The Capacity of APOB-Depleted Plasma in Inducing ATP-Binding Cassette A1/G1-Mediated Macrophage Cholesterol Efflux-But Not Gut Microbial-Derived Metabolites-Is Independently Associated with Mortality in Patients with ST-Segment Elevation Myocardial Infarction.

Marina Canyelles,Francisco Blanco-Vaca,Jordi Ordóñez-Llanos,Noemi Rotllan,Aitor Alquézar-Arbé,Joan Carles Escolà-Gil,Oscar Yanes,Álvaro García-Osuna,Josep Julve,Mireia Tondo,David Santos,Jordi Sans-Roselló,Alexandra Junza,Núria Puig,Alessandro Sionis

doi:10.3390/biomedicines9101336

Abstract

Impaired HDL-mediated macrophage cholesterol efflux and higher circulating concentrations of trimethylamine N-oxide (TMAO) levels are independent risk factors for cardiovascular mortality. The TMAO precursors, γ-butyrobetaine (γBB) and Trimethyllysine (TML), have also been recently associated with cardiovascular death, but their interactions with HDL-mediated cholesterol efflux remain unclear. We aimed to determine the associations between APOB depleted plasma-mediated macrophage cholesterol efflux and plasma TMAO, γBB, and TML concentrations and explore their association with two-year follow-up mortality in patients with acute ST-elevation myocardial infarction (STEMI) and unstable angina (UA). Baseline and ATP-binding cassette transporter ABCA1 and ABCG1 (ABCA1/G1)-mediated macrophage cholesterol efflux to APOB-depleted plasma was decreased in patients with STEMI, and the latter was further impaired in those who died during follow-up. Moreover, the circulating concentrations of TMAO, γBB, and TML were higher in the deceased STEMI patients when compared with the STEMI survivors or UA patients. However, after statistical adjustment, only ABCA1/G1-mediated macrophage cholesterol efflux remained significantly associated with mortality. Furthermore, neither the TMAO, γBB, nor TML levels altered the HDL-mediated macrophage cholesterol efflux in vitro. We conclude that impaired ABCA1/G1-mediated macrophage cholesterol efflux is independently associated with mortality at follow-up in STEMI patients.

Highlights

The ability of high-density lipoprotein (HDL) particles to stimulate cholesterol efflux from macrophage foam cells, the first step of reverse cholesterol transport (RCT), is one major recognized HDL cardioprotective function [1]
HDL cholesterol (HDL-C) concentrations were significantly lower in patients with ST-elevation myocardial infarction (STEMI) compared to those with unstable angina (UA) but not different between the survivors and deceased STEMI patients
The estimate the glomerular filtration rate (eGFR) was significantly lower in the deceased STEMI patients when compared with the STEMI survivors and those admitted with UA (Table 1)

Summary

Introduction

The ability of high-density lipoprotein (HDL) particles to stimulate cholesterol efflux from macrophage foam cells, the first step of reverse cholesterol transport (RCT), is one major recognized HDL cardioprotective function [1]. The importance of HDL-mediated cholesterol efflux in atheroprotection emerged from a study reporting a strong inverse association between the ex vivo cholesterol efflux capacity of APOB-depleted serum, measured in cultured mouse macrophage foam cells, and the carotid intima-media thickness and likelihood of angiographical-defined coronary artery disease [2]. The HDL-mediated cholesterol efflux ability in mouse macrophage foam cells was further found inversely associated with cardiovascular mortality in patients with chronic coronary artery disease [6,7,8]. A recent report showed that the serum cholesterol efflux capacity measured in human macrophages was a strong predictor of all-cause mortality after a MI, but the study did not find any association with HDL-mediated efflux or ABCA1-dependent and SR-BI-mediated serum efflux capacities [9]

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