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

α₂-macroglobulin (α₂M) is a versatile endopeptidase inhibitor that plays a role in cell growth, inflammation and coagulation. α₂M 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 α₂M levels and cardiovascular events in a subset of the general Italian population.

We determined α₂M 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.

α₂M 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 α₂M 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 α₂M 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).

We show in a prospective cohort that high levels of α₂M could be a risk factor for cardiovascular events, especially coronary heart disease events.