Implications of Premature Coronary Artery Calcification in Primary and Secondary Prevention of Atherosclerotic Cardiovascular Disease

Hypothetical Clinical Vignette

A healthy 45-year-old man presented to an emergency department after 3 days of fever, cough, and dyspnea. Computed tomography (CT) of the chest suggested a viral pneumonia and incidentally revealed mild coronary artery calcification (CAC) by qualitative assessment. After the (hypothetical) patient’s discharge, his primary care physician ordered a formal CAC score, which was 50 Agatston units (91st percentile for age, sex, and ethnicity). His blood pressure was 128/77 mm Hg. Laboratory values were as follows: total serum cholesterol, 189 mg/dL; low-density lipoprotein cholesterol (LDL-C), 122 mg/dL; high-density lipoprotein cholesterol (HDL-C), 45 mg/dL (to convert to millimoles per liter, multiply by 0.0259); and triglycerides, 109 mg/dL (to convert to millimoles per liter, multiply by 0.0113). He had a hemoglobin A_1c level of 5.4 (to convert to a proportion of total hemoglobin, multiply by 0.01). He was a lifelong nonsmoker with no family history of premature coronary artery disease or myocardial infarction. The pooled cohort equations estimated a 10-year atherosclerotic cardiovascular disease (ASCVD) event risk of 1.2%. The primary care physician wondered whether to recommend lifestyle modification alone (given the low 10-year ASCVD risk) or also to initiate preventive statin therapy (given the presence of subclinical atherosclerosis).

Implications and Decisions

This hypothetical vignette highlights an increasingly common predicament in managing prevention of ASCVD events, as well as a ripe opportunity to begin prevention in early middle age.

We currently dichotomize decisions on initiation or intensification of statin therapy for lowering LDL-C whether the purpose is for primary (no known symptomatic disease) or secondary (presence of symptomatic atherosclerosis) ASCVD prevention.¹ In primary prevention, the decision to initiate statin therapy is guided by 10-year estimated ASCVD event risk based on traditional risk factors. Secondary prevention guidelines advise high-intensity statin therapy irrespective of baseline LDL-C and addition of adjunctive treatments (eg, ezetimibe, PCSK9 inhibitors) for high-risk patients with persistent LDL-C levels greater than 70 mg/dL despite maximally tolerated statin treatment.¹ Now, increased identification of subclinical coronary and extracoronary atherosclerosis has obscured these distinctions.

Coronary artery calcification scoring has allowed quantification of atherosclerosis across a gradient of severity in asymptomatic individuals.² Prospective studies of CAC and incident ASCVD risk from the Multi-ethnic Study of Atherosclerosis and others demonstrate a strong correlation between increased CAC and risk of future ASCVD events.² Coronary artery calcification scores greater than 100 or greater than the 75th percentile for age, sex, and ethnicity correlate strongly with increased 10-year ASCVD risk and may tip the balance toward recommending statin therapy for intermediate-risk individuals. Additionally, 1 study of 8549 asymptomatic individuals³ showed that those with family history of coronary artery disease had an increased burden of CAC, suggesting this may be a group to consider for earlier CAC screening in conjunction with traditional risk factors.

We envision CAC being a powerful contributor to risk prediction in young individuals (ie, those <45 years). Our patient in the vignette with detectable CAC had low calculated 10-year ASCVD risk owing to relatively young age but represented high lifetime risk for ASCVD. In the Coronary Artery Risk Development in Young Adults (CARDIA) study,⁴ less than 10% of participants had detectable CAC at a median age of 40.3 years, and those participants had a 5-fold risk of coronary heart disease events. (CARDIA was a prospective study begun in 1984 with a population of Black and White women and men aged 18–30 years at the time.) The presence of CAC in younger individuals has been shown to confer 2-fold to 4.9-fold higher risk of incident ASCVD events across studies of individuals younger than 50 years at recruitment.⁵ Screening for CAC using the presence of ASCVD risk factors may improve the diagnostic yield of CAC scoring.⁴

These studies collectively support the notion that CAC screening in younger middle-aged patients represents a powerful potential indicator of incident ASCVD events and should be used in concert with other traditional risk factors to identify premature disease. As suggested in the 2020 National Lipid Association CAC guidelines,⁶ the utility of CAC observations also extends beyond guidance on lipid-lowering therapy to antihypertensives and aspirin. While CAC scores themselves are thought to provide the best estimate of absolute risk in an immediate 5- to 10-year period and influence near-term disease management, CAC percentiles based on age, sex, and race may be better estimators of lifetime risk.⁶ The National Lipid Association guidelines⁶ recommend using CAC percentiles in individuals aged 50 to 70 years, and they support statin initiation for CAC scores lower than the 75th percentile.

One group for which data are even more limited on utility and implications of CAC scoring is patients younger than 40 years. Among the limited published studies, one of 384 participants aged 27 to 33 years identified 31% of males and 10% of females with CAC.⁷ The Muscatine Study, using a subset from CARDIA of individuals aged 33 to 39 years, found a 5.5% prevalence of CAC.⁸ Both the CARDIA and Muscatine studies found up to 3-fold higher prevalence of CAC in males.^7,8 Despite existence of CAC in this age group, guidance remains unclear on whom to screen before 40 years, how to interpret stark sex differences, and how to use the information we identify.

While current studies have focused on the clinical utility of CAC identification in initiating statin therapy, CAC scores may also help prioritize more costly medications (eg, proprotein convertase subtilisin/kexin type 9 inhibitors, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide 1 receptor agonists). In this vein, codifying the implications of nonzero CAC scores in this younger age group may help define an additional population for which CAC-informed treatment identifies an additional prevention population for which these more costly medications may be of particular benefit.⁹

Even less information exists on the actionability for ASCVD prevention of nongated CT identification of atherosclerotic plaque and extracoronary atherosclerosis. For example, it remains unclear how one should approach initiation of statin therapy for coronary or extracoronary atherosclerosis incidentally found on CT, particularly in the setting of low calculated ASCVD risk. Currently the Society of Cardiovascular Computed Tomography provides a class I recommendation for at least qualitative reporting of CAC in all chest CTs, regardless of indication,⁶ when moderate or severe qualitatively observed CAC correlates with a CAC score of 100 or higher.¹⁰ The benefits of such opportunistic early detection of subclinical atherosclerosis must be tempered with the potential for increased testing in asymptomatic individuals, making this workup inherently an individualized assessment.

Opportunity for Early Prevention

Turning back to our clinical vignette, we posit that the preponderance of data supports aggressive risk-factor reduction initiating high-intensity statin therapy. However, the above unanswered questions highlight a significant knowledge gap for treating such patients and argue for prospective studies on the application of imaging for refinement of ASCVD risk assessment tools. These efforts will enable preventive medicine to move beyond traditional designations of primary vs secondary prevention, particularly for premature CAC, and thus facilitate precision prevention across the spectrum of risk and across the life course.