Implications of ADP-Stimulated Cross-Bridge Cycling for Diastolic and Systolic Heart Failure

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Background: ADP-stimulated tension can develop in skinned myocytes from animals in the absence of Ca. It is, however, unknown whether these effects impair the human heart, where energetic imbalance causes high ADP. Moreover, the free Ca transient range in cardiomyocytes varies during HF, which suggests that cytosolic changes of ADP are likely in concert with changes in intracellular Ca. Here, we provide evidence that physiological ADP (20 and 100 μM) accumulation may link myocardial energetics and contractile dysfunction in the failing human heart.Methods: Force measurements were performed in single skinned myocytes isolated from failing human hearts at sarcomere length of 2.2 μm. Cells were activated in solutions containing: 1) ADP (without Ca); 2) Ca (without ADP) and 3) Ca in the presence of ADP. Moreover, cross-bridge cycling kinetics was assessed. Exogenous protein kinase A (PKA)-treatment was performed to determine whether myofilaments activated with ADP (without Ca) are sensitive to kinase treatment.Results: We show that ADP, in the absence of Ca, accelerates cross-bridge cycling and force development in cardiomyocytes from HF patients, which was sensitive to PKA-mediated phosphorylation (i.e. decreased sensitivity to ADP). Ca-sensitivity increased in the presence of increasing [ADP] and was accompanied by significant slowing cross-bridge cycling kinetics. This was correlated with significant increases in residual force enhancement (i.e. high initial tension recovery).Conclusions: The current data show that high [ADP] reduces the ability to desensitize myofilaments to Ca, which likely compromises restoration of end-diastolic length. High ADP increased cross-bridge strain (i.e. diastolic dysfunction) and depressed myofilament cycling kinetics, which may limit muscle shortening (i.e. systolic dysfunction). The present study suggests that inability to lower myocardial ADP levels can be a primary determinant of contractile dysfunction and disease progression in human HF.