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.
Despite increased dyspnea and abnormal exercise responses, detailed neurophysiological
mechanisms of dyspnea in the post-PE syndrome have not been undertaken. Accordingly, our
recent study is the first to demonstrate that exertional dyspnea is increased in post-PE
patients without resting pulmonary hypertension (Appendix I: Figure 1A) and highly correlated
with magnitude of IND (r=0.761, p<0.01) (Figure 1B), secondary to elevated ventilatory demand
during exercise (Figure 1C) in the absence of significant hypoxemia (Figure 1D). The current
study extends our previous work by testing the strength of the association between high IND
and high VE/VCO2 by selective pharmacological manipulation of the independent variable
(VE/VCO2).
Extending CTEPH therapies to post-PE syndrome:
CTEPH is characterized by dual vascular abnormalities within the pulmonary artery tree:
organized thromboembolic material in the large pulmonary arteries and a secondary
vasculopathy in the small pulmonary arterioles with intimal thickening and remodeling.
Surgical pulmonary endarterectomy (PEA) targets proximal pulmonary artery obstruction
successfully in CTEPH with decrease in dead space, symptoms, and increased survival and has
been extended to CTED. PEA however carries risk of complications occurring in up to 40% of
patients perioperatively.
Multiple factors lead to small vessel vasculopathy in CTEPH including redirection of blood
flow from areas obstructed by chronic emboli to non-obstructed vessels, contributing to
pulmonary arteriole remodeling and altering endogenous NO production. Endogenous NO is
synthesized by vascular endothelial cells, diffuses to vascular smooth muscle to activate
soluble guanylate cyclase, and leads to smooth muscle relaxation. Medical treatment in
inoperable or persistent CTEPH with Riociguat, a soluble guanylate cyclase stimulator,
improves exercise capacity and reduces pulmonary vascular resistance (PVR) by acting in this
pathway promoting smooth muscle relaxation. Due to rapid inactivation by heme moieties
following administration, iNO acts in isolation on the pulmonary vasculature.
During right heart catheterization iNO is used in acute vasoreactivity testing for pulmonary
hypertension. iNO decreases PVR and mPAP in animal models of acute pulmonary embolism and has
been employed as adjunct therapy in intermediate risk acute PE in humans with improved
residual volume (RV) function on echocardiography. Recent work has shown that iNO improved
ventilatory efficiency (lower VE/VCO2) and exercise capacity (VO2peak) in mild chronic
obstructive pulmonary disease (COPD) (manuscript in review). Although iNO in acute PE and the
effect of vasodilators in CTEPH have been studied, to our knowledge manipulation of the
physiologic responses to exercise in CTED and post-PE related dyspnea with iNO has not
previously been undertaken.
Significance of the study:
The degree of pulmonary arteriole microvasculopathy and vascular dysfunction in the post-PE
syndrome outside of CTEPH is an area of ongoing research. The common pattern of physiologic
response to exercise in CTED and post-PE related dyspnea suggests that ventilatory
inefficiency due to increased dead space plays a role in increased IND and exertional dyspnea
throughout the spectrum of post-PE syndrome. Targeted manipulation of the pulmonary
microvasculature to improve pulmonary blood flow and reduce dead space with iNO will allow
for assessment of mechanisms of dyspnea and its relief in post-PE patients. A positive
response to iNO will provide a physiological rationale for clinical assessment of medical
therapies acting on the NO pathway in this population.
This proposed study will set the stage for new physiological studies to evaluate pulmonary
vascular hemodynamics during exercise with echocardiography.
Trial Objectives:
Primary: To compare the acute effects of inhaled nitric oxide to placebo on dyspnea intensity
(measured by 10-Point Borg Dyspnea Index) and inspiratory neural drive (IND) by diaphragm
activation (EMGdi/EMGdi max) at rest, isotime and end-exercise during cardiopulmonary
exercise testing (cycle ergometer).
Secondary: To compare the acute effects of inhaled nitric oxide to placebo on lung volumes,
VE/VCO2 nadir, and dynamic respiratory mechanics at rest, isotime and end-exercise during
cardiopulmonary exercise testing (cycle ergometer).
Hypothesis:
The following hypothesis will be tested 1) acute administration of inhaled nitric oxide
(compared with placebo) will be associated with reduced VE/VCO2 nadir, IND, dyspnea, and
increased exercise endurance time in patients with CTED or post-PE syndrome. The reduced
ventilatory demand and breathing pattern alterations following inhaled vasodilator will be
associated with delay in the onset of mechanical limitation to exercise.
