Species-Dependent Limitations of Murine Myocardium for Investigating the Combined Inotropic Effects of SERCA2a Stimulation and Myofilament Ca2+ Sensitization

In murine multicellular myocardium and ventricular cardiomyocytes, levosimendan (LEVO) shows limited responsiveness, so combining it with SERCA2a activator istaroxime (ISTA) yields no additional mechanical inotropy.

• Why it matters: The additive positive inotropy seen in failing human myocardium with ISTA plus LEVO cannot be mechanistically dissected in multicellular human tissue.
• What they did: Murine preparations and cardiomyocytes were treated with ISTA (20 M), LEVO (0.5 M), or both, with contractile performance and Ca2+ dynamics measured; LEVO effects were also tested after cilostamide.
• The result: ISTA improved force and Ca2+ handling, but adding LEVO produced no further mechanical benefit and only minor Ca2+ changes; LEVO alone caused heterogeneous responses and increased myofilament Ca2+ sensitivity in only a minority, while consistently accelerating Ca2+ transient decay, reproduced with cilostamide.

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