CHANGES IN GENE-EXPRESSION IN THE INTACT HUMAN HEART - DOWN-REGULATION OF ALPHA-MYOSIN HEAVY-CHAIN IN HYPERTROPHIED, FAILING VENTRICULAR MYOCARDIUM

Using quantitative RT-PCR in RNA from right ventricular (RV) endomyoca rdial biopsies from intact nonfailing hearts, and subjects with modera te 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 al so assessed in LV (left ventricular) and RV free wall and RV endomyoca rdium of hearts from end-stage IDC subjects undergoing heart transplan tation or from nonfailing donors. In intact failing hearts, downregula tion of beta(1)-receptor mRNA and protein, upregulation of atrial natr iuretic peptide mRNA expression, and increased myocyte diameter indica ted similar degrees of failure and hypertrophy in the IDC and PPH phen otypes. The only molecular phenotypic difference between PPH and IDC R Vs was upregulation of beta(2)-receptor gene expression in PPH but not IDC. The major new findings were that (a) both nofailing intact and e xplanted human ventricular myocardium expressed substantial amounts of alpha-myosin heavy chain mRNA (alpha-MHC, 23-34% of total), and (b) i n heart failure alpha-MHC was down-regulated (by 67-84%) and beta-MHC gene expression was up-regulated. We conclude that at the mRNA level n onfailing human heart expresses substantial alpha-MHC. In myocardial f ailure this alteration in gene expression of MHC isoforms, if translat ed into protein expression, would decrease myosin ATPase enzyme veloci ty and slow speed of contraction.