Reduced length-dependent cross-bridge recruitment in skinned fiber preparations of human failing myocardium

A depressed activity of myosin ATPase has been described in human failing myocardium. Since alterations in cross-bridge kinetics may affect both systolic and diastolic cardiac function, the present study simultaneously investigated Ca²⁺-dependent tension and actomyosin ATPase activity (MYO) in triton X-skinned fiber preparations of human non-failing (donor hearts, n=8) and failing (dilated cardiomyopathy, n=11) left ventricular myocardium at increasing sarcomeric length (1.9 and 2.1 µm, α-actinin staining). The MYO/tension ratio was analyzed as a parameter characterizing myofibrillar energetics. At a sarcomere length of 1.9 µm, the Ca²⁺ sensitivity of tension was significantly increased in human failing compared to non-failing myocardium. In human non-failing myocardium, maximal Ca²⁺-activated tension [1.9 µm vs. 2.1 µm, 23.7 (1.9) vs. 28.3 (1.9) mN/mm²] and the Ca²⁺ sensitivity of tension [EC₅₀Ca²⁺ (pCa): 5.67 (0.06) vs. 7.07 (0.11)] were increased by increasing sarcomere length. This was accompanied by an enhancement in Ca²⁺-dependent MYO [+72 (11) vs. +101 (9) µM ADP/s] as well as an increase in the Ca²⁺-sensitivity of MYO [EC₅₀Ca²⁺ (pCa): 5.84 (0.08) vs. 6.86 (0.08)]. In human failing myocardium, only Ca²⁺ sensitivity of tension (but not of MYO) increased. Tension cost was increased in failing vs. non-failing tissue [1.9 µm: 4.18 (0.06) vs. 3.53 (0.06) (mN·s)/(mm²·µM ADP); 2.1 µm: 4.28 (0.13) vs. 3.52 (0.05) (mN·s)/(mm²·µM ADP)]. We concluded that, in human failing myocardium, the length-dependent force generation may be blunted due to an already increased Ca²⁺ affinity of troponin C as well as an impairment of length-dependent cross-bridge recruitment.