Angiotensin-Converting Enzyme Inhibition and the Progression of Congestive Cardiomyopathy
Authors: Spinale Francis G. , Holzgrefe Henry H. , Mukherjee Rupak , Hird R. Barry , Walker Jennifer D. , Arnim-Barker Alice , Powell James R. , Koster William H. 
Published: June 2012

Background
Clinical trials have demonstrated that angiotensin-converting enzyme inhibition (ACEI) improves survival in patients with long-term left ventricular (LV) dysfunction. However, it remained unclear from these clinical reports whether the beneficial effects of ACEI were due to direct improvements in LV myocardial structure and function. Accordingly, the overall objective of the present study was to examine the 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 mg/kg BID, n=6). LV ejection fraction fell with RVP compared with control 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 increased with RVP compared with control values (78±7 versus 101±7 cm
3
,
P
<.05) and was lower with RVP/ACEI (82±3 cm
3
,
P
<.05). Isolated myocyte length increased with RVP (182±1 versus 149±1 μm), and the velocity of shortening decreased (36±1 versus 57±1 μm/s) compared with control values (
P
<.05). With RVP/ACEI, myocyte length was reduced (169±1 μm) and velocity of shortening was increased (45±1 μm/s) compared with RVP values (
P
<.05). Myocyte velocity of shortening after β-adrenergic receptor stimulation with 25 nmol/L isoproterenol was reduced with RVP compared with control values (142±5 versus 193±8 μm/s,
P
<.05) and significantly improved with RVP/ACEI (166±6 μm/s,
P
<.05). In the RVP group, β-adrenergic receptor density fell 26%, and cAMP production with β-adrenergic receptor stimulation was reduced 48% from control values. RVP/ACEI resulted in a normalization of β-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 RVP 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 β-adrenergic responsiveness. Contributory cellular and extracellular mechanisms for the beneficial effects of ACEI in this model of dilated cardiomyopathy included a normalization of β-adrenergic receptor function and enhanced myocardial collagen support. The results from this study provide evidence that ACEI during the development of cardiomyopathic disease provided beneficial effects on LV myocyte contractile processes and myocardial structure.