We sought to determine whether the cardiac renin-angiotensin system (RAS) is activated
in human aortic valve disease depending on left ventricular function, and we analyzed
the concomitant regulation of the extracellular matrix components.
In animal models with pressure or volume load, activation of the cardiac RAS increases
fibrosis. In human aortic valve disease, the ventricular collagen protein content
is increased, but only scarce data on the activation state of the cardiac RAS and
its effects on collagen and fibronectin messenger ribonucleic acid (mRNA) are available.
In left ventricular biopsies from patients with aortic valve stenosis (AS) and aortic
valve regurgitation and from control subjects, we quantitated mRNAs for angiotensin-converting
enzyme (ACE), chymase, transforming growth factor-beta1 (TGF-beta1), collagen I, collagen
III and fibronectin by reverse-transcription polymerase chain reaction. Proteins were
localized by immunohistochemistry; ACE activity was determined by high performance
liquid chromatography; and TGF-beta protein by quantitative enzyme immunoassay.
Protein, ACE and TGF-beta1 mRNA were significantly increased in patients with AS and
AR (1.5- to 2.1-fold) and correlated with each other. The increase occurred also in
patients with normal systolic function. Collagen I and III and fibronectin mRNAs were
both upregulated about twofold in patients with AS and AR. In AS, collagen and fibronectin
mRNA expression levels were positively correlated with left ventricular end-diastolic
pressure and inversely with left ventricular ejection fraction (LVEF).
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.