A quantitative analysis of cardiac myocyte relaxation: A simulation study

¹ University of Auckland
² Auckland Univ.

^* To whom correspondence should be addressed. E-mail: s.niederer{at}auckland.ac.nz.

Submitted on July 26, 2005
Revised on September 27, 2005
Accepted on 14 November 2005

	Abstract

The determinants of relaxation in cardiac muscle are poorly understood and yet compromised relaxation accompanies various pathologies and impaired pump function. In this study we develop a model of active contraction to elucidate the relative importance of the [Ca²⁺]_i transient magnitude, the unbinding of Ca²⁺ from troponin C (TnC) and the length dependence of tension and Ca²⁺ sensitivity on relaxation. Using the framework proposed by Hunter et al., (65) we extensively reviewed experimental literature, to quantitatively characterise the binding of Ca²⁺ to TnC, the kinetics of tropomyosin, the availability of binding sites and the kinetics of crossbridge binding following perturbations in sarcomere length. Model parameters were determined from multiple experimental results and modalities (skinned and intact preparations) and model results were validated against data from length step, caged Ca²⁺, isometric twitches and the half time to relaxation with increasing sarcomere length experiments. A factorial analysis found that the [Ca²⁺]_i transient and the unbinding of Ca²⁺ from TnC were the primary determinants of relaxation with a five fold greater effect than that of length dependent maximum tension and twice the effect of tension dependent binding of Ca²⁺ to TnC and length dependent Ca²⁺ sensitivity. The affects of the [Ca²⁺]_i transient and the unbinding rate of Ca²⁺ from TnC were tightly coupled with the effect of increasing either factor depending on the reference [Ca²⁺]_i transient and unbinding rate.

Key Words: Cardiac, Contraction, Modeling, Relaxation

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