HFpEF: more than just the heart - Why the mitochondria and capillaries matter

HFpEF：不仅仅是心脏 - 为什么线粒体和毛细血管很重要

基本信息

批准号：
9013212
负责人：
Payman Zamani
金额：
$ 17.47万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-10 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9013212
关键词：
Admission activity Aerobic Affect Age Award Biology Blood capillaries Cardiac Output Cells Collaborations Complex Diagnosis Diffusion Disease Dose Dyspnea EFRAC Epidemic Exercise Exercise Physiology Faculty Functional disorder Goals Heart Heart Transplantation Heart failure Hospitals Image Impairment Individual Investigation Left Left ventricular structure Life Experience Limb structure Magnetic Resonance Imaging Measurement Measures Mentors Mentorship Mitochondria Morbidity - disease rate Muscle Muscle Mitochondria Near-Infrared Spectroscopy Nitrates Nitric Oxide Oxygen Patients Pennsylvania Peripheral Play Prevalence Process Quality of life Randomized Role Shortness of Breath Skeletal Muscle Societies Supplementation Syndrome Techniques Training Translating United States Universities Venous blood sampling Work aging population base capillary career development design exercise capacity exercise intolerance experience hemodynamics improved member mortality novel novel therapeutics oxygen transport patient oriented patient oriented research pressure public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Heart failure (HF) is responsible for over a million hospital admissions annually in the US, and is the leading discharge diagnosis for patients over 65. Nearly half of the people admitted for HF have HF with preserved ejection fraction (HFpEF). HFpEF is associated with reduced quality of life and reduced survival, equal to that of patients with heart failure with reduced ejection fraction (HFrEF). Unfortunately, there are no known pharmacologic therapies that consistently improve either the morbidity or mortality associated with HFpEF. Several large trials of neurohormonal antagonists, agents known to improve survival in HFrEF, failed to establish benefit in HFpEF, suggesting that the mechanisms at play in HFpEF may be inadequately explained by those implicated in HFrEF. An early paradigm of HFpEF pathophysiology was that a stiff left ventricle leads to elevated filling pressures during exercise, resulting in shortness of breath. However, it is now recognized that HFpEF is a much more complex syndrome with important contributions from the periphery-including the skeletal muscle and the microvasculature. The broad working hypothesis of this proposal is that abnormalities in the skeletal muscle and the microvasculature play important roles in the exercise limitation seen in heart failure, in general, and in HFpEF specifically. This proposal seeks to demonstrate the relationships between exercise and (1) skeletal muscle mitochondrial oxidative capacity and (2) the diffusion capacity of oxygen to move from the capillary to the mitochondria. In Aim 1, skeletal muscle mitochondrial oxidative capacity will be determined non-invasively using MRI and near-infrared spectroscopy techniques, while Aim 2 will investigate diffusion capacity through maximal limb exercise with concurrent sampling of venous blood and measurements of arterial inflow. We hypothesize that patients with HFpEF will have greater impairments in mitochondrial function and diffusion capacity than patients with HFrEF or hypertensive controls. In Aim 3, we will randomize patients with HFpEF to inorganic nitrate, an agent known to improve exercise capacity and with the potential to affect both skeletal muscle mitochondrial oxidative capacity and diffusion capacity, to determine the relative contributions of these peripheral mechanisms to exercise capacity in HFpEF. Demonstration of an important role of these peripheral factors would open new avenues of investigation into ways to improve exercise capacity in HFpEF. Dr. Zamani is a heart failure and transplant cardiologist with experience in patient-oriented research in HFpEF. His long-term goal is to become a leader in the peripheral manifestations of heart failure and identify how abnormalities in the periphery impact exercise capacity. His patient-oriented career development training plan includes mentoring by experts in heart failure, exercise physiology, mitochondrial function, nitric oxide biology, and arterial hemodynamics. His proposed studies leverage the facilities and expertise available to him at the University of Pennsylvania, with important collaborations with outside faculty members.

描述（由适用提供）：心力衰竭（HF）每年在美国负责超过一百万个医院入院，并且是65岁以上患者的领先出院诊断。几乎一半的HF患者的HF患者具有保留的射血分数（HFPEF）。 HFPEF与降低的生活质量和降低的生存有关，等于射血分数降低（HFREF）的心力衰竭患者。不幸的是，尚无已知的药理学疗法，可以持续改善与HFPEF相关的发病率或死亡率。几项对神经激素拮抗剂的大型试验，即已知可以改善HFREF生存的药物，未能在HFPEF中建立益处，这表明HFPEF中的机制可能会被HFREF所隐含的机制不充分解释。 HFPEF病理生理学的早期范式是，左心室僵硬会导致运动过程中的填充压力升高，导致呼吸急促。但是，现在已经认识到，HFPEF是一种更复杂的综合征，其中包括骨骼肌和微脉管系统的周围贡献。该提议的广泛工作假设是，骨骼肌和微脉管系统的异常在限制运动中，通常是心力衰竭，通常是HFPEF中的重要作用。该提议旨在证明运动与（1）骨骼肌线粒体氧化能力和（2）氧气从毛细管转移到线粒体的扩散能力。在AIM 1中，将使用MRI和近红外光谱技术非侵入性地确定骨骼肌线粒体氧化能力，而AIM 2将通过最大的肢体运动与同时对静脉血和动脉流动的测量进行最大程度的采样来研究扩散能力。我们假设与HFREF或高血压控制患者相比，HFPEF患者的线粒体功能和扩散能力的损害更大。在AIM 3中，我们将将HFPEF患者随机为无机硝酸盐，这是一种已知的药物，可提高运动能力并影响骨骼肌肉线粒体氧化能力和扩散能力，以确定确定的相对贡献，以确定这些外围机制以在HFPEF中行使能力。这些外围因素的重要作用的证明将为提高HFPEF运动能力的方式开放新的投资途径。 Zamani博士是一名心力衰竭和移植心脏病专家，在HFPEF中以患者为导向的研究经验。他的长期目标是成为心力衰竭周围表现的领导者，并确定外围影响运动能力异常。他以患者为导向的职业发展培训计划包括心力衰竭专家，运动生理，线粒体功能，一氧化氮生物学和动脉血流动力学的心理。他的拟议研究利用了宾夕法尼亚大学提供的设施和专业知识，并与外部教职员工合作。