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.