Journal of Cardiac Failure
Volume 15, Issue 9 , Pages 805-811, November 2009

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

  • Takemi Handa, MD

      Affiliations

    • Department of Cardiovascular Control, Kochi Medical School, Nankoku, Japan
    • Department of Cardiovascular Surgery, Kochi Medical School, Nankoku, Japan
    • Corresponding Author InformationCorrespondence to: Takemi Handa, Department of Cardiovascular Control, Kochi Medical School, Nankoku, Kochi 783-8505, Japan. Tel: (+81) 88-880-2309; Fax: (+81) 88-880-2310.
    • ,
  • Rajesh G. Katare, MD

      Affiliations

    • Department of Cardiovascular Control, Kochi Medical School, Nankoku, Japan
    • ,
  • Yoshihiko Kakinuma, MD

      Affiliations

    • Department of Cardiovascular Control, Kochi Medical School, Nankoku, Japan
    • ,
  • Mikihiko Arikawa, PhD

      Affiliations

    • Department of Cardiovascular Control, Kochi Medical School, Nankoku, Japan
    • ,
  • Motonori Ando, PhD

      Affiliations

    • Department of Cardiovascular Control, Kochi Medical School, Nankoku, Japan
    • ,
  • Shiro Sasaguri, MD

      Affiliations

    • Department of Cardiovascular Surgery, Kochi Medical School, Nankoku, Japan
    • ,
  • Fumiyasu Yamasaki, MD

      Affiliations

    • Department of Clinical Laboratory, Kochi Medical School, Nankoku, Japan
    • ,
  • Takayuki Sato, MD

      Affiliations

    • Department of Cardiovascular Control, Kochi Medical School, Nankoku, Japan

Received 22 December 2008; received in revised form 17 April 2009; accepted 7 May 2009. published online 29 June 2009.

Abstract 

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 an 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, an 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.

Key Words: Acetylcholine, heart failure, survival, vagus nerve

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 Supported by a grant-in-aid for scientific research (19659355) from the Ministry of Education, Science, Sports, and Culture of Japan, and by a Health and Labor Sciences research grant (H15-KOKORO-019, H16-NANO-005) from the Ministry of Health, Labor, and Welfare of Japan.

PII: S1071-9164(09)00165-1

doi:10.1016/j.cardfail.2009.05.008

Journal of Cardiac Failure
Volume 15, Issue 9 , Pages 805-811, November 2009

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