Blood Protein Scores Predict Heart Attack and Stroke Risk Differently in Men and Women With Hypertension

Millions of people live with high blood pressure, take their medications, and assume their hearts are protected. Yet a substantial number of them still go on to suffer heart attacks and strokes, a phenomenon clinicians call residual cardiovascular risk. A new study suggests that the missing warning signs may be circulating in the blood itself, and that men and women carry strikingly different molecular signatures of that hidden danger.

Researchers analyzing data from 27,510 hypertensive participants in the UK Biobank Pharma Proteomics Project have developed separate protein-based risk scores for men and women that substantially improve the prediction of major adverse cardiovascular events, or MACE, over a ten-year horizon. The work, published in Biology of Sex Differences, harnessed large-scale plasma proteomic profiling to capture biological information that conventional clinical risk models simply do not see.

The team, led by researchers at Jilin University in China, applied a sex-stratified machine learning strategy known as Least Absolute Shrinkage and Selection Operator, or LASSO, regression to sift through thousands of circulating proteins. This technique penalizes complexity and selects only the most informative features, producing lean statistical models built from the proteins most strongly associated with future cardiovascular events. The result was a panel of 28 priority proteins for men and 23 for women, with only five proteins shared between the sexes: MMP12, NT-proBNP, NEFL, BCAN, and ADAMTS13.

That limited overlap is one of the most intriguing findings of the study. MMP12 is a matrix metalloproteinase involved in tissue remodeling and inflammation, while NT-proBNP is a well-established marker of cardiac strain. NEFL, a neurofilament light chain protein, signals neuronal injury, and ADAMTS13 is an enzyme that regulates blood clotting by cleaving von Willebrand factor. BCAN, brevican, is less familiar in cardiovascular circles, being primarily associated with the extracellular matrix of the brain. The fact that these five proteins anchor both models while the remaining two dozen or so differ suggests that the molecular pathways driving cardiovascular risk in hypertensive men and women are only partially shared.

The predictive power of the scores was considerable. In the validation set, participants in the highest protein risk group faced dramatically elevated odds of a major cardiovascular event compared with those in the lowest group. For men, the adjusted hazard ratio was 2.68, with a 95 percent confidence interval of 1.97 to 3.64. For women, it was even higher at 3.12, with a confidence interval of 2.20 to 4.43. In practical terms, a hypertensive person whose blood protein profile placed them in the top risk tier was roughly three times as likely to suffer a heart attack, stroke, or cardiovascular death within a decade as someone in the bottom tier.

Crucially, the protein scores added value on top of SCORE2, the standard European clinical tool for estimating ten-year cardiovascular risk. When the protein scores were integrated into the SCORE2 framework, the C-statistic, a measure of how well a model discriminates between people who do and do not experience events, rose from 0.627 to 0.667 for men and from 0.657 to 0.695 for women. Category-based net reclassification improvement, which quantifies how many people are correctly shifted into more accurate risk categories, reached 22.4 percent for men and 14.0 percent for women. These are meaningful gains in a field where incremental improvements in prediction can translate into lives saved through earlier intervention.

Recognizing that a 28-protein panel may be impractical for routine clinical testing, the researchers also constructed simplified scores using only the ten most heavily weighted proteins for each sex. In the simplified models, just two proteins overlapped between men and women, underscoring how divergent the sex-specific signatures are. Remarkably, these pared-down scores maintained predictive performance comparable to the full models, suggesting that a compact blood test measuring a handful of proteins could one day flag high-risk hypertensive patients who appear deceptively healthy by conventional measures.

Pathway enrichment analyses of the male and female protein panels revealed that the biological processes represented in the two models partially overlap, while others receive different relative emphasis. The authors are careful to note that these findings support sex-stratified prediction strategies rather than proving fundamentally distinct disease mechanisms between the sexes. The differences in protein selection may reflect genuine biological divergence, but they may also stem from differences in how proteins correlate with risk in each population. Either way, the study adds to mounting evidence that cardiovascular medicine, which has historically been built on data from men, should routinely stratify its models by sex.

The clinical implications are tantalizing. Hypertension is among the most prevalent and serious cardiovascular risk factors worldwide, and current risk prediction tools rely almost exclusively on conventional clinical variables such as age, cholesterol, smoking status, and systolic blood pressure. These tools cannot see the inflammatory, thrombotic, and cardiac stress processes that proteins like MMP12, ADAMTS13, and NT-proBNP reveal. A proteomic layer of risk assessment could identify which hypertensive patients need more aggressive therapy, closer monitoring, or novel interventions long before symptoms appear.

Important caveats remain. The scores were developed and validated within the UK Biobank, a cohort that is not fully representative of global populations, and the researchers emphasize that external validation in independent and more diverse cohorts is required before the scores can be considered clinically transportable. The study also relied on internal validation, and the modest though significant gains in discrimination must be weighed against the cost and complexity of proteomic testing. Still, as large-scale protein measurement becomes faster and cheaper, the prospect of a routine blood panel that reads the molecular weather forecast for the cardiovascular system is moving closer to reality. For the millions of people with hypertension whose risk is invisible to today’s models, that forecast could not come soon enough.

Subject of Research: Sex-stratified proteomic risk scores for predicting major adverse cardiovascular events in hypertensive patients

Article Title: Sex-specific proteomic risk scores reveal distinct cardiovascular risk profiles and improve prediction of major adverse cardiovascular events in hypertension

Article References: Ding, J., Li, J., Xu, W., Zhang, W., Gao, Y., & Cheng, L. (2026). Sex-specific proteomic risk scores reveal distinct cardiovascular risk profiles and improve prediction of major adverse cardiovascular events in hypertension. Biology of Sex Differences. https://doi.org/10.1186/s13293-026-00984-9

Image Credits: AI Generated

DOI: 10.1186/s13293-026-00984-9

Keywords: hypertension, proteomics, cardiovascular risk, UK Biobank, SCORE2, biomarkers, sex differences, LASSO regression, MACE, risk prediction, NT-proBNP, precision medicine