Levosimendan beyond inotropy and acute heart failure: Evidence of pleiotropic effects on the heart and other organs: An expert panel position paper

Abstract

Levosimendan is a positive inotrope with vasodilating properties (inodilator) indicated for decompensated heart failure (HF) patients with low cardiac output. Accumulated evidence supports several pleiotropic effects of levosimendan beyond inotropy, the heart and decompensated HF. Those effects are not readily explained by cardiac function enhancement and seem to be related to additional properties of the drug such as anti-inflammatory, anti-oxidative and anti-apoptotic ones. Mechanistic and proof-of-concept studies are still required to clarify the underlying mechanisms involved, while properly designed clinical trials are warranted to translate preclinical or early-phase clinical data into more robust clinical evidence. The present position paper, derived by a panel of 35 experts in the field of cardiology, cardiac anesthesiology, intensive care medicine, cardiac physiology, and cardiovascular pharmacology from 22 European countries, compiles the existing evidence on the pleiotropic effects of levosimendan, identifies potential novel areas of clinical application and defines the corresponding gaps in evidence and the required research efforts to address those gaps.

Inotropes and vasopressors

“…Since it does not act through adrenergic receptors, β blockade does not influence the hemodynamic effects of levosimendan (10). Although it is primarily used for treatment of patients with heart failure, there is growing evidence of its benefit in patients undergoing cardiac surgery (16,32). In a recently published article, it is recommended that levosimendan be used in the preoperative setting in cardiac surgery (16).…”

“…In addition to its use in the treatment of heart failure and cardiac surgery, there is growing evidence of beneficial effect when levosimendan is used in other settings. Although there is strong evidence of its renoprotective effect, there are still some conflicting results (31,32). Furthermore, there is evidence that levosimendan reduces mortality in patients with severe sepsis and septic shock (33).…”

Preferential Vasodilator Effects of Levosimendan in Resistance Pulmonary Arteries in a Rodent Pulmonary Embolism Model

“…Levosimendan is a positive inotropic agent (by increasing the sensitivity of troponin C to calcium) with vasodilating properties (by lowering of intracellular free Ca++, opening of different potassium channels and the inhibition of phosphodiesterase type III), also termed inodilator [3,4]. There are several animals studies in different acute pulmonary hypertension (PH) models secondary to thromboxane A2 infusion [5], endotoxemia [6], acute pulmonary embolism (PE) [7,8], and hypoxia [9] and some clinical studies that demonstrated the vasodilator effect of levosimendan on the pulmonary circulation, restoring right ventricular-arterial coupling as it increased right ventricular contractility concomitantly [10,11].…”

Levosimendan: New hope therapy for takotsubo syndrome

“…Levosimendan exerts both inotropic and vasodilatatory effects via increasing cardiac contractility mediated by calcium sensitization of troponin C and producing vasodilation through opening adenosine triphosphate (ATP)-sensitive potassium channels in vascular smooth muscle cells. Aside from its clinical indication in treating acute decompensated HF, benefits of levosimendan have been demonstrated in other clinical conditions including cardiogenic or septic shock, cardiac surgery and advanced chronic HF [8][9][10]. First evidence for the use of levosimendan comes from 4 case reports who developed TS-related cardiogenic shock [11][12][13] or sepsisassociated TS [14].…”