November 1, 1997Journal of Clinical Investigation505 citationsOpen Access
Changes in gene expression in the intact human heart. Downregulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium.
Key Result
In failing human ventricular myocardium, alpha-myosin heavy chain mRNA expression was downregulated by 67-84% and beta-myosin heavy chain was upregulated compared to nonfailing hearts.
Study Design
Type
Observational (n=56)
Multicenter
Yes
Structured PICO
Does heart failure from primary pulmonary hypertension or idiopathic dilated cardiomyopathy alter the gene expression of myosin heavy chain isoforms and adrenergic receptors in human ventricular myocardium?
P
Population
56 subjects, including 7 with primary pulmonary hypertension (PPH) with moderate RV failure, 29 with idiopathic dilated cardiomyopathy (IDC) with biventricular failure, 8 nonfailing controls undergoing RV endomyocardial biopsy, plus 6 end-stage IDC explanted hearts and 6 nonfailing explanted donor hearts.
C
Comparator
Nonfailing control hearts (intact biopsies and explanted donor hearts)
O
Outcome
Gene expression (mRNA abundance) of alpha-MHC, beta-MHC, beta1-adrenergic receptor, beta2-adrenergic receptor, ANP, and SRCAsurrogate
The failing human heart exhibits significant downregulation of alpha-myosin heavy chain and beta1-adrenergic receptor gene expression, which may contribute to decreased contractility.
Main Result
Absolute Event Rate: 7.6% vs 23.1%
p-value: p=<0.001
Limitations
- Cannot directly infer changes in MHC protein levels from mRNA data
- Lack of wall stress measurements
- Better methods of measuring RV systolic function required to more precisely examine the relationship between downregulation and depression of systolic performance
Abstract
Using quantitative RT-PCR in RNA from right ventricular (RV) endomyocardial biopsies from intact nonfailing hearts, and subjects with moderate RV failure from primary pulmonary hypertension (PPH) or idiopathic dilated cardiomyopathy (IDC), we measured expression of genes involved in regulation of contractility or hypertrophy. Gene expression was also assessed in LV (left ventricular) and RV free wall and RV endomyocardium of hearts from end-stage IDC subjects undergoing heart transplantation or from nonfailing donors. In intact failing hearts, downregulation of beta1-receptor mRNA and protein, upregulation of atrial natriuretic peptide mRNA expression, and increased myocyte diameter indicated similar degrees of failure and hypertrophy in the IDC and PPH phenotypes. The only molecular phenotypic difference between PPH and IDC RVs was upregulation of beta2-receptor gene expression in PPH but not IDC. The major new findings were that (a) both nonfailing intact and explanted human ventricular myocardium expressed substantial amounts of alpha-myosin heavy chain mRNA (alpha-MHC, 23-34% of total), and (b) in heart failure alpha-MHC was downregulated (by 67-84%) and beta-MHC gene expression was upregulated. We conclude that at the mRNA level nonfailing human heart expresses substantial alpha-MHC. In myocardial failure this alteration in gene expression of MHC isoforms, if translated into protein expression, would decrease myosin ATPase enzyme velocity and slow speed of contraction.
Cite This Study
Lowes et al. (1997) conducted an observational in Heart failure (Primary pulmonary hypertension and Idiopathic dilated cardiomyopathy) (n=56). Heart failure (Idiopathic dilated cardiomyopathy) vs. Nonfailing hearts was evaluated on Percentage of total myosin heavy chain represented by the alpha-MHC isoform (p=<0.001). In failing human ventricular myocardium, alpha-myosin heavy chain mRNA expression was downregulated by 67-84% and beta-myosin heavy chain was upregulated compared to nonfailing hearts.