ANGIOTENSIN-CONVERTING ENZYME-INHIBITION AND THE PROGRESSION OF CONGESTIVE CARDIOMYOPATHY - EFFECTS ON LEFT-VENTRICULAR AND MYOCYTE STRUCTURE AND FUNCTION

Background Clinical trials have demonstrated that angiotensin-converti ng enzyme inhibition (ACEI) improves survival in patients with long-te rm left ventricular (LV) dysfunction. However, it remained unclear fro m these clinical reports whether the beneficial effects of ACEI were d ue to direct improvements in LV myocardial structure and function. Acc ordingly, the overall objective of the present study was to examine th e direct effects of ACEI on both LV and myocyte structure and function in the setting of cardiomyopathic disease. Methods and Results LV and isolated myocyte function and structure were examined in control dogs (n=6), in dogs after the development of dilated cardiomyopathy caused by rapid ventricular pacing (RVP, 216 beats per minute, 4 weeks, n=6) , and in dogs with RVP and concomitant ACEI (RVP/ACEI, fosinopril 30 m g/kg BID, n=6). LV ejection fraction fell with RVP compared with contr ol values (35+/-3 versus 73+/-2%, P<.05) and was higher with RVP/ACEI compared with RVP values (41+/-4%, P=.048). LV end-diastolic volume in creased with RVP compared with control values (78+/-7 versus 101+/-7 c m(3), P<.05) and was lower with RVP/ACEI (82+/-3 cm(3), P<.05). Isolat ed myocyte length increased with RVP (182+/-1 versus 149+/-1 mu m), an d the velocity of shortening decreased (36+/-1 versus 57+/-1 mu m/s) c ompared with control values (P<.05). With RVP/ACEI, myocyte length was reduced (169+/-1 mu m) and velocity of shortening was increased (45+/ -1 mu m/s) compared with RVP values (P<.05). Myocyte velocity of short ening after beta-adrenergic receptor stimulation with 25 nmol/L isopro terenol was reduced with RVP compared with control values (142+/-5 ver sus 193+/-8 mu m/s, P<.05) and significantly improved with RVP/ACEI (1 66+/-6 mu m/s, P<.05). In the RVP group, beta-adrenergic receptor dens ity fell 26%, and cAMP production with beta-adrenergic receptor stimul ation was reduced 48% from control values. RVP/ACEI resulted in a norm alization of beta-adrenergic receptor density and cAMP production. LV myosin heavy-chain content when normalized to dry weight of myocardium was unchanged with RVP (149+/-11 mg per gram dry weight of myocardium [gdwt]) and RVP/ACEI (150+/-4 mg/gdwt) compared with control values ( 165+/-4 mg/gdwt). LV collagen content decreased with RWP compared with control values (7.6+/-0.4 versus 9.6+/-0.8 mg per gram wet weight of myocardium [gwwt], P<.05) but was increased with RVP/ACEI (14.4+/-1.3 mg/gwwt, P<.05). Conclusions Concomitant ACEI with chronic tachycardia reduced LV chamber dilation and improved myocyte contractile function and beta-adrenergic responsiveness. Contributory cellular and extrace llular mechanisms for the beneficial effects of ACEI in this model of dilated cardiomyopathy included a normalization of beta-adrenergic rec eptor function and enhanced myocardial collagen support. The results f rom this study provide evidence that ACEI during the development of ca rdiomyopathic disease provided beneficial effects on LV myocyte contra ctile processes and myocardial structure.