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Compromised Cerebrovascular Regulation and Cerebral Oxygenation in Pulmonary Arterial Hypertension.

ABSTRACT: 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.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).These findings provide comprehensive evidence for physiologically and clinically relevant impairments in cerebral hemodynamic regulation and oxygenation in PAH.

SUBMITTER: Malenfant S

PROVIDER: S-EPMC5721836 | biostudies-other | 2017 Oct

REPOSITORIES: biostudies-other

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Compromised Cerebrovascular Regulation and Cerebral Oxygenation in Pulmonary Arterial Hypertension.

Malenfant Simon S Brassard Patrice P Paquette Myriam M Le Blanc Olivier O Chouinard Audrey A Nadeau Valérie V Allan Philip D PD Tzeng Yu-Chieh YC Simard Sébastien S Bonnet Sébastien S Provencher Steeve S

Journal of the American Heart Association 20171012 10

<h4>Background</h4>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.<h4>Methods and results</h4>Resting mean flow velocity in the middle cerebral artery mean flow velo ...[more]

PMID: 29025748

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Project description: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 (?cTOI) and cerebral deoxyhemoglobin (?cHHb); 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, ?cTOI 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 ?cTOI 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.

Project description:BackgroundMetabolic alterations provide substrates that influence chromatin structure to regulate gene expression that determines cell function in health and disease. Heightened proliferation of smooth muscle cells (SMC) leading to the formation of a neointima is a feature of pulmonary arterial hypertension (PAH) and systemic vascular disease. Increased glycolysis is linked to the proliferative phenotype of these SMC.MethodsRNA sequencing was applied to pulmonary arterial SMC (PASMC) from PAH patients with and without a BMPR2 (bone morphogenetic receptor 2) mutation versus control PASMC to uncover genes required for their heightened proliferation and glycolytic metabolism. Assessment of differentially expressed genes established metabolism as a major pathway, and the most highly upregulated metabolic gene in PAH PASMC was aldehyde dehydrogenase family 1 member 3 (ALDH1A3), an enzyme previously linked to glycolysis and proliferation in cancer cells and systemic vascular SMC. We determined if these functions are ALDH1A3-dependent in PAH PASMC, and if ALDH1A3 is required for the development of pulmonary hypertension in a transgenic mouse. Nuclear localization of ALDH1A3 in PAH PASMC led us to determine whether and how this enzyme coordinately regulates gene expression and metabolism in PAH PASMC.ResultsALDH1A3 mRNA and protein were increased in PAH versus control PASMC, and ALDH1A3 was required for their highly proliferative and glycolytic properties. Mice with Aldh1a3 deleted in SMC did not develop hypoxia-induced pulmonary arterial muscularization or pulmonary hypertension. Nuclear ALDH1A3 converted acetaldehyde to acetate to produce acetyl coenzyme A to acetylate H3K27, marking active enhancers. This allowed for chromatin modification at NFYA (nuclear transcription factor Y subunit α) binding sites via the acetyltransferase KAT2B (lysine acetyltransferase 2B) and permitted NFY-mediated transcription of cell cycle and metabolic genes that is required for ALDH1A3-dependent proliferation and glycolysis. Loss of BMPR2 in PAH SMC with or without a mutation upregulated ALDH1A3, and transcription of NFYA and ALDH1A3 in PAH PASMC was β-catenin dependent.ConclusionsOur studies have uncovered a metabolic-transcriptional axis explaining how dividing cells use ALDH1A3 to coordinate their energy needs with the epigenetic and transcriptional regulation of genes required for SMC proliferation. They suggest that selectively disrupting the pivotal role of ALDH1A3 in PAH SMC, but not endothelial cells, is an important therapeutic consideration.

Dataset Information

Compromised Cerebrovascular Regulation and Cerebral Oxygenation in Pulmonary Arterial Hypertension.

Publications

Compromised Cerebrovascular Regulation and Cerebral Oxygenation in Pulmonary Arterial Hypertension.

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