38 research outputs found

    Complex electrophysiological remodeling in postinfarction ischemic heart failure

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    Heart failure (HF) following myocardial infarction (MI) is associated with high incidence of cardiac arrhythmias. Development of therapeutic strategy requires detailed understanding of electrophysiological remodeling. However, changes of ionic currents in ischemic HF remain incompletely understood, especially in translational large-animal models. Here, we systematically measure the major ionic currents in ventricular myocytes from the infarct border and remote zones in a porcine model of post-MI HF. We recorded eight ionic currents during the cell's action potential (AP) under physiologically relevant conditions using (self)AP-clamp sequential dissection. Compared with healthy controls, HF-remote zone myocytes exhibited increased late Na(+) current, Ca(2+)-activated K(+) current, Ca(2+)-activated Cl(-) current, decreased rapid delayed rectifier K(+) current, and altered Na(+)/Ca(2+) exchange current profile. In HF-border zone myocytes, the above changes also occurred but with additional decrease of L-type Ca(2+) current, decrease of inward rectifier K(+) current, and Ca(2+) release-dependent delayed after-depolarizations. Our data reveal that the changes in any individual current are relatively small, but the integrated impacts shift the balance between the inward and outward currents to shorten AP in the border zone but prolong AP in the remote zone. This differential remodeling in post-MI HF increases the inhomogeneity of AP repolarization, which may enhance the arrhythmogenic substrate. Our comprehensive findings provide a mechanistic framework for understanding why single-channel blockers may fail to suppress arrhythmias, and highlight the need to consider the rich tableau and integration of many ionic currents in designing therapeutic strategies for treating arrhythmias in HF

    Modeling cardiomyocyte mechanics and autoregulation of contractility by mechano-chemo-transduction feedback.

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    The heart pumps blood into circulation against vascular resistance and actively regulates the contractile force to compensate for mechanical load changes. Our experimental data show that cardiomyocytes have a mechano-chemo-transduction (MCT) mechanism that increases intracellular Ca2+ transient to enhance contractility in response to increased mechanical load. This study advances the cardiac excitation- Ca2+ signaling-contraction (E-C) coupling model on conceptual and technical fronts. First, we developed analytical and computational models to perform 3-dimensional mechanical analysis of cardiomyocytes contracting in a viscoelastic medium under mechanical load. Next, we proposed an MCT feedback loop in the E-C coupling dynamic system to shift the feedforward paradigm of cardiac E-C coupling to an autoregulation model. Our combined modeling and experimental studies reveal that MCT enables autoregulation of E-C coupling and contractility in single cardiomyocytes, which underlies the heart's intrinsic autoregulation in compensatory response to load changes in order to maintain the stroke volume and cardiac output
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