Anti-Alzheimer's Drug, Donepezil, Markedly Improves Long-Term Survival After Chronic Heart Failure in Mice

Background: We previously reported that chronic vagal nerve Stimulation markedly improved long-term survival after chronic heart failure (CHF) in rats through cardioprotective effects of acetylcholine, independent of the heart rate-slowing mechanism. However, such ail approach is invasive and its safety is unknown in clinical settings. To develop an alternative therapy with a clinically available drug, we examined the chronic effect of oral donepezil, in acetylcholinesterase inhibitor against Alzheimer's disease, on cardiac remodeling and survival with a murine model of volume-overloaded CHF. Methods and Results: Four weeks after surgery of aortocaval shunt, CHF mice were randomized into untreated and donepezil-treated groups. Donepezil was orally given at a dosage of 5 mg.kg(-1).day(-1). After 4 weeks of treatment, we evaluated in situ left ventricular (LV) pressure, ex vivo LV pressure-volume relationships, and LV expression of brain natriuretic peptides (BNP). We also observed Survival for 50 days. When compared with the untreated group, the donepezil-treated group had significantly low LV end-diastolic pressure, high LV contractility, and low LV expression of BNP. Donepezil significantly reduced the heart weight and markedly improved the Survival rate during the 50-day treatment period (54% versus 81%, P < .05). Conclusions: Oral donepezil improves Survival of CHF mice through prevention of pumping failure and cardiac remodeling. (J Cardiac Fail 2009;15:805-811)