Oxygen Pathway Limitations in Patients With Chronic Thromboembolic Pulmonary Hypertension

Abstract

Background: Exertional intolerance is a limiting and often crippling symptom in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Traditionally the etiology has been attributed to central factors, including ventilation-perfusion mismatch, increased pulmonary vascular resistance and right heart dysfunction and uncoupling. Pulmonary endarterectomy and, balloon pulmonary angioplasty provide substantial improvement of functional status and hemodynamics. However, despite normalization of pulmonary hemodynamics, exercise capacity often does not return to age-predicted. By systematically evaluating the oxygen (O 2 ) pathway we aimed to elucidate the cause/s of functional limitations in CTEPH patients before and after pulmonary vascular intervention. Methods: Using exercise cardiac magnetic resonance (CMR) imaging with simultaneous invasive hemodynamic monitoring, we sought to quantify the steps of the O2 transport cascade from the mouth to the mitochondria in patients with CTEPH (n=20) as compared to healthy subjects (n=10). Furthermore we evaluated the effect of pulmonary vascular intervention (pulmonary endarterectomy or balloon angioplasty) on the individual components of the cascade (n=10). Results: Peak VO2 was significantly reduced in CTEPH patients relative to controls (56±17 vs 112±20% of predicted, p<0.0001). The difference was due to impairments in multiple steps of the O 2 cascade, including O 2 delivery (product of cardiac output and arterial O 2 content), skeletal muscle diffusion capacity, and pulmonary diffusion. The total O 2 extracted in the periphery, i.e. ΔAVO 2 , was not different. Following pulmonary vascular intervention, peak VO 2 increased significantly (12.5±4.0 to 17.8±7.5 ml/kg/min, p=0.036) but remained below age-predicted (70±11%). The O 2 delivery was improved due to an increase in peak cardiac output and lung diffusion capacity. However, peak exercise ΔAVO2 was unchanged, as was skeletal muscle diffusion capacity. Conclusions: We demonstrated that CTEPH patients have significant impairment of all steps in the O 2 utilisation cascade resulting in markedly impaired exercise capacity. Pulmonary vascular intervention increased peak VO 2 , by partly correcting O 2 delivery but having no impact on abnormalities in peripheral O 2 extraction. This suggests that current interventions only partially address patients' limitations and that additional therapies may improve functional capacity.

Diffusing Capacity for Carbon Monoxide Predicts Response to Balloon Pulmonary Angioplasty in Patients With Inoperable Chronic Thromboembolic Pulmonary Hypertension

“…Previous studies showed that concomitant microvasculopathy had a strong influence on the outcome of PEA ( 2 , 21 ). Moreover, microvasculopathy is irreversible, and patients with advanced microvascular impairment can still suffer from exercise intolerance and hypoxia even after normalization of pulmonary hemodynamics by PEA or BPA ( 22 , 23 ). In the present study, the DLCO was comparable between the baseline and follow-up, which was consistent with previous studies ( 24 , 25 ) and suggested a limited effect of BPA on microvasculopathy.…”

Phenotyping long COVID

“…Combining CPET with right heart catheterization or cardiac imaging may uncover exercise pulmonary hypertension, uncoupling of the right heart from the pulmonary circulation or altered matching of convective and diffusive O 2 transport mechanisms [ 29 ]. Such analyses were recently reported in patients with chronic thromboembolic pulmonary hypertension [ 30 ] or heart failure [ 31 ]. There is an intriguing tendency to exercise hyperventilation in long COVID [ 13 , 14 ], which may relate to persistent lung thrombotic or fibrotic changes, anemia, hypoxemia or altered chemosensitivity.…”

“…The third study by Motiejunaite et al reports on 114 patients evaluated 3 months after hospital discharge [ 14 ]. Median values of VO 2 max, maximum O 2 pulse and V E /VCO 2 slope were respectively at 18 (IQ 15–21) mL·kg·min −1 , 10 [ 8 – 12 ] mL and 33 [ 30 – 33 , 34–38]. The authors insisted on the contribution of increased V E /VCO 2 , which was higher than the upper limit of normal of 35 in one fourth of the patients, to exercise dyspnea, but otherwise confirmed a deconditioning CPET profile with lower VO 2 max than in other studies tentatively explained by comorbidities and more severe initial disease.…”

Different response of the oxygen pathway in patients with chronic thromboembolic pulmonary hypertension treated with pulmonary endarterectomy versus balloon pulmonary angioplasty

“…Previous pathological studies have reported frequent presentation of the thickened alveolar wall and deficient angiogenesis in the lungs of CTEPH patients ( 28 ), suggesting that the abnormalities of both the alveolar membrane and pulmonary capillary might contribute to the decrease of DLCO in CTEPH. Howden et al have reported a decrease in oxygen delivery in CTEPH patients at peak exercise ( 15 ), and the mean oxygen delivery at rest was < 645 ml/min in CTEPH patients in our study, which we think was below the normal level, and the reasons for which were as follows: (i) The oxygen delivery is determined by cardiac output and arterial oxygen content, which could be affected by any pathophysiology with an impact on these indices ( 19 ); (ii) The arterial oxygen content is a parameter derived from SaO 2 and PaO 2 ( 19 ); and (iii) The cardiac output index (< 1.9 L/min/m 2 ), SaO 2 (< 93%), and PaO 2 (< 67 mmHg) in CTEPH patients were all below normal levels in this study. The oxygen extraction of patients with CTEPH in our study was less than 180 ml/min (reference value for adults: 250 ml/min) ( 29 ), indicating a secondary impairment of oxygen use in the periphery in patients with CTEPH.…”

“…In patients with CTEPH, occlusion of the pulmonary artery can reduce lung perfusion, causing mismatched ventilation/perfusion and an abnormality in lung function, particularly a decreased lung diffusion capacity ( 13 , 14 ). Moreover, a recent seminal study found that in addition to the pulmonary gas exchange, multiple steps of the oxygen pathway were defective in patients with CTEPH, including oxygen extraction by peripheral tissues, and pulmonary vascular interventions could partly correct the impaired oxygen pathway ( 15 ), in which only 10 patients had available data on the oxygen pathway after intervention. Despite the improved outcomes of CTEPH patients treated with PEA and BPA, the effects of these two interventions on the oxygen pathway are not well demonstrated and have not yet been compared.…”