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International audience; Increased nitric oxide (NO) bioavailability may improve exercise performance and vascular function. It remains unclear whether older adults who experience a decreased NO bioavailability may benefit from chronic NO precursor supplementation. This randomised, double-blind, trial aims to assess the effect of chronic NO precursor intake on vascular function and exercise performance in older adults (60-70 years old). Twenty-four healthy older adults (12 females) performed vascular function assessment and both local (knee extensions) and whole-body (incremental cycling) exercise tests to exhaustion before and after one month of daily intake of a placebo (PLA) or a nitrate-rich salad and citrulline (N+C, 520mg nitrate and 6g citrulline) drink. Arterial blood pressure (BP) and stiffness, post-ischemic, hypercapnic and hypoxic vascular responses were evaluated. Prefrontal cortex and quadriceps oxygenation was monitored by near-infrared spectroscopy. N+C supplementation reduced mean BP (-3.3mmHg; p=0.047) without altering other parameters of vascular function and oxygenation kinetics. N+C supplementation reduced heart rate and oxygen consumption during submaximal cycling and increased maximal power output by 5.2% (p

Background Excessive ventilation (VE) and abnormal gas exchange during exercise are features of chronic thromboembolic pulmonary hypertension (CTEPH). In selected CTEPH patients, balloon pulmonary angioplasty (BPA) improves symptoms and exercise capacity. How BPA affects exercise hyperventilation and gas exchange is poorly understood. Methods In this longitudinal observational study, symptom-limited cardio-pulmonary exercise tests and carbon monoxide lung diffusion (DLCO) were performed before and after BPA (interval, mean (SD): 3.1 (2.4) months) in 36 CTEPH patients without significant cardiac and/or pulmonary comorbidities. Results Peak work rate improved by 20% after BPA whilst VE at peak did not change despite improved ventilatory efficiency (lower VE with respect to CO2 output [VCO2]). At the highest identical work rate pre- and post-BPA (75 (30) watts), VE and the ideal alveolar-arterial oxygen gradient (P(Ai-a)O2) decreased by 17% and 19% after BPA, respectively. The physiological dead space fraction of tidal volume (VD/VT), calculated from measurements of arterial and mixed expired CO2, decreased by 20%. In the meantime, DLCO did not change. The best correlates of P(Ai-a)O2 measured at peak exercise were physiological VD/VT before BPA and DLCO after BPA. Conclusions Ventilatory efficiency, physiological VD/VT and pulmonary gas exchange improved after BPA. The fact that DLCO did not change suggests that the pulmonary capillary blood volume and probably the true alveolar dead space were unaffected by BPA. The correlation between DLCO measured before BPA and P(Ai-a)O2 measured after BPA suggests that DLCO may provide an easily accessible marker to predict the response to BPA in terms of pulmonary gas exchange.

International audience; Purpose: A decision tree based on a clinico-physiological score (SHAI score) has been developed to detect subjects susceptible to Severe High Altitude Illness (SHAI). We aimed to validate this decision tree, to rationalize the prescription of acetazolamide (ACZ) and to specify the rule for a progressive acclimatization.Methods: Data were obtained from 641 subjects in 15 European medical centers before and during a sojourn at high altitude. Depending on the value of SHAI score, advice was given and ACZ was eventually prescribed. The outcome was the occurrence of SHAI at high altitude as a function of SHAI score, ACZ prescription and use and fulfillment of the acclimatization rule.Results: The occurrence of SHAI was 22.6%, similar to what was observed 18 years before (23.7%), while life-threatening forms of SHAI (High Altitude Pulmonary and Cerebral Edema) were less frequent (2.6% to 0.8%, P=0.007). The negative predictive value of the decision tree based was 81%, suggesting that the procedure is efficient to detect subjects who will not suffer from SHAI, therefore limiting the use of ACZ. The maximal daily altitude gain that limits the occurrence of SHAI was established at 400 m. The occurrence of SHAI was reduced from 27% to 12% when the recommendations for ACZ use and 400 m daily altitude gain were respected (P

International audience; Little is known about hemostasis modifications induced by chronic hypoxic exposure in high-altitude residents, especially in those who develop excessive erythrocytosis (EE, i.e. hemoglobin concentration ≥ 21 g·dL-1 in male and ≥ 19 g·dL-1 in female). The aim of this preliminary study was to assess coagulation alterations in highlanders with or without EE using simple hemostatic tests such as bleeding (BT) and clotting (CT) times. Eighty-one male (43 ± 7 years), permanent residents from La Rinconada (Peru), the highest city in the world (5,100-5,300 m), were evaluated. Thirty-six subjects (44 %) presented with EE. EE subjects compared to non-EE subjects had lower BT (3.6 ± 1.2 vs. 7.0 ± 1.9 min, p < 0.001) and CT (11.7 ± 1.7 vs. 15.1 ± 2.3 min, p < 0.001). These results support the notion that highlanders with EE are in a state of hypercoagulability and call for further hemostasis investigations in this population using more detailed hemostatic methods.

In response to chronic hypobaric hypoxia, residents at altitude develop physiological adaptations. Despite these adaptations, chronic mountain sickness (CMS) can be observed in 5-33% of individuals residing at high altitude. CMS frequently triggers cardiorespiratory diseases such as pulmonary hypertension and right or left heart failure. Ambient hypoxia further amplifies sleep-related disorders so that sleep disturbance is an important feature of CMS. Our aim was to characterize nocturnal hypoxemia and the associated sleep and ambulatory (A) blood pressure (BP) changes in highlanders. Methods: Cardiorespiratory sleep and 24h ABP monitoring studies were performed in highlanders living in Puno (3800m) and La Rinconada (5100m), Peru. Subjects were divided in groups according to CMS severity scale. Results: 77 males were evaluated (age 43 [34-49] yr, BMI 25 [23-27] kg/m2). Subjects with CMS showed higher 24 h and daytime systolic and diastolic BP than those with no CMS. Highlanders with CMS were characterized by a lower nocturnal oxygen saturation (SpO2) mean, nocturnal SpO2 nadir and a higher oxygen desaturation index than those with no CMS. No difference was found in terms of apnea-hypopnea index. Altitude (β -4.3, p=0.02) and CMS class (β -0.5, p=0.01) were significant predictors of a lower nocturnal SpO2. Conclusions: At altitude lower mean nocturnal SpO2 and frequent desaturations might be implicated in CMS pathogenesis. Moreover, CMS subjects showed higher ABP, which might contribute to their reported worse cardiovascular prognosis as compared with no-CMS highlanders. Further pathophysiological and therapeutic intervention studies are needed for a better management of CMS.

BACKGROUND Sleep‐disordered breathing is associated with a poor prognosis (mortality) in patients with ischemic cardiomyopathy. The understanding of mechanisms linking intermittent hypoxia (IH), the key feature of sleep‐disordered breathing, to ischemic cardiomyopathy progression is crucial for identifying specific actionable therapeutic targets. The aims of the present study were (1) to evaluate the impact of IH on the time course evolution of cardiac remodeling and contractile dysfunction in a rat model of ischemic cardiomyopathy; and (2) to determine the impact of IH on sympathetic activity, hypoxia inducible factor‐1 activation, and endoplasmic reticulum stress in the time course of ischemic cardiomyopathy progression. METHODS AND RESULTS Ischemic cardiomyopathy was induced by a permanent ligature of the left coronary artery in male Wistar rats (rats with myocardial infarction). Rats with myocardial infarction were then exposed to either IH or normoxia for up to 12 weeks. Cardiac remodeling and function were analyzed by Sirius red and wheat germ agglutinin staining, ultrasonography, and cardiac catheterization. Sympathetic activity was evaluated by spectral analysis of blood pressure variability. Hypoxia‐inducible factor‐1α activation and burden of endoplasmic reticulum stress were characterized by Western blots. Long‐term IH exposure precipitated cardiac remodeling (hypertrophy and interstitial fibrosis) and contractile dysfunction during the time course evolution of ischemic cardiomyopathy in rodents. Among associated mechanisms, we identified the early occurrence and persistence of sympathetic activation, associated with sustained hypoxia‐inducible factor‐1α expression and a delayed pro‐apoptotic endoplasmic reticulum stress. CONCLUSIONS Our data provide the demonstration of the deleterious impact of IH on post–myocardial infarction remodeling and contractile dysfunction. Further studies are needed to evaluate whether targeting sympathetic nervous system or HIF‐1 overactivities could limit these effects and improve management of coexisting ischemic cardiomyopathy and sleep‐disordered breathing.

Moderate-intensity continuous exercise (MICE) improves fat oxidation. High-intensity intermittent exercise (HIIE) is thought to have a greater potential for fat oxidation but it might be too demanding in the long term for patients. We hypothesized that an initial bout of HIIE could maximize fat oxidation during MICE and the following passive recovery. Eighteen healthy participants performed two acute isocaloric exercise sessions at random. MICE consisted of 45-min cycling at 50% of maximal aerobic power (Pmax). COMB began with five 1-min bouts of HIIE at Pmax (interspaced with 1-min recovery periods) followed by 35-min MICE. Gas exchange allowed substrate oxidation rate assessment.Expressed as a % of energy expenditure, fat oxidation (%) increased during in the passive recovery following COMB (Recovery: 36.0 ± 19.4 vs 23.0 ± 20.3%; ES: 0.66; p 0.0001). An initial bout of HIIE preceding a prolonged moderate-intensity exercise may potentiate fat oxidation during the following recovery. This might be relevant for health management of overweight/obese persons.

International audience; Introduction: Combining exercise training with hypoxic exposure has been recently proposed as a new therapeutic strategy to improve health status of obese individuals. Whether hypoxic exercise training (HET) provides greater benefits regarding body composition and cardiometabolic parameters than normoxic exercise training (NET) remains, however, unclear. We hypothesized that HET would induce greater improvement in exercise capacity and health status than NET in overweight and obese individuals.Methods: Twenty-three subjects were randomized into 8-wk HET (11 men and 1 woman; age, 52 ± 12 yr; body mass index, 31.2 ± 2.4 kg·m) or NET (eight men and three women; age, 56 ± 11 yr; body mass index, 31.8 ± 3.2 kg·m) programs (three sessions per week; constant-load cycling at 75% of maximal heart rate; target arterial oxygen saturation for HET 80%, FiO2 ~0.13, i.e., ~3700 m a.s.l.). Before and after the training programs, the following evaluations were performed: incremental maximal and submaximal cycling tests, measurements of pulse-wave velocity, endothelial function, fasting glucose, insulin and lipid profile, blood NO metabolites and oxidative stress, and determination of body composition by magnetic resonance imaging.Results: Peak oxygen consumption and maximal power output increased significantly after HET only (peak oxygen consumption HET + 10% ± 11% vs NET + 1% ± 10% and maximal power output HET + 11% ± 7% vs NET + 3% ± 10%, P < 0.05). Submaximal exercise responses improved similarly after HET and NET. Except diastolic blood pressure which decreased significantly after both HET and NET, no change in vascular function, metabolic status and body composition was observed after training. Hypoxic exercise training only increased nitrite and reduced superoxide dismutase concentrations.Conclusions: Combining exercise training and hypoxic exposure may provide some additional benefits to standard NET for obese individual health status.

International audience; Introduction: Nitric oxide (NO) precursor supplementation has been shown to increase NO bioavailability and can potentially improve vascular function and exercise performance. It remains unclear whether the combination of NO precursor supplementation and exercise training has synergic effects on exercise performance. This study aims to assess the effect of chronic nitrate and citrulline intake on exercise training adaptations in healthy young individuals.Methods: In this randomized, double-bind trial, 24 healthy young (12 females) subjects performed vascular function assessment (blood pressure, pulse wave velocity, postischemia vasodilation, and cerebrovascular reactivity) and both local (submaximal isometric unilateral knee extension) and whole-body (incremental cycling) exercise tests to exhaustion before and after a 2-month exercise training program and daily intake of a placebo or a nitrate-rich salad and citrulline (N + C, 520 mg nitrate and 6 g citrulline) drink. Prefrontal cortex and quadriceps oxygenation was monitored continuously during exercise by near-infrared spectroscopy.Results: N + C supplementation had no effect on vascular function and muscle and cerebral oxygenation during both local and whole-body exercise. N + C supplementation induced a significantly larger increase in maximal knee extensor strength (+5.1 ± 3.5 vs +0.2 ± 5.5 kg, P = 0.008) as well as a trend toward a larger increase in knee extensor endurance (+35.2 ± 26.1 vs +24.0 ± 10.4 contractions, P = 0.092) than placebo, but no effect on exercise training-induced maximal aerobic performance improvement.Conclusion: These results suggest that chronic nitrate and citrulline supplementation enhances the effect of exercise training on quadriceps muscle function in healthy active young individuals, but this does not translate into improved maximal aerobic performances.

In this study, we hypothesized that adding CO2 to an inhaled hypoxic gas mixture will limit the rise of pulmonary artery pressure (PAP) induced by a moderate exercise. Eight 20-year-old males performed four constant-load exercise tests on cycle at 40% of maximal oxygen consumption in four conditions: ambient air, normobaric hypoxia (12.5% O2), inhaled CO2 (4.5% CO2), and combination of hypoxia and inhaled CO2. Doppler echocardiography was used to measure systolic (s)PAP, cardiac output (CO). Total pulmonary resistance (TPR) was calculated. Arterialized blood pH was 7.40 at exercise in ambient and hypoxia conditions, whereas CO2 inhalation and combined conditions showed acidosis. sPAP increases from rest in ambient air to exercise ranged as follows: ambient + 110%, CO2 inhalation + 135%, combined + 184%, hypoxia + 217% (p

Summary Background The new North American guidelines for participation in competitive sport in patients with coronary artery disease (CAD) are less restrictive than previous guidelines. Aim To evaluate the incidence of major adverse cardiac events (MACE) in men with CAD who practise intensive physical activity after a stenting procedure. MACE included in-stent restenosis (SR), stent thrombosis (ST), new coronary stenosis (NCS), myocardial infarction, heart failure, cardiac arrest or cardiac death. Methods Asymptomatic men with CAD and a coronary stent who practised regular (>4 h/week) sport were included in this retrospective multicentre observational study. All patients presented with left ventricular ejection fraction ≥ 50%, no residual stenosis, and no inducible ischaemia or arrhythmias. Three groups were compared: those undertaking moderate leisure-time sport (MLS), intensive leisure-time sport (ILS) or competitive sport (CS). During follow-up, all patients had a yearly routine cardiology evaluation. Results A total of 108 men with CAD (57.3 ± 9.1 years) were included: 29 MLS, 58 ILS, and 21 CS. During follow-up (57.6 ± 46.0 months) the incidence of MACE was 15.7% (SR = 5, SR + NCS = 4, ST = 4, NCS = 4) and occurred during physical exertion in 59% of patients. ST was more frequent in the CS (n = 3) than in the MLS (n = 1) or ILS (n = 0) groups, especially in patients with bare-metal stents. Conclusions The incidence of MACE was 15.7%, and only ST was significantly more frequent in CS patients than in MLS or ILS patients. Our data support the new US guidelines for exercise eligibility in men with CAD.

International audience; Purpose: The aim of this study was to assess the acute cardiorespiratory as well as muscle and cerebral tissue oxygenation responses to submaximal constant-load (CL) and high-intensity interval (HII) cycling exercise performed in normoxia and in hypoxia at similar intensity, reproducing whole-body endurance exercise training sessions as performed in sedentary and clinical populations.Methods: Healthy subjects performed two CL (30 min, 75% of maximal heart rate, n = 12) and two HII (15 times 1-min high-intensity exercise-1-min passive recovery, n = 12) cycling exercise sessions in normoxia and in hypoxia [mean arterial oxygen saturation 76 ± 1% (clamped) during CL and 77 ± 5% (inspiratory oxygen fraction 0.135) during HII]. Cardiorespiratory and near-infrared spectroscopy parameters as well as the rate of perceived exertion were continuously recorded.Results: Power output was 21 ± 11% and 15% (according to protocol design) lower in hypoxia compared to normoxia during CL and HII exercise sessions, respectively. Heart rate did not differ between normoxic and hypoxic exercise sessions, while minute ventilation was higher in hypoxia during HII exercise only (+ 13 ± 29%, p < 0.05). Quadriceps tissue saturation index did not differ significantly between normoxia and hypoxia (CL 60 ± 8% versus 59 ± 5%; HII 59 ± 10% versus 56 ± 9%; p > 0.05), while prefrontal cortex deoxygenation was significantly greater in hypoxia during both CL (66 ± 4% versus 56 ± 6%) and HII (58 ± 5% versus 55 ± 5%; p < 0.05) sessions. The rate of perceived exertion did not differ between normoxic and hypoxic CL (2.4 ± 1.7 versus 2.9 ± 1.8) and HII (6.9 ± 1.4 versus 7.5 ± 0.8) sessions (p > 0.05).Conclusion: This study indicates that at identical heart rate, reducing arterial oxygen saturation near 75% does not accentuate muscle deoxygenation during both CL and HII exercise sessions compared to normoxia. Hence, within these conditions, larger muscle hypoxic stress should not be expected.

INTRODUCTION The goal of this study was to compare the effects of downhill (DH), uphill (UH), and UH-DH exercise training, at the same metabolic rate, on exercise capacity and skeletal muscle mitochondrial function. METHODS Thirty-two Wistar rats were separated into a control and 3 trained groups. The trained groups exercised for 4 weeks, 5 times per week at the same metabolic rate, either in UH, DH, or combined UH-DH. Twenty-four hours after the last training session, the soleus, gastrocnemius, and vastus intermedius muscles were removed for assessment of mitochondrial respiration. RESULTS Exercise training, at the same metabolic rate, improved maximal running speed without specificity for exercise modalities. Maximal fiber respiration was enhanced in soleus and vastus intermedius in the UH group only. CONCLUSIONS Exercise training, performed at the same metabolic rate, improved exercise capacity, but only UH-trained rats enhanced mitochondrial function in both soleus and vastus intermedius skeletal muscle. Muscle Nerve 54: 925-935, 2016.

Introduction Living in high altitude is challenging for the cardiovascular system, and some of highlanders develop a chronic mountain sickness (CMS). Only few data are available above the altitude of 4380 m. La Rinconada is the highest mining city in the world at an altitude of 5100 m. Objective To describe heart remodeling and pulmonary hemodynamic and study the relationship with CMS. Method Rest and exercise echocardiography were performed in Lima (sea level, n = 18), Puno (3810 m, n = 23) and La Rinconada (n = 55). Results Age and BMI were higher in La Rinconada (30 ± 2; 32 ± 3; 43 ± 2 years and 24 ± 1; 25.4 ± 0.8 and 25.9 ± 0.4 kg.m-2 in Lima, Puno and La Rinconada respectively). Mean arterial pressure were normal and comparable regardless of altitude. As expected, hematocrit significantly (P Fig. 1 ). Conclusion These are the first data of a population living permanently above 5100 m. Eccentric LV remodeling, larger right cavities, lowering myocardial strain in both ventricle are the main findings. The higher rest and exercise TVR in altitude are only related to the hematocrit level.

Background The importance of exercise electrocardiogram (ECG) has been controversial in the prevention of cardiac events among sportsmen. The aim of this study was to determine the frequency of silent myocardial ischemia (SMI) from an exercise ECG and its relationship with induced coronary angiographic assessment and potentially preventable cardiac events. Methods This prospective cohort study included leisure time asymptomatic sportsmen over 35years old, referred from 2011 to 2014 in the Sports Medicine Unit of the University Hospital of Saint-Etienne. Results Of the cohort of 1500 sportsmen (1205 men; mean age 50.7±9.4years; physical activity level 32.8±26.8MET-h/week), 951 (63%) had at least one cardiovascular disease (CVD) risk factor. Family history, medical examination and standard resting 12-lead were collected. A total of 163 exercise ECGs (10.9%) were defined as positive, most of them due to SMI (n=129, 8.6%). SMI was an indication for coronary angiography in 23 cases, leading to 17 documented SMIs (1.1%), including 11 significant stenoses requiring revascularization. In multivariate logistic regression analysis, a high risk of CVD (OR=2.65 [CI 95%: 1.33–5.27], p = 0.005 ) and an age >50years (OR=2.71 [CI 95%: 1.65–4.44], p 0.0001 ) were independently associated with confirmed SMI. Conclusions The association of positive exercise ECG with significant coronary stenosis was stronger among sportsmen with CVD risk factors and older than 50years. Screening by exercise ECG can lower the risk of cardiac events in middle-aged and older sportsmen. One hundred tests would be enough to detect one silent myocardial ischemia at risk for cardiac event.

Background— Pathological T-wave inversion (PTWI) is rarely observed on the ECG of healthy athletes, whereas it is common in patients with certain cardiac diseases. All ECG interpretation guidelines for use within athletes state that PTWI (except in leads aVR, III and V1 and in V1–V4 when preceded by domed ST segment in asymptomatic Afro-Caribbean athletes only) cannot be considered a physiological adaptation. The aims of the present study were to prospectively determine the prevalence of cardiac pathology in athletes presenting with PTWI, and to examine the efficacy of cardiac magnetic resonance in the work-up battery of further examinations. Methods and Results— Athletes presenting with PTWI (n=155) were investigated with clinical examination, ECG, echocardiography, exercise testing, 24h Holter ECG, and cardiac magnetic resonance. Cardiac disease was established in 44.5% of athletes, with hypertrophic cardiomyopathy (81%) the most common pathology. Echocardiography was abnormal in 53.6% of positive cases, and cardiac magnetic resonance identified a further 24 athletes with disease. Five athletes (7.2%) considered normal on initial presentation subsequently expressed pathology during follow-up. Familial history of sudden cardiac death and ST-segment depression associated with PTWI were predictive of cardiac disease. Conclusions— PTWI should be considered pathological in all cases until proven otherwise, because it was associated with cardiac pathology in 45% of athletes. Despite echocardiography identifying pathology in half of these cases, cardiac magnetic resonance must be considered routine in athletes presenting with PTWI with normal echocardiography. Although exclusion from competitive sport is not warranted in the presence of normal secondary examinations, annual follow-up is essential to ascertain possible disease expression.

Maximal aerobic capacity is a strong health predictor and peak oxygen consumption (V′O2peak) is considered a reflection of total body health. No systematic reviews or meta-analyses to date have synthesised the existing data regardingV′O2peakin patients with obstructive sleep apnoea (OSA).A systematic review of English and French articles using PubMed/MEDLINE and Embase included studies assessingV′O2peakin OSA patients either in mL·kg−1·min−1compared with controls or in % predicted. Two independent reviewers analysed the studies, extracted the data and assessed the quality of evidence.MeanV′O2peakexpressed in mL·kg−1·min−1was significantly lower in patients with OSA than in controls (mean difference −2.7 mL·kg−1·min−1; pV′O2peakwas found to be larger in non-obese patients (body mass index −2). MeanV′O2peak% pred was 89.9% in OSA patients (n=643).OSA patients have reduced maximal aerobic capacity, which can be associated with increased cardiovascular risks and reduced survival in certain patient subgroups. Maximal exercise testing can be useful to characterise functional limitation and to evaluate health status in OSA patients.

Background: The prevalence of obstructive sleep apnea (OSA) in heart failure (HF) patients ranges from 12 to 53% and is independently associated with a poor prognosis. Chronic Intermittent hypoxia (IH), a hallmark feature of OSA, is associated with sympathetic activation (SA) and could therefore aggravate post-ischemic HF. Purpose: To determine the time course evolution of cardiac remodeling and contractile dysfunction in post-ischemic HF rats exposed 1 to 12 weeks of IH.Methods: Wistar male rats with permanent occlusion of left coronary artery were exposed to IH (21–5% FiO2, 60s cycle, 8h/day) or normoxia (N) for 1, 4 and 12 weeks. A longitudinal follow-up of rat left ventricular (LV) dimensions and function was performed by cardiac ultrasonography. At the end of IH or N exposure, blood pressure (BP) was recorded for power spectral analysis and a pressure-volume conductance catheter system was used to evaluate LV parameters. Results: Although cardiac structure seems to be preserved during the first weeks of IH exposure (lesser LV dilation and posterior wall thinning, p Conclusion: Chronic IH magnifies LV contractile dysfunction in a post-ischemic heart failure model, possibly through exaggerated SA.

Nitric oxide (NO) is implicated in vasomotor control mechanisms altering the diameter of the vessels under various physiological and pathological conditions. There are 2 main NO production pathways, 1 NO synthase (NOS) independent (nitrate–nitrite–NO) and the other is NOS dependent (citrulline–arginine–NO). The objective of the study was to evaluate the effect of acute nitrate and citrulline supplementation on post-ischemic vascular response in healthy subjects. Fourteen subjects performed 2-leg vascular occlusion tests, 3 days apart. They were randomly assigned to consume a drink containing 1200 mg (19.4 mmol) of nitrate and 6 g of citrulline (N+C) or a placebo (Pl). Changes in total hemoglobin (Hbtot) and oxyhemoglobin (HbO2) concentrations were recorded by near-infrared spectroscopy on the thigh and calf muscles. No differences between N+C and Pl were observed during the ischemic period. Hbtot increased to a larger extent during the reperfusion period for the thigh (e.g., area under the curve, 821 ± 324 vs. 627 ± 381 mmol·s−1, p = 0.003) and the calf (515 ± 285 vs. 400 ± 275 mmol·s−1, p = 0.029) in the N+C versus Pl conditions. Similar results were found regarding HbO2 for the thigh (e.g., area under the curve, 842 ± 502 vs. 770 ± 491 mmol·s−1, p = 0.077) and the calf (968 ± 536 vs. 865 ± 275 mmol·s−1, p = 0.075). The larger postocclusive Hbtot and HbO2 responses observed after N+C intake suggests a greater post-ischemic vasodilation, which may be due to increased NO availability, via the activation of the 2 main NO production pathways.

Summary Background Cardiovascular events related to high-intensity sport practice are rare but dramatic. Coronary artery disease (CAD) is the leading cause of these events after the age of 35 years. The value of a maximal exercise test (ET) for detection of athletes at risk remains a matter of debate. Aim The aim of this prospective multicentre study was to clarify the medical value and cost-effectiveness of an ET in middle-aged white asymptomatic athletes who participate in high-intensity sport. Methods All athletes had a physical examination, assessment of cardiovascular risk factors, a resting electrocardiogram and an ET. In case of abnormal ET, complementary cardiovascular evaluation was performed, when requested, to detect potential cardiovascular disease. Results 1361 asymptomatic athletes (mean age 50.4 ± 9.6 years; mean training 5.1 ± 3.2 h/week; 10.4% women) with a normal resting electrocardiogram and without cardiovascular disease were consecutively included. An abnormal ET was reported in 144 subjects (94% men); this was positively related to the subject's age and cardiovascular risk level. Cardiac arrhythmias (48%) and CAD symptoms (33.3%) were mainly reported. Cardiovascular disease was confirmed in 24 cases (1.7% from the whole population; 16.7% from those with an abnormal ET) – mainly CAD (n = 12) and arterial hypertension (n = 8). Seventy athletes presented significant unexplained arrhythmias. The cost was approximately €8450 for every confirmed case of cardiovascular disease. Conclusions In this multicentre study in middle-aged athletes, a systematic ET was abnormal in 10.6% of cases. About 2% of subjects had cardiovascular disease, mainly arrhythmias and CAD. From these results, it seems that in a trained population aged >35 years, ET should be targeted at men with at least two cardiovascular risk factors, with acceptable cost-effectiveness.

Introduction: The effect of eccentric (ECC) versus concentric (CON) training on metabolic properties in skeletal muscle is understood poorly. We determined the responses in oxidative capacity and mitochondrial H2O2 production after eccentric (ECC) versus concentric (CON) training performed at similar mechanical power. Methods: Forty-eight rats performed 5- or 20-day eccentric (ECC) or concentric (CON) training programs. Mitochondrial respiration, H2O2 production, citrate synthase activity (CS), and skeletal muscle damage were assessed in gastrocnemius (GAS), soleus (SOL) and vastus intermedius (VI) muscles. Results: Maximal mitochondrial respiration improved only after 20 days of concentric (CON) training in GAS and SOL. H2O2 production increased specifically after 20 days of eccentric ECC training in VI. Skeletal muscle damage occurred transiently in VI after 5 days of ECC training. Conclusions: Twenty days of ECC versus CON training performed at similar mechanical power output do not increase skeletal muscle oxidative capacities, but it elevates mitochondrial H2O2 production in VI, presumably linked to transient muscle damage. Muscle Nerve 50: 803–811, 2014

International audience; Physical performance relies on the concerted action of myriad responses, many of which are under circadian clock control. Little is known, however, regarding the time-dependent effect on exercise performance at the molecular level. We found that both mice and humans exhibit daytime variance in exercise capacity between the early and late part of their active phase. The daytime variance in mice was dependent on exercise intensity and relied on the circadian clock proteins PER1/2. High-throughput gene expression and metabolic profiling of skeletal muscle revealed metabolic pathways that are differently activated upon exercise in a daytime-dependent manner. Remarkably, we discovered that ZMP, an endogenous AMPK activator, is induced by exercise in a time-dependent manner to regulate key steps in glycolytic and fatty acid oxidation pathways and potentially enhance exercise capacity. Overall, we propose that time of day is a major modifier of exercise capacity and associated metabolic pathways.

Summary Hepatopulmonary syndrome (HPS) is of prognostic value in patients awaiting for orthotopic liver transplantation (OLT), but little is known about the effect of cirrhotic cardiomyopathy (CCM). The aim of the present study was to estimate the prevalence and possible relation between respiratory and cardiac abnormalities in a same series of patients awaiting OLT. Special attention was paid to the prognostic value of CCM in comparison to HPS. Eighty-three patients were included (19 females, 64 males; 52.1 ± 10.0 yrs). All had lung function testing with arterial blood gases and echocardiographic evaluation at rest with a contrast echocardiography in case of arterial oxygenation defect. To estimate the presence of CCM, patients underwent a complete left and right echocardiography and Doppler examination. Complete echocardiographic assessment could be obtained in 64 of the 83 patients of the study. HPS was observed in 16.9% (14/83) and CCM in 23.4% (15/64) of patients. There was a tendency of more serious adverse events before and after OLT in patients with HPS in comparison to others but CCM was not of prognostic value. HPS and CCM were frequent in these patients awaiting OLT but both abnormalities were not found in the same patients. CCM was neither related to death before OLT nor to death or serious adverse events after OLT.

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. METHODS AND RESULTS 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

It was previously shown that dehydroepiandrosterone (DHEA) reverses chronic hypoxia-induced pulmonary hypertension (PH) in rats, but whether DHEA can improve the clinical and hemodynamic status of patients with PH associated to chronic obstructive pulmonary disease (PH-COPD) has not been studied whereas it is a very severe poorly treated disease.Eight patients with PH-COPD were treated with DHEA (200mg daily orally) for 3 months. The primary end-point was the change in the 6-minute walk test (6-MWT) distance. Secondary end-points included pulmonary hemodynamics, lung function tests and tolerance of treatment.The 6-MWT increased in all cases, from 333m (median [IQR]) (257; 378) to 390m (362; 440) (P0.05). Mean pulmonary artery pressure decreased from 26mmHg (25; 27) to 21.5mmHg (20; 25) (P0.05) and pulmonary vascular resistance from 4.2UI (3.5; 4.4) to 2.6UI (2.5; 3.8) (P0.05). The carbon monoxide diffusing capacity of the lung (DLCO % predicted) increased significantly from 27.4% (20.1; 29.3) to 36.4% (14.6; 39.6) (P0.05). DHEA treatment did not change respiratory parameters of gas exchange and the 200mg per day of DHEA used was perfectly tolerated with no side effect reported.DHEA treatment significantly improves 6-MWT distance, pulmonary hemodynamics and DLCO of patients with PH-COPD, without worsening gas exchange, as do other pharmacological treatments of PH (trial registration NCT00581087).

Background: Increased brain natriuretic peptide (BNP) in cardiovascular disease is thought to be a compensatory protective mechanism allowing to delay the occurrence of terminal heart failure. Heart transplantation should normalize the neuroendocrine balance but BNP remains elevated in stable heart-transplant recipients (Htx). Such increase has been related to persistent endothelial and cardiac dysfunctions. The purpose of this study was to determine whether selected Htx, presenting with normal hemodynamic and cardiac systolic and diastolic functions on both side of the heart, show a normalization of their BNP plasma values. Methods: Of a cohort of well-being 26 Htx, we selected 12 patients with normal hemodynamics and left and right heart systolic and diastolic functions and compared their circulating BNP, cyclic guanosine monophosphate (cGMP) (the BNP second messenger) and endothelin-1 (ET) values with that of 12 age-, body mass index- and mean arterial pressure-matched controls. Cardiac function determination by echodoppler included cardiac filling pressures assessment using tissue Doppler imaging. Blood samples for biological and hormonal determinations were drawn at rest, within 15 min before echocardiography. Results: As selected, hemodynamic and left and right heart systolic and diastolic functions were located in the normal range in Htx. Plasma ET value was also similar in Htx and controls (20.7 ± 0.9 vs. 19.6 ± 0.9 fmol/mL). However, circulating BNP, like cGMP, was still significantly increased after heart transplantation, when compared with controls (33.8 ± 8.5 vs. 4.0 ± 0.9 pg/mL, p = 0.002 and 8.2 ± 1.1 vs. 4.4 ± 0.3 nmol/L, p = 0.003) for BNP and cGMP, respectively, in Htx and controls. Interestingly, the sole correlation observed was between BNP and cGMP (r = 0.85, p

Improvement of exercise capacity by continuous (CT) versus interval training (IT) remains debated. We tested the hypothesis that CT and IT might improve peripheral and/or central adaptations, respectively, by randomly assigning 10 healthy subjects to two periods of 24 trainings sessions over 8 weeks in a cross-over design, separated by 12 weeks of detraining. Maximal oxygen uptake (VO2max), cardiac output (Qmax) and maximal arteriovenous oxygen difference (Da-vO2max) were obtained during an exhaustive incremental test before and after each training period. VO2max and Qmax increased only after IT (from 26.3 +/- 1.6 to 35.2 +/- 3.8 ml min(-1) kg(-1) and from 17.5 +/- 1.3 to 19.5 +/- 1.8 l min(-1), respectively; P < 0.01). Da-vO2max increased after both protocols (from 11.0 +/- 0.8 to 12.7 +/- 1.0; P < 0.01 and from 11.0 +/- 0.8 to 12.1 +/- 1.0 ml 100 ml(-1), P < 0.05 in CT and IT, respectively). At submaximal intensity a significant rightward shift of the Q/Da-vO2 relationship appeared only after CT. These results suggest that in isoenergetic training, central and peripheral adaptations in oxygen transport and utilization are training-modality dependant. IT improves both central and peripheral components of Da-vO2max whereas CT is mainly associated with greater oxygen extraction.

Metabolic demand and muscle mechanical tension are closely coupled during exercise, making their respective drives to the circulatory response difficult to establish. This coupling being altered in eccentric cycling, we implemented an experimental design featuring eccentric vs. concentric constant-load cycling bouts to gain insights into the control of the exercise-induced circulatory response in humans. Heart rate (HR), stroke volume (SV), cardiac output (Q̇), oxygen uptake (V̇o2), and electromyographic (EMG) activity of quadriceps muscles were measured in 11 subjects during heavy concentric (heavy CON: 270 ± 13 W; V̇o2 = 3.59 ± 0.20 l/min), heavy eccentric (heavy ECC: 270 ± 13 W, V̇o2 = 1.17 ± 0.15 l/min), and light concentric (light CON: 70 ± 9 W, V̇o2 = 1.14 ± 0.12 l/min) cycle bouts. Using a reductionist approach, the circulatory responses observed between heavy CON vs. light CON (difference in V̇o2 and power output) was ascribed either to metabolic demand, as estimated from heavy CON vs. heavy ECC (similar power output, different V̇o2), or to muscle mechanical tension, as estimated from heavy ECC vs. light CON (similar V̇o2, different power output). 74% of the Q̇ response was determined by the metabolic demand, also accounting for 65% and 84% of HR and SV responses, respectively. Consequently, muscle mechanical tension determined 26%, 35%, and 16% of the Q̇, HR, and SV responses, respectively. Q̇ was significantly related to V̇o2 ( r2 = 0.83) and EMG activity ( r2 = 0.82; both P < 0.001). These results suggest that the exercise-induced circulatory response is mainly under metabolic control and support the idea that the level of muscle activation plays a role in the cardiovascular regulation during cycle exercise in humans.

Summary Background Eccentric exercise training has been shown to improve muscle force strength without excessive cardiovascular stress. Such an exercise modality deserves to be tested in pulmonary arterial hypertension. Aim We aimed to assess the effects of an eccentric training modality on cardiac function and survival in an experimental monocrotaline-induced model of pulmonary arterial hypertension with right ventricular dysfunction. Methods Forty rats were randomly assigned to one of four groups: 40 mg/kg monocrotaline-injected sedentary rats; 40 mg/kg monocrotaline-injected eccentric-trained rats; sedentary control rats; or eccentric-trained control rats. Eccentric exercise training consisted of downhill running on a treadmill with a −15° slope for 30 minutes, 5 days a week for 4 weeks. Training tolerance was assessed by echocardiography, right ventricle catheterization and the rats’ maximal eccentric speed. Results Survival in monocrotaline-injected eccentric-trained rats was not different from that in monocrotaline-injected sedentary rats. Monocrotaline-injected eccentric-trained rats tolerated this training modality well, and haemodynamic status did not deteriorate further compared with monocrotaline-injected sedentary rats. The eccentric maximal speed decline was less pronounced in trained compared with sedentary pulmonary arterial hypertension rats. Conclusions Eccentric exercise training had no detrimental effects on right heart pressure, cardiac function and survival in rats with stable monocrotaline-induced pulmonary hypertension.

In middle-aged persons, moderate physical activity energy expenditure (PAEE) has been shown to be associated with increased vagal-related heart rate variability (HRV) indexes and better health status. The purpose of this study was to determine whether a very high PAEE has greater effect on vagal-related HRV indexes and self-estimates of well-being in middle-aged subjects having distinct long-term physical activity profiles. Forty-four subjects were divided into three groups on the basis of the sport score of the Modified Baecke Questionnaire for Older Adults: sedentary (SED, n = 15), moderately-trained (MT, n = 16), and highly-trained subjects (HT, n = 13). PAEE was estimated by triaxial accelerometry during one week. Time and frequency domain HRV indexes were determined during quiet periods in the morning on 5-min R-R interval segments under controlled breathing. Quality of life was evaluated using the SF-36 health survey questionnaire. PAEE was significantly different for each group (374.5 +/- 13.8, 616.8 +/- 22.4, and 1086.6 +/- 43.2 kcal . day (-1) for SED, MT, and HT, respectively, p < 0.001). MT presented significantly higher vagal-related HRV indexes than SED and HT (p < 0.05). None of the HRV indexes was significantly greater in HT than in SED. MT and HT had similar health status scores, which were significantly higher than for SED. These results indicate that in middle-aged subjects, habitual moderate PAEE is associated with greater vagal tone and self-estimates of well-being compared to low PAEE. In contrast, very high PAEE is associated with similar vagal-related indexes as low PAEE, despite better overall health status.

The purpose of the study was to determine the potential beneficial effect of six weeks oral L-arginine supplementation (LAS) on endurance exercise, an important determinant of daily-life activity in patients with chronic stable heart failure (CHF). After an initial incremental maximal exercise test, CHF patients performed an identical thirty-minute interval endurance exercise test before and after six weeks with (L-arginine group; ARG) or without LAS (control group; CTL). Hemodynamic, respiratory, and metabolic parameters were determined at rest, during exercise, and during recovery. Mean heart rate decreased throughout exercise and recovery after LAS (- 8.2 +/- 1.4 b x min(-1); p = 0.003 and - 6.7 +/- 1.6 b x min(-1); p < 0.001, respectively), systemic blood pressure and respiratory parameters remaining unchanged. Resting L-argininaemia increased from 102 +/- 11 to 181 +/- 37 micromol x l(-1) (p < 0.004) and exercise-induced peak increase in plasma lactate was blunted after LAS (4.13 +/- 0.75 vs. 3.13 +/- 0.39 mmol x l(-1); p = 0.02). No significant change was observed in the control group. In heart failure patients, six weeks oral LAS enhances endurance exercise tolerance, reducing both heart rate and circulating lactates. This suggests that chronic LAS might be useful as a therapeutic adjuvant in order to improve the patient's physical fitness.

This study investigates whether a 6-wk intermittent hypoxia training (IHT), designed to avoid reductions in training loads and intensities, improves the endurance performance capacity of competitive distance runners. Eighteen athletes were randomly assigned to train in normoxia [Nor group; n = 9; maximal oxygen uptake (V̇o2 max) = 61.5 ± 1.1 ml·kg−1·min−1] or intermittently in hypoxia (Hyp group; n = 9; V̇o2 max= 64.2 ± 1.2 ml·kg−1·min−1). Into their usual normoxic training schedule, athletes included two weekly high-intensity (second ventilatory threshold) and moderate-duration (24–40 min) training sessions, performed either in normoxia [inspired O2fraction (FiO2) = 20.9%] or in normobaric hypoxia (FiO2= 14.5%). Before and after training, all athletes realized 1) a normoxic and hypoxic incremental test to determine V̇o2 maxand ventilatory thresholds (first and second ventilatory threshold), and 2) an all-out test at the pretraining minimal velocity eliciting V̇o2 maxto determine their time to exhaustion (Tlim) and the parameters of O2uptake (V̇o2) kinetics. Only the Hyp group significantly improved V̇o2 max(+5% at both FiO2, P < 0.05), without changes in blood O2-carrying capacity. Moreover, Tlimlengthened in the Hyp group only (+35%, P < 0.001), without significant modifications of V̇o2kinetics. Despite similar training load, the Nor group displayed no such improvements, with unchanged V̇o2 max(+1%, nonsignificant), Tlim(+10%, nonsignificant), and V̇o2kinetics. In addition, Tlimimprovements in the Hyp group were not correlated with concomitant modifications of other parameters, including V̇o2 maxor V̇o2kinetics. The present IHT model, involving specific high-intensity and moderate-duration hypoxic sessions, may potentialize the metabolic stimuli of training in already trained athletes and elicit peripheral muscle adaptations, resulting in increased endurance performance capacity.

To evaluate the role of central and peripheral contributions to exercise limitation after transplantation, we compared, during exercise, 2 groups of very well-trained heart transplants recipients (HTRs) and kidney transplant recipients (KTRs) with a group of control subjects (CSs), matched for physical level.Nineteen male subjects, 7 HTRs, 6 KTRs and 6 CSs, participated in the study. All transplant patients were in sinus rhythm and were matched for immunosuppressive therapy, none of whom had therapy with chronotropic effects. Exercise capacities were evaluated using a symptom-limited treadmill test. Oxygen consumption (VO2) and heart rate (HR) were measured continuously. Heart rate reserve (HRR) was defined as peak HR minus resting HR; resting HR was the stabilized HR measured in the supine position before the treadmill test.Functional capacities were evaluated for all HTRs, KTRs and CSs, according to maximal VO2 (41.5 +/- 4.0, 52.0 +/- 8.7 and 50.6 +/- 9.0 ml/kg per min, respectively), maximal treadmill speed (9.9 +/- 1.2, 12.7 +/- 1.9 and 15.5 +/- 1.5 km/h) and HRR (65 +/- 17, 101 +/- 12 and 110 +/- 11 beats per minute [bpm]), which were significantly lower in the HTR group (p0.05). Regardless of type of organ transplant, both HTR and KTR patients had a similar VO2/treadmill speed relationship, significantly higher than in the CS group. HRR correlated with maximal VO2 for HTRs (r = 0.72, p0.05).Despite regular training, the decreased mechanical efficiency reflected by an increased VO2/treadmill speed relationship suggests a peripheral limitation in both heart and kidney transplant patients. Furthermore, exercise limitations in HTRs likely arose from both central and peripheral factors, in view of their specific HRR reduction. These factors probably contributed to the decreased speed and VO2 observed in the HTR group.

Objectives : Circulating adrenomedullin (ADM), a potent vasorelaxing and natriuretic peptide involved in cardiovascular homeostasis, is increased after cardiac and renal transplantation. ADM is also implicated in hemodynamic abnormalities during liver cirrhosis, but whether ADM is increased late after liver transplantation is unknown. Patients : A total of 18 subjects—10 liver-transplant patients (Ltx) and 8 healthy subjects—were enrolled in the study. Design and measurements : After a 15-min rest period in supine position, heart rate and systemic blood pressure were determined in all subjects. Then, venous blood samples were obtained in order to simultaneously determine the cyclosporine through levels, the biological (cyclosporine, renal and hepatic functions) and hormonal (ADM and atrial natriuretic peptide (ANP)) characteristics of the Ltx. Results : ADM (27.2±4.1 vs. 53.8±6.9 pmol/l, P =0.02), and ANP (5.9±0.9 vs. 12.8±1.4 pmol/l, P =0.001) were significantly increased in late, stable Ltx (35.4±9.6 months after transplantation). Furthermore, increased ADM correlated positively with elevated creatinine ( r =0.76, P =0.01) and ANP ( r =0.64, P =0.04) after liver transplantation. Conclusions : Liver-transplant patients exhibit a sustained increase in circulating ADM. Such an increase likely results from renal impairment associated with volume regulation abnormalities, suggesting a potential role for ADM in volume regulation after liver transplantation.

To investigate the effect of L-arginine supplementation (L-ARG) on physiological and metabolic changes during exercise, we determined in a double-blind study the cardiorespiratory (heart rate, oxygen consumption (VO(2)) and carbon dioxide production (VCO(2)) and the metabolic (lactate and ammonia) responses to maximal exercise after either an intravenous L-ARG hydrochloride salt or placebo load in 8 healthy subjects. Exercise-induced increases in heart rate, VO(2) and VCO(2) were not significantly different after L-ARG or placebo. By contrast, peak plasma ammonia and lactate were significantly decreased after L-ARG load (60.6 +/- 8.2 vs. 73.1 +/- 9.1 micro mol x l(-1), p < 0.01 and 7.1 +/- 0.7 vs. 8.2 +/- 1.1 mmol x l(-1), p < 0.01, for ammonia and lactate, respectively). Plasma L-citrulline increased significantly during exercise only after L-ARG load, despite a concomitant decrease in plasma L-ARG. Furthermore, a significant inverse relationship was observed between changes in lactate and L-citrulline concentrations after L-ARG load (r = -0.84, p = 0.009). These results demonstrate that intravenous L-ARG reduces significantly exercise-induced increase in plasma lactate and ammonia. Taken together, the specific L-citrulline increase and the inverse relationship observed between L-citrulline and plasma lactate after L-ARG might support that L-ARG supplementation enhances the L-arginine-nitric oxide (NO) pathway during exercise.

We investigated the hemodynamic, renal, and hormonal responses to neutral endopeptidase (NEP) inhibition during a 6-h, double-blind, randomized, placebo-controlled study in seven chronic, stable heart transplant patients. Baseline characteristics were similar during both experiments, and no significant changes were observed after placebo. NEP inhibition increased circulating endothelin-1 (from 2.01 ± 0.1 to 2.90 ± 0.2 pmol/l; P < 0.01), atrial natriuretic peptide (ANP; from 21.5 ± 2.7 to 29.6 ± 3.7 pmol/l; P < 0.01), and the ANP second messenger cGMP. Noteworthy, systemic blood pressure did not increase. Renal plasma flow and glomerular filtration rate remained unmodified after NEP inhibition. Filtration fraction (33 ± 13%), diuresis (196 ± 62%), and natriuresis (315 ± 105%) increased significantly in relation to ANP and cGMP. A strong inverse relationship was observed between excreted cGMP and sodium reabsorption ( r = −0.71, P < 0.0001). Thus, despite significantly increasing endothelin-1, NEP inhibition did not adversely influence systemic or renal hemodynamics in transplant patients. ANP, possibly through a tubular action, enhances the natriuresis observed after NEP inhibition.

One of the greatest challenges in exercise physiology is to develop a valid, reliable, non-invasive and affordable measurement of cardiac output (CO). The purpose of this study was to evaluate the reproducibility and accuracy of a new impedance cardiograph device, the Physio Flow, during a 1-min step incremental exercise test from rest to maximal peak effort. A group of 12 subjects was evaluated to determine the reproducibility of the method as follows: (1) each subject performed two comparable tests while their CO was measured by impedance cardiography using the new device (COImp1, COImp2), and (2) in a subgroup of 7 subjects CO was also determined by the direct Fick method (COFick) during the second test. The mean difference between the values obtained by impedance (i.e. COImp1-COImp2) was -0.009 l.min-1 (95% confidence interval: -4.2 l.min-1, 4.2 l.min-1), and CO ranged from 3.55 l.min-1 to 26.75 l.min-1 (n = 146). When expressed as a percentage, the difference (COImp1-COImp2) did not vary with increasing CO. The correlation coefficient between the values of COImp and COFick obtained during the second exercise test was r = 0.94 (P < 0.01, n = 50). The mean difference expressed as percentage was -2.78% (95% confidence interval: -27.44%, 21.78%). We conclude that COImp provides a clinically acceptable evaluation of CO in healthy subjects during an incremental exercise.

Phosphoglucomutase type 1 (PGM1) deficiency is a rare metabolic myopathy in which symptoms are provoked by exercise.Because the metabolic block is proximal to the entry of glucose into the glycolytic pathway, we hypothesized that iv glucose could improve the exercise intolerance experienced by the patient.This was an experimental intervention study.The study was conducted in an exercise laboratory.Subjects were a 37-year-old man with genetically and biochemically verified PGM1 deficiency and 6 healthy subjects.Cycle ergometer, peak and submaximal exercise (70% of peak oxygen consumption), and exercise with an iv glucose infusion tests were performed.Peak work capacity and substrate metabolism during submaximal exercise with and without an iv glucose infusion were measured.Peak work capacity in the patient was normal, as were increases in plasma lactate during peak and submaximal exercise. However, the heart rate decreased 11 beats minute⁻¹, the peak work rate increased 12.5%, and exercise was rated as being easier with glucose infusion in the patient. These results were in contrast to those in the control group, in whom no improvements occurred. In addition, the patient tended to become hypoglycemic during submaximal exercise.This report characterizes PGM1 deficiency as a mild metabolic myopathy that has dynamic exercise-related symptoms in common with McArdle disease but no second wind phenomenon, thus suggesting that the condition clinically resembles other partial enzymatic defects of glycolysis. However, with glucose infusion, the heart rate decreased 11 beats min⁻¹, the peak work rate increased 12.5%, and exercise was considered easier by the patient.

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.

Objective: To examine metabolism during exercise in 2 patients with muscle phosphorylase kinase (PHK) deficiency and to further define the phenotype of this rare glycogen storage disease (GSD). Methods: Patient 1 (39 years old) had mild exercise-induced forearm pain, and EMG showed a myopathic pattern. Patient 2 (69 years old) had raised levels of creatine kinase (CK) for more than 6 months after statin treatment. Both patients had increased glycogen levels in muscle and PHK activity PHKA1 gene. The metabolic response to anaerobic forearm exercise and aerobic cycle exercise was studied in the patients and 5 healthy subjects. Results: Ischemic exercise showed a normal 5-fold increase in plasma lactate (peak 5.7 and 6.9 mmol/L) but an exaggerated 5-fold increase in ammonia (peak 197 and 171 μmol/L; control peak range 60–113 μmol/L). An incremental exercise test to exhaustion revealed a blunted lactate response (5.4 and 4.8 mmol/L) vs that for control subjects (9.6 mmol/L; range 7.1–14.3 mmol/L). Fat and carbohydrate oxidation rates at 70% of peak oxygen consumption were normal. None of the patients developed a second wind phenomenon or improved their work capacity with an IV glucose infusion. Conclusion: Our findings demonstrate that muscle PHK deficiency may present as an almost asymptomatic condition, despite a mild impairment of muscle glycogenolysis, raised CK levels, and glycogen accumulation in muscle. The relative preservation of glycogenolysis is probably explained by an alternative activation of myophosphorylase by AMP and P i at high exercise intensities. Neurology ® 2012;78:265–268

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, a 6-wk LAS improved quality of life in HTx recipients (mean 6 SEM Minnesota Score: from 15.3 6 1.3 to 10.6 6 1.1; P , 0.001) and their submaximal exercise capacity. The distance walked during the 6MWT increased (from 525 6 20 to 580 6 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 6 0.38 to 3.31 6 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. Am J Clin Nutr doi: 10.3945/ajcn.2009.27881.

This study investigates the role of central vs. peripheral factors in the limitation of maximal oxygen uptake (V̇o2max) with moderate hypoxia [inspired fraction (FiO2) =14.5%]. Fifteen endurance-trained athletes performed maximal cycle incremental tests to assess V̇o2max, maximal cardiac output (Q̇max), and maximal arteriovenous oxygen (a-vO2) difference in normoxia and hypoxia. Muscle biopsies of vastus lateralis were taken 1 wk before the cycling tests to evaluate maximal muscle oxidative capacity (V̇max) and sensitivity of mitochondrial respiration to ADP ( Km) on permeabilized muscle fibers in situ. Those athletes exhibiting the largest reduction of V̇o2max in moderate hypoxia (Severe Loss group: −18 ± 2%) suffered from significant reductions in Q̇max (−4 ± 1%) and maximal a-vO2 difference (−14 ± 2%). Athletes who well tolerated hypoxia, as attested by a significantly smaller drop of V̇o2max with hypoxia (Moderate Loss group: −7 ± 1%), also display a blunted Q̇max (−9 ± 2%) but, conversely, were able to maintain maximal a-vO2 difference (+1 ± 2%). Though V̇max was similar in the two experimental groups, the smallest reduction of V̇o2max with moderate hypoxia was observed in those athletes presenting the lowest apparent Km for ADP in the presence of creatine ( Km+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 FiO2, 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.

The goal of the study was to determine the effects of continuous (CT) vs. intermittent (IT) training yielding identical mechanical work and training duration on skeletal muscle and cardiorespiratory adaptations in sedentary subjects. Eleven subjects (6 men and 5 women, 45 ± 3 years) were randomly assigned to either of the two 8-wk training programs in a cross-over design, separated by 12 wk of detraining. Maximal oxygen uptake (V̇o2max) increased after both trainings (9% with CT vs. 15% with IT), whereas only IT was associated with faster V̇o2kinetics (τ: 68.0 ± 1.6 vs. 54.9 ± 0.7 s, P < 0.05) measured during a test to exhaustion (TTE) and with improvements in maximal cardiac output (Qmax, from 18.1 ± 1.1 to 20.1 ± 1.2 l/min; P < 0.01). Skeletal muscle mitochondrial oxidative capacities ( Vmax) were only increased after IT (3.3 ± 0.4 before and 4.5 ± 0.6 μmol O2·min−1·g dw−1after training; P < 0.05), whereas capillary density increased after both trainings, with a two-fold higher enhancement after CT (+21 ± 1% for IT and +40 ± 3% after CT, P < 0.05). The gain of Vmaxwas correlated with the gain of TTE and the gain of V̇o2maxwith IT. The gain of Qmaxwas also correlated with the gain of VO2max. These results suggest that fluctuations of workload and oxygen uptake during training sessions, rather than exercise duration or global energy expenditure, are key factors in improving muscle oxidative capacities. In an integrative view, IT seems optimal in maximizing both peripheral muscle and central cardiorespiratory adaptations, permitting significant functional improvement. These data support the symmorphosis concept in sedentary subjects.

To determine whether the six-minute walk test (6MWT) might predict peak oxygen consumption (VO2peak) after heart transplantation.Case-control prospective study.Public hospital.Patients with heart transplant (n=22) and age-matched sedentary male subjects (n=13).Not applicable.Exercise performance using a maximal exercise test, distance walked using the 6MWT, heart rate, and VO2peak.Compared with controls, exercise performance was decreased in patients with heart transplant with less distance ambulated (516+/-13m vs 592+/-13m; P.001) and a decrease in mean VO2peak (23.3+/-1.3 vs 29.6+/-1mL x min(-1) x kg(-1); P.001). Patients with heart transplant showed an increased resting heart rate, a response delayed both at the onset of exercise and during recovery. However, the patient's heart rate at the end of the 6MWT was similar to that obtained at the ventilatory threshold. The formula did not predict measured VO2, with a weak correlation observed between the six-minute walk distance and both VO2peak (r=.53; P.01) and ventilatory threshold (r=.53; P.01) after heart transplantation. Interestingly, when body weight was considered, correlations coefficient increased to .74 and .77, respectively (P.001).In heart transplant recipients, the 6MWT is a safe, practical, and submaximal functional test. The distance-weight product can be used as an alternative method for assessing the functional capacity after heart transplantation but cannot totally replace maximal VO2 determination.

We hypothesized that specific muscular transcript level adaptations participate in the improvement of endurance performances following intermittent hypoxia training in endurance-trained subjects. Fifteen male high-level, long-distance runners integrated a modified living low-training high program comprising two weekly controlled training sessions performed at the second ventilatory threshold for 6 wk into their normal training schedule. The athletes were randomly assigned to either a normoxic (Nor) (inspired O2fraction = 20.9%, n = 6) or a hypoxic group exercising under normobaric hypoxia (Hyp) (inspired O2fraction = 14.5%, n = 9). Oxygen uptake and speed at second ventilatory threshold, maximal oxygen uptake (V̇o2 max), and time to exhaustion (Tlim) at constant load at V̇o2 maxvelocity in normoxia and muscular levels of selected mRNAs in biopsies were determined before and after training. V̇o2 max(+5%) and Tlim (+35%) increased specifically in the Hyp group. At the molecular level, mRNA concentrations of the hypoxia-inducible factor 1α (+104%), glucose transporter-4 (+32%), phosphofructokinase (+32%), peroxisome proliferator-activated receptor gamma coactivator 1α (+60%), citrate synthase (+28%), cytochrome oxidase 1 (+74%) and 4 (+36%), carbonic anhydrase-3 (+74%), and manganese superoxide dismutase (+44%) were significantly augmented in muscle after exercise training in Hyp only. Significant correlations were noted between muscular mRNA levels of monocarboxylate transporter-1, carbonic anhydrase-3, glucose transporter-4, and Tlim only in the group of athletes who trained in hypoxia ( P < 0.05). Accordingly, the addition of short hypoxic stress to the regular endurance training protocol induces transcriptional adaptations in skeletal muscle of athletic subjects. Expressional adaptations involving redox regulation and glucose uptake are being recognized as a potential molecular pathway, resulting in improved endurance performance in hypoxia-trained subjects.

The purpose of this study was to determine, in heart failure patients (HF), whether acute or chronic L-arginine supplementation (LAS) might delay the ventilatory threshold (VT) and whether chronic LAS might reduce exercise-induced plasma lactate increase. HF patients undertook 4 cardiopulmonary bicycle exercises tests. The first 3 were maximal without (EX1), after acute (EX2), or chronic (EX3) oral LAS (6 gm twice a day for 6 weeks). The 4th test (EX4), performed after chronic LAS, was similar to the first in order to investigate the effect of chronic LAS on circulating lactate levels. Results showed that acute LAS failed to improve both submaximal and maximal exercise capacities. Similarly, maximal exercise capacity remained unmodified after chronic LAS. Nevertheless, chronic LAS delayed significantly the patients' ventilatory threshold. Thus exercise duration prior to VT increased (mean ± SEM) from 6.04 ± 0.9 to 7.7 ± 1.03 min (p = 0.04), resulting in a significant increase in oxygen uptake (1.05 ± 0.08 to 1.24 ± 0.12 L•min−1; p = 0.03), CO2 release (0.94 ± 0.10 to 1.2 ± 0.12 L•min−1; p = 0.018), minute ventilation (29.31 ± 2.8 to 34.5 ± 2.7 L; p = 0.009), and workload (60.7 ± 9.8 to 78.5 ± 10.2 watts; p = 0.034). Furthermore, chronic LAS significantly reduced the exercise-induced increase in postexercise plasma lactate concentration (−21 ± 7%). In conclusion, unlike acute supplementation, chronic LAS significantly delays the ventilatory threshold, and chronic LAS reduces circulating plasma lactate in HF patients. These data suggest that chronic LAS might improve the ability of HF patients to perform their daily-life activities. Key words: maximal exercise, heart device, vasodilator

Aims: As cardiac metabolic flexibility is crucial, this study examined whether acute ischaemia can induce specific qualitative alterations of the mitochondrial metabolic pathways as well as energy transfer systems.Methods: Left descending coronary artery ligation was performed after sternotomy in eight pigs and the heart was excised after 45 min of ischaemia. Maximal O2 uptake (V(max), micromol O2 min(-1) g(-1) dry weight) of saponin-skinned myofibres were measured from ischaemic and non-ischaemic area of ventricular myocardium.Results: V(max) decreased by approximately 20% in ischaemic myocardium with both glutamate-malate (18.1 +/- 1.3 vs. 22.1 +/- 1.7 in control, P < 0.05) and pyruvate substrates (19.3 +/- 1.0 vs. 23.3 +/- 2.0 in control, P < 0.05) whereas no difference was observed with palmitoyl carnitine (15.6 +/- 1.8 vs. 16.6 +/- 0.9 in control). The K(m) of mitochondrial respiration for ADP decreased in ischaemic heart by 24% (679 +/- 79 vs. 899 +/- 84 microm of ADP in control, P < 0.05). Moreover, the mitochondrial creatine kinase efficacy (K(m) without creatine/K(m) with creatine), representative of the coupling of oxidative phosphorylation process with the mitochondrial creatine kinase, was reduced in ischaemic heart (11.6 +/- 2.5 in ischaemic vs. 18.0 +/- 2.2 in control, P < 0.05).Conclusions: These findings argue for specific mitochondrial impairments at the level of pyruvate oxidation and creatine kinase channelling system after an acute period of in vivo ischaemia, whereas the lipid mitochondrial oxidation pathway seems to be preserved. Such a loss of metabolic flexibility following acute ischaemia could become an early feature of metabolic dysregulation of the heart.

International audience; Purpose: Endurance training is an important component of rehabilitation in patients with chronic obstructive pulmonary disease (COPD). In our study, we investigated the pulmonary hemodynamics' adaptation during a high-intensity intermittent exercise in such patients.Methods: Eight patients underwent a 30-min exercise, alternating a 4-min work set at their first ventilatory threshold with a 1-min exercise set at 90% of their maximal tolerated power output. Pulmonary arterial pressure was measured by means of a right heart catheter. Cardiac output was calculated using the Fick's principle applied to oxygen.Results: VO(2), cardiac output, and ventilation increased during the first minutes of exercise and remained stable thereafter. Heart rate increased significantly and progressively to its maximal value from rest to the end of the test (P < 0.001). After an initial increase, stroke volume decreased significantly (P < 0.05). Pulmonary arterial pressure increased from rest (mean +/- SEM 23.9 +/- 2.1 mm Hg) to the fifth minute of exercise (41.6 +/- 2.8 mm Hg), and decreased significantly thereafter (35.2 +/- 3.3 mm Hg at the 30th minute) (P < 0.001). Total pulmonary vascular resistance decreased from rest to the end of the test (P < 0.001).Conclusion: The high-intensity 1-min bouts of work of our intermittent work exercise are well tolerated without pushing the pulmonary arterial pressure dramatically high in COPD patients.