Effects of Levosimendan on the Energy Balance: Preclinical and Clinical Evidence

Abstract

Levosimendan is a novel inodilator agent, which enhances myocardial performance without substantial changes in oxygen consumption. The combination of positive inotropic and vasodilator effects of levosimendan relates to its Ca-sensitizing and K channel opening effects. Levosimendan is one of the best documented pharmacological agents used in the management of acute heart failure syndromes. Interest in levosimendan has recently been renewed owing to its potential in supporting cardiac function in patients with ischemic heart disease and cardiogenic or septic shock. It has been also demonstrated that levosimendan can be used as a bridge therapy for the perioperative phase of cardiac surgery. The ability of levosimendan to improve myocardial function without substantially increasing oxygen consumption may appear paradoxical but is indeed possible via improved efficacy, not only with regard to the effects on the contractile apparatus of the cardiomyocytes but also when its composite hemodynamic effects are considered. The energy balance equation, therefore, should take into account the effect of levosimendan on all energy-consuming and energy-producing paths. Moreover, levosimendan-evoked KATP channel opening may possess favorable effects on mitochondrial adenosine triphosphate synthesis conferring cardioprotection during ischemic insults.

Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore

“…Subsequent assays identified the Z -diastereomer as being more active with molecular modeling suggesting a key hydrogen bond between the nitrile nitrogen and a tyrosine hydroxyl group in tubulin 144 . 61 (levosimendan, Simdax) is a novel inodilator used to manage acute or chronic heart failure 145. As with many Ca 2+ sensitization and K + channel-mediators, the enzyme-inhibitor interactions are not fully resolved.…”

Solution structure of the regulatory domain of human cardiac troponin C in complex with the switch region of cardiac troponin I and W7: The basis of W7 as an inhibitor of cardiac muscle contraction

“…Toward this goal, a group of Ca 2+ -sensitizing drugs have been developed. One example is levosimendan, a novel Ca 2+ -sensitizer discovered by using cTnC as a target protein (for a recent review, see [4]). This drug has been proved to be a well-tolerated, effective treatment for patients with severe decompensated heart failure.…”

Levosimendan: Molecular mechanisms and clinical implications

“…Clinical data evaluating the effects of levosimendan on cardiovascular energetics in patients suggested either neutral impact on left ventricular efficiency and O 2 consumption [61,62], or decreased myocardial oxygen extraction and improved myocardial efficiency. Altogether, the effects of levosimendan on cardiovascular energy requirements are reassuring, particularly when levosimendan is compared with other positive inotropes [57].…”

“…When the effects on cardiovascular energy balance are addressed all the myocardial and systemic effects of levosimendan and of its metabolite have to be taken into account including positive inotropy, peripheral and coronary vasodilation, potential mitochondrial effects and parallel neurohumoral alterations [57]. In short, a Ca 2+ -sensitizing mechanism at the level of the cardiomyocytes is energetically advantageous, because in the absence of augmented Ca 2+ transients no extra energy requirement is imposed on cardiomyocytes [58].…”