Contribution of Impaired Parasympathetic Activity to Right Ventricular Dysfunction and Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension

Bós, Denielli da Silva Gonçalves; Bruggen, Cathelijne E. E. van der; Kurakula, Kondababu; Sun, Xiao Qing; Casali, Karina Rabello; Casali, Adenauer G.; Rol, Nina; Szulcek, Robert; Remedios, Cris dos; Guignabert, Christophe; Tu, Ly; Dorfmüller, Peter; Humbert, Marc; Wijnker, Paul J.M.; Kuster, Diederik W.D.; Velden, Jolanda van der; Goumans, Marie–José; Bogaard, Harm Jan; Vonk‐Noordegraaf, Anton; Man, Frances S. de; Handoko, M. Louis

doi:10.1161/circulationaha.117.027451

Cited by 95 publications

(107 citation statements)

References 48 publications

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“…Several investigators have demonstrated an autonomic imbalance in PAH (Lima-Seolin et al, 2017;Rigatto, Casali, Shenoy, Katovich, & Raizada, 2013;Wensel et al, 2009). Various reports have indicated the efficacy of autonomic modulatory therapies, such as pulmonary arterial denervation, -blocker and acetylcholine esterase inhibitor (Bogaard et al, 2010;Chen et al, 2013;da Silva Gonçalves Bós et al, 2018). We also have shown the impairment of baroreflex function in the present study by identifying the characteristics of baroreflex subsystems and the total arc in rats with MCT-induced PAH.…”

Section: Discussionsupporting

confidence: 66%

“…They also reported that the baroreflex dynamic function does not change significantly in spontaneously hypertensive rats compared with normal rats (Kawada et al, 2011). This resulted in attenuation of the AP reduction in the steady-state in response to step increases of CSP ( Figure 7c; (Bogaard et al, 2010;Chen et al, 2013;da Silva Gonçalves Bós et al, 2018). Monocrotaline decreased the dynamic gain of the baroreflex total arc at 0.01 Hz (Figure 7b; Table 2) by >55% compared with CTL rats, without changes in the corner frequencies.…”

Section: Baroreflex Dynamic Total Arc Functionmentioning

confidence: 89%

“…Although direct and indirect effects of sympathoexcitation on pulmonary vascular remodelling and worsening of right heart function have been reported (Bogaard et al, 2010;Chen et al, 2013;da Silva Gonçalves Bós et al, 2018), it remains unknown how sympathetic nerve activity (SNA) is regulated in PAH and how SNA impacts haemodynamics in this condition.…”

Section: Introductionmentioning

confidence: 99%

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Suppressed baroreflex peripheral arc overwhelms augmented neural arc and incapacitates baroreflex function in rats with pulmonary arterial hypertension

Shinoda

Saku

Oga

et al. 2019

Experimental Physiology

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New Findings What is the central question of this study?The impact of pulmonary arterial hypertension on open‐loop baroreflex function, which determines how powerfully and rapidly the baroreflex operates to regulate arterial pressure, remains poorly understood. What is the main finding and its importance?The gain of the baroreflex total arc, indicating the baroreflex pressure‐stabilizing function, is markedly attenuated in rats with monocrotaline‐induced pulmonary arterial hypertension. This is caused by a rightward shift of the baroreflex neural arc and a downward shift of the peripheral arc. These findings contribute greatly to our understanding of arterial pressure regulation by the sympathetic nervous system in pulmonary arterial hypertension. Abstract Sympathoexcitation has been documented in patients with established pulmonary arterial hypertension (PAH). Although the arterial baroreflex is the main negative feedback regulator of sympathetic nerve activity (SNA), the way in which PAH impacts baroreflex function remains poorly understood. In this study, we conducted baroreflex open‐loop analysis in a rat model of PAH. Sprague–Dawley rats were injected with monocrotaline (MCT) s.c. to induce PAH (60 mg kg−1; n = 11) or saline as a control group (CTL; n = 8). At 3.5 weeks after MCT injection, bilateral carotid sinuses were isolated, and intrasinus pressure (CSP) was controlled while SNA at the coeliac ganglia and arterial pressure (AP) were recorded. To examine the static baroreflex function, CSP was increased stepwise while steady‐state AP (total arc) and SNA (neural arc) responses to CSP and the AP response to SNA (peripheral arc) were measured. Monocrotaline significantly decreased the static gain of the baroreflex total arc at the operating AP compared with CTL (−0.80 ± 0.31 versus −0.22 ± 0.22, P < 0.05). Given that MCT markedly increased plasma noradrenaline, an index of SNA, by approximately 3.6‐fold compared with CTL, calibrating SNA by plasma noradrenaline revealed that MCT shifted the neural arc to a higher SNA level and shifted the peripheral arc downwards. Monocrotaline also decreased the dynamic gain of the baroreflex total arc (−0.79 ± 0.16 versus −0.35 ± 0.17, P < 0.05), while the corner frequencies that reflect the speed of the baroreflex remained unchanged (0.06 ± 0.02 versus 0.08 ± 0.02 Hz, n.s.). In rats with MCT‐induced PAH, the suppressed baroreflex peripheral arc overwhelms the augmented neural arc and, in turn, attenuates the gain of the total arc, which determines the pressure‐stabilizing capacity of the baroreflex.

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Section: Discussionsupporting

confidence: 66%

Section: Baroreflex Dynamic Total Arc Functionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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Suppressed baroreflex peripheral arc overwhelms augmented neural arc and incapacitates baroreflex function in rats with pulmonary arterial hypertension

Shinoda

Saku

Oga

et al. 2019

Experimental Physiology

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“…; Da Silva Gonçalves Bós et al . ). Our group, for example, reported reduced HRR in patients with pulmonary arterial hypertension (PAH), which independently predicted all‐cause mortality (Ramos et al .…”

Section: Introductionmentioning

confidence: 97%

Carotid chemoreflex activity restrains post‐exercise cardiac autonomic control in healthy humans and in patients with pulmonary arterial hypertension

Paula‐Ribeiro

Ribeiro

Aranda

et al. 2019

The Journal of Physiology

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Key pointsr Dysfunction of post-exercise cardiac autonomic control is associated with increased mortality risk in healthy adults and in patients with cardiorespiratory diseases.r The afferent mechanisms that regulate the post-exercise cardiac autonomic control remain unclear.r 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).r 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.r 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 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% O 2 (hyperoxia) to inhibit the carotid chemoreceptor activity, or 21% O 2 (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.

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“…Parasympathetic activity is suppressed, whereas the sympathetic nervous system is upregulated. [1][2][3] Increased sympathetic activity is associated with clinical deterioration and mortality, which may cause further compromise RV function. [3][4][5] Consequently, therapies that restore autonomic balance by inhibiting sympathetic activity, such as beta-blocker therapy, have been of interest for the past decades.…”

Section: Introductionmentioning

confidence: 99%

Bisoprolol therapy does not reduce right ventricular sympathetic activity in pulmonary arterial hypertension patients

et al. 2020

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Right ventricular (RV) function and autonomic dysfunction are important determinants of morbidity and mortality in patients with pulmonary arterial hypertension (PAH). Although successful in animal studies, effects of beta-blocker therapy on RV function in clinical trials were disappointing. To understand this discrepancy, we studied whether beta-blocker therapy changes RV sympathetic activity. Idiopathic PAH (IPAH) patients received beta-blocker therapy (uptitrated to a maximal tolerated dose) and underwent cardiac magnetic resonance imaging, right heart catheterization, and a [ 11 C]-hydroxyephedrine positron emission tomography ([ 11 C]HED PET) scan at baseline to determine, respectively, RV ejection fraction (RVEF), RV pressures, and sympathetic activity.[ 11 C]HED, a norepinephrine analogue, allows determination of sympathetic innervation of the RV. [ 11 C]HED retention index reflects norepinephrine transporter activity. As a consequence of excessive catecholamine levels in the synaptic cleft, this transporter may be downregulated. Therefore, low [ 11 C]HED retention index indicates high sympathetic activity. 13 IPAH patients underwent [ 11 C]HED PET scans at baseline and after bisoprolol treatment. Although heart rate was reduced, systemic modulation of autonomic activity by bisoprolol did not affect local RV sympathetic nerve activity, RV function, or RV wall tension. In PAH patients, RV [ 11 C]HED retention index was lower compared to LV tracer uptake (p<0.01) and was related to systolic wall tension (R 2 ¼ 0.4731, p<0.01) and RV function (R 2 ¼ 0.44, p ¼ 0.01). In RV failure, the tolerated dosage of bisoprolol did not result in an improvement of RV function nor in a reduction in RV sympathetic activity.

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Contribution of Impaired Parasympathetic Activity to Right Ventricular Dysfunction and Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension

Cited by 95 publications

References 48 publications

Suppressed baroreflex peripheral arc overwhelms augmented neural arc and incapacitates baroreflex function in rats with pulmonary arterial hypertension

Suppressed baroreflex peripheral arc overwhelms augmented neural arc and incapacitates baroreflex function in rats with pulmonary arterial hypertension

Carotid chemoreflex activity restrains post‐exercise cardiac autonomic control in healthy humans and in patients with pulmonary arterial hypertension

Bisoprolol therapy does not reduce right ventricular sympathetic activity in pulmonary arterial hypertension patients

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