Silent Heart Disease Risk: How Age and Sex Affect Early Plaque Buildup in Healthy Asian Adults

Table of Contents

• Key Points
• Background: The Silent Early Stages of Heart Disease
• Study Methods: How the Research Was Conducted
• Key Findings: What the Researchers Discovered
• Age and Sex Differences in Disease Burden
• Which Risk Factors Matter Most?
• The Impact on Risk Scoring and Prevention
• How These Results Compare With Other Studies
• Study Limitations: What This Research Couldn't Prove
• Recommendations: What This Means for Patients
• Frequently Asked Questions
• Source Information

Key Points

• In 663 healthy Asian adults without heart disease or diabetes, 29.3% had silent coronary artery calcium.
• Men had over twice the prevalence of plaque as women: 43.1% versus 18.0%.
• Prevalence rose steeply with age, from 1.9% at ages 30-39 to 66.3% at ages 60 and older.
• Independent risk factors for any plaque were age, male sex, systolic blood pressure, glucose, and LDL cholesterol.
• LDL cholesterol was significantly more associated with plaque in women than in men; CAC score reclassified 5.56% to elevated risk.

Background: The Silent Early Stages of Heart Disease

Atherosclerosis—the progressive buildup of fat, inflammation, scar tissue, and calcium inside artery walls—is a long and complex process that often begins early in life. For many people, this process goes completely unnoticed for decades because it produces no symptoms until it has advanced significantly. By the time someone experiences chest pain, a heart attack, or a stroke, the disease has typically been developing silently for years.

This has led to a major shift in cardiovascular medicine toward what doctors call "primordial prevention"—identifying and addressing risk factors before the disease even takes hold. The logic is simple: if we can detect atherosclerosis in its earliest, preclinical (pre-symptomatic) stage, we may be able to intervene and stop it from ever progressing to a clinical event.

The influence of age and sex on full-blown coronary artery disease (CAD) is well established in medical literature. Epidemiological, clinical, and experimental studies have consistently shown sex-specific differences in how heart disease develops, how it presents, and how it progresses. Women, for example, tend to develop clinical CAD about 10 years later than men on average. Prevention and treatment outcomes also differ significantly across age groups and between sexes.

What has been less clear, however, is whether these age and sex differences extend to the very earliest, preclinical stage of the disease—before any symptoms appear. This question carries important implications for screening programs and early prevention strategies designed for asymptomatic individuals.

To study this, researchers turned to a well-established tool: the coronary artery calcium (CAC) score. This is a highly specific and validated marker of subclinical (pre-symptomatic) coronary atherosclerosis, with consistent evidence linking CAC levels to major cardiovascular outcomes. In this study, the researchers used CAC scoring to measure the extent of early plaque in a healthy Asian population, examining how age and sex influence the burden of this silent disease.

Study Methods: How the Research Was Conducted

This research was part of the SingHEART study, a prospective, population-based study of healthy Asian adults living in Singapore. The study was designed to evaluate how cardiovascular disease develops among asymptomatic healthy individuals, with participants recruited from the general population between October 2015 and July 2020.

To be included in the study, participants had to meet specific criteria:

• No known history of any prior cardiovascular disease, including ischemic heart disease, stroke, or peripheral vascular disease
• No known history of cancer, autoimmune or genetic diseases, endocrine diseases, diabetes mellitus, psychiatric illness, asthma, chronic lung disease, or chronic infectious diseases
• No family medical history of cardiomyopathies

Participants completed standardized questionnaires covering demographics, lifestyle factors, and medical history. Clinical measurements were taken for height, weight, and blood pressure, and fasting blood samples were collected to measure lipid (fat) levels and glucose (sugar). Written informed consent was obtained from all volunteers, and the study received approval from the institutional ethics review board (SingHealth CIRB ref: 2015/2601).

All subjects aged 30 years and older underwent a single CAC assessment at baseline. The scans were performed using a 320 × 0.5 mm detector row CT system (Canon Medical Systems) with prospective ECG triggering—a technique that synchronizes the scan with the heart's rhythm to produce the clearest images. The scans covered a single heartbeat with a gantry rotation and x-ray exposure time of 0.35 seconds and 0.5 mm slice collimation.

CAC scores were calculated using the Agatston method, a standardized scoring system named after its developer, Arthur Agatston. Scores were classified into standard categories:

• 0 – No calcified plaque present
• 1 to 10 – Minimal plaque
• 11 to 100 – Mild plaque
• >100 – Moderate to severe plaque

The researchers also used the MESA (Multi-Ethnic Study of Atherosclerosis) coronary heart disease (CHD) risk score to classify participants by cardiovascular risk. This algorithm incorporates traditional risk factors to predict the 10-year risk of developing coronary heart disease. Two versions of the score were generated: one relying on traditional Framingham risk variables, and another that additionally incorporates the CAC score. A 10-year risk score of less than 7.5% was considered "low," while a score of 7.5% or higher was considered "elevated," following general ACC/AHA cardiovascular risk assessment guidelines.

Key Findings: What the Researchers Discovered

A total of 800 participants were initially recruited for the study. Of these, 135 (16.8%) were younger than 30 years and did not undergo CT evaluation, and an additional 2 people refused the CT scan. This left a final study population of 663 individuals.

The average age of participants was 49.4 ± 9.2 years, and 297 (44.8%) were men. All participants had normal kidney function, with an estimated glomerular filtration rate (eGFR) above 55 mL/min/1.73 m².

The overall prevalence of any coronary artery calcium (defined as a CAC score greater than 0) was 29.3% (95% CI: 25.8%–32.9%). Breaking this down by severity:

• 47 people (7.1%) had CAC scores between 1 and 10 (minimal plaque)
• 87 people (13.1%) had CAC scores between 10 and 100 (mild plaque)
• 60 people (9.0%) had CAC scores greater than 100 (moderate to severe plaque)
• 17 people (2.6%) had CAC scores greater than 400 (extensive plaque)

When comparing people with any CAC to those without any calcium buildup, the differences were striking. People with CAC were significantly more likely to be older, to be men, and to have higher systolic blood pressure, diastolic blood pressure, fasting glucose, total cholesterol, LDL cholesterol, and triglyceride levels—all with statistical significance of P < 0.001.

Among those who did have CAC, participants who were older, male, and smokers were more likely to have moderate-to-severe plaque (CAC > 100) rather than milder forms.

Key Numbers at a Glance

• 29.3% – Prevalence of any coronary artery calcium in the overall population
• 43.1% vs 18.0% – Prevalence in men vs women (P < 0.001)
• 1.9% to 66.3% – Prevalence range from age 30–39 to age ≥60
• 9.0% – Percentage with moderate-to-severe plaque (CAC > 100)

Age and Sex Differences in Disease Burden

One of the most significant findings was how dramatically the prevalence of CAC increased with age. Across the entire population, the rate of any CAC rose from just 1.9% in people aged 30–39 to 17.8% in those aged 40–49, then to 36.0% in those aged 50–59, and finally to 66.3% in those aged 60 and older (P < 0.001 for trend).

Sex differences were equally pronounced. Men had more than double the prevalence of any CAC compared to women: 43.1% vs 18.0% (P < 0.001). This pattern held across all severity categories:

• CAC 1–10: 9.4% of men vs 5.2% of women (P = 0.035)
• CAC 10–100: 17.8% of men vs 9.3% of women (P = 0.001)
• CAC >100: 15.8% of men vs 3.6% of women (P < 0.001)

Perhaps most revealing was the difference in when moderate-to-severe disease began to appear. In men, the prevalence of moderate-to-severe CAC (scores >100) started rising noticeably from age 40 onward, reaching 5.6% in the 40–49 age group, 17.2% in the 50–59 group, and a striking 44.9% in men aged 60 and older.

In women, the pattern was different. Moderate-to-severe CAC remained quite low through middle age—just 1.6% in the 40–49 group and 1.5% in the 50–59 group—before jumping to 18.4% in women aged 60 and older. This delayed rise in women aligns with a well-established clinical observation: significant coronary artery disease often occurs about 10 years later in women than in men, likely related to the loss of protective effects of estrogen after menopause.

The researchers noted that this age gap, long known in clinical heart disease, extends all the way back to the preclinical stage—meaning the biological processes driving sex differences begin much earlier than when symptoms first appear.

Which Risk Factors Matter Most?

The researchers used multivariable logistic regression models to determine which clinical factors were independently associated with the presence of coronary artery calcium. These models were carefully adjusted for a fixed set of traditional cardiovascular risk factors: age, sex, smoking, sedentary behavior (defined by participant occupation), body mass index (BMI), systolic blood pressure, glucose, LDL cholesterol, and HDL cholesterol.

After adjustment, five factors emerged as independently associated with the presence of any CAC:

• Age: each additional year increased the odds by 13% (OR: 1.13; 95% CI: 1.10–1.17)
• Male sex: men had 3.45 times higher odds compared to women (OR: 3.45; 95% CI: 2.19–5.43)
• Systolic blood pressure: each additional mmHg increased odds by 2% (OR: 1.02; 95% CI: 1.01–1.03)
• Glucose level: each additional mmol/L increased odds by 44% (OR: 1.44; 95% CI: 1.04–1.99)
• LDL cholesterol: each additional mmol/L increased odds by 38% (OR: 1.38; 95% CI: 1.08–1.78)

When looking at different levels of CAC severity, the associations varied. Increasing age and male sex were significantly associated with all degrees of CAC severity. But other factors showed more specific patterns:

• LDL cholesterol was associated with minimal plaque (CAC 1–10; OR: 1.60; 95% CI: 1.09–2.35)
• Systolic blood pressure and glucose were associated with mild plaque (CAC 10–100; OR: 1.02 and 1.56, respectively)
• Systolic blood pressure and glucose were also associated with moderate-to-severe plaque (CAC >100; with glucose showing an OR of 2.04; 95% CI: 1.20–3.46)

Notably, smoking and BMI were not associated with CAC in the multivariable models. The researchers suggested this could be explained by the very low rates of smoking (7.69%) and obesity (5.3%) in this unusually healthy population. Similarly, HDL ("good") cholesterol was not associated with CAC—a finding consistent with recent evidence questioning whether absolute HDL levels are reliably predictive of cardiovascular outcomes in all populations.

A Key Sex Difference: LDL Cholesterol Affects Women More

One of the most interesting findings involved how risk factors differed between men and women. When the researchers analyzed data separately by sex, they found that in men, age was the only factor independently associated with any CAC (OR: 1.13; 95% CI: 1.09–1.18).

In women, however, the picture was broader. After multivariable adjustment, age, smoking, sedentary behavior, systolic blood pressure, and LDL cholesterol were all independently associated with the presence of any CAC.

Specific numbers for women:

• Smoking: OR 4.74 (95% CI: 1.09–20.7) in multivariate analysis
• Systolic blood pressure: OR 1.03 (95% CI: 1.01–1.05)
• LDL cholesterol: OR 2.00 (95% CI: 1.44–3.00)

Formal interaction testing confirmed that LDL cholesterol was significantly more associated with CAC in women than in men (adjusted P for interaction = 0.022). This is noteworthy because traditionally, LDL cholesterol has been thought to carry a greater atherogenic (plaque-causing) risk in men than women. The researchers proposed two possible explanations for this surprising reversal.

First, over half of the female participants were aged 50 years or older, meaning many were likely postmenopausal. The loss of estrogen's protective effects on traditional cardiovascular risk factors could amplify the impact of LDL cholesterol in older women. Second, there may have been a form of selection bias: older men with high-risk lipid profiles might have already developed clinical heart disease and therefore been excluded from this "healthy" population, whereas comparable women—whose disease typically manifests later—would still qualify for the study.

The researchers also acknowledged that atherosclerosis is a complex process, and sex-specific differences extend beyond lipids to include differences in systemic and vascular inflammation, as well as the role of sex hormones in modulating immune responses. These inflammatory mechanisms may contribute to different atherosclerotic phenotypes across sexes, though research on this remains limited.

The Impact on Risk Scoring and Prevention

An important practical question is whether measuring CAC actually changes how doctors assess a patient's risk. To explore this, the researchers calculated each participant's 10-year coronary heart disease risk using the MESA risk score—both with and without incorporating their CAC score.

They found that participants with higher CAC scores indeed had higher 10-year CHD risk scores (Fisher's exact P < 0.001). Specifically:

• 16.7% of participants with CAC >100 had 10-year CHD risk scores of 5% or higher
• In contrast, only 1.5% of participants with a CAC score of 0 had risk scores at that level (P < 0.001)

After incorporating CAC scores into the risk calculation, there was a significant increase in the mean 10-year CHD risk score for the entire population, from 1.78% to 2.20% (P < 0.001). More importantly, the researchers observed significant reclassification of individual risk: 35 individuals (5.56% of the cohort) were moved from a "low" risk category to an "elevated" risk category after their CAC scores were considered (P < 0.001).

This reclassification matters because these individuals might otherwise have fallen below typical thresholds for cardiovascular risk factor monitoring. In other words, without a CAC scan, they would not have been flagged for more aggressive preventive measures—even though they had silent plaque buildup that significantly raises their actual risk.

How These Results Compare With Other Studies

The prevalence of 29.3% found in this study aligns closely with rates reported in other large studies of similar populations:

• The MESA study reported a prevalence of 33.7% in its nondiabetic, healthy subset—though it's worth noting the MESA cohort had a higher mean age (62 years) than the SingHEART population (49.4 years)
• Lee et al. reported 34% prevalence (mean age 53.8 years)
• Van Wagner et al. reported 27.1% prevalence (mean age 50.1 years)
• Kim et al. reported 31.1% prevalence (mean age 54 years)

The patterns of higher disease burden in men and increasing prevalence with age in both sexes have been observed not only at the level of clinical CAD but also at the preclinical level, using both CAC scores and carotid intima-media thickness (ultrasound measurements of artery wall thickness) in other populations.

These comparative data are especially valuable given the relative scarcity of population-based data on preclinical atherosclerosis in Asian populations—despite Asia rapidly becoming a global epicenter for cardiovascular disease. The consistency of findings across different countries and ethnicities strengthens confidence in the generalizability of the results.

Study Limitations: What This Research Couldn't Prove

Like all scientific studies, this research has important limitations that should be considered when interpreting the results.

1. Cross-sectional design. This was a cross-sectional study, meaning all measurements were taken at a single point in time. The researchers could identify associations between risk factors and the presence of CAC, but they could not establish causality or track how the disease progressed over time. Longitudinal follow-up of these participants will be needed to understand how early plaques evolve.

2. "Healthy" population selection. The inclusion criteria were intentionally strict—excluding anyone with diabetes, prior cardiovascular disease, cancer, and many other conditions. While this was necessary to study the earliest stages of disease, it means the results may not apply to the broader population, including people with existing health conditions.

3. Low prevalence of certain risk factors. The very low rates of smoking (7.69%) and obesity (5.3%) in this cohort may have limited the statistical power to detect associations between these factors and CAC. The lack of association between smoking or BMI and CAC should not be interpreted as proof that these factors are harmless.

4. Limited diversity. The study population was entirely Asian, living in Singapore. While this fills an important research gap, the findings may not directly translate to other ethnic groups.

5. Possible selection bias. As the researchers themselves noted, the design of enrolling "healthy" individuals may have inadvertently excluded older men with high-risk lipid profiles who had already developed clinical disease, while including comparable women whose disease typically manifests later. This could influence the sex-specific comparisons.

6. No inflammatory markers. The study did not comprehensively assess inflammatory markers or sex hormone levels—factors that may play important roles in the sex differences observed but were not measured.

7. MESA risk score thresholds. The researchers noted that stratification thresholds specific to the MESA risk score have not yet been fully established, so the use of the 7.5% cutoff (borrowed from ACC/AHA guidelines) may not be perfectly calibrated for all populations.

Recommendations: What This Means for Patients

This study provides several practical messages for patients and their doctors, particularly for those of Asian descent:

1. Silent disease is common, even in "healthy" people. Nearly one-third of people with no symptoms, no diabetes, and no known heart disease had measurable plaque in their coronary arteries. Feeling healthy does not guarantee that your arteries are healthy.
2. Age matters—a lot. The dramatic jump in prevalence from 1.9% in the 30s to 66.3% by age 60 highlights that atherosclerosis accumulates steadily over time. This supports the concept of starting cardiovascular risk assessment early in adulthood, not waiting until symptoms appear.
3. Men and women have different risk curves. Men show significant plaque buildup starting in their 40s, while women tend to catch up only after age 60. For women, maintaining control of modifiable risk factors—particularly LDL cholesterol and blood pressure—may be especially important in the postmenopausal years.
4. Traditional risk factors predict early disease. The associations between blood pressure, glucose, LDL cholesterol, and CAC confirm that even at the preclinical stage, the same risk factors that drive clinical heart disease are already at work. This reinforces the importance of regular checkups that measure blood pressure and fasting blood work, even when you feel well.
5. LDL cholesterol may deserve special attention in women. The finding that LDL had a stronger association with plaque in women than men (P for interaction = 0.022) suggests that women's cholesterol levels should be managed with at least as much rigor as men's—if not more.
6. CAC scoring can reclassify risk. More than 1 in 20 participants (5.56%) were reclassified from low to elevated risk after a CAC scan. For individuals whose risk falls in a borderline zone based on traditional factors alone, a CAC scan may provide valuable information that changes preventive treatment decisions—such as whether to start a statin.
7. Prevention is the most powerful tool. Because early atherosclerosis is detectable and its risk factors are modifiable, lifestyle measures and, where appropriate, medications can potentially slow or halt the progression from silent plaque to clinical heart disease. The strong evidence supporting statin therapy for primary prevention, including its anti-inflammatory effects, is particularly relevant given the LDL findings in this study.

The researchers emphasized that this study was designed not to alarm healthy people but to better inform individualized future risk management strategies. By understanding how age and sex shape the earliest stages of atherosclerosis, doctors may be better equipped to prevent the development and progression of coronary artery disease within individuals who currently have no signs of trouble.

Frequently Asked Questions

What did this study measure, and in whom?

The study used coronary artery calcium (CAC) scans to look for silent plaque buildup in 663 healthy Asian adults aged 30 and older without known heart disease or diabetes. Overall, 29.3% had detectable calcium. Researchers examined how age and sex affected the likelihood of having this early sign of atherosclerosis.

How much more common was silent plaque in men than in women?

In this healthy Asian population, 43.1% of men had detectable coronary artery calcium, compared with 18.0% of women. Men also had higher rates of moderate-to-severe plaque. The sex difference appeared early: men showed significant plaque from their 40s, while women caught up only after age 60.

How did age affect the chances of having silent plaque?

Age strongly influenced plaque prevalence. Among people aged 30-39, only 1.9% had any coronary calcium. This rose to 17.8% at ages 40-49, 36.0% at ages 50-59, and 66.3% at age 60 and older. The study authors suggested cardiovascular risk assessment should start early in adulthood, not wait for symptoms.

Which traditional risk factors were linked to silent plaque?

After adjusting for other factors, older age, male sex, higher systolic blood pressure, higher fasting glucose, and higher LDL cholesterol were each independently associated with having any coronary calcium. Smoking and BMI were not linked in this particular healthy group, possibly because very few participants smoked or were obese.

Did LDL cholesterol affect men and women differently?

Yes. In women, higher LDL cholesterol was independently linked to silent plaque, with an odds ratio of 2.00 per mmol/L. In men, age was the only independent factor. Formal testing showed LDL was significantly more associated with plaque in women than in men, suggesting women's cholesterol levels deserve at least as much attention as men's.

Source Information

Original article title: Impact of Age and Sex on Subclinical Coronary Atherosclerosis in a Healthy Asian Population

Authors: Mark Yu Zheng Wong, Jonathan Yap, MD, Weiting Huang, MD, Swee Yaw Tan, MD, Khung Keong Yeo, MD (Drs. Wong and Yap contributed equally to this work)

Journal: JACC: Asia, Vol. 1, No. 1, 2021, pages 93–102

Publication date: June 2021 (manuscript received April 18, 2021; revised May 3, 2021; accepted May 3, 2021)

Affiliations: Department of Cardiology, National Heart Centre Singapore; School of Clinical Medicine, University of Cambridge, United Kingdom; Duke-NUS Medical School, Singapore

DOI: https://doi.org/10.1016/j.jacasi.2021.05.002

Funding/Disclosures: The authors stated they are in compliance with human studies committees and animal welfare regulations, including patient consent where appropriate.

This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and should not replace professional medical advice. Always consult your healthcare provider about your personal cardiovascular risk and preventive strategies.