Levosimendan in Cardiac Surgery: A Unique Drug for the Treatment of Perioperative Left Ventricular Dysfunction or Just Another Inodilator Searching for a Clinical Application?

Abstract

Paul S. Pagel, MD, PhD The myofilament calcium (Ca ) sensitizers are a class of positive inotropic, vasodilating drugs (“inodilators”) that augment myocardial contractility by increasing the Ca sensitivity of the contractile apparatus without altering intracellular Ca concentration (1). Ca sensitizers (including levosimendan, pimobendan, sulmazole, EMD 57033, and MCI-154) have received considerable attention for the treatment of acute and chronic congestive heart failure because, unlike 1-adrenoceptor agonists or cardiac phosphodiesterase (PDE) III inhibitors that stimulate cyclic adenosine monophosphate (cAMP)mediated signaling and increase intracellular Ca concentration, these drugs do not adversely affect myocardial oxygen supply-demand relations (2), produce cardiotoxicity, or predispose to the development of arrhythmias (3). Levosimendan was developed over a decade ago, and based on a large body of accumulated experimental and clinical evidence, appears to be the most promising of these drugs. Levosimendan has already been approved for the treatment of acute exacerbation of chronic heart failure in several European countries following European Society of Cardiology guidelines (4,5). The drug is currently undergoing Phase III clinical trials in the United States (REVIVE study) to evaluate its utility for the acute or chronic management of heart failure, and has received “fast-track” status from the Food and Drug Administration. The mechanisms by which levosimendan enhances the inotropic state and produces vasodilation have been extensively studied (1). Briefly, levosimendan binds to the regulatory protein troponin C (TnC) (6) and stabilizes the Ca -bound conformation of TnC, thereby allowing unopposed interaction between actin and myosin filaments and enhancing the rate and extent of myocyte contraction (7). A unique feature of levosimendan-TnC binding is its dependence on intracellular Ca concentration that facilitates the interaction between TnC and Ca during systole, while simultaneously allowing Ca to dissociate from the protein during diastole (8). This Ca -dependence of TnC binding prevents deleterious abnormalities in relaxation that would otherwise be expected to occur (9). Preservation of lusitropic function is also facilitated by the PDE-inhibiting properties of levosimendan that occur at higher doses of the drug (10). Levosimendan-induced systemic, pulmonary, and coronary vasodilation occurs as a result of at least three distinct mechanisms. Levosimendan opens several types of potassium (K ) channels (including voltagedependent, ATP-sensitive, and Ca -activated forms) in conductance and resistance vessels, actions that reduce intracellular Ca concentration in vascular smooth muscle (11). Levosimendan induces Ca desensitization of the contractile apparatus in vascular smooth muscle that does not contain TnC independent of intracellular Ca concentration (12). PDE inhibition may also play a role in vasodilation produced by higher doses of the drug. Unlike other inotropic drugs, levosimendan may exert important antiischemic effects by virtue of its actions as a KATP channel opener. Levosimendan From the Anesthesia Service, the Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin. Accepted for publication December 7, 2006. Address correspondence to Paul S. Pagel, MD, PhD, Clement J. Zablocki Veterans Affairs Medical Center, Anesthesia Service, 5000 W. National Ave., Milwaukee, WI 53295. Address e-mail to paul.pagel@med.va.gov. Copyright © 2007 International Anesthesia Research Society DOI: 10.1213/01.ane.0000256864.75206.6d