All-Extremity Exercise as a Novel Strategy for Optimizing Cardiovascular Function during Chemotherapy for Breast Cancer

摘要 目前，美国有350万乳腺癌幸存者，这一数字预计将 急剧增加。早期乳腺癌幸存者更有可能死于心血管疾病(CVD) 而不是乳腺癌。暴露于化疗可能会加剧现有的心血管危险因素，或可能导致急性 和长期的心血管毒性。关于化疗对心血管影响的研究通常 重点关注急性心脏毒性效应。但化疗对血管的影响，可能会有更长的时间 术语后果，并没有很好地刻画。最近，越来越多的证据表明，化疗可能会 导致内皮功能障碍，这是心血管疾病发展过程中导致动脉粥样硬化保护丧失的关键早期事件 并独立预测CVD事件和进展。因此，预防乳腺癌心血管疾病的策略 接受化疗的患者具有重要的临床意义。有氧运动在乳房期间被认为是安全的 癌症化疗可能是预防心血管毒性的有效策略，但有 在人体中的数据有限，没有随机对照试验。急性化疗引起的副作用(例如， 疲劳、肌肉无力、平衡问题、摔倒风险增加)带来了独特的挑战，可能 影响运动的可行性和耐受性，进而影响运动的有效性。我们最近开发了一种全- 肢体非负重运动干预是一种很有前途的新颖创新运动 适用于乳腺癌患者化疗期间的方法，可能优于其他广泛推荐的方法 锻炼的形式。我们的中心假设是，ANE是可行的，并将导致更大的心血管 在乳腺癌化疗期间提供保护，而且比步行耐受性更好。这样做的目的是 探索性/发育性R21在非转移性乳腺癌患者中的应用 正在接受化疗的癌症患者：1)ANE、跑步机运动(TE)和常规护理(UC)对患者的影响 血管内皮细胞和心功能；2)ANE与TE的可行性、耐受性和安全性。乳房 癌症患者将被随机分配到接受12周监督的ANE、TE或UC期间 化疗。运动训练将受到监督，运动处方将根据他们的初始情况进行个性化 健康水平，并将逐渐进步到峰值心率的70%，50分钟/次，每周3天。初级阶段 重点将通过高分辨率的肱动脉血流介导的扩张来评估内皮功能 超声心动图和斑点追踪超声心动图评估整体纵向应变。心血管病 评估和其他研究措施将在化疗开始前和化疗结束后完成 干预。在整个干预过程中，将监测可行性、耐受性和安全性。这 探索性/发育性R21将提供早期证据，表明我们有希望的AND干预 是可行的，在减少心血管毒性方面更有效，在乳房期间比TE耐受性更好 癌症化疗。我们的发现将为第三阶段临床试验奠定基础。

ABSTRACT Currently, there are 3.5 million breast cancer survivors in the United States and this number is expected to increase dramatically. Early stage breast cancer survivors are more likely to die of cardiovascular disease (CVD) than breast cancer. Exposure to chemotherapy may exacerbate existing CVD risk factors or may lead to acute and long-term cardiovascular toxicity. Studies on the cardiovascular impact of chemotherapy have typically focused on acute cardiotoxic effects. However, the vascular impact of chemotherapy, which may have longer term consequences, is not well characterized. Recently, there is increasing evidence that chemotherapy may cause endothelial dysfunction, a key early event in CVD development which leads to loss of atheroprotection and independently predicts CVD events and progression. Therefore, strategies to prevent CVD in breast cancer patients undergoing chemotherapy are clinically important. Aerobic exercise is considered safe during breast cancer chemotherapy and may be an effective strategy for guarding against cardiovascular toxicity but there are limited data in humans and no randomized controlled trials. Acute chemotherapy-induced side effects (e.g., fatigue, muscle weakness, balance problems, increased risk of falls) present unique challenges that may influence the feasibility and tolerability of exercise, and in turn its efficacy. We have recently developed an all- extremity non-weight-bearing exercise (ANE) intervention which is a promising novel and innovative exercise approach for breast cancer patients during chemotherapy and may be superior to other widely recommended forms of exercise. Our central hypothesis is that ANE will be feasible and will lead to greater cardiovascular protection during breast cancer chemotherapy and will be better tolerated than walking. The aims of this exploratory/developmental R21 application are to investigate in patients with primary non-metastatic breast cancer who are undergoing chemotherapy: 1) the effect of ANE, treadmill exercise (TE) and usual care (UC) on endothelial and cardiac function; and 2) the feasibility, tolerability and safety of ANE compared with TE. Breast cancer patients will be randomly assigned to receive 12 weeks of supervised ANE, TE or UC during chemotherapy. Exercise training will be supervised, and exercise prescription will be personalized to their initial fitness level and will gradually progress to 70% of peak heart rate, 50 min/session, 3 days/week. The primary focus will be on endothelial function assessed by brachial artery flow-mediated dilation via high-resolution ultrasonography and global longitudinal strain assessed by speckle tracking echocardiography. Cardiovascular assessments and other study measures will be completed before initiation of chemotherapy and after the intervention. Feasibility, tolerability, and safety will be monitored throughout the intervention. This exploratory/developmental R21 will provide early evidence on whether our promising ANE intervention is feasible, more effective in mitigating cardiovascular toxicity and better tolerated than TE during breast cancer chemotherapy. Our findings will lay the foundation for a Phase III clinical trial.