High alpha-2-macroglobulin levels are a risk factor for cardiovascular disease events: A Moli-sani cohort study

Background: alpha 2-macroglobulin (alpha 2M) is a versatile endopeptidase inhibitor that plays a role in cell growth, inflammation and coagulation. alpha 2M is an inhibitor of key coagulation enzyme thrombin. Hypercoagulability due to an excess of thrombin production can cause thrombotic events. Therefore, we investigated the association of alpha 2M levels and cardiovascular events in a subset of the general Italian population. Methods: We determined alpha 2M levels in the baseline samples of a prospective cohort (n = 19,688; age: 55 +/- 12 years; 47.8 % men) of the Moli-sani study and investigated the association with the cardiovascular events (n = 432, 2.2 %) in the median follow-up period of 4.3 years. Hazard ratios (HR) with 95 % confidence intervals (CI) were calculated by multivariable Cox regression and adjusted for a large panel of confounding factors. Results: alpha 2M levels above the 90th percentile were significantly associated with cardiovascular disease (CVD) events after full adjustment for age, sex, current smoking, BMI, oral contraceptive use, cardiovascular diseases, hypertension, hypercholesterolemia, diabetes and history of cancer (HR: 1.36; CI: 1.06-1.74). Moreover, high alpha 2M was associated with coronary heart disease (CHD; HR: 1.47; CI: 1.12-1.91), but not stroke. Stratification for CVD at baseline showed that high alpha 2M levels are associated with CHD events in subjects without CVD at baseline (HR: 1.40; CI: 1.00-1.95) and subjects with CVD at baseline (HR: 1.58; CI: 1.02-2.44). Conclusion: We show in a prospective cohort that high levels of alpha 2M could be a risk factor for cardiovascular events, especially coronary heart disease events.