Why Levosimendan improves the clinical condition of patients with advanced heart failure : a holistic approach

Background: In advanced heart failure (HF), Levosimendan increases peak oxygen uptake (peakVO2). We investigated whether peakVO2 increase is linked to cardiovascular, respiratory or muscular performance changes. Methods and results: Twenty patients hospitalized for advanced HF underwent, before and shortly after Levosimendan infusion, two different cardiopulmonary exercise tests (CPET): a) a personalized ramp protocol with repeated arterial blood gas analysis and standard spirometry including alveolar-capillary gas diffusion measurements at rest and at peak exercise, and b) a step incremental workload CPET with continuous near-infrared spectroscopy analysis and cardiac output (CO) assessment by bioelectrical impedance analysis. Levosimendan significantly reduced natriuretic peptides, improved peakVO2 (11.3 [IQR 10.1-12.8] to 12.6 [10.2-14.4] ml/Kg/min, p<0.01) and reduced VE/VCO2 slope (47.7±10.7 to 43.4±8.1, p<0.01). In parallel, spirometry showed only a minor increase in forced expiratory volume, while peak exercise dead space ventilation was unchanged. However, during exercise, a smaller edema formation was observed after Levosimendan infusion, as inferable from the changes in diffusion components, i.e. membrane diffusion and capillary volume. The end-tidal pressure of CO2 (PetCO2) during the isocapnic buffering period increased after Levosimendan (from 28±3 mmHg to 31±2 mmHg, p<0.01). During exercise, CO increased in parallel with VO2. After Levosimendan, total and oxygenated tissue hemoglobin, but not deoxygenated hemoglobin, increased in all exercise phases. Conclusion: In advanced HF, Levosimendan increases peakVO2, reduces the formation of exercise-induced lung edema, increases ventilation efficiency due to a reduction of reflex hyperventilation, and increases CO and muscular oxygen delivery and extraction.