Symptoms and Skeletal Muscle in Persons with Heart Failure with Preserved Ejection Fraction

摘要 这项研究将探讨慢性高血压左心室肥厚的心力衰竭子集 与保留射血分数（HFpEF）连接骨骼肌超微结构和生化， 症状、生活质量和功能能力。包括高血压，久坐不动的生活方式， 肌肉失调和肥胖导致多种细胞变化，如心脏肥大， 神经激素失调和蛋白质稳态紊乱。这些过程导致 发生HFpEF，伴有呼吸困难和疲乏的下游后遗症，功能能力下降， 和结构性肌肉损伤高血压是心脏相关死亡率的最大贡献者之一 并且是作为左心室肥大的结果的HFpEF的主要原因。这项研究假设， 心力衰竭（HF）症状和功能能力与骨骼肌超微结构有关， 射血分数正常的心力衰竭（HFpEF）患者的生物化学。这两年的横截面 研究将招募40名HFpEF参与者，并使用健康对照的储存样本检查骨骼 肌肉结构和功能。患者问卷将用于评估疲劳、呼吸困难严重程度和 HFpEF患者的生活质量。此外，运动的感知障碍和益处将 通过问卷进行评估。将使用六分钟步行测试和运动来评估功能状态 跑台试验将进行肌肉活检以研究骨骼肌的结构和功能方面 确定功能能力，包括定量纤维类型的常规评估， 截面积，毛细血管密度和线粒体功能，并进一步探索一个新的发现， 研究了心肌细胞超微结构损伤的一种假定机制，即糜蛋白酶诱导的结蛋白分解 和线粒体功能障碍，作为HFpEF患者功能能力的重要因素。通过 重点关注一个明确的高血压和左心室肥大患者的子集， 研究可用于创建HFpEF预防和治疗，靶向治疗， 更好地预测这一高死亡率人群的结局。

ABSTRACT The proposed study will examine the chronic hypertensive left ventricular hypertrophy subset of heart failure with preserved ejection fraction (HFpEF) to connect skeletal muscle ultrastructure and biochemistry to symptoms, quality of life, and functional capacity. Conditions including hypertension, sedentary lifestyle, muscular deconditioning, and obesity result in a variety of cellular changes, such as cardiac hypertrophy, neurohormonal dysregulation and derangements in protein homeostasis. These processes result in the development of HFpEF with the downstream sequelae of dyspnea and fatigue, decreased functional capacity, and structural muscle damage. Hypertension is one of the greatest contributors to cardiac-related mortality and is a primary cause of HFpEF as a result of left ventricular hypertrophy. This study hypothesizes that that heart failure (HF) symptoms and functional capacity are connected to skeletal muscle ultrastructure and biochemistry in persons with heart failure with preserved ejection fraction (HFpEF). This 2-year cross-sectional study will enroll 40 participants with HFpEF and use stored samples from healthy controls to examine skeletal muscle structure and function. Patient questionnaires will be used to assess fatigue, dyspnea severity and quality of life in persons with HFpEF. In addition, perceived barriers to and benefits of exercise will be assessed via questionnaire. Functional status will be assessed using the six-minute walk test and an exercise treadmill test. Muscle biopsies will be performed to study structural and functional aspects of skeletal muscle that determine functional capacity including the conventional assessment of quantification of fiber types, cross- sectional area, capillary density, and mitochondrial function, and to further explore a novel finding that examines a putative mechanism of myocyte ultrastructural damage, chymase-induced breakdown of desmin and mitochondrial dysfunction, as an important factor of functional capacity in persons with HFpEF. By focusing on a subset of patients with well-defined hypertension and left ventricular hypertrophy, data from this study can be used to create precision medicine in HFpEF prevention and treatment, targeted therapies, and better prediction of outcomes in this high mortality population.