Response to Aerobic Exercise in Patients with Pulmonary Hypertension

该研究于2015年结束招募，并继续进行数据分析。我们的工作为肺动脉高压（PH）辅助治疗的循证指南做出了重大贡献。我们的RCT研究结果为美国心脏病学会（ACC）发布的更新治疗算法做出了贡献，其中对PH患者的康复和运动训练建议升级为1级，证据等级为a级（Galie et al, 2013）。虽然有氧训练对慢性阻塞性肺疾病和慢性心力衰竭患者的益处是众所周知的，但它在PH患者中的效用尚不清楚。在我们的研究中，我们旨在了解限制PH患者峰值耗氧量（VO2）的心肺机制，并确定这些机制是否可以通过有氧运动训练逆转。我们还研究了机制指标与功能表现之间的关系（如6分钟步行距离、跑步机峰值工作速率和峰值运动时间）。一组自我报告量表也被用来调查有氧运动训练对情绪、身体活动、疲劳和运动准备的影响。因此，我们的临床试验考察了PH患者心肺功能受限的主要机制，并确定有氧运动训练是否能逆转这一机制。我们还研究了限制机制的逆转在多大程度上实际上改善了身体表现，以及有氧运动训练对健康相关的生活质量和身体活动的影响。

This study was closed in 2015 to recruitment and continues in data analysis. Our work has contributed significantly to evidence-based guidelines for adjunct therapy in the treatment of pulmonary hypertension (PH). Findings from our RCT contributed to the updated treatment algorithm published by the American College of Cardiology (ACC), where the recommendation for rehabilitation and exercise training for patients with PH was upgraded to Class 1 with A-Level of Evidence (Galie et al, 2013). While the benefits of aerobic training are known for patients who have chronic obstructive pulmonary disease and chronic heart failure, its utility among patients with PH has been unclear. In our study, we aim to understand the cardiorespiratory mechanisms that limit peak oxygen consumption (VO2) in patients with PH, and to determine whether these mechanisms are reversible with aerobic exercise training. We also examine the relationship between indices of mechanism and functional performance (such as 6-minute walk distance, peak treadmill work rate, and peak exercise time). A battery of self-report scales are also utilized to investigate the effect of aerobic exercise training on mood, physical activity, fatigue, and exercise readiness. Thus, our clinical trial examines the gross mechanism by which cardiorespiratory function is limited in patients with PH, and determines whether aerobic exercise training reverses this mechanism. We also examine the extent to which reversal of the limiting mechanism actually improves physical performance, and the effect of aerobic exercise training on health related quality of life and physical activity. This project has two main clinical research arms. The first is a phase II clinical trial that evaluates the safety and effectiveness of aerobic exercise training on cardiorespiratory fitness and health related quality of life in patients with PH. After screening and physician exam, qualifying patients first complete a 6-minute walk test. After a 45-minute rest period, the patient then completes self-report questionnaires on general fatigue, mood, physical activity and overall quality of life. Patients then undergo symptom-limited peak treadmill exercise tests to volitional exhaustion. During the treadmill tests, cardiorespiratory measurements are made including pulmonary gas analyses, cardiac output, and near infrared spectroscopic measures of muscle oxygen extraction. After the test battery is completed, the patient is randomized to one of two groups for 10-weeks; either patient education conducted with aerobic exercise training or patient education only (i.e. controls). Those in the education plus exercise group attends classes geared towards topics related to disease management as well as thrice weekly sessions of 30 to 45 minutes of treadmill walking at a vigorous exercise intensity. The education only group receives identical education classes but do not perform exercise. Patients in both groups repeat all assessments (i.e., 6-minute walk test, questionnaires, and treadmill test) following their 10 weeks of participation. Pre- and post-exercise training changes are compared between the groups. Main outcome variables are peak oxygen consumption and 6-minute walk test distance. In the second arm of the project, sedentary but otherwise healthy control subjects will also perform the same baseline assessments as the patients with PH. We will examine whether differences are observed in the treadmill test in terms of an exercise response, muscle oxygen extraction and cardiac output. This study arm will help us determine whether patients with PH have abnormal responses to exercise, and if exercise training can induce physiological changes toward a normal response. There are also two sub-studies in this project. In the first sub-study, subjects randomized to the education only group will crossover to perform an exercise training regimen that is identical to the education plus exercise group. This group will also complete all assessments (i.e., 6-minute walk test, questionnaires, and treadmill test) following completion of the 10-week exercise training regimen. This sub-study will discern the cardiorespiratory adaptations to exercise between the education plus exercise group and the group originally receiving only education. In the second sub-study, we are examining the training adaptation in patients with interstitial lung disease (ILD) who do not have PH. Patients with ILD will undergo an exercise training regimen identical to the one used for training patients with PH. Responses and adaptations to exercise training will be compared. This sub-study is important for data interpretation since many of our patients with PH also have ILD. Total Number of Subjects Enrolled = 91 Total Number of Subjects Enrolled in the current year = 0 (study open for data analysis only) Total Number of Subjects Enrolled that dropped = 9 Total Number of Subjects Enrolled that dropped this year = 0 (study open for data analysis only) Pulmonary Hypertension = 28 Interstitial Lung Disease = 14 Healthy = 40 Although the sample size was small, our RCT has shown that patients with PH can attain exercise-induced benefits that include higher levels of physical activity, decreased fatigue severity, improved functional and physical work capacity, and greater patient-reported quality of life as compared with patients that did not perform exercise (i.e. control arm). Our research was also referenced in a panel discussion on Exercise and Pulmonary Rehabilitation at the 2014 International PH Association Conference in Indianapolis, IN, where the consensus of medical opinion stated exercise in a supervised setting is critical for PH patients (Bull et al, 2014). Interpreting our findings to date has provided our team with opportunities to identify additional important research questions pertinent to rehabilitation of patients with PH. We will also utilize the data collected from the healthy participants for comparisons to a follow-up randomized controlled exercise trial for patients with ILD (14-CC-0027). The basis for the randomized trial in patients with ILD was established by the sub-study of the current work, where we observed more efficient cardiorespiratory function, increased physical work capacity, and improved health related quality of life (HRQoL), following exercise training in an uncontrolled arm of patients with ILD uncomplicated by PH. In FY22, other data analysis and manuscript preparations are in progress and will be forthcoming.