Pulmonary arterial hypertension: the case for a bioelectronic treatment

Pulmonary arterial hypertension (PAH) is a rare disease of unknown etiology that progresses to right ventricular failure. It has a complex pathophysiology, which involves an imbalance between vasoconstrictive and vasodilative processes in the pulmonary circulation, pulmonary vasoconstriction, vascular and right ventricular remodeling, systemic inflammation, and autonomic imbalance, with a reduced parasympathetic and increased sympathetic tone. Current pharmacological treatments for PAH include several classes of drugs that target signaling pathways in vascular biology and cardiovascular physiology, but they can have severe unwanted effects and they do not typically stop the progression of the disease. Pulmonary artery denervation has been tested clinically as a method to suppress sympathetic overactivation, however it is a nonspecific and irreversible intervention. Bioelectronic medicine, in particular vagus nerve stimulation (VNS), has been used in cardiovascular disorders like arrhythmias, heart failure and arterial hypertension and could, in principle, be tested as a treatment in PAH. VNS can produce pulmonary vasodilation and renormalize right ventricular function, via activation of pulmonary and cardiac vagal fibers. It can suppress systemic inflammation, via activation of fibers that innervate the spleen. Finally, VNS can gradually restore the balance between parasympathetic and sympathetic tone by regulating autonomic reflexes. Preclinical studies support the feasibility of using VNS in PAH. However, there are challenges with such an approach, arising from the need to affect a relatively small number of relevant vagal fibers, and the potential for unwanted cardiac and noncardiac effects of VNS in this sensitive patient population.