What is the mechanism of action of the Coronary Sinus Reducer in refractory angina? A randomised placebo-controlled study

随着人口老龄化和心脏病存活率的提高，越来越多的人患有冠状动脉疾病。冠状动脉疾病的主要治疗目标之一是预防心绞痛，这是一种因运动引起的胸痛。治疗心绞痛的常规疗法包括药物治疗、冠状动脉支架（冠状动脉成形术）和冠状动脉搭桥手术。尽管有这些干预措施，大约10%的冠状动脉疾病患者仍有持续的胸痛（难治性心绞痛）。直到最近，这些患者还没有可用的治疗选择。难治性心绞痛是一种使人极度衰弱的疾病，由于剧烈的胸痛，患者常常被限制在家中，导致大多数人的生活质量较差。难治性心绞痛患者经常以胸痛就诊全科医生和急诊科。他们经常在没有治疗的情况下反复进行侵入性冠状动脉造影，直到最近，医生们还没有为这些患者提供有效的治疗方法。一种治疗难治性心绞痛的新设备应运而生，以满足这一未被满足的临床需求——冠状动脉窦减速器（CSR）。它是一个沙漏形状的不锈钢网，被植入冠状窦（从心肌中排出血液的血管）。这是一个在局部麻醉下进行的简单手术，大约需要30分钟。它被认为可以改善流向心脏肌肉的血液。在一项安慰剂对照组的随机试验中，与安慰剂相比，CSR改善了心绞痛（冠状动脉窦减压剂治疗难治性心绞痛试验- COSIRA）。目的社会责任发挥其作用的机制尚不清楚，本研究旨在发现它。在小动物研究中，外科缝合用于缩小冠状动脉窦导致血液在心肌中的重新分配，有利于最需要的区域。这被认为是CSR的作用方式，但这从未在人类身上得到证实。由于我们不知道它是如何工作的，我们无法确定最有可能从该设备中受益的患者。在本研究中，我将研究CSR如何在难治性心绞痛患者中起作用。方法入选40例难治性心绞痛患者。我将使用心脏成像和核磁共振扫描来评估心肌的血流量，并使用超声波来测量冠状动脉的血流量。我们将通过问卷调查、锻炼时间和症状智能手机应用程序来评估患者的症状，患者可以在整个研究过程中每天输入他们的症状。这项研究将采用安慰剂对照，这样我们就可以了解该设备的真实效果。患者将以1:1的比例随机分配到治疗组，他们将以正常方式接受CSR，或对照组，他们将接受安慰剂程序。参与者和研究人员将对治疗组进行盲测。在6个月的随访期结束时，将重复基线测试。该研究是与NHLI ORBITA重点小组合作设计的，重点小组是有稳定型心绞痛生活经历的患者。我将在MRI上发现CSR是否会改善心肌的血流量，并将症状和运动时间的变化与血流量的基线测试联系起来，以更好地了解谁将从该设备中受益。这项研究将确定CSR对难治性心绞痛患者的影响，提高我们对其机制的理解，并提高我们在这一治疗不足的患者群体中靶向治疗的能力。

BackgroundWith an ageing population and improved survival from heart attacks, a growing number of people are living with coronary artery disease. One of the main treatment aims in coronary artery disease is the prevention of angina, which is chest pain that comes on with exertion. Conventional therapies for angina include medications, coronary stents (coronary angioplasty) and coronary artery bypass surgery. Despite these interventions, approximately 10% of patients with coronary artery disease have ongoing chest pain (refractory angina). Until recently, these patients have had no available treatment options. Refractory angina is an extremely debilitating condition and patients are often confined to their homes due to severe exertional chest pain, leading to a poor quality of life for the majority. Patients with refractory angina frequently visit their general practitioner and emergency departments with chest pain. They often have repeated invasive coronary angiograms without treatment and until recently physicians have not been equipped with an effective therapy to offer to these patients.A novel device for treatment of refractory angina was developed in response to this unmet clinical need - the Coronary Sinus Reducer (CSR). It is an hourglass shaped, stainless steel mesh which is implanted in the coronary sinus (the vessel which drains blood from the heart muscle). This is a simple procedure performed under local anaesthetic, which takes approximately 30 minutes. It is thought to improve the flow of blood to the heart muscle. In a randomised trial with a placebo control arm, CSR improved angina compared to placebo (Coronary Sinus Reducer for treatment of Refractory Angina Trial - COSIRA). ObjectivesThe mechanism through which the CSR exerts its effect is unknown and this fellowship is designed to discover it. In small animal studies, a surgical stitch used to narrow the coronary sinus caused redistribution of blood in the heart muscle, favouring the areas which were most in need. This is thought to be how the CSR acts, but this has never been demonstrated in humans. As we do not know how it works, we cannot identify patients who are most likely to benefit from the device. In this fellowship I will study the how the CSR works in patients with refractory angina.MethodsThis study will enrol 40 patients with refractory angina. I will use cardiac imaging with MRI scans to assess blood flow in the heart muscle and will use ultrasound to measure blood flow in the coronary arteries. We will assess patients' symptoms, using questionnaires, exercise time and a symptom smartphone application, into which patients can input their symptoms daily throughout the study. This study will utilise a placebo control, so that we can understand the true effects of the device. Patients will be randomly assigned 1:1 to the treatment arm, where they will receive a CSR in the normal fashion, or the control arm, where they will have a placebo procedure. Participants and researchers will be blinded to treatment arm. At the end of a 6 month follow up period, the baseline tests will be repeated. The study has been designed in collaboration with the NHLI ORBITA focus group of patients with lived experience of stable angina. I will discover whether the CSR causes improved blood flow to the heart muscle on MRI and I will correlate changes in symptoms and exercise time, with the baseline tests of blood flow, to better understand who would benefit from the device. This fellowship will define the effect that the CSR has on patients with refractory angina, improve our understanding of its mechanism and advance our ability to target therapy in this undertreated group of patients.