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

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

Author Bos, Denielli da Silva Goncalves Google Scholar
Van Der Bruggen, Cathelijne E. E. Google Scholar
Kurakula, Kondababu Google Scholar
Sun, Xiao-Qing Google Scholar
Casali, Karina R. Autor UNIFESP Google Scholar
Casali, Adenauer G. Autor UNIFESP Google Scholar
Rol, Nina Google Scholar
Szulcek, Robert Google Scholar
dos Remedios, Cris Google Scholar
Guignabert, Christophe Google Scholar
Tu, Ly Google Scholar
Dorfmueller, Peter Google Scholar
Humbert, Marc Google Scholar
Wijnker, Paul J. M. Google Scholar
Kuster, Diederik W. D. Google Scholar
van der Velden, Jolanda Google Scholar
Goumans, Marie-Jose Google Scholar
Bogaard, Harm-Jan Google Scholar
Vonk-Noordegraaf, Anton Google Scholar
de Man, Frances S. Google Scholar
Handoko, M. Louis Google Scholar
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 (alpha-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, alpha-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 alpha-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, pulmonary
parasympathetic nervous system
xmlui.dri2xhtml.METS-1.0.item-coverage Philadelphia
Language English
Sponsor Science Without Borders grant, Conselho Nacional de Desenvolvimento Cientifico e Tecnologico
VICI grant from the Netherlands Organization for Scientific Research (NWO)
Sao Paulo Research Foundation
Netherlands CardioVascular Research Initiative grant
VENI grant from NWO
L'Oreal/UNESCO for Women in Science
Netherlands Institute for Advanced Studies (NIAS)
American Thoracic Society (ATS: Jerry Wojciechowski Memorial Pulmonary Hypertension Research Grant)
European Respiratory Society
Institute for Cardiovascular Research (ICaR-VU)
Grant number CNPq-Brasil-245849/2012-2
Netherlands CardioVascular Research Initiative grant: CVON 2012-08
VENI grant from NWO: 916.14.099
Date 2018
Published in Circulation. Philadelphia, v. 137, n. 9, p. 910-924, 2018.
ISSN 0009-7322 (Sherpa/Romeo, impact factor)
Publisher Lippincott Williams & Wilkins
Extent 910-924
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000426206800006

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