Coronary microvascular dysfunction and Dysregulated nNOS signalling as patho-mechanisms in Heart Failure with Preserved Ejection Fraction (HFpEF)

冠状动脉微血管功能障碍和 nNOS 信号传导失调作为射血分数保留的心力衰竭 (HFpEF) 的病理机制

• 批准号: MR/Y001311/1
• 负责人: Kevin O'Gallagher
• 金额: $ 179.61万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY001311%2F1
• 关键词: Coronary; microvascular; dysfunction; Dysregulated; nNOS

Heart Failure with Preserved Ejection Fraction (HFpEF) is a heart condition that severely affects patients' quality of life and can be fatal. In HFpEF, although the heart pumps with adequate strength, the heart muscle is unable to relax properly after each squeeze. This leads to accumulation of fluid and shortness of breath, which can be so severe that it requires admission to hospital.We do not fully understand what causes the heart dysfunction that is seen in HFpEF. Perhaps because of this lack of understanding, there are only few proven medicines for HFpEF. It has been suggested that abnormalities in the function of the tiny, microscopic arteries in the heart ("coronary microvascular dysfunction") may play a role in the development of HFpEF, as may abnormalities in the production of nitric oxide, a small molecule that has an important role in heart relaxation. It is thought that there may be too much nitric oxide produced within the heart due to abnormal increases in activity of a particular enzyme called neuronal nitric oxide synthase ('nNOS'). Across three studies, the proposed research will seek to explore in detail the relationship between coronary microvascular dysfunction and abnormal nitric oxide signalling with heart function in patients with HFpEF.Patients with HFpEF often undergo hospital tests to check the heart arteries and to measure the pressures within the heart, a procedure called cardiac catheterisation. In Aim 1, we will perform measures of coronary microvascular function and heart function in patients with HFpEF during their cardiac catheterisation test. We will place special wires in the heart arteries and within the heart to measure the coronary microvascular function and heart function both at rest and during exercise. We have performed similar research procedures with many patients in previous research studies and we know that these techniques are safe. By combining the information from the heart arteries and from the heart function, this will allow us to understand how the coronary microvascular function affects heart function in HFpEF. Aim 2 will also involve patients with HFpEF who are undergoing cardiac catheterisation tests. We will give patients a drug that is known to temporarily block the function of nNOS to see what the effect is on heart function both at rest and during exercise. The effect in patients with HFpEF will be compared with the effect in patients without HFpEF. The results of this study are important because if it confirmed that nNOS activity is abnormally high in HFpEF then new treatments could be designed to decrease nNOS activity and potentially improve heart relaxation in HFpEF.In Aim 3 we will compile a database, or registry, of patients with HFpEF who have been assessed for coronary microvascular dysfunction. This will include the patients in Aims 1 and 2 but may also include any patient with HFpEF who has had scans such as heart ultrasound or MRI to assess for heart artery disease. We will record information on patients when we first meet them and then again after 1 year. This will give us important information as to whether patients with HFpEF and coronary microvascular dysfunction have worse symptoms and more hospitalisations that those without coronary microvascular dysfunction. Overall, the results of the three studies should provide important information on the heart abnormalities that lead to HFpEF. It is hoped that the results may lead the way to new treatments for HFpEF that are targeted at the underlying abnormalities that cause HFpEF.

射血分数保留的心力衰竭 (HFpEF) 是一种严重影响患者生活质量并可能致命的心脏病。在 HFpEF 中，尽管心脏以足够的力量泵血，但心肌在每次挤压后无法适当放松。这会导致体液积聚和呼吸短促，严重时需要入院治疗。我们还不完全了解导致 HFpEF 中出现的心脏功能障碍的原因。也许由于缺乏了解，目前只有少数经过验证的 HFpEF 药物。有人提出，心脏中微小动脉的功能异常（“冠状动脉微血管功能障碍”）可能在 HFpEF 的发生中发挥作用，一氧化氮（一种小分子，具有对心脏放松有重要作用。人们认为，由于一种称为神经元一氧化氮合酶（“nNOS”）的特定酶的活性异常增加，心脏内可能产生过多的一氧化氮。通过三项研究，拟议的研究将寻求详细探讨 HFpEF 患者冠状动脉微血管功能障碍和异常一氧化氮信号传导与心脏功能之间的关系。 HFpEF 患者经常接受医院检查以检查心脏动脉并测量内部压力心脏，一种称为心导管插入术的手术。在目标 1 中，我们将在 HFpEF 患者心导管检查期间测量冠状动脉微血管功能和心脏功能。我们将在心脏动脉和心脏内放置特殊的导线，以测量休息和运动时的冠状微血管功能和心脏功能。我们在之前的研究中对许多患者进行了类似的研究程序，我们知道这些技术是安全的。通过结合来自心脏动脉和心脏功能的信息，这将使我们能够了解冠状动脉微血管功能如何影响 HFpEF 中的心脏功能。目标 2 还将涉及正在接受心导管检查的 HFpEF 患者。我们将为患者提供一种已知可暂时阻断 nNOS 功能的药物，以观察其对休息时和运动时的心脏功能有何影响。将比较 HFpEF 患者的效果与无 HFpEF 患者的效果。这项研究的结果很重要，因为如果它证实 HFpEF 中的 nNOS 活性异常高，那么可以设计新的治疗方法来降低 HFpEF 中的 nNOS 活性，并可能改善 HFpEF 中的心脏松弛。在目标 3 中，我们将编制一个数据库或注册表，其中包含以下内容：已接受冠状动脉微血管功能障碍评估的 HFpEF 患者。这将包括目标 1 和 2 中的患者，但也可能包括任何接受过心脏超声或 MRI 等扫描以评估心脏病的 HFpEF 患者。我们将在第一次见到患者时记录其信息，并在一年后再次记录。这将为我们提供重要信息，说明患有 HFpEF 和冠状动脉微血管功能障碍的患者是否比没有冠状动脉微血管功能障碍的患者有更严重的症状和更多的住院治疗。总体而言，三项研究的结果应提供有关导致 HFpEF 的心脏异常的重要信息。希望这些结果可以为 HFpEF 的新治疗方法指明道路，这些治疗针对的是导致 HFpEF 的潜在异常。