Altered myocardial force generation in end-stage human heart failure

This study aimed to elucidate the molecular background of increased Ca²⁺ sensitivity of force production in cardiomyocytes of end-stage human heart failure.

Ca²⁺ -activated isometric force and the cross-bridge specific rate of force redevelopment (k_tr ) were determined in Triton-skinned myocytes from end-stage failing and non-failing donor hearts. Measurements (control: pH 7.2, 0 mM inorganic phosphate (P_i )) were performed under test conditions that probed either the Ca²⁺ -regulatory function of the thin filaments (pH 6.5), the kinetics of the actin-myosin cross-bridge cycle (10 mM P_i ), or both (pH 6.5, 10 mM P_i ). The control maximal Ca²⁺ -activated force (F_o ) and k_trmax did not differ between failing and non-failing myocytes. At submaximal [Ca²⁺ ], however, both force and k_tr were higher in failing than in donor myocytes. The difference in the Ca²⁺ sensitivities of force production was preserved when the thin filament regulatory function was perturbed by acidosis (pH 6.5) but was abolished by cross-bridge modulation (i.e. by P_i ) both at pH 7.2 and at pH 6.5. P_i induced a larger reduction in force but a smaller increase in k_tr in the failing myocytes than in the non-failing myocytes at submaximal [Ca²⁺ ].

The enhanced P_i sensitivity of the actin-myosin interaction suggests that the P_i release step of the actin-myosin cross-bridge cycle is modified during end-stage human heart failure. This might be of functional importance when P_i accumulates (e.g. during cardiac ischaemia). Moreover, this alteration can influence cardiac energetics and the clinical efficacy of sarcomere targeted agents in human heart failure.