Highlights
- Cumulative exposure to atherogenic lipoprotein particles in young adults robustly predicts incident atherosclerotic cardiovascular disease (ASCVD) events after 40 years of age.
- Apolipoprotein B (apoB), low-density lipoprotein particles (LDL-P), and triglyceride-rich lipoprotein particles (TRL-P) each independently associate with increased future ASCVD risk, with hazard ratios (HRs) ~1.30 after covariate adjustment.
- Usual apoB exposure above ~75 mg/dL during 18 to <40 years marks a point where ASCVD risk significantly increases, suggesting a potential target lipid threshold for young adults.
- Findings support the importance of early-life lipid management to prevent long-term cardiovascular disease, emphasizing cumulative burden rather than single time-point lipid measurements.
Background
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality worldwide. Decades of epidemiological and clinical research have established atherogenic lipoproteins, particularly low-density lipoprotein cholesterol (LDL-C) and associated apolipoprotein B-containing particles, as central causal drivers of atherosclerosis. However, traditionally, lipid assessment and intervention have focused on middle-aged and older adults, with less emphasis on the impact of lipid exposure during young adulthood.
Recent insights suggest that early adult life represents a critical window wherein cumulative exposure to atherogenic lipoproteins sets the trajectory for subsequent ASCVD development. The burden of atherogenic particles over a prolonged period appears to influence not only the presence but also the progression and vulnerability of atherosclerotic plaques, underscoring the need to characterize these relationships using longitudinal cohort data.
The Coronary Artery Risk Development in Young Adults (CARDIA) study offers a valuable resource with serial measurements of lipoprotein particle concentration and apolipoprotein B (apoB) over a 22-year period starting in early adulthood. The investigation by Zheutlin et al. (2025) leverages CARDIA data to quantify cumulative exposures to apoB, LDL-P, and triglyceride-rich lipoprotein particles (TRL-P) and their association with incident ASCVD beyond age 40, aiming to identify meaningful exposure thresholds predictive of future disease.
Key Content
Longitudinal Relationships between Atherogenic Lipoproteins and Incident ASCVD
The CARDIA cohort, enrolling 4366 participants aged 18 to less than 40 years, was followed for a mean of 19.3 years post age 40 to ascertain incident ASCVD events, including myocardial infarction, stroke, and coronary revascularization. Serial measurements of apoB, LDL-P, and TRL-P were aggregated over the 22-year exposure window spanning ages 18 to <40 years to derive cumulative and ‘usual’ (average yearly) exposure metrics.
Analyses revealed that each 1 standard deviation (SD) increment in cumulative apoB, LDL-P, and TRL-P was associated with unadjusted hazard ratios of 1.53, 1.54, and 1.48 respectively for incident ASCVD events after 40 years of age. Adjusted for relevant covariates including demographic factors, lifestyle behaviors, and clinical risk markers, these associations remained statistically significant with HRs around 1.30, highlighting an independent relationship beyond traditional risk factors.
These data confirm that the aggregate atherogenic lipoprotein burden during young adult life contributes meaningfully to ASCVD risk decades later, thereby elevating the clinical importance of earlier lipid surveillance and control.
Delineation of Key Lipoprotein Thresholds and Their Clinical Implications
One of the study’s pivotal findings was the identification of an apoB concentration threshold of approximately 75 mg/dL as the point at which the ASCVD hazard ratio begins to climb notably. This finding is particularly informative against the backdrop of clinical guidelines, where apoB is emerging as a superior marker for atherosclerotic risk compared to LDL-C alone given its direct representation of atherogenic particle number.
Maintaining apoB levels below this threshold throughout young adulthood may represent an achievable target to sustain low lifetime ASCVD risk. This is a substantial shift from traditional approaches focusing predominantly on LDL-C targets in older populations and underscores the cumulative damage imposed by prolonged exposure to atherogenic particles.
Further, triglyceride-rich lipoproteins (TRL-P) demonstrated similar associations, emphasizing their contributory role, potentially mediated through remnant cholesterol and associated inflammatory effects. This expands the paradigm beyond LDL-centric strategies towards broader lipid management.
Contextualizing Findings within the Wider Literature
Previous studies have demonstrated the predictive value of apoB and LDL particle measures for cardiovascular events; however, few have longitudinally quantified cumulative exposure starting in early adulthood. Meta-analyses (e.g., Moran et al., 2022; Emerging Risk Factors Collaboration, 2018) and Mendelian randomization studies corroborate apoB as a causal factor in atherosclerosis.
The CARDIA-based findings align with the paradigm that cumulative exposure to atherogenic lipoproteins over the life course is critical. For instance, the Young Finns Study (Juonala et al., 2013) similarly showed correlations between early-life lipid levels and carotid intima-media thickness, a surrogate of subclinical atherosclerosis.
RCTs have consistently demonstrated the benefit of lipid-lowering therapies (e.g., statins, PCSK9 inhibitors) in secondary and primary prevention, but initiation in young adults remains debated. These longitudinal observational data provide a rationale for earlier intervention, particularly for individuals with elevated apoB or lipoprotein particle concentrations, potentially refining risk stratification beyond traditional tools like the Framingham Risk Score.
Expert Commentary
The study by Zheutlin et al. contributes a critical piece to the evolving understanding of lipid biology and cardiovascular risk accumulation. By focusing on cumulative rather than single time-point measures in young adults, it highlights the notion of “lipoprotein burden,” akin to the concept of pack-years in smoking and its impact on disease risk.
Guidelines such as the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) and 2018 AHA/ACC cholesterol guidelines increasingly recognize apoB as a key marker and recommend its use particularly in patients with hypertriglyceridemia or metabolic syndrome. However, the utility of apoB-based screening in asymptomatic young adults has been limited by lack of prospective data – a gap this study begins to fill.
Nonetheless, certain limitations warrant discussion. The observational nature limits causal inference, although the consistency with genetic and mechanistic data strengthens the argument for apoB causality. The CARDIA cohort’s demographic diversity enhances generalizability but residual confounding may remain. Additionally, the availability and standardization of particle measurement techniques (NMR spectroscopy for LDL-P and TRL-P) may limit immediate clinical application in some settings.
Mechanistically, apoB-containing lipoproteins, particularly LDL-P and remnant TRL-P, penetrate the arterial intima, triggering inflammation, foam cell formation, and plaque evolution. Persistently elevated particle concentrations during formative years may promote cumulative endothelial injury and plaque burden, reinforcing the concept of early lipid control.
Clinically, these findings encourage clinicians to consider a life-course approach to lipid management. Integrating apoB measurements into young adult risk assessment may identify high-risk individuals suitable for lifestyle modification or pharmacotherapy earlier than currently practiced. Implementation research and large-scale trials examining early lipid-lowering interventions are required to determine the impact on long-term outcomes.
Conclusion
Cumulative exposure to atherogenic lipoprotein particles—apoB, LDL-P, and TRL-P—during young adulthood significantly increases the risk of ASCVD events after age 40. A usual apoB exposure threshold of about 75 mg/dL signals increased future risk, suggesting a potential intervention target to maintain low lifetime cardiovascular risk. These findings advocate for earlier lipid screening and potential risk mitigation strategies in young adults to alter the natural history of atherosclerosis.
Future research should focus on clinical trials targeting young adults with elevated apoB, cost-effectiveness of early screening, and long-term safety of early lipid-lowering interventions. The integration of particle-based lipid metrics into routine cardiovascular risk assessment holds promise to refine prevention paradigms, improve outcomes, and reduce global ASCVD burden.
References
- Zheutlin AR, Handoo F, Luebbe S, Ning H, Sniderman A, Stone NJ, Otvos JD, Jacobs DR Jr, Allen N, Kohli-Lynch CN, Lloyd-Jones DM, Wilkins JT. Cumulative exposure to atherogenic lipoprotein particles in young adults and subsequent incident atherosclerotic cardiovascular disease. Eur Heart J. 2025 Nov 3;46(41):4302-4312. doi: 10.1093/eurheartj/ehaf472. PMID: 40613415.
- Juonala M, Kahonen M, Laitinen T, et al. Childhood levels of serum lipids and predicting carotid artery intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study. Circulation. 2013;128(10):1130-1139. PMID: 23704198.
- Moran AE, Forouzanfar MH, Roth GA, et al. The global burden of cardiovascular diseases and risk factors, 1990-2019: update from the Global Burden of Disease Study. J Am Coll Cardiol. 2022;79(9):1035-1057. PMID: 34954142.
- Emerging Risk Factors Collaboration et al. Apolipoprotein B, risk of cardiovascular events, and the role of LDL cholesterol. Lancet. 2018;391(10117):1946-1957. PMID: 29528106.
- Stone NJ, Robinson JG, Lichtenstein AH, et al. 2018 ACC/AHA Guideline on the Management of Blood Cholesterol. J Am Coll Cardiol. 2019;73(24):e285-e350. PMID: 31802428.
