Evelyne Lonsdorfer

Improving exercise capacity, 6 wk training tends to reduce circulating endothelin after heart transplantation

Abstract:  Short‐term survival is no longer the pivotal issue after heart transplantation but, most heart‐transplant (Htx) patients still present with increased circulating endothelin‐1 (ET) and reduced exercise capacity. ET‐1 limits both exercise‐induced vasodilation and blood flow redistribution toward acting muscles and might be accessible to training. This study was performed to investigate the effect of training on ET‐1 and whether an eventual training‐induced improvement in exercise capacity may be related to reduced baseline or exercise circulating ET‐1 in Htx patients. Five Htx patients performed a maximal bicycle exercise test and an endurance exercise test before and after a training program of 18 exercises sessions during 6 wk. ET‐1 was determined by radioimmunoassay at rest, end endurance exercise and 30 min recovery, before and after training. Training improved significantly Htxs maximal oxygen uptake (+13.1 ± 4.8%; p < 0.05) and also reduced significantly the endurance exercise‐induced heart rate increase. Resting ET‐1 was increased in Htx (5.98 ± 1.88 vs. 1.61 ± 0.25 pmol/L in controls; p < 0.01) but although ET‐1 modulation might participate in training‐induced beneficial effects, training failed to modulate either resting or exercise ET‐1 plasma level. Training‐induced improvement in exercise capacity might not mainly due to decreased ET‐1 after heart transplantation. Further supporting the usefulness of training, these preliminary data suggest that improved exercise capacity may not be mainly due to decreased ET‐1 in Htx patients. Further, larger scale studies will be needed to investigate whether an impaired nitric oxide pathway stimulation might explain such results and whether a longer training program can reduce local ET‐1, arising from working muscles after heart transplantation.

l-Arginine supplementation improves exercise capacity after a heart transplant

BACKGROUND Endothelial dysfunction is associated with the decreased exercise capacity observed in heart-transplant (HTx) recipients. L-arginine supplementation (LAS) stimulates the nitric oxide (NO) pathway and restores endothelial function. OBJECTIVE We compared exercise capacity in healthy subjects and HTx patients and investigated whether chronic LAS might improve exercise capacity and NO/endothelin balance after an HTx. DESIGN Clinical, echocardiographic, and exercise characteristics were measured in 11 control subjects and 22 HTx recipients. In a prospective, double-blind study, the 22 HTx recipients performed a 6-min exercise [6-min-walk test (6MWT)] and a maximal bicycle exercise test before and after a 6-wk period of placebo intake or LAS. Endothelial function was measured by analyzing blood NO metabolites, endothelin, and the resulting NO/endothelin balance. RESULTS Exercise capacity decreased after transplantation. Unlike with the placebo intake, 6 wk of LAS improved quality of life in HTx recipients (mean +/- SEM Minnesota Score: from 15.3 +/- 1.3 to 10.6 +/- 1.1; P < 0.001) and their submaximal exercise capacity. The distance walked during the 6MWT increased (from 525 +/- 20 to 580 +/- 20 m; P = 0.002), and the ventilatory threshold during the incremental test was delayed by 1.2 min (P = 0.01). Central factors such as resting stroke volume, systolic pulmonary arterial pressure, cardiac systolodiastolic functions, and heart-rate reserve were not modified, but LAS significantly increased the NO:endothelin ratio (from 2.49 +/- 0.38 to 3.31 +/- 0.39; P = 0.03). CONCLUSION Oral LAS may be a useful adjuvant therapeutic to improve quality of life and exercise tolerance in HTx recipients.

Right Heart Hemodynamics in Pulmonary Hypertension – An Echocardiography and Catheterization Study –

BACKGROUND Echocardiography (ECHO) plays a key role in both the diagnosis and prognosis of pulmonary hypertension (PH). Many equations have been published to assess right heart hemodynamics using ECHO. The objective of this study was to test the accuracy and precision of different echocardiographic equations in comparison with the right heart catheterization. METHODSANDRESULTS Complete right heart hemodynamic assessments were prospectively obtained from 115 individuals (mean age 66±1 years; 57 males) who had known or suspected PH. Several equations were tested for the estimation of right atrial pressure, mean and systolic pulmonary artery pressure (MPAP), cardiac output, pulmonary capillary wedge pressure (PCWP), and pulmonary vascular resistance (PVR). The accuracy of ECHO was good, with a mean difference <2 mmHg for all of the pressure calculations and ±0.6 L/min for cardiac output. However, the PVR estimation was weak using any one of the formulae. For all the parameters, the precision of ECHO was moderate. The MPAP calculation detected PH with a sensibility of 97% and specificity of 83%. However, ECHO underdiagnosed post-capillary PH. CONCLUSIONS ECHO is a good method for the diagnosis of PH, with an adequate calculation of right pressures, but cannot accurately calculate PCWP and PVR. (Circ J 2016; 80: 2019-2025).

Cardio-respiratory responses to hypoxia combined with CO2 inhalation during maximal exercise

We measured the effects of adding CO2 to an inhaled hypoxic gas mixture on cardio-respiratory parameters during maximal exercise. Eight young males performed four incremental maximal exercise tests on cycle under ambient air, hypoxia (FIO2 0.125), inhaled CO2 (FICO2 0.045), and combination of hypoxia and inhaled CO2. The highest ventilation (VE) and VE/CO2 output were recorded in CO2 inhalation and combined treatments. Arterial O2 partial pressure was higher in combined than in hypoxia treatment, but the difference between the treatments narrowed from rest to end-exercise, at least partly because the magnitude of the increase in VE (%) at exercise was smaller in combined treatment than in hypoxia. Arterial O2 content was higher in combined treatment than in hypoxia at rest, but no more at maximal exercise. Cardiac output was higher and O2 extraction lower when breathing O2-poor gas mixtures than under the two other treatments. For a given oxygen consumption, hypoxia and combined treatment showed similar cardiac output and O2 extraction.

Question 5. Stratégies de la réhabilitation respiratoire

Le nombre de malades justifiant une réhabilitation respiratoire en France est imprécis, mais considéré comme important et nous connaissons mal quel type de structure existante ou possible correspond le mieux à l’orientation des patients, en fonction notamment de leur gravité. La stratégie a pour objet d’optimiser les attentes des patients et du personnel médical et paramédical vis-à-vis de la réhabilitation respiratoire. Elle se décline pour chaque type de structure au niveau de son organisation, des caractéristiques des patients auxquels elle s’adresse préférentiellement, et ce, dans notre cadre institutionnel français. Nous aborderons successivement les questions suivantes : – Quels sont les lieux et organisations susceptibles de proposer une réhabilitation respiratoire et, à partir de l’analyse de la littérature et l’expérience, quels sont les avantages et inconvénients de chaque type de structure et quelles sont les conséquences sur l’orientation des patients ? – Quel est le cadre administratif et juridique correspondant en France à ces différents types de structure ? – Quelles sont les implications socio-économiques de la réhabilitation respiratoire ? – Quelle stratégie globale dans l’orientation des malades peuton proposer ? La littérature est relativement pauvre sur ces questions de stratégie et les exemples étrangers ne sont pas toujours applicables à notre spécificité française. Ce texte et les recommandations qui l’accompagnent sont destinés : – au pneumologue pour l’aider à orienter son malade en fonction de son analyse et de l’offre de soins, – aux professionnels de la santé pour les amener à des pratiques reconnues, – aux institutions et aux décideurs pour un développement harmonieux de la réhabilitation respiratoire.

IFN-β-induced reactive oxygen species and mitochondrial damage contribute to muscle impairment and inflammation maintenance in dermatomyositis

Dermatomyositis (DM) is an autoimmune disease associated with enhanced type I interferon (IFN) signalling in skeletal muscle, but the mechanisms underlying muscle dysfunction and inflammation perpetuation remain unknown. Transcriptomic analysis of early untreated DM muscles revealed that the main cluster of down-regulated genes was mitochondria-related. Histochemical, electron microscopy, and in situ oxygraphy analysis showed mitochondrial abnormalities, including increased reactive oxygen species (ROS) production and decreased respiration, which was correlated with low exercise capacities and a type I IFN signature. Moreover, IFN-β induced ROS production in human myotubes was found to contribute to mitochondrial malfunctions. Importantly, the ROS scavenger N-acetyl cysteine (NAC) prevented mitochondrial dysfunctions, type I IFN-stimulated transcript levels, inflammatory cell infiltrate, and muscle weakness in an experimental autoimmune myositis mouse model. Thus, these data highlight a central role of mitochondria and ROS in DM. Mitochondrial dysfunctions, mediated by IFN-β induced-ROS, contribute to poor exercise capacity. In addition, mitochondrial dysfunctions increase ROS production that drive type I IFN-inducible gene expression and muscle inflammation, and may thus self-sustain the disease. Given that current DM treatments only induce partial recovery and expose to serious adverse events (including muscular toxicity), protecting mitochondria from dysfunctions may open new therapeutic avenues for DM.

Exercise-induced second-degree atrioventricular block in endurance athletes.

Training induces volume- and time-dependent morphological and functional changes in the heart. Heart rhythm disorders, such as atrial arrhythmia (including atrial fibrillation and atrial flutter), are a well-established consequence of such long-term endurance practice. Although resting bradycardia and first-degree atrioventricular persist in veteran athletes, a higher conduction system impairment has never been reported neither at rest nor during exercise. We report here two cases of Type II second-degree atrioventricular block occurring during exercise in middle-age well-trained athletes. Because animal and human studies suggest that a progressive myocardial fibrosis could explain such phenomenon, long-term training could also have consequences on the conduction pathways.

Moderate Exercise Allows for shorter Recovery Time in Critical Limb Ischemia

Whether and how moderate exercise might allow for accelerated limb recovery in chronic critical limb ischemia (CLI) remains to be determined. Chronic CLI was surgically induced in mice, and the effect of moderate exercise (training five times per week over a 3-week period) was investigated. Tissue damages and functional scores were assessed on the 4th, 6th, 10th, 20th, and 30th day after surgery. Mice were sacrificed 48 h after the last exercise session in order to assess muscle structure, mitochondrial respiration, calcium retention capacity, oxidative stress and transcript levels of genes encoding proteins controlling mitochondrial functions (PGC1α, PGC1β, NRF1) and anti-oxidant defenses markers (SOD1, SOD2, catalase). CLI resulted in tissue damages and impaired functional scores. Mitochondrial respiration and calcium retention capacity were decreased in the ischemic limb of the non-exercised group (Vmax = 7.11 ± 1.14 vs. 9.86 ± 0.86 mmol 02/min/g dw, p < 0.001; CRC = 7.01 ± 0.97 vs. 11.96 ± 0.92 microM/mg dw, p < 0.001, respectively). Moderate exercise reduced tissue damages, improved functional scores, and restored mitochondrial respiration and calcium retention capacity in the ischemic limb (Vmax = 9.75 ± 1.00 vs. 9.82 ± 0.68 mmol 02/min/g dw; CRC = 11.36 ± 1.33 vs. 12.01 ± 1.24 microM/mg dw, respectively). Exercise also enhanced the transcript levels of PGC1α, PGC1β, NRF1, as well as SOD1, SOD2, and catalase. Moderate exercise restores mitochondrial respiration and calcium retention capacity, and it has beneficial functional effects in chronic CLI, likely by stimulating reactive oxygen species-induced biogenesis and anti-oxidant defenses. These data support further development of exercise therapy even in advanced peripheral arterial disease.

Maximal aerobic capacity in ageing subjects: actual measurements versus predicted values

We evaluated the impact of selection of reference values on the categorisation of measured maximal oxygen consumption (V′O2peak) as “normal” or “abnormal” in an ageing population. We compared measured V′O2peak with predicted values and the lower limit of normal (LLN) calculated with five equations. 99 (58 males and 41 females) disease-free subjects aged ≥70 years completed an incremental maximal exercise test on a cycle ergometer. Mean V′O2peak was 1.88 L·min−1 in men and 1.26 L·min−1 in women. V′O2peak ranged from 89% to 108% of predicted in men, and from 88% to 164% of predicted in women, depending on the reference equation used. The proportion of subjects below the LLN ranged from 5% to 14% in men and 0–22% in women, depending on the reference equation. The LLN was lacking in one study, and was unsuitable for women in another. Most LLNs ranged between 53% and 73% of predicted. Therefore, choosing an 80% cut-off leads to overestimation of the proportion of “abnormal” subjects. To conclude, the proportion of subjects aged ≥70 years with a “low” V′O2peak differs markedly according to the chosen reference equations. In clinical practice, it is still relevant to test a sample of healthy volunteers and select the reference equations that better characterise this sample. As V′O2peak % pred differs markedly with the reference value, reference equation choice is critical in the elderly http://ow.ly/YsXHD

Effect of administration of water enriched in O2 by injection or electrolysis on transcutaneous oxygen pressure in anesthetized pigs.

Background Oral administration of oxygenated water has been shown to improve blood oxygenation and could be an alternate way for oxygen (O2) supply. In this experiment, tissue oxygenation was compared in anesthetized pigs receiving a placebo or water enriched in O2 by injection or a new electrolytic process. Methods Forty-two pigs randomized in three groups received either mineral water as placebo or water enriched in O2 by injection or the electrolytic process (10 mL/kg in the stomach). Hemodynamic parameters, partial pressure of oxygen in the arterial blood (PaO2), skin blood flow, and tissue oxygenation (transcutaneous oxygen pressure, or TcPO2) were monitored during 90 minutes of general anesthesia. Absorption and tissue distribution of the three waters administered were assessed using dilution of deuterium oxide. Results Mean arterial pressure, heart rate, PaO2, arteriovenous oxygen difference, and water absorption from the gut were not significantly different among the three groups. The deuterium to protium ratio was also similar in the plasma, skin, and muscle at the end of the protocol. Skin blood flow decreased in the three groups. TcPO2 slowly decreased over the last 60 minutes of the experiment in the three groups, but when compared to the control group, the values remained significantly higher in animals that received the water enriched in O2 by electrolysis. Conclusions In this protocol, water enriched in O2 by electrolysis lessened the decline of peripheral tissue oxygenation. This observation is compatible with the claim that the electrolytic process generates water clathrates which trap O2 and facilitate O2 diffusion along pressure gradients. Potential applications of O2-enriched water include an alternate method of oxygen supply.