Cardiovascular effects of the calcium sensitizer, levosimendan, in heart failure induced by rapid pacing in the presence of aortic constriction

Abstract

1 The haemodynamic effects of a novel cardiotonic drug, levosimendan, which has both calciumsensitizing and phosphodiesterase III (PDE III) inhibitory properties, were studied in conscious dogs in which heart failure had been induced by prolonged cardiac pacing in the presence of aortic constriction. These effects were compared with those in sham-operated dogs with essentially normal cardiac function. 2 Eighteen mongrel dogs were instrumented for the measurement of left ventricular pressure (LVSP, LVEDP) and contractile function (dP/dt; dP/dt/P). In twelve dogs a balloon catheter, positioned in the thoracic aorta, was inflated producing an approximate 60% reduction in effective aortic diameter. Twenty min later rapid ventricular pacing (240 beats mean-1) was commenced and maintained for 48 h by means of a bipolar pacing electrode introduced into the right ventricle. This electrode served also for recording changes in the endocardial electrogram in the absence of pacing. Six of these dogs were used to evaluate the haemodynamic changes of pacing-induced heart failure; a further six of these dogs the haemodynamic changes elicited by levosimendan under these conditions. Six sham-operated dogs (group 2) served as controls. 3 In six dogs (group 1) the haemodynamic alterations were assessed after the development of heart failure. In the presence of aortic constriction, 48 h continuous rapid cardiac pacing resulted in a marked deterioration in left ventricular function which remained stable for at least 48 h after cessation of pacing.Thus, there was a marked reduction in LVSP (15%), +dP/atma,, (35%), -dP/dtaax (36%) and also in dP/dt/P (29%), whereas LVEDP was increased considerably (from 6.4 ± 1.4 to 20.0 ± 2.2 mmHg). A marked elevation occurred in endocardial ST-segment (138%), lasting for 20 min. 4 Levosimendan was administered intravenously in doses of 0.005, 0.01 and 0.03 gmol kg-' to 2 groups of conscious dogs. In the sham-operated dogs (group 2), only the higher dose (0.03 ILmol kg-') produced significant increases in LVSP (19%), + dP/dtmax (37%), and in dP/dt/P (32%). In dogs with heart failure (group 3) doses of 0.005, 0.01 and 0.03 pmol kg-' levosimendan resulted in an improvement in +dP/dtmax (26%, 38% and 49%), -dP/dtmax (20%, 25% and 38%) and in dP/dt/P (19%, 34% and 50%) and reduction in the elevated LVEDP (from 20 ± 2.2 mmHg to 16 + 1.0, 10 ± 1.3 and 9 ± 1.0 mmHg, respectively). 5 Levosimendan proved to be a potent cardiotonic drug at the doses used, and was approximately three times more effective under conditions of impaired left ventricular function than in normal hearts.

Levosimendan: A promising agent for the treatment of hospitalized patients with decompensated heart failure

“…In anesthetized dogs intravenous levosimendan produced a dose-dependent increase in peak +dP/dt of up to 60% in the dose range 0.01 to 0.1 mg/kg [26]. Maximum inotropic effect is seen approximately 10 min after the administration of intravenous levosimendan and is sustained up to 30 min [27]. Studies in conscious dogs treated with oral levosimendan (1 mol/kg/d for 14 days) established that the positive inotropic effects of the drug were sustained in continuous use [28].…”

Levosimendan: A calcium-sensitizing agent for the treatment of patients with decompensated heart failure

“…Data from studies in vitro indicate that the positive inotropic effect of levosimendan in human cardiac tissue is not attenuated by disease, even though there is lot of variability in the inotropic response [21]. In dogs, intravenous levosimendan produced a dose-dependent increase in peak +dP/ dt of up to 60% in the dose range 0.01 to 0.1 mg/kg without impairment of diastolic function [24,25,26]. The positive inotropic effects of the drug are sustained in continuous use.…”

Refractory heart failure

“…This drug is a novel agent with positive inotropic and peripheral vasodilatory effects that are related to three different pharmacologic actions [55][56][57]. Levosimendan enhances the calcium sensitivity of the myofilament by binding to troponin C, stimulates the sodium/calcium exchanger in cardiac muscle and peripheral vasculature, and is a selective inhibitor of phosphodiesterase II.…”