Heart failure (HF) with reduced ejection fraction (HFrEF) is associated with high morbidity and mortality despite the use of evidence-based optimal medical and device therapy.1 This is particularly true in patients with advanced HF, who may benefit from specific treatments, such as heart transplantation, assist devices or palliative care.2 Aside from the use of such therapeutic options, a 24-hour infusion of levosimendan has been used to transiently improve the clinical status of patients with advanced HF.3–6 Moreover, levosimendan has been used in protocols of adjusted (reduced) dose and repeated infusions in the outpatient setting with encouraging results,7–9 as supported by data from the LION-HEART and LAICA trials.10,11

Levosimendan is an inotropic drug with three mechanisms of action: positive inotropy, vasodilation, and cardioprotection.12–16 Its pharmacokinetics means that its metabolite OR1896 has a longer duration of action than other catecholaminergic inotropes.17 It is well known that a 24-hour levosimendan infusion in patients hospitalized for HF improves their hemodynamic status.3,4,6 However, there are no available data on the hemodynamic effects of adjusted-dose levosimendan infusion in the outpatient context, since the assessment of hemodynamic data in this setting is hampered by logistic constraints. Moreover, the hemodynamic effects of adjusted-dose levosimendan infusion in the outpatient setting may differ from the effects of a 24-hour full-dose infusion and from its effects in acute decompensated HF. The availability of daily hemodynamic data after outpatient levosimendan infusion could contribute to a better understanding of the mechanisms that lead to clinical improvement following the infusions and possibly to optimization of the infusion protocol.

Remote invasive monitoring using the CardioMEMS™ system (Abbott Scientific, Atlanta, GA, USA) enables daily assessment of pulmonary artery pressure (PAP) and estimation of cardiac output (CO).18 It is currently approved for chronic HF patients in New York Heart Association (NYHA) functional class III and with at least one prior hospitalization for HF within the previous year, regardless of ejection fraction.1 Of note, PAP measurements using CardioMEMS™ show a strong correlation with PAP obtained using a Swan-Ganz catheter.19 The CardioMEMS™ system may thus enable accurate daily hemodynamic assessment of therapeutic interventions in the outpatient setting.

We aimed to assess the hemodynamic effects of levosimendan infusion in the outpatient setting using the CardioMEMS™ system. To the best of our knowledge, there are no published data on this subject.

A total of 25 sessions were carried out in three patients (six sessions in patient 1, 17 in patient 2, and two in patient 3). All patients reached and tolerated the 0.2 mg/kg/min levosimendan infusion dose, without the need for dose reduction, throughout all sessions.

Hemodynamic data according to levosimendan infusions

There were no transmission failures of the CardioMEMS™ system and reading compliance was 95% during the study period.

Figure 1 presents systolic, mean and diastolic PAP, CO, and HR before and after each levosimendan infusion. There was an early reduction in diastolic PAP on the first day following levosimendan infusion compared to the day prior to the infusion (baseline) (24.1±4.1 mmHg vs. 21.6±2.9 mmHg, p=0.006). Thereafter, diastolic PAP remained stable and significantly lower than baseline up to day 10 after the infusion. There were no significant differences in systolic or mean PAP before and after levosimendan infusion at any timepoint analyzed or significant changes in CO, HR, or SV after levosimendan infusion compared to baseline. There was a nonsignificant increase in CO compared to baseline with a peak at day 6 after the infusion (4.0 l/min vs. 3.8 l/min, p=0.105), followed by a decline in CO in the following days.

Figure 1.

Hemodynamic data before and up to day 13 after six-hour levosimendan infusion. CO: cardiac output; dPAP: diastolic pulmonary artery pressure; HR: heart rate; mPAP: mean pulmonary artery pressure; sPAP: systolic pulmonary artery pressure. 0 (zero) corresponds to the CardioMEMS™ measurement on the day before the infusion.

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To our knowledge, this is the first study assessing the day-to-day hemodynamic effects of levosimendan infusion in the outpatient setting using the CardioMEMS™ system. In 25 sessions of levosimendan infusion performed in three patients with advanced HF, the main finding was a significant early reduction in diastolic PAP after each infusion, an effect that was maintained up to 10 days. This may provide insights into the mechanisms underlying clinical improvement following levosimendan infusion and supports the time intervals between infusions used in the protocol.

Levosimendan is an inotropic drug that interacts with cardiac troponin C, which increases the calcium sensitivity of myocardial contractile units, thus increasing cardiac contractility and enhancing rapid ventricular filling,13 without increasing myocardial oxygen consumption.12 Additionally, it promotes opening of adenosine triphosphate-dependent potassium (KATP) channels on vascular smooth muscle cells, which results in vasodilatation, causing a reduction in right ventricular preload and afterload.14,15 The effect of levosimendan in opening KATP channels in the mitochondrial inner membrane can reduce the production of free radicals within the cells, conferring cardioprotection.12,16 The effects of levosimendan and its metabolite OR1896 reportedly last up to seven days.17

Previous studies have reported that the maximum effect of 24-hour infusion of levosimendan on pulmonary capillary wedge pressure (PCWP) and CO in patients with HF occurred within 24 hours4–6 and the estimated duration of the decrease in PCWP was 7–9 days, while the increase in CO lasted for 12–13 days.25 Nieminen et al.4 assessed the hemodynamic effects of levosimendan in hospitalized patients with NYHA class II–IV stable HF of ischemic etiology. A 10-min intravenous bolus of three, six, 12, 24 or 36 μg/kg was followed by a 24-hour infusion of 0.05, 0.1, 0.2, 0.4 or 0.6 μg/kg/min, respectively. Hemodynamic parameters were measured using a Swan-Ganz catheter. A clear and consistent relationship was observed between the levosimendan dose and hemodynamic responses. At 24 hours, all doses produced significant decreases in PCWP, and infusions of 0.4 and 0.6 μg/kg/min produced significant increases in CO. Significant linear reductions in mean PAP, systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) were also demonstrated. In patients with decompensated HF, Moertl et al.5 showed that levosimendan infusion over 24 hours was associated with an increase in CO and decreases in PCWP, PAP and SVR with sustained effects after 48 hours as assessed by a Swan-Ganz catheter. Also, in patients with decompensated HF, Slawsky et al.6 showed short-term effects (up to six hours) of levosimendan in hemodynamic parameters (measured by a pulmonary artery catheter): an hourly bolus of 6 μg/kg, followed by a continuous infusion initially at a rate of 0.1 μg/kg/min uptitrated to a maximum rate of 0.4 μg/kg/min led to decreases in mean PCWP, mean right atrial pressure, mean PAP, SVR and PVR. Cardiac index and SV increased at all infusion rates.

In addition to inpatient use, levosimendan has also been used in an outpatient setting, which is supported by data from the LION-HEART and LAICA trials.10,11 These trials of intermittent levosimendan infusion demonstrated significant improvements in symptoms, quality of life, HF hospitalizations, and HF-related mortality, along with improvement in surrogate markers, such as levels of cardiac biomarkers. However, the hemodynamic effects of intermittent levosimendan infusions in the outpatient setting are not known. Indeed, the hemodynamic effects of levosimendan using such protocols may theoretically differ from those previously described of a full-dose 24-hour infusion and/or in-hospital levosimendan infusion during HF decompensation.

It is recognized that levosimendan's effectiveness may vary across different severities of HF and be reduced in more advanced stages according to the INTERMACS scale, as indicated by previous studies and clinical experience. Moreover, while we are aware that HFpEF patients were not included in the LION-HEART and LAICA trials, in our center CardioMEMS™ is implanted regardless of ejection fraction, in accordance with the results of clinical trials.26–28 Including HF with preserved ejection fraction (HFpEF) patients could have provided valuable insights into the broader applicability of levosimendan therapy across different HF subtypes, even though we anticipated recruiting few HFpEF patients. In fact, no patients with HFpEF met the inclusion criteria and therefore our findings are only applicable to patients with HFrEF.

The results of this study are in line with those reported with 24-hour infusion protocols regarding the significant early reduction in diastolic PAP. Our results point to a later peak in CO, which may occur in the following days. Regarding the duration of the effects, the reduction in diastolic PAP was sustained up to day 10 after the infusion, which is consistent with the reported duration of the effect on PCWP of 24-hour levosimendan infusion. Of note, the observed effect of levosimendan on diastolic PAP supports the scheduled period of 14 days between infusions.

Also of note, the main hemodynamic effect of levosimendan was observed in diastolic PAP, which is clinically significant. Diastolic PAP is an appropriate surrogate for PCWP and left atrial pressure.29 Measuring PCWP reveals the cumulative hemodynamic impact of ventriculoatrial coupling and its operating compliance on the pulmonary circulation, on the basis of which the dosage of diuretic drugs to reduce pulmonary venous and capillary pressure can be titrated.25,30 Baseline diastolic PAP can predict HF events28 and changes in PAP can be used to predict both HF hospitalization and mortality.31,32 Diastolic PAP is the target parameter of remote monitoring of HF using the CardioMEMS™ system in most centers.32 The reduction of diastolic PAP with levosimendan infusion may explain the early symptomatic improvement after infusion, even without a significant increase in CO, in the absence of changes in diuretic or vasodilator therapies.

It should be borne in mind that interpreting clinical benefits in more advanced HF patients is complex and multifactorial. The primary objective of this study was to assess the hemodynamic effects of outpatient levosimendan infusion irrespective of their role in clinical improvement. Regardless, the relatively modest reduction in diastolic PAP may have contributed to clinical improvement, although other factors may also be involved, such as the benefit of periodic inotrope infusions and their relation to the frequent reassessment of these very severe patients.

The CardioMEMS™ system is approved for use in patients with HF to reduce the risk of hospitalization, and has also been extremely useful for a better understanding of the pathophysiology of HF.1,18,32 By providing daily assessment of hemodynamic parameters, including PAP and CO, it enables continuous characterization of the effects of therapeutic interventions in HF over time.33 Of note, PAP pressures assessed in the hospital setting, including those measured by RHC, are significantly different from those obtained in the outpatient setting.34 PAP values are known to rise in the days following hospital discharge.34 This discrepancy may be due to fasting before invasive procedures, different compositions of meals, including lower salt content in hospital meals, and greater adherence to medical therapy during hospitalization.34 The CardioMEMS™ system may therefore offer a more representative and clinically meaningful characterization of the hemodynamic effects of levosimendan infusion than other invasive methods performed in the hospital setting.

Outpatient six-hour levosimendan infusions were associated with an early reduction in diastolic PAP (a surrogate of left filling pressures) that lasted for 10 days. The CardioMEMS™ system may enable a better understanding of outpatient hemodynamics in advanced HF.

This research has received no external funding.

The authors have no conflicts of interest to declare.