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

Adewale S Adebayo,Mustafa Zakkar,Will Dott,Bony Anthony,Florence Y Lai,Marius Roman,Bryony Eagle-Hemming,Julian L Griffin,Lathishia Joel-David,Syabira Yusoff,Sophia Sheikh,Hardeep Aujla,Antonio Murgia,Melanie Gulston,Gavin J Murphy,Marcin J Woźniak,Tracy Kumar

doi:10.1038/s41598-022-05562-8

Adewale S Adebayo, Mustafa Zakkar + Show 15 more

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https://doi.org/10.1038/s41598-022-05562-8

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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-six 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 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.

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We hypothesized that body mass index (BMI) dependent changes in myocardial gene expression and energy-related metabolites underlie the biphasic association between Body Mass Index (BMI) and mortality in cardiac surgery
We hypothesized that changes in expression of mitochondrial genes and metabolites may contribute to the biphasic association between BMI and adverse events following cardiac surgery
Sixty-eight consecutive patients were recruited to the study, with one protocol violation recorded and one participant withdrew from the study (Fig. 1A)

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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. 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. People with BMI between 25 and 35 have paradoxically better survival than those with low or normal BMI, or very high BMI (> 35)[2] These observations may be attributable to reverse epidemiology where people who are underweight or who have severe obesity have worse outcomes attributable to frailty or sarcopenia, or to unmeasured confounding such as fitness, or the presence or absence of metabolic syndrome. Both severe obesity and frailty lead to mitochondrial dysfunction[7] and dysregulated

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