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

 描述（由申请人提供）：心力衰竭（HF）是美国每年超过一百万例住院的原因，是65岁以上患者的主要出院诊断。近一半因HF入院的患者患有射血分数保留的HF（HFpEF）。HFpEF与生活质量降低和生存期缩短相关，与射血分数降低的心力衰竭（HFrEF）患者相同。不幸的是，没有已知的药物治疗，一贯改善与HFpEF相关的发病率或死亡率。几项大型神经激素拮抗剂试验（已知可改善HFrEF患者生存率的药物）未能确定HFpEF的获益，这表明HFrEF中涉及的机制可能无法充分解释HFpEF中起作用的机制。HFpEF病理生理学的早期范例是左心室僵硬导致运动期间充盈压升高，导致呼吸短促。然而，现在认识到HFpEF是一种复杂得多的综合征，其重要作用来自外周，包括骨骼肌和微血管。该建议的广泛工作假设是骨骼肌和微血管系统的异常在心力衰竭中观察到的运动限制中起重要作用，一般而言，特别是在HFpEF中。该建议旨在证明运动与（1）骨骼肌线粒体氧化能力和（2）氧从毛细血管向线粒体扩散能力之间的关系。在目标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，而目标2将通过最大肢体运动研究扩散能力，同时采样静脉血和测量动脉流入。我们假设HFpEF患者的线粒体功能和弥散能力比HFrEF或高血压对照患者受损更严重。在目标3中，我们将HFpEF患者随机分配至无机硝酸盐组，无机硝酸盐是一种已知可提高运动能力并有可能影响骨骼肌线粒体氧化能力和扩散能力的药物，以确定 这些外周机制来锻炼HFpEF中的能力。这些外围因素的重要作用的证明将开辟新的途径，调查如何提高HFpEF的运动能力。Zamani博士是一位心力衰竭和移植心脏病专家，在HFpEF患者导向研究方面拥有丰富经验。他的长期目标是成为心力衰竭外周表现的领导者，并确定外周异常如何影响运动能力。他以患者为导向的职业发展培训计划包括心力衰竭、运动生理学、线粒体功能、一氧化氮生物学和动脉血流动力学专家的指导。他提出的研究利用宾夕法尼亚大学的设施和专业知识，与外部教师进行重要合作。

 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.