The Impact of Inhaled Nitric Oxide (iNO) on the Neurophysiological Mechanisms of Dyspnea in Chronic Thromboembolic Disease and Post-Pulmonary Embolism (Post-PE) Related Dyspnea

Background:

Following acute pulmonary embolism (PE), up to a third of patients develop post-PE syndrome characterized by persistent breathlessness (dyspnea), impaired exercise capacity, and reduced quality of life. Although therapies exist for the most severe manifestation of the post-PE syndrome [chronic thromboembolic pulmonary hypertension (CTEPH)] - for most patients there are no available disease specific therapies that reduce symptoms. In a preliminary study, it was observed that exertional dyspnea in post-PE syndrome was strongly associated with increased inspiratory neural drive (IND) to the diaphragm. High IND represents increased chemo-stimulation of medullary control centers due to the negative effects of increased ventilatory inefficiency measured as the ratio of ventilation to carbon-dioxide output (VE/VCO2). In a pilot study increased IND during exercise in the post-PE group was present despite the absence of measurable pulmonary hypertension at rest or exertional hypoxemia and was associated with increased VE/VCO2. The underlying mechanism for increased VE/VCO2 and IND during exercise in post-PE syndrome is currently unclear. Moreover, the contribution of adaptive changes by the respiratory controller, including altered chemosensitivity, to increased VE/VCO2 during exercise has not been determined. However, based on experiments to-date, the investigators propose that pulmonary microvascular abnormalities and hypoperfusion of pulmonary capillaries are potentially key pathophysiologic mechanisms. Accordingly, the purpose of the current application is to determine the degree of reversible vascular dysfunction that exists in these patients and to test the hypothesis that improved pulmonary gas exchange following an inhaled selective pulmonary vasodilator will reduce IND and exertional dyspnea intensity. The investigators plan to undertake a prospective, randomized, double-blind, placebo-controlled study of the effects of inhaled nitric oxide (iNO) on dyspnea intensity, IND, and physiologic responses to exercise to determine whether therapies acting on the NO pathway can reduce dyspnea and improve exercise capacity in the post-PE syndrome.

The post-PE syndrome encompasses the small minority of patients who develop CTEPH, defined as thrombotic occlusion of the pulmonary arteries with pulmonary hypertension. The post-PE syndrome also includes patients with chronic thromboembolic disease (CTED) with obstruction of the pulmonary arteries in the absence of pulmonary hypertension, and post-PE related dyspnea in patients with persistent symptoms in the absence of clear thrombotic occlusion or pulmonary hypertension.

Physiologic responses to exercise in the post-PE syndrome:

Cardiopulmonary exercise testing (CPET) is clinically useful in identifying CTEPH and deconditioning following PE. Exercise responses in CTEPH include increased ventilation (VE), dead space (regions of alveolar ventilation without perfusion), and VE/VCO2 as well as reduced peak oxygen uptake (VO2). Ventilatory inefficiency is increased in CTED and correlated with increased mean pulmonary artery pressure (mPAP)/cardiac output (CO) slope and physiological dead space.