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

Author(s):Show less -

Bos, Denielli da Silva Goncalves ^[1] ; Van Der Bruggen, Cathelijne E. E. ^[1] ; Kurakula, Kondababu ^[2] ; Sun, Xiao-Qing ^[1] ; Casali, Karina R. ^[3] ; Casali, Adenauer G. ^[3] ; Rol, Nina ^[1] ; Szulcek, Robert ^[1] ; dos Remedios, Cris ^{[4, 5]} ; Guignabert, Christophe ^{[6, 7]} ; Tu, Ly ^{[6, 7]} ; Dorfmueller, Peter ^{[6, 7]} ; Humbert, Marc ^{[6, 7]} ; Wijnker, Paul J. M. ^[8] ; Kuster, Diederik W. D. ^[8] ; van der Velden, Jolanda ^[8] ; Goumans, Marie-Jose ^[2] ; Bogaard, Harm-Jan ^[1] ; Vonk-Noordegraaf, Anton ^[1] ; de Man, Frances S. ^[1] ; Handoko, M. Louis ^[9]

Affiliation

^[1] Vrije Univ Amsterdam Med Ctr, Amsterdam Cardiovasc Sci, Dept Pulmonol, Amsterdam - Netherlands

^[2] Leiden Univ, Med Ctr, Dept Mol Cell Biol, Lab Expt Cardiol, Leiden - Netherlands

^[3] Univ Fed Sao Paulo, Inst Sci & Technol, Sao Paulo - Brazil

^[4] Univ Sydney, Heart & Lung Transplant Unit, St Vincents Hosp, Sydney, NSW - Australia

^[5] Univ Sydney, Bosch Inst, Sydney, NSW - Australia

^[6] Univ Paris Saclay, Univ Paris Sud, Le Kremlin Bicetre - France

^[7] INSERM, UMR S 999, Le Plessis Robinson - France

^[8] Vrije Univ Amsterdam Med Ctr, Amsterdam Cardiovasc Sci, Dept Physiol, Amsterdam - Netherlands

^[9] Vrije Univ Amsterdam Med Ctr, Amsterdam Cardiovasc Sci, Dept Cardiol, Amsterdam - Netherlands

• Document type: Journal article
• Source: Circulation; v. 137, n. 9, p. 910-924, FEB 27 2018.
• Web of Science Citations: 17

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. (AU)

• FAPESP's process: 16/08263-9 - Standardization, validation and characterization of a novel index of brain complexity
• Grantee: Adenauer Girardi Casali
• Support Opportunities: Research Grants - Young Investigators Grants