HCMR Novel Markers of Prognosis in Hypertrophic Cardiomyopathy

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1/500），也是年轻人心脏性猝死（SCD）的最常见原因。其特征是原因不明的左心室肥大（LVH），弥漫性和斑片状纤维化，和肌原纤维紊乱。虽然大多数患者保持无症状，但在患有SCD或进展为心力衰竭（HF）的亚组中预后不良。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，也不能预防HF的发展。因此，新的风险标志物的鉴定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诊断和风险分层的有力工具，包括评估LV质量和肥大模式。CMR的晚期钆增强是局灶性心肌纤维化的标志，被认为是致瘤基质的基础，并促进HF的发展。我们假设，HCM患者的主要结局事件发生率较高，可以通过新的CMR结果进行识别。大多数HCM病例为常染色体显性遗传，约60%由编码心肌肌节蛋白的基因突变引起。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，具有更高的主要结局事件发生率和更显著的CMR心肌病理。此外，肌节突变和纤维化之间可能存在联系，因为具有明显HCM的突变携带者以及没有肥大的突变携带者具有升高的胶原蛋白周转标志物。因此，我们假设HCM中胶原代谢的血清生物标志物将预测结果。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与结果相关的人口统计学、临床和新CMR、遗传和生物标志物变量，以及2）从预测模型中开发评分，该评分可以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。我们建议对2750例临床诊断为HCM的患者进行一项自然史研究，在基线时研究新的CMR、基因分型和胶原蛋白周转和心肌损伤的血清生物标志物，招募时间超过2年，随访3-5年（平均4年）。本研究将有把握识别主要终点风险比为1.5或更高的风险标志物，主要终点为心源性死亡（包括SCD和HF死亡）、SCD流产（植入式心律转复除颤器的适当放电）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、房颤和卒中。

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.