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An abstract of the article "The Intrinsic Mitochondrial Oxidative Capacity of Human Failing Hearts Is Depressed and Relates to Disease Severity But Keeps Normal Regulatory Properties," by B. Mettauer and colleagues, is presented.

An abstract of the article "Quantitative and Qualitative Mitochondrial Adaptations of Substrates Utilization in Cardiac and Skeletal Muscles," by E. Ponsot and colleagues, is presented.

The pulmonary diffusing capacity for carbon monoxide (DLCO) is reduced in chronic heart failure and remains decreased after heart transplantation. This decrease in DLCO may depend on a permanent alteration after transplantation of one or the other of its components: diffusion of the alveolar capillary membrane or the pulmonary capillary blood volume (Vc). Therefore, we measured DLCO, the membrane conductance, and Vc before and after heart transplantation. At the time of hemodynamic measurements, the Roughton and Forster method of measuring DLCO at varying alveolar oxygen concentrations was used to determine the membrane conductance, Vc, DLCO/alveolar volume (VA), the membrane conductance/VA and thetaVc/VA (theta = carbon monoxide conductance of blood, VA = alveolar volume) in 21 patients with class III to IV heart failure before and after transplantation, and in 21 healthy controls. Transplantation normalized pulmonary capillary pressure and increased cardiac index. DLCO was decreased before transplantation (7.11 vs 10.0 mmol/min/kPa in controls), but DLCO/VA was normal (1.67+/-0.44 vs 1.71+/-0.26 mmol/min/kPa/L in controls). DLCO/VA remained unchanged after transplantation, because the decrease in Vc (82+/-30 vs 65+/-18 ml before and after transplantation) and thetaVc/VA was not compensated by the changes in membrane conductance (11+/-4 vs 12+/-5 mmol/min/kPa before and after transplantation, respectively) and membrane conductance/VA. We conclude that the decrease in DLCO in patients with chronic heart failure is due to a restrictive ventilatory pattern because their DLCO/VA remains normal; the decrease in the membrane conductance is compensated by the increase in Vc. After transplantation, the decrease in Vc due to normalization of pulmonary hemodynamics is not completely compensated for by an increase in membrane conductance. Because the membrane conductances, measured before and after transplantation, are negatively correlated with duration of heart failure, its abnormal pulmonary hemodynamics may have irreversibly altered the alveolar capillary membrane. [ABSTRACT FROM AUTHOR]

Chronic immunosuppressive treatment was suspected to alter maximal muscle oxidative capacity (Vmax ) of heart transplant recipients, leading to a limitation of their exercise tolerance. It remains undefined whether the mitochondrial respiratory chain (MRC) of right ventricle (RV) and vastus lateralis (VL) muscles were altered by immunosuppressants and/or their vehicles. Vmax was measured polarographically in saponin-skinned fibres of RV and VL biopsies of patients and compared with Vmax of healthy VL and myocardium. Effects of increasing concentrations (1-10-100 μM) of Sandimmune(®) , its vehicle, Cyclosporine (CsA) in ethanol (EtOH), or EtOH alone were tested. The vehicle's effects on MRC complexes were investigated using specific substrates and inhibitors. Ten months after grafting, Vmax of RV and VL of immunosuppressed patients were similar to their Vmax at time of transplantation and to that of control tissues. In Vitro, Sandimmune(®) significantly decreased Vmax while CsA in EtOH or EtOH exerted small and similar effects. Effects of the vehicle were higher than (RV) or identical to (VL) those of Sandimmune(®) . The sites of action of the vehicle on MRC were located on complexes I and IV. While unchanged under chronic immunosuppressive therapy, Vmax of RV and VL muscles was depressed by acute exposure to intravenous Sandimmune(®) in vitro, an effect attributed to its vehicle by inhibition of complexes I and IV of the MRC. This work provides an in vitro proof of a toxic effect on the mitochondria respiratory chain of the vehicle used in the intravenous formulation of Sandimmune(®) but with no clinical consequences in chronically immunosuppressed patients., (© 2012 The Authors Fundamental and Clinical Pharmacology © 2012 Société Française de Pharmacologie et de Thérapeutique.)

This study investigates the role of central vs. peripheral factors in the limitation of maximal oxygen uptake (Vo(2max)) with moderate hypoxia [inspired fraction (Fi(O(2))) =14.5%]. Fifteen endurance-trained athletes performed maximal cycle incremental tests to assess Vo(2max), maximal cardiac output (Q(max)), and maximal arteriovenous oxygen (a-vO(2)) difference in normoxia and hypoxia. Muscle biopsies of vastus lateralis were taken 1 wk before the cycling tests to evaluate maximal muscle oxidative capacity (V(max)) and sensitivity of mitochondrial respiration to ADP (K(m)) on permeabilized muscle fibers in situ. Those athletes exhibiting the largest reduction of Vo(2max) in moderate hypoxia (Severe Loss group: -18 +/- 2%) suffered from significant reductions in Q(max) (-4 +/- 1%) and maximal a-vO(2) difference (-14 +/- 2%). Athletes who well tolerated hypoxia, as attested by a significantly smaller drop of Vo(2max) with hypoxia (Moderate Loss group: -7 +/- 1%), also display a blunted Q(max) (-9 +/- 2%) but, conversely, were able to maintain maximal a-vO(2) difference (+1 +/- 2%). Though V(max) was similar in the two experimental groups, the smallest reduction of Vo(2max) with moderate hypoxia was observed in those athletes presenting the lowest apparent K(m) for ADP in the presence of creatine (K(m+Cr)). In already-trained athletes with high muscular oxidative capacities, the qualitative, rather than quantitative, aspects of the mitochondrial function may constitute a limiting factor to aerobic ATP turnover when exercising at low Fi(O(2)), presumably through the functional coupling between the mitochondrial creatine kinase and ATP production. This study suggests a potential role for peripheral factors, including the alteration of cellular homeostasis in active muscles, in determining the tolerance to hypoxia in maximally exercising endurance-trained athletes.

Background: Evidence is emerging to support the concept that the failing heart is "energy depleted" and that defects in energy metabolism are important determinants in the development and the progression of the disease. We have shown previously that depressed mitochondrial function in cardiac and skeletal muscles in chronic heart failure is linked to decreased expression of the gene encoding transcriptional proliferator-activated receptor-gamma coactivator-1alpha, the inducible regulator of mitochondrial biogenesis and its transcription cascade, leading to altered expression of mitochondrial proteins. However, oxidative capacity of the myocardium of patients treated for chronic heart failure and pathophysiological mechanisms of mitochondrial dysfunction are still largely unknown., Methods and Results: In patients with chronic heart failure treated with angiotensin-converting enzyme inhibition, cardiac oxidative capacity, measured in saponin-permeabilized fibers, was 25% lower, and proliferator-activated receptor-gamma coactivator-1alpha protein content was 34% lower compared with nonfailing controls. In a rat model of myocardial infarction, angiotensin-converting enzyme inhibition therapy was only partially able to protect cardiac mitochondrial function and transcription cascade. Expression of proliferator-activated receptor-gamma coactivator-1alpha and its transcription cascade were evaluated after a 48-hour exposure of cultured adult rat ventricular myocytes to endothelin-1, angiotensin II, aldosterone, phenylephrine, or isoprenaline. Endothelin-1 (-30%) and, to a lesser degree, angiotensin II (-20%) decreased proliferator-activated receptor-gamma coactivator-1alpha mRNA content, whereas other hormones had no effect (phenylephrine) or even increased it (aldosterone, isoprenaline)., Conclusions: Taken together, these results show that, despite angiotensin-converting enzyme inhibition treatment, oxidative capacity is reduced in human and experimental heart failure and that endothelin-1 and angiotensin II could be involved in the downregulation of the mitochondrial transcription cascade.