Commentary based on Williams KJ. Eradicating atherosclerotic events by targeting early subclinical disease: it is time to retire the therapeutic paradigm of too much, too late. Aterioscler Thromb Vasc Biol 2024;44:48-64.¹

Introduction
Cardiovascular disease (CVD) remains the leading cause of death and disability worldwide.² Early intervention and strict control of modifiable CV risk factors in adolescents and young adults will likely reduce the significant morbidity, mortality, and socioeconomic burden associated with the condition. As such, there is mounting interest in changing the paradigm to identify and treat earlier in life to prevent later, end-stage manifestations of longstanding atherosclerotic cardiovascular disease (ASCVD) such as stroke, myocardial infarction, peripheral arterial disease, and heart failure (HF).

Discussion
Post-mortem studies have demonstrated that ASCVD begins early in life. Greater cumulative exposure to low-density lipoprotein cholesterol (LDL-C) and other CV risk factors such as obesity during young adulthood and middle age are associated with increased risk of ASCVD later in life.³ However, current approaches to therapy in young adults (<40 years old) focus on patients only with established disease or those with markedly elevated lipids or blood pressure (BP). Further, optimal treatment targets in this group may be difficult to achieve. Critical trial data has been limited by the challenges in undertaking CVD outcomes trials in this age group due to low incidence of short-term (<5 year) events and adequate duration of follow-up required to obtain sufficient numbers of CV events.

The ongoing Prevent Coronary Artery Disease (PRECAD) trial was developed to provide data regarding the benefits of early, strict CV risk factor control. This longitudinal randomized controlled trial is examining aggressive risk factor modification (LDL-C <70 mg/dL, systolic blood pressure [SBP] <120 mmHg, and glycated hemoglobin <6.5%) on progression of atherosclerosis burden in young adults (20-39 years old) as compared with the current standard of care. The primary endpoint for the study is progression of atherosclerosis burden as measured by change in global plaque volume on 3D vascular ultrasound over a period of 5 years.⁴ The study has the potential to provide much needed, randomized controlled data to support strict control of CV risk factors in young adults (Table 1).

Table 1

Similarly, the Progression of Early Subclinical Atherosclerosis (PESA) prospective cohort study enrolled 4,184 healthy middle-aged individuals (40-54 years old) and aims to characterize the presence of subclinical atherosclerosis (SA) and factors associated with its progression or regression over a period of 19 years. The study uses multiple imaging modalities (three-dimensional vascular ultrasound, fludeoxyglucose-18 positron emission tomography, computed tomography, and magnetic resonance imaging) to monitor plaque development and progression.⁵ At baseline, 63% of patients had evidence of SA (including ~40% of participants classified at low long-term risk). At 6-year follow-up, progression of SA occurred in 32.7% of individuals. The strongest predictors of SA progression were older age, higher LDL-C, male sex, active smoking, and higher SBP. SA regression occurred in 8% of individuals and was inversely related to older age, higher LDL-C, male sex, and active smoking. The impact of baseline LDL-C and SBP on SA progression was more pronounced among younger patients suggesting that more aggressive risk factor control at younger ages could have a greater long-term impact on preventing SA progression.⁶

The ASCVD Risk Estimator Plus does not incorporate patients <40 years old and there is limited data to direct management of ASCVD risk factors in such patients. To target younger adults who would benefit from more aggressive early risk factor modification, novel prediction calculators are needed. Coronary artery calcium (CAC) scores are a powerful tool for ASCVD risk prediction. While its value in younger patients is reduced due to the paucity of calcified plaque and greater incidence of non-calcified, or 'soft', plaque in this group, there may still be utility among younger patients with multiple traditional risk factors given a higher likelihood of the presence of any CAC (i.e. CAC>0).⁷

The recently validated PREVENT™ Online Calculator was developed with these limitations in mind. This equation includes patients ages 30-79 years old using traditional risk factors (smoking status, cholesterol, SBP, antihypertensive and statin use, diabetes) as well as body mass index, estimated glomerular filtration rate, urine albumin-creatinine ratio and HbA1c to provide a 10- and 30-year risk of global CVD events (ASCVD and HF).⁸

Despite the relative sparsity of risk prediction tools to guide ASCVD management for younger individuals, there are several guideline-directed opportunities for management. It is important to address modifiable risk factors such as diet and exercise, weight, tobacco use, BP control, cholesterol, and glycemic control at every visit. Current guidelines recommend 30 minutes of physical activity, 5-7 days per week to improve CV health and prevent weight gain. Medical nutrition therapy can produce modest weight reduction and pharmacotherapy (such as glucagon-like peptide-1 receptor agonists) can be considered in those eligible and not attaining healthy weight targets with lifestyle measures. Notably, data from the Coronary Artery Risk Development in Young Adults (CARDIA) study demonstrated that cumulative BP from young adulthood to middle age is associated with ASCVD and HF, providing incremental predictive and discriminatory value.⁹ This further underscores the importance of longitudinal BP control amongst this group. Additionally, young adults with LDL ≥160 mg/dL or a strong family history of premature ASCVD should prompt more intensive evaluation and lifestyle improvements and consideration of statin treatment.¹⁰

Importantly, while age is a major risk factor for the development of atherosclerosis, ASCVD is not an inevitable consequence of aging. As demographic trends shift toward an aging population with increasing prevalence of coronary artery disease, there has been a growing interest in defining healthy vascular aging. For instance, changes such as increasing arterial stiffness and intimal medial thickening may be expected in healthy older patients in the absence of atherosclerosis. Identifying how age-related vascular changes may result in susceptibility or resilience to atherosclerosis is critical to the development of novel therapeutic targets for ASCVD prevention.¹¹

Conclusions
The traditional approach to ASCVD prevention has focused on those with established ASCVD and those with marked hyperlipidemia. LDL-C lowering therapies and control of other modifiable risk factors remain the cornerstone of primary and secondary prevention. However, many patients identified as low-risk by traditional risk-estimating calculators continue to slowly develop SA, which may ultimately manifest as potentially preventable end-stage ASCVD events. A paradigm shift is needed to address lifetime risk of CVD and promote healthy vascular aging. The development of novel risk prediction calculators that incorporate longer duration of risk and cumulative risk is a critical step. Additionally randomized controlled trial data, such as PRECAD, will be integral to supporting this shift to early intervention from 'too much, too late'.

References

1. Williams KJ. Eradicating atherosclerotic events by targeting early subclinical disease: it is time to retire the therapeutic paradigm of too much, too late. Aterioscler Thromb Vasc Biol 2024;44:48-64.
2. Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, et al.; on behalf of the American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics—2020 update: a report from the American Heart Association. Circulation 2020;141:e139-e596.
3. Zhang Y, Pletcher MJ, Vittinghoff E, Clemons AM, Jacobs DR Jr, Allen NB, et al. Association between cumulative low-density lipoprotein cholesterol exposure during young adulthood and middle age and risk of cardiovascular events. JAMA Cardiol 2021;6:1406-13.
4. Devesa A, Ibanez B, Malick WA, Tinuoye EO, Bustamante J, Peyra C, et al. Primary prevention of subclinical atherosclerosis in young adults. J Am Coll Cardiol 2023;82:2152-62.
5. Ibanez B, Fernández-Ortiz A, Fernández-Friera L, García-Lunar I, Andrés V, Fuster V. Progression of Early Subclinical Atherosclerosis (PESA) study: JACC Focus Seminar 7/8. J Am Coll  Cardiol 2021;78:156-79.
6. Mendieta G, Pocock S, Mass V, Moreno A, Owen R, García-Lunar I, et al. Determinants of progression and regression of subclinical atherosclerosis over 6 years. J Am Coll Cardiol 2023;82:2069-83.
7. Mortensen MB, Gaur S, Frimmer A, Bøtker HE, Sørensen HT, Kragholm KH, et al. Association of age with the diagnostic value of coronary artery calcium score for ruling out coronary stenosis in symptomatic patients. JAMA Cardiol 2022;7:36-44.
8. Khan SS, Matsushita K, Sang Y, Ballew SH, Grams ME, Surapaneni A, et al.; on behalf of Chronic Kidney Disease Prognosis Consortium and the American Heart Association Cardiovascular-Kidney-Metabolic Science Advisory Group.  Development and validation of the American Heart Association's PREVENT Equations. Circulation 2024;149:430-49.
9. Nwabuo CC, Appiah D, Moreira HT, Vasconcellos HD, Yano Y, Reis JP, et al. Long-term cumulative blood pressure in young adults and incident heart failure, coronary heart disease, stroke, and cardiovascular disease: the CARDIA study. Eur J Prev Cardiol 2021;28:1445-51.
10. Stone NJ, Smith SC Jr, Orringer CE, Rigotti NA, Navar AM, Khan SS, et al. Managing atherosclerotic cardiovascular risk in young adults. J Am Coll Cardiol 2022;79:819-36.
11. Cheng DCY, Climie RE, Shu M, Grieve SM, Kozor R, Figtree GA. Vascular aging and cardiovascular disease: pathophysiology and measurement in the coronary arteries. Front Cardiovasc Med 2023;10:1206156.