Determining Potential Mechanisms of Worse Outcomes in Black HCM Patients

确定黑人 HCM 患者出现更糟糕结果的潜在机制

• 批准号: 10717764
• 负责人: SHARON CRESCI
• 金额: $ 77.75万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-10 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10717764
• 关键词: Adult; Age; Arrhythmia; Biological Assay; Biological Markers; Biological Models; Black Populations; Black race; Cardiac; Cardiac Myocytes; Cessation of life; Clinical; Clinical Data; Data; Development; Diagnosis; Disease; Disparity; Disparity in diagnosis; Echocardiography; Electrocardiogram; Electrophysiology (science); Exhibits; Fibrosis; Functional disorder; Genetic; Genotype; Goals; Health Status; Heart; Heart Diseases; Heart failure; Heritability; Hospitalization; Human; Hypertension; Hypertrophic Cardiomyopathy; Hypertrophy; Implantable Defibrillators; In Vitro; Individual; Intervention; Left Ventricular Ejection Fraction; Left Ventricular Hypertrophy; Mechanics; Medical Genetics; Modeling; Molecular; Mutation; Myocardium; Outcome; Pathogenicity; Pathway interactions; Patient Care; Patient-Focused Outcomes; Patients; Phenotype; Physicians; Physiology; Plasma; Population; Predisposition; Proteomics; Quality of life; Research Personnel; Resistance; Rest; Risk; Risk Factors; Sarcomeres; Tissue Engineering; Variant; adverse outcome; black patient; cardiac tissue engineering; cardiogenesis; cohort; course development; genetic testing; genetic variant; genome editing; improved; in vitro Model; induced pluripotent stem cell; induced pluripotent stem cell derived cardiomyocytes; induced pluripotent stem cell technology; insight; miniaturize; mortality; mouse model; novel; peer; pressure; racial disparity; research clinical testing; risk stratification; sudden cardiac death; tool; variant of interest; variant of unknown significance; young adult

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.

肥厚型心肌病(HCM)是最常见的遗传性心脏病。患有肥厚型心肌炎的人有 据估计，不良的临床后果包括心力衰竭、心律失常和心脏性猝死(SCD) 。 在美国，每7个人中就有6个人不知道自己的诊断结果。有公认的种族 肥厚型心肌炎诊断上的差异。而黑人个体被观察到有更多的临床和心电图 应促进考虑诊断为肥厚型心肌病的体征，在黑人患者中，肥厚型心肌病被低估了。 此外，即使一旦确诊，黑人和白人患者之间也存在着公认的差异 HCM；黑人患者转诊到HCM中心、转诊进行基因检测、转诊为SCD的比率较低 风险分层，并转诊进行介入治疗，如间隔缩小治疗和植入性心脏复律- 放置除颤器(ICD)。较低的转诊率与数据直接相反，数据显示， 与白人相比，患有肥厚性心肌病的黑人患上SCD和发展为 III级或IV级(中度或严重)心力衰竭。有几个潜在的因素导致了这些种族 差距。肥厚性心肌病通常使用常规超声心动图诊断，临床基因检测用于 帮助诊断不明确的案例。患有肥胖症的黑人更有可能有模棱两可的陈述 临床测试没有那么有用，因为与白人相比，患有肥厚性心肌炎的黑人患者患肥厚性心肌炎的可能性低约40%。 发现一种致病或可能致病的(P/LP)肉瘤变异体，有40%以上的可能性 不确定意义的变种(VU)。此外，高血压(HTN)在黑人中更普遍 医生可能会将患者的左心室肥厚归因于HTN，而不考虑肥厚性心肌病。 此外, 最近的证据表明，HTN可能是一种环境修饰物/更严重疾病的触发因素 胡志明市。Huebsch博士是这项提议的联合研究员，他创建了一个体外微型心脏(μHM)模型系统，该模型系统由 含有单一肌节突变的人诱导多能干细胞(IPSC)来源的心肌细胞 并使用该模型系统来帮助梳理后负荷和遗传学在HCM中的作用。我们 假设(1)多种肉瘤变异体和(2)HTN的存在会导致更差的结果 在黑人肥厚型心肌病患者中观察到。目的1.评估黑人肥厚型心肌病患者的不良结局 (A)一个以上的变体(即2个P/LP变体或1个P/LP变体+1个或更多VU)和(B)HTN，在2个真实世界中 美国肥厚型心肌炎患者队列。用Somascan分析鉴定新血浆的探索性分析 不良结果的蛋白质组生物标记物也将被执行。目标2.描述多个因素的影响 在我们的新型体外μHM模型中，心脏生理学和纤维化的变异受到增加的后负荷的影响。 将患者临床数据与IPSC技术、基因组编辑和组织等强大的体外工具相结合 工程学，将使我们能够获得对潜在触发因素和机制的重要见解和理解 导致黑人肥厚型心肌炎患者预后更差。