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

Abstract

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.)

Endurance training or beta-blockade can partially block the energy metabolism remodeling taking place in experimental chronic left ventricle volume overload

“…It could be suggested that dilation may not be homogeneous through the LV was and that the observed metabolic changes in the LV myocardium may reflect this. We already observed the opposite situation in the AR rat where fatty acid uptake was reduced in the same LV region where we now observe an increase in glucose uptake [25]. Concentric LV hypertrophy is associated with a shift in substrate preference from free fatty acids to glucose [35].…”

“…The only solution available for now remains valve replacement surgery when the left ventricle becomes too dilated, systolic indices progressively decrease or when symptoms occur. Over the years, we have showed that treatment targeting the renin-angiotensin-aldosterone or the adrenergic systems can help reduce LH hypertrophy, maintain cardiac function and improve survival in a rat model of chronic AR [22–25]. We did observe a similar effect by non-pharmaceutical strategy i.e.…”

“…Enzyme activity assays are described in details in the supplementary section (Additional file 1, Methods) [25, 27, 34]. …”

Female rats with severe left ventricle volume overload exhibit more cardiac hypertrophy but fewer myocardial transcriptional changes than males

“…We previously demonstrated that blocking these systems (adrenergic and/or renin-angiotensin-aldosterone) led to decreased LV hypertrophy in the AR rat model and better survival 19–21 . Dent and collaborators demonstrated the presence of sex differences in neurohormonal activation in the arteriovenous fistula (ARF) VO model.…”

Drug Therapy for Heart Valve Diseases

“…In experimental severe AR, ACEIs improved myocardial metabolism and survival in association with reduction of LV hypertrophy and other structural changes 57 . In patients with chronic AR, ACEI diminished regurgitant volume 49 .…”