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)在美国每年导致100多万人入院，是65岁以上患者出院诊断的主要原因。近一半因心力衰竭入院的患者心力衰竭的射血分数(HFpEF)保持不变。HFpEF与生活质量下降和生存期减少有关，与心力衰竭患者射血分数降低(HFrEF)的情况相同。不幸的是，目前还没有已知的药物疗法可以持续改善与HFpEF相关的发病率或死亡率。几个神经激素拮抗剂的大型试验，已知可以改善HFrEF的存活率，但未能证明在HFpEF中有益，这表明HFrEF中涉及的机制可能不能充分解释HFpEF中发挥作用的机制。早期的HFpEF病理生理学范式是，在运动过程中，左心室僵硬会导致充盈压力升高，导致呼吸短促。然而，现在人们认识到HFpEF是一种更复杂的综合征，有来自外周的重要贡献-包括骨骼肌和微血管系统。这一建议的广泛工作假设是，骨骼肌和微血管系统的异常在运动受限的心力衰竭中起着重要作用，特别是在HFpEF中。这一建议试图证明运动与(1)骨骼肌线粒体氧化能力和(2)氧从毛细血管向线粒体移动的扩散能力之间的关系。在目标1中，骨骼肌线粒体氧化能力将使用核磁共振成像和近红外光谱技术进行非侵入性测定，而目标2将通过同时采集静脉血和测量动脉流入来研究最大限度的肢体运动的扩散能力。我们假设，与HFrEF或高血压对照组相比，HFpEF患者在线粒体功能和扩散能力方面的损害更大。在目标3中，我们将HFpEF患者随机分为无机硝酸盐组，无机硝酸盐是一种已知可以提高运动能力的药物，可能会影响骨骼肌线粒体的氧化能力和扩散能力，以确定 这些外周机制能锻炼HFpEF的能力。证明这些外围因素的重要作用将为研究如何提高HFpEF的运动能力开辟新的途径。扎马尼博士是一名心力衰竭和移植心脏病学家，在HFpEF以患者为中心的研究方面经验丰富。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。他的以病人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方面的专家指导。他提议的研究利用了他在宾夕法尼亚大学的设施和专业知识，并与外部教职员工进行了重要的合作。

 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.