Calcium-sensitizing inotropic agents in the treatment of heart failure: A critical view

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Abstract
Interventions that augment the contractile state of the heart are associated with, or caused by, alterations in Ca2+ exchange in heart muscles. New inotropic agents have been developed that increase the sensitivity of the myofilaments to Ca2+. To examine the effect of calcium-sensitizing agents on force development, we measured systolic and diastolic intracellular Ca2+ concentration ([Ca2+]i) and constructed [Ca2+]i-force relationships in normal (n=6) and myopathic human hearts (n=10). Using the bioluminescent calcium indicator aequorin, we found that the diastolic [Ca2+]i was 225±52 nM in normal muscles, whereas in myopathic muscles diastolic [Ca2+]i was significantly higher at 361±68 nM. Calcium-sensitizing agents that shift the [Ca2+]i-force relationship toward lower [Ca2+]i increase the diastolic force of myopathic hearts significantly more than in normal human hearts. This leads us to the conclusion that inotropic agents that increase the sensitivity of the myofilaments to Ca2+ further impair relaxation in myopathic hearts, resulting in a reduced contractile reserve and diminished actice force production.