Gender differences of echocardiographic and gene expression patterns in human pressure overload left ventricular hypertrophy

Abstract

Gender influence on left ventricular (LV) remodeling associated to aortic valve stenosis (AS) has been long recognized, but underlying myocardial gene expression patterns have not been explored. We studied whether sex differences in echocardiographic LV anatomy and function in AS patients are associated with specific changes in myocardial mRNA expression of remodeling proteins. AS ( n = 39) and control ( n = 23) patients were assessed echocardiographically, and LV myocardial mRNA levels were quantified by PCR. AS patients exhibit increased wall thicknesses and LV mass index (LVMI), but only men show chamber dilation. Collagens and fibronectin mRNA levels increased correlatively to transforming growth factor-β1 (TGF-β1). In AS women, collagen I upregulation was proportionally higher than other extracellular matrix (ECM) components. No changes in matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 were detected. Gene expressions of sarcomeric proteins (β-myosin heavy chain and myosin light chain-2) and TGF-β1were directly correlated with each other. Myosin light chain-2 mRNA levels increased proportionally to the transvalvular gradient, but women did so in a greater extent than men for a given gradient. In women, the hypertrophic growth response, reflected by LVMI, was proportional to the expression of genes encoding sarcomeric proteins and TGF-β1. In men, chamber dilation and deterioration of LVEF was proportional to collagens, fibronectin, and TGF-β1 gene expression levels. We evidenced gender biased gene expression patterns of the intracellular TGF-β pathways involving the Smad branch, but not the TAK-1 branch, that could contribute to the remodeling differences observed in AS men and women. Based on these findings, a gender specific therapeutic approach of pressure overload LV hypertrophy could be justified.