Partitioning the Role of Myocardial Steatosis on Left Ventricular Function

Abstract

**Please note that the full text is embargoed until 8/1/2025** ABSTRACT: Preclinical studies have long suggested that excess lipid accumulation within cardiomyocytes (myocardial steatosis) leads to adverse cardiac remodeling and ventricular systolic and diastolic dysfunction. Whether myocardial steatosis negatively affects the human heart is less clear. Innovations in 1H magnetic resonance spectroscopy (MRS), introduced nearly 20 years ago, provide a method for in vivo quantification of myocardial triglyceride content that has been used to describe myocardial steatosis in obesity, type-2 diabetes, and across multiple disease states. However, most of this literature consists of cross-sectional observations. While these studies identify associations between myocardial steatosis and adverse remodeling and/or cardiac function, the presence of concurrent comorbidities may be confounding these results. Accordingly, this dissertation focused on studying myocardial steatosis and its effect on cardiac function, independent of underlying comorbidities, in humans. First, we utilized a 48-hour fasting model in young, healthy adults to elicit an acute increase in myocardial triglyceride content that contributed to left ventricular (LV) diastolic dysfunction. Although we were encouraged by these findings, we considered whether fasting-induced metabolic shifts (i.e., increased circulating ketones and non-esterified fatty acids[NEFAs]) may have influenced our results. Therefore, we performed separate studies manipulating each, independent of changes in myocardial triglyceride content, and demonstrated that neither metabolic shift influence LV diastolic function in young, healthy adults. We also maximized technical advancements in 1H MRS to highlight the complex lipid environment within the myocardium beyond that traditionally assessed as total myocardial triglyceride content. Together, the work performed herein supports the independent effect of myocardial steatosis on LV function and offers an opportunity for future research to expand our understanding of this deleterious effect.