Role of Ca²⁺ availability to myofilaments and their sensitivity to Ca²⁺ in myocyte contractile dysfunction in heart failure

Objective: Contractile function is depressed at the isolated myocyte level in heart failure (HF), which could result from the decreased availability of intracellular calcium ([Ca²⁺]i) to the myofibrils and/or the depressed sensitivity of myofilaments to [Ca²⁺]i. However, the cellular basis of contractile dysfunction remains unestablished. Methods: We isolated left ventricular myocytes from dogs with rapid pacing-induced HF. Cell shortening and [Ca²⁺]i transients were measured by indo-1 fluorescence and the myofilament Ca²⁺ sensitivity was analyzed by the shortening-[Ca²⁺]i relation in intact myocytes as well as by the pCa-tension relation in skinned cells. Results: Peak cell shortening magnitude was depressed in HF, associated with a parallel decrease of [Ca²⁺]i transient amplitude. There was a significant positive correlation between these two variables (r=0.71, P<0.01). In contrast, myofibrillar sensitivity to Ca²⁺, determined by both intact and skinned myocytes, was comparable between control and HF. Further, there was no significant difference in Ca²⁺ sensitivity between control and HF even at shorter (1.8 μm) or longer (2.2 μm) sarcomere length. Conclusions: Using both intact and skinned cellular preparations, a potential defect in myocyte contractile function in HF was a reduction in Ca²⁺ availability to the myofilaments, rather than the inherent defects in myofilament sensitivity to Ca²⁺. Copyright (C) 1999 Elsevier Science B.V.