Contribution of impaired parasympathetic activity to right ventricular dysfunction and pulmonary vascular remodeling in pulmonary arterial hypertension

Denielli Da Silva Gonçalves Bós, Cathelijne E.E. Van Der Bruggen, Kondababu Kurakula, Xiao Qing Sun, Karina R. Casali, Adenauer G. Casali, Nina Rol, Robert Szulcek, Cris Dos Remedios, Christophe Guignabert, Ly Tu, Peter Dorfmüller, Marc Humbert, Paul J.M. Wijnker, Diederik W.D. Kuster, Jolanda Van Der Velden, Marie José Goumans, Harm Jan Bogaard, Anton Vonk-Noordegraaf, Frances S. De Man & 1 others M. Louis Handoko

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

BACKGROUND: The beneficial effects of parasympathetic stimulation have been reported in left heart failure, but whether it would be beneficial for pulmonary arterial hypertension (PAH) remains to be explored. Here, we investigated the relationship between parasympathetic activity and right ventricular (RV) function in patients with PAH, and the potential therapeutic effects of pyridostigmine (PYR), an oral drug stimulating the parasympathetic activity through acetylcholinesterase inhibition, in experimental pulmonary hypertension (PH). METHODS: Heart rate recovery after a maximal cardiopulmonary exercise test was used as a surrogate for parasympathetic activity. RV ejection fraction was assessed in 112 patients with PAH. Expression of nicotinic (a-7 nicotinic acetylcholine receptor) and muscarinic (muscarinic acetylcholine type 2 receptor) receptors, and acetylcholinesterase activity were evaluated in RV (n=11) and lungs (n=7) from patients with PAH undergoing heart/lung transplantation and compared with tissue obtained from controls. In addition, we investigated the effects of PYR (40 mg/kg per day) in experimental PH. PH was induced in male rats by SU5416 (25 mg/kg subcutaneously) injection followed by 4 weeks of hypoxia. In a subgroup, sympathetic/parasympathetic modulation was assessed by power spectral analysis. At week 6, PH status was confirmed by echocardiography, and rats were randomly assigned to vehicle or treatment (both n=12). At the end of the study, echocardiography was repeated, with additional RV pressure-volume measurements, along with lung, RV histological, and protein analyses. RESULTS: Patients with PAH with lower RV ejection fraction (<41%) had a significantly reduced heart rate recovery in comparison with patients with higher RV ejection fraction. In PAH RV samples, a-7 nicotinic acetylcholine receptor was increased and acetylcholinesterase activity was reduced versus controls. No difference in muscarinic acetylcholine type 2 receptor expression was observed. Chronic PYR treatment in PH rats normalized the cardiovascular autonomic function, demonstrated by an increase in parasympathetic activity and baroreflex sensitivity. PYR improved survival, increased RV contractility, and reduced RV stiffness, RV hypertrophy, RV fibrosis, RV inflammation, and RV a-7 nicotinic acetylcholine receptor and muscarinic acetylcholine type 2 receptor expression, as well. Furthermore, PYR reduced pulmonary vascular resistance, RV afterload, and pulmonary vascular remodeling, which was associated with reduced local and systemic inflammation. CONCLUSIONS: RV dysfunction is associated with reduced systemic parasympathetic activity in patients with PAH, with an inadequate adaptive response of the cholinergic system in the RV. Enhancing parasympathetic activity by PYR improved survival, RV function, and pulmonary vascular remodeling in experimental PH.

Original languageEnglish
Pages (from-to)910-924
Number of pages15
JournalCirculation
Volume137
Issue number9
DOIs
Publication statusPublished - 1 Jan 2018

Cite this

Da Silva Gonçalves Bós, Denielli ; Van Der Bruggen, Cathelijne E.E. ; Kurakula, Kondababu ; Sun, Xiao Qing ; Casali, Karina R. ; Casali, Adenauer G. ; Rol, Nina ; Szulcek, Robert ; Dos Remedios, Cris ; Guignabert, Christophe ; Tu, Ly ; Dorfmüller, Peter ; Humbert, Marc ; Wijnker, Paul J.M. ; Kuster, Diederik W.D. ; Van Der Velden, Jolanda ; Goumans, Marie José ; Bogaard, Harm Jan ; Vonk-Noordegraaf, Anton ; De Man, Frances S. ; Handoko, M. Louis. / Contribution of impaired parasympathetic activity to right ventricular dysfunction and pulmonary vascular remodeling in pulmonary arterial hypertension. In: Circulation. 2018 ; Vol. 137, No. 9. pp. 910-924.
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abstract = "BACKGROUND: The beneficial effects of parasympathetic stimulation have been reported in left heart failure, but whether it would be beneficial for pulmonary arterial hypertension (PAH) remains to be explored. Here, we investigated the relationship between parasympathetic activity and right ventricular (RV) function in patients with PAH, and the potential therapeutic effects of pyridostigmine (PYR), an oral drug stimulating the parasympathetic activity through acetylcholinesterase inhibition, in experimental pulmonary hypertension (PH). METHODS: Heart rate recovery after a maximal cardiopulmonary exercise test was used as a surrogate for parasympathetic activity. RV ejection fraction was assessed in 112 patients with PAH. Expression of nicotinic (a-7 nicotinic acetylcholine receptor) and muscarinic (muscarinic acetylcholine type 2 receptor) receptors, and acetylcholinesterase activity were evaluated in RV (n=11) and lungs (n=7) from patients with PAH undergoing heart/lung transplantation and compared with tissue obtained from controls. In addition, we investigated the effects of PYR (40 mg/kg per day) in experimental PH. PH was induced in male rats by SU5416 (25 mg/kg subcutaneously) injection followed by 4 weeks of hypoxia. In a subgroup, sympathetic/parasympathetic modulation was assessed by power spectral analysis. At week 6, PH status was confirmed by echocardiography, and rats were randomly assigned to vehicle or treatment (both n=12). At the end of the study, echocardiography was repeated, with additional RV pressure-volume measurements, along with lung, RV histological, and protein analyses. RESULTS: Patients with PAH with lower RV ejection fraction (<41{\%}) had a significantly reduced heart rate recovery in comparison with patients with higher RV ejection fraction. In PAH RV samples, a-7 nicotinic acetylcholine receptor was increased and acetylcholinesterase activity was reduced versus controls. No difference in muscarinic acetylcholine type 2 receptor expression was observed. Chronic PYR treatment in PH rats normalized the cardiovascular autonomic function, demonstrated by an increase in parasympathetic activity and baroreflex sensitivity. PYR improved survival, increased RV contractility, and reduced RV stiffness, RV hypertrophy, RV fibrosis, RV inflammation, and RV a-7 nicotinic acetylcholine receptor and muscarinic acetylcholine type 2 receptor expression, as well. Furthermore, PYR reduced pulmonary vascular resistance, RV afterload, and pulmonary vascular remodeling, which was associated with reduced local and systemic inflammation. CONCLUSIONS: RV dysfunction is associated with reduced systemic parasympathetic activity in patients with PAH, with an inadequate adaptive response of the cholinergic system in the RV. Enhancing parasympathetic activity by PYR improved survival, RV function, and pulmonary vascular remodeling in experimental PH.",
keywords = "Autonomic nervous system, Cholinesterase inhibitors, Heart failure, Hypertension, Parasympathetic nervous system, Pulmonary",
author = "{Da Silva Gon{\cc}alves B{\'o}s}, Denielli and {Van Der Bruggen}, {Cathelijne E.E.} and Kondababu Kurakula and Sun, {Xiao Qing} and Casali, {Karina R.} and Casali, {Adenauer G.} and Nina Rol and Robert Szulcek and {Dos Remedios}, Cris and Christophe Guignabert and Ly Tu and Peter Dorfm{\"u}ller and Marc Humbert and Wijnker, {Paul J.M.} and Kuster, {Diederik W.D.} and {Van Der Velden}, Jolanda and Goumans, {Marie Jos{\'e}} and Bogaard, {Harm Jan} and Anton Vonk-Noordegraaf and {De Man}, {Frances S.} and Handoko, {M. Louis}",
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Contribution of impaired parasympathetic activity to right ventricular dysfunction and pulmonary vascular remodeling in pulmonary arterial hypertension. / Da Silva Gonçalves Bós, Denielli; Van Der Bruggen, Cathelijne E.E.; Kurakula, Kondababu; Sun, Xiao Qing; Casali, Karina R.; Casali, Adenauer G.; Rol, Nina; Szulcek, Robert; Dos Remedios, Cris; Guignabert, Christophe; Tu, Ly; Dorfmüller, Peter; Humbert, Marc; Wijnker, Paul J.M.; Kuster, Diederik W.D.; Van Der Velden, Jolanda; Goumans, Marie José; Bogaard, Harm Jan; Vonk-Noordegraaf, Anton; De Man, Frances S.; Handoko, M. Louis.

In: Circulation, Vol. 137, No. 9, 01.01.2018, p. 910-924.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Contribution of impaired parasympathetic activity to right ventricular dysfunction and pulmonary vascular remodeling in pulmonary arterial hypertension

AU - Da Silva Gonçalves Bós, Denielli

AU - Van Der Bruggen, Cathelijne E.E.

AU - Kurakula, Kondababu

AU - Sun, Xiao Qing

AU - Casali, Karina R.

AU - Casali, Adenauer G.

AU - Rol, Nina

AU - Szulcek, Robert

AU - Dos Remedios, Cris

AU - Guignabert, Christophe

AU - Tu, Ly

AU - Dorfmüller, Peter

AU - Humbert, Marc

AU - Wijnker, Paul J.M.

AU - Kuster, Diederik W.D.

AU - Van Der Velden, Jolanda

AU - Goumans, Marie José

AU - Bogaard, Harm Jan

AU - Vonk-Noordegraaf, Anton

AU - De Man, Frances S.

AU - Handoko, M. Louis

PY - 2018/1/1

Y1 - 2018/1/1

N2 - BACKGROUND: The beneficial effects of parasympathetic stimulation have been reported in left heart failure, but whether it would be beneficial for pulmonary arterial hypertension (PAH) remains to be explored. Here, we investigated the relationship between parasympathetic activity and right ventricular (RV) function in patients with PAH, and the potential therapeutic effects of pyridostigmine (PYR), an oral drug stimulating the parasympathetic activity through acetylcholinesterase inhibition, in experimental pulmonary hypertension (PH). METHODS: Heart rate recovery after a maximal cardiopulmonary exercise test was used as a surrogate for parasympathetic activity. RV ejection fraction was assessed in 112 patients with PAH. Expression of nicotinic (a-7 nicotinic acetylcholine receptor) and muscarinic (muscarinic acetylcholine type 2 receptor) receptors, and acetylcholinesterase activity were evaluated in RV (n=11) and lungs (n=7) from patients with PAH undergoing heart/lung transplantation and compared with tissue obtained from controls. In addition, we investigated the effects of PYR (40 mg/kg per day) in experimental PH. PH was induced in male rats by SU5416 (25 mg/kg subcutaneously) injection followed by 4 weeks of hypoxia. In a subgroup, sympathetic/parasympathetic modulation was assessed by power spectral analysis. At week 6, PH status was confirmed by echocardiography, and rats were randomly assigned to vehicle or treatment (both n=12). At the end of the study, echocardiography was repeated, with additional RV pressure-volume measurements, along with lung, RV histological, and protein analyses. RESULTS: Patients with PAH with lower RV ejection fraction (<41%) had a significantly reduced heart rate recovery in comparison with patients with higher RV ejection fraction. In PAH RV samples, a-7 nicotinic acetylcholine receptor was increased and acetylcholinesterase activity was reduced versus controls. No difference in muscarinic acetylcholine type 2 receptor expression was observed. Chronic PYR treatment in PH rats normalized the cardiovascular autonomic function, demonstrated by an increase in parasympathetic activity and baroreflex sensitivity. PYR improved survival, increased RV contractility, and reduced RV stiffness, RV hypertrophy, RV fibrosis, RV inflammation, and RV a-7 nicotinic acetylcholine receptor and muscarinic acetylcholine type 2 receptor expression, as well. Furthermore, PYR reduced pulmonary vascular resistance, RV afterload, and pulmonary vascular remodeling, which was associated with reduced local and systemic inflammation. CONCLUSIONS: RV dysfunction is associated with reduced systemic parasympathetic activity in patients with PAH, with an inadequate adaptive response of the cholinergic system in the RV. Enhancing parasympathetic activity by PYR improved survival, RV function, and pulmonary vascular remodeling in experimental PH.

AB - BACKGROUND: The beneficial effects of parasympathetic stimulation have been reported in left heart failure, but whether it would be beneficial for pulmonary arterial hypertension (PAH) remains to be explored. Here, we investigated the relationship between parasympathetic activity and right ventricular (RV) function in patients with PAH, and the potential therapeutic effects of pyridostigmine (PYR), an oral drug stimulating the parasympathetic activity through acetylcholinesterase inhibition, in experimental pulmonary hypertension (PH). METHODS: Heart rate recovery after a maximal cardiopulmonary exercise test was used as a surrogate for parasympathetic activity. RV ejection fraction was assessed in 112 patients with PAH. Expression of nicotinic (a-7 nicotinic acetylcholine receptor) and muscarinic (muscarinic acetylcholine type 2 receptor) receptors, and acetylcholinesterase activity were evaluated in RV (n=11) and lungs (n=7) from patients with PAH undergoing heart/lung transplantation and compared with tissue obtained from controls. In addition, we investigated the effects of PYR (40 mg/kg per day) in experimental PH. PH was induced in male rats by SU5416 (25 mg/kg subcutaneously) injection followed by 4 weeks of hypoxia. In a subgroup, sympathetic/parasympathetic modulation was assessed by power spectral analysis. At week 6, PH status was confirmed by echocardiography, and rats were randomly assigned to vehicle or treatment (both n=12). At the end of the study, echocardiography was repeated, with additional RV pressure-volume measurements, along with lung, RV histological, and protein analyses. RESULTS: Patients with PAH with lower RV ejection fraction (<41%) had a significantly reduced heart rate recovery in comparison with patients with higher RV ejection fraction. In PAH RV samples, a-7 nicotinic acetylcholine receptor was increased and acetylcholinesterase activity was reduced versus controls. No difference in muscarinic acetylcholine type 2 receptor expression was observed. Chronic PYR treatment in PH rats normalized the cardiovascular autonomic function, demonstrated by an increase in parasympathetic activity and baroreflex sensitivity. PYR improved survival, increased RV contractility, and reduced RV stiffness, RV hypertrophy, RV fibrosis, RV inflammation, and RV a-7 nicotinic acetylcholine receptor and muscarinic acetylcholine type 2 receptor expression, as well. Furthermore, PYR reduced pulmonary vascular resistance, RV afterload, and pulmonary vascular remodeling, which was associated with reduced local and systemic inflammation. CONCLUSIONS: RV dysfunction is associated with reduced systemic parasympathetic activity in patients with PAH, with an inadequate adaptive response of the cholinergic system in the RV. Enhancing parasympathetic activity by PYR improved survival, RV function, and pulmonary vascular remodeling in experimental PH.

KW - Autonomic nervous system

KW - Cholinesterase inhibitors

KW - Heart failure

KW - Hypertension

KW - Parasympathetic nervous system

KW - Pulmonary

UR - http://www.scopus.com/inward/record.url?scp=85047755442&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.117.027451

DO - 10.1161/CIRCULATIONAHA.117.027451

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EP - 924

JO - Circulation

JF - Circulation

SN - 0009-7322

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