Defining the Functional Effects of Titin Gene Mutations on the Pathophysiology of Dilated Cardiomyopathy and their Clinical Significance

在英国，心力衰竭影响着超过75万人。扩张性心肌病（DCM）是第二常见的原因，每500人中就有1人发生。什么是扩张型心肌病？扩张型心肌病是心肌变弱（心肌病）和心脏变大（扩张）的一种情况。人们可能会出现肺部积液问题，危险的心律，在某些情况下，最终心脏虚弱到需要移植。在绝大多数情况下，我们并不完全了解是什么原因首先导致心脏受损。这意味着我们没有任何针对性的治疗方法可以提供给这些患者。我们目前在所有心肌衰弱的患者中使用相同的药物，无论原因如何。不幸的是，患有这种疾病的人可能直到疾病的晚期才有任何症状，这意味着我们所做的治疗可能无法修复或停止对心脏的损害。这项研究试图达到什么目的？我们小组的研究人员最近与哈佛大学的合作者一起完成的工作表明，四分之一的人，我们以前认为没有可识别的心脏衰弱原因，有一个基因（称为TTN）异常，负责制造心肌中最大的蛋白质（肌联蛋白）。我们想更详细地研究它对携带这种基因的人意味着什么。谁在做这项研究？这项工作是皇家布朗普顿医院心脏磁共振成像部门与伦敦皇家布朗普顿和帝国理工学院遗传学团队的合作。帝国理工学院和皇家布朗普顿医院共同组成了英国最大的专业心肺中心。他们拥有国际知名的研究声誉，最适合进行这项研究。异常基因（TTN）的发现构成了这项研究的关键部分，是由一位研究主管在合作工作中完成的。我们将如何进行这项研究？我们想使用一种先进的心脏扫描，称为心脏MRI，看看是否有一个模式的疾病，在患者的心肌异常基因。我们将邀请我们的病人，我们知道有扩张型心肌病和异常TTN基因有一个MRI扫描他们的心脏。心脏的MRI扫描非常擅长观察心肌的详细结构，可以发现其他测试（例如超声心动图）无法发现的变化。MRI扫描是安全、无创和无痛的检查。在MRI扫描中，我们将寻找疾病的早期迹象，如心脏瘢痕-称为纤维化和血液供应（微循环）异常。我们知道异常基因可以在家庭中运行，所以我们也会邀请扩张型心肌病患者的亲属进行异常基因检测。如果他们有异常基因，我们将为他们提供机会，对他们的心脏进行核磁共振扫描，看看他们的心脏是否有任何细微的变化，即使他们没有任何症状。为什么这很重要？至关重要的是，一旦我们完成了详细的MRI扫描，我们还将对扩张型心肌病患者进行随访，看看我们是否可以在他们的基因或扫描中识别出与长期预后不良相关的任何特定模式。如果是这样的话，那么我们将来就可以为这些患者提供更早、更密集的治疗，以帮助防止他们最终患上严重的疾病，这些信息也可能有助于我们开发新的治疗方法。对于那些感觉良好但被告知他们有异常基因的人，我们将在他们的扫描中查看是否有任何心脏病的早期迹象。如果是这样的话，那么在未来，我们可能能够更快地开始正确的治疗，以避免进展到晚期疾病，并保持他们的心脏健康。

Heart failure affects over 750,000 people in the UK. Dilated cardiomyopathy (DCM) is the second commonest cause and occurs in up to 1 in every 500 people. What is dilated cardiomyopathy? Dilated cardiomyopathy is a condition where the heart muscle becomes weaker (cardiomyopathy) and the heart becomes bigger (dilated). People can develop problems with fluid on their lungs, dangerous heart rhythms, and in some cases, ultimately a heart weak enough to need replacing with a transplant.In the vast majority of cases, we do not fully understand what causes the damage to the heart in the first place. This means that we do not have any targeted treatments to offer these patients. We currently use the same medicines in all patients with weak heart muscle, whatever the cause. Unfortunately, people with this condition may not have any symptoms until very advanced stages of the disease which means that the treatment we do have may not be able to do very much to repair or halt the damage to the heart. What is this research trying to achieve?Recent work done by researchers in our group, working with collaborators at Harvard University, has shown that a quarter of people who we previously thought had no identifiable cause for the weak heart, had an abnormality in a gene (called TTN) responsible for making the biggest protein in heart muscle (titin). We would like to study in more detail what it means for people who carry this gene.Who is doing this research? This work is a collaboration between the cardiac MRI imaging department at the Royal Brompton Hospital and the genetics team at the Royal Brompton and Imperial College in London. Together, Imperial College and the Royal Brompton Hospital form the largest specialist heart and lung centre in the UK. They have an internationally renowned research reputation and are best placed to conduct this research. The discovery of the abnormal gene (TTN) that forms a key part of this research was done in collaborative work by one of the research supervisors. How are we going to do this research? We would like to use an advanced scan of the heart called cardiac MRI to see if there is a pattern of disease in the heart muscle of patients with the abnormal gene. We will invite our patients who we know have both dilated cardiomyopathy and the abnormal TTN gene to have an MRI scan of their heart. MRI scans of the heart are very good at looking at the detailed structure of the heart muscle and can pick up changes that other tests (for example echocardiograms) cannot. MRI scans are safe, non invasive and painless tests. On the MRI scan, we will look for early signs of disease such as scarring in the heart - called fibrosis and abnormalities in the blood supply (microcirculation).We know that the abnormal gene can run in families so we will also invite the relatives of people with dilated cardiomyopathy to be tested for the abnormal gene. If they have the abnormal gene we will offer them the opportunity to have an MRI scan of their heart to see if they have any subtle changes in their heart, even when they do not have any symptoms. Why is this important? Crucially, once we have done the detailed MRI scan, we will also follow up the patients with dilated cardiomyopathy to see if we can identify any particular patterns in their genes or scans that are associated with a worse outcome in the long term. If this is the case, then we may be able to offer these patients earlier and more intensive treatment in the future to help prevent them from ending up with severe disease and this information might also help us to develop new treatments.For those people who feel well but have been told they have the abnormal gene, we will see if there are any early signs of heart disease on their scans. If this is the case, then in the future, we may be able to start them on the right treatment sooner to avoid progressing to advanced disease and keeping their hearts healthy.