Premature Atherosclerotic Cardiovascular Disease in a Middle Eastern Cohort: A Risk-Accumulation Perspective on Shared Determinants and Temporal Exposure Patterns

Background: Premature atherosclerotic cardiovascular disease (ASCVD) represents a growing clinical and public health concern, particularly in regions with a high burden of modifiable risk factors. Whether premature ASCVD reflects a distinct pathophysiological entity or an earlier manifestation of shared risk exposures remains incompletely understood. This study aimed to characterize the clinical profile of premature ASCVD and to examine its relationship with conventional cardiovascular risk factors within a Middle Eastern cohort. Methods: This pooled observational analysis included 2763 adults with established ASCVD derived from multiple cardiovascular registries and a prospective cohort. Premature ASCVD was defined using sex-specific age thresholds (<55 years in men and <65 years in women). Multivariable logistic regression analyses, including sex-stratified models, were performed to evaluate associations between premature presentation and cardiovascular risk factors, including smoking, family history, lipid parameters, and cardiometabolic comorbidities. Results: Among 2763 participants in the pooled clinical cohort, 1335 (48.3%) met the study definition of premature ASCVD. Compared with later-onset disease, premature ASCVD was strongly associated with current smoking, family history of premature cardiovascular disease, and a more atherogenic lipid profile, including higher levels of low-density lipoprotein cholesterol, triglycerides, and non-high-density lipoprotein cholesterol. In contrast, later-onset ASCVD was characterized by a higher prevalence of hypertension and diabetes mellitus. These patterns were consistent across sex-stratified analyses. Despite high rates of secondary prevention therapy use, a substantial residual atherogenic burden was observed among patients with premature ASCVD. Conclusions: In this predominantly coronary cohort, the findings suggest that premature and later-onset ASCVD occur within a broadly overlapping risk-factor landscape, but that the relative distribution of these factors differs according to age at first clinical presentation. The greater prevalence of smoking, family history, and atherogenic lipid abnormalities among younger patients may reflect earlier or greater exposure to these factors, whereas the greater burden of hypertension, diabetes mellitus, and other chronic comorbidities among older patients is consistent with their progressive accumulation with age. These cross-sectional associations should not be interpreted as demonstrating distinct causal mechanisms or age-independent risk profiles.