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（由申请人提供）：肥厚性心肌病（HCM）是最常见的单基因疾病（500分之1），也是年轻人心脏死亡（SCD）的最常见原因。它的特征是无法解释的左心室肥大（LVH），弥漫性和斑块纤维化以及肌原纤维混乱。尽管大多数患者仍然无症状，但在患有SCD或进展为心力衰竭（HF）的子集中的预后较差。预测这些不良事件和目标治疗风险的当前方法是有限的。当前的医疗疗法不能防止SCD，也不能阻止HF的发展。因此，对新型风险标志物的识别将有助于开发旨在改变表型表达以影响自然史的治疗靶标，尤其是SCD和HF。心血管磁共振（CMR）成为HCM中诊断和风险分层的强大工具，包括评估LV质量和肥大模式。 CMR通过CMR增强的晚期是局灶性心肌纤维化的标志物，被认为是心律不齐底物的基础，并促进了HF的发展。我们假设具有较高原发性结果事件率的HCM患者可以通过新颖的CMR发现来确定。大多数HCM病例是常染色体显性症，约60％是由编码心脏肉瘤蛋白的基因突变引起的。然而，遗传突变，疾病表型和临床结局之间的关系仍然很少了解。我们假设患有HCM HCM突变的HCM患者将具有更高的主要结局事件率，并且在CMR上的心肌病理学更为明显。此外，由于具有公开HCM的突变载体以及没有肥大的突变载体，肌肉突变与纤维化之间可能存在联系。因此，我们假设HCM中胶原蛋白代谢的血清生物标志物将预测结果。因此，具体目的是在HCM中开发一种预测性的心血管结局的预测模型：1）使用探索性数据挖掘方法来识别人口统计学，临床和新颖的CMR，遗传和生物标志物变量与结果相关的遗传和生物标志物变量，以及2）与预测模型相关的临床，从而降低了临床的成绩，从而降低了临床的跨性别，从而促进了跨越风险的构建，从而构成了跨越风险的组合。 HCM以具有成本效益的方式。我们提出了一项自然史研究，对2750例临床诊断患者的HCM患者在基线上进行了新的CMR，基因分型和胶原蛋白转移和心肌损伤的血清生物标志物，并在2年内参加了3 - 5年（平均4年）。这项研究将有动力确定主要终点的危险比为1.5或更高的风险标志物，这将是心脏死亡（包括SCD和HF死亡），中止SCD（适当排出可植入的心脏逆变器 - 清除纤维器），并需要进行心脏移植。次要终点包括全部导致死亡率，心室心律失常，心力衰竭住院，心房颤动和中风。