Efficacy of the New Inotropic Agent Istaroxime in Acute Heart Failure

Figures

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  Figure 1. Istaroxime inhibits the Na+/K+-ATPase (NAK) pump. (A) NAK actively transports three Na+-ions through the cell membrane outside the cytosol in exchange for two K+ ions inside the cytoplasm. (B) Istaroxime inhibits NAK by binding it from the extracellular side with a consequent raise of [Na+] in the intracellular side. (C) Increased [Na+] leads to the activation of the Na+/Ca2+ exchanger (NCX), which exchanges three Na+ ions for one Ca2+ ion, eventually increasing intracytoplasmatic [Ca2+].

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  Figure 2. Istaroxime activates SERCA2a. (A) PLB, in its dephosphorylated form, inhibits SERCA2a. (B) PKA phosphorylates PLB releasing SERCA2a inhibition, thereby Ca2+ can be re-uptaken from the cytosol to the sarcoplasmic reticulum (SR). (C) Istaroxime activates SERCA2a with a direct interaction with the SERCA2a/PLB complex, independent of PLB phosphorylation. PKA: protein kinase A; PLB: phospholamban; SERCA2a: sarco/endoplasmic reticulum Ca2+ ATPase 2a.

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  Figure 3. Dual mechanism of action of istaroxime. Istaroxime (structure depicted on the left) inhibits NAK by binding it from the extracellular side. NAK inhibitions increase [Na+] inside the cytoplasm, activating NCX that expels three Na+ -ions in one Ca2+ ion exchange, raising [Ca2+] inside the cytoplasm, increasing myocardial contractility (inotropic effect); istaroxime activates SERCA with a direct interaction with the complex formed by SERCA2a and PLB, independent of PLB phosphorylation. SERCA2a stimulation triggers an influx of Ca2+ against the gradient from the cytosol to the SR, guaranteeing the relaxation of cardiac muscle fibers (lusitropic effect) and a sufficient amount of Ca2+ storage in the SR that can be utilized to start a new contractile activity for the ensuing contraction (empowerment of inotropic effect). NAK: Na+/K+-ATPase pump; NCX: Na+/Ca2+ exchanger; PKA: protein kinase A; PLB: phospholamban; SERCA: sarco/endoplasmic reticulum Ca2+ ATPase.