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Chemomechanical Energy Transduction in the Failing Heart

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Abstract

Human heart failure carries with it high mortal risks. The deficit in ventricular function results from a depression in power along with a blunting of the force-frequency relationship. Mechanical, myothermal and molecular biological analysis are used to uncover the mechanistic basis for the deficit in performance. At the cross-bridge level the average isometric force-time integral is increased in failing hearts. Despite this increase, the isometric peak force and rate of relaxation are markedly depressed and correlate with a substantial decrease in the amount and rate of calcium cycling per beat. The blunting of the force frequency relationship is shown to be directly related to the frequency dependence of the calcium concentration which in turn can be accounted for by alterations in the SERCA 2 calcium pump and the sarcolemmal Na/Ca exchange protein. There is a positive correlation between sarcoplasmic reticular calcium ATPase and frequency dependent changes in twitch tension and an inverse correlation between Na/Ca exchange protein and diastolic force. This analysis allows the hearts to be divided into two groups based on the Na/Ca exchange and SR calcium ATPase levels that separates the hearts that develop increased diastolic force from those that do not. In both groups of failing hearts the ratio of the Na/Ca exchange protein to the SERCA 2 pump is substantially increased. The phenotypic alterations in Na/Ca exchange protein, SERCA 2 calcium pump and the TnT isoform shift can account for the depression in power output and the associated ventricular dysfunction found in heart failure.

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Authors and Affiliations

  1. Department of Molecular Physiology and Biophysics, Vermont

    Norman R. Alpert & Louis A. Mulieri

  2. Division of Cardiology University of Vermont, College of Medicine, Burlington, Vermont

    Martin LeWinter

  3. Klinikum der Georg-August Universitat, Zentrum Innere Medizin, Gottingen, Germany

    Gerd Hasenfuss

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  1. Norman R. Alpert
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  2. Martin LeWinter
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  3. Louis A. Mulieri
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  4. Gerd Hasenfuss
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Alpert, N.R., LeWinter, M., Mulieri, L.A. et al. Chemomechanical Energy Transduction in the Failing Heart. Heart Fail Rev 4, 281–295 (1999). https://doi.org/10.1023/A:1009818225222

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