Trimethylamine N-oxide and the reverse cholesterol transport in cardiovascular disease: a cross-sectional study

Laura Bordoni,Leszek Kalinowski,Rosita Gabbianelli,Robert A Olek,Adrianna Radulska,Lukasz Lewicki,Joanna J Samulak,Iwona Pelikant-Malecka,Angelika K Sawicka

doi:10.1038/s41598-020-75633-1

Abstract

The early atherosclerotic lesions develop by the accumulation of arterial foam cells derived mainly from cholesterol-loaded macrophages. Therefore, cholesterol and cholesteryl ester transfer protein (CETP) have been considered as causative in atherosclerosis. Moreover, recent studies indicate the role of trimethylamine N-oxide (TMAO) in development of cardiovascular disease (CVD). The current study aimed to investigate the association between TMAO and CETP polymorphisms (rs12720922 and rs247616), previously identified as a genetic determinant of circulating CETP, in a population of coronary artery disease (CAD) patients (n = 394) and control subjects (n = 153). We also considered age, sex, trimethylamine (TMA) levels and glomerular filtration rate (GFR) as other factors that can potentially play a role in this complex picture. We found no association of TMAO with genetically determined CETP in a population of CAD patients and control subjects. Moreover, we noticed no differences between CAD patients and control subjects in plasma TMAO levels. On the contrary, lower levels of TMA in CAD patients respect to controls were observed. Our results indicated a significant correlation between GFR and TMAO, but not TMA. The debate whether TMAO can be a harmful, diagnostic or protective marker in CVD needs to be continued.

Highlights

The early atherosclerotic lesions develop by the accumulation of arterial foam cells derived mainly from cholesterol-loaded macrophages
Since most of the coronary artery disease (CAD) patients were treated with statins, we relied on a Mendelian randomization-based approach to study the impact of cholesteryl ester transfer protein (CETP) and high-density lipoprotein (HDL)-cholesterol on TMA and trimethylamine N-oxide (TMAO)
We found no association between TMAO levels and genetically determined CETP in a population of CAD patients and control subjects

Summary

Introduction

The early atherosclerotic lesions develop by the accumulation of arterial foam cells derived mainly from cholesterol-loaded macrophages. Cholesterol and cholesteryl ester transfer protein (CETP) have been considered as causative in atherosclerosis. Abbreviations CAD Coronary artery disease CVD Cardiovascular disease TMA Trimethylamine TMAO Trimethylamine N-oxide CETP Cholesteryl ester transfer protein GFR Glomerular filtration rate. The absence of cholesteryl ester transfer protein (CETP) in mice causes lower plasma cholesterol levels, with high-density lipoprotein (HDL) as the major circulating lipoprotein[6,7]. Genetic modifications, such as low-density lipoprotein (LDL) receptor deficient (LDLR−/−) and apolipoprotein E knockout ( ApoE−/−), have been applied to induce hypercholesterolemia in m ice[8,9,10,11,12]. Recent clinical studies have shown a positive correlation between elevated plasma TMAO and an increased risk for major adverse cardiovascular events defined as death, myocardial infarction, or s troke[20,21]

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