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: 8705001
• 负责人: CHRISTOPHER M. KRAMER
• 金额: $ 333.25万
• 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/8705001
• 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) 是最常见的单基因心脏病（患病率为五百分之一），也是年轻人心源性猝死 (SCD) 的最常见原因。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无症状，但一小部分患有 SCD 或进展为心力衰竭 (HF) 的患者预后较差。目前预测这些不良事件风险和靶向治疗的方法是有限的。目前的药物治疗不能预防心源性猝死，也不能预防心力衰竭的发生。因此，识别新的风险标志物将有助于开发旨在改变表型表达以影响自然史的治疗靶点，特别是 SCD 和 HF。心血管磁共振 (CMR) 正在成为 HCM 诊断和风险分层的强大工具，包括评估左室质量和肥厚模式。 CMR 的晚期钆增强是局灶性心肌纤维化的标志，被认为是致心律失常的基础并促进心力衰竭的发展。我们假设新的 CMR 研究结果可以识别具有较高主要结局事件发生率的 HCM 患者。大多数 HCM 病例为常染色体显性遗传，约 60% 是由编码心脏肌节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。我们假设，与没有肌节 HCM 突变的 HCM 患者相比，具有肌节 HCM 突变的 HCM 患者将具有更高的主要结局事件发生率和更明显的 CMR 心肌病理。此外，肌节突变和纤维化之间可能存在联系，因为患有明显 HCM 的突变携带者以及那些没有肥大的突变携带者的胶原蛋白更新标志物均升高。因此，我们假设 HCM 中胶原代谢的血清生物标志物可以预测结果。因此，具体目标是通过以下方式开发 HCM 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、临床和新的 CMR、与结果相关的遗传和生物标志物变量，2) 根据预测模型可用于评估给定患者的风险因素组合的风险，从而建立证据基础，使临床试验设计能够以具有成本效益的方式降低 HCM 的发病率和死亡率。我们提议对 2750 名临床诊断的 HCM 患者进行自然史研究，在基线时使用新型 CMR、基因分型以及胶原更新和心肌损伤的血清生物标志物进行研究，入组为期 2 年，并随访 3-5 年（平均 4 年）。年）。该研究将有能力识别主要终点风险比为 1.5 或更高的风险标志物，其中包括心源性死亡（包括心源性猝死和心力衰竭死亡）、中止心源性猝死（植入式心律转复除颤器的适当放电）以及需要用于心脏移植。次要终点包括全因死亡率、室性快速心律失常、心力衰竭住院、心房颤动和中风。