Evaluating sex specific differences in dilated cardiomyopathy

全球有2600万人患有心力衰竭。它是住院和早期死亡的主要原因，也是一个主要的经济负担，占国民保健制度预算的1-2%。第二常见的原因是扩张性心肌病，这是一种心肌疾病，每250人中就有1人患病，在英国有24万人。不幸的是，尽管有最好的治疗，这个相对年轻的人群（中位年龄40岁）的死亡率仍然很高。大约一半的50岁扩张型心肌病和心脏瘢痕患者在10年内死亡或进行心脏移植。我们迫切需要改善对这种疾病患者的护理方式。性别（男性或女性）可能在疾病进展中起关键作用。我的研究表明：(i)扩张型心肌病影响的男性是女性的两倍。要么男性更危险，要么女性受到保护。（ii）扩张型心肌病患者的心脏与女性不同。与男性相比，女性的心脏更小，但心脏功能更好。（三）尽管如此，妇女患并发症的风险比男子高两倍。50岁以后，女性的并发症是男性的两倍，而男性的并发症与年龄无关。这表明，尽管患有“轻度”疾病，但女性患并发症的风险更大，而且这种风险在绝经后会增加。尽管有这些观察结果，我们目前对待男性和女性完全一样。在本研究项目中，我将研究扩张型心肌病对男性和女性在其一生中的不同影响，目的是改善所有扩张型心肌病患者的诊断、治疗和预后。我将做三个主要的研究：1。女性会经历许多与荷尔蒙变化有关的独特生活事件，比如怀孕和更年期。然而，我们不知道它们对扩张型心肌病及其并发症的影响。我将在我们的专业研究中心研究这些药物对患者的影响，并使用大型全科医学研究数据库对普通人群进行研究。2. 扩张型心肌病没有性别特异性的治疗建议。我开展了一项国际研究，整理了约6500名患者的数据。我将开发一个对女性有效的风险预测模型。风险预测模型利用患者的危险因素来预测预后。我还将研究我们是否应该对男性和女性的风险因素采用不同的截止值。3. 虽然我们知道男性和女性在心脏结构上存在差异，但我们不知道原因。其中一个原因可能是由于男性和女性心脏基因的开启方式不同。我将寻找与健康心脏相比，患有扩张型心肌病的男性和女性心脏组织中基因信号的变化。谁参与了这项研究？我将领导这项研究，并与具有成功完成这项研究所需专业知识的人合作。我在国际和英国有一个来自不同学科的合作者团队，包括流行病学、内分泌学、生物统计学和遗传学。本研究将对患者、临床医生和政策制定者产生直接影响。确定男性和女性扩张型心肌病如何以及为什么不同，将有助于我们理解患者经历的健康结果范围。这项研究的结果可以应用于诊断和风险分层（即患者是高风险还是低风险的并发症），并可能导致针对性别的治疗建议。这将导致所有扩张型心肌病患者健康状况的现实改善，重新评估我们目前治疗男性和女性相同的模式。患者和国家患者团体（Cardiomyopathy UK, Pumping Marvellous）参与了本研究的所有阶段。他们说，这是一个极其重要的以患者为中心的项目，针对的是一个未被满足的主要需求。

Context Heart failure affects 26 million people globally. It is a leading cause of hospitalisations and early deaths and is a major economic burden, making up 1-2% of the NHS budget. The second commonest cause is dilated cardiomyopathy, a heart muscle condition that affects up to 1 in 250 people, or 240,000 people in the UK. Unfortunately, despite best treatment, mortality for this relatively young population (median age 40) remains high. Approximately half of patients aged 50 with dilated cardiomyopathy and scarring in the heart die or have a heart transplant within 10 years. We urgently need to improve how we care for patients with this condition. Sex (being male or female) may play a critical role in disease progression. My research shows that:(i) Dilated cardiomyopathy affects twice as many men as women. Either men are more at risk or women are protected.(ii) The hearts of men and women with dilated cardiomyopathy differ. Compared to men, women have smaller hearts and better heart function. (iii) Despite this, women have a two-fold increased risk of complications compared to men. Women get twice as many complications after 50 whilst men have the same number of complications regardless of age. This suggests that women are more at risk of complications despite a 'milder' disease and this risk increases after menopause. Despite these observations, we currently treat men and women exactly the same. Aims and objectives In this research programme, I will study how dilated cardiomyopathy affects men and women differently across their lifespan with the aim of improving diagnosis, treatment and prognosis for all patients with dilated cardiomyopathy. I will do three main studies: 1. Women experience a number of unique life events linked to major hormonal changes such as pregnancy and menopause. However, we do not know their impact on dilated cardiomyopathy or its complications. I will study the effect of these on patients in our specialist research centre and in the general population using a large general practice research database. 2. There are no sex specific treatment recommendations in dilated cardiomyopathy. I have developed an international study collating data on ~6500 patients. I will develop a risk prediction model which works well in women. Risk prediction models use patient risk factors to predict prognosis. I will also study whether we should apply different cut offs for risk factors in men and women. 3. Whilst we know there are differences in heart structure between men and women, we do not know why. One reason could be due to differences in how the heart genes are switched on in men versus women. I will look for changes in gene signals in heart tissue from men and women with dilated cardiomyopathy compared to healthy hearts. Who is involved in this research? I will lead this research and collaborate with people with the expertise needed to successfully complete this research. I have a team of collaborators internationally and in the UK from different disciplines including epidemiology, endocrinology, biostatistics, and genetics. Potential impact This study will have immediate impact for patients, clinicians and policy makers. Identifying how and why dilated cardiomyopathy differs in men and women will help us to make sense of the range of health outcomes that patients experience.The results of this study can be applied to diagnosis and risk stratification (i.e. whether patients are at high or low risk of complications) and could lead to sex-specific treatment recommendations. This would lead to realistic improvements in the health of all patients with dilated cardiomyopathy, re-evaluating our current model of treating men and women the same.Patients and national patient groups (Cardiomyopathy UK, Pumping Marvellous) have been engaged in all stages of this study. They say this is an incredibly important patient centred project targeting a major unmet need.