Cited by 262Lipoproteins and Cardiovascular HealthDiabetes, Cardiovascular Risks, and LipoproteinsCholesterol and Lipid Metabolism

The DOI matches its Crossref record; 23 of the 23 references it cites were found in a registry or an index; 10 of the 13 sources its claims cite were checked for support.

Association of Apolipoprotein B–Containing Lipoproteins and Risk of Myocardial Infarction in Individuals With and Without Atherosclerosis

Open access

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.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In a large primary-prevention cohort and two secondary-prevention trial cohorts, apolipoprotein B (apoB) was the only lipid parameter independently associated with myocardial infarction after full adjustment. Neither lipid content nor lipoprotein type added risk beyond the number of apoB-containing particles.

Key findings

In 389,529 primary-prevention individuals not on lipid-lowering therapy, apoB, non–HDL-C, and TG were each individually associated with incident MI, but after full adjustment only apoB remained associated (aHR per 1 SD, 1.27; 95% CI, 1.15-1.40; P < .001).

  • In the same cohort, TG was associated with MI in clinically adjusted models (aHR per 1 SD, 1.16; 95% CI, 1.13-1.19; P < .001), but not after full clinical and lipid adjustment (aHR per 1 SD, 1.00; 95% CI, 0.96-1.04; P = .71).
  • In 40,430 patients with established atherosclerosis receiving statin treatment, only apoB was associated with MI; TG was not associated in clinically adjusted (aHR per 1 SD, 1.03; 95% CI, 0.99-1.07) or clinically and lipid-adjusted models (aHR per 1 SD, 0.94; 95% CI, 0.89-1.00).
  • Adjusting for apoB, the TG/LDL-C ratio was not associated with MI (aHR per 1 SD, 1.04; 95% CI, 0.99-1.09; P = .12), suggesting that for a given concentration of apoB-containing lipoproteins, particle type did not confer additional risk.

Methods

Prospective cohort analysis using UK Biobank primary-prevention individuals without lipid-lowering therapy (n = 389,529) and pooled secondary-prevention patients with established atherosclerosis from FOURIER and IMPROVE-IT receiving lipid-lowering therapy (n = 40,430). Median follow-up was 11.1 years in UK Biobank and 2.5 years in the clinical trials.

  • Exposures were apoB, non–HDL-C, LDL-C, and TG; the primary outcome was fatal or nonfatal MI.
  • Cox proportional hazards models estimated adjusted hazard ratios per 1 SD higher lipid parameter, with clinical adjustment and further adjustment for HDL-C, TG, non–HDL-C, and apoB; the TG/LDL-C ratio was evaluated with adjustment for apoB.

Limitations

The paper states that lipid values were measured using conventional lipid profiles rather than nuclear magnetic resonance spectroscopy, which would more accurately determine the VLDL-to-LDL ratio than the TG/LDL-C surrogate used.

  • The paper states that UK Biobank lipid values and lipid-lowering therapy data were collected at baseline and may have changed during follow-up; because individuals with higher lipid values would be most likely to start lipid-lowering therapy, this may have attenuated associations. The study was also not enriched for severe hypertriglyceridemia.
  • Evident from the text: the analysis is observational, limiting causal inference; the trial cohorts excluded patients with TG ≥400 mg/dL in FOURIER and ≥350 mg/dL in IMPROVE-IT, so severe hypertriglyceridemia is not represented.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1001/jamacardio.2021.5083

Cites

23 of 23 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

35 Own result · 9 Own interpretation · 8 Own method · 5 No basis given · 4 Supported · 2 Partly supported · 2 No full text of the sources · accuracy not yet measured

  • Probably not a substantial claim. 19
  • It may state two separate claims as one. 14
27 of 27
  • The paper relies on this without support.

    There is exactly one apoB-100 molecule on each atherogenic apoB-containing particle (LDL, IDL, and VLDL).

    “As there is exactly 1 apoB-100 on each of the atherogenic apoB-containing particles (ie, LDL, IDL, and VLDL)”
  • The paper relies on this without support.

    Measures of cholesterol and triglycerides provide information on the lipids in the blood and thus only indirectly on the types of lipoproteins and their composition, and not on the number of lipoproteins.

    “However, measures of cholesterol and TG provide information on the lipids in the blood and thus only indirectly on the types of lipoproteins and their composition, and not on the number of lipoproteins.”
  • The paper relies on this without support.

    Fatal or nonfatal myocardial infarction can be known with high precision and is strongly associated with dyslipidemia.

    “The end point of interest in both cohorts was fatal or nonfatal MI, a cardiovascular outcome that can be known with high precision and is strongly associated with dyslipidemia.”
  • The paper relies on this without support.

    The ratio of triglycerides to LDL-C is a surrogate for the ratio of triglyceride-rich lipoproteins to LDL.

    “the ratio of TG to LDL-C (a surrogate for the ratio of TG-rich lipoproteins to LDL)”
  • The paper relies on this without support.

    ApoB is in a 1:1 association with atherogenic lipoprotein particles.

    “given the 1:1 association between apoB and atherogenic lipoprotein particles.”
  • The paper relies on this without support.

    TG estimates TG-rich lipoproteins (VLDL and IDL) and LDL-C estimates LDL particles.

    “TG-rich lipoproteins (ie, VLDL and IDL, estimated by TG) or LDL particle (estimated by LDL-C).”
  • The paper relies on this without support.

    Individuals with higher lipid values are most likely to start lipid-lowering therapy.

    “Because individuals with higher lipid values would be most likely to start lipid-lowering therapy”
7 of 7

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

2 of 2

Citations

Cites

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Cited by

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Metadata

Authors
Marston, N. A., Giugliano, R. P., Melloni, G. E. M., Park, J.-G., Morrill, V., Blazing, M. A., Ference, B., Stein, E., Stroes, E. S., Braunwald, E., Ellinor, P. T., Lubitz, S. A., Ruff, C. T., & Sabatine, M. S.
Affiliations
  • Brigham and Women's Hospital (US)
  • Broad Institute (US)
  • Duke University (US)
  • University of Cambridge (GB)
  • Metabolic and Atherosclerosis Research Center, Cincinnati, Ohio
  • Amsterdam University Medical Centers (NL)
  • Thrombolysis in Myocardial Infarction (TIMI) Study Group, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
Corresponding author
Marston, Nicholas A.
Venue
JAMA Cardiology
Published
2022-03-01
Volume
7
Issue
3
Pages
250
ISSN
2380-6583 (ISSN-L)
OpenAlex
W3213895219
Cited by
262
References
23
Citations by year
2026: 43 · 2025: 50 · 2024: 67 · 2023: 68 · 2022: 32
FWCI
35.66
Type
journal article
Language
en
Open access
Locations
  • JAMA Cardiology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion)
Funders
  • British Heart Foundation (CH/1996001/9454)
  • Medical Research Council (MC_PC_17228)
  • National Heart, Lung, and Blood Institute (K08HL153950)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
Keywords
apolipoprotein B, apoB-containing lipoproteins, myocardial infarction, atherosclerosis, non-HDL cholesterol, triglycerides, LDL cholesterol, VLDL, cardiovascular risk, statin therapy, primary prevention, lipid control, FOURIER trial, IMPROVE-IT trial, UK Biobank
MeSH terms
Apolipoproteins B, Cholesterol, Female, Humans, Lipoproteins, Cholesterol, LDL, Male, Myocardial Infarction, Prospective Studies, Cohort Studies, Atherosclerosis

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