Coordinate changes in myosin heavy chain isoform gene expression are selectively associated with alterations in dilated cardiomyopathy phenotype

W. T. Abraham, E. M. Gilbert, B. D. Lowes, W. A. Minobe, P. Larrabee, R. L. Roden, D. Dutcher, J. Sederberg, J. A. Lindenfeld, E. E. Wolfel, S. F. Shakar, D. Ferguson, K. Volkman, J. V. Linseman, R. A. Quaife, A. D. Robertson, Michael R. Bristow

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

Background: The most common cause of chronic heart failure in the US is secondary or primary dilated cardiomyopathy (DCM). The DCM phenotype exhibits changes in the expression of genes that regulate contractile function and pathologic hypertrophy. However, it is unclear if any of these alterations in gene expression are disease producing or modifying. Materials and Methods: One approach to providing evidence for cause-effect of a disease-influencing gene is to quantitatively compare changes in phenotype to changes in gene expression by employing serial measurements in a longitudinal experimental design. We investigated the quantitative relationships between changes in gene expression and phenotype n 47 patients with idiopathic DCM. In endomyocardial biopsies at baseline and 6 months later, we measured mRNA expression of genes regulating contractile function (β-adrenergic receptors, sarcoplasmic reticulum Ca2+ ATPase, and α- and β-myosin heavy chain isoforms) or associated with pathologic hypertrophy (β-myosin heavy chain and atrial natriuretic peptide), plus β-adrenergic receptor protein expression. Left ventricular phenotype was assessed by radionuclide ejection fraction. Results: Improvement in DCM phenotype was directly related to a coordinate increase in α- and a decrease in β-myosin heavy chain mRNA expression. In contrast, modification of phenotype was unrelated to changes in the expression of β1- or β2-adrenergic receptor mRNA or protein, or to the mRNA expression of sarcoplasmic reticulum Ca2+ ATPase and atrial natriuretic peptide. Conclusion: We conclude that in human DCM, phenotypic modification is selectively associated with myosin heavy chain isoform changes. These data support the hypothesis that myosin heavy chain isoform changes contribute to disease progression in human DCM.

Original languageEnglish (US)
Pages (from-to)750-760
Number of pages11
JournalMolecular Medicine
Volume8
Issue number11
StatePublished - Nov 1 2002

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Abraham, W. T., Gilbert, E. M., Lowes, B. D., Minobe, W. A., Larrabee, P., Roden, R. L., Dutcher, D., Sederberg, J., Lindenfeld, J. A., Wolfel, E. E., Shakar, S. F., Ferguson, D., Volkman, K., Linseman, J. V., Quaife, R. A., Robertson, A. D., & Bristow, M. R. (2002). Coordinate changes in myosin heavy chain isoform gene expression are selectively associated with alterations in dilated cardiomyopathy phenotype. Molecular Medicine, 8(11), 750-760.