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Angiotensin-converting enzyme inhibition and the progression of congestive cardiomyopathy. Effects on left
F G Spinale1, H H Holzgrefe, R Mukherjee
1Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston 29425, USA.
Insights
Angiotensin-converting enzyme inhibition (ACEI) directly improves left ventricular (LV) function and myocyte structure in a canine model of dilated cardiomyopathy. ACEI normalizes beta-adrenergic receptor function and enhances myocardial collagen, offering protective effects.
Area of Science:
- Cardiology
- Pharmacology
- Cellular Biology
Background:
- Clinical trials show Angiotensin-Converting Enzyme Inhibition (ACEI) improves survival in patients with left ventricular (LV) dysfunction.
- Direct effects of ACEI on LV myocardial structure and function in cardiomyopathic disease remained unclear.
Purpose of the Study:
- To examine the direct effects of ACEI on LV and myocyte structure and function in a canine model of dilated cardiomyopathy.
- To investigate the cellular and extracellular mechanisms underlying ACEI's beneficial effects.
Main Methods:
- Dilated cardiomyopathy induced in dogs via rapid ventricular pacing (RVP).
- Treatment groups: Control, RVP, and RVP with concomitant ACEI (fosinopril).
- Assessment of LV function, isolated myocyte function and structure, beta-adrenergic responsiveness, and myocardial collagen content.
Main Results:
- RVP significantly reduced LV ejection fraction and increased LV end-diastolic volume.
- ACEI (RVP/ACEI) improved LV ejection fraction and reduced LV end-diastolic volume compared to RVP alone.
- Isolated myocytes showed improved length and velocity of shortening with ACEI.
- ACEI normalized beta-adrenergic receptor density and cAMP production, and increased myocardial collagen content.
Conclusions:
- Concomitant ACEI with chronic tachycardia reduced LV chamber dilation and improved myocyte contractile function and beta-adrenergic responsiveness.
- ACEI's benefits in this model involve normalization of beta-adrenergic receptor function and enhanced myocardial collagen.
- ACEI provides direct beneficial effects on LV myocyte contractile processes and myocardial structure in dilated cardiomyopathy.
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 cm3, P < .05) and was lower with RVP/ACEI (82 +/- 3 cm3, P < .05). Isolated myocyte length increased with RVP (182 +- 1 versus 149 +/- 1 micron), and the velocity of shortening decreased (36 +/- 1 versus 57 +/- 1 micron/s) compared with control values (P < .05). With RVP/ACEI, myocyte length was reduced (169 +/- 1 micron) and velocity of shortening was increased (45 +/- 1 micron/s) compared with RVP values (P < .05). Myocyte velocity of shortening after beta-adrenergic receptor stimulation with 25 nmol/L isoproterenol was reduced with RVP compared with control values (142 +/- 5 versus 193 +/- 8 micron/s, P < .05) and significantly improved with RVP/ACEI (166 +/- 6 micron/s, P < .05). In the RVP group, beta-adrenergic receptor density fell 26%, and cAMP production with beta-adrenergic receptor stimulation was reduced 48% from control values. RVP/ACEI resulted in a normalization 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 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 beta-adrenergic responsiveness. Contributory cellular and extracellular mechanisms for the beneficial effects of ACEI in this model of dilated cardiomyopathy included a normalization of beta-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.