Haptoglobin and IgA2 predict major cardiovascular adverse events and all-cause death independently of Framingham Risk Score in asymptomatic American adults, and their combined measurement may enhance cardiovascular risk stratification in primary prevention.
Key Findings
Results
Haptoglobin and IgA2 plasma levels significantly correlated with carotid plaque burden and coronary artery calcium, independent of Framingham Risk Score.
Study population consisted of 5328 asymptomatic US adults with mean age 69 years and 56.9% women from the BioImage study (NCT00738725)
Subclinical atherosclerosis was assessed by carotid plaque burden via ultrasound and coronary artery calcium via computed tomography
Haptoglobin and IgA2 were measured by immunoturbidimetry at baseline
Correlations with imaging markers were independent of traditional Framingham Risk Score
Results
Haptoglobin and IgA2 independently predicted the composite outcome of major cardiovascular adverse events and all-cause death over a median follow-up of 4.6 years.
466 participants (8.8%) experienced the composite outcome during follow-up
Median follow-up duration was 4.6 years
Associations remained significant after further adjustment for carotid plaque burden or coronary artery calcium
Predictive associations were independent of Framingham Risk Score
Results
High-sensitivity C-reactive protein showed similar results for predictive capacity as haptoglobin and IgA2.
High-sensitivity C-reactive protein was compared as a reference inflammatory biomarker
Similar predictive performance was observed for the composite outcome
This comparison was performed in the same BioImage study cohort of 5328 asymptomatic adults
Results
Individuals with high levels of all biomarkers (above the median for haptoglobin, IgA2, and high-sensitivity C-reactive protein) had a 2-fold higher event rate compared with those with low levels.
The threshold for 'high' was defined as above the median for each biomarker
A 2-fold higher composite event rate was observed in the high-biomarker group
The composite outcome included major cardiovascular adverse events and all-cause death
This finding highlights the additive prognostic value of combining multiple biomarkers
Results
Combined biomarker assessment modestly but significantly improved risk prediction beyond Framingham Risk Score and vascular imaging.
Improvement in risk prediction was statistically significant despite being described as modest
Enhancement was demonstrated beyond both traditional risk scoring (Framingham Risk Score) and imaging modalities (carotid plaque burden and coronary artery calcium)
The findings suggest combined measurement may enhance cardiovascular risk stratification in primary prevention
Results validate prior findings from European cohorts in an American population
Background
The study validated previously reported associations of haptoglobin and IgA2 with subclinical atherosclerosis, originally found in European cohorts, in a US population.
The BioImage study enrolled asymptomatic US adults, providing a North American validation cohort
Prior associations had been established in European cohorts
The study specifically sought to determine whether these biomarkers predict outcomes beyond traditional risk scales or vascular imaging
The population was at-risk, as described by the study subtitle: 'A Clinical Study of Burden of Atherosclerotic Disease in an At-Risk Population'
What This Means
This research examined whether two blood proteins — haptoglobin and immunoglobulin A2 (IgA2) — could help predict the risk of heart attacks, strokes, and death in people who appear healthy and have no known cardiovascular disease. The study analyzed over 5,300 American adults with an average age of 69, tracking them for nearly five years. It found that people with higher blood levels of these proteins were more likely to have early signs of artery disease (detected by ultrasound and CT scans) and were more likely to experience serious heart events or die during follow-up, even after accounting for standard risk factors like the Framingham Risk Score.
A key finding was that when haptoglobin, IgA2, and a standard inflammation marker (high-sensitivity C-reactive protein) were all elevated above the midpoint level, individuals had twice the rate of cardiovascular events compared to those with lower levels of all three markers. Adding these biomarkers to standard risk assessment tools and imaging tests modestly but meaningfully improved the ability to identify who was truly at higher risk.
This research suggests that measuring haptoglobin and IgA2 in the blood — alone or alongside imaging tests — could provide additional useful information for identifying people at higher cardiovascular risk before symptoms appear. This could be especially relevant for primary prevention, meaning catching risk early in people who feel well, potentially enabling earlier or more targeted intervention. These findings in a large US population also confirm earlier results from European studies, strengthening the case for further investigation of these biomarkers in clinical practice.
García-Álvarez A, Fuster V, Nuñez E, Owen R, Ortega-Villanueva L, Mass V, et al.. (2026). Haptoglobin and Immunoglobulin A2 Predict Cardiovascular Risk in Asymptomatic Subjects: The BioImage Study.. Journal of the American Heart Association. https://doi.org/10.1161/JAHA.125.048286