Personalized Exercise Training to Improve Functional Capacity in Transthyretin Cardiac Amyloidosis

项目摘要 心力衰竭(HF)影响着超过500万65岁以上的成年人。心脏转甲状腺素淀粉样变性(ATTR-CM) 在大约10%的老年人中是心力衰竭的原因之一，并导致显著的发病率和死亡率。肌肉骨骼 临床表现在ATTR-CM中很常见，发生在心力衰竭发病前5-10年。运动不耐受，a 主要特征，传统上被归因于心脏功能障碍，但促成全身机制并不是 已经评估过了。他法米司是一种转甲状腺素稳定剂，是唯一被批准的治疗ATTR-CM的药物。它可以延缓疾病 进展，延长生命，减少心衰住院。然而，它并没有提高功能容量- 在ATTR-CM中还没有显示出这样做的治疗干预。这项提议的中心前提是 淀粉样变性和心力衰竭引起的骨骼肌功能障碍严重限制了有氧能力，从而限制了患者的生活质量 有针对性的运动训练将通过改善骨骼肌来提高生活质量 表现和有氧能力。心肺运动试验(CPET)与短程体检 性能电池(SBBP)，包括腿部伸肌力量评估将用于实现 以下是特定的目标：1)比较ATTR-CM和非淀粉样蛋白HF患者的骨骼肌表现；以及2) 确定12周监督运动训练对有氧能力和生活质量的改善 在ATTR-CM患者中。为了实现第二个目标，我们使用了开发的个性化运动干预 并由Bhasin博士在波士顿老年美国人独立中心(波士顿OAIC)的团队领导。 卡迪博士是哈佛医学院和布里格姆妇女医院(BWH)的医学讲师 他有很高的资历和投资来领导这项研究。她是一位心脏病专家和心脏病专家。 淀粉样变性，有成功研究的记录，包括出版物和奖项。她长期的职业生涯 目标是成为一名临床科学家，站在优化成人ATTR-CM生活质量的前沿。这 将在综合职业发展方案的背景下完成研究，旨在 为应聘者提供成为简历医学领域独立内科科学家所需的技能， 由莎米拉·多巴拉博士领导的一支资质良好的导师团队。在本提案中收集的关于系统性的数据 这一人群中的功能障碍和运动训练的有效性最终将为未来的治疗试验提供信息。 一个由心血管医学领域的知名科学家组成的杰出的指导团队和咨询委员会， 简历成像、衰老和功能促进疗法将指导候选人过渡到科学 在获奖期内保持独立性。

Project Summary Heart failure (HF) affects over 5 million adults over the age of 65. Cardiac transthyretin amyloidosis (ATTR-CM) is a cause of HF in ~10% of older adults and leads to significant morbidity and mortality. Musculoskeletal manifestations are common in ATTR-CM and occur 5-10 years prior to onset of HF. Exercise intolerance, a cardinal feature, is traditionally attributed to cardiac dysfunction but contributing systemic mechanisms have not been evaluated. Tafamidis, a transthyretin stabilizer, is the only approved therapy for ATTR-CM. It slows disease progression, prolongs life, and reduces HF hospitalizations. However, it does not improve functional capacity- no therapeutic intervention has been shown to do so in ATTR-CM. The central premise of this proposal is that skeletal muscle dysfunction from amyloidosis and HF severely limits aerobic capacity and, thus, quality of life in ATTR-CM, and that targeted exercise training will improve quality of life by improving skeletal muscle performance and aerobic capacity. Cardiopulmonary exercise testing (CPET) and the short physical performance battery (SBBP), including a leg extensor muscle power assessment will be used to achieve the following specific aims; 1) to compare skeletal muscle performance in ATTR-CM and non-amyloid HF; and 2) to determine improvements in aerobic capacity and quality of life due to 12 weeks of supervised exercise training in patients with ATTR-CM. To achieve the second aim, we use a personalized exercise intervention developed and led by Dr Bhasin’s team at the Boston Older Americans Independence Center (Boston OAIC) at BWH. Dr. Cuddy is an Instructor of Medicine at Harvard Medical School and Brigham and Women’s Hospital (BWH) who is highly qualified and invested in leading this study. She is a cardiologist and an expert in cardiac amyloidosis with a track record of successful research, including publications and awards. Her long-term career goal is to be become a clinician-scientist at the forefront of optimizing quality of life in adults with ATTR-CM. This research will be accomplished in the setting of a comprehensive career development program designed to provide the candidate with the skills needed to become an independent physician-scientist in CV medicine, with a well-qualified mentorship team led by Dr. Sharmila Dorbala. Data collected in this proposal on systemic dysfunction and the efficacy of exercise training in this population will ultimately inform future therapeutic trials. An outstanding mentoring team and advisory committee of established scientists in the fields of CV medicine, CV imaging, Aging, and Function-promoting therapies, will guide the candidate in her transition to scientific independence over the course of the award period.