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

心力衰竭伴保留射血分数(HFpEF)是一种严重影响患者生活质量的心脏疾病，可能是致命的。在HFpEF中，尽管心脏以足够的力量泵入，但在每次挤压后，心肌无法正常放松。这会导致液体堆积和呼吸急促，这种情况可能非常严重，需要住院治疗。我们还不完全清楚是什么导致了HFpEF中出现的心脏功能障碍。也许正是由于缺乏了解，治疗HFpEF的有效药物寥寥无几。有人认为心脏微小动脉的功能异常(冠脉微血管功能障碍)可能在HFpEF的发展中起作用，一氧化氮的产生也可能起作用，一氧化氮是一种在心脏松弛中起重要作用的小分子。据认为，由于一种名为神经元型一氧化氮合酶(NNOS)的特定酶的活性异常增加，心脏内可能产生了过多的一氧化氮。这项拟议的研究将通过三项研究，试图详细探索HFpEF患者冠状动脉微血管功能障碍与异常一氧化氮信号与心功能之间的关系。HFpEF患者经常接受医院测试，以检查心脏动脉并测量心脏内压力，这一过程被称为心导管术。在目标1中，我们将在心导管检查期间对HFpEF患者的冠状动脉微血管功能和心功能进行测量。我们将在心脏动脉和心脏内放置特殊的导线，测量静息和运动时的冠状动脉微血管功能和心功能。在之前的研究中，我们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功能的信息，这将使我们能够了解冠脉微血管功能如何影响HFpEF的心功能。AIM 2还将涉及正在接受心脏插管测试的HFpEF患者。我们将给患者一种已知可以暂时阻断nNOS功能的药物，看看这种药物对休息和运动时的心功能有什么影响。使用HFpEF的患者的效果将与未使用HFpEF的患者的效果进行比较。这项研究的结果很重要，因为如果证实HFpEF的nNOS活性异常高，那么可以设计新的治疗方法来降低HFpEF的nNOS活性，并潜在地改善HFpEF的心脏松弛。在目标3中，我们将编制一个数据库或登记，这些患者已经被评估为冠状动脉微血管功能障碍。这将包括AIMS 1和AIMS 2中的患者，但也可能包括任何接受过心脏超声或MRI扫描以评估心脏动脉疾病的HFpEF患者。我们会在第一次见到病人时记录他们的信息，然后在一年后再次记录。这将为我们提供重要的信息，即有HFpEF和冠脉微血管功能障碍的患者是否比没有冠脉微血管功能障碍的患者症状更严重，住院时间更长。总体而言，这三项研究的结果应该会为导致HFpEF的心脏异常提供重要信息。希望这一结果可以为针对导致HFpEF的潜在异常的HFpEF的新治疗方法指明方向。

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.