Coronary artery calcium (CAC) scoring has changed the game for preventive cardiovascular care, giving clinicians a way to directly measure atherosclerosis burden and accurately estimate cardiovascular risk. With this technique, a simple, non-invasive CT scan produces a number that correlates tightly with risk of future major adverse cardiovascular events (MACE), helping to guide treatment decisions.
The catch is that CAC only measures what it can see—calcification—leaving non-calcified, high-risk plaque invisible. This blind spot is especially problematic in women.
CAC scores 101
Long before it can be detected with CAC scoring, atherosclerosis is progressing in blood vessels. The process begins with the accumulation of apoB lipid particles in the artery wall, where they become oxidized and trigger an immune reaction. White blood cells rush in, engulf the lipids, and turn into “foam cells.” As inflammation and remodeling continue, these fatty streaks evolve into more complex lesions called plaques. Some plaques remain soft and lipid-rich, while others become more fibrous (tissue that is more scar-like). With time, they begin to calcify—the stage quantified with CAC scoring.
This calcification is quantified using non-contrast CT. Each calcified lesion in the coronary arteries is identified and scored based on its area and density. These values are then summed to create the Agatston score (named after Arthur Agatston, a cardiologist who, along with Warren Janowitiz, described the method in 1990). Scores are typically grouped into categories (0, 1–99, 100–399, ≥400) that track with increasing risk. In general, the higher the score, the greater the atherosclerotic burden, and the more compelling the case for aggressive therapy, such as with statins or other lipid-lowering medications, to prevent MACE.
But there’s an important problem with this system: it is actually the non-calcified plaques that are most likely to destabilize and rupture or erode, triggering heart attacks and strokes. Calcification is the body’s attempt at healing the lesion. Laying down calcium stabilizes the plaque, thus reducing the likelihood of one of these rupture events. In fact, one of the mechanisms by which statins reduce cardiovascular risk is through calcification of the more vulnerable, non-calcified plaques. So while CAC is invaluable for quantifying calcified plaque, this measurement doesn’t capture the highest-risk plaque and is therefore only capturing the tip of the iceberg when it comes to cardiovascular risk. The bulk of the threat—the non-calcified, unstable plaque—remains unseen, and the impact of this oversight is not uniform across individuals.
Implications are more concerning in women
The inability of CAC scoring to capture non-calcified plaque is especially problematic in women, particularly in their pre- and perimenopausal years. During this period of a woman’s life, non-calcified plaques predominate, with calcification tending to appear about a decade later in women than in men.1 The sex difference in prevalence of calcium deposits is exemplified in the Multi-Ethnic Study of Atherosclerosis (MESA), in which 62% of women had a CAC of zero compared with 40% of men.2 As a result of these differences in calcification rates, men are more likely to have detectable calcium by midlife, while women often carry lipid-rich, non-calcified plaques through their 40s and 50s. The catch-up in calcification usually comes after menopause—creating a diagnostic blind spot during midlife, when risk may be rising but CAC still reads zero.
Pathology and imaging studies confirm these sex differences. Women are more likely to experience plaque erosion—a disruption of the endothelial surface over a non-calcified plaque—while men more often present with plaque rupture in lesions with fibrous caps and some calcium.3 Both mechanisms can trigger MACE, but only rupture reliably shows up on CAC. And when advanced imaging is used, the disparity is striking: high-risk plaque features predict events in both sexes but do so far more strongly in women (odds ratio 34.5 in women vs. 4.1 in men).4 In short, the plaques most likely to harm women are the very ones CAC cannot see.
Importantly, none of this means CAC is completely irrelevant in women. Once calcification is present, risk rises with CAC score just as it does in men. In fact, these scores may be even more indicative of risk in women: data from the CAC Consortium show that among people with detectable calcium, women are 30% more likely to die a cardiovascular-related death compared to men.1 In other words, CAC is still predictive in women—it just underestimates risk early in the disease process, when non-calcified plaque predominates.
This lag in calcium presentation in women creates the potential for missed prevention. Take a 52-year-old man with a CAC score of 72 and his 50-year-old wife with several high-risk non-calcified plaques. If we were to base intervention strategies only on CAC score, the man’s CAC score would provide a clear signal to start aggressive lipid-lowering therapy. His wife, on the other hand, would leave with a score of zero and the impression that everything is fine. By the time she’s 60, her scan finally lights up—but she’s had ten years of missed preventive opportunity.
So how can we close this gap?
Clinical implications
Realistically, the clinical implications of CAC are the same in men and women. A high score is bad news in both sexes, and a low or zero score can be reassuring only if the rest of the risk profile is clean. In either sex, if other major risk factors are present—high apoB, hypertension, diabetes, or smoking—they warrant intervention, regardless of what the calcium scan shows. Having a CAC test does not reduce the importance of monitoring other risk factors, and a CAC score of zero should never overrule obvious risk apparent in those other metrics.
When uncertainty remains, especially in women with intermediate risk and a low appetite for pharmacologic intervention, additional imaging can help contextualize risk. Coronary CT angiography (CCTA) is a more sensitive test that can reveal non-calcified plaque and provide a more complete picture of disease, though it comes with trade-offs: the use of contrast dyes, higher radiation exposure than CAC, and limited value in low-risk patients. But for carefully selected patients, those trade-offs may be justified and worth discussing.
The bottom line
CAC is a great tool for quantifying coronary plaque burden and refining cardiovascular risk. In both men and women, higher scores predict higher risk. The difference lies at the low end of the scale. In men, a CAC of zero combined with low risk factors usually signals a truly low short-term risk. But in women, especially before menopause, the same score could be misleading. Non-calcified plaque may still be present, carrying risk that the scan cannot show.
The clinical rules are the same: treat risk factors aggressively when they are present, regardless of what the scan says. A zero score should be taken as reassurance only if the rest of the profile is clean, not as a pass to ignore risk.
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References
1. Shaw LJ, Min JK, Nasir K, et al. Sex differences in calcified plaque and long-term cardiovascular mortality: observations from the CAC Consortium. Eur Heart J. 2018;39(41):3727-3735. doi:10.1093/eurheartj/ehy534
2. McClelland RL, Chung H, Detrano R, Post W, Kronmal RA. Distribution of coronary artery calcium by race, gender, and age: results from the Multi-Ethnic Study of Atherosclerosis (MESA): Results from the Multi-Ethnic Study of Atherosclerosis (MESA). Circulation. 2006;113(1):30-37. doi:10.1161/CIRCULATIONAHA.105.580696
3. Bigeh A, Shekar C, Gulati M. Sex differences in coronary artery calcium and long-term CV mortality. Curr Cardiol Rep. 2020;22(4):21. doi:10.1007/s11886-020-1267-94.
4. Plank F, Beyer C, Friedrich G, Wildauer M, Feuchtner G. Sex differences in coronary artery plaque composition detected by coronary computed tomography: quantitative and qualitative analysis. Neth Heart J. 2019;27(5):272-280. doi:10.1007/s12471-019-1234-5
