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Molecular and Cellular Basis for Diastolic Dysfunction

  • Prevention of Heart Failure After Myocardial Infarction (M St. John Sutton, Section Editor)
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Abstract

Heart failure with preserved ejection fraction (HFpEF) is highly prevalent and is frequently associated with metabolic risk factors. Patients with HFpEF have only a slightly lower mortality than patients with HF and reduced EF. The pathophysiology of HFpEF is currently incompletely understood, which precludes specific therapy. Both HF phenotypes demonstrate distinct cardiac remodeling processes at the macroscopic, microscopic, and ultrastructural levels. Increased diastolic left-ventricular (LV) stiffness and impaired LV relaxation are important features of HFpEF, which can be explained by changes in the extracellular matrix and the cardiomyocytes. In HFpEF, elevated intrinsic cardiomyocyte stiffness contributes to high diastolic LV stiffness. Posttranslational changes in the sarcomeric protein titin, affecting titin isoform expression and phosphorylation, contribute to elevated cardiomyocyte stiffness. Increased nitrosative/oxidative stress, impaired nitric oxide bioavailability, and down-regulation of myocardial cyclic guanosine monophosphate and protein kinase G signaling could trigger posttranslational modifications of titin, thereby augmenting cardiomyocyte and LV diastolic stiffness.

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Acknowledgments

L. van Heerebeek, C.P.M. Franssen, N. Hamdani, and W.J. Paulus are funded through a grant from European Commission FP7 Health 2010, Large Collaborative Research Project on Diastolic Heart Failure MEDIA (261409).

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Authors and Affiliations

  1. Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands

    Loek van Heerebeek, Constantijn P. M. Franssen, Nazha Hamdani & Walter J. Paulus

  2. Department of Cardiology, Onze Lieve Vrouwe Gasthuis, Oosterpark 9, 1091 AC, Amsterdam, The Netherlands

    Loek van Heerebeek, Freek W. A. Verheugt & G. Aernout Somsen

  3. ICaR-VU, VU University Medical Center, Van der Boechorststraat 7, 1081 BT, Amsterdam, The Netherlands

    Walter J. Paulus

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  1. Loek van Heerebeek
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Correspondence to Walter J. Paulus.

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van Heerebeek, L., Franssen, C.P.M., Hamdani, N. et al. Molecular and Cellular Basis for Diastolic Dysfunction. Curr Heart Fail Rep 9, 293–302 (2012). https://doi.org/10.1007/s11897-012-0109-5

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