Silent ischaemia – why are we still missing them?

19th September 2026, A/Prof Chee L Khoo

First event

We know that atherosclerosis is likely to be present for years or decades before clinical disease becomes manifest. Current primary prevention of cardiovascular events is guided largely by calculated risk-factor scores or symptoms of ischaemia. However, these scores are strongly influenced by age and tend to assign low risk to young adults, even in the presence of relevant risk-factor exposure. In practice, we are still missing many CV events because at least 50% had no documented prior cardiac symptoms before their first MI (1). These are the so-called silent ischaemia. Can we find them prior to their first event?

This change in coronary artery disease treatment paradigm is relatively new. Lancet Commission on coronary artery disease (CAD) suggests that we should not be focussing on ischaemia but rather treating the disease, atherosclerotic cardiovascular disease (ASCVD) (2).

Most large imaging cohorts have enrolled participants who were middle aged and older, whereas studies involving adults younger than 40 years of age have often been small, limited to selected populations. We need more information on the prevalence of ASCVD in the younger population and perhaps, theorised as to their trajectory over a life span. We should also utilise all the imaging and biomarkers we have at our disposal to categorise these silent ischaemia better. We need to know who are likely to have early ASCVD and whom amongst these are more likely to progress and develop acute events in the near future. This is true primary prevention.

In BioImage (A Clinical Study of Burden of Atherosclerotic Disease in an At-Risk Population), which enrolled asymptomatic participants 55 to 80 years of age, atherosclerosis was present in 58% of participants, and greater carotid artery plaque and coronary-artery calcium levels independently predicted cardiovascular events and death (3,4). In MESA (Multi-Ethnic Study of Atherosclerosis), which enrolled participants 45 to 84 years of age, about half the participants had detectable levels of coronary calcium, which predicted coronary events independent of traditional risk factors (5).

In the PESA (Progression of Early Subclinical Atherosclerosis) study, which included participants 40 to 54 years of age, silent atherosclerosis in any of the following territories was present in 63% of participants: the carotid, iliac, and femoral arteries; the aorta; and the coronary arteries (6).

REACT is a multicentre Danish and Spanish prospective cohort study designed to answer many of the questions (7). 16,808 adults aged between 18-70 years old were enrolled for the study. These individuals were without known clinical atherosclerotic cardiovascular disease, using standardized multimodal imaging of the carotid, femoral, and coronary arteries together with comprehensive clinical and biologic phenotyping. Importantly, to gauge a snapshot of the prevalence of CAD across the lifespan, they recruited ~2000 participants each in the 18-to-29–years and 60-to-70–years age strata and approximately 4000 participants each in the 30-to-39–years, 40-to-49–years, and 50-to 59–years age strata, with balance according to country and sex within each stratum.

Carotid and femoral atherosclerosis was assessed with three-dimensional vascular ultrasound. Coronary atherosclerosis was assessed with coronary CT angiography, and coronary calcification with non-contrast CT. Cardiovascular risk was estimated with the use of the Systematic Coronary Risk Evaluation 2 (SCORE2) framework, which predicts the 10-year risk of fatal and non-fatal cardiovascular disease in European persons 40 to 69 years of age, with higher scores indicating higher risk.

The primary outcome was the presence of silent atherosclerosis, defined as plaque in at least one examined vascular territory. Key secondary outcomes were the presence of plaque in each vascular territory, plaque volume in each territory, global peripheral plaque volume, coronary plaque volume and coronary-artery–calcium score.

What did they find?

The mean age of the participants was 45±12 years, and 51.4% were women. Imaging for analysis was available for the carotid arteries in 16,317 participants, the femoral arteries in 15,844, and the coronary arteries in 14,140. Complete three-territory imaging was available for 13,186 participants, who constituted the primary analysis population for prevalence.

Age groups

  • Overall, silent atherosclerosis in at least one vascular territory was present in 57.1% of participants with complete imaging – 63.4% of men and 50.9% of women
  • In the 18 to 29 years of age, silent atherosclerosis was detectable in 8.7% of men and 6.7% of women
  • In the 30 to 39 years of age, silent atherosclerosis was present in 34.6% of men and 21.3% of women.
  • The prevalence of silent atherosclerosis increased with the age strata in both sexes (adjusted odds ratio per 10-year increase, 4.52 for men, 3.85 for women.
  • In men, the prevalence of silent atherosclerosis increased starting with the stratum of 30 to 39 years, and began to plateau by midlife; in women, the steepest increase oc curred in the age strata after 40 years of age, narrowing the sex difference with increasing age
  • By the time you get to 60 to 70 years of age, only 1.9% of men and 8.1%  of women had no plaque detected in any examined territory

The vascular beds involved

  • The prevalence of carotid, femoral, and coronary atherosclerosis increased broadly in parallel in men. in women, carotid atherosclerosis predominated and femoral and coronary involvement were less frequent until later age
  • Among younger participants, silent atherosclerosis was usually identified in the peripheral arteries, confined to a single vascular territory, and most often detected in the carotid arteries.
  • Coronary plaque was frequently present without the presence of detectable calcium, particularly in participants at younger ages.
  • Among participants 30 to 39 years of age with coronary plaque, 41.8% of men and 48.4% of women had a coronary-artery calcium score of 0. That’s almost one in two people with zero calcium score have coronary plaque/s
  • Among participants with coronary-artery plaque, 82.0% also had peripheral artery plaque, as compared with 41.5% among those who did not have coronary-artery plaque
  • The probability of coronary-artery atherosclerosis increased with greater peripheral plaque volume, with odds ratios of 1.32, 1.85, and 3.70 across increasing plaque-volume quartiles, respectively, as compared with no peripheral plaque
  • Among participants 30 to 39 years of age, two or three territories were involved in 6.0% of men and 2.6% of women
  • Amongst those 60 to 70 years of age, all three territories (coronary, femoral, and carotid) were involved in 56.3% of men and 30.7% of women

How useful are CV risk calculators?

  • Participants with silent atherosclerosis were of older age and had more cardiovascular risk factors and higher SCORE2 risk than those without plaque
  • SCORE2 classification identified only 17 participants (0.5%) with single-territory silent atherosclerosis and 97 participants (3.8%) with combined peripheral and coronary-artery silent atherosclerosis as being in the high 10-year risk category.
  • A high SCORE2 risk was highly specific (99.8%) but had low sensitivity (1.9%) for silent atherosclerosis, whereas a moderate-to-high SCORE2 risk had a specificity of 87.9% and a sensitivity of 34.1%. The discordance was most pronounced in younger participants and varied according to individual risk factors. In other words, a high score from a CV risk calculator is very useful but a low score in patients known to be high risk, should not be reassuring

Silent atherosclerosis was already detectable in approximately 1 in 13 participants who were 18 to 29 years of age, and the prevalence increased to 9 in 10 participants by 60 to 70 years of age. The process of ASCVD starts young in many of our patients and represents a terrific opportunity in primary care to intervene early. The trick is who to suspect may have silent ischaemia so that we may begin pharmacotherapy as well as lifestyle measures early.

A subset of high-risk asymptomatic individuals will remain off the radar because they are asymptomatic and, in some cases, do not have traditional risk factors present (8). Identification of these individuals would require screening strategies at the high-risk population level. Sadly, a substantial proportion of these individuals see us and their ASCVD risk factors may be documented yet remained untreated at the time of their first myocardial infarction. This potentially reflect the low perceived risk, therapeutic inertia and patient-related barriers.

References

  1. Nick S Nurmohamed, Quyen Ngo-Metzger, Pam R Taub, Kausik K Ray, Gemma A Figtree, et al. First myocardial infarction: risk factors, symptoms, and medical therapy, European Heart Journal, Volume 46, Issue 38, 7 October 2025, Pages 3762–3772
  2. Zaman S et al. The Lancet Commission on Rethinking Coronary Artery Disease: Moving From Ischaemia to Atheroma. The Lancet 2025; 405(10486): 1264-1312. 
  3. Baber U, Mehran R, Sartori S, et al. Prevalence, impact, and predictive value of detecting subclinical coronary and carotid atherosclerosis in asymptomatic adults: the BioImage study. J Am Coll Car diol 2015; 65: 1065-74.
  4. Fuster V, García-Álvarez A, Devesa A, et al. Influence of subclinical atheroscle rosis burden and progression on mortal ity. J Am Coll Cardiol 2024; 84: 1391-403. 7.
  5. Detrano R, Guerci AD, Carr JJ, et al. Coronary calcium as a predictor of coro nary events in four racial or ethnic groups. N Engl J Med 2008; 358: 1336-45.
  6. Fernández-Friera L, Peñalvo JL, Fernández-Ortiz A, et al. Prevalence, vas cular distribution, and multiterritorial extent of subclinical atherosclerosis in a middle-aged cohort: the PESA (Progres sion of Early Subclinical Atherosclerosis) study. Circulation 2015; 131: 2104-13.
  7. Bundgaard H, García-Lunar I, Kofoed KF, et al. REACT Investigators. Prevalence of Silent Atherosclerosis across Adult Life. N Engl J Med. 2026 Aug 29.
  8. Chunawala ZS, Caughey MC, Bhatt DL, Hendrickson M, Arora S, Bangalore S, et al. Mortality in patients hospitalized with acute myocardial infarction without standard modifiable risk factors: the ARIC study community surveillance. J Am Heart Assoc 2023 Jul 4;12:e027851