Activation of the cardiac renin-angiotensin system and increased myocardial collagen expression in human aortic valve disease

OBJECTIVES We sought to determine whether the cardiac renin-angiotensin sys tem (RAS) is activated in human aortic valve disease depending on left vent ricular function, and We analyzed the concomitant regulation of the extrace llular matrix components. BACKGROUND In animal models with pressure or volume load, activation of the cardiac RAS increases fibrosis. In human aortic valve disease, the ventric ular collagen protein content is increased, but only scarce data on the act ivation state of time cardiac RAS and its effects on collagen and fibronect in messenger ribonucleic acid (mRNA) are available. METHODS In left ventricular biopsies from patients with aortic valve stenos is (AS) and aortic valve regurgitation and from control subjects, we quanti tated mRNAs for angiotensin-converting enzyme (ACE), chymase, transforming growth factor-beta, (TGF-beta(1)), collagen I, collagen III and fibronectin by reverse-transcription polymerase chain reaction. RESULTS Proteins were localized by immunohistochemistry; ACE activity was d etermined by high performance liquid chromatography; and TGF-beta protein b y quantitative enzyme immunoassay. Protein, ACE and TGF-beta(1) mRNA were s ignificantly increased in patients with AS and AR (1.5- to 2.1-fold) and co rrelated with each other. The increase occurred also in patients with norma l systolic function. Collagen I and III and fibronectin mRNAs were both upr egulated about twofold in patients with AS and AR. In AS, collagen and fibr onectin mRNA expression levels were positively correlated with left ventric ular end-diastolic pressure and inversely with left ventricular ejection fr action (LVEF). CONCLUSION In human hearts, pressure and volume overload increases cardiac ACE and TGF-beta, in the early stages. This activation of the cardiac RAS m ay contribute to the observed increase in collagen I and III and fibronecti n mRNA expression. The increase in extracellular matrix already exists in p atients with a normal LVEF, and it increases with functional impairment. a Am Coil Cardiol 2001;37:1143-9) (C) 2001 by the American College of Cardiol ogy.