Haptoglobin and Immunoglobulin A2 Predict Cardiovascular Risk in Asymptomatic Subjects: The BioImage Study

Background Plasma levels of haptoglobin and IgA2 (immunoglobulin A2) have recently been associated with subclinical atherosclerosis in European cohorts. We sought to validate these findings in an American population and to determine whether these biomarkers predict all‐cause mortality or major cardiovascular adverse events beyond traditional risk scales (Framingham Risk Score) or vascular imaging. Methods We analyzed 5328 asymptomatic US adults (mean age 69 years, 56.9% women) from the BioImage study (A Clinical Study of Burden of Atherosclerotic Disease in an At‐Risk Population; NCT00738725). Subjects underwent carotid plaque burden assessment by ultrasound, coronary artery calcium by computed tomography, and baseline plasma haptoglobin and IgA2 levels measurement by immunoturbidimetry. The end point was a composite of major cardiovascular adverse events and all‐cause death during follow‐up. Results Haptoglobin and IgA2 correlated significantly with carotid plaque burden and coronary artery calcium, independent of Framingham Risk Score. After a median follow‐up of 4.6 years, 466 participants (8.8%) experienced the composite outcome. Haptoglobin and IgA2 independently predicted the outcome, and associations remained significant after further adjustment for carotid plaque burden or coronary artery calcium. Similar results were observed for predictive capacity of high‐sensitivity C‐reactive protein. Individuals with high levels of all biomarkers (above the median) had a 2‐fold higher event rate compared with those with low levels. Combined biomarker assessment, albeit modestly, significantly improved risk prediction beyond Framingham Risk Score and imaging. Conclusions Haptoglobin and IgA2 predict the composite outcome of major cardiovascular adverse events and all‐cause death, independently to Framingham Risk Score, in asymptomatic American adults. Their measurement, alone or in combination with imaging, may enhance cardiovascular risk stratification in primary prevention.