In human hearts, pressure and volume overload increases cardiac ACE and TGF-beta1 in the early stages. This activation of the cardiac RAS may contribute to the observed increase in collagen I and III and fibronectin mRNA expression. The increase in extracellular matrix already exists in patients with a normal LVEF, and it increases with functional impairment.

In the human heart, Ang II does not directly increase collagen or fibronectin mRNA, but it does increase TGFbeta-1 and osteopontin mRNA expression. Since TGFbeta-1 induces collagen I and III mRNA in atrial samples and in isolated cardiac fibroblasts, it may represent a necessary mediator of the Ang II effects in the human heart.

Background-Estrogen receptor (ER)-mediated effects have been associated with the modulation of myocardial hypertrophy in animal models and in humans, but ER expression in the human heart and its relation to hypertrophymediated gene expression have not yet been analyzed. We therefore investigated sex-and disease-dependent alterations of myocardial ER expression in human aortic stenosis together with the expression of hypertrophy-related genes. Methods and Results-ER-␣ and -␤, calcineurin A-␤, and brain natriuretic peptide (BNP) mRNA were quantified by real-time polymerase chain reaction in left ventricular biopsies from patients with aortic valve stenosis (nϭ14) and control hearts with normal systolic function (nϭ17). ER protein was quantified by immunoblotting and visualized by immunofluorescence confocal microscopy. ER-␣ mRNA and protein were increased 2.6-fold (Pϭ0.003) and 1.7-fold (Pϭ0.026), respectively, in patients with aortic valve stenosis. Left ventricular ER-␤ mRNA was increased 2.6-fold in patients with aortic valve stenosis (PϽ0.0001). ER-␣ and -␤ were found in the cytoplasm and nuclei of human hearts. A strong inverse correlation exists between ER-␤ and calcineurin A-␤ mRNA in patients with aortic valve stenosis (rϭϪ0.83, Pϭ0.002) but not between ER-␣ or -␤ and BNP mRNA. Conclusions-ER-␣ and -␤ in the human heart are upregulated by myocardial pressure load.

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