Contribution of Impaired Parasympathetic Activity to Right Ventricular Dysfunction and Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension
© 2017 American Heart Association, Inc..
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 (α-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, α-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 α-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.
| Errataetall: |
CommentIn: Circulation. 2018 Feb 27;137(9):925-927. - PMID 29483171 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:137 |
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| Enthalten in: |
Circulation - 137(2018), 9 vom: 27. Feb., Seite 910-924 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
da Silva Gonçalves Bós, Denielli [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 22.05.2019 Date Revised 22.05.2019 published: Print-Electronic CommentIn: Circulation. 2018 Feb 27;137(9):925-927. - PMID 29483171 Citation Status MEDLINE |
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| doi: |
10.1161/CIRCULATIONAHA.117.027451 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM278332633 |
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| 245 | 1 | 0 | |a Contribution of Impaired Parasympathetic Activity to Right Ventricular Dysfunction and Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension |
| 264 | 1 | |c 2018 | |
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| 500 | |a Date Completed 22.05.2019 | ||
| 500 | |a Date Revised 22.05.2019 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: Circulation. 2018 Feb 27;137(9):925-927. - PMID 29483171 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2017 American Heart Association, Inc. | ||
| 520 | |a 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) | ||
| 520 | |a 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 (α-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 | ||
| 520 | |a 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, α-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 α-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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a autonomic nervous system | |
| 650 | 4 | |a cholinesterase inhibitors | |
| 650 | 4 | |a heart failure | |
| 650 | 4 | |a hypertension, pulmonary | |
| 650 | 4 | |a parasympathetic nervous system | |
| 650 | 7 | |a Cholinesterase Inhibitors |2 NLM | |
| 650 | 7 | |a Pyridostigmine Bromide |2 NLM | |
| 650 | 7 | |a KVI301NA53 |2 NLM | |
| 700 | 1 | |a Van Der Bruggen, Cathelijne E E |e verfasserin |4 aut | |
| 700 | 1 | |a Kurakula, Kondababu |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Xiao-Qing |e verfasserin |4 aut | |
| 700 | 1 | |a Casali, Karina R |e verfasserin |4 aut | |
| 700 | 1 | |a Casali, Adenauer G |e verfasserin |4 aut | |
| 700 | 1 | |a Rol, Nina |e verfasserin |4 aut | |
| 700 | 1 | |a Szulcek, Robert |e verfasserin |4 aut | |
| 700 | 1 | |a Dos Remedios, Cris |e verfasserin |4 aut | |
| 700 | 1 | |a Guignabert, Christophe |e verfasserin |4 aut | |
| 700 | 1 | |a Tu, Ly |e verfasserin |4 aut | |
| 700 | 1 | |a Dorfmüller, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Humbert, Marc |e verfasserin |4 aut | |
| 700 | 1 | |a Wijnker, Paul J M |e verfasserin |4 aut | |
| 700 | 1 | |a Kuster, Diederik W D |e verfasserin |4 aut | |
| 700 | 1 | |a van der Velden, Jolanda |e verfasserin |4 aut | |
| 700 | 1 | |a Goumans, Marie-José |e verfasserin |4 aut | |
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| 700 | 1 | |a Handoko, M Louis |e verfasserin |4 aut | |
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