Exercise intolerance in pulmonary arterial hypertension: insight into central and peripheral pathophysiological mechanisms.

Exercise intolerance is a cardinal symptom of pulmonary arterial hypertension (PAH) and strongly impacts patients' quality of life (QoL). Although central cardiopulmonary impairments limit peak oxygen consumption (V' O2peak ) in patients with PAH, several peripheral abnormalities have been described over the recent decade as key determinants in exercise intolerance, including impaired skeletal muscle (SKM) morphology, convective O2 transport, capillarity and metabolism indicating that peripheral abnormalities play a greater role in limiting exercise capacity than previously thought. More recently, cerebrovascular alterations potentially contributing to exercise intolerance in patients with PAH were also documented. Currently, only cardiopulmonary rehabilitation has been shown to efficiently improve the peripheral components of exercise intolerance in patients with PAH. However, more extensive studies are needed to identify targeted interventions that would ultimately improve patients' exercise tolerance and QoL. The present review offers a broad and comprehensive analysis of the present literature about the complex mechanisms and their interactions limiting exercise in patients and suggests several gaps in knowledge that need to be addressed in the future for a better understanding of exercise intolerance in patients with PAH.

Novel insights on the pulmonary vascular consequences of COVID-19.

In the last few months, the number of cases of a new coronavirus-related disease (COVID-19) rose exponentially, reaching the status of a pandemic. Interestingly, early imaging studies documented that pulmonary vascular thickening was specifically associated with COVID-19 pneumonia, implying a potential tropism of the virus for the pulmonary vasculature. Moreover, SARS-CoV-2 infection is associated with inflammation, hypoxia, oxidative stress, mitochondrial dysfunction, DNA damage, and lung coagulopathy promoting endothelial dysfunction and microthrombosis. These features are strikingly similar to what is seen in pulmonary vascular diseases. Although the consequences of COVID-19 on the pulmonary circulation remain to be explored, several viruses have been previously thought to be involved in the development of pulmonary vascular diseases. Patients with preexisting pulmonary vascular diseases also appear at increased risk of morbidity and mortality. The present article reviews the molecular factors shared by coronavirus infection and pulmonary vasculature defects, and the clinical relevance of pulmonary vascular alterations in the context of COVID-19.

Continuous reduction in cerebral oxygenation during endurance exercise in patients with pulmonary arterial hypertension.

BACKGROUND: Patients with pulmonary arterial hypertension (PAH) have lower cerebral blood flow (CBF) and oxygenation compared to healthy sedentary subjects, the latter negatively correlating with exercise capacity during incremental cycling exercise. We hypothesized that patients would also exhibit altered CBF and oxygenation during endurance exercise, which would correlate with endurance time. METHODS: Resting and exercise cardiorespiratory parameters, blood velocity in the middle cerebral artery (MCAv; transcranial doppler) and cerebral oxygenation (relative changes in cerebral tissue oxygenation index (ΔcTOI) and cerebral deoxyhemoglobin (ΔcHHb); near-infrared spectroscopy) were continuously monitored in nine PAH patients and 10 healthy-matched controls throughout endurance exercise. Cardiac output (CO), systemic blood pressure (BP) and oxygen saturation (SpO2 ), ventilatory metrics and end-tidal CO2 pressure (PET CO2 ) were also assessed noninvasively. RESULTS: Despite a lower workload and endurance oxygen consumption, similar CO and systemic BP, ΔcTOI was lower in PAH patients compared to controls (p < .01 for interaction). As expected during exercise, patients were characterized by an altered MCAv response to exercise, a lower PET CO2 and SpO2 , as wells as a higher minute-ventilation/CO2 production ratio ( V˙E/V˙CO2 ratio). An uncoupling between changes in MCAv and PET CO2 during the cycling endurance exercise was also progressively apparent in PAH patients, but absent in healthy controls. Both cHHb and ΔcTOI correlated with V˙E/V˙CO2 ratio (r = 0.50 and r = -0.52; both p < .05 respectively), but not with endurance time. CONCLUSION: PAH patients present an abnormal cerebrovascular profile during endurance exercise with a lower cerebral oxygenation that correlate with hyperventilation but not endurance exercise time. These findings complement the physiological characterization of the cerebral vascular responses to exercise in PAH patients.

Six weeks of high-intensity interval training to exhaustion attenuates dynamic cerebral autoregulation without influencing resting cerebral blood velocity in young fit men.

Elevated cardiorespiratory fitness (CRF) is associated with reduced dynamic cerebral autoregulation (dCA), but the impact of exercise training per se on dCA remains equivocal. In addition, resting cerebral blood flow (CBF) and dCA after high-intensity interval training (HIIT) in individuals with already high CRF remains unknown. We examined to what extent 6 weeks of HIIT affect resting CBF and dCA in cardiorespiratory fit men and explored if potential changes are intensity-dependent. Endurance-trained men were assigned to group HIIT85 (85% of maximal aerobic power, 1-7 min effort bouts, n = 8) and HIIT115 (115% of maximal aerobic power, 30 sec to 1 min effort bouts, n = 9). Training sessions were completed until exhaustion 3 times/week over 6 weeks. Mean arterial pressure (MAP) and middle cerebral artery mean blood velocity (MCAvmean ) were measured continuously at rest and during repeated squat-stands (0.05 and 0.10 Hz). Transfer function analysis (TFA) was used to characterize dCA on driven blood pressure oscillations during repeated squat-stands. Neither training nor intensity had an effect on resting MAP and MCAvmean (both P > 0.05). TFA phase during 0.10 Hz squat-stands decreased after HIIT irrespective of intensity (HIIT85 : 0.77 ± 0.22 vs. 0.67 ± 0.18 radians; HIIT115 : pre: 0.62 ± 0.19 vs. post: 0.59 ± 0.13 radians, time effect P = 0.048). These results suggest that HIIT over 6 weeks have no apparent benefits on resting CBF, but a subtle attenuation in dCA is seen posttraining irrespective of intensity training in endurance-trained men.

Strong Relationship Between Vascular Function in the Coronary and Brachial Arteries.

Early detection of coronary artery dysfunction is of paramount cardiovascular clinical importance, but a noninvasive assessment is lacking. Indeed, the brachial artery flow-mediated dilation test only weakly correlated with acetylcholine-induced coronary artery function ( r=0.36). However, brachial artery flow-mediated dilation methodologies have, over time, substantially improved. This study sought to determine if updates to this technique have improved the relationship with coronary artery function and the noninvasive indication of coronary artery dysfunction. Coronary artery and brachial artery function were assessed in 28 patients referred for cardiac catheterization (61±11 years). Coronary artery function was determined by the change in artery diameter with a 1.82 µg/min intracoronary acetylcholine infusion. Based on the change in vessel diameter, patients were characterized as having dysfunctional coronary arteries (>5% vasoconstriction) or relatively functional coronary arteries (<5% vasoconstriction). Brachial artery function was determined by flow-mediated dilation, adhering to current guidelines. The acetylcholine-induced change in vessel diameter was smaller in patients with dysfunctional compared with relatively functional coronary arteries (-11.8±4.6% versus 5.8±9.8%, P<0.001). Consistent with this, brachial artery flow-mediated dilation was attenuated in patients with dysfunctional compared with relatively functional coronaries (2.9±1.9% versus 6.2±4.2%, P=0.007). Brachial artery flow-mediated dilation was strongly correlated with the acetylcholine-induced change in coronary artery diameter ( r=0.77, P<0.0001) and was a strong indicator of coronary artery dysfunction (receiver operator characteristic=78%). The current data support that updates to the brachial artery flow-mediated dilation technique have strengthened the relationship with coronary artery function, which may now provide a clinically meaningful indication of coronary artery dysfunction.

Dynamic cerebral autoregulation is attenuated in young fit women.

Young women exhibit higher prevalence of orthostatic hypotension with presyncopal symptoms compared to men. These symptoms could be influenced by an attenuated ability of the cerebrovasculature to respond to rapid blood pressure (BP) changes [dynamic cerebral autoregulation (dCA)]. The influence of sex on dCA remains unclear. dCA in 11 fit women (25 ± 2 years) and 11 age-matched men (24 ± 1 years) was compared using a multimodal approach including a sit-to-stand (STS) and forced BP oscillations (repeated squat-stand performed at 0.05 and 0.10 Hz). Prevalence of initial orthostatic hypotension (IOH; decrease in systolic ≥ 40 mmHg and/or diastolic BP ≥ 20 mmHg) during the first 15 sec of STS was determined as a functional outcome. In women, the decrease in mean middle cerebral artery blood velocity (MCAvmean ) following the STS was greater (-20 ± 8 vs. -11 ± 7 cm sec-1 ; P = 0.018) and the onset of the regulatory change (time lapse between the beginning of the STS and the increase in the conductance index (MCAvmean /mean arterial pressure) was delayed (P = 0.007). Transfer function analysis gain during 0.05 Hz squat-stand was ~48% higher in women (6.4 ± 1.3 vs. 3.8 ± 2.3 cm sec-1 mmHg-1 ; P = 0.017). Prevalence of IOH was comparable between groups (women: 4/9 vs. men: 5/9, P = 0.637). These results indicate the cerebrovasculature of fit women has an attenuated ability to react to rapid changes in BP in the face of preserved orthostasis, which could be related to higher resting cerebral blood flow allowing women to better face transient hypotension.

Diminished dynamic cerebral autoregulatory capacity with forced oscillations in mean arterial pressure with elevated cardiorespiratory fitness.

The effect that cardiorespiratory fitness has on the dynamic cerebral autoregulatory capacity during changes in mean arterial pressure (MAP) remains equivocal. Using a multiple-metrics approach, challenging MAP across the spectrum of physiological extremes (i.e., spontaneous through forced MAP oscillations), we characterized dynamic cerebral autoregulatory capacity in 19 male endurance athletes and eight controls via three methods: (1) onset of regulation (i.e., time delay before an increase in middle cerebral artery (MCA) conductance [MCA blood velocity (MCAv)/MAP] and rate of regulation, after transient hypotension induced by sit-to-stand, and transfer function analysis (TFA) of MAP and MCAv responses during (2) spontaneous and (3) forced oscillations (5-min of squat-stand maneuvers performed at 0.05 and 0.10 Hz). Reductions in MAP and mean MCAv (MCAVmean) during initial orthostatic stress (0-30 sec after sit-to-stand) and the prevalence of orthostatic hypotension were also determined. Onset of regulation was delayed after sit-to-stand in athletes (3.1 ± 1.7 vs. 1.5 ± 1.0 sec; P = 0.03), but rate of regulation was not different between groups (0.24 ± 0.05 vs. 0.21 ± 0.09 sec-1; P = 0.82). While both groups had comparable TFA metrics during spontaneous oscillations, athletes had higher TFA gain during 0.10 Hz squat-stand versus recreational controls (P = 0.01). Reductions in MAP (P = 0.15) and MCAVmean (P = 0.11) during orthostatic stress and the prevalence of initial orthostatic hypotension (P = 0.65) were comparable between groups. These results indicate an intact ability of the cerebral vasculature to react to spontaneous oscillations but an attenuated capability to counter rapid and large changes in MAP in individuals with elevated cardiorespiratory fitness.

Compromised Cerebrovascular Regulation and Cerebral Oxygenation in Pulmonary Arterial Hypertension.

BACKGROUND: Functional cerebrovascular regulatory mechanisms are important for maintaining constant cerebral blood flow and oxygen supply in heathy individuals and are altered in heart failure. We aim to examine whether pulmonary arterial hypertension (PAH) is associated with abnormal cerebrovascular regulation and lower cerebral oxygenation and their physiological and clinical consequences. METHODS AND RESULTS: Resting mean flow velocity in the middle cerebral artery mean flow velocity in the middle cerebral artery (MCAvmean); transcranial Doppler), cerebral pressure-flow relationship (assessed at rest and during squat-stand maneuvers; analyzed using transfer function analysis), cerebrovascular reactivity to CO2, and central chemoreflex were assessed in 11 patients with PAH and 11 matched healthy controls. Both groups also completed an incremental ramp exercise protocol until exhaustion, during which MCAvmean, mean arterial pressure, cardiac output (photoplethysmography), end-tidal partial pressure of CO2, and cerebral oxygenation (near-infrared spectroscopy) were measured. Patients were characterized by a significant decrease in resting MCAvmean (P<0.01) and higher transfer function gain at rest and during squat-stand maneuvers (both P<0.05). Cerebrovascular reactivity to CO2 was reduced (P=0.03), whereas central chemoreceptor sensitivity was increased in PAH (P<0.01), the latter correlating with increased resting ventilation (R2=0.47; P<0.05) and the exercise ventilation/CO2 production slope (V˙E/V˙CO2 slope; R2=0.62; P<0.05) during exercise for patients. Exercise-induced increases in MCAvmean were limited in PAH (P<0.05). Reduced MCAvmean contributed to impaired cerebral oxygen delivery and oxygenation (both P<0.05), the latter correlating with exercise capacity in patients with PAH (R2=0.52; P=0.01). CONCLUSIONS: These findings provide comprehensive evidence for physiologically and clinically relevant impairments in cerebral hemodynamic regulation and oxygenation in PAH.

Uncoupling between cerebral perfusion and oxygenation during incremental exercise in an athlete with postconcussion syndrome: a case report.

High-intensity exercise may pose a risk to patients with postconcussion syndrome (PCS) when symptomatic during exertion. The case of a paralympic athlete with PCS who experienced a succession of convulsion-awakening periods and reported a marked increase in postconcussion symptoms after undergoing a graded symptom-limited aerobic exercise protocol is presented. Potential mechanisms of cerebrovascular function failure are then discussed.

Evidence for hysteresis in the cerebral pressure-flow relationship in healthy men.

The cerebrovasculature is more efficient at compensating for pharmacologically induced transient hypertension versus transient hypotension. Whether this phenomenon exists during nonpharmacologically induced hypertension and hypotension is currently unknown. We compared the percent change in mean velocity in the middle cerebral artery (MCAvmean) per percent change in mean arterial pressure (MAP) (%ΔMCAVmean/%ΔMAP) during transient hypertension and hypotension induced during squat-stand maneuvers performed at 0.05 Hz (20-s cycles) and 0.10 Hz (10-s cycles) in 58 male volunteers. %ΔMCAvmean/%ΔMAP was attenuated by 25% (P = 0.03, 0.05 Hz) and 47% (P < 0.0001, 0.10 Hz) during transient hypertension versus hypotension. Thus, these findings indicate that the brain in healthy men is better adapted to compensate for physiologically relevant transient hypertension than hypotension.NEW & NOTEWORTHY The novel finding of this study is that the change in middle cerebral artery mean flow velocity is attenuated during hypertension compared with hypotension physiologically induced by oscillations in blood pressure in men. These results support that the human brain is more effective at compensating for transient hypertension than hypotension.

Impaired Skeletal Muscle Oxygenation and Exercise Tolerance in Pulmonary Hypertension.

BACKGROUND: Limb muscle dysfunction is documented in pulmonary arterial hypertension (PAH), but little is known regarding muscle oxygen (O2) supply and its possible effects on exercise tolerance in PAH. METHODS: Ten patients with PAH and 10 matched controls underwent progressive maximal cardiopulmonary exercise test, voluntary and nonvolitional dominant quadriceps muscle strength measures, and nondominant quadriceps biopsy to assess maximal oxygen uptake, muscle function, and lower limb fiber type and capillarity, respectively. Both groups then performed normoxic and hyperoxic submaximal intensity exercise protocol at the same absolute workload during which muscle O2 supply was assessed by measuring changes in myoglobin-deoxyhemoglobin level (Δ[Mb-HHb]) and tissue oxygenation index in the dominant quadriceps using near-infrared spectroscopy. Changes in cardiac output, estimated systemic O2 delivery, and systemic O2 saturation were also assessed noninvasively throughout both submaximal exercises. RESULTS: Patients with PAH displayed lower maximal oxygen uptake (P < 0.01), skeletal muscle strength (P < 0.05), and capillarity (P = 0.01). Throughout the normoxic submaximal exercise protocol, Δ[Mb-HHb] (P < 0.01) was higher whereas changes in tissue oxygenation index (P < 0.01) and systemic O2 saturation (P = 0.01) were lower in patients with PAH compared with those in controls. Conversely, changes in cardiac output and estimated systemic O2 delivery were similar between groups. Muscle oxygenation remained unchanged with O2 supplementation. Among variables known to influence tissue oxygenation, only quadriceps capillarity density correlated with Δ[Mb-HHb] (r = -0.66, P < 0.01), which in turn correlated with maximal oxygen uptake (r = -0.64, P < 0.01), 6-min walked distance (r = -0.74, P = 0.01), and both voluntary (r = -0.46, P = 0.04) and nonvolitional (r = -0.50, P = 0.02) quadriceps strength. CONCLUSIONS: Capillary rarefaction within the skeletal muscle influences exercise tolerance and quadriceps strength at least partly through impaired muscle oxygen supply in PAH.

Skeletal muscle proteomic signature and metabolic impairment in pulmonary hypertension.

UNLABELLED: Exercise limitation comes from a close interaction between cardiovascular and skeletal muscle impairments. To better understand the implication of possible peripheral oxidative metabolism dysfunction, we studied the proteomic signature of skeletal muscle in pulmonary arterial hypertension (PAH). Eight idiopathic PAH patients and eight matched healthy sedentary subjects were evaluated for exercise capacity, skeletal muscle proteomic profile, metabolism, and mitochondrial function. Skeletal muscle proteins were extracted, and fractioned peptides were tagged using an iTRAQ protocol. Proteomic analyses have documented a total of 9 downregulated proteins in PAH skeletal muscles and 10 upregulated proteins compared to healthy subjects. Most of the downregulated proteins were related to mitochondrial structure and function. Focusing on skeletal muscle metabolism and mitochondrial health, PAH patients presented a decreased expression of oxidative enzymes (pyruvate dehydrogenase, p < 0.01) and an increased expression of glycolytic enzymes (lactate dehydrogenase activity, p < 0.05). These findings were supported by abnormal mitochondrial morphology on electronic microscopy, lower citrate synthase activity (p < 0.01) and lower expression of the transcription factor A of the mitochondria (p < 0.05), confirming a more glycolytic metabolism in PAH skeletal muscles. We provide evidences that impaired mitochondrial and metabolic functions found in the lungs and the right ventricle are also present in skeletal muscles of patients. KEY MESSAGE: • Proteomic and metabolic analysis show abnormal oxidative metabolism in PAH skeletal muscle. • EM of PAH patients reveals abnormal mitochondrial structure and distribution. • Abnormal mitochondrial health and function contribute to exercise impairments of PAH. • PAH may be considered a vascular affliction of heart and lungs with major impact on peripheral muscles.

Alternatives to the six-minute walk test in pulmonary arterial hypertension.

INTRODUCTION: The physiological response during the endurance shuttle walk test (ESWT), the cycle endurance test (CET) and the incremental shuttle walk test (ISWT) remains unknown in PAH. We tested the hypothesis that endurance tests induce a near-maximal physiological demand comparable to incremental tests. We also hypothesized that differences in respiratory response during exercise would be related to the characteristics of the exercise tests. METHODS: Within two weeks, twenty-one PAH patients (mean age: 54(15) years; mean pulmonary arterial pressure: 42(12) mmHg) completed two cycling exercise tests (incremental cardiopulmonary cycling exercise test (CPET) and CET) and three field tests (ISWT, ESWT and six-minute walk test (6MWT)). Physiological parameters were continuously monitored using the same portable telemetric device. RESULTS: Peak oxygen consumption (VO(2peak)) was similar amongst the five exercise tests (p = 0.90 by ANOVA). Walking distance correlated markedly with the VO(2peak) reached during field tests, especially when weight was taken into account. At 100% exercise, most physiological parameters were similar between incremental and endurance tests. However, the trends overtime differed. In the incremental tests, slopes for these parameters rose steadily over the entire duration of the tests, whereas in the endurance tests, slopes rose sharply from baseline to 25% of maximum exercise at which point they appeared far less steep until test end. Moreover, cycling exercise tests induced higher respiratory exchange ratio, ventilatory demand and enhanced leg fatigue measured subjectively and objectively. CONCLUSION: Endurance tests induce a maximal physiological demand in PAH. Differences in peak respiratory response during exercise are related to the modality (cycling vs. walking) rather than the progression (endurance vs. incremental) of the exercise tests.

Impaired angiogenesis and peripheral muscle microcirculation loss contribute to exercise intolerance in pulmonary arterial hypertension.

RATIONALE: Pulmonary arterial hypertension (PAH) is characterized by significant exercise intolerance, which is multifactorial and involves skeletal muscle alterations. There is growing evidence that microRNAs (miRs) are involved in PAH pathogenesis. OBJECTIVES: We hypothesized that miR-126, an endothelial-specific, proangiogenic miR, is down-regulated in the peripheral muscles of patients with PAH, which would account for skeletal muscle microcirculation loss and exercise intolerance. MEASUREMENTS AND MAIN RESULTS: Patients with PAH displayed decreases in exercise capacity ([Formula: see text]o2max) and microcirculation loss on quadriceps muscle biopsy (in CD31(+) immunofluorescence experiments) compared to control subjects. Exercise capacity correlated with muscle capillarity (r = 0.84, P < 0.01). At the cellular level, vascular endothelial growth factor (VEGF) and VEGF receptor 2 expression were similar in both groups. Conversely, PAH was associated with a 60% decrease in miR-126 expression in a quantitative reverse transcriptase polymerase chain reaction experiment (P < 0.01), resulting in up-regulation of its targeted protein, Sprouty-related, EVH1 domain-containing protein 1 (SPRED-1), and a marked decrease in the downstream effectors of the VEGF pathway, p-Raf/Raf and p-ERK/ERK, as determined by immunoblot analysis. Using freshly isolated CD31(+) cells from human quadriceps biopsies, we found that the down-regulation of miR-126 in PAH triggered the activation of SPRED-1, impairing the angiogenic response (Matrigel assay). These abnormalities were reversed by treating the PAH cells with miR-126 mimic, whereas inhibition of miR-126 (antagomir) in healthy CD31(+) cells fully mimicked the PAH phenotype. Finally, miR-126 down-regulation in skeletal muscle of healthy rats decreased muscle capillarity in immunofluorescence assays (P < 0.05) and exercise tolerance in treadmill tests (P < 0.05), whereas miR-126 up-regulation increased them in monocrotaline PAH rats. CONCLUSIONS: We demonstrate for the first time that exercise intolerance in PAH is associated with skeletal muscle microcirculation loss and impaired angiogenesis secondary to miR-126 down-regulation.

Signal transduction in the development of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a unique disease. Properly speaking, it is not a disease of the lung. It can be seen more as a microvascular disease occurring mainly in the lungs and affecting the heart. At the cellular level, the PAH paradigm is characterized by inflammation, vascular tone imbalance, pulmonary arterial smooth muscle cell proliferation and resistance to apoptosis and the presence of in situ thrombosis. At a clinical level, the aforementioned abnormal vascular properties alter physically the pulmonary circulation and ventilation, which greatly influence the right ventricle function as it highly correlates with disease severity. Consequently, right heart failure remains the principal cause of death within this cohort of patients. While current treatment modestly improve patients' conditions, none of them are curative and, as of today, new therapies are lacking. However, the future holds potential new therapies that might have positive influence on the quality of life of the patient. This article will first review the clinical presentation of the disease and the different molecular pathways implicated in the pathobiology of PAH. The second part will review tomorrow's future putative therapies for PAH.

The emergence of new therapeutic targets in pulmonary arterial hypertension: from now to the near future.

Pulmonary arterial hypertension (PAH) is a vascular remodeling disease that pathologically increases pulmonary vascular resistance. Ultimately, this leads to right ventricular failure and premature death. Current therapeutic strategies are mainly designed to induce relaxation of the pulmonary arteries, but are not directly aimed to improve vascular remodeling that characterize PAH. Although these treatments modestly improve patient symptoms, pulmonary hemodynamics and survival, none of them are curative and approximately 15% of patients die within 1 year of medical follow-up despite treatment. Within the last 5 years, tremendous advances in our understanding of the PAH pathophysiology have arisen. These advances have a high potential for the development of better patient care by providing novel therapeutic targets. The goal of this report is to review the current PAH treatments, as well as novel therapies that will pave the future in this devastating disease.

Repeatability and responsiveness of exercise tests in pulmonary arterial hypertension.

Exercise tolerance in pulmonary arterial hypertension (PAH) is most commonly assessed by the 6-min walk test (6MWT). Whether endurance exercise tests are more responsive than the 6MWT remains unknown. 20 stable PAH patients (mean±sd age 53±15 years and mean pulmonary arterial pressure 44±16 mmHg) already on PAH monotherapy completed the 6MWT, the endurance shuttle walk test (ESWT) and the cycle endurance test (CET) before and after the addition of sildenafil citrate 20 mg three times daily or placebo for 28 days in a randomised double-blind crossover setting. Pre- or post-placebo tests were used to assess repeatability of each exercise test, whereas pre- or post-sildenafil citrate tests were used to assess their responsiveness. Sildenafil citrate led to placebo-corrected changes in exercise capacity of 18±25 m (p = 0.02), 58±235 s (p = 0.58) and 29±77 s (p = 0.09) for the 6MWT, the ESWT and the CET, respectively. The 6MWT was associated with a lower coefficient of variation between repeated measures (3% versus 18% versus 13%), resulting in a higher standardised response mean compared with endurance tests (0.72, 0.25 and 0.38 for the 6MWT, the ESWT and the CET, respectively). The 6MWT had the best ability to capture changes in exercise capacity when sildenafil citrate was combined with patients' baseline monotherapy, supporting its use as an outcome measure in PAH.

The incidence of behaviours associated with body checking among youth ice hockey players.

OBJECTIVES: To determine if a difference exists between the incidence and intensity of the physical contacts of Pee Wee (aged 11-12 years) ice hockey players according to whether the players participate in a league in which body checking is permitted (Calgary, Canada) compared to a league in which body checking is not permitted (Québec City, Canada). DESIGN: Cohort study conducted in Québec City and Calgary during the 2007-2008 Pee Wee ice hockey season. METHODS: Ten games were randomly selected for each city (n=20) and analysed. Games were videotaped and subsequently analysed with a validated observation system allowing quantification of the intensity of the various physical contacts. Incidence rate ratios (RR) based on multivariate Poisson regression were used to compare the physical contacts between provinces. All analyses were controlling for game period, score difference, and zone on the playing surface. RESULTS: A total of 2418 physical contacts with the trunk and 757 other physical contacts were observed. Very light intensity trunk physical contacts were more frequent in Québec City (adjusted incidence RR [ARR]: 0.68; 95% CI: 0.48-0.97). Very high intensity trunk physical contacts were more frequent in Calgary (ARR: 12.72; 95% CI: 4.48-36.14). Hooking (ARR: 0.89; 95% CI: 0.84-0.95) and slashing (ARR: 0.91; 95% CI: 0.85-0.97) were more frequent in Québec City. CONCLUSIONS: Results suggest that players' behaviours are different in leagues where body checking is permitted compared to leagues where it is not permitted. Policy allowing body checking in Pee Wee ice hockey increases the frequency and intensity of physical contacts.

Assessment of daily life physical activities in pulmonary arterial hypertension.

BACKGROUND: In pulmonary arterial hypertension (PAH), the six-minute walk test (6MWT) is believed to be representative of patient's daily life physical activities (DL(PA)). Whether DL(PA) are decreased in PAH and whether the 6MWT is representative of patient's DL(PA) remain unknown. METHODS: 15 patients with idiopathic PAH (IPAH) and 10 patients with PAH associated with limited systemic sclerosis (PAH-SSc) were matched with 15 healthy control subjects and 10 patients with limited systemic sclerosis without PAH. Each subject completed a 6MWT. The mean number of daily steps and the mean energy expenditure and duration of physical activities >3 METs were assessed with a physical activity monitor for seven consecutive days and used as markers of DL(PA). RESULTS: The mean number of daily steps and the mean daily energy expenditure and duration of physical activities >3 METs were all reduced in PAH patients compared to their controls (all p<0.05). The mean number of daily steps correlated with the 6MWT distance for both IPAH and PAH-SSc patients (r = 0.76, p<0.01 and r = 0.85, p<0.01), respectively. CONCLUSION: DL(PA) are decreased in PAH and correlate with the 6MWT distance. Functional exercise capacity may thus be a useful surrogate of DL(PA) in PAH.