Low-density lipoprotein electronegativity and risk of death after acute coronary syndromes: A case-cohort analysis

Simon Kraler; Florian A Wenzl; Jody Vykoukal; Johannes F Fahrmann; Ming-Yi Shen; Der-Yuan Chen; Kuan-Cheng Chang; Ching-Kun Chang; Arnold von Eckardstein; Lorenz Räber; François Mach; David Nanchen; Christian M Matter; Luca Liberale; Giovanni G Camici; Alexander Akhmedov; Chu-Huang Chen; Thomas F Lüscher; SPUM-ACS investigators

doi:10.1016/j.atherosclerosis.2023.05.014

Low-density lipoprotein electronegativity and risk of death after acute coronary syndromes: A case-cohort analysis

Atherosclerosis. 2023 Jul:376:43-52. doi: 10.1016/j.atherosclerosis.2023.05.014. Epub 2023 May 24.

Authors

Simon Kraler¹, Florian A Wenzl¹, Jody Vykoukal², Johannes F Fahrmann², Ming-Yi Shen³, Der-Yuan Chen⁴, Kuan-Cheng Chang⁵, Ching-Kun Chang⁴, Arnold von Eckardstein⁶, Lorenz Räber⁷, François Mach⁸, David Nanchen⁹, Christian M Matter¹⁰, Luca Liberale¹¹, Giovanni G Camici¹, Alexander Akhmedov¹², Chu-Huang Chen¹³, Thomas F Lüscher¹⁴; SPUM-ACS investigators

Affiliations

¹ Center for Molecular Cardiology, University of Zurich, 8952, Schlieren, Switzerland.
² Department of Clinical Cancer Prevention, The University of Texas, Houston, TX, 77030, USA.
³ Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 404, Taiwan.
⁴ Rheumatology and Immunology Center, China Medical University Hospital, Taichung, 404, Taiwan.
⁵ Division of Cardiovascular Medicine, China Medical University Hospital, Taichung, Taiwan.
⁶ Institute of Clinical Chemistry, University Hospital of Zurich, Zurich, Switzerland.
⁷ Department of Cardiology, Bern University Hospital, University of Bern, Bern, Switzerland.
⁸ Cardiology, University Hospital Geneva, Geneva, Switzerland.
⁹ Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland.
¹⁰ Department of Cardiology, University Hospital Zurich, Zurich, Switzerland.
¹¹ First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 16132, Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 16132, Genoa, Italy.
¹² Center for Molecular Cardiology, University of Zurich, 8952, Schlieren, Switzerland. Electronic address: alexander.akhmedov@uzh.ch.
¹³ Vascular and Medicinal Research, Texas Heart Institute, Houston, TX, 77030, USA; New York Heart Research Foundation, Mineola, NY, 11501, USA. Electronic address: cchen@texasheart.org.
¹⁴ Center for Molecular Cardiology, University of Zurich, 8952, Schlieren, Switzerland; Royal Brompton and Harefield Hospitals and Imperial College, London, United Kingdom; School of Cardiovascular Medicine and Sciences, Kings College London, London, UK. Electronic address: t.luescher@rbht.nhs.uk.

PMID: 37285778
DOI: 10.1016/j.atherosclerosis.2023.05.014

Abstract

Background and aims: Low-density lipoprotein (LDL)-cholesterol (LDL-C) promotes atherosclerotic cardiovascular disease (ASCVD), with changes in LDL electronegativity modulating its pro-atherogenic/pro-thrombotic effects. Whether such alterations associate with adverse outcomes in patients with acute coronary syndromes (ACS), a patient population at particularly high cardiovascular risk, remains unknown.

Methods: This is a case-cohort study using data from a subset of 2619 ACS patients prospectively recruited at four university hospitals in Switzerland. Isolated LDL was chromatographically separated into LDL particles with increasing electronegativity (L1-L5), with the L1-L5 ratio serving as a proxy of overall LDL electronegativity. Untargeted lipidomics revealed lipid species enriched in L1 (least) vs. L5 (most electronegative subfraction). Patients were followed at 30 days and 1 year. The mortality endpoint was reviewed by an independent clinical endpoint adjudication committee. Multivariable-adjusted hazard ratios (aHR) were calculated using weighted Cox regression models.

Results: Changes in LDL electronegativity were associated with all-cause mortality at 30 days (aHR, 2.13, 95% CI, 1.07-4.23 per 1 SD increment in L1/L5; p=.03) and 1 year (1.84, 1.03-3.29; p=.04), with a notable association with cardiovascular mortality (2.29; 1.21-4.35; p=.01; and 1.88; 1.08-3.28; p=.03). LDL electronegativity superseded several risk factors for the prediction of 1-year death, including LDL-C, and conferred improved discrimination when added to the updated GRACE score (area under the receiver operating characteristic curve 0.74 vs. 0.79, p=.03). Top 10 lipid species enriched in L1 vs. L5 were: cholesterol ester (CE) (18:2), CE (20:4), free fatty acid (FA) (20:4), phosphatidyl-choline (PC) (36:3), PC (34:2), PC (38:5), PC (36:4), PC (34:1), triacylglycerol (TG) (54:3), and PC (38:6) (all p < .001), with CE (18:2), CE (20:4), PC (36:3), PC (34:2), PC (38:5), PC (36:4), TG (54:3), and PC (38:6) independently associating with fatal events during 1-year of follow-up (all p < .05).

Conclusions: Reductions in LDL electronegativity are linked to alterations of the LDL lipidome, associate with all-cause and cardiovascular mortality beyond established risk factors, and represent a novel risk factor for adverse outcomes in patients with ACS. These associations warrant further validation in independent cohorts.

Keywords: Lipidomics; Low-density lipoprotein; Residual cardiovascular risk; Risk prediction modelling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acute Coronary Syndrome*
Atherosclerosis* / epidemiology
Cholesterol
Cholesterol, LDL
Cohort Studies
Humans
Risk Factors
Triglycerides

Substances

Cholesterol, LDL
Triglycerides
Cholesterol