Highlights
- •Plasma levels of oxidized phospholipids carried on apolipoprotein B-100 are predictive of coronary heart disease.
- •Plasma levels of oxidized phospholipids carried on plasminogen and plasminogen were unrelated to risk of coronary heart disease.
- •The effects of oxidized phospholipids on risk of coronary heart disease are chiefly mediated by their carriage on Lp(a).
Abstract
Background and aims
Oxidized phospholipids carried on the apolipoprotein B-100 (OxPL-apoB) component of
Lp(a) are predictive of coronary heart disease (CHD), but the role of oxidized phospholipids
carried on plasminogen (OxPL-PLG) is unknown. We examined the independent effects
of OxPL-apoB and OxPL-PLG for risk of CHD before and after adjustment for Lp(a).
Methods
Plasma levels of OxPL-apoB, OxPL-PLG, plasminogen and Lp(a) were measured in the PROCARDIS
study of early-onset CHD (906 cases/858 controls). Multivariable logistic regression
was used to estimate the odds ratios (OR) for each biomarker with CHD after adjustment
for established risk factors.
Results
Mean levels of OxPL-apoB were higher in cases than controls, but levels of OxPL-PLG
and plasminogen were similar. For OxPL-apoB, individuals in the top vs bottom fifth
had 2-fold higher age and sex-adjusted OR of CHD (OR = 2.61 [95%CI: 1.91, 3.55]),
which were partially attenuated after adjustment for established risk factors. The
findings for OxPL-apoB and CHD in PROCARDIS were comparable with those of a meta-analysis
of all such studies. However, the associations of OxPL-apoB with CHD were fully attenuated
by additional adjustment for Lp(a) (OR = 0.93 [0.54,1.60]). Neither OxPL-PLG nor plasminogen
were associated with CHD. Overall, there were no differences in the predictive value
for CHD of high vs normal levels (<20th or >80th percentile) of OxPL-apoB, OxPL-PLG,
plasminogen or Lp(a) after stratifying for each other.
Conclusions
These results highlight the context-dependency of OxPL in plasma and suggest that
their associated risk of CHD is chiefly mediated by their carriage on Lp(a).
Graphical abstract
Graphical Abstract
Keywords
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References
- Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity.N. Engl. J. Med. 1989; 320: 915-924
- Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a).J. Lipid Res. 2013; 54: 2815-2830
- A novel function of lipoprotein [a] as a preferential carrier of oxidized phospholipids in human plasma.J. Lipid Res. 2008; 49: 2230-2239
- Lipoprotein(a), diagnosis, prognosis, controversies, and emerging therapies.J. Am. Coll. Cardiol. 2017; 69: 692-711
- Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a).J. Lipid Res. 2013; 54: 2815-2828
- Oxidized phospholipids are present on plasminogen, affect fibrinolysis, and increase following acute myocardial infarction.J. Am. Coll. Cardiol. 2012; 59: 1426-1437
- Naturally occurring human plasminogen, like genetically related apolipoprotein(a), contains oxidized phosphatidylcholine adducts.Biochim. Biophys. Acta. 2010; 1801: 738-745
- Circulating levels of plasminogen and oxidized phospholipids bound to plasminogen distinguish between atherothrombotic and non-atherothrombotic myocardial infarction.J. Thromb. Thrombolysis. 2016; 42: 61-76
- Short-term regulation of hematopoiesis by lipoprotein(a) results in the production of pro-inflammatory monocytes.Int. J. Cardiol. 2020; 315: 81-85
- Genetic variants associated with Lp(a) lipoprotein level and coronary disease.N. Engl. J. Med. 2009; 361: 2518-2528
- Oxidized phospholipids predict the presence and progression of carotid and femoral atherosclerosis and symptomatic cardiovascular disease: five-year prospective results from the Bruneck study.J. Am. Coll. Cardiol. 2006; 47: 2219-2228
- Report of the national heart, lung, and blood Institute workshop on lipoprotein(a) and cardiovascular disease: recent advances and future directions.Clin. Chem. 2003; 49: 1785-1796
- Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER trial (justification for the use of statins in prevention an intervention trial evaluating rosuvastatin).Circulation. 2014; 129: 635-642
- Plasma cytokines and risk of coronary heart disease in the PROCARDIS study.Open Heart. 2018; 5 (eCollection 2018)e000807https://doi.org/10.1136/openhrt-2018-000807
- Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease.N. Engl. J. Med. 2005; 353: 46-57
- Oxidation-specific biomarkers, lipoprotein(a), and risk of fatal and nonfatal coronary events.J. Am. Coll. Cardiol. 2010; 56: 946-955
- Oxidation-specific biomarkers, prospective 15-year cardiovascular and stroke outcomes, and net reclassification of cardiovascular events.J. Am. Coll. Cardiol. 2012; 60: 2218-2229
- Relationship of oxidized phospholipids on apolipoprotein B-100 to cardiovascular outcomes in patients treated with intensive versus moderate atorvastatin therapy: the TNT trial.J. Am. Coll. Cardiol. 2015; 65: 1286-1295
- SPARCL trial investigators. Oxidized phospholipids on apolipoprotein B-100 and recurrent ischemic events following stroke or transient ischemic attack.J. Am. Coll. Cardiol. 2017; 69: 147-158
- The LPA gene, ethnicity, and cardiovascular events.Circulation. 2016; 135: 251-263
- Improved estimates of floating absolute risk.Stat. Med. 2004; 23: 93-104
- Lipoprotein(a), fibrin binding, and plasminogen activation.Arteriosclerosis. 1990; 10: 240-245
- Plasminogen levels in healthy volunteers: influence of age, sex, smoking and oral contraceptives.Thromb. Haemostasis. 1992; 68: 506-510
- Temporal increases in plasma markers of oxidized low-density lipoprotein strongly reflect the presence of acute coronary syndromes.J. Am. Coll. Cardiol. 2003; 41: 360-370
- Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering Study I. High-dose atorvastatin reduces total plasma levels of oxidized phospholipids and immune complexes present on apolipoprotein B-100 in patients with acute coronary syndromes in the MIRACL trial.Circulation. 2004; 110: 1406-1412
- Percutaneous coronary intervention results in acute increases in oxidized phospholipids and lipoprotein(a): short-term and long-term immunologic responses to oxidized low-density lipoprotein.Circulation. 2004; 109: 3154-3170
- The role of oxidised phospholipids, lipoprotein (a) and biomarkers of oxidized lipoproteins in chronically occluded coronary arteries in sudden cardiac death and following successful percutaneous revascularisation.Cardiovasc. Revascularization Med. 2012; 13: 11-19
- Release and capture of bioactive oxidized phospholipids and oxidized cholesteryl esters during percutaneous coronary and peripheral arterial interventions in humans.J. Am. Coll. Cardiol. 2014; 63: 1961-1971
- Effect of therapeutic interventions on oxidised phospholipids on apolipoprotein B100 and lipoprotein (a).J Clin Lipidol. 2016; 10: 594-603
- Pro-inflammatory interleukin-1 genotypes potentiate the risk of coronary artery disease and cardiovascular events mediated by oxidized phospholipids and lipoprotein(a).J. Am. Coll. Cardiol. 2014; 63: 1724-1734
- Low-density lipoprotein cholesterol corrected for lipoprotein(a) cholesterol, risk thresholds, and cardiovascular events.J. Am. Heart Assoc. 2020; 9e016318
- Effect of pelacarsen on lipoprotein(a) cholesterol and corrected low-density lipoprotein cholesterol.J. Am. Coll. Cardiol. 2022; 79: 1035-1046
- Statin therapy increases lipoprotein(a) levels.Eur. Heart J. 2020; 41: 2275-2284
- Potent lipoprotein(a) lowering following apolipoprotein(a) antisense treatment reduces the pro-inflammatory activation of circulating monocytes in patients with elevated lipoprotein(a).Eur. Heart J. 2020; 41: 2262-2271
- Lipoprotein(a) reduction in persons with cardiovascular disease.N. Engl. J. Med. 2020; 382: 244-255
Article Info
Publication History
Published online: June 24, 2022
Accepted:
June 22,
2022
Received in revised form:
June 16,
2022
Received:
January 20,
2022
Identification
Copyright
Crown Copyright © 2022 Published by Elsevier B.V. All rights reserved.
