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

Autor:	da Silva Gonçalves Bós D; Department of Pulmonology (D.d.S.G.B., C.E.V.D.B., X.-Q.S., N.R., R.S., H.-J.B., A.V.-N. F.S.d.M.)., Van Der Bruggen CEE; Department of Pulmonology (D.d.S.G.B., C.E.V.D.B., X.-Q.S., N.R., R.S., H.-J.B., A.V.-N. F.S.d.M.)., Kurakula K; VU University Medical Center / Amsterdam Cardiovascular Sciences, The Netherlands.. Department of Molecular Cell Biology, Laboratory of Experimental Cardiology, Leiden University Medical Center, The Netherlands (K.K., M.-J.G.)., Sun XQ; Department of Pulmonology (D.d.S.G.B., C.E.V.D.B., X.-Q.S., N.R., R.S., H.-J.B., A.V.-N. F.S.d.M.)., Casali KR; Institute of Science and Technology, Universidade Federal de São Paulo, Brazil (K.R.C., A.G.C.)., Casali AG; Institute of Science and Technology, Universidade Federal de São Paulo, Brazil (K.R.C., A.G.C.)., Rol N; Department of Pulmonology (D.d.S.G.B., C.E.V.D.B., X.-Q.S., N.R., R.S., H.-J.B., A.V.-N. F.S.d.M.)., Szulcek R; Department of Pulmonology (D.d.S.G.B., C.E.V.D.B., X.-Q.S., N.R., R.S., H.-J.B., A.V.-N. F.S.d.M.)., Dos Remedios C; Heart & Lung Transplant Unit, St. Vincent's Hospital and Bosch Institute, University of Sydney, Australia (C.d.R.)., Guignabert C; University of Paris-Sud, Université Paris-Saclay, Le Kremlin Bicêtre, France (C.G., L.T., P.D., M.H.).; INSERM UMR_S 999, Le Plessis-Robinson, France (C.G., L.T., P.D., M.H.)., Tu L; University of Paris-Sud, Université Paris-Saclay, Le Kremlin Bicêtre, France (C.G., L.T., P.D., M.H.).; INSERM UMR_S 999, Le Plessis-Robinson, France (C.G., L.T., P.D., M.H.)., Dorfmüller P; University of Paris-Sud, Université Paris-Saclay, Le Kremlin Bicêtre, France (C.G., L.T., P.D., M.H.).; INSERM UMR_S 999, Le Plessis-Robinson, France (C.G., L.T., P.D., M.H.)., Humbert M; University of Paris-Sud, Université Paris-Saclay, Le Kremlin Bicêtre, France (C.G., L.T., P.D., M.H.).; INSERM UMR_S 999, Le Plessis-Robinson, France (C.G., L.T., P.D., M.H.)., Wijnker PJM; Department of Physiology (P.J.M.W., D.W.D.K., J.v.d.V.)., Kuster DWD; Department of Physiology (P.J.M.W., D.W.D.K., J.v.d.V.)., van der Velden J; Department of Physiology (P.J.M.W., D.W.D.K., J.v.d.V.)., Goumans MJ; VU University Medical Center / Amsterdam Cardiovascular Sciences, The Netherlands.. Department of Molecular Cell Biology, Laboratory of Experimental Cardiology, Leiden University Medical Center, The Netherlands (K.K., M.-J.G.)., Bogaard HJ; Department of Pulmonology (D.d.S.G.B., C.E.V.D.B., X.-Q.S., N.R., R.S., H.-J.B., A.V.-N. F.S.d.M.)., Vonk-Noordegraaf A; Department of Pulmonology (D.d.S.G.B., C.E.V.D.B., X.-Q.S., N.R., R.S., H.-J.B., A.V.-N. F.S.d.M.)., de Man FS; Department of Pulmonology (D.d.S.G.B., C.E.V.D.B., X.-Q.S., N.R., R.S., H.-J.B., A.V.-N. F.S.d.M.)., Handoko ML; Department of Cardiology (M.L.H.) ml.handoko@vumc.nl fs.deman@vumc.nl.
Jazyk:	angličtina
Zdroj:	Circulation [Circulation] 2018 Feb 27; Vol. 137 (9), pp. 910-924. Date of Electronic Publication: 2017 Nov 22.
DOI:	10.1161/CIRCULATIONAHA.117.027451
Abstrakt:	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. (© 2017 American Heart Association, Inc.)
Databáze:	MEDLINE
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