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.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Aortic Valve Insufficiency/drug therapy , Captopril/pharmacology , Energy Metabolism/drug effects , Myocardium/enzymology , Ventricular Remodeling/drug effects , Animals , Aortic Valve Insufficiency/diagnosis , Aortic Valve Insufficiency/enzymology , Aortic Valve Insufficiency/physiopathology , Disease Models, Animal , Echocardiography , Extracellular Matrix/metabolism , Fatty Acids/metabolism , G-Protein-Coupled Receptor Kinase 5/metabolism , Hypertrophy, Left Ventricular/diagnosis , Hypertrophy, Left Ventricular/enzymology , Hypertrophy, Left Ventricular/physiopathology , Hypertrophy, Left Ventricular/prevention & control , Myocardium/pathology , Positron-Emission Tomography , Proto-Oncogene Proteins c-akt/metabolism , Rats , Severity of Illness Index , Time Factors , Ventricular Function, Left/drug effectsABSTRACT
BACKGROUND AND AIM OF THE STUDY: Aortic regurgitation (AR) is a disease for which there is currently no effective medical treatment. It has been shown previously in an experimental model of AR that the renin-angiotensin-aldosterone system (RAAS) plays a major role, and that medications blocking the RAAS are effective to protect against left ventricular (LV) hypertrophy and also help to maintain a normal systolic function. The role of aldosterone receptor blockers in this disease has never been evaluated. Thus, the effects were studied of the aldosterone receptor blocking agent spironolactone in a model of chronic AR in rats. METHODS: The effects of a six-month treatment with spironolactone were evaluated in adult Wistar rats with severe AR, compared to sham-operated and untreated AR animals. RESULTS: Spironolactone treatment decreased the total heart weight. In addition, the LV expression of atrial natriuretic peptide mRNA was decreased by spironolactone treatment, as was the expression of collagen 1 and LOX1 mRNAs. Left ventricular fibrosis was decreased by spironolactone treatment. CONCLUSION: Spironolactone protected against volume-overload cardiomyopathy in this model of aortic valve regurgitation. The predominant protective effect was a decrease in myocardial fibrosis.
Subject(s)
Aortic Valve Insufficiency/drug therapy , Cardiomegaly/drug therapy , Mineralocorticoid Receptor Antagonists/pharmacology , Spironolactone/pharmacology , Animals , Aortic Valve Insufficiency/diagnostic imaging , Aortic Valve Insufficiency/physiopathology , Blood Pressure/drug effects , Cardiomegaly/diagnostic imaging , Cardiomegaly/physiopathology , Chronic Disease , Diastole/physiology , Disease Models, Animal , Echocardiography , Heart Rate/drug effects , Male , Rats , Rats, Wistar , Ventricular Pressure/physiologyABSTRACT
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 ß-blockade with metoprolol exerted beneficial effects on left ventricular remodeling and survival. Despite the recent publication of promising human data, ß-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 ß-blocking and α-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. ß1-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 ß-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 ß-blockers in chronic aortic valve regurgitation.
