• John T Parissis, Ioanna Andreadou, Vassiliki Bistola, Ioannis Paraskevaidis, Gerasimos Filippatos, and Dimitrios T Kremastinos.
• University of Athens and Attikon General Hospital, Heart Failure Clinic and Second Cardiology Department, Navarinou 13, 15122 Maroussi, Athens, Greece. jparissis@yahoo.com
• Expert Opin Investig Drugs. 2008 Aug 1;17(8):1143-50.

BackgroundCalcium sensitizers belong to a new class of cardiac enhancers that stimulate cardiac contractility without causing intracellular calcium overload or increasing myocardial oxygen demand. Levosimendan, the most well-studied calcium sensitizer in the real clinical practice, produces greater hemodynamic and symptomatic improvement in patients with acute heart failure than traditional inotropes.ObjectiveTo review the recent experimental and clinical evidence on novel biologic mechanisms explaining the pleiotropic effects of levosimendan on the failing heart.MethodsA systematic search of peer-reviewed publications was performed on Medline and EMBASE from January 1995 to December 2007. The results of unpublished trials were obtained from presentations at national and international meetings.ResultsLevosimendan has a unique dual mechanism of action by enhancing cardiac contractility and causing peripheral vasodilatation. Immunomodulatory and antiapoptotic properties of levosimendan may be an additional biologic mechanism that prevents further cytotoxic and hemodynamic consequences of abnormal immune and neurohormonal responses in acute heart failure, leads to cardioprotection, and beneficially intervenes in the progression of syndrome. Experimental data show that levosimendan exerts its cardioprotective effects through its antioxidant properties and seems to be a potent inhibitor of H2O2-induced cardiomyocyte apoptotic cell death. Clinical data demonstrate that levosimendan does not increase markers of oxidative and nitrosative stress, in contrast to placebo treatment, in advanced chronic heart failure patients. Levosimendan has also been shown to activate mitoK(ATP) channels which are important mediators of ischemic preconditioning. Pharmacological modulation of K(ATP) channels may prove beneficial in patients at risk of myocardial ischemia, particularly those requiring inotropic support.ConclusionPleiotropic effects of levosimendan appear to have important clinical and prognostic implications in acute heart failure syndromes and ischemic heart disease.

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