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Comment
. 2022 Mar 1;7(3):250-256.
doi: 10.1001/jamacardio.2021.5083.

Association of Apolipoprotein B-Containing Lipoproteins and Risk of Myocardial Infarction in Individuals With and Without Atherosclerosis: Distinguishing Between Particle Concentration, Type, and Content

Nicholas A Marston  1 , Robert P Giugliano  1 , Giorgio E M Melloni  1 , Jeong-Gun Park  1 , Valerie Morrill  2 , Michael A Blazing  3 , Brian Ference  4 , Evan Stein  5 , Erik S Stroes  6 , Eugene Braunwald  1 , Patrick T Ellinor  2   7   8 , Steven A Lubitz  2   7   8 , Christian T Ruff  1 , Marc S Sabatine  1
Affiliations
Comment

Association of Apolipoprotein B-Containing Lipoproteins and Risk of Myocardial Infarction in Individuals With and Without Atherosclerosis: Distinguishing Between Particle Concentration, Type, and Content

Nicholas A Marston et al. JAMA Cardiol. .

Abstract

Importance: Lipid management typically focuses on levels of low-density lipoprotein cholesterol (LDL-C) and, to a lesser extent, triglycerides (TG). However, animal models and genetic studies suggest that the atherogenic particle subpopulations (LDL and very-low-density lipoprotein [VLDL]) are both important and that the number of particles is more predictive of cardiac events than their lipid content.

Objective: To determine whether common measures of cholesterol concentration, TG concentration, or their ratio are associated with cardiovascular risk beyond the number of apolipoprotein B (apoB)-containing lipoproteins.

Design, setting, and participants: This prospective cohort analysis included individuals from the population-based UK Biobank and from 2 large international clinical trials, FOURIER and IMPROVE-IT. The median (IQR) follow-up was 11.1 (10.4-11.8) years in UK Biobank and 2.5 (2.0-4.7) years in the clinical trials. Two populations were studied in this analysis: 389 529 individuals in the primary prevention group who were not taking lipid-lowering therapy and 40 430 patients with established atherosclerosis who were receiving statin treatment.

Exposures: ApoB, non-high-density lipoprotein cholesterol (HDL-C), LDL-C, and TG.

Main outcome and measures: The primary study outcome was incident myocardial infarction (MI).

Results: Of the 389 529 individuals in the primary prevention group, 224 097 (58%) were female, and the median (IQR) age was 56.0 (49.5-62.5) years. Of the 40 430 patients with established atherosclerosis, 9647 (24%) were female, and the median (IQR) age was 63 (56.2-69.0) years. In the primary prevention cohort, apoB, non-HDL-C, and TG each individually were associated with incident MI. However, when assessed together, only apoB was associated (adjusted hazard ratio [aHR] per 1 SD, 1.27; 95% CI, 1.15-1.40; P < .001). Similarly, only apoB was associated with MI in the secondary prevention cohort. Adjusting for apoB, there was no association between the ratio of TG to LDL-C (a surrogate for the ratio of TG-rich lipoproteins to LDL) and risk of MI, implying that for a given concentration of apoB-containing lipoproteins, the relative proportions of particle subpopulations may no longer be a predictor of risk.

Conclusions and relevance: In this cohort study, risk of MI was best captured by the number of apoB-containing lipoproteins, independent from lipid content (cholesterol or TG) or type of lipoprotein (LDL or TG-rich). This suggests that apoB may be the primary driver of atherosclerosis and that lowering the concentration of all apoB-containing lipoproteins should be the focus of therapeutic strategies.

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Conflict of interest statement

Conflict of Interest Disclosures: Drs Giugliano Park, Braunwald, Ruff, and Sabatine report grants from Abbott, Amgen, Anthos Therapeutics, ARCA Biopharma, AstraZeneca, Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Daiichi Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, the Medicines Company, Medimmune, Merck, the National Institutes of Health, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Roche, Siemens Healthcare Diagnostics, and Zora Biosciences paid to the TIMI Study Group at Brigham and Women’s Hospital during the conduct of the study. Dr Giugliano reports personal fees from Amarin, Amgen, Centrix, Cryolife, CSL Behring, CVS Caremark, Daiichi Sankyo, Dr Reddy’s Laboratories, Esperion; Gilead, Hengrui, Inari, Janssen, Medical Education Resources, Medscape, Menarini, Merck, Novartis, Pfizer, PhaseBio Pharmaceuticals, St. Lukes, SAJA Pharmaceuticals, Samsung, Servier, Shanghai Medical Telescope, and Voxmedia outside the submitted work. Dr Ference reports grants from Amgen, Esperion, Merck, and Novartis and personal fees from Amgen, the American College of Cardiology, AstraZeneca, CiVi Pharma, Daiichi Sankyo, dalCOR, Eli Lilly, the European Atherosclerosis Society, the European Society of Cardiology, Ionis Pharmaceuticals, KrKa Pharmaceuticals, The Medicines Company, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, Sanofi, Silence Therapeutics, and Viatris outside the submitted work. Dr Stein reports personal fees from Amgen outside the submitted work. Dr Stroes reports personal fees from Amgen, Sanofi-Regeneron, and Esperion outside the submitted work. Dr Braunwald reports personal fees from Amgen, Boehringer Ingelheim, Cardurion, Eli Lilly, MyoKardia, NovoNordisk, and Verve outside the submitted work. Dr Ellinor reports grants from Bayer and personal fees from Bayer, MyoKardia, and Novartis during the conduct of the study, as well as grants from IBM Health outside the submitted work. Dr Lubitz reports grants from the American Heart Association, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Fitbit, IBM, the National Institutes of Health, and Pfizer and personal fees from Bayer AG, Blackstone Life Sciences, Bristol Myers Squibb, and Pfizer outside the submitted work. Dr Ruff reports personal fees from Anthos, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, and Janssen Pfizer outside the submitted work. Dr Sabatine reports personal fees from Althera, Amgen, Anthos Therapeutics, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, DalCor, Dr. Reddy’s Laboratories, Fibrogen, IFM Therapeutics, Intarcia, MedImmune, Merck, Moderna, and Novo Nordisk outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Lipid Parameters and Risk of Myocardial Infarction
All models were adjusted for age, sex, body mass index (calculated as weight in kilograms divided by height in meters squared), smoking status, hypertension, diabetes, ethnicity, and kidney function. The secondary prevention cohort was also adjusted for prior myocardial infarction, stroke, and peripheral artery disease. Clinically and lipid-adjusted models also included apolipoprotein B, non–high-density lipoprotein cholesterol, triglycerides, and high-density lipoprotein cholesterol in addition to the clinical variables.
Figure 2.
Figure 2.. Relative Importance of Lipoprotein Type After Adjusting for Apolipoprotein B Concentration in Individuals Not Receiving Lipid-Lowering Therapy
TG indicates triglyceride-rich lipoprotein; LDL-C, low-density lipoprotein cholesterol particles. The solid line represents the hazard at a given TG/LDL-C ratio compared with the hazard at the median TG/LDL-C ratio. Shaded area indicates 95% CIs. The slope of the line is not statistically different from 0 (P = .12). Adjusted for age, sex, ethnicity, body mass index (calculated as weight in kilograms divided by height in meters squared), smoking status, diabetes, creatine clearance, high-density lipoprotein, and apolipoprotein B.
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