Contribution of Impaired Parasympathetic Activity to Right Ventricular Dysfunction and Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension
Background—Beneficial effects of parasympathetic stimulation have been reported in left heart failure, however, 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 PAH-patients, and the potential therapeutic effects of pyridostigmine (PYR), an oral drug stimulating the parasympathetic activity through acetylcholinesterase (AchE) inhibition, in experimental pulmonary hypertension (PH).
Methods—Heart rate recovery (HRR) after maximal cardiopulmonary exercise test was used as a surrogate for parasympathetic activity. RV ejection fraction (RVEF) was assessed in 112 PAH-patients. Expression of nicotinic (α-7nAchR) and muscarinic (m2AchR) receptors, and AchE activity were evaluated in RV (n=11) and lungs (n=7) from PAH-patients undergoing heart/lung transplantation and compared with tissue obtained from controls. In addition, we investigated the effects of PYR (40 mg/kg/day) in experimental PH. PH was induced in male rats by SU5416 (25 mg/kg; s.c.) 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 randomized to vehicle or treatment (both n=12). At the end-of-study, echocardiography was repeated, with additional RV pressure-volume measurements, along with lung, RV histological and protein analyses.
Results—PAH-patients with lower RVEF (<41%) had a significantly reduced HRR in comparison to patients with higher RVEF. In PAH RV-samples, α-7nAchR was increased and AchE activity was reduced versus controls. No difference in m2AchR 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, as well as RV α-7nAchR and m2AchR expression. 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 PAH-patients, with an inadequate adaptive response of the cholinergic system in the right ventricle. Enhancing parasympathetic activity by PYR improved survival, RV function and pulmonary vascular remodeling in experimental-PH.
- parasympathetic nervous system
- cholinesterase inhibitors
- pulmonary hypertension
- right ventricular failure
- autonomic nervous system
- Received January 18, 2017.
- Revision received October 17, 2017.
- Accepted October 31, 2017.