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Tuning cardiac performance in ischemic heart disease and failure by modulating myofilament function

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Abstract

The cardiac myofilaments are composed of highly ordered arrays of proteins that coordinate cardiac contraction and relaxation in response to the rhythmic waves of [Ca2+] during the cardiac cycle. Several cardiac disease states are associated with altered myofilament protein interactions that contribute to cardiac dysfunction. During acute myocardial ischemia, the sensitivity of the myofilaments to activating Ca2+ is drastically reduced, largely due to the effects of intracellular acidosis on the contractile machinery. Myofilament Ca2+ sensitivity remains compromised in post-ischemic or “stunned” myocardium even after complete restoration of blood flow and intracellular pH, likely because of covalent modifications of or proteolytic injury to contractile proteins. In contrast, myofilament Ca2+ sensitivity can be increased in chronic heart failure, owing in part to decreased phosphorylation of troponin I, the inhibitory subunit of the troponin regulatory complex. We highlight, in this paper, the central role of the myofilaments in the pathophysiology of each of these distinct disease entities, with a particular focus on the molecular switch protein troponin I. We also discuss the beneficial effects of a genetically engineered cardiac troponin I, with a histidine button substitution at C-terminal residue 164, for a variety of pathophysiologic conditions, including hypoxia, ischemia, ischemia–reperfusion and chronic heart failure.

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Authors and Affiliations

  1. Department of Internal Medicine, University of Michigan, 1150 W. Medical Center Drive, 7301 MSRB III, Ann Arbor, MI, 48109-0644, USA

    Sharlene M. Day

  2. Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI, 48109-0644, USA

    Margaret V. Westfall

  3. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109-0644, USA

    Margaret V. Westfall & Joseph M. Metzger

  4. Department of Internal Medicine, University of Michigan, 1301 E. Catherine St, 7730 Medical Science II, Ann Arbor, MI, 48109-0622, USA

    Joseph M. Metzger

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  1. Sharlene M. Day
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  2. Margaret V. Westfall
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  3. Joseph M. Metzger
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Correspondence to Sharlene M. Day.

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Day, S.M., Westfall, M.V. & Metzger, J.M. Tuning cardiac performance in ischemic heart disease and failure by modulating myofilament function. J Mol Med 85, 911–921 (2007). https://doi.org/10.1007/s00109-007-0181-6

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