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

Dimitrios Georgakopoulos, Michael E. Christe, Michael Giewat, Christine M. Seidman, J. G. Seidman, David A Kass

Research output: Contribution to journalArticle

Abstract

Familial hypertrophic cardiomyopathy (FHC) is a genetic disorder resulting from mutations in genes encoding sarcomeric proteins. This typically induces hyperdynamic ejection, impaired relaxation, delayed early filling, myocyte disarray and fibrosis, and increased chamber end-systolic stiffness. 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 mutation, and used newly developed methods for assessing in situ pressure-volume relations. 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.

Original languageEnglish (US)
Pages (from-to)327-330
Number of pages4
JournalNature Medicine
Volume5
Issue number3
DOIs
StatePublished - 1999

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Familial Hypertrophic Cardiomyopathy
Cardiac Myosins
Myosin Heavy Chains
Missense Mutation
Stiffness
Kinetics
Gene encoding
Pressure
Pressure gradient
Fibrosis
Inborn Genetic Diseases
Defects
Fibers
Muscle Cells
Disease Progression
Blood Pressure
Proteins
Mutation
Genes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

The pathogenesis of familial hypertrophic cardiomyopathy : Early and evolving effects from an α-cardiac myosin heavy chain missense mutation. / Georgakopoulos, Dimitrios; Christe, Michael E.; Giewat, Michael; Seidman, Christine M.; Seidman, J. G.; Kass, David A.

In: Nature Medicine, Vol. 5, No. 3, 1999, p. 327-330.

Research output: Contribution to journalArticle

Georgakopoulos, Dimitrios ; Christe, Michael E. ; Giewat, Michael ; Seidman, Christine M. ; Seidman, J. G. ; Kass, David A. / The pathogenesis of familial hypertrophic cardiomyopathy : Early and evolving effects from an α-cardiac myosin heavy chain missense mutation. In: Nature Medicine. 1999 ; Vol. 5, No. 3. pp. 327-330.
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