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The pathogenesis of familial hypertrophic cardiomyopathy: Early and evolving effects from an α-cardiac myosin heavy chain missense mutation

Nature Medicine volume 5, pages 327–330 (1999)Cite this article

Abstract

Familial hypertrophic cardiomyopathy (FHC) is a genetic disorder resulting from mutations in genes encoding sarcomeric proteins1,2. This typically induces hyperdynamic ejection3, impaired relaxation, delayed early filling4, myocyte disarray and fibrosis, and increased chamber end-systolic stiffness5,6. To better understand the disease pathogenesis, early (primary) abnormalities must be distinguished from evolving responses to the genetic defect. We did in vivo analysis using a mouse model of FHC with an Arg403Gln α-cardiac myosin heavy chain missense mutation7, and used newly developed methods for assessing in situ pressure–volume relations8. Hearts of young mutant mice (6 weeks old), which show no chamber morphologic or gross histologic abnormalities, had altered contraction kinetics, with considerably delayed pressure relaxation and chamber filling, yet accelerated systolic pressure rise. Older mutant mice (20 weeks old), which develop fiber disarray and fibrosis, had diastolic and systolic kinetic changes similar to if not slightly less than those of younger mice. However, the hearts of older mutant mice also showed hyperdynamic contraction, with increased end-systolic chamber stiffness, outflow tract pressure gradients and a lower cardiac index due to reduced chamber filling; all 'hallmarks' of human disease. These data provide new insights into the temporal evolution of FHC. Such data may help direct new therapeutic strategies to diminish disease progression.

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Figure 1: a, Baseline in vivo tracings of left ventricular (LV) pressure (upper) and the first derivative of ventricular pressure (dP/dt; lower) for young and older mice in both groups.
Figure 2: a, Baseline pressure–volume loops from control and mutant mice.

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Authors and Affiliations

  1. Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, 600 N. Wolfe Street, Baltimore, 21287, Maryland, USA

    Dimitrios Georgakopoulos & David A. Kass

  2. Department of Genetics Howard Hughes Medical Institute, Howard Hughes Medical Institute, Brigham and Women's Hospital, 200 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Michael E. Christe, Michael Giewat & J.G. Seidman

  3. Division of Cardiology, Howard Hughes Medical Institute Brigham and Women's Hospital, 200 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Christine M. Seidman

Authors
  1. Dimitrios Georgakopoulos
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  2. Michael E. Christe
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  3. Michael Giewat
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  4. Christine M. Seidman
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  5. J.G. Seidman
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  6. David A. Kass
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Correspondence to David A. Kass.

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Georgakopoulos, D., Christe, M., Giewat, M. et al. The pathogenesis of familial hypertrophic cardiomyopathy: Early and evolving effects from an α-cardiac myosin heavy chain missense mutation. Nat Med 5, 327–330 (1999). https://doi.org/10.1038/6549

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