Abstract
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. 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 (beta-adrenergic receptors, sarcoplasmic reticulum Ca(2) + ATPase, and alpha- and beta-myosin heavy chain isoforms) or associated with pathologic hypertrophy (beta-myosin heavy chain and atrial natriuretic peptide), plus beta-adrenergic receptor protein expression. Left ventricular phenotype was assessed by radionuclide ejection fraction. Improvement in DCM phenotype was directly related to a coordinate increase in alpha- and a decrease in beta-myosin heavy chain mRNA expression. In contrast, modification of phenotype was unrelated to changes in the expression of beta(1)- or beta(2)-adrenergic receptor mRNA or protein, or to the mRNA expression of sarcoplasmic reticulum Ca(2) + ATPase and atrial natriuretic peptide. 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.
Highlights
Disease phenotypes are the result of changes in gene expression
We utilized the substantial changes in the dilated cardiomyopathy phenotype that occur variably in chronic heart failure patients treated with -blockade or placebo to create a dynamic phenotypic model suitable for investigation of the molecular basis of myocardial failure
Improvement in dilated cardiomyopathy phenotype in response to blocker therapy involves an increase in velocity of ventricular pressure development [16], an upward and leftward shift in depressed left [16] and right [20] ventricular function curves indicative of improved intrinsic systolic function, and a decrease in ventricular volume [16,17,18,19,20,21] and mass [16,17,21]
Summary
Disease phenotypes are the result of changes in gene expression. In the chronically failing hypertrophied human heart, selective changes in the expression of genes that could potentially modify phenotype have been reported [1,2,3,4,5,6,7,8], typically in explanted human hearts at the end stage of the disease process [1,2,3,4,5,6]. Reported alterations in gene expression in this setting include changes in the mRNA or protein expression of components of -adrenergic signal transduction [2,3,4], calcium handling proteins [1,5], and contractile proteins [6]. Studies in the intact heart may be conducted longitudinally employing serial measurements [8,10,11,12], which theoretically allows for detection of gene expression changes more directly associated with phenotypic modification. The DCM phenotype exhibits changes in the expression of genes that regulate contractile function and pathologic hypertrophy. It is unclear if any of these alterations in gene expression are disease producing or modifying. In endomyocardial biopsies at baseline and 6 months later, we measured mRNA expression of genes regulating contractile function
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