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Coordinate Changes in Myosin Heavy Chain Isoform Gene Expression Are Selectively Associated With Alterations in Dilated Cardiomyopathy Phenotype

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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.

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Acknowledgments

This investigation was sponsored by NIH Grants 1R01 HL48013 from the NHLBI, M01-RR00051 and M01-RR00064 from the National Center for Research Resources, and by GlaxoSmithKline Company. The authors are grateful to Laurel Hunter for her assistance in manuscript and figure preparation.

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Authors and Affiliations

  1. Division of Cardiology, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Campus, Box B139, Denver, Colorado, 80262, USA

    W. T. Abraham, B. D. Lowes, W. A. Minobe, R. L. Roden, D. Dutcher, J. Sederberg, J. A. Lindenfeld, E. E. Wolfel, S. F. Shakar, D. Ferguson, J. V. Linseman, R. A. Quaife, A. D. Robertson & Michael R. Bristow (Head)

  2. Division of Cardiology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA

    P. Larrabee & K. Volkman

  3. Division of Cardiovascular Medicine, University of Kentucky College of Medicine, Lexington, Kentucky, USA

    E. M. Gilbert

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  1. W. T. Abraham
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Correspondence to Michael R. Bristow.

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Abraham, W.T., Gilbert, E.M., Lowes, B.D. et al. Coordinate Changes in Myosin Heavy Chain Isoform Gene Expression Are Selectively Associated With Alterations in Dilated Cardiomyopathy Phenotype. Mol Med 8, 750–760 (2002). https://doi.org/10.1007/BF03402039

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