Project Summary
Atrial fibrillation (AF) is the most common arrhythmia affecting well over 2 million people in the US with
projections that it will affect 8-12 million people by 2050. It is responsible for >$6 billion in annual health care
expenditures in the United States. While catheter ablation is a somewhat effective treatment for AF, its
application generates additional left atrial (LA) fibrosis, an approach that can be associated with proarrhythmia
and reduction in left atrial function. Thus, it would be desirable to identify new targets for prevention and
treatment of AF that focus on the underlying pathophysiologic abnormalities which may vary among patients.
Obesity and epicardial adipose tissue (EAT) have been associated with AF. LAEAT, due to its contiguity to the
LA, may directly influence LA substrate via profibrotic, inflammatory, and other adipocytokines. It has been
shown that EAT may play an independent role in the progression, development and recurrence of AF after
catheter ablation. There are known racial/ethnic differences in the incidence of AF that parallel the noted racial
differences in EAT. Yet, the precise role of EAT and, in particular, LAEAT in the pathogenesis of AF is not well
characterized. A 2016 State-of-the-Art review in the Journal of the American College of Cardiology noted “the
integration of metabolomics with other ‘omics’ platforms will allow us to gain insight into pathophysiological
interactions of metabolites, proteins, genes, and disease states, while advancing personalized medicine”. This
novel approach has not been implemented in AF. The overall goal of this study is to evaluate the role of EAT
and, in particular, LAEAT in the pathogenesis of AF using a multi-omic (proteome, metabolome, transcriptome)
approach in order to identify novel potential diagnostics and therapeutic targets. Our specific aims are to: 1) In
a multiracial/ethnic population, evaluate associations of LAEAT with plasma biomarkers known to be
associated with AF. We will enroll 120 patients with AF and 120 controls from the outpatient cardiology practice
– 40 white, 40 black, and 40 Hispanic in each group of both patients and controls and evaluate the effects of
race/ethnicity on the relationship of LAEAT to biomarkers of fibrosis and inflammation, among others. 2)
Examine the LAEAT transcriptome in patients with and without AF. We will enroll 60 patients undergoing
cardiac surgery and obtain EAT biopsies for analysis for upregulation of genes encoding for factors that can
promote atrial fibrosis. RNA-seq analysis will cover all aspects of the transcriptome without any prior
knowledge of it, allowing for the analysis of novel transcripts, splice variants and noncoding RNAs. 3)
Determine cross-sectional associations between EAT and metabolomic features derived from metabolomics of
stored blood specimens in the Multi-Ethnic Study of Atherosclerosis and the Rotterdam Study and test for
associations between the identified metabolites and incident AF. We will perform an external validation in the
Dallas Heart Study. In the aggregate, these 3 aims will provide a novel platform for the diagnostic evaluation of
AF which may enable development of targeted treatments based on addressing the pathogenesis of AF.