Cardiovascular Biomarkers: Oxidized LDL

Optimal Takeaways

Oxidized low-density lipoprotein (oxLDL) is LDL that has been modified through oxidation and carries compounds that contribute to the development of atherosclerosis. High levels of oxLDL are linked with multiple health issues such as obesity, metabolic syndrome, hypothyroidism, coronary artery disease, and others, mainly due to the compound's pro-inflammatory nature and ability to exacerbate endothelial damage. Smaller, denser LDL particles are particularly prone to oxidation, but this can be mitigated through dietary changes such as increased consumption of high-antioxidant foods and omega-3 fatty acids. Evaluating levels of oxLDL, alongside other markers, is crucial in assessing cardiometabolic risk, as it's not only a marker of existing oxidative stress but also a driver of such stress, activating monocytes and promoting atherosclerosis. Furthermore, studies have suggested that high levels of oxLDL could indicate early stages of coronary artery disease and metabolic syndrome.

Please note that Quest and other labs have a different unit and reference range for this biomarker.

Standard Range:

Quest: below 60.00 U/L  

Labcorp: 10.00 – 170.00 ng/mL  

The ODX Range: 0.00 – 37.00 U/L or 0.00 – 108.00 ng/mL  [LabCorp]

Low levels of oxidized LDL suggest decreased oxidative stress and higher total antioxidant capacity.

High levels of oxidized LDL are associated with insufficiency of antioxidants (Holvoet 2008), oxidative stress, metabolic syndrome (Ali 2017), impaired glucose tolerance, type 2 diabetes, decreased total antioxidant capacity (Nour Eldin 2014), obesity, hypercholesterolemia, impaired fasting LDL-C, hypertriglyceridemia, carotid intima-media thickness, unstable atherosclerotic plaque, endothelial dysfunction, and coronary artery disease (Ramos-Arellano 2014).

Elevated oxLDL is also associated with hypothyroidism, elevated Lp(a) and ApoB (Bansal 2016), smaller LDL particles (Gao 2018, Bansal 2016), increased risk of future cardiac events in the absence of heart disease (Meisinger 2005), cardiac dysfunction in hemodialysis patients (Raikou 2018), and serum uric acid, a marker of oxidative stress (Cicero 2014).

Overview

Oxidized low-density lipoprotein (oxLDL) is LDL that has been modified by oxidation and carries pro-atherogenic compounds, including peroxides, hydroxides, 7 ketocholesterol, and aldehydes such as malondialdehyde (MDA). The presence of circulating MDA and myeloperoxidase enzymes may be related to the degree of oxidation and severity of associated atherosclerosis. Both lipid and protein or amino acid components of LDL can become oxidized and contribute to atherogenicity. Polyunsaturated fats carried on LDL are more prone to oxidation than monounsaturated fats. Other lipoproteins, including VLDL and HDL, are also susceptible to oxidation (Parthasarathy 2010).

Oxidation, along with desialylation, is one of the ways LDL becomes atherogenic. Oxidized LDL accumulates in the blood vessel wall and sets off a series of reactions, including an immune response involving macrophages. These white blood cells then engulf the oxidized lipoprotein and become foam cells, an early sign of atherosclerosis (Poznyak 2020). Native non-oxidized LDL does not promote intracellular cholesterol and foam cell formation like oxLDL (Gao 2018).

Smaller, denser LDL particles (sdLDL) are more prone to oxidation, likely due to lower concentrations of antioxidants (Holvoet 2008), and are especially atherogenic (Ivanova 2017). Fortunately, simple dietary changes such as increased consumption of high-antioxidant plant-based foods (e.g., berries and nuts) and omega-3 fatty acids have been associated with reduced sdLDL and oxidized LDL (Talebi 2020). A small study also found that coffee consumption reduced the oxidation of LDL, possibly due to its phenolic content (Natella 2007).

The pro-inflammatory toxic nature of oxLDLs promotes atherosclerosis by exacerbating endothelial damage, accumulation of cholesterol, forming foam cells, and destabilizing atherosclerotic plaque. The byproducts of lipid peroxidation further contribute to a pathological cycle by increasing endothelial cell permeability and the influx and oxidation of LDL. OxLDLs may also trigger an autoimmune response that produces a variety of autoantibodies that can be detected in plaque. Exogenous antioxidants from food (vitamin C, vitamin E, carotenoids, lycopene, flavonoids, polyphenols, anthocyanins, carnosine, etc.) and endogenous antioxidants (coenzyme Q10, glutathione, lipoic acid, uric acid, bilirubin, melatonin, etc.) may help counter excess reactive oxygen species and oxidative stress (Salvayre 2016)

Oxidative stress must be considered when evaluating total cardiometabolic risk. Both the LDL carrier (Linton 2019) and LDL cholesterol can become oxidized due to excess oxidative stress or insufficient antioxidant activity. This results in an increased risk of atherosclerosis and cardiovascular disease (Weigel 2019).

Circulating oxLDL is considered a sensitive marker of coronary artery disease (CAD). One study of 304 subjects over age 45 revealed that oxidized LDL levels were significantly higher in those with CAD and that oxLDL can help identify early disease. Researchers note that total cholesterol, LDL cholesterol, and total to HDL cholesterol ratio didn’t identify CAD in this study. In those without clinical signs of CAD, elevated oxLDL correlated with established CVD risk factors, including hypercholesterolemia, BMI, dyslipidemia, type 2 diabetes, and age, suggesting identification of future risk (Holvoet 2001).                            

In a prospective general population-based cohort study, 804 subjects free of CVD at baseline were followed up over ten years to investigate the association between oxLDL and carotid artery atherosclerosis. Those in the highest tertile of oxLDL (58.4-74.9 U/L) had significantly greater atherosclerosis progression than those in the intermediate and lowest tertiles, 44.3-51.2 U/L and 25.6-37.4 U/L, respectively. Those with the highest oxLDL also had significantly higher fasting blood glucose, total cholesterol, LDL-C, non-LDL-C, triglycerides, lipoprotein(a), and hypertension. Those with the highest oxLDL also had significantly more small LDL particles and were likelier to be on statin drugs (Gao 2018).

Oxidized LDL is also associated with metabolic syndrome, a disorder characterized by obesity, insulin resistance, hyperglycemia, hypertension, inflammation, dyslipidemia, and oxidative stress. OxLDL is a marker of existing oxidative stress and drives oxidative stress by activating monocytes and enhancing their ability to infiltrate the blood vessels and promote atherosclerosis. Oxidative stress also damages cell membranes and impairs normal cell function, contributing to cardiometabolic pathology. A cross-sectional study of 124 individuals observed oxLDL levels of 108.36 ng/mL in healthy controls, 195.87 ng/mL in type 2 diabetics, 200.24 ng/mL in metabolic syndrome, and 213.36 in T2DM + hypertension. Researchers recommend a cut-off greater than 124.2 ng/mL for identifying metabolic syndrome (Ali 2017). [PLEASE NOTE: ng/ml is not the standard unit for OxLDL. Ng/ml is a unit used by LabCorp. LabCorp's range for OxLDL is 0 - 170 ng/ml]

Oxidized LDL levels also correlate with the individual components of metabolic syndrome, i.e., abdominal obesity, hypertriglyceridemia, and hyperglycemia, factors that did not correlate with LDL cholesterol levels in a study of 1,889 individuals. Higher oxLDL was also associated with elevated C-reactive protein and low adiponectin. The highest quintile for oxLDL was 97.4 U/L or above, while the lowest quintile assessed was below 55.4 U/L (Holvoet 2008).

Hypothyroidism is also associated with higher levels of oxidized LDL. In a study of 260 individuals, oxLDL was significantly higher at 48.12 U/L in those with hypothyroidism versus 17.22 U/L in controls. Those with hypothyroidism also had significantly higher total cholesterol, triglycerides, LDL-C, Lp(a), ApoB, and significantly smaller LDL particles (Bansal 2016).

One study of 188 subjects found that the highest levels of oxLDL (above 48 U/L) were associated with hypercholesterolemia, impaired fasting LDL-C, impaired fasting glucose, hypertriglyceridemia, and obesity. Elevated oxLDL was also associated with significant elevations in CD36, a marker seen with obesity, insulin resistance, T2DM, fatty liver, and atherosclerosis. Mean oxLDL was below 38 U/L in those who did not have hypercholesterolemia, impaired fasting LDL-C, impaired fasting glucose, hypertriglyceridemia, or hypertension (Ramos-Arellano 2014).

References

Ali, Wahid, et al. "Oxidized LDL as a biomarker in metabolic syndrome." J Diabetes Metab 8.764 (2017): 2.

Bansal, Sanjiv Kumar, and Rakhee Yadav. “A Study of the Extended Lipid Profile including Oxidized LDL, Small Dense LDL, Lipoprotein (a) and Apolipoproteins in the Assessment of Cardiovascular Risk in Hypothyroid Patients.” Journal of clinical and diagnostic research : JCDR vol. 10,6 (2016): BC04-8. doi:10.7860/JCDR/2016/19775.8067

Cicero, Arrigo F G et al. “Serum uric acid and markers of low-density lipoprotein oxidation in nonsmoking healthy subjects: data from the Brisighella Heart Study.” Polskie Archiwum Medycyny Wewnetrznej vol. 124,12 (2014): 661-8. doi:10.20452/pamw.2548

Gao, Shen et al. “Circulating Oxidized Low-Density Lipoprotein Levels Independently Predict 10-Year Progression of Subclinical Carotid Atherosclerosis: A Community-Based Cohort Study.” Journal of atherosclerosis and thrombosis vol. 25,10 (2018): 1032-1043. doi:10.5551/jat.43299  

Holvoet, P et al. “Circulating oxidized LDL is a useful marker for identifying patients with coronary artery disease.” Arteriosclerosis, thrombosis, and vascular biology vol. 21,5 (2001): 844-8. doi:10.1161/01.atv.21.5.844

Holvoet, Paul et al. “Association between circulating oxidized low-density lipoprotein and incidence of the metabolic syndrome.” JAMA vol. 299,19 (2008): 2287-93. doi:10.1001/jama.299.19.2287

Ivanova, Ekaterina A et al. “Small Dense Low-Density Lipoprotein as Biomarker for Atherosclerotic Diseases.” Oxidative medicine and cellular longevity vol. 2017 (2017): 1273042. doi:10.1155/2017/1273042

Linton, MacRae F, et al. “The Role of Lipids and Lipoproteins in Atherosclerosis.” Endotext, edited by Kenneth R Feingold et. al., MDText.com, Inc., 3 January 2019.

Meisinger, Christa et al. “Plasma oxidized low-density lipoprotein, a strong predictor for acute coronary heart disease events in apparently healthy, middle-aged men from the general population.” Circulation vol. 112,5 (2005): 651-7. doi:10.1161/CIRCULATIONAHA.104.529297

Natella, Fausta et al. “Coffee drinking induces incorporation of phenolic acids into LDL and increases the resistance of LDL to ex vivo oxidation in humans.” The American journal of clinical nutrition vol. 86,3 (2007): 604-9. doi:10.1093/ajcn/86.3.604

Nour Eldin, Essam Eldin Mohamed et al. “Oxidized low density lipoprotein and total antioxidant capacity in type-2 diabetic and impaired glucose tolerance Saudi men.” Diabetology & metabolic syndrome vol. 6,1 94. 30 Aug. 2014, doi:10.1186/1758-5996-6-94

Parthasarathy, Sampath et al. “Oxidized low-density lipoprotein.” Methods in molecular biology (Clifton, N.J.) vol. 610 (2010): 403-17. doi:10.1007/978-1-60327-029-8_24

Poznyak, Anastasia V et al. “Oxidative Stress and Antioxidants in Atherosclerosis Development and Treatment.” Biology vol. 9,3 60. 21 Mar. 2020, doi:10.3390/biology9030060

Raikou, Vaia et al. “Oxidized Low-Density Lipoprotein Serum Concentrations and Cardiovascular Morbidity in End Stage of Renal Disease.” Journal of cardiovascular development and disease vol. 5,3 35. 21 Jun. 2018, doi:10.3390/jcdd5030035

Ramos-Arellano, Luz E et al. “Circulating CD36 and oxLDL levels are associated with cardiovascular risk factors in young subjects.” BMC cardiovascular disorders vol. 14 54. 28 Apr. 2014, doi:10.1186/1471-2261-14-54

Salvayre, R et al. “Oxidative theory of atherosclerosis and antioxidants.” Biochimie vol. 125 (2016): 281-96. doi:10.1016/j.biochi.2015.12.014

Weigel, Thaddeus K et al. “Oxidized cholesterol species as signaling molecules in the brain: diabetes and Alzheimer's disease.” Neuronal signaling vol. 3,4 (2019): NS20190068. doi:10.1042/NS20190068