Effect of changes in action potential spike configuration, junctional sarcoplasmic reticulum micro-architecture and altered t-tubule structure in human heart failure

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Using a Monte–Carlo model of L-type Ca2+ channel (DHPR) gating, we have examined the effect of changes in the early time course of the action potential as seen in human heart failure on excitation contraction coupling. The time course of DHPR Ca2+ influx was coupled into a simple model of sarcoplasmic reticulum Ca2+ release. Our model shows that the loss of the initial spike in human heart failure should reduce the synchrony of Ca2+ spark production and lead to the appearance of late Ca2+ sparks and greater non-uniformity of intracellular Ca2+. Within the junctional space of the cardiac dyad, a small increase in the mean distance of a DHPR from a RyR results in a marked decrease in the ability of the DHPR-mediated increase in local [Ca2+] concentration to activate RyRs. This suggests that the efficiency of EC coupling may be reduced if changes in micro-architecture develop and such effects have been noted in experimental models of heart failure. High resolution imaging of t-tubules in tachycardia-induced heart failure show deranged t-tubule structure. While in normal human hearts t-tubules run mainly in a radial direction, t-tubules in the heart failure samples were oriented more toward the long axis of the cell. In addition, t-tubules may become dilated and bifurcated. Our data suggest that changes in the micro-architecture of the cell and membrane structures associated with excitation–contraction coupling, combined with changes in early action potential configuration can reduce the efficiency by which Ca2+ influx via DHPRs can activate SR calcium release and cardiac contraction. While the underlying cause of these effects is unclear, our data suggest that geometric factors can play an important role in the pathophysilogy of the human heart in failure.

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