Simon Malenfant

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 patients daily life physical activities (DLPA). Whether DLPA are decreased in PAH and whether the 6MWT is representative of patients DLPA 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 DLPA. 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 DLPA are decreased in PAH and correlate with the 6MWT distance. Functional exercise capacity may thus be a useful surrogate of DLPA in PAH.

Skeletal muscle proteomic signature and metabolic impairment in pulmonary hypertension.

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.

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.

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.

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.

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 (VO2peak) was similar amongst the five exercise tests (p = 0.90 by ANOVA). Walking distance correlated markedly with the VO2peak 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.

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.

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 CO 2, 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 CO 2, 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 CO 2 was reduced (P=0.03), whereas central chemoreceptor sensitivity was increased in PAH (P<0.01), the latter correlating with increased resting ventilation (R 2=0.47; P<0.05) and the exercise ventilation/CO2 production slope (V˙E/V˙CO2 slope; R 2=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 (R 2=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.

β-blockers in pulmonary arterial hypertension: generation might matter.

We read with great interest the article from Bandyopadhyay et al. [1] regarding the outcomes of β-blockers use in pulmonary arterial hypertension (PAH). This study adds another piece in the very controversial debate opposing pro- and anti-supporters of β-blockers use in PAH. In this study, patients had idiopathic PAH (IPAH) or connective tissue disease-associated PAH. PAH patients receiving β-blockers had a similar survival and time to clinical worsening events compared with patients not receiving them. Functional outcomes were similar, although β-blocker use was associated with a tendency towards shorter walking distance. Malenfant and Perros discuss the potential usefulness of third generation β-blockers in pulmonary hypertension http://ow.ly/VKMFn