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 (VO₂). We investigated whether peak VO₂ 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, 2 different cardiopulmonary exercise tests: (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 cardiopulmonary exercise testing with continuous near-infrared spectroscopy analysis and cardiac output assessment by bioelectrical impedance analysis.Levosimendan significantly decreased natriuretic peptides, improved peak VO₂ (11.3 [interquartile range 10.1-12.8] to 12.6 [10.2-14.4] mL/kg/min, P < .01) and decreased minute ventilation to carbon dioxide production relationship slope (47.7 ± 10.7 to 43.4 ± 8.1, P < .01). In parallel, spirometry showed only a minor increase in forced expiratory volume, whereas the 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, that is, the membrane diffusion and capillary volume. The end-tidal pressure of CO₂ during the isocapnic buffering period increased after levosimendan (from 28 ± 3 mm Hg to 31 ± 2 mm Hg, P < .01). During exercise, cardiac output increased in parallel with VO₂. After levosimendan, the total and oxygenated tissue hemoglobin, but not deoxygenated hemoglobin, increased in all exercise phases.

Conclusions: In advanced HF, levosimendan increases peak VO₂, decreases the formation of exercise-induced lung edema, increases ventilation efficiency owing to a decrease of reflex hyperventilation, and increases cardiac output and muscular oxygen delivery and extraction.