Risk Profile and Prognostic Implications of Premature Advanced Coronary Atherosclerotic Disease Among Young to Early Middle-Aged Adults

Dr. Ellen BoakyeResident Research Spotlight

European Journal of Preventive Cardiology, 2026View Publication →

Study Overview

The coronary artery calcium (CAC) score is an established tool for cardiovascular risk stratification, but most prior research has focused on older adults or on absolute CAC scores. For young and early middle-aged adults, an absolute score can be misleadingly modest even when a patient's burden is high relative to peers their age. This study asked a different question: what are the risk profile and long-term mortality implications for young adults whose CAC is not just present, but falls at or above the 90th percentile for their age, sex, and race?

Dr. Ellen Boakye and colleagues used data from the CAC Consortium, a retrospectively assembled multicenter cohort of individuals without prior cardiovascular disease who were referred for CAC scanning between 1991 and 2010 at four institutions. The analytic sample included 44,047 participants between the ages of 30 and 55 (men) or 30 and 65 (women). CAC was categorized as absent, present but below the 90th percentile, or at or above the 90th percentile, using age-, sex-, and race-specific reference values from cac-tools.com. Mortality was ascertained through the Social Security Administration Death Master File and cause of death through the National Death Index. Over a mean follow-up of 12.5 years, the team assessed whether this "premature advanced" phenotype carried a distinct prognostic risk compared with lower-burden CAC and absent CAC.

Key Findings

Of the 44,047 participants, 6,680 (15.2%) had CAC at or above the 90th percentile. Among those with any CAC, more than one in three fell into this advanced category.
The advanced group had a markedly different atherosclerotic burden: 76.4% had multivessel CAC (vs. 40.6% below the 90th percentile), 21.8% had left main involvement (vs. 9.9%), and 32.6% had thoracic aortic calcification. The median CAC score was 178 AU (IQR 65-398) in this group vs. 14 AU (IQR 4-40) in those below the 90th percentile.
All-cause mortality incidence was 2.93 per 1,000 person-years in the advanced group, compared with 1.85 and 1.11 in the below-90th-percentile and absent-CAC groups, respectively. Stepwise gradients were seen for cardiovascular and CHD mortality as well.
In multivariable-adjusted models (referencing absent CAC), CAC at or above the 90th percentile was associated with a 2.2-fold higher risk of all-cause mortality (HR 2.17, 95% CI 1.83-2.57), a 3.9-fold higher risk of CVD mortality (SHR 3.89, 95% CI 2.78-5.44), and a 5.5-fold higher risk of CHD mortality (SHR 5.45, 95% CI 3.38-8.78).
Importantly, CAC below the 90th percentile did not differ significantly from absent CAC for cardiovascular or CHD mortality, suggesting that the 90th percentile marks a clinically meaningful threshold rather than a point on a continuous gradient.
The association between advanced CAC and mortality was consistent across sexes, with no significant interaction between sex and CAC category.

Clinical Significance

Current ACC/AHA guidelines recommend considering the 75th CAC percentile or an absolute score of 100 AU as a threshold for initiating statin therapy in intermediate-risk individuals. This study makes a compelling case that the 90th percentile represents a qualitatively distinct disease phenotype in young adults, one characterized by diffuse, multivessel calcification and a mortality risk that far exceeds that of peers with lower-burden CAC.

The authors propose that future prevention guidelines explicitly recognize CAC at or above the 90th percentile as an indication for the most aggressive preventive pharmacotherapy available, including statin up-titration with lower LDL targets, ezetimibe, PCSK9 inhibitors, and bempedoic acid. They coin the term "premature advanced subclinical atherosclerosis" to signal that this is not merely a quantitative increment but a distinct clinical entity warranting its own classification and management approach.

For residents, this study reinforces an important principle: in young patients, a seemingly modest absolute CAC score may represent extreme relative burden. A 32-year-old with a CAC of 50 AU is in a very different situation than a 62-year-old with the same score. Knowing where a patient falls within their peer group, not just on an absolute scale, changes the conversation about risk and the urgency of preventive therapy.

📊 Methods Highlight

Competing Risks Regression (Fine-Gray Model)

When studying cause-specific mortality, standard Cox regression has a subtle but important limitation: it treats death from other causes as a censored observation, as though those patients simply dropped out of follow-up. But a patient who dies from cancer cannot later die from heart disease. Their non-cardiovascular death is a competing risk, an event that permanently prevents the outcome of interest from occurring.

The Fine and Gray model addresses this directly. Rather than the cause-specific hazard (which conditions on surviving all competing events), it models the sub-distribution hazard, reflecting how the cumulative incidence of the event of interest evolves across the entire cohort, including those who die from competing causes.

In this paper, standard Cox regression was used for all-cause mortality, since there are no competing events when death from any cause is the outcome.
Fine-Gray regression was used for CVD and CHD mortality specifically, because participants could die from non-cardiovascular causes first, and ignoring this would overestimate the cardiovascular risk.
The resulting sub-distribution hazard ratios (SHRs) reflect the net clinical impact on cumulative incidence, which is what matters most for a patient's actual prognosis.

Tip: When you see cause-specific mortality as an outcome in a paper, check whether the authors used competing risks regression. Ignoring competing events can inflate apparent risk differences and mislead clinical interpretation, particularly in populations where death from non-cardiovascular causes is common.