The levels of MDA-LDL in circulating immune complexes predict myocardial infarction in the VADT study

Abstract

Objective: Circulating immune complexes (IC) containing modified forms of LDL (mLDL) are strongly pro-inflammatory and strong predictors of cardiovascular disease (CVD) progression in type 1 diabetes. The present study was undertaken to determine whether the levels of oxidized LDL (oxLDL), malondialdehyde-LDL (MDA-LDL) and advanced glycation end products-LDL (AGE-LDL) in IC predict incident CVD events in type 2 diabetes (VADT cohort).

Methods and results: Levels of mLDL in IC were measured in 907 patients of the VADT cohort, a median of two years after entry into the study. Participants were followed for an average of 3.7 years for vascular outcomes. Hazard ratios (HRs) for CV endpoints in relation to mLDL-IC quartiles were calculated by Cox proportional hazard models. The primary composite CVD endpoint included documented myocardial infarction (MI); stroke; death from CVD; congestive heart failure; cardiac, cerebrovascular, or peripheral VD surgical intervention; inoperable CVD; and amputation for ischemic gangrene. During follow-up, 4.7% and 16.8% of participants had an MI or a composite endpoint, respectively. After adjustments by conventional risk factors, individuals in the highest quartile of MDA-LDL-IC were at higher risk of MI [HR = 2.44 (95% CI: 1.03, 5.77)] and composite endpoint [HR = 1.71 (95% CI: 1.04, 2.80)], relative to individuals in the lowest quartile. Similar comparisons for oxLDL and AGE-LDL levels yielded HR values of 1.08 and 1.31 for MI and 0.91 and 1.34 for composite endpoint.

Conclusions: Our study indicates that high levels of MDA-LDL in isolated IC predict future MI and acute CV events in patients with type 2 diabetes.

Figure 1

Adjusted* hazard ratios with 95% CI (calculated from Cox proportional hazard models) for given levels of MDA, oxLDL, and AGE-LDL in isolated IC, LDL cholesterol, systolic blood pressure (SBP) and HbA1c (levels in the 2^nd, 3^rd and 4^th quartiles relative to quartile 1) to predict MI. MDA-IC categories are 5–52, 52–83, 83–128 and 128–607 mg/L; oxLDL-IC categories are 13.5–172, 172–257, 258–389 and 389–1712 mg/L; AGE-LDL-IC categories are 0.6–6.2, 6.2–10.8, 10.8–19.8, 19.8–103 mg/L; LDL categories are 20–74, 75–92, 93–111 and 112–234 mg/dL; SBP categories are 82–117, 118–126, 127–135 and 136–198 mmHg; HbA1c categories are 5.2–6.8, 6.9–7.7, 7.8–8.8 and 8.9–15.0%. * Adjusted for age, ethnic minority, treatment arm and prior event with the exception of HbA1c which was not adjusted for treatment arm