Angiotensin-converting enzyme inhibition prolongs survival and modifies the transition to heart failure in rats with pressure overload hypertrophy due to ascending aortic stenosis.
BACKGROUND
We tested the hypotheses that long-term administration of the angiotensin-converting enzyme (ACE) inhibitor fosinopril will regress hypertrophy, modify the transition to heart failure, and prolong survival in rats with chronic left ventricular (LV) pressure overload due to ascending aortic stenosis.


RESULTS
Aortic stenosis was created in weanling male Wistar rats by a stainless steel clip placed on the ascending aorta. Age-matched control animals underwent a sham operation (Sham group, n = 57). Six weeks after surgery, rats with aortic stenosis were randomized to receive either oral fosinopril 50 mg.kg-1.d-1 (Fos/LVH group, n = 38) or no drug (LVH group, n = 36) for 15 weeks. Pilot studies confirmed that this dosage produced significant inhibition of LV tissue ACE in vivo. Animals were monitored daily, and survival during the 15-week treatment period was assessed by actuarial analysis. At 15 weeks, in vivo LV systolic and diastolic pressures and heart rate were measured. To assess contractile function, the force-calcium relation was evaluated by use of the isovolumic buffer-perfused, balloon-in-LV heart preparation at comparable coronary flow rates per gram LV weight. Quantitative morphometry was performed. Mortality during the 15-week trial was significantly less in the Fos/LVH group than in the LVH group (3% versus 31%, P < .005). No deaths occurred in the Sham group. In vivo LV systolic pressure was similar between Fos/LVH and LVH hearts (223 +/- 10 versus 232 +/- 9 mm Hg) and significantly higher than the Sham group (99 +/- 3 mm Hg, P < .05). In vivo LV diastolic pressure was significantly lower in Fos/LVH hearts than in LVH hearts (10 +/- 2 versus 15 +/- 2 mm Hg), and both were significantly higher than in the Sham group (5 +/- 1 mm Hg, P < .05). Heart rate was similar among all groups. Despite equivalent elevation of LV systolic pressure, fosinopril resulted in regression of myocyte hypertrophy in Fos/LVH versus LVH (myocyte cell width, 14.8 +/- 0.5 versus 20.8 +/- 2.2 microns, P < .05) to normal levels (Sham, 16.3 +/- 0.9 microns). Quantitative morphometry demonstrated that the regression of LV myocyte hypertrophy in the Fos/LVH group was associated with a relative increase in the fractional volume of fibrillar collagen and noncollagen interstitium. In the isolated heart experiments, LV systolic developed pressure relative to perfusate [Ca2+] was significantly higher in Fos/LVH hearts than in LVH hearts. The improvement in systolic function was not related to any difference in myocardial high-energy phosphate levels, since LV ATP and creatine phosphate levels were similar in Fos/LVH and LVH hearts.


CONCLUSIONS
In rats with ascending aortic stenosis, chronic ACE inhibition with fosinopril improved survival, decreased the extent of LV hypertrophy, and improved cardiac function despite persistent elevation of LV systolic pressure. The favorable effects of fosinopril may be related in part to inhibition of the effects of cardiac ACE on myocyte hypertrophy rather than to systemic hemodynamic mechanisms.
Weinberg
E O
EO
Charles A. Dana Research Institute, Boston, MA.
Schoen
F J
FJ
George
D
D
Kagaya
Y
Y
Douglas
P S
PS
Litwin
S E
SE
Schunkert
H
H
Benedict
C R
CR
Lorell
B H
BH
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001024:Aortic Valve Stenosis / Q000150:complications*; D001794:Blood Pressure / Q000187:drug effects; D002303:Cardiac Output, Low / Q000209:etiology*; D004452:Echocardiography; D017328:Fosinopril / Q000494:pharmacology; D006973:Hypertension / Q000150:complications* / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000150:complications* / Q000401:mortality / Q000473:pathology; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D016019:Survival Analysis; D016277:Ventricular Function, Left
D000806:Angiotensin-Converting Enzyme Inhibitors; D017328:Fosinopril