Central and peripheral chemoreflexes in humans with treated hypertension.

Increased peripheral chemoreflex sensitivity is a pathogenic feature of human hypertension (HTN), while both central and peripheral chemoreflex sensitivities are reportedly augmented in animal models of HTN. Herein, we tested the hypothesis that both central and combined central and peripheral chemoreflex sensitivities are augmented in HTN. Fifteen HTN participants (68 ± 5 years; mean ± SD) and 13 normotensives (NT; 65 ± 6 years) performed two modified rebreathing protocols in which the partial pressure of end-tidal carbon dioxide ( P ETC O 2 ${P_{{\rm{ETC}}{{\rm{O}}_2}}}$ ) progressively increased while the partial pressure of end-tidal oxygen was clamped at either 150 mmHg (isoxic hyperoxia; central chemoreflex activation) or 50 mmHg (isoxic hypoxia; combined central and peripheral chemoreflex activation). Ventilation ( V ̇ E ${\dot{V}}_{\rm{E}}$ ; pneumotachometer) and muscle sympathetic nerve activity (MSNA; microneurography) were recorded, and ventilatory ( V ̇ E ${\dot{V}}_{\rm{E}}$ vs. P ETC O 2 ${P_{{\rm{ETC}}{{\rm{O}}_2}}}$  slope) and sympathetic (MSNA vs. P ETC O 2 ${P_{{\rm{ETC}}{{\rm{O}}_2}}}$ slope) chemoreflex sensitivities and recruitment thresholds (breakpoint) were calculated. Global cerebral blood flow (gCBF; duplex Doppler) was measured, and the association with chemoreflex responses was examined. Central ventilatory and sympathetic chemoreflex sensitivities were greater in HTN than NT (2.48 ± 1.33 vs. 1.58 ± 0.42 L min-1  mmHg-1 , P = 0.030: 3.32 ± 1.90 vs. 1.77 ± 0.62 a.u. mmHg-1 , P = 0.034, respectively), while recruitment thresholds were not different between groups. HTN and NT had similar combined central and peripheral ventilatory and sympathetic chemoreflex sensitivities and recruitment thresholds. A lower gCBF was associated with an earlier recruitment threshold for V ̇ E ${\dot{V}}_{\rm{E}}$ (R2  = 0.666, P < 0.0001) and MSNA (R2  = 0.698, P = 0.004) during isoxic hyperoxic rebreathing. These findings indicate that central ventilatory and sympathetic chemoreflex sensitivities are augmented in human HTN and perhaps suggest that targeting the central chemoreflex may help some forms of HTN. KEY POINTS: In human hypertension (HTN) increased peripheral chemoreflex sensitivity has been identified as a pathogenic feature, and in animal models of HTN, both central and peripheral chemoreflex sensitivities are reportedly augmented. In this study, the hypothesis was tested that both central and combined central and peripheral chemoreflex sensitivities are augmented in human HTN. We observed that both central ventilatory and sympathetic chemoreflex sensitivities were augmented in HTN compared to age-matched normotensive controls, but no difference was found in the combined central and peripheral ventilatory and sympathetic chemoreflex sensitivities. During central chemoreflex activation, the ventilatory and sympathetic recruitment thresholds were lower in those with lower total cerebral blood flow. These results indicate a potential contributory role of the central chemoreceptors in the pathogenesis of human HTN and support the possibility that therapeutic targeting of the central chemoreflex may help some forms of HTN.

Venous capacity and compliance in hypertensive adults: influence of hypoxia and hyperoxia.

In hypertension, the cardiorespiratory responses to peripheral chemoreflex activation (hypoxia) and inactivation (hyperoxia) are reportedly augmented, but the impact on peripheral venous function is unknown. We tested the hypothesis that in hypertensives, both hypoxia and hyperoxia evoke more pronounced changes in lower limb venous capacity and compliance, than in age-matched normotensives. In 10 hypertensive [HTN: 7 women; age: 71.7 ± 3.7 yr, mean blood pressure (BP): 101 ± 10 mmHg, mean ± SD] and 11 normotensive (NT: 6 women; age: 67.7 ± 8.0 yr, mean BP 89 ± 11 mmHg) participants, great saphenous vein cross-sectional area (GSV CSA; Doppler ultrasound) was measured during a standard 60 mmHg thigh cuff inflation-deflation protocol. Separate conditions of room air, hypoxia [fraction of inspired oxygen ([Formula: see text]): 0.10] and hyperoxia ([Formula: see text]: 0.50) were tested. In HTN, GSV CSA was decreased in hypoxia (5.6 ± 3.7 mm2, P = 0.041) compared with room air (7.3 ± 6.9 mm2), whereas no change was observed with hyperoxia (8.0 ± 9.1 mm2, P = 0.988). In NT, no differences in GSV CSA were observed between any condition (P = 0.299). Hypoxia enhanced GSV compliance in HTN (-0.0125 ± 0.0129 vs. -0.0288 ± 0.0090 mm2·100 mm2·mmHg-1, room air vs. hypoxia, respectively; P = 0.004), but it was unchanged in NT (-0.0139 ± 0.0121 vs. -0.0093 ± 0.0066 mm2·100 mm2·mmHg-1, room air vs. hypoxia, respectively; P < 0.541). Venous compliance was unaltered with hyperoxia in both groups (P < 0.05). In summary, compared with NT, hypoxia elicits a decrease in GSV CSA and enhanced GSV compliance in HTN, indicating enhanced venomotor responsiveness to hypoxia.NEW & NOTEWORTHY Hypertension remains a significant global health problem. Although hypertension research and therapies are keenly focused on the heart and arterial circulation, the venous circulation has been neglected comparatively. We determined whether hypoxia, known to cause peripheral chemoreflex activation, evoked more pronounced changes in lower limb venous capacity and compliance in hypertensives (HTN) than in age-matched normotensives (NT). We found that hypoxia reduced venous capacity in the great saphenous vein in HTN and increased its compliance twofold. However, hypoxia did not affect venous function in NT. Our data indicate the venomotor response to hypoxia is enhanced in hypertension, and this may contribute to the hypertensive state.

Sex differences in the sympathetic neurocirculatory responses to chemoreflex activation.

The purpose of this study was to determine whether there are sex differences in the cardiorespiratory and sympathetic neurocirculatory responses to central, peripheral, and combined central and peripheral chemoreflex activation. Ten women (29 ± 6 years, 22.8 ± 2.4 kg/m2 : mean ± SD) and 10 men (30 ± 7 years, 24.8 ± 3.2 kg/m2 ) undertook randomized 5 min breathing trials of: room air (eucapnia), isocapnic hypoxia (10% oxygen (O2 ); peripheral chemoreflex activation), hypercapnic hyperoxia (7% carbon dioxide (CO2 ), 50% O2 ; central chemoreflex activation) and hypercapnic hypoxia (7% CO2 , 10% O2 ; central and peripheral chemoreflex activation). Control trials of isocapnic hyperoxia (peripheral chemoreflex inhibition) and hypocapnic hyperoxia (central and peripheral chemoreflex inhibition) were also included. Muscle sympathetic nerve activity (MSNA; microneurography), mean arterial pressure (MAP; finger photoplethysmography) and minute ventilation ( V̇$\dot{\rm{V}}$E ; pneumotachometer) were measured. Total MSNA (P = 1.000 and P = 0.616), MAP (P = 0.265) and V̇$\dot{\rm{V}}$E (P = 0.587 and P = 0.472) were not different in men and women during eucapnia and during isocapnic hypoxia. Women exhibited attenuated increases in V̇$\dot{\rm{V}}$E during hypercapnic hyperoxia (27.3 ± 6.3 vs. 39.5 ± 7.5 l/min, P < 0.0001) and hypercapnic hypoxia (40.9 ± 9.1 vs. 53.8 ± 13.3 l/min, P < 0.0001) compared with men. However, total MSNA responses were augmented in women (hypercapnic hyperoxia 378 ± 215 vs. 258 ± 107%, P = 0.017; hypercapnic hypoxia 607 ± 290 vs. 362 ± 268%, P < 0.0001). No sex differences in total MSNA, MAP or V̇$\dot{\rm{V}}$E were observed during isocapnic hyperoxia and hypocapnic hyperoxia. Our results indicate that young women have augmented sympathetic responses to central chemoreflex activation, which explains the augmented MSNA response to combined central and peripheral chemoreflex activation. KEY POINTS: Sex differences in the control of breathing have been well studied, but whether there are differences in the sympathetic neurocirculatory responses to chemoreflex activation between healthy women and men is incompletely understood. We observed that, compared with young men, young women displayed augmented increases in muscle sympathetic nerve activity during both hypercapnic hyperoxia (central chemoreflex activation) and hypercapnic hypoxia (central and peripheral chemoreflex activation) but had attenuated increases in minute ventilation. In contrast, no sex differences were found in either muscle sympathetic nerve activity or minute ventilation responses to isocapnic hypoxia (peripheral chemoreceptor stimulation). Young women have blunted ventilator, but augmented sympathetic responses, to central (hypercapnic hyperoxia) and combined central and peripheral chemoreflex activation (hypercapnic hypoxia), compared with young men. The possible causative association between the reduced ventilation and heightened sympathetic responses in young women awaits validation.

Effects of hypoxia and hyperoxia on venous capacity and compliance in healthy men and women.

Blood oxygen is an important modulator of arterial function, but its impact on peripheral venous function is incompletely understood. Herein, we sought to determine the effect of hypoxia and hyperoxia on venous capacity and compliance in the lower limb. In 16 healthy individuals (7 women; age: 28.3 ± 7.6 yr, mean ± SD), we assessed peripheral oxygen saturation ([Formula: see text]), the cross-sectional area (CSA) of the great saphenous vein (GSV; Doppler ultrasound), and calf volume (strain-gauge plethysmography) during a standard 60 mmHg thigh cuff inflation-deflation protocol. Separate trials were undertaken during breathing of room air, hypoxia [fraction in inspired oxygen ([Formula: see text]): 0.10], and hyperoxia ([Formula: see text]: 0.50), according to a single-blinded, randomized design. Lower limb pressure-CSA and pressure-volume relationships were modeled using a quadratic regression equation and compliance derived. [Formula: see text] was decreased by hypoxia (83.6 ± 5.6%) and increased by hyperoxia (98.7 ± 0.5%) compared with room air (96.4 ± 1.0%, P < 0.001). Compared with room air (17.0 ± 7.9 mm2), hypoxia decreased GSV CSA (13.4 ± 5.7 mm2, P < 0.001), whereas no change was observed with hyperoxia (17.1 ± 8.7 mm2, P = 0.883). GSV compliance derived from the pressure-CSA relationships was elevated approximately twofold with hyperoxia (-0.0061 ± 0.0046 a.u.) when compared with room air (-0.0029 ± 0.002 a.u., P = 0.027) and hypoxia (-0.0030 ± 0.0032 a.u., P = 0.007). No differences were observed in calf pressure-volume parameters with either hypoxia or hyperoxia (P > 0.05). Our data indicate that GSV capacity is reduced by hypoxia, and that GSV compliance is increased by hyperoxia, thus highlighting the often overlooked role of oxygen in the regulation of venous circulation.

Increased muscle sympathetic nerve activity and impaired baroreflex control in isolated REM-sleep behavior disorder.

OBJECTIVE: Changes in baroreflex sensitivity have been reported in patients with idiopathic Parkinson's disease (PD). We sought to investigate the hypothesis that patients with isolated rapid eye movement (REM)-sleep behavior disorder (iRBD), known to be a prodromal stage for PD, will show abnormalities in baroreflex control. METHODS: Ten iRBD patients were compared to 10 sex- and age-matched healthy controls. Their cardiovascular parameters and muscle sympathetic nerve activity (MSNA) were evaluated at rest and during baroreflex stimulation. RESULTS: MSNA at rest was higher in iRBD patients (burst frequency [BF]: 44 ± 3 bursts/min; burst incidence [BI]: 60 ± 8 bursts/100 heartbeats) as compared to the controls (BF: 29 ± 3 bursts/min, p < 0.001; BI: 43 ± 9 bursts/100 heartbeats, p < 0.001). During baroreflex stimulation, iRBD patients showed increased absolute values of MSNA (BF: F = 62.728; p < 0.001; BI: F = 16.277; p < 0.001) as compared to the controls. The iRBD patients had decreased diastolic blood pressure at baseline and during lower body negative pressure, but the level of significance was not met. CONCLUSION: Our study shows increased MSNA and impaired baroreflex control in iRBD patients. We propose that the inhibitory effect of locus coeruleus on baroreflex function might be impaired, leading to the disinhibition of sympathetic outflow. SIGNIFICANCE: These findings might reflect the destruction of brain areas due to the ascending P-α-synuclein deposits in iRBD patients.

Clinical utility of ventilatory and gas exchange evaluation during low-intensity exercise for risk stratification and prognostication in pulmonary arterial hypertension.

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 PET CO2 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 PET CO2 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 PET CO2 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 PET CO2 (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 PET CO2 < 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 PET CO2 during FW is associated with reduced pVO2 in PAH and provides predictive information for PAH risk stratification and prognostication.

Characterization of Cardiopulmonary Exercise Testing Variables in Patients with Endomyocardial Fibrosis after Endocardial Resection / Caracterização das Variáveis do Teste de Esforço Cardiopulmonar em Pacientes com Endomiocardiofibrose após Cirurgia de Ressecção Endocárdica

Abstract Background: Endomyocardial fibrosis (EMF) is a rare disease, characterized by diastolic dysfunction which leads to reduced peak oxygen consumption (VO2). Cardiopulmonary exercise testing (CPET) has been proved to be a fundamental tool to identify central and peripheral alterations. However, most studies prioritize peak VO2 as the main variable, leaving aside other important CPET variables that can specify the severity of the disease and guide the clinical treatment. Objective: The aim of this study was to evaluate central and peripheral limitations in symptomatic patients with EMF by different CPET variables. Methods: Twenty-six EMF patients (functional class III, NYHA) were compared with 15 healthy subjects (HS). Functional capacity was evaluated using CPET and diastolic and systolic functions were evaluated by echocardiography. Results: Age and gender were similar between EMF patients and HS. Left ventricular ejection fraction was normal in EMF patients, but decreased compared to HS. Peak heart rate, peak workload, peak VO2, peak oxygen (O2) pulse and peak pulmonary ventilation (VE) were decreased in EMF compared to HS. Also, EMF patients showed increased Δ heart rate /Δ oxygen uptake and Δ oxygen uptake /Δ work rate compared to HS. Conclusion: Determination of the aerobic capacity by noninvasive respiratory gas exchange during incremental exercise provides additional information about the exercise tolerance in patients with EMF. The analysis of different CPET variables is necessary to help us understand more about the central and peripheral alterations cause by both diastolic dysfunction and restrictive pattern.

Resumo Fundamento: A endomiocardiofibrose (EMF) é uma doença rara, caracterizada por disfunção diastólica que leva à redução consumo de oxigênio (VO2) pico. O teste de esforço cardiopulmonar (TECP) tem se mostrado uma ferramenta fundamental na identificação de alterações centrais e periféricas. No entanto, a maioria dos estudos prioriza o VO2 pico como a variável principal, em detrimento de outras importantes variáveis do TECP que poderiam identificar a gravidade da doença e direcionar o tratamento clínico. Objetivo: O objetivo deste estudo foi avaliar limitações centrais e periféricas em pacientes com EMF sintomáticos por meio de variáveis do TECP. Métodos: Vinte e seis pacientes com EMF (classe funcional III, NYHA) foram comparados com 15 indivíduos controle saudáveis (CS). A capacidade funcional foi avaliada por TECP e funções sistólicas e diastólicas por ecocardiografia. Resultados: A idade e o gênero foram similares entre pacientes com EMF e CS. A fração de ejeção do ventrículo esquerdo foi normal em pacientes com EMF, porém diminuída em comparação aos CS. Os picos de frequência cardíaca, carga de trabalho, VO2, pulso de oxigênio (O2) e da ventilação pulmonar (VE) estavam diminuídos em pacientes com EMF em comparação aos CS. Ainda, os pacientes com EMF apresentaram Δ frequência cardíaca /Δ consumo de oxigênio e Δ consumo de oxigênio /Δ taxa de trabalho aumentados em comparação aos CS. Conclusão: A determinação da capacidade aeróbica por troca respiratória não invasiva durante exercício progressivo fornece informações sobre a tolerância ao exercício em pacientes com EMF. É necessária uma análise das diferentes variáveis do TECP para nos ajudar a compreender mais acerca das alterações centrais e periféricas causadas tanto pela disfunção diastólica como pelo padrão restritivo.

Cardiac and peripheral autonomic control in restrictive cardiomyopathy.

AIMS: Autonomic dysfunction determines the advance of dilated cardiomyopathy (DCM) and is related to poor outcomes. However, this autonomic imbalance is unknown in patients with restrictive cardiomyopathy (RCM) even though they have similar symptoms and poor quality of life as DCM patients have. The aim of this study was to evaluate if autonomic and neurovascular controls were altered in RCM patients. METHODS AND RESULTS: Fifteen RCM patients, 10 DCM patients, and 10 healthy subjects were evaluated. Heart rate and blood pressure (BP) were recorded. Peripheral sympathetic activity [muscle sympathetic nerve activity (MSNA)] by microneurography and cardiac sympathetic activity by power spectrum analysis of heart rate variability. Spontaneous baroreflex sensitivity (BRS) was evaluated by the sequence method and forearm blood flow by venous occlusion plethysmography. Both cardiomyopathy groups had higher MSNA frequency (P < 0.001) and MSNA incidence (P < 0.001), higher cardiac sympathovagal balance (P < 0.02), reduced BRS for increase (P = 0.002) and for decrease in BP (P = 0.002), and lower forearm blood flow (P < 0.001) compared with healthy subjects. We found an inverse correlation between BRS for increase and decrease in BP and peripheral sympathetic activity (r = -0.609, P = 0.001 and r = -0.648, P < 0.001, respectively) and between BRS for increase and decrease in BP and cardiac sympathetic activity (r = -0.503, P = 0.03 and r = -0.487, P = 0.04, respectively). CONCLUSIONS: The RCM patients had cardiac and peripheral autonomic dysfunctions associated with peripheral vasoconstriction. Nonetheless, the presence of normal ejection fraction underestimates the evolution of the disease and makes clinical treatment difficult. These alterations could lead to a similar cardiovascular risk as that observed in DCM patients.

Characterization of Cardiopulmonary Exercise Testing Variables in Patients with Endomyocardial Fibrosis after Endocardial Resection.

BACKGROUND: Endomyocardial fibrosis (EMF) is a rare disease, characterized by diastolic dysfunction which leads to reduced peak oxygen consumption (VO2). Cardiopulmonary exercise testing (CPET) has been proved to be a fundamental tool to identify central and peripheral alterations. However, most studies prioritize peak VO2 as the main variable, leaving aside other important CPET variables that can specify the severity of the disease and guide the clinical treatment. OBJECTIVE: The aim of this study was to evaluate central and peripheral limitations in symptomatic patients with EMF by different CPET variables. METHODS: Twenty-six EMF patients (functional class III, NYHA) were compared with 15 healthy subjects (HS). Functional capacity was evaluated using CPET and diastolic and systolic functions were evaluated by echocardiography. RESULTS: Age and gender were similar between EMF patients and HS. Left ventricular ejection fraction was normal in EMF patients, but decreased compared to HS. Peak heart rate, peak workload, peak VO2, peak oxygen (O2) pulse and peak pulmonary ventilation (VE) were decreased in EMF compared to HS. Also, EMF patients showed increased Δ heart rate /Δ oxygen uptake and Δ oxygen uptake /Δ work rate compared to HS. CONCLUSION: Determination of the aerobic capacity by noninvasive respiratory gas exchange during incremental exercise provides additional information about the exercise tolerance in patients with EMF. The analysis of different CPET variables is necessary to help us understand more about the central and peripheral alterations cause by both diastolic dysfunction and restrictive pattern.