Selective activation of fibrogenetic growth factors addresses the pattern of hypertrophy in human aortic valve disease

Background. Myocardial fibrosis develops only in some models of hemodynamic overload suggesting the involvement of non-hemodynamic trophic stimuli in the regulation of connective tissue growth. The aim of the present study was to investigate cardiac expression of fibrogenetic growth factors (GFs) in patients with concentric or eccentric myocardial hypertrophy undergoing aortic valve replacement for pure form of aortic stenosis (n=16) or regurgitation (n=14). Methods. Cardiac platelet derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) formation was evaluated by measuring gene expression in ventricular biopsies collected at cardiac surgery (RT-PCR) and peptide release in coronary circulation. The control group was made of 5 tentative donors, excluded from organ donation for noncardiac reasons and 11 subjects with atypical chest pain undergoing diagnostic cardiac catheterization. Results. In control subjects and in patients with aortic regurgitation PDGF and bFGF cardiac gene expression was undetectable and peptide coronary release was negligeable. Conversely, in patients with aortic stenosis myocardial expression of mRNAs for PDGF-A and -B chains and for bFGF were all significantly increased as well as the PDGF-AB and bFGF release in the coronary circulation (p<0.01 vs controls and vs patients with aortic regurgitation for all). In situ hybridization localized growth factor mRNAs in interstitial cells. At multivariate stepwise regression analysis the relative wall thickness was selected as the most predictive independent variable for PDGF (r=0.72, p<0.01) and FGF (r=0.62, p<0.01) peptide cardiac release with no significant relationship with indexes of cardiac function or afterload mismatch. Conclusion. The present results indicate that 1) the gene expression and cardiac formation of fibrogenetic GFs are selectively activated only in aortic stenosis with 2) gene expression mainly sustained by interstitial cells and 3) stepwise regression analysis revealing the significant association between GFs cardiac formation and the pattern of hypertrophy.