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Heart failure (HF) remains to be the leading cause of death in developed countries, and the prevalence of HF worldwide continues to escalate.1 Despite enormous efforts made to improve our understanding of the molecular mechanisms of HF and to develop effective therapies, HF remains to be a therapeutic challenge. One hallmark of HF is altered cardiac myofilament responsiveness to intracellular Ca2+, resulting in depressed contraction. Although increasing intracellular Ca2+ is a possible strategy for strengthening contraction, currently available inotropic agents, such as β-agonists and phosphodiesterase inhibitors, which raise intracellular cAMP levels can lead to deleterious side effects when given as a long-term therapy.2 Recently, promising inotropic agents targeting novel mechanisms have been developed, including (1) nitroxyl (HNO) released from HNO donors, (2) istaroxime, an inhibitor of Na+/K+-ATPase and an activator of the sarcoplasmic reticulum Ca2+ pump (SERCA), (3) cardiac myosin activator, and (4) ryanodine receptor stabilizer.2 In this issue, Gao et al3 report that HNO can increase myofilament Ca2+ responsiveness by inducing disulfide bonds between key cysteine residues in the myofilament, suggesting that HNO donors may improve cardiac function in patients with HF without the possible deleterious consequences of continued Ca2+ manipulation (Figure).Figure. Schematic representation of nitroxyl (HNO)-induced disulfide effects on cardiac myofilaments . A , Chemical reactions showing (1) the release of HNO from nitrosocyclohexyl acetate (NCA) by hydrolysis; (2) reaction of HNO with thiols on cysteine forming N-hydroxysulfenamide intermediates, which leads to sulfinamide or disulfide formation in the presence of an additional free thiol. B, Schematic drawing showing that disulfide bond formation between key cysteines in actin and tropomyosin and in myosin light chain 1 (MLC1) and myosin heavy chain (MHC) increases maximum force and Ca2+ sensitivity. Modified with permission from Moss …

Nitroxyl, Redox Switches, Cardiac Myofilaments, and Heart Failure