Personalized Exercise Training to Improve Functional Capacity in Transthyretin Cardiac Amyloidosis

项目摘要 心力衰竭（HF）影响超过500万65岁以上的成年人。心脏甲状腺素运载蛋白淀粉样变性（ATTR-CM） 在约10%的老年人中是HF的原因，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HF发作前5-10年。运动不耐受，a 主要特征，传统上归因于心功能不全，但贡献全身机制尚未 被评估。Tafamidis是一种甲状腺素运载蛋白稳定剂，是唯一获批的ATTR-CM治疗药物。它能减缓疾病 进展，延长寿命，并减少HF住院治疗。但是，它并没有提高功能能力- 在ATTR-CM中没有治疗干预显示出这样的作用。这一建议的核心前提是， 淀粉样变性和HF引起的骨骼肌功能障碍严重限制了有氧能力，因此， ATTR-CM，并且有针对性的运动训练将通过改善骨骼肌来改善生活质量 性能和有氧能力。心肺功能运动试验（CPET）和短期体格检查 性能电池（SBBP），包括腿部伸肌肌力评估将用于实现 以下具体目的：1）比较ATTR-CM和非淀粉样蛋白HF中的骨骼肌性能;和2） 确定有氧能力和生活质量的改善，由于12周的监督运动训练 在ATTR-CM患者中。为了实现第二个目标，我们使用个性化的运动干预开发 由BWH的波士顿老年美国人独立中心（Boston Older Americans Independence Center）的Bhasin博士团队领导。 博士Cuddy是哈佛医学院和布里格姆妇女医院（BWH）的医学讲师 他是一位高素质的领导者，并致力于领导这项研究。她是一名心脏病专家， 淀粉样变性的成功研究的跟踪记录，包括出版物和奖项。她的长期职业生涯 目标是成为一名临床科学家，站在优化ATTR-CM成人生活质量的最前沿。这 研究将在一个全面的职业发展计划，旨在 为候选人提供成为CV医学独立医生-科学家所需的技能， 由Sharmila Dorbala博士领导的高素质导师团队。本提案中收集的系统性数据 功能障碍和运动训练在这一人群中的疗效将最终为未来的治疗试验提供信息。 由CV医学领域的知名科学家组成的杰出指导团队和咨询委员会， CV成像，衰老和功能促进疗法，将指导候选人过渡到科学 在授标期间保持独立性。

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.