These exploratory findings highlight the feasibility of implementing genotype-first recruitment for prevention trials and reveal a large proportion of 'silent' high-genetic risk individuals with subclinical plaque for whom pharmacotherapy could be beneficial but who remain undetected by standard clinical assessments.
Key Findings
Results
Among 64,092 genotyped biobank participants, only 3.9% met eligibility criteria for high CAD polygenic risk score without cardiovascular disease or lipid-lowering therapy.
2,495 of 64,092 genotyped participants were eligible with high CAD PRS
Eligible individuals had low clinical risk despite high genetic risk, with a median 10-year pooled cohort equations risk for atherosclerotic cardiovascular disease of 3% (Q1-Q3: 1%-8%)
Eligibility criteria included adults aged 40 to 75 years, no prior cardiovascular disease, and not on lipid-lowering therapy
This represents individuals 'flying under the radar' in contemporary clinical practice
Results
The genotype-first callback strategy demonstrated moderate recruitment engagement, with 21.5% of invited individuals opting in and 15.5% completing baseline imaging.
Among 1,314 invited individuals, 283 (21.5%) opted in to the study
Participants who opted in had higher specialty care engagement compared with those who did not opt in
Participants who opted in lived closer to the study site compared with those who did not opt in
Results
One-half of enrolled participants with high CAD polygenic risk score had subclinical coronary plaque detected on coronary computed tomographic angiography despite low clinical risk.
102 of 204 participants (50%) had subclinical plaque on coronary CTA
The first 204 participants had a mean age of 56.3 ± 8.5 years and 69% were women
Participants had favorable cardiovascular health with a mean Life's Essential 8 score of 73.3 ± 11.5, compared to the U.S. average of approximately 65
Enrollment was completed among participants enrolled by January 31, 2025
Results
Subclinical coronary plaque prevalence showed a marked sex difference, occurring in 76.2% of men and 38.3% of women among high CAD PRS participants.
Subclinical plaque prevalence was 76.2% in men
Subclinical plaque prevalence was 38.3% in women
Plaque prevalence was high across age groups in both sexes
The overall cohort was 69% women, meaning the high plaque prevalence in men was observed in a relatively smaller male subgroup
Background
The PROACT trials use a genotype-first, biobank-enabled design to prospectively identify high genetic risk individuals, quantify subclinical coronary plaque, and test pharmacologic interventions to slow plaque progression.
PROACT 1 (NCT05819814) focuses on detection of subclinical coronary atherosclerosis and change in cardiovascular health
PROACT 2 (NCT05850091) tests intervention with statin and colchicine
The trial invites individuals identified through a hospital-based biobank based on CAD PRS results
Coronary computed tomographic angiography is used as the primary imaging modality to quantify subclinical plaque
Conclusions
High CAD polygenic risk score identified individuals with subclinical atherosclerosis who would not be flagged for preventive treatment by standard clinical risk assessment tools.
Median 10-year ASCVD risk was only 3% among eligible high PRS participants, well below typical treatment thresholds
Participants had favorable cardiovascular health metrics (mean Life's Essential 8 score 73.3 ± 11.5)
Despite favorable clinical profiles, 50% of participants had subclinical plaque detectable by coronary CTA
These individuals 'remain undetected by standard clinical assessments' according to the authors
What This Means
This research suggests that using genetic information — specifically a 'polygenic risk score' that estimates a person's inherited risk for coronary artery disease based on many genetic variants — can identify people who have dangerous silent plaque buildup in their heart arteries even though standard medical checks show them as low-risk. The PROACT trials recruited participants from a hospital genetic database, inviting those with high genetic risk for heart disease who were not already on cholesterol-lowering medications. Among the first 204 people who joined, half were found to have coronary plaque they did not know about, despite having seemingly good cardiovascular health scores and a very low estimated 10-year risk of heart attack by conventional calculators. Men were particularly affected, with more than three-quarters showing plaque compared to about 38% of women.
The study also examined whether this type of 'genetics-first' recruitment approach was practical. Of roughly 64,000 people in the biobank, only about 4% met the eligibility criteria. When those people were invited to participate, about 1 in 5 agreed to join, and about 1 in 6 completed the heart imaging scan. People who lived closer to the study site and had more prior engagement with specialty medical care were more likely to participate, suggesting there may be access and awareness barriers that could affect who benefits from this kind of genetic screening.
This research matters because it suggests that relying solely on traditional risk factors like cholesterol levels, blood pressure, and age may miss a meaningful group of people who are silently developing coronary artery disease due to their genetics. These individuals might benefit from preventive medications like statins or anti-inflammatory drugs — which PROACT 2 is now testing — but would never be identified or treated under current standard-of-care guidelines. The findings open a potential new pathway for earlier, genetically-informed heart disease prevention.
R. Abou-Karam, Min Seo Kim, So Mi Jemma Cho, F. Bitar, Shoshana Gady, Fangzhou Cheng, et al.. (2026). Polygenic Risk Based Detection and Treatment of Subclinical Coronary Atherosclerosis in the PROACT Clinical Trials.. Journal of the American College of Cardiology. https://doi.org/10.1016/j.jacc.2025.12.032