Comparative Study of Vasodilators in an Animal Model of Chronic Volume Overload Caused by Severe Aortic Regurgitation

Abstract

Background-Aortic regurgitation (AR) is a disease of chronic left ventricular (LV) volume overload. Over time, AR will lead to LV dilatation, hypertrophy, and loss of function. There is currently no medical treatment proven effective to slow the evolution of this cardiomyopathy. Vasodilators were once thought to have protective effects, but recent publications have cast some doubts about their effectiveness. We hypothesized that drugs targeting the renin-angiotensin system should be more effective than those having no direct effect on the renin-angiotensin system. Methods and Results-We designed a protocol comparing the effects of 3 vasodilators in a rat AR model (nϭ9 to 11 animals per group). The effects of a 6-month treatment of (1) nifedipine, (2) captopril, or (3) losartan were compared in male AR rats. Sham-operated and untreated AR animals were used as controls. Nifedipine-treated animals displayed hemodynamics, LV dilatation, hypertrophy, and loss of function similar to those of the untreated group. Both captopril and losartan were effective in improving hemodynamics, slow LV dilatation, hypertrophy, and dysfunction. Gene expression analysis confirmed the lack of effects of the nifedipine treatment at the molecular level. Conclusions-Using an animal model of severe AR, we found that vasodilators targeting the renin-angiotensin system were effective to slow the development of LV remodeling and to preserve LV function. As recently shown in the most recent human clinical trial, nifedipine was totally ineffective. Targeting the renin-angiotensin system seems a promising avenue in the treatment of this disease, and clinical trials should be carefully designed to re-evaluate the effectiveness of angiotensin I-converting enzyme inhibitors or angiotensin II receptor blockers in AR. (Circ Heart Fail. 2009;2:25-32.)

Angiotensin II–Converting Enzyme Inhibition Improves Survival, Ventricular Remodeling, and Myocardial Energetics in Experimental Aortic Regurgitation

“…A 7-month follow-up may reflect the subacute period in humans, and it does enclose a true chronic phase in rats because we have previously shown in a paper characterizing this animal model. 6,8 Our results show a clear effect on LV dilatation, hypertrophy, systolic function, myocardial metabolism, and more importantly on survival. These results provide support for the need to reevaluate ACEI in humans with AR in a large prospective clinical trial.…”

“…We previously showed that blood pressure in AR animals treated with Cpt is only slightly reduced and had similar findings in this protocol. 6 This suggests that the hemodynamic contribution to the benefits of angiotensin-converting enzyme (ACE) inhibition although present is not the main and only factor involved. 6 The previously reported shift toward glucose use by the myocardium in compensated hypertrophy was not observed in our Cpt-treated AR rats.…”

“…6 This suggests that the hemodynamic contribution to the benefits of angiotensin-converting enzyme (ACE) inhibition although present is not the main and only factor involved. 6 The previously reported shift toward glucose use by the myocardium in compensated hypertrophy was not observed in our Cpt-treated AR rats. We have recently reported this shift in substrate uptake in 8-week AR animals.…”

“…4 We have previously shown in a controlled animal model of pure severe aortic valve regurgitation that ACEI captopril (Cpt) reduced LV hypertrophy and protected LV systolic function. 5,6 However, we could not provide a clear mechanism to explain those protective effects. We also had not evaluated the effects of the treatment on the long-term clinical outcome of the animals treated with Cpt.…”

Insights Into the Activation and Inhibition of Angiotensin II Type 1 Receptor in the Mechanically Loaded Heart

“…53 Correspondingly, ARBs have paved a promising path in the treatment of VO cardiac hypertrophy. 46, 54 The widespread experimental findings and clinical applications of ARBs to ameliorate cardiac remodeling under PO and VO are testament to the importance of the AT1-R. Yet, questions remain.…”