Determining Potential Mechanisms of Worse Outcomes in Black HCM Patients

肥厚型心肌病（HCM）是最常见的遗传性心脏病。HCM患者有 不良临床结局，包括心力衰竭、心律失常和心源性猝死（SCD）。 . 在美国，7个HCM患者中有6个不知道自己的诊断。有公认的种族 HCM的诊断差异。虽然黑人个体被观察到有更多的临床和心电图 应该促进考虑HCM诊断的迹象，HCM在黑人患者中诊断不足。 此外，即使一旦确诊，黑人和白色患者之间也存在公认的差异， HCM;黑人患者转介到HCM中心，转介基因检测，转介SCD的比率较低 风险分层，并转诊进行间隔缩小治疗和植入式心脏复律器等干预- 除颤器（ICD）放置。较低的转诊率与数据直接相反，数据显示， 与白人相比，患有HCM的黑人个体患SCD的风险约为2倍， III或IV级（中度或重度）心力衰竭。有几个潜在的贡献者，这些种族 差距。HCM通常使用常规超声心动图诊断，临床基因检测用于 帮助诊断模棱两可的病例。患有HCM的黑人更有可能有模糊的陈述 和临床测试是不太有用的，因为，与白人相比，HCM的黑人患者有~40%的可能性， 鉴定出致病性或可能致病性（P/LP）的肉瘤变异体， 不确定意义的变体（VUS）。此外，高血压（HTN）在黑人中更为普遍 医生可能将患者的左心室肥大归因于HTN而不考虑HCM。 此外，本发明还提供了一种方法， 最近的证据表明，HTN可能是一种环境修饰剂/“触发器”， HCM。Huebsch博士是该提案的共同研究者，他创建了一个体外微型心脏（μHM）模型系统， 来源于携带单个肌节突变的人诱导多能干细胞（iPSC）的心肌细胞 并使用该模型系统来帮助梳理HCM中后负荷和遗传学的贡献。我们 假设（1）多个肉瘤变异体和（2）HTN的存在导致了更差的结果 在黑人HCM患者中观察到。AIM 1.评估黑色HCM患者的不良结局（与无） (A)在2个真实世界中，超过1个变体（即2个P/LP变体或1个P/LP变体+ 1个或多个VUS）和（B）HTN 美国HCM患者的队列。使用Somascan分析鉴定新型血浆的探索性分析 还将进行不良结果的蛋白质组生物标志物研究。AIM 2.为了描述多重 在我们的新的体外μHM模型中，心脏生理学和纤维化的变异受到增加的后负荷。 将患者临床数据与iPSC技术、基因组编辑和组织工程等强大的体外工具相结合 工程，将使我们获得重要的见解和理解的潜在触发器和机制 导致黑人HCM患者的预后更差。

Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiac disease. Individuals with HCM have adverse clinical outcomes, including heart failure, arrhythmias, and sudden cardiac death (SCD) It is estimated . that, in the U.S., 6 out of 7 individuals with HCM are unaware of their diagnosis. There are recognized racial disparities in the diagnosis of HCM. While Black individuals have been observed to have more clinical and ECG signs that should promote consideration of the diagnosis of HCM, HCM is underdiagnosed in Black patients. Furthermore, even once diagnosed, there are well-recognized disparities between Black and White patients with HCM; Black patients have lower rates of referral to HCM Centers, referral for genetic testing, referral for SCD risk stratification, and referral for interventions such as septal reduction therapy and implantable cardioverter- defibrillator (ICD) placement. The lower rates of referral are in direct opposition to the data that shows that, compared to Whites, Black individuals with HCM have approximately 2-fold the risk of SCD and development of class III or IV (moderate or severe) heart failure. There are several potential contributors to these racial disparities. HCM is typically diagnosed using routine echocardiography and clinical genetic testing is used to help diagnose ambiguous cases. Black individuals with HCM are more likely to have ambiguous presentations and clinical testing is less useful as, compared to Whites, Black patients with HCM are ~40% less likely to have a pathogenic or likely pathogenic (P/LP) sarcomeric variant identified and more than 40% more likely to have variants of uncertain significance (VUS). Furthermore, hypertension (HTN) is more prevalent in Black individuals and physicians may attribute the patient’s left ventricular hypertrophy to HTN and not consider HCM. In addition, recent evidence suggests that HTN may be an environmental modifier /”trigger” of worse disease in patients with HCM. Dr. Huebsch, Co-investigator on this proposal, created an in vitro micro-heart (μHM) model system from cardiomyocytes derived from human induced pluripotent stem cells (iPSC) harboring single sarcomere mutations and has used this model system to help tease apart the contributions of afterload and genetics in HCM. We hypothesize that the presence of (1) multiple sarcomeric variants and (2) HTN contribute to the worse outcomes observed in Black HCM patients. AIM 1. To assess adverse outcomes in Black HCM patients with (vs without) (A) more than one variant (i.e. 2 P/LP variants or 1 P/LP variant + 1 or more VUS) and (B) HTN, in 2 real-world U.S. cohorts of HCM patients. An exploratory analysis using Somascan assays to identify novel plasma proteomic biomarkers of adverse outcomes will also be performed. AIM 2. To characterize the effects of multiple variants on cardiac physiology and fibrosis in our novel in vitro μHM model subjected to increased afterload. Combining patient clinical data with powerful in vitro tools of iPSC technology, genome editing and tissue engineering, will allow us to gain important insights and understanding of potential triggers and mechanisms contributing to worse outcomes in Black HCM patients.