Regression of myocardial fibrosis in hypertensive heart disease: diverse effects of various antihypertensive drugs.
OBJECTIVE
In left ventricular hypertrophy (LVH) due to systemic hypertension, myocardial fibrosis is an important determinant of pathologic hypertrophy. Therefore, it is most relevant to utilize an antihypertensive regimen that permits a regression in myocardial fibrosis along with blood pressure normalization and regression of LVH.


METHODS
To address this issue we examined 60 Sprague-Dawley rats. We treated 16-week-old rats having established LVH and myocardial fibrosis due to 8-week renovascular hypertension (RHT) with either 6 mg/kg/day zofenopril (ZOF), 30 mg/kg/day nifedipine (NIF) or 40 mg/kg/day labetalol (LAB) for 12 weeks. Systolic arterial pressure (SAP, mmHg), left ventricular/body weight ratio (LV/BW, mg/g), and left and right ventricular collagen volume fractions (LVCVF, RVCVF, %) were obtained and compared with age/sex matched untreated rats with RHT and sham-operated controls.


RESULTS
In RHT, SAP was significantly elevated compared with controls (188+/-11 vs. 125+/-5 mmHg; P<0.001) while in each treated group SAP was normalized. LV/BW was significantly increased in RHT (2.61+/-0.12 mg/g; P<0.00001) while in each treated group LVH was completely regressed (P<0.002 vs. untreated RHT) with LV/BW values comparable to controls (1.82+/-0.03 mg/g) irrespective of the utilized antihypertensive agent. In untreated RHT, myocardial fibrosis was present in the left (LVCVF: 12.3+/-1.9%; P<0.0005 vs. 4.5+/-0.2% of controls) and right ventricles (RVCVF: 20.6+/-2.5%; P<0.00005 vs. 8.8+/-0.4% of controls). In rats treated with ZOF or NIF, LVCVF was significantly reduced to 5.6+/-0.4 and 5.4+/-0.6%, respectively (P<0.005 vs. untreated RHT), and RVCVF was decreased as well (ZOF: 11.0+/-0.9%; NIF: 10.4+/-2.4%; P<0.007 vs. untreated RHT) where no significant difference to controls remained. In contrast, treatment with LAB did not affect myocardial fibrosis where LVCVF was 9.3+/-1.3% and RVCVF was 19.8+/-2.8%, i.e., remained significantly elevated compared with controls (P<0.007).


CONCLUSIONS
In rats with renovascular hypertension and hypertensive heart disease that included LVH and fibrosis, equipotent doses of ZOF, NIF, and LAB normalized arterial pressure associated with regression of LVH while only ZOF and NIF were found to regress myocardial fibrosis.
Brilla
C G
CG
Center of Internal Medicine, Division of Cardiology, Philipps University of Marburg, Baldingerstrasse, D-35033, Marburg, Germany. brilla@t-online.de
D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D002216:Captopril / Q000031:analogs & derivatives / Q000627:therapeutic use; D003094:Collagen / Q000378:metabolism; D005355:Fibrosis; D006978:Hypertension, Renovascular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D007741:Labetalol / Q000627:therapeutic use; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009543:Nifedipine / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric
D000959:Antihypertensive Agents; C044958:zofenopril; D003094:Collagen; D002216:Captopril; D009543:Nifedipine; D007741:Labetalol