Letter by Guarracino et al Regarding Article, “Direct Myocardial Effects of Levosimendan in Humans With Left Ventricular Dysfunction: Alteration of Force-Frequency and Relaxation-Frequency Relationships”
To the Editor:
We appreciated the article by Givertz et al that was recently published in Circulation.1 The authors aimed to determine the effect of levosimendan on myocardial contractility and diastolic function in failing human myocardium, with special attention on investigating whether levosimendan exerts heart rate–dependent effects on systolic or diastolic function. This was accomplished by administering intracoronary levosimendan at low and high doses in 10 instrumented patients. The studied patients had a mean ejection fraction of 27% and were in different New York Heart Association functional classes. The results showed that intracoronary low-dose levosimendan caused only modest dose-dependent increases in left ventricular peak +dP/dt and no effect on τ, and high-dose levosimendan caused only modest effect on both LV peak +dP/dt and τ and did not reduce left ventricular end-diastolic pressure. Furthermore, levosimendan had no effect on the slopes of either the force-frequency or relaxation-frequency relationship.
We found the investigation very interesting and believe it may confirm our previous data in human failing hearts treated with levosimendan.2 On the basis of measurement of ventriculoarterial coupling performed in patients with depressed left ventricular function, we too think the drug has favorable effects on contractility. However, we found that the influence of levosimendan on contractility depends the basal level of myocardial function. The greater the myocardial dysfunction, the lower the inotropic effect is on contractility. We found that levosimendan improved ventriculoarterial coupling by acting on both myocardial and arterial elastance, with a predominant effect on the latter when contractility was severely impaired. In our opinion, when using levosimendan, we should consider the effect it exerts on ATP-dependent K+ channels, as this may be the predominant mechanism through which the drug improves the mechanical efficiency of the cardiovascular system in critical conditions. In fact, arterial stiffening also has important implications for coronary vasomotion, which is mediated by nitric oxide and by calcium-sensitive K+ channels. In patients with deranged ventriculoarterial coupling, a “destiffening” strategy could be of therapeutic value. Hence, the use of levosimendan offers the amusing perspective of combining “ventriculoarterial destiffening” with contractile improvement. Ventriculoarterial uncoupling is worse than the hypocontractile state itself in many conditions, ranging from chronic cardiomyopathy to acute myocardial infarction and septic myocardial depression, and we feel that the very favorable effect of levosimendan is mainly exerted by optimizing the ratio between arterial and myocardial elastances, rather than by increasing myocardial contractility itself, as confirmed by the results of Givertz et al in their elegant and stimulating investigation.