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Objectives: Understanding the changed ability of cardiac myofilaments to produce pump work requires knowledge of kinetics of crossbridge function as well as more widely studied parameters such as Ca-sensitivity and isometric force development. We tested the hypothesis that altered crossbridge kinetics contribute to reduced myofilament work in early-stage heart failure (left ventricular dysfunction, LVD)., Methods: The sinusoidal oscillation technique can yield insights into crossbridge function. Dynamic stiffness, oscillatory work and power were assessed in chemically skinned, Ca-activated trabeculae from rabbit ventricles in early-stage failure, 8 weeks after infarction induced by coronary artery ligation (LIG). Results were compared with sham-operated controls (SH). LVD was assessed by echocardiography., Results: Ca-activated force and myofilament Ca-sensitivity were not significantly altered at this early stage of LVD. In maximally Ca-activated preparations, the frequency of minimal dynamic stiffness (f(min)) was 23% lower in LIG. f(min) increases by >80% between pCa 5.8 and 4 in SH but not in LIG. Maximal phase lead and lag angles (between length and tension) were lower in LIG at frequencies near f(min), lowering oscillatory work and power. The Lissajous figures (oscillatory work loops) of imposed length vs. tension are often asymmetric near f(min). The degree of asymmetry was greater in LIG., Conclusions: Reduced capacity for mechanical power, consistent with depressed haemodynamic performance in LVD hearts, is only partially attributable to crossbridge slowing; changes in the phase relationship will also contribute. These changes are not readily attributable to known alterations in contractile protein isoforms. Some deductions are drawn about which steps in the crossbridge cycle are modified in this model of LVD. Altered cardiac myocyte Ca-transients, reported to be associated with LVD, will be translated into pump work by a contractile machinery that is functionally altered, even though isometric force and myofilament Ca-sensitivity might remain near-normal at this stage.

Objectives: Assessment of sarcoplasmic reticulum calcium-loading ability, myofilament force production and myofilament calcium sensitivity in ventricular trabeculae from patients with heart failure., Methods: Right ventricular trabeculae (diameter 150-250 microns) were obtained from 18 patients undergoing elective cardiac transplantation. These were mounted for isometric tension measurement and treated with saponin which permeabilises the sarcolemma leaving the sarcoplasmic reticulum (SR) functionally intact. The trabecula was bathed in a mock intracellular solution containing ATP and weakly buffered [Ca2+] at various concentrations (150-400 nM). The amplitude of caffeine-induced contractures was used as a quantitative measure of the SR calcium content and was correlated with the clinical severity of heart failure. The same trabecula was then exposed to a solution containing Triton-X100 (1%) which destroys all cell membranes leaving only the myofilaments intact. The maximum calcium-activated force (Cmax) and myofilament responsiveness to calcium was assessed., Results: Patients with ischaemic heart disease (IHD) and severe heart failure (PCWP > 20 mm Hg, ejection fraction < 15%, n = 8) demonstrated low SR Ca(2+)-loading ability compared with patients with IHD and moderate heart failure (PCWP-20 mmHg, LV ejection fraction > 20%, n = 6). Patients with dilated cardiomyopathy (DCM) (n = 4) demonstrated SR Ca(2+)-loading ability which was lower than either of the two IHD groups. Myofilament force production (per unit cross-sectional area) was not significantly different between the three groups. Myofilament responsiveness to Ca2+ demonstrated no relationship with severity of heart failure., Conclusions: In human heart failure, SR Ca(2+)-loading ability diminishes with increasing severity of heart failure. Myofilament force production and sensitivity to calcium are unaffected by severity of heart failure.

Objective: The aim was to determine the effects of the superoxide anion, hydrogen peroxide, and hypochlorous acid on in situ cardiac sarcoplasmic reticulum., Methods: Simultaneous measurement of caffeine induced calcium release from the sarcoplasmic reticulum and subsequent myofilament tension generation was made on saponin permeabilised rat ventricular trabeculae before, during, and after exposure to various reactive oxygen species. The superoxide anion (O2.-) was generated using the xanthine-xanthine oxidase system, hypochlorous acid (HOCl) was prepared from NaOCl, and hydrogen peroxide (H2O2) was added from a 30% stock solution., Results: At [O2.-] sufficient to abolish tension generation by the myofilaments completely, the associated caffeine induced calcium release was unaffected. Both H2O2 and HOCl diminished caffeine induced calcium release but had differential effects on the associated tension response. Exposure to HOCl favoured the occurrence of spontaneous calcium releases from the sarcoplasmic reticulum., Conclusions: The reactive oxygen species H2O2 and HOCl reduced the amount of calcium release from the sarcoplasmic reticulum while O2.- was without effect. In some preparations it was observed that HOCl favoured spontaneous calcium release which might additionally reduce the calcium content of the sarcoplasmic reticulum.