The failing cardiomyocyte

Alexander Lyon and Sian Harding

in Oxford Textbook of Heart Failure

Published on behalf of Oxford University Press

ISBN: 9780199577729
Published online July 2011 | e-ISBN: 9780199697809 | DOI:

Series: Oxford Textbooks

The failing cardiomyocyte

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The human myocardium consists of a variety of different cell types. The cell that has been most extensively studied is the cardiomyocyte, which represents the single contracting unit of the myocardium. It has been estimated that there are 3 billion cardiomyocytes in the human ventricular myocardium, organized into the complex three-dimensional architecture of the ventricular myocardial tissue. Conceptually there are two underlying pathophysiological problems at the level of the cardiomyocyte which drive the functional deterioration of the failing heart. The first is numerical loss of cardiomyocytes, due both to the underlying causal disease process, such as acute myocardial infarction or chemotherapy, and to further loss secondary to apoptosis and necrosis triggered by theneurohormonal and inflammatory activation in the failing myocardium irrespective of the initial injury. Secondly, the remaining viable cardiomyocytes are required to provide sufficient contractile force to maintain an adequate cardiac output, despite loss of significant numbers and abnormal stress–strain relationships resulting from altered chamber geometry and extracellular matrix remodelling. The surviving cardiomyocytes compensate temporarily via transition to an adaptive hypertrophic state, which is associated with activation of fetal gene expression patterns. However, the persistent drive from the neurohormonal activation to maintain cardiac output, and activation of systemic inflammatory systems secondary to tissue hypoperfusion and congestion, combined with reduced metabolic efficiency in the hypertrophied cardiomyocytes, results in the development of contractile dysfunction of the hypertrophied cardiomyocyte. This is independent of the underlying cause of heart failure (HF), some of which cause further continuing impairment of cardiomyocyte function, such as familial dilated cardiomyopathy due to mutations in the cytoskeletal or sarcomeric proteins. The common endpoint for the failing heart, irrespective of underlying aetiology, is characterized at a cellular and molecular level by a distinctive failing signature. Cardiomyocytes isolated from failing human and animal hearts demonstrate impairment of both contraction (inotropy) and relaxation (lusitropy). Mechanical dysfunction of failing cardiomyocytes is amplified at higher beating frequencies, increased calcium concentration or during catecholamine stimulation. The loss of the force-frequency response (the Treppe or Bowditch effect) is a hallmark characteristic of HF. A variety of different pathophysiological factors have been proposed to underlie these mechanical alterations, including abnormal morphological and structural remodelling, and functional changes in signalling pathways, ionic fluxes, organelle function, and gene expression. It is becoming increasingly apparent that these are not independent processes; rather, crosstalk and interplay between the different pathophysiological processes serve to amplify the abnormalities and drive the deterioration of the failing cardiomyocyte phenotype.

Chapter.  7760 words.  Illustrated.

Subjects: Cardiovascular Medicine

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