Compromised Cerebrovascular Regulation and Cerebral Oxygenation in Pulmonary Arterial Hypertension

Abstract

BackgroundFunctional 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 ResultsResting 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 (trueV˙normalE/normalV˙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).ConclusionsThese findings provide comprehensive evidence for physiologically and clinically relevant impairments in cerebral hemodynamic regulation and oxygenation in PAH.

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

“…Care was taken to recruit healthy women using similar contraceptive measures as their paired PAH counterpart. Although this study was part of a larger study that examined the influence of PAH on key determinants and exercise‐induced changes in CBF and oxygenation at rest and during an incremental cycling protocol to exhaustion (Malenfant et al, 2017), the current study addressed an experimental question determined a priori. Participants were instructed to refrain from exercise, alcohol, caffeine consumption, and heavy meal 12 hr prior to experimental testing.…”

“…Participants reported to the laboratory 48 hr after completion of the main protocol (refer to [Malenfant et al, 2017]) to perform a cycling endurance test on an electromagnetically braked ergocycle (Lode BV Corival, Groningen, The Netherlands) according to the current guidelines (American Thoracic & American College of Chest, 2003). Following a 5‐min rest period and 1 min of unloaded pedaling, the endurance cycling protocol was initiated at 75% of the maximal work rate achieved during the incremental cardiopulmonary exercise test (Malenfant et al, 2017). Patients were instructed to cycle at a minimum cadence of 60 rpm.…”

“…Most PAH patients’ complaints refer to exertional dyspnea. While the neurophysiology of dyspnea has yet to be explained in PAH, several lines of evidence suggest that lower prefrontal oxygenation recently described in these patients during incremental exercise testing (Malenfant et al, 2017; Muller‐Mottet et al, 2015) could be involved. Indeed, based on the multichannel near‐infrared spectroscopy (NIRS) technique, Higashimoto et al demonstrated that exertional dyspnea was associated with both prefrontal and premotor cortex overactivation in chronic obstructive pulmonary disease (COPD) patients (Higashimoto et al, 2011, 2015).…”

“…As such, it is now recognized that skeletal muscle impairments contribute to exercise intolerance, including weakness (Bauer et al, 2007; Mainguy et al, 2010), poor capillary density and oxygenation (Malenfant, Potus, Mainguy, et al, 2015; Potus et al, 2014), and poor mitochondrial oxidative phosphorylation and metabolism (Batt, Ahmed, Correa, Bain, & Granton, 2014; Malenfant, Potus, Fournier, et al, 2015). Recent studies have also proposed impaired cerebral blood flow (CBF) (Malenfant et al, 2017) and oxygenation (Malenfant et al, 2017; Muller‐Mottet et al, 2015) as limiting factors for maximal exercise capacity in these patients.…”

“…Indeed, based on the multichannel near‐infrared spectroscopy (NIRS) technique, Higashimoto et al demonstrated that exertional dyspnea was associated with both prefrontal and premotor cortex overactivation in chronic obstructive pulmonary disease (COPD) patients (Higashimoto et al, 2011, 2015). Prefrontal oxygenation during incremental exercise to exhaustion also correlated with exercise capacity in PAH (Malenfant et al, 2017). However, dyspnea is most commonly reported at submaximal exercise level in PAH (Mainguy, Provencher, Maltais, Malenfant, & Saey, 2011).…”