Lipoprotein (a) [Lp(a)] could contribute to coronary artery disease (CAD) through proinflammatory effects. The neutrophil to lymphocyte ratio (NLR) is an inflammatory biomarker. We consecutively enrolled 7,922 CAD patients to investigate the synergistic association of Lp(a) and NLR with prognosis in patients undergoing percutaneous coronary intervention (PCI). NLR was calculated as the neutrophil count divided by the lymphocyte count. Cutoff for NLR was a median of 2.07. The threshold value was set at 30 mg/dL for Lp(a). The primary endpoint was major adverse cardiac events (MACEs), including all-cause mortality and myocardial infarction. During 2 years follow-up, 111 (1.40%) MACEs occurred. Lp(a) > 30 mg/dL was associated with an increased MACE risk in participants with NLR ≥2.07 [adjusted hazard ratio (HR), 1.84; 95% CI, 1.12–3.03], but not in participants with NLR <2.07 (adjusted HR, 0.74; 95% CI, 0.38–1.45) (Pinteraction = 0.021). Subgroup analysis demonstrated that the synergistic association of Lp(a) and NLR with prognosis was more pronounced in female patients (Pinteraction = 0.028). This study suggested that combining Lp(a) and NLR may be useful for risk stratification in CAD population.
DuarteLFGiuglianoRP. Lipoprotein(a) and its significance in cardiovascular disease: a Review. JAMA Cardiol2022; 7: 760–9.
2.
PuriRNissenSEArsenaultBJ, et al.Effect of C-reactive protein on lipoprotein(a)-associated cardiovascular risk in optimally treated patients with high-risk vascular disease: a prespecified secondary analysis of the ACCELERATE trial. JAMA Cardiol2020; 5: 1136–43.
3.
CagdasMRencuzogullariIKarakoyunS, et al.Assessment of relationship between C-reactive protein to albumin ratio and coronary artery disease severity in patients with acute coronary syndrome. Angiology2019; 70: 361–8.
4.
KarabagYCagdasMRencuzogullariI, et al.Usefulness of the C-Reactive Protein/Albumin Ratio for Predicting No-Reflow in ST-elevation myocardial infarction treated with primary percutaneous coronary intervention. Eur J Clin Invest2018; 48: e12928.
5.
ZhangWSpeiserJLYeF, et al.High-sensitivity C-reactive protein modifies the cardiovascular risk of lipoprotein(a): multi-ethnic study of atherosclerosis. J Am Coll Cardiol2021; 78: 1083–94.
6.
BuonaceraAStancanelliBColaciMMalatinoL. Neutrophil to lymphocyte ratio: an emerging marker of the relationships between the immune system and diseases. Int J Mol Sci2022; 23: 3636.
7.
SagerHBKoenigW. Immune cell-based cardiovascular risk assessment: spotlight on the neutrophil-lymphocyte ratio. Eur Heart J2021; 42: 904–6.
8.
AgarwalRAuroraRGSiswantoBBMuliawanHS. The prognostic value of neutrophil-to-lymphocyte ratio across all stages of coronary artery disease. Coron Artery Dis2022; 33: 137–43.
9.
AdamsteinNHMacFadyenJGRoseLM, et al.The neutrophil-lymphocyte ratio and incident atherosclerotic events: analyses from five contemporary randomized trials. Eur Heart J2021; 42: 896–903.
10.
LawlerPRBhattDLGodoyLCLüscherTFBonowROVermaS, et al.Targeting cardiovascular inflammation: next steps in clinical translation. Eur Heart J2021; 42: 113–31.
11.
XuNTangX-FYaoY, et al.Lipoprotein(a) levels are associated with coronary severity but not with outcomes in Chinese patients underwent percutaneous coronary intervention. Nutr Metabol Cardiovasc Dis2020; 30: 265–73.
12.
HeJBianXSongCZhangRYuanSYinD, et al.High neutrophil to lymphocyte ratio with type 2 diabetes mellitus predicts poor prognosis in patients undergoing percutaneous coronary intervention: a large-scale cohort study. Cardiovasc Diabetol2022; 21: 156.
13.
KronenbergFMoraSStroesESG, et al.Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J2022; 43: 3925–46.
14.
AssociationAD2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2022. Diabetes Care2022; 45: S17–S38.
15.
ThygesenKAlpertJSJaffeAS, et al.Third universal definition of myocardial infarction. Eur Heart J2012; 33: 2551–67.
16.
CutlipDEWindeckerSMehranR, et al.Clinical end points in coronary stent trials: a case for standardized definitions. Circulation2007; 115: 2344-51.
17.
ClarkeRPedenJFHopewellJC, et al.Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med2009; 361: 2518–28.
18.
Emerging Risk FactorsCErqouSKaptogeS, et al.Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA2009; 302: 412–23.
19.
KamstrupPRTybjaerg-HansenASteffensenRNordestgaardBG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA2009; 301: 2331–9.
20.
WilleitPRidkerPMNestelPJ, et al.Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials. Lancet2018; 392: 1311-20.
21.
LiuH-HGuoY-LZhuC-G, et al.Synergistic effect of the commonest residual risk factors, remnant cholesterol, lipoprotein(a), and inflammation, on prognosis of statin-treated patients with chronic coronary syndrome. J Transl Med2022; 20: 243.
22.
PuriRNissenSEArsenaultBJ, et al.Effect of C-reactive protein on lipoprotein(a)-associated cardiovascular risk in optimally treated patients with high-risk vascular disease: a prespecified secondary analysis of the ACCELERATE trial. JAMA Cardiol2020; 5: 1136–43.
23.
RidkerPMEverettBMThurenT, et al.Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med2017; 377: 1119–31.
24.
TardifJCKouzSWatersDD, et al.Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med2019; 381: 2497–505.
25.
RidkerPMDevalarajaMBaeresFMM, et al.IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet2021; 397: 2060–9.
26.
AfsharMPiloteLDufresneLEngertJCThanassoulisG. Lipoprotein(a) interactions with low-density lipoprotein cholesterol and other cardiovascular risk factors in premature acute coronary syndrome (ACS). J Am Heart Assoc2016; 5: e003012.
27.
NakaKKBechlioullisAMariniA, et al.Interleukin-1 genotypes modulate the long-term effect of lipoprotein(a) on cardiovascular events: the Ioannina Study. J Clin Lipidol2018; 12: 338–47.
28.
DangasGMehranRHarpelPC, et al.Lipoprotein(a) and inflammation in human coronary atheroma: association with the severity of clinical presentation. J Am Coll Cardiol1998; 32: 2035–42.
29.
ZhangWSpeiserJLYeF, et al.High-sensitivity C-reactive protein modifies the cardiovascular risk of lipoprotein(a): multi-ethnic study of atherosclerosis. J Am Coll Cardiol2021; 78: 1083–94.
30.
DuarteLFGiuglianoRP. Lipoprotein(a) and its significance in cardiovascular disease: a Review. JAMA Cardiol2022; 7: 760–9.
31.
PatelAPWangMPirruccelloJPEllinorPTNgKKathiresanS, et al.Lp(a) (Lipoprotein[a]) concentrations and incident atherosclerotic cardiovascular disease: new insights from a large national biobank. Arterioscler Thromb Vasc Biol2021; 41: 465–74.
32.
PostorinoGAltavillaRGuerriniMForconiS. The association of serum lipoprotein(a) levels with myocardial infarction and ictus cerebri in the elderly. Arch Gerontol Geriatr1996; 22: 213–6.
33.
SimonySBMortensenMBLangstedAAfzalSKamstrupPRNordestgaardBG. Sex differences of lipoprotein(a) levels and associated risk of morbidity and mortality by age: the Copenhagen General Population Study. Atherosclerosis2022; 355: 76–82.
34.
Roeters van LennepJETokgozogluLSBadimonL, et al.Women, lipids, and atherosclerotic cardiovascular disease: a call to action from the European Atherosclerosis Society. Eur Heart J2023; 44: 4157–73.
35.
AkpekMKayaMGLamYY, et al.Relation of neutrophil/lymphocyte ratio to coronary flow to in-hospital major adverse cardiac events in patients with ST-elevated myocardial infarction undergoing primary coronary intervention. Am J Cardiol2012; 110: 621–7.
36.
SenNAfsarBOzcanF, et al.The neutrophil to lymphocyte ratio was associated with impaired myocardial perfusion and long term adverse outcome in patients with ST-elevated myocardial infarction undergoing primary coronary intervention. Atherosclerosis2013; 228: 203–10.
37.
AdamsteinNHMacFadyenJGRoseLM, et al.The neutrophil-lymphocyte ratio and incident atherosclerotic events: analyses from five contemporary randomized trials. Eur Heart J2021; 42: 896–903.
38.
SchmidtKNoureenAKronenbergFUtermannG. Structure, function, and genetics of lipoprotein (a). J Lipid Res2016; 57: 1339–59.
39.
van der ValkFMBekkeringSKroonJ, et al.Oxidized phospholipids on lipoprotein(a) elicit arterial wall inflammation and an inflammatory monocyte response in humans. Circulation2016; 134: 611–24.
40.
SoehnleinO. Multiple roles for neutrophils in atherosclerosis. Circ Res2012; 110: 875–888.
41.
SwirskiFKNahrendorfM. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science2013; 339: 161–6.
42.
DoringYSoehnleinOWeberC. Neutrophil extracellular traps in atherosclerosis and atherothrombosis. Circ Res2017; 120: 736–43.
43.
LibbyPPasterkampGCreaFJangIK. Reassessing the mechanisms of acute coronary syndromes. Circ Res2019; 124: 150–60.
44.
NunezJSanchisJBodiV, et al.Relationship between low lymphocyte count and major cardiac events in patients with acute chest pain, a non-diagnostic electrocardiogram and normal troponin levels. Atherosclerosis2009; 206: 251–7.
45.
FiarresgaAJFerreiraRCFelicianoJ, et al.Prognostic value of neutrophil response in the era of acute myocardial infarction mechanical reperfusion. Rev Port Cardiol2004; 23: 1387–96.
46.
Lamon-FavaSMarcovinaSMAlbersJJ, et al.Lipoprotein(a) levels, apo(a) isoform size, and coronary heart disease risk in the Framingham Offspring Study. J Lipid Res2011; 52: 1181–7.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
