Abstract 043: Circulating Monocyte Gene Expression Profiles of Cardiac Remodeling and Incident Heart Failure: the Multi-Ethnic Study of Atherosclerosis

Introduction: The role of circulating monocytes in non-ischemic cardiac remodeling and heart failure (HF) is complex and unclear, due in part to monocyte heterogeneity and plasticity. We assessed the hypothesis that monocyte gene expression profiles reflecting activation and tissue inflammation are associated with cardiac structure and function and incident adjudicated HF in the Multi-Ethnic Study of Atherosclerosis. Methods: Monocytes were isolated from peripheral blood, and RNA was quantified using an Illumina BeadChip microarray. Cardiac magnetic resonance was performed concurrently. We used multivariable linear regression to estimate cross-sectional associations between gene expression levels and cardiac structure and function and Cox regression to estimate associations with time to incident HF. Results: We studied 12,369 transcripts mapping to 9,430 genes among 813 participants (mean age 69±9 years; 50% female; 22% Black; 29% Hispanic). Independent of traditional risk factors, expression levels of 55 transcripts were associated with left ventricular (LV) ejection fraction, 1136 with LV strain, 16 with LV geometry, 1020 with myocardial interstitial fibrosis, and 483 with left atrial size (FDR<0.05). Enrichment analysis implicated T and B cell activation, cytokine production, phagocytosis, wound healing, oxidative stress, and cell migration. Expression levels of three genes—PCCB, MTCP1, and VIM—were associated with more than one cardiac metric as well as time to clinical HF ( n =45 events over a median follow-up of 7.7 years). Conclusion: These unique data support an association between monocyte-mediated immune processes and subclinical cardiac remodeling and incident HF in the absence of ischemic injury. Agnostically identified profiles were enriched for processes related to both pro-inflammatory and pro-resolving activated monocyte function and immunometabolism, as well as tissue migration and homeostasis. These insights may help generate hypotheses toward novel therapeutic targets for HF.