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The Structural Basis of Cardiac Dysfunction in Human Heart Failure

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Molecular Defects in Cardiovascular Disease

Abstract

In this chapter we describe the structural alterations observed in failing human myocardium. We review the current literature and compare these reports with our own findings. One of the earliest significant structural changes is the occurrence of myocyte hypertrophy and a significant degree of reactive fibrosis, which are the major factors causing diastolic dysfunction. Furthermore, we describe equivalents of systolic dysfunction: the ultrastructural changes indicating myocyte degeneration characterized by the reduction of myofilaments, an increase in cytoplasm, and the occurrence of small mitochondria with less cristae. The cytoskeleton: the microtubuli showed densification and desmin was augmented and irregularly arranged, most probably a mechanism compensatory for reduced cellular stability because of loss of sarcomeres. The remaining sarcomeres showed less elements of the sarcomeric skeleton, i.e., of titin, α-actinin, and myomesin, which contributes to sarcomeric instability. Membrane damage leads to ionic imbalance and is caused by either loss or increase of the membrane proteins dystrophin, the vinculin–talin–­integrin complex, and of spectrin. The gap junctional protein connexin 43 of the intercalated disc is likewise reduced and represents the basis of defects of the excitation–contraction coupling. In the extracellular space, an accumulation of blood borne cells indicates a process of chronic low-grade inflammation, which is injurious to the sarcolemma of the myocyte. These different processes involving the interstitium as well as almost all cellular components of the cardiomyocytes will finally lead to myocyte death, either autophagic or oncotic but less apoptotic. It is postulated that fibrosis and myocyte hypertrophy combined with loss of sarcomeres are the structural equivalent of diastolic dysfunction. Systolic dysfunction occurs at a later stage of ­progression to heart failure and is caused by damage of the various ­components of the myocytes in addition to cellular hypertrophy and ­fibrosis. In conclusion, the development of heart failure is a multifactorial event involving the extracellular matrix and almost all cellular components of the myocytes. Therefore; fibrosis as well as myocyte degeneration and cell death are the structural factors determining cardiac dysfunction.

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Authors and Affiliations

  1. Department of Cardiac Surgery, Kerckhoff Clinic, Bad Nauheim, Germany

    Stefan Hein

  2. Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany

    Sawa Kostin & Jutta Schaper

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  1. Stefan Hein
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  2. Sawa Kostin
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  3. Jutta Schaper
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Correspondence to Jutta Schaper .

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  1. St. Boniface General Hospital, Research Centre, Institute of Cardiovascular Sciences, Tache Avenue 351, Winnipeg, R2H 2A6, Manitoba, Canada

    Naranjan S. Dhalla

  2. Jikei University School of Medicine, Shibuya-ku, Ebisu 3-31-6, Tokyo, 150-0013, Japan

    Makoto Nagano

  3. Czech Republic, Institute of Physiology, Academy of Sciences of the, Videnska 1083, Prague, 142 20, Czech Republic

    Bohuslav Ostadal

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Hein, S., Kostin, S., Schaper, J. (2011). The Structural Basis of Cardiac Dysfunction in Human Heart Failure. In: Dhalla, N., Nagano, M., Ostadal, B. (eds) Molecular Defects in Cardiovascular Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-7130-2_15

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