Vasodilator therapy in patients with aortic insufficiency: A systematic review

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.)

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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

Plante

Lachance

Beaudoin

et al. 2009

“…[2][3][4] Based on the hypothesis that the adrenergic system is overactivated early in the course of chronic AR even before heart failure occurs, we have previously evaluated the effects of ␤-blockade with metoprolol in an animal model of chronic AR and found that it improved LV function, reduced LV hypertrophy, and increased survival. 5,6 Recently, Sampat et al 7 reported beneficial effects of ␤-blockers in a retrospective study of 756 patients.…”

Section: Clinical Perspective On P 213mentioning

confidence: 99%

Usefulness of Carvedilol in the Treatment of Chronic Aortic Valve Regurgitation

Zendaoui

Lachance

Roussel

et al. 2011

Background-Aortic regurgitation (AR) is a chronic disease for which there is currently no approved medical treatment.We previously reported in an animal model that ␤-blockade with metoprolol exerted beneficial effects on left ventricular remodeling and survival. Despite the recent publication of promising human data, ␤-blockade in chronic AR remains controversial. More data are needed to support this potentially new treatment strategy. We hypothesized that carvedilol might be another safe treatment option in chronic AR, considering its combined ␤-blocking and ␣-blocking effects and proven efficacy in patients with established heart failure. Methods and Results-The effects of a 6-month treatment with carvedilol 30 mg/kg/d orally were evaluated in adult Wistar rats with severe AR. Sham-operated and untreated AR animals were used as controls. Carvedilol treatment resulted in less left ventricular hypertrophy and dilatation. Ejection fraction was improved and filling pressures were reduced by carvedilol. ␤1-Receptor expression was also improved as well as myocardial capillary density. Those beneficial effects were noted despite the presence of drug-induced bradycardia. Conclusions-Carvedilol exerted protective effects against volume-overload cardiomyopathy in this model of aortic valve regurgitation with preserved ejection fraction. These results suggest a protective class effect of ␤-blockers. Combined with the recent publication of promising human data, our findings support the need to carefully design a prospective study in humans to evaluate the effects of ␤-blockers in chronic aortic valve regurgitation. (Circ Heart Fail. 2011;4: 207-213.)

“…It has been suggested that trial design and/or patient selection may be at least, in part, responsible for the inconsistency of the results. 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.…”

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confidence: 99%

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

Arsenault

Zendaoui

Roussel

et al. 2013

Background-Aortic valve regurgitation (AR) is a volume-overload disease causing severe eccentric left ventricular (LV) hypertrophy and eventually heart failure. There is currently no approved drug to treat patients with AR. Many vasodilators including angiotensin-converting enzyme inhibitors have been evaluated in clinical trials, but although some results were promising, others were inconclusive. Overall, no drug has yet been able to improve clinical outcome in AR and the controversy remains. We have previously shown in an animal model that captopril (Cpt) reduced LV hypertrophy and protected LV systolic function, but we had not evaluated the clinical outcome. This protocol was designed to evaluate the effects of a long-term Cpt treatment on survival in the same animal model of severe aortic valve regurgitation. Methods and Results-Forty Wistar rats with AR were treated or untreated with Cpt (1 g/L in drinking water) for a period of 7 months to evaluate survival, myocardial remodeling, and function by echocardiography as well as myocardial metabolism by µ positron emission tomography scan. Survival was significantly improved in Cpt-treated animals with a survival benefit visible as soon as after 4 months of treatment. Cpt reduced LV dilatation and LV hypertrophy. It also significantly improved the myocardial metabolic profile by restoring the level of fatty acids metabolic enzymes and use. Conclusions-In a controlled animal model of pure severe aortic valve regurgitation, Cpt treatment reduced LV remodeling and LV hypertrophy and improved myocardial metabolic profile and survival. These results support the need to reevaluate the role of angiotensin-converting enzyme inhibitors in humans with AR in a large, carefully designed prospective clinical trial. (Circ Heart Fail. 2013;6:1021-1028.)