Left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHR) is accompanied by a structural remodeling of the myocardium that includes myocyte
hypertrophy and interstitial and perivascular
fibrosis of intramyocardial coronary arteries. The structural abnormalities related to fibrous tissue accumulation lead to increased myocardial diastolic stiffness and ultimately impaired systolic function of the left ventricle. It has been shown in 14-week-old SHR with early hypertensive
heart disease that myocardial
fibrosis could be reversed and myocardial diastolic stiffness normalized by 12-week treatment with the
angiotensin-converting enzyme inhibitor lisinopril. Whether such functional defects of the myocardium, based on adverse structural changes, are also reversible in advanced hypertensive
heart disease has been questioned. Therefore, we treated 78-week-old male SHR that had chronic
hypertension and advanced LVH with severe myocardial
fibrosis and age- and sex-matched normotensive Wistar-Kyoto rats (WKY) with 20 mg/kg per day oral
lisinopril for 8 months. Compared with untreated SHR or WKY, we found the following: (1) Systolic arterial pressure was normalized (P < .025) and LVH completely reversed (P < .025) in SHR, with no significant reduction in systolic arterial pressure or left ventricular mass in WKY; (2) morphometrically determined myocardial
fibrosis in SHR was significantly reversed (P < .025) and associated with improved diastolic stiffness (P < .05), which was measured in the isolated heart by calculation of the stiffness constant of the myocardium; no significant changes occurred in WKY; (3) reversal of myocardial
fibrosis was accompanied by an increase (P < .025) in myocardial
matrix metalloproteinase 1 activity determined by degradation of [14C]
collagen with myocardial
tissue extracts after
trypsin activation of myocardial promatrix
metalloproteinase 1; matrix metalloproteinase 1 activity remained unchanged in WKY treated with
lisinopril; and (4) systolic dysfunction, measured by a significantly (P < .025) diminished slope of the systolic stress-strain relation under isovolumic conditions of the left ventricle, was found in 110-week-old SHR, and it could be prevented by
lisinopril treatment. Thus, long-term
angiotensin-converting enzyme inhibition with
lisinopril normalized arterial pressure and LVH, reversed myocardial
fibrosis, and improved abnormal myocardial diastolic stiffness in advanced hypertensive
heart disease in SHR. In addition, systolic dysfunction of the left ventricle could be prevented. The fibrolytic response to
lisinopril was at least partly due to enhanced
collagen degradation by activation of tissue
matrix metalloproteinase 1.