Circulating monocyte gene expression profiles associated with cardiac remodeling and incident heart failure in the Multi-Ethnic Study of Atherosclerosis

The role of circulating monocytes in non-ischemic cardiac remodeling and heart failure (HF) is complex and unclear. We assessed monocyte gene expression profiles associated with cardiac imaging metrics and incident HF among participants of the Multi-Ethnic Study of Atherosclerosis free of ischemic heart disease. Circulating CD14+ monocytes were isolated, and RNA was quantified using an Illumina microarray. Contrast-enhanced cardiac magnetic resonance was performed concurrently. We studied 12,369 transcripts mapping to 9,430 genes among 1195 community-based participants (mean age 69 ± 9 years; 52% female; 22% Black; 32% Hispanic). We used multivariable linear regression to estimate cross-sectional associations between monocyte gene expression levels and cardiac structure and function, adjusting for key confounders and risk factors. Cox regression was used to assess time to incident HF ( n = 45 events over a median follow-up of 7.7 years). Here we identify monocyte expression profiles associated with cardiac structure, function, and fibrosis that implicate lymphocyte activation, cytokine production, phagocytosis, wound healing, oxidative stress, and cell migration. Monocyte expression of PCCB was associated with left ventricular strain, left atrial size, myocardial fibrosis, and time to incident HF, and was validated using Mendelian randomization with peripheral monocyte-specific cis -eQTLs. In a community-based cohort, monocyte expression profiles reflecting both pro-inflammatory and pro-resolving activity, as well as tissue migration and homeostasis, are associated with subclinical cardiac remodeling and fibrosis. Monocyte expression of PCCB and related immunometabolism may be an especially strong candidate for future mechanistic investigation in non-ischemic HF.