Genomic and Clinical Mechanisms and Prognostic Implications of Myocardial Lipomatous Metaplasia

Myocardial fibrosis (MF) has been traditionally considered the critical anatomic substrate for cardiac dysfunction, remodeling, and malignant arrhythmia. During my postdoctoral training, supervised by Dr. Saman Nazarian, I adopted a multimodal strategy to characterize myocardial lipomatous metaplasia (LM) from cardiac CT images and scar from cardiac MRI images. We discovered that myocardial LM is prevalent in ischemic and non-ischemic cardiomyopathy, exhibiting distinct electrical features from MF and playing a more crucial role in cardiac electrophysiological remodeling. This challenges the conventional understanding of pathologic cardiac architecture and suggests new therapeutic targets. The proposed work builds on my ongoing postdoctoral research to investigate myocardial LM using data from the Penn Medicine Biobank (PMBB), which includes 23,940 participants (by 2024) with genotypes and cardiac CT images. We have developed and validated a deep-learning model that accurately segments myocardial LM from CT images. We will apply this model to PMBB CT images to achieve the following aims: Aim 1: Establish the phenotypic profile of LM across etiologies of cardiomyopathy and assess its association with outcomes. o Specific Aim 1a: To define the prevalence, distribution, volume, and patterns of LM stratified by underlying cardiomyopathy PMBB (K99 stage). This aim will mitigate current hurdles in recognizing cardiomyopathy etiologies, allowing for earlier disease-specific interventions. o Specific Aim 1b. Assess the association of LM and composite outcome, including heart failure, ventricular tachycardia, stroke, or all-cause mortality in PMBB (R00 Stage). This aim will enhance risk stratification of cardiomyopathy patients, enabling early prophylactic or therapeutic strategies. Aim 2: Characterize the genetic architecture of LM and estimate its association with that of cardiac adiposity and myocardial fibrosis. o Specific Aim 2a: Assess the heritable basis of LM and its relationship to cardiometabolic traits. (K99 Stage). This may lead to mechanistic and translational studies of LM focused on precision medicine. o Specific Aim 2b: Estimate the contribution of cardiac adiposity and myocardial fibrosis to LM formation using a Mendelian randomization (MR) framework (R00 Stage). This aim could aid in identifying candidate therapeutic targets for preventing LM formation or alleviating LM burden in patients with cardiomyopathy. In conclusion, this study will unravel the biological and genetic mechanisms that underly myocardial LM, recently recognized as the most potent determinant of cardiac dysfunction and malignant arrhythmia. Project Summary Project Number: 1K99HL183672-01 | Fiscal Year: 2026 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Lingyu Xu | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $169,020 | Activity Code: K99 | Study Section: Special Emphasis Panel[ZRG1 IVBH-A (90)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K99HL18367201