Every year, thousands of people experience a first heart attack despite being classified as “low risk” by traditional cardiovascular screening tools. This unexpected reality has given rise to what researchers increasingly describe as the myocardial infarction (MI) paradox.
For decades, preventive cardiology has followed a relatively simple framework: identify risk factors. Estimate cardiovascular risk. Treat high-risk individuals. Wait for symptoms to trigger further testing. This approach has undoubtedly saved millions of lives. Yet a growing body of evidence suggests it may be missing a substantial number of people who are already developing coronary artery disease.
The paradox is straightforward: although high-risk individuals have the greatest individual likelihood of suffering a myocardial infarction, many heart attacks occur in people who are considered low or intermediate risk and who have little or no warning symptoms.
In their 2025 study published in JACC: Advances, Mueller and colleagues found that nearly half of patients presenting with a first MI would not have qualified for preventive intervention using traditional atherosclerotic cardiovascular disease (ASCVD) risk assessment, while most reported no symptoms until shortly before the event.
The findings raise an uncomfortable question:
If current screening tools are designed to identify future heart attack patients, why are so many first heart attacks occurring outside the traditionally high-risk population?
Age, cholesterol levels, diabetes, blood pressure and smoking remain important predictors of cardiovascular risk. However, none of these factors is the disease itself.
The killer responsible for most heart attacks is coronary atherosclerosis. It is the accumulation of plaque within the coronary arteries that matters. A patient can have:
and still harbor significant coronary plaque. Coronary artery disease often develops silently over decades before a patient experiences chest pain or other signs of ischemia.
The myocardial infarction (MI) paradox challenges one of the most common assumptions in cardiovascular prevention: that heart attacks primarily occur in people who are already known to be at high risk. In reality, many first MIs strike individuals who have never been diagnosed with cardiovascular disease, have no prior warning symptoms, and may not even have recognized risk factors.
A large real-world analysis of more than 4.6 million patients with a first MI found that over half had no documented antecedent symptoms before their event, while nearly one in five had no previously identified standard modifiable cardiovascular risk factors [2]. The study also revealed that many patients were not receiving preventive therapy before their infarction, despite previous contact with healthcare providers.
Another study, published in The International Journal of Cardiovascular Imaging, offers an important clue. Researchers used AI-assisted quantitative coronary CT analysis (AI-QCT) to compare coronary calcium scores (CAC) with direct measures of plaque burden. They found substantial discordance between the two methods. Most notably, among patients with a CAC score of zero, 95% still had non-calcified plaque detectable by AI-based coronary CT analysis [1]. Only 4% of CAC=0 patients had neither calcium nor plaque detected.
This matters because coronary calcium scoring method, while extremely valuable, detects only calcified plaque. It does not directly identify non-calcified one, which is often more common in younger individuals and women. The findings suggest that relying on calcium scoring alone may underestimate total plaque burden in some patients.
Advances in coronary CT angiography (CCTA), AI-enabled plaque quantification, and CAD-RADS 2.0 are beginning to move cardiology toward direct assessment of plaque burden. The emerging model is:
This does not mean risk factors become irrelevant. Rather, risk factors may become one component of a broader strategy focused on identifying subclinical atherosclerosis before symptoms appear.
Today, preventive cardiology may be approaching pivotal transition. The question is no longer simply: “Who looks high-risk?” The more important question may be: “Who already has coronary plaque?”
The answer could reshape how we identify risk, allocate preventive therapy, and ultimately reduce the number of first heart attacks occurring in patients who never knew they had coronary artery disease.
REFERENCES:
[1] Khan, N.A., Wesbey III, G., Cobb, G. et al. Using AI-Quantitative CT to evaluate the relationship between coronary artery calcium and segment involvement scores in quantifying coronary plaque burden. Int J Cardiovasc Imaging 42, 49–59 (2026). https://doi.org/10.1007/s10554-025-03569-6
[2] Nick S Nurmohamed, Quyen Ngo-Metzger, Pam R Taub, Kausik K Ray, Gemma A Figtree, Marc P Bonaca, Judith A Hsia, Santosh Angadageri, James P Earls, Fatima Rodriguez, Alexander T Sandhu, James K Min, Udo Hoffmann, David J Maron, Deepak L Bhatt, First myocardial infarction: risk factors, symptoms, and medical therapy, European Heart Journal, Volume 46, Issue 38, 7 October 2025, Pages 3762–3772, https://doi.org/10.1093/eurheartj/ehaf390
