation.

Publication Plans:

A summary of the workshop proceedings and recommendations will also be published in a peer-reviewed scientific journal.

NHLBI Contact:

David A. Lathrop, Ph.D, NHLBI, NIH
lathropd@mail.nih.gov

Rosalie Dunn, Ph.D., NHLBI, NIH
dunnr@mail.nih.gov

Last updated: October 28, 2005