Breaking the mold: embracing early detection of coronary artery disease by coronary computed tomography angiography and the role of cumulative risk factor exposure

This editorial refers to ‘Interaction between risk factors, coronary calcium, and CCTA plaque characteristics in patients aged 18–45 years’, by D. Lorenzatti et al., https://doi.org/10.1093/ehjci/jeae094. In the intricate narrative of cardiovascular health, the evolution of coronary artery disease (CAD) unfolds as a dynamic interplay of genetic predisposition, lifestyle factors, and the relentless march of time. Traditionally, the focus of CAD prevention has centred on discrete risk factors and singular measurements, often later in life. In this regard, the current atherosclerotic cardiovascular disease (ASCVD) risk estimation by the pooled cohort equation only includes individuals older than 40 years of age.1 Nevertheless, it is now indisputable that CAD begins in youth, with some speculating that the process of atherosclerosis may commence even before birth.2 Although it is recognized that CAD may develop as a subclinical condition in early life with varying rates of progression among individuals, the optimal method for predicting ASCVD risk in young adults remains uncertain. Recent data indicate a troubling trend of rising annual admissions for acute myocardial infarction (MI) among young adults aged 35–54 years.3 This finding challenges the conventional wisdom that CAD prevention should begin in later decades, and relying solely on risk estimation tools may overlook the opportunity to alter the course of plaque development at its inception. Lorenzatti et al.4 present an interesting study that sheds light on the prevalence and predictors of coronary artery calcium (CAC), plaque subtypes, and plaque burden in young symptomatic patients. This study, encompassing 907 individuals aged 18–45 years undergoing coronary computed tomography angiography (CCTA) for chest pain evaluation, uncovers crucial insights into the early stages of atherosclerosis, as well as the influence of risk factor exposures on cardiovascular health.4 In this young cohort, 15% of the population was found to have atherosclerotic plaque of calcified or non-calcified nature, and the risk of developing plaque rose steadily with an increasing burden of CAD risk factors. Additionally, age ≥35 years [odds ratio (OR) 3.61, 95% confidence interval (CI) 1.93–6.76] was identified as the most significant independent predictor of plaque presence, followed by a family history of premature CAD (OR 2.89, 95% CI 1.71–4.88) and male gender (OR 2.57, 95% CI 1.66–3.97).4 Age is a crucial factor in assessing the 10-year risk of ASCVD.5 Its importance is further emphasized when comparing the 10-year ASCVD risk assessment with the lifetime prediction of ASCVD. These comparisons show that while some adults may have a low 10-year ASCVD risk, their lifetime predicted ASCVD risk can be much higher.6,7 This underscores the effect of cumulative exposure to risk factors over a longer period of time on cardiovascular health. Moreover, historically associated with the male gender, CAD saw a significant shift in perception due to the findings of the Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients study. This study delved into the clinical characteristics and outcomes of young patients experiencing MI with non-obstructive coronary arteries (MINOCA) vs. those with obstructive disease [MI due to CAD (MI-CAD)]. A surprising 11.1% of the study population fell into the MINOCA category, with a higher representation of women, non-white individuals, and younger patients. Patients with MINOCA were less likely to be prescribed secondary prevention medications and cardiac rehabilitation upon discharge. They also tended to present with non-ST-segment elevation MI as opposed to patients with MI-CAD. Interestingly, patients with MINOCA exhibited fewer traditional cardiac risk factors.8 Lorenzatti et al. demonstrated that although the majority of study participants with atherosclerotic plaques had a CAC score >0 (11%), the prevalence of any coronary plaque on CCTA among those with CAC = 0 was not trivial (5%, n = 43). This study elucidated that a family history of premature CAD was the sole independent predictor of exclusively non-calcified plaque (OR 2.29, 95% CI 1.08–4.86).4 The development and progression of atheroma are now understood to be a dynamic and discontinuous process, influenced by episodes of systemic and regional inflammation. Several mechanisms are thought to play a role in atherogenesis, including the passage of low-density lipoprotein (LDL) particles through the endothelium via transcytosis with the help of proteins such as cavelolin-1, activin receptor–like kinase 1, and scavenger receptor Class B Type 1. LDL can also bind to plasminogen, potentially triggering fibrinolysis, which paradoxically contributes to atherogenesis despite its thrombolytic effects. Although native LDL is a mild trigger for innate immune activation, when LDL aggregates in the intima, it is absorbed by macrophages in the plaques. Subsequently, the interaction between T lymphocytes and innate immune cells in the intima can further fuel atherogenesis. This collaboration among immune cells leads to the release of pro-inflammatory cytokines, sustaining local inflammation.9,10 The creation of pro-osteogenic agents such as minimally modified LDL and oxidized phospholipids, due to oxidative stress, may later serve as the vital connection between inflammation and the progression of the non-calcified plaque to the calcified form.11 The impact of inflammation on atherosclerosis is further demonstrated in a study by Lerman et al., which investigated the connection between psoriasis and CAD. The researchers found that individuals with psoriasis had a greater burden of non-calcified plaque compared with patients with high cholesterol, although they were younger and had fewer conventional cardiovascular risk factors. Intriguingly, a subset of patients with psoriasis monitored for a year showed that as their psoriasis symptoms alleviated, there was a corresponding decrease in the quantity of plaque in their coronary arteries.12 Knowing that a non-calcified plaque is the precursor to calcified plaque formation, it becomes apparent that relying on a CAC score in young adults, especially those at the initial stages of plaque development, poses a limitation. It is safe to consider that when it comes to young individuals, particularly those under age 40, the absence of CAC may not hold the same weight in negative predictive value as it does in older individuals. It is very important to highlight that the detection of calcified and mixed plaques in young adults should prompt further investigation with an emphasis on preventative measures when compared with the older demographics. This discovery suggests an accelerated build-up of plaque in the presence of a heightened risk for atherosclerosis. Conditions that frequently underlie premature atherosclerosis should come to mind, including diabetes mellitus, familial hypercholesterolaemia, and elevated Lp(a), to mention a few.13,14 Remarkably, in this study, after accounting for clinical risk factors, LDL-cholesterol levels, and ethnicity, the presence of chest pain did not raise the likelihood of having plaque.4 This may reinforce the notion that when it comes to cardiovascular health in younger demographics, devising a tailored approach is essential. Early screening and a vigilant approach for those at risk should be implemented before symptoms manifest, as relying on symptoms for addressing cardiovascular health in young individuals is clearly not a reliable factor. Our knowledge of atherosclerosis and its risk factors is continually advancing, with a growing focus on investigating the impact of non-traditional factors that can act independently or exacerbate the traditional risk factors. This is why when assessing ASCVD risk in younger adults, special attention should be paid to inflammatory conditions such as autoimmune diseases, as well as environmental factors such as air pollution and sleep disturbances.15,16 By combining these approaches with intensive lipid-lowering therapies using statins, proprotein convertase subtilisin kexin Type 9 inhibitors, and selective cholesterol-absorption inhibitors, such as ezetimibe alongside statins, we can gain significant advantages and align with primary prevention efforts. As we delve deeper into the labyrinthine pathways of CAD pathogenesis, it becomes increasingly apparent that the trajectory of atherosclerotic progression is principally shaped by the relentless toll of cumulative risk factor exposure. This paradigm shift prompts a re-evaluation of primary prevention strategies, advocating for an earlier initiation of preventive measures to intercept the insidious onset of atherosclerosis in a timely manner, closer in time to its inception rather than its clinical manifestations. Shifting our focus on primary prevention towards a younger age group could potentially alter the course of CAD development and enhance cardiovascular health, leading to a quicker decline in morbidity and mortality rates for people of all ages across the globe. In conclusion, the findings of this important study underscore the imperative of early identification and risk factor modification in young patients. The authors offer insights into the utility of CCTA and CAC score as two complementary diagnostic tools in evaluating coronary plaque burden. The implications of these findings extend to the broader context of cardiovascular disease prevention, emphasizing the significance of personalized risk stratification and early intervention strategies to mitigate long-term cardiovascular risks in young individuals. None declared. No new data were generated or analysed in support of this research.