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The baroreflex integrity in early-stage pulmonary arterial hypertension (PAH) remains uninvestigated. A potential baroreflex impairment could be functionally relevant and possibly mediated by enhanced peripheral chemoreflex activity. Thus, we investigated 1) the cardiac baroreflex in nonhypoxemic PAH; 2) the association between baroreflex indexes and peak aerobic capacity [i.e., peak oxygen consumption (Vo2peak)]; and 3) the peripheral chemoreflex contribution to the cardiac baroreflex. Nineteen patients and 13 age- and sex-matched healthy adults (HA) randomly inhaled either 100% O2 (peripheral chemoreceptor inhibition) or 21% O2 (control session) while at rest and during a repeated sit-to-stand maneuver. Beat-by-beat analysis of R-R intervals and systolic blood pressure provided indexes of cardiac baroreflex sensitivity (cBRS) and effectiveness (cBEI). The PAH group had lower cBEI for all sequences (cBEIALL) at rest [means ± SD: PAH = 0.5 ± 0.2 vs. HA = 0.7 ± 0.1 arbitrary units (a.u.), P = 0.02] and lower cBRSALL (PAH = 6.8 ± 7.0 vs. HA = 9.7 ± 5.0 ms·mmHg-1, P < 0.01) and cBEIALL (PAH = 0.4 ± 0.2 vs. HA= 0.6 ± 0.1 a.u., P < 0.01) during the sit-to-stand maneuver versus the HA group. The cBEI during the sit-to-stand maneuver was independently correlated to Vo2peak (partial r = 0.45, P < 0.01). Hyperoxia increased cBRS and cBEI similarly in both groups at rest and during the sit-to-stand maneuver. Therefore, cardiac baroreflex dysfunction was observed under spontaneous and, most notably, provoked blood pressure fluctuations in nonhypoxemic PAH, was not influenced by the peripheral chemoreflex, and was associated with lower Vo2peak, suggesting that it could be functionally relevant. [ABSTRACT FROM AUTHOR]

Background and objective: Peak oxygen consumption (pVO2), determined from CPET, provides a valuable indication of PAH severity and patient prognosis. However, CPET is often contraindicated in severe PAH and frequently terminated prior to achievement of a sufficient exercise effort. We sought to determine whether in PAH low‐intensity [i.e. freewheeling exercise (FW)] exercise reveals abnormal VE/VCO2 and PETCO2 responses that are associated with pVO2 and serve as indices of PAH risk stratification and mortality. Methods: Retrospective analysis of CPET from 97 PAH patients and 20 age‐matched controls was undertaken. FW VE/VCO2 and PETCO2 were correlated with pVO2% age‐predicted. Prognostication analysis was conducted using pVO2 > 65% age‐predicted, as known to represent a low mortality risk. Primary outcome was mortality from any cause. Results: FW PETCO2 was correlated with pVO2 (P < 0.0001; r = 0.52), while FW VE/VCO2 was not (P = 0.13; r = −0.16). ROC curve analyses showed that FW PETCO2 (AUC = 0.659), but not FW VE/VCO2 (AUC = 0.587), provided predictive information identifying pVO2 > 65% age‐predicted (best cut‐off value of 28 mm Hg). By Cox analysis, FW PETCO2 < 28 mm Hg remained a predictor of mortality after adjusting for age and PAH aetiology (HR: 2.360, 95% CI: 1.144–4.866, P = 0.020). Conclusion: Low PETCO2 during FW is associated with reduced pVO2 in PAH and provides predictive information for PAH risk stratification and prognostication. [ABSTRACT FROM AUTHOR]

Key points: Dysfunction of post‐exercise cardiac autonomic control is associated with increased mortality risk in healthy adults and in patients with cardiorespiratory diseases.The afferent mechanisms that regulate the post‐exercise cardiac autonomic control remain unclear.We found that afferent signals from carotid chemoreceptors restrain the post‐exercise cardiac autonomic control in healthy adults and patients with pulmonary arterial hypertension (PAH).Patients with PAH had higher carotid chemoreflex sensitivity, and the magnitude of carotid chemoreceptor restraint of autonomic control was greater in patients with PAH as compared to healthy adults.The results demonstrate that the carotid chemoreceptors contribute to the regulation of post‐exercise cardiac autonomic control, and suggest that the carotid chemoreceptors may be a potential target to treat post‐exercise cardiac autonomic dysfunction in patients with PAH. Dysfunction of post‐exercise cardiac autonomic control predicts mortality, but its underlying mechanisms remain unclear. We tested whether carotid chemoreflex activity restrains post‐exercise cardiac autonomic control in healthy adults (HA), and whether such restraint is greater in patients with pulmonary arterial hypertension (PAH) who may have both altered carotid chemoreflex and altered post‐exercise cardiac autonomic control. Twenty non‐hypoxaemic patients with PAH and 13 age‐ and sex‐matched HA pedalled until 90% of peak work rate observed in a symptom‐limited ramp‐incremental exercise test. Recovery consisted of unloaded pedalling for 5 min followed by seated rest for 6 min. During recovery, subjects randomly inhaled either 100% O2 (hyperoxia) to inhibit the carotid chemoreceptor activity, or 21% O2 (normoxia) as control. Post‐exercise cardiac autonomic control was examined via heart rate (HR) recovery (HRR; HR change after 30, 60, 120 and 300 s of recovery, using linear and non‐linear regressions of HR decay) and HR variability (HRV; time and spectral domain analyses). As expected, the PAH group had higher carotid chemosensitivity and worse post‐exercise HRR and HRV than HA. Hyperoxia increased HRR at 30, 60 and 120 s and absolute spectral power HRV in both groups. Additionally, hyperoxia resulted in an accelerated linear HR decay and increased time domain HRV during active recovery only in the PAH group. In conclusion, the carotid chemoreceptors restrained recovery of cardiac autonomic control from exercise in HA and in patients with PAH, with the restraint greater for some autonomic indexes in patients with PAH. Key points: Dysfunction of post‐exercise cardiac autonomic control is associated with increased mortality risk in healthy adults and in patients with cardiorespiratory diseases.The afferent mechanisms that regulate the post‐exercise cardiac autonomic control remain unclear.We found that afferent signals from carotid chemoreceptors restrain the post‐exercise cardiac autonomic control in healthy adults and patients with pulmonary arterial hypertension (PAH).Patients with PAH had higher carotid chemoreflex sensitivity, and the magnitude of carotid chemoreceptor restraint of autonomic control was greater in patients with PAH as compared to healthy adults.The results demonstrate that the carotid chemoreceptors contribute to the regulation of post‐exercise cardiac autonomic control, and suggest that the carotid chemoreceptors may be a potential target to treat post‐exercise cardiac autonomic dysfunction in patients with PAH. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is associated with increased right ventricular (RV) afterload, RV dysfunction and decreased peak oxygen uptake (pVO 2). However, the pulmonary hemodynamic mechanisms measured by exercise right heart catheterization (RHC) that contribute to reduced pVO 2 in idiopathic PAH (IPAH) are not completely characterized. Therefore, we sought to evaluate the exercise RHC determinants of pVO 2 in patients with IPAH. 519 consecutive patients with suspected and/or confirmed pulmonary hypertension were prospectively screened to identify 20 patients with IPAH. All IPAH patients were prospectively evaluated with resting and exercise RHC and cardiopulmonary exercise testing. 85% of the patients were female; the median age was 34[29–42] years old. At peak exercise, mean pulmonary arterial (PA) pressure was 76 ± 17 mmHg, PA wedge pressure was 14 ± 5 mmHg, cardiac output (CO) was 5.7 ± 1.9 L/min, pulmonary vascular resistance was 959 ± 401 dynes/s/cm5 and PA compliance was 0.9[0.6–1.2] ml/mmHg. On univariate analysis, pVO2 positively correlated to peak CO, peak cardiac index, peak stroke volume index, peak RV stroke work index (RVSWI) and peak oxygen saturation. There was a negative correlation between pVO 2 and Δ (rest to peak change) PA compliance. In age-adjusted multivariate model, peak RVSWI (Coefficient = 0.15, Beta = 0.63, 95% CI [0.07–0.22], p < 0.01) and ΔPA compliance (Coefficient = −2.51, Beta = −0.43, 95% CI [−4.34-(−0.68)], p = 0.01) had the best performance predicting pVO 2 (R2 = 0.66). In conclusion, a load dependent measurement of RV function (RVSWI) and the pulsatile component of RV afterload (ΔPA compliance) significantly influence pVO 2 in IPAH, further highlighting the pivotal role of hemodynamic coupling to IPAH exercise capacity. • The dynamic interplay between pulmonary vascular reserve, RV performance and pVO 2 remains incompletely characterized in idiopathic PAH. • Reduced pulmonary vascular reserve and decreased exercise RV work impact pVO 2 in idiopathic PAH. • The findings point to the central role of load dependent measures of RV function and pulsatile RV afterload to idiopathic PAH exercise capacity. • The findings further highlight the pivotal role of hemodynamic coupling in determining exercise capacity in idiopathic PAH patients. [ABSTRACT FROM AUTHOR]

Hypocapnia and endothelial dysfunction might impair microvascular cerebral blood flow (CBF micr ) and cerebrovascular reactivity to CO 2 (CVR CO2 ). Pulmonary arterial hypertension (PAH) is characteristically associated with chronic alveolar hyperventilation and microvascular endothelial dysfunction. We therefore determined CBF micr (pre-frontal blood flow index (BFI) by the indocyanine green-near infrared spectroscopy methodology) during hypocapnia and hypercapnia in 25 PAH patients and 10 gender- and age-matched controls. Cerebral BFI was lower in patients than controls at similar transcutaneous PCO 2 (P tc CO 2 ) levels in both testing conditions. In fact, while BFI increased from hypocapnia to hypercapnia in all controls, it failed to increase in 17/25 (68%) patients. Thus, BFI increased to a lesser extent from hypo to hypercapnia (“Δ”) in patients, i.e., they showed lower Δ BFI/Δ P tc CO 2 ratios than controls. In conclusion, CBF micr and CVR CO2 are lessened in clinically stable, mildly-impaired patients with PAH. These abnormalities might be associated with relevant clinical outcomes (hyperventilation and dyspnea, cognition, cerebrovascular disease) being potentially amenable to pharmacological treatment. [ABSTRACT FROM AUTHOR]