Gene and metabolite expression dependence on body mass index in human myocardium

Abstract

We hypothesized that body mass index (BMI) dependent changes in myocardial gene expression and energy-related metabolites underlie the biphasic association between BMI and mortality (the obesity paradox) in cardiac surgery. We performed transcriptome profiling and measured a panel of 144 metabolites in 53 and 55, respectively, myocardial biopsies from a cohort of sixty-seven adult patients undergoing coronary artery bypass grafting (registration: NCT02908009). The initial analysis identified 239 transcripts with biphasic BMI dependence. 120 displayed u-shape and 119 n-shape expression patterns. The identified local minima or maxima peaked at BMI 28-29. Based on these results and to best fit the WHO classification, we grouped the patients into three groups: BMI<25, 25≤BMI≤32, and BMI>32. The group analysis indicated that protein translation-related pathways were downregulated in 25≤BMI≥32 compared with BMI<25 patients. Muscle contraction transcripts were upregulated in 25≤BMI≥32 patients, and cholesterol synthesis and innate immunity transcripts were upregulated in the BMI>32 group. Transcripts involved in translation, muscle contraction and lipid metabolism also formed distinct correlation networks with biphasic dependence on BMI. Metabolite analysis identified acylcarnitines and ribose-5-phosphate increasing in the BMI>32 group and α-ketoglutarate increasing in the BMI<25 group. Molecular differences in the myocardium mirror the biphasic relationship between BMI and mortality.