(Hypertension. 1996;28:269-275.)
© 1996 American Heart Association, Inc.
Articles |
Advanced Hypertensive Heart Disease in Spontaneously Hypertensive Rats
Lisinopril-Mediated Regression of Myocardial Fibrosis
the Center of Internal Medicine, Division of Cardiology, Philipps University of Marburg (Germany) (C.G.B.), and Department of Internal Medicine, Division of Cardiology, University of Missouri–Columbia.
Correspondence to Christian G. Brilla, MD, PhD, Division of Cardiology, Center of Internal Medicine, Philipps University of Marburg, Baldingerstr., D-35033 Marburg, FRG.
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.
Key Words: myocardium • fibrosis • collagen • hypertrophy, left ventricular
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