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Oxidized LDL in risk prediction

Is oxLDL, as measured with the Mercodia Oxidized LDL ELISA, just another assay for LDL-cholesterol or does oxLDL provide any additional information? The overall correlation of oxLDL to LDL-cholesterol is about 0.70 (R2=0.4886) (Figure). However, if the LDL-cholesterol levels are divided into quartiles, the correlation of oxLDL to LDL-cholesterol decreases with increasing blood levels of LDL-cholesterol with a slight increase in correlation in the highest quartile. In a study of 148 subjects blood levels of oxLDL and LDL-cholesterol were measured. LDL- cholesterol levels were divided into quartile I (0.8-2.6 mM), II (2.6-3.2 mM), III (3.3-3.8 mM) and IV (3.8-5.8 mM). The correlation of oxLDL to LDL- cholesterol was 0.65 (R2=0.42) in quartile I, 0.17 (R2=0.0285) in quartile II, 0.13 (R2=0.0168) in quartile III and 0.29 (R2=0.0814) in quartile IV (Table). Thus, the correlation of oxLDL to LDL-cholesterol is lost at elevated LDL-cholesterol levels.

Subclinical atherosclerosis: oxidized LDL as a marker of asymptomatic cardiovascular disease

In 1998, Holvoet at the Katholieke Universiteit Leuven, Belgium demonstrated for the first time that elevated circulating levels of oxLDL were found in most untreated patients with both stable CAD and acute coronary syndromes (unstable angina and acute MI). In this study, oxLDL levels were measured in plasma with an ELISA procedure using the monoclonal antibody 4E6, originally developed by professor Holvoet and colleagues. Since Holvoet’s landmark discovery and the commercial introduction of the Mercodia oxLDL ELISAs, based on the same antibody, the literature has been extensive in providing further support for Holvoet’s 1998 findings and expanding the importance of oxLDL as a marker of cardiovascular disease.

Figure. Compared to controls, oxidized LDL levels ar elevated in patients with stable angina, unstable angina and acute myocardial infarction (AMI). Published data by Holvoet et al. (1998).

 

In 2002, Hulthe and Fagerberg at the Sahlgrenska University Hospital, Gothenburg, Sweden tested 391 clinically healthy 58-year old Swedish men from the AIR study and found that oxidized LDL was associated with subclinical atherosclerosis (clinically silent atherosclerotic changes in the carotid and femoral arteries assessed by ultrasound). Otherwise healthy patients with at least one plaque in the carotid or femoral arteries were shown to have higher oxidized LDL levels compared to patients with no plaques. The results support the concept that oxidatively modified LDL may play a major role in the development of atherosclerosis.

Furthermore, baseline oxidized LDL levels have also been found to predict the progression of subclinical atherosclerosis. In a study by Wallenfeldt and colleagues at the Sahlgrenska University Hospital, Gothenburg, Sweden in 2004, the oxLDL levels at entry of the study correlated significantly with the number and size of plaques at 3-year follow-up, demonstrating that oxLDL in plasma is a prognostic biomarker of the subclinical atherosclerosis development. Oxidized LDL at entry, but not LDL cholesterol, was associated with the number and size of plaques present, and proved to be a strong predictor of the progression of atherosclerosis in the carotid arteries.

Liu and colleagues at the Helsinki University Central Hospital, Finland analyzed the potential determinants of circulating oxLDL in familial combined hyperlipidemia (FCHL) family members without clinical CAD. FCHL is associated with early atherosclerosis and is responsible for more than 10% of premature CAD and is characterized by enhanced generation of free radicals. OxLDL was found to be independently associated with carotid intima media thickness in asymptomatic FCHL family members as well as being a potential marker for early atherosclerosis in FCHL.

Oxidized LDL improved identification of coronary artery disease patients

In 2006, Johnston and coworkers at the University Hospital, Uppsala, Sweden demonstrated that the oxLDL-to-HDL ratio was the best method to discriminate between apparently healthy men and women without clinical evidence of coronary artery disease and coronary artery disease patients, who participated in the Second Fragmin and Fast Revascularization During Instability in Coronary Artery Disease (FRISC-II) trial. This study showed that the oxLDL-to-HDL ratio could identify more patients with coronary artery disease than any other currently available blood lipid biomarker test, including, total cholesterol, triglycerides, LDL-cholesterol, HDL-cholesterol, total cholesterol/ HDL-cholesterol ratio test, and Lp-PLA2.

Oxidized LDL predicts future cardiovascular events

In 2005, Meisinger and colleagues at the Institute of Epidemiology, Neuherberg, Germany studied apparently healthy men from the MONICA/KORA study. Compared to controls, baseline mean plasma levels of oxLDL were significantly higher in subjects who subsequently experienced a CHD event. Elevated plasma levels of oxLDL were the strongest predictor of future CHD events, and this association was independent of the conventional lipoprotein profile and other traditional risk factors for CHD such as CRP. Thus the additional measurement of oxLDL may improve prediction of atherosclerotic CHD complications.

In 2006, Johnston and coworkers examined the relationship between levels of circulating oxLDL and outcomes in patients with unstable CAD at long term follow-up, and compared the prognostic value of oxLDL at 2 year follow-up with that of other well established cardiovascular risk markers in patients with unstable CAD included in the FRISC-II trial. Oxidized LDL proved to be an independent predictor of MI, but not mortality and their findings suggest that oxLDL might identify unstable CAD patients at risk for future MI, particularly in the absence of myocardial necrosis.

The diabetes connection

The association between diabetes and cardiovascular disease has emerged. The prevalence of, incidence of, and mortality from all forms of cardiovascular disease are two- to eight-fold higher in persons with diabetes than in those without diabetes. The pathogenesis of atherosclerosis in diabetes is complex and multifactorial, but one thing is very clear, there is an increase in lipid and lipoprotein peroxidation within the arterial wall of diabetic patients, which could result in the enhanced biosynthesis of oxLDL within the atherosclerotic lesion. Kopprasch and investigators at the Technischen Universität Dresden, Germany used the oral glucose tolerance test to distinguish between normal glucose tolerance and impaired glucose tolerance in middle-aged subjects from the RIAD cohort. They found that the metabolic situation of impaired glucose tolerance and newly diagnosed diabetes is associated with diabetic dyslipidemia that particularly affects the level of circulating oxLDL.

The presence of an atherogenic lipid profile is common in diabetic patients. Scheffer and colleagues at the VU University Medical Centre, Amsterdam, the Netherlands found that patients with higher HbA1C and higher fasting glucose levels also had higher levels of small, dense LDL. The researchers also found that the prevalence of small, dense LDL particles correlated with high circulating levels of oxLDL in Type 2 diabetic patients. Together, these data suggest that measuring oxLDL may be useful in identifying type 2 diabetic patients with accelerated atherosclerosis.

The Metabolic Syndrome

The metabolic syndrome is associated with high risk for CHD, and persons with the metabolic syndrome are at increased risk for developing CHD as well as increased mortality from CHD. Holvoet and colleagues examined the relationship between the metabolic syndrome components and circulating oxLDL in the Health ABC cohort. They showed for the first time that in a population cohort the metabolic syndrome is associated with higher levels of circulating oxLDL and that this association was consistent across gender and race. As in previous studies the metabolic syndrome showed predictive value for CHD and increased the risk for incident MI. However, a new and important finding was that oxLDL increased the risk of incident of MI, suggesting an effect of oxidized LDL on myocardial infarction independent of the metabolic syndrome, adding prognostic information concerning future risk for MI.

Sigurdardottir and colleagues at the Sahlgrenska University Hospital, Gothenburg, Sweden studied the link between the presence of oxLDL in these healthy patients and factors related to the metabolic syndrome in subjects from the AIR study. They found that baseline levels of oxLDL add clinically important prognostic information to the metabolic syndrome. The metabolic syndrome was found to be associated with high levels of circulating oxLDL with the underlying mechanism seeming to be linked to the occurrence of small, dense LDL particles. The proposed pro-atherogenic properties of small LDL particles relate to their ability to penetrate the arterial wall, to bind more easily to arterial proteoglycans, and thus be more susceptible to oxidation.