Angioplasty, bypass surgery or medical treatment: how should we decide?

Coronary revascularisation continues to be underused despite evidence that this results in poorer outcome

The meaning of operationalised subsidiarity in the European Union

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Sarcoplasmic reticulum and myofilament function in chemically-treated ventricular trabeculae from patients with heart failure

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 μm) 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 Ca2+-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 Ca2+-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 Ca2+-loading ability diminishes with increasing severity of heart failure. Myofilament force production and sensitivity to calcium are unaffected by severity of heart failure

Effects of cyclic adenosine monophosphate (cAMP) on sarcoplasmic reticulum Ca 2+ -loading in failing rabbit and human cardiac trabeculae

The response of cardiac SR Ca2+-loading to cAMP in failing rabbit and human myocardium was examined. Right ventricular (RV) trabeculae were isolated and mounted for isometric tension measurement. They were treated with saponin to permeabilise the sarcolemma but retain SR function, and bathed in a mock intracellular solution including adenosine triphosphate (ATP) and buffered calcium. Caffeine (10 mM) was used to release calcium from the SR. The amplitude of the caffeine-induced contracture was used as a quantitative gauge of the calcium content of the SR. Trabeculae were isolated from rabbits with coronary ligation-induced heart failure (LIG, n=11), sham operated controls (SH, n=10), isoprenaline-infused rabbits (ISO, 7 days mini-osmotic pump 100 μg/kg·h; n=7) and saline-infused controls (SAL, n=7). Failing human RV trabeculae were obtained at the time of cardiac transplantation. Failing rabbit trabeculae demonstrated increased baseline caffeine-induced contractures compared with controls, the response to cAMP was similar in the two groups (LIG 9.3±2.8 vs SH 10.6±3.2% Fmax; P=0.55). There was no difference in the baseline SR Ca2+-loading in ISO trabeculae compared with SAL controls but there was a marked difference in the response to cAMP (11.1±5.4 vs 4.2±2.1% Fmax, P=0.02). SR Ca2+-loading in failing human RV trabeculae was related to the severity of LV dysfunction (r=0.59, P=0.04) and demonstrated a marked cAMP-induced enhancement of caffeine-contracture (20.2±4.7% increase of Fmax) which was greater in patients with low compared with high ejection fraction. While β-receptors are known to be down regulated in heart failure these results suggest that the scope for cAMP-mediated enhancement of SR Ca2+-loading is maintained

Enhanced SR function in saponin-treated ventricular trabeculae from rabbits with heart failure

Cardiac sarcoplasmic reticulum (SR) Ca(2+)-loading ability was assessed in a coronary artery ligation model of heart failure. Heart failure was produced in New Zealand White rabbits by ligation of the left marginal coronary artery. Sham-operated animals were used as controls. After hemodynamic and echocardiographic assessment 8 wk after coronary ligation, a free-running trabecula was isolated from the left or right ventricle, mounted for isometric tension measurement, and permeabilized with the chemical skinning agent saponin, leaving the SR functionally intact. The SR was Ca2+ loaded by exposure of the preparation to a mock intracellular solution with a Ca2+ concentration ([Ca2+]) of 150-300 nM. The amplitude of the caffeine-induced contracture was used as a measure of Ca2+ loaded by the SR. The same preparation was then treated with Triton X-100 to disrupt all cell membranes, and Ca2+ sensitivity {expressed as [Ca2+] required to produce 50% of maximal activation (pCa50)} of isometric tension production and maximum Ca2+ activated force (Cmax) were measured. Ligated animals demonstrated enhanced SR Ca(2+)-loading ability that correlated with the degree of left ventricular dysfunction. Enhanced SR Ca2+ loading was associated with evidence of SR Ca2+ overload revealed as spontaneous tension oscillations. Cmax and pCa50 were not significantly different from controls. Increased SR Ca(2+)-loading ability may predispose the SR to Ca2+ overload and could contribute to both contractile dysfunction and arrhythmogenesis in heart failure

Auto-titrating continuous positive airway pressure therapy in patients with chronic heart failure and obstructive sleep apnoea: a randomized placebo-controlled trial

Aims Obstructive sleep apnoea (OSA) is highly prevalent in patients with chronic heart failure (CHF) and may contribute to CHF progression. We aimed to determine whether treatment of OSA with continuous positive airway pressure (CPAP) would improve subjective and objective measures of heart failure severity in patients with CHF and OSA. Methods and results Twenty-six patients with stable symptomatic CHF and OSA were randomized to nocturnal auto-titrating CPAP or sham CPAP for 6 weeks each in crossover design. Study co-primary endpoints were changes in peak VO2 and 6 min walk distance. Secondary endpoints were changes in left ventricular ejection fraction, VE/VCO2 slope, plasma neurohormonal markers, and quality-of-life measures. Twenty-three patients completed the study protocol. Mean CPAP and sham CPAP usage were 3.5 ± 2.5 and 3.3 ± 2.2 h/night, respectively (P = 0.31). CPAP treatment was associated with improvements in daytime sleepiness (Epworth Sleepiness Score 7 ± 4 vs. 8 ± 5, P = 0.04) but not in other quality-of-life measures. There were no changes in other study endpoints. Conclusion In patients with CHF and OSA, auto-titrating CPAP improves daytime sleepiness but not other subjective or objective measures of CHF severity. These data suggest that the potential therapeutic benefits of CPAP in CHF are achieved by alleviation of OSA rather than by improvement in cardiac function