This expert opinion is based on Primary Prevention of Subclinical Atherosclerosis in Young Adults: JACC Review Topic of the Week.¹

The development of cardiovascular risk factors (CVRFs) and subclinical atherosclerosis (SA) begins early in life and is associated with a higher prevalence of major cardiovascular events in later life. Even young, low-risk patients (by current standards) may have evidence of plaque development on imaging, especially if they have a family history of premature atherosclerotic cardiovascular disease (ASCVD) (Table 1). Cumulative exposure to risk factors, including elevated low-density lipoprotein (LDL-C), hemoglobin A1c (HbA1c), and systolic blood pressure (SBP), all contribute to SA, even when considered at "normal" levels.²

Table 1: Studies Assessing Subclinical Atherosclerosis in Young Adult Populations

Results from the CARDIA (Coronary Artery Risk Development in Young Adults) study suggest typically normal targets for these risk factors for the young adult population (i.e., SBP <120 mm Hg, HbA1c levels 5.7-6.4%) may still contribute to SA in young adults (<40 years of age).² This has also been demonstrated in patients with familial hypercholesterolemia (FH), where individuals who have lifelong exposure to markedly elevated LDL-C levels have increased likelihood of developing cardiovascular disease (CVD).³ The same principle is thought to apply to individuals without FH.¹ This has led clinicians and researchers to seek out CVRF targets specifically for the young adult population (Table 1).

Current Research Gaps

Current guidelines emphasize the use of lifetime ASCVD risk estimation, instead of 10-year estimation, as the pooled cohort equations have not been validated in younger adults. Further, they recommend assessment of traditional risk factors every 4-6 years.⁴ Among those 20-39 years of age, statin therapy is considered for those with LDL-C >160 mg/dL and with family history of premature ASCVD.⁴ However, there are currently limited primary prevention recommendations for otherwise healthy individuals 20-39 years of age and limited understanding of the degree that young adults' CVRFs should be treated. Therefore, the PRECAD (Prevent Coronary Artery Disease) study was designed to determine if strictly controlling LDL-C to levels below 70 mg/dL while also controlling for SBP and glycemic control in young adults (20-39 years of age) leads to decreased atherosclerotic burden over time.¹

Perspective

For young adults, the US Preventive Services Task Force suggests screening and recommendations for treatment for various CVRFs (hyperlipidemia, diabetes mellitus, hypertension, etc.); however, it is unclear if this screening and the targets are stringent enough to prevent SA from developing, for which the PRECAD study is designed.⁵ Specifically, this study may provide information to modify guidelines and identify individuals who warrant further screening studies as they age.

For pharmacologic interventions, there is some concern regarding adherence in the young adult population. Medications for primary prevention likely have lower adherence than for secondary prevention; in addition, young, otherwise healthy adults are generally not accustomed to taking daily medications, which could further affect adherence.¹

Coronary artery calcium (CAC) scores could be used to further risk stratify these individuals and make a potential case for pharmacotherapy at earlier ages; however, further randomized controlled trials are needed before recommendations regarding primary prevention therapies can be made in a younger population. Further trials with favorable evidence may lead to insurance reimbursement changes that drive down the cost of preventive medicines with the intention of reducing future acute cardiac events.

In terms of nonpharmacologic interventions in young adults, one glaring lifestyle factor is physical activity. The Centers for Disease Control (CDC) estimates that only 24.2% of adults 18 years of age and above meet the recommended levels of physical activity for both aerobic and muscle-strengthening activities.⁶ The CDC has emphasized the importance of physical activity in its ability to reduce risk of CVD and currently recommends 60 min of moderate-vigorous exercise daily in adolescents. Despite this, a significant portion of the population, most notably children and adolescents, do not meet this recommendation. This may be attributed to various factors, but one systematic factor is the opportunity of physical education classes in school has plummeted, which de-emphasizes the importance of exercise and impairs formation of habits in young adulthood and onwards.⁷ Additionally, it is curious to see the potential impact of this research to further efforts in primordial prevention of CVRFs.

The obesity epidemic specifically in children in the United States has prompted efforts to incorporate healthy diet and exercise into school programming, as well as putting a finer focus on maternal health during pregnancy and breastfeeding periods. Seemingly, these efforts (e.g., the Health Hunger Free Kids Act and the FAMILIA [Family-Based Approach in a Minority Community Integrating Systems-Biology for Promotion of Health] trial) have also been associated with primordial prevention of CVD.⁸ However, there are currently no formal guidelines outlining target for diet, physical activity, and other factors which could serve as foundations for primordial prevention efforts. The research being suggested in PRECAD could further thwart efforts into setting guidelines and goals in even younger populations.

Considering data that consistently demonstrate the presence of calcific coronary disease among younger adults with multiple CVRFs, future studies and research should also explore the utility of obtaining CAC scores in people identified with multiple CVRFs earlier in life as a means of identifying higher ASCVD risk individuals.^1,2,9,10 Notably though, CAC does have limitations in younger populations given it does not rule out the presence of noncalcified plaque. Early and aggressive CVRF control (LDL-C goal <70 mg/dL and strict blood pressure and glucose control), such as that offered by PRECAD, also holds the promise of developing clinically relevant cutoffs to guide the practice of primary prevention in young adults.

References

1. Devesa A, Ibanez B, Malick WA, et al. Primary prevention of subclinical atherosclerosis in young adults. J Am Coll Cardiol 2023;82:2152-62.
2. Javaid A, Dardari ZA, Mitchell JD, et al. Distribution of coronary artery calcium by age, sex, and race among patients 30-45 years old J Am Coll Cardiol 2022;79:1873-86.
3. Horton JD, Cohen JC, Hobbs HH. PCSK9: a convertase that coordinates LDL catabolism. J Lipid Res 2009;50:S172-S177.
4. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:e285-e350.
5. Lipid Disorders in Adults (Cholesterol, Dyslipidemia): Screening (USPSTF website). 2013. Available at: https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/lipid-disorders-in-adults-cholesterol-dyslipidemia-screening-2008. Accessed 04/30/2024.
6. Elgaddal N, Kramarow EA, Reuben C. Physical activity among adults aged 18 and over: United States, 2020. NCHS Data Brief 2022:1-8.
7. Physical Activity Facts (CDC website). 2022. Available at: https://www.cdc.gov/healthyschools/physicalactivity/facts.htm. Accessed 04/30/2024.  
8. Ferdinand KC. Primordial prevention of cardiovascular disease in childhood. J Am Coll Cardiol 2019;73:2022-24.
9. Nasir K, Cainzos-Achirica M, Valero-Elizondo J, et al. Coronary atherosclerosis in an asymptomatic U.S. population: Miami Heart Study at Baptist Health South Florida. JACC: Cardiovasc Imaging 2022;15:1604-18.
10. Fuchs A, Kühl JT, Sigvardsen PE, et al. Subclinical coronary atherosclerosis and risk for myocardial infarction in a Danish cohort: a prospective observational cohort study. Ann Intern Med 2023;176:433-42.