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Am J Physiol Heart Circ Physiol (June 22, 2007). doi:10.1152/ajpheart.00609.2007
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Submitted on May 24, 2007
Accepted on June 22, 2007

Characterizing the contribution of voltage- and calcium-dependent coupling to action potential stability: implications for repolarization alternans

Peter N Jordan1 and David J Christini2*

1 Physiology and Biophysics, Weill Graduate School of Medical Sciences of Cornell University, New York, New York, United States
2 Cardiology, Weill Cornell Medical College, New York, New York, United States; Physiology and Biophysics, Weill Graduate School of Medical Sciences of Cornell University, New York, New York, United States

* To whom correspondence should be addressed. E-mail: dchristi{at}med.cornell.edu.

Experiments have provided suggestive but inconclusive insights into the relative contributions of transmembrane voltage and intracellular calcium handling to the development of cardiac electrical instabilities such as repolarization alternans. In this study, we applied a novel combination of techniques - action potential voltage clamping, calcium-transient clamping, and stability analysis - to cardiac cell models in order to more clearly determine the roles that voltage- and calcium-dependent coupling play in regulating action potential stability and the development of alternans subsequent to the loss of stability. Using these techniques, we are able to demonstrate that voltage- and calcium-dependent coupling exhibit varying degrees of influence on action potential stability across models. Our results indicate that cellular dynamical instabilities such as alternans may be initiated by either voltage- or calcium-dependent mechanisms, or by some combination of the two. Based on these modeling results, we propose novel single-cell experiments that incorporate action-potential voltage clamping, calcium imaging, and real-time measurement of action potential stability. These experiments will make it possible to experimentally determine the relative contribution of voltage coupling to the regulation of action potential stability in real cardiac myocytes, thereby providing further insights into the mechanism of alternans.







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