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 w...