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Pharmacological mechanisms contributing to the clinical efficacy of levosimendan Papp Z; Csapo K; Pollesello P; Haikala H; Edes ICardiovasc Drug Rev 2005[Spr]; 23 (1): 71-98Acute decompensation of chronic heart failure is a direct life-threatening situation with short-term mortality approaching 30%. A number of maladaptive changes are amplified within the cardiovascular system during the progression of chronic heart failure that makes the decompensation phase difficult to handle. Levosimendan is a new Ca2+-sensitizer for the treatment of acutely decompensated heart failure that has proved to be effective during the decompensation of chronic heart failure and acute myocardial infarction. Levosimendan differs from other cardiotonic agents that are used for acute heart failure in that it utilizes a unique dual mechanism of action: Ca2+-sensitization through binding to troponin C in the myocardium, and the opening of ATP-sensitive K+ channels in vascular smooth muscle. In general, these mechanisms evoke positive inotropy and vasodilation. Clinical studies suggested long-term benefits on mortality following short-term administration. It may, therefore, be inferred that levosimendan has additional effects on the cardiovascular system that are responsible for the prolongation of survival. Results of preclinical and clinical investigations suggest that the combination of levosimendan-induced cardiac and vascular changes has favorable effects on the coronary, pulmonary and peripheral circulations. Redistribution of the circulating blood offers an improved hemodynamic context for the development of a positive inotropic effect through Ca2+-sensitization of the contractile filaments, without a proportionate increase in myocardial oxygen consumption or the development of arrhythmias. Activation of ATP-sensitive K+ channels, both on sarcolemma and mitochondria, may protect against myocardial ischemia, and decreased levels of cytokines may prevent the development of further myocardial remodeling. Collectively, these effects of levosimendan shift the disturbed cardiovascular parameters towards normalization, thereby halting the perpetuation of the vicious cycle of heart failure progression. This may contribute to stabilization of the circulation and improved life expectancy of patients with chronic heart failure.|*Treatment Outcome[MESH]|Animals[MESH]|Chronic Disease[MESH]|Heart Failure/drug therapy[MESH]|Humans[MESH]|Hydrazones/metabolism/*pharmacology/*therapeutic use[MESH]|Pyridazines/metabolism/*pharmacology/*therapeutic use[MESH]|Simendan[MESH] |
