Original Research|Articles in Press

Impact of Triglyceride-rich lipoproteins on Early In-stent neoatherosclerosis formation in patients undergoing statin treatment

Published:January 26, 2023DOI:


      • OCT assessed neoatherosclerosis (NA) in statin-treated patients.
      • TG-rich lipoprotein (TRL) levels were significantly higher in the NA group.
      • Apolipoprotein (apo) C3, TRL-C, and apoB levels were risk factors for NA
      • LDL-C levels were similar in the NA and non-NA group.


      Neoatherosclerosis (NA), which refers to neointimal atherosclerosis within a stent, is considered one of the underlying causes of late-phase stent failure following a newer generation drug-eluting stent (DES) placement procedure. Even contemporary guideline-directed medical therapy may be insufficient to prevent NA.


      This study aimed to investigate how intricately lipid markers are associated with NA formation in the early phase of treatment with well-maintained low-density lipoprotein cholesterol (LDL-C) levels.


      We enrolled 114 consecutive patients undergoing statin treatment and percutaneous coronary intervention (PCI) with current-generation DES for coronary artery disease. At a median 12 months after PCI, optical coherence tomography (OCT) was performed. Various lipid markers, including LDL-C, triglyceride (TG), triglyceride-rich lipoprotein cholesterol (TRL-C), non-high-density lipoprotein cholesterol (non-HDL-C), malondialdehyde-modified LDL (MDA-LDL), and several apolipoproteins, were also evaluated.


      NA was observed in 17 (14.9%) patients. The LDL-C level was equivalent in patients with or without NA (77.2 vs. 69.8 mg/dL; p=0.15). However, the levels of TG, apolipoprotein C3 (apoC3), TRL-C, non-HDL-C, and apolipoprotein B (apoB), and MDA-LDL were significantly higher in the patients with NA. Furthermore, multivariate logistic regression adjusting for HbA1c and stent duration revealed apoC3, TRL-C, non-HDL-C, apoB, and MDA-LDL levels as risk factors for NA. However, when apoB was included as a covariate, other factors became nonsignificant.


      Abnormal triglyceride-rich lipoprotein metabolism and high atherogenic apoB-containing lipoprotein particle numbers are associated with the formation of NA in patients undergoing statin treatment at a median 12 months post-PCI.

      Graphical abstract



      AA (indicates Arachidonic acid), ACS (Acute coronary syndrome), Apo (Apolipoprotein), AUC (Area under the curve), CAD (Coronary artery disease), CI (Confidence interval), DES (Drug eluting stent), eGFR (estimated glomerular filtration rate), EPA (Eicosapentaenoic acid), HbA1c (Glycated hemoglobin), HDL-C (High-density lipoprotein-cholesterol), Hs-CRP (High-sensitivity C-reactive protein), LDL-C (Low-density lipoprotein-C), MACE (Major adverse cardiovascular event), MDA-LDL (Malondialdehyde-modified low-density lipoprotein), NA (Neoatherosclerosis), Non-HDL-C (Non-high-density lipoprotein cholesterol), NT-proBNP (N-terminal pro-brain natriuretic peptide), OCT (Optical coherence tomography), OR (Odds ratio), PCI (Percutaneous coronary intervention), Sd-LDL-C (Small dense LDL-C), TG (Triglyceride), TRL-C (Triglyceride-rich lipoprotein-cholesterol), TRLs (Triglyceride-rich lipoproteins)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Clinical Lipidology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Nakazawa G
        • Otsuka F
        • Nakano M
        • et al.
        The pathology of neoatherosclerosis in human coronary implants bare-metal and drug-eluting stents.
        J Am Coll Cardiol. 2011; 57: 1314-1322
        • Otsuka F
        • Byrne RA
        • Yahagi K
        • et al.
        Neoatherosclerosis: overview of histopathologic findings and implications for intravascular imaging assessment.
        Eur Heart J. 2015; 36: 2147-2159
        • Kuroda M
        • Otake H
        • Shinke T
        • et al.
        The impact of in-stent neoatherosclerosis on long-term clinical outcomes: an observational study from the Kobe University Hospital optical coherence tomography registry.
        EuroIntervention. 2016; 12: e1366-e1374
        • Lee SY
        • Hur SH
        • Lee SG
        • et al.
        Optical coherence tomographic observation of in-stent neoatherosclerosis in lesions with more than 50% neointimal area stenosis after second-generation drug-eluting stent implantation.
        Circ Cardiovasc Interv. 2015; 8e001878
        • Lee SY
        • Shin DH
        • Mintz GS
        • et al.
        Optical coherence tomography-based evaluation of in-stent neoatherosclerosis in lesions with more than 50% neointimal cross-sectional area stenosis.
        EuroIntervention. 2013; 9: 945-951
        • Kim C
        • Kim BK
        • Lee SY
        • et al.
        Incidence, clinical presentation, and predictors of early neoatherosclerosis after drug-eluting stent implantation.
        Am Heart J. 2015; 170: 591-597
        • Larsen AI
        • Tomey MI
        • Mehran R
        • et al.
        Comparison of outcomes in patients with ST-segment elevation myocardial infarction discharged on versus not on statin therapy (from the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction Trial).
        Am J Cardiol. 2014; 113: 1273-1279
        • Catapano AL
        • Graham I
        • De Backer G
        • et al.
        2016 ESC/EAS guidelines for the management of dyslipidaemias.
        Eur Heart J. 2016; 37: 2999-3058
        • Sampson UK
        • Fazio S
        • Linton MF.
        Residual cardiovascular risk despite optimal LDL cholesterol reduction with statins: the evidence, etiology, and therapeutic challenges.
        Curr Atheroscler Rep. 2012; 14: 1-10
        • Boekholdt SM
        • Arsenault BJ
        • Mora S
        • et al.
        Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis.
        JAMA. 2012; 307: 1302-1309
        • Nordestgaard BG.
        Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology.
        Circ Res. 2016; 118: 547-563
        • Jang IK
        • Bouma BE
        • Kang DH
        • et al.
        Visualization of coronary atherosclerotic plaques in patients using optical coherence tomography: comparison with intravascular ultrasound.
        J Am Coll Cardiol. 2002; 39: 604-609
        • Park SJ
        • Kang SJ
        • Virmani R
        • Nakano M
        • Ueda Y.
        In-stent neoatherosclerosis: a final common pathway of late stent failure.
        J Am Coll Cardiol. 2012; 59: 2051-2057
        • Ito Y
        • Fujimura M
        • Ohta M
        • Hirano T.
        Development of a homogeneous assay for measurement of small dense LDL cholesterol.
        Clin Chem. 2011; 57: 57-65
        • Elshazly MB
        • Mani P
        • Nissen S
        • et al.
        Remnant cholesterol, coronary atheroma progression and clinical events in statin-treated patients with coronary artery disease.
        Eur J Prev Cardiol. 2020; 27: 1091-1100
        • Matsumoto D
        • Shite J
        • Shinke T
        • et al.
        Neointimal coverage of sirolimus-eluting stents at 6-month follow-up: evaluated by optical coherence tomography.
        Eur Heart J. 2007; 28: 961-967
        • Tearney GJ
        • Regar E
        • Akasaka T
        • et al.
        Consensus standards for acquisition, measurement, and reporting of intravascular optical coherence tomography studies: a report from the International Working Group for Intravascular Optical Coherence Tomography Standardization and Validation.
        J Am Coll Cardiol. 2012; 59: 1058-1072
        • Finn AV
        • Joner M
        • Nakazawa G
        • et al.
        Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialization.
        Circulation. 2007; 115: 2435-2441
      1. Tg, Hdl Working Group of the Exome Sequencing Project NHL, Blood I, et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease.
        N Engl J Med. 2014; 371: 22-31
        • Scheffer PG
        • Teerlink T
        • Dekker JM
        • et al.
        Increased plasma apolipoprotein C-III concentration independently predicts cardiovascular mortality: the Hoorn Study.
        Clin Chem. 2008; 54: 1325-1330
        • van Capelleveen JC
        • Bernelot Moens SJ
        • Yang X
        • et al.
        Apolipoprotein C-III levels and incident coronary artery disease risk: The EPIC-Norfolk PROSPECTIVE POPULATION STudy.
        Arterioscler Thromb Vasc Biol. 2017; 37: 1206-1212
        • Katzmann JL
        • Werner CM
        • Stojakovic T
        • Marz W
        • Scharnagl H
        • Laufs U.
        Apolipoprotein CIII predicts cardiovascular events in patients with coronary artery disease: a prospective observational study.
        Lipids Health Dis. 2020; 19: 116
        • Sekimoto T
        • Koba S
        • Mori H
        • et al.
        Small dense low-density lipoprotein cholesterol: a residual risk for rapid progression of non-culprit coronary lesion in patients with acute coronary syndrome.
        J Atheroscler Thromb. 2021;
        • Taskinen MR
        • Packard CJ
        • Boren J.
        Emerging evidence that ApoC-III inhibitors provide novel options to reduce the residual CVD.
        Curr Atheroscler Rep. 2019; 21: 27
        • Tardif JC
        • Karwatowska-Prokopczuk E
        • Amour ES
        • et al.
        Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk.
        Eur Heart J. 2022; 43: 1401-1412
        • Fujihara Y
        • Nakamura T
        • Horikoshi T
        • et al.
        Remnant lipoproteins are residual risk factor for future cardiovascular events in patients with stable coronary artery disease and on-statin low-density lipoprotein cholesterol levels <70 mg/dL.
        Circ J. 2019; 83: 1302-1308
        • Jepsen AM
        • Langsted A
        • Varbo A
        • Bang LE
        • Kamstrup PR
        • Nordestgaard BG.
        Increased remnant cholesterol explains part of residual risk of all-cause mortality in 5414 patients with ischemic heart disease.
        Clin Chem. 2016; 62: 593-604
        • Lin A
        • Nerlekar N
        • Rajagopalan A
        • et al.
        Remnant cholesterol and coronary atherosclerotic plaque burden assessed by computed tomography coronary angiography.
        Atherosclerosis. 2019; 284: 24-30
        • Johannesen CDL
        • Mortensen MB
        • Langsted A
        • Nordestgaard BG.
        Apolipoprotein B and Non-HDL cholesterol better reflect residual risk than LDL cholesterol in statin-treated patients.
        J Am Coll Cardiol. 2021; 77: 1439-1450
        • Mach F
        • Baigent C
        • Catapano AL
        • et al.
        2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.
        Eur Heart J. 2020; 41: 111-188
        • Yonetsu T
        • Kim JS
        • Kato K
        • et al.
        Comparison of incidence and time course of neoatherosclerosis between bare metal stents and drug-eluting stents using optical coherence tomography.
        Am J Cardiol. 2012; 110: 933-939
        • Kim JS
        • Hong MK
        • Shin DH
        • et al.
        Quantitative and qualitative changes in DES-related neointimal tissue based on serial OCT.
        JACC Cardiovasc Imag. 2012; 5: 1147-1155
        • Tian F
        • Chen Y
        • Liu H
        • Zhang T
        • Guo J
        • Jin Q
        Assessment of characteristics of neointimal hyperplasia after drug-eluting stent implantation in patients with diabetes mellitus: an optical coherence tomography analysis.
        Cardiology. 2014; 128: 34-40
        • Yonetsu T
        • Kato K
        • Kim SJ
        • et al.
        Predictors for neoatherosclerosis: a retrospective observational study from the optical coherence tomography registry.
        Circ Cardiovasc Imaging. 2012; 5: 660-666
        • Yoshimura M
        • Umemoto S
        • Kawano R
        • et al.
        Non-fasting hypertriglyceridemia as an independent risk factor for coronary in-stent restenosis after primary bare metal stent implantation in patients with coronary artery disease.
        Int Heart J. 2021; 62: 970-979
        • Ito T
        • Fujita H
        • Tani T
        • Ohte N.
        Malondialdehyde-modified low-density lipoprotein is a predictor of cardiac events in patients with stable angina on lipid-lowering therapy after percutaneous coronary intervention using drug-eluting stent.
        Atherosclerosis. 2015; 239: 311-317
        • Gao L
        • Park SJ
        • Jang Y
        • et al.
        Comparison of Neoatherosclerosis and neovascularization between patients with and without diabetes: an optical coherence tomography study.
        JACC Cardiovasc Interv. 2015; 8: 1044-1052
        • Pahud de Mortanges A
        • Sinaci E
        • Salvador Jr., D
        • et al.
        GLP-1 receptor agonists and coronary arteries: from mechanisms to events.
        Front Pharmacol. 2022; 13856111
        • Scisciola L
        • Cataldo V
        • Taktaz F
        • et al.
        Anti-inflammatory role of SGLT2 inhibitors as part of their anti-atherosclerotic activity: Data from basic science and clinical trials.
        Front Cardiovasc Med. 2022; 91008922
        • Sniderman AD
        • Couture P
        • Martin SS
        • et al.
        Hypertriglyceridemia and cardiovascular risk: a cautionary note about metabolic confounding.
        J Lipid Res. 2018; 59: 1266-1275