HCMR Novel Markers of Prognosis in Hypertrophic Cardiomyopathy

肥厚型心肌病预后的 HCMR 新标志物

• 批准号: 8577787
• 负责人: CHRISTOPHER M. KRAMER
• 金额: $ 336.75万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-22 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8577787
• 关键词: Adverse event; Affect; Atrial Fibrillation; Biological Markers; Cardiac; Cardiac Death; Cardiovascular system; Cessation of life; Clinical; Clinical Trials; Clinical Trials Design; Collagen; Collection; Cox Models; Data; Development; Diagnosis; Diffuse; Disease Progression; Edema; Enrollment; Event; Fibrosis; Future; Gadolinium; Gene Mutation; Genes; Genetic; Genetic Markers; Genotype; Goals; Gold; Heart Diseases; Heart Transplantation; Heart failure; Hospitalization; Hypertrophic Cardiomyopathy; Hypertrophy; Image; Imaging Device; Implantable Defibrillators; Individual; Inherited; Injury; Lead; Left Ventricular Hypertrophy; Left Ventricular Mass; Link; Longitudinal Studies; Magnetic Resonance; Medical; Metabolism; Methods; Monitor; Morbidity - disease rate; Mutation; Myocardial; Myocardial dysfunction; Myocardial tissue; Natural History; Observational Study; Outcome; Pathology; Patients; Pattern; Predictive Value; Prevalence; Proteins; Quality of life; Risk; Risk Factors; Risk Marker; Serum; Stratification; Stroke; Surrogate Endpoint; Tachyarrhythmias; Ventricular; autosomal dominant trait; clinical risk; cohort; cost; cost effective; data mining; disease phenotype; disorder risk; evidence base; gadolinium oxide; hazard; improved; mortality; mutation carrier; new therapeutic target; novel; novel marker; older patient; outcome forecast; predictive modeling; prevent; primary outcome; public health relevance; sudden cardiac death; therapeutic target; tool; treatment response

DESCRIPTION (provided by applicant): Hypertrophic cardiomyopathy (HCM) is the most common monogenic heart disease (prevalence 1 in 500) and the most frequent cause of sudden cardiac death (SCD) in the young. It is characterized by unexplained left ventricular hypertrophy (LVH), diffuse and patchy fibrosis, and myofibrillar disarray. While the majority of patients remain asymptomatic, prognosis is poor in a subset who present with SCD or progress to heart failure (HF). Current methods to predict risk of these adverse events and to target therapy are limited. Current medical therapy does not protect against SCD, nor does it prevent development of HF. Therefore, the identification of novel risk markers would help develop therapeutic targets aimed at altering the phenotypic expression to impact the natural history, especially SCD and HF. Cardiovascular magnetic resonance (CMR) is emerging as a powerful tool for diagnosis and risk stratification in HCM including assessment of LV mass and pattern of hypertrophy. Late gadolinium enhancement by CMR is a marker of focal myocardial fibrosis which is thought to underlie the arrhythmogenic substrate as well as promote development of HF. We hypothesize that HCM patients with a higher primary outcome event rate can be identified by novel CMR findings. The majority of cases of HCM are autosomal dominant and about 60% are caused by mutations in genes encoding cardiac sarcomeric proteins. However, the relationship between genetic mutation, disease phenotype, and clinical outcomes remains poorly understood. We hypothesize that HCM patients with sarcomeric HCM mutations will have a higher primary outcome event rate and more marked myocardial pathology on CMR than those without. Furthermore, there may be a link between sarcomeric mutations and fibrosis, as mutation carriers with overt HCM as well as those without hypertrophy has elevated markers of collagen turnover. We therefore hypothesize that serum biomarkers of collagen metabolism in HCM will predict outcomes. Thus, the Specific Aim is to develop a predictive model of cardiovascular outcomes in HCM by: 1) using exploratory data mining methods to identify demographic, clinical, and novel CMR, genetic and biomarker variables associated with the outcomes and 2) develop a score from the predictive model that can be used to assess risk given a patient's combination of risk factors, thus establishing the evidence base to enable clinical trial design to reduce morbidity and mortality in HCM in a cost-effective manner. We propose a natural history study of 2750 patients with clinically diagnosed HCM studied at baseline with novel CMR, genotyping, and serum biomarkers of collagen turnover and myocardial injury, enrolled over a 2-year period and followed for 3-5 years (mean of 4 years). The study will be powered to identify risk markers with a hazard ratio of 1.5 or greater for the primary endpoint, which will be cardiac death (including SCD and HF death), aborted SCD (appropriate discharge of an implantable cardioverter-defibrillator), and need for heart transplantation. Secondary endpoints include all- cause mortality, ventricular tachyarrhythmias, hospitalization for heart failure, atrial fibrillation, and stroke.

描述(申请人提供)：肥厚性心肌病(HCM)是最常见的单基因心脏病(患病率为1/500)，也是年轻人心源性猝死(SCD)最常见的原因。其特征是不明原因的左心室肥厚(LVH)，弥漫性和斑片状纤维化，以及肌原纤维紊乱。虽然大多数患者仍然没有症状，但出现SCD或进展为心力衰竭(HF)的一小部分患者预后较差。目前预测这些不良事件风险和靶向治疗的方法有限。目前的药物治疗不能预防SCD，也不能阻止HF的发展。因此，识别新的危险标记将有助于开发旨在改变表型表达的治疗靶点，以影响自然病程，特别是SCD和HF。心血管磁共振(CMR)已成为肥厚性心肌病诊断和危险分层的有力工具，包括评价左心室重量和肥厚类型。CMR晚期Gd增强是局灶性心肌纤维化的标志，后者被认为是导致心律失常的底物，并促进了心衰的发展。我们假设，通过新的CMR发现可以确定具有较高主要结局事件发生率的肥厚型心肌病患者。大多数肥厚性心肌病是常染色体显性遗传的，大约60%是由编码心肌肌瘤蛋白的基因突变引起的。然而，基因突变、疾病表型和临床结果之间的关系仍然知之甚少。我们推测，与无肌瘤突变的患者相比，肌瘤基因突变的肥厚型心肌病患者具有更高的主要预后事件发生率和更明显的心肌病理改变。此外，肌瘤突变和纤维化之间可能存在联系，因为有明显的肥厚性肥厚的突变携带者和没有肥厚的突变携带者都有胶原转化的标志升高。因此，我们假设血清胶原代谢生物标记物将预测肥厚性心肌病的预后。因此，本研究的具体目的是通过以下方式开发一种预测肥厚型心肌病心血管结局的模型：1)使用探索性数据挖掘方法来确定与预后相关的人口学、临床和新的CMR、遗传学和生物标记物变量；2)从预测模型中开发可用于评估风险的评分，该评分可用于在给定患者的风险因素组合的情况下评估风险，从而建立证据基础，从而使临床试验设计能够以经济高效的方式降低肥厚型心肌病的发病率和死亡率。我们建议对2750名临床诊断为肥厚型心肌炎的患者进行自然病史研究，研究对象为新的CMR、基因分型以及胶原周转和心肌损伤的血清生物标记物，入选时间为2年，随访时间为3-5年(平均4年)。这项研究将有能力确定风险比为1.5或更高的主要终点的风险标记物，即心脏性死亡(包括SCD和HF死亡)、流产的SCD(适当释放植入型心律转复除颤器)和需要心脏移植。次要终点包括全因死亡率、室性快速性心律失常、因心力衰竭住院、房颤和中风。