Abstract
Cardiovascular diseases (CVD) are the leading cause of mortality in individuals with obesity. Epicardial adipose tissue (EAT) dysfunction serves as a link between obesity and CVD, promoting inflammatory and metabolic alterations that increase CVD risk. While EAT normally supports cardiac health, obesity-induced adipocyte hypertrophy triggers excessive fatty acid and cytokine release, driving myocardial lipotoxicity and inflammation that impair electrophysiology and metabolism, leading to beating irregularities, insulin resistance, and heart failure. The lack of sufficient EAT in small animal models and the impracticality of using large mammals hinder insights into the effects of EAT hypertrophy on the myocardium. To address this gap, a human-derived 3D bioprinted coculture of obese adipocytes and cardiomyocytes (CMs) is developed using patient-derived adipocytes and human induced pluripotent stem cell (hiPSC)-derived atrial CMs (a-iCMs). This platform enables the investigation of both cell-cell and paracrine interactions between hypertrophic adipocytes and a-iCMs, allowing assessment of electrophysiological, structural, and proteomic changes to uncover mechanisms linking EAT hypertrophy to obesity-related atrial dysfunction. Screening of metformin, a cardioprotective drug, reveals improvement in electrophysiological function in hypertrophic adipocyte-a-iCM cocultures. 3D bioprinted fat-myocardium model provides a high-throughput platform to study obesity-induced atrial dysfunction and facilitate the discovery of therapies for the obese heart.