Novel biologic mechanisms of levosimendan and its effect on the failing heart.
BACKGROUND
Calcium 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.


OBJECTIVE
To review the recent experimental and clinical evidence on novel biologic mechanisms explaining the pleiotropic effects of levosimendan on the failing heart.


METHODS
A 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 The results of unpublished trials were obtained from presentations at national and international meetings.


RESULTS
Levosimendan 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.


CONCLUSIONS
Pleiotropic effects of levosimendan appear to have important clinical and prognostic implications in acute heart failure syndromes and ischemic heart disease.
Parissis
John T
JT
University of Athens and Attikon General Hospital, Heart Failure Clinic and Second Cardiology Department, Navarinou 13, 15122 Maroussi, Athens, Greece. jparissis@yahoo.com
Andreadou
Ioanna
I
Bistola
Vassiliki
V
Paraskevaidis
Ioannis
I
Filippatos
Gerasimos
G
Kremastinos
Dimitrios T
DT
D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006835:Hydrazones / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D009200:Myocardial Contraction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D011724:Pyridazines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D000077464:Simendan; D016896:Treatment Outcome
D002316:Cardiotonic Agents; D006835:Hydrazones; D011724:Pyridazines; D000077464:Simendan