Baker Heart and Diabetes Institute (E.J.H., S.R.-C., A.L.G., G.C.), Melbourne, Australia.
Cambridge Baker Systems Genomics Initiative (S.R.-C.), Melbourne, Australia.
Circulation. 2021 May 25;143(21):2061-2073. doi: 10.1161/CIRCULATIONAHA.120.052899. Epub 2021 Apr 15.
Exertional intolerance is a limiting and often crippling symptom in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Traditionally the pathogenesis 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 levels. By systematically evaluating the oxygen pathway, we aimed to elucidate the causes of functional limitations in patients with CTEPH before and after pulmonary vascular intervention.
Using exercise cardiac magnetic resonance imaging with simultaneous invasive hemodynamic monitoring, we sought to quantify the steps of the O transport cascade from the mouth to the mitochondria in patients with CTEPH (n=20) as compared with healthy participants (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).
Peak Vo (oxygen uptake) was significantly reduced in patients with CTEPH relative to controls (56±17 versus 112±20% of predicted; <0.0001). The difference was attributable to impairments in multiple steps of the O cascade, including O delivery (product of cardiac output and arterial O content), skeletal muscle diffusion capacity, and pulmonary diffusion. The total O extracted in the periphery (ie, ΔAVo [arteriovenous O content difference]) was not different. After pulmonary vascular intervention, peak Vo increased significantly (from 12.5±4.0 to 17.8±7.5 mL/[kg·min]; =0.036) but remained below age-predicted levels (70±11%). The O delivery was improved owing to an increase in peak cardiac output and lung diffusion capacity. However, peak exercise ΔAVo was unchanged, as was skeletal muscle diffusion capacity.
We demonstrated that patients with CTEPH have significant impairment of all steps in the O use cascade, resulting in markedly impaired exercise capacity. Pulmonary vascular intervention increased peak Vo by partly correcting O delivery but had no effect on abnormalities in peripheral O extraction. This suggests that current interventions only partially address patients' limitations and that additional therapies may improve functional capacity.
运动不耐受是慢性血栓栓塞性肺动脉高压（CTEPH）患者的一种限制，且常导致残疾的症状。传统上，其发病机制归因于中央因素，包括通气/灌注不匹配、肺动脉阻力增加以及右心功能障碍和去耦。肺动脉内膜切除术和球囊肺动脉成形术可显著改善功能状态和血流动力学。然而，尽管肺血流动力学正常化，运动能力通常仍无法恢复到年龄预测的水平。通过系统评估氧途径，我们旨在阐明 CTEPH 患者在肺血管干预前后功能受限的原因。
我们使用运动心脏磁共振成像和同时进行的有创血流动力学监测，来比较 CTEPH 患者（n=20）与健康参与者（n=10）从口到线粒体的 O 转运级联的各个步骤。此外，我们评估了肺血管干预（肺动脉内膜切除术或球囊血管成形术）对级联中各个组成部分的影响（n=10）。
与对照组相比，CTEPH 患者的峰值 Vo（摄氧量）明显降低（56±17 对 112±20%的预测值；<0.0001）。差异归因于 O 级联的多个步骤受损，包括 O 输送（心输出量和动脉 O 含量的乘积）、骨骼肌扩散能力和肺扩散。外周提取的总 O（即 ΔAVo [动静脉 O 含量差]）没有差异。肺血管干预后，峰值 Vo 显著增加（从 12.5±4.0 增加到 17.8±7.5 mL/[kg·min]；=0.036），但仍低于年龄预测值（70±11%）。由于峰值心输出量和肺扩散能力的增加，O 输送得到改善。然而，峰值运动 ΔAVo 保持不变，骨骼肌扩散能力也是如此。
我们证明 CTEPH 患者的 O 使用级联中的所有步骤均有明显受损，导致运动能力明显受损。肺血管干预通过部分纠正 O 输送增加了峰值 Vo，但对周围 O 提取异常没有影响。这表明目前的干预措施仅部分解决了患者的局限性，并且可能需要额外的治疗方法来改善功能能力。
