NHLBI Working Group
Modifiers of Arrhythmias: New Targets for Therapy and Prevention
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.
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.
- 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
A summary of the workshop proceedings and recommendations will also be
published in a peer-reviewed scientific journal.
David A. Lathrop, Ph.D, NHLBI, NIH
Rosalie Dunn, Ph.D., NHLBI, NIH
Last updated: October 28, 2005