Roger S. Blumenthal

Background: Premature atherosclerotic cardiovascular disease (pASCVD) represents a major public health concern worldwide. This meta-analysis aimed to assess the (1) global and regional prevalence of cardiovascular risk factors (RFs) and genetic polymorphisms and (2) identify key predictors and clinically relevant cutoff values associated with pASCVD.Methods: We systematically searched electronic databases through December 2025 for studies comparing patients with pASCVD to age-matched healthy controls. Primary outcomes were global and regional prevalences of demographic, lifestyle, clinical, biochemical, and genetic risk factors. The secondary outcome was the assessment of their predictive power and determination of optimal cutoff values.Results: We included 290 studies with 8,871,668 participants (361,019 patients and 8,510,649 controls; mean age 43.2±1.3 years). Patients with pASCVD had higher prevalences of male sex, smoking, physical inactivity, high alcohol use, and other clinical risk factors and biomarkers compared with controls (all p<0.05). Genetic polymorphisms affecting endothelial function, oxidative stress, thrombosis, homocysteine metabolism, and lipid metabolism were more common in persons with pASCVD; low density lipoprotein receptor (LDLR) variants showed the strongest association with pASCVD (OR 7.97; p<0.001). The pooled prevalence of risk factors were: male sex 70%, current smoking 49%, dyslipidemia 46%, hypertension 36%, overweight 38%, obesity 29%, family history 36%, excessive alcohol use 35%, and diabetes 16%. The prevalence of current smoking was the highest in Europe (51%) and Asia (45%), hypertension was more common in the Americas, Europe, and Oceania (47, 36 and 35%, respectively); obesity was highest in the Americas and Europe (34 and 31%, respectively). Family history of CVD was similar across continents (35–42%). Smoking and overweight predominated in low-income regions, while obesity, dyslipidemia, hypertension, diabetes, and high alcohol use increased with rising income. Men had higher rates of smoking and dyslipidemia; women had higher rates of hypertension and obesity. Male sex and White and Black race were associated with increased pASCVD risk, while normal BMI was a protective factor (OR 0.50). Current smoking was the strongest lifestyle predictor (OR 3.05), followed by former smoking (OR 1.47), physical inactivity (OR 1.81), and high alcohol consumption (OR 1.85). Major clinical predictors included familial hypercholesterolemia (OR 4.05), diabetes (OR 3.65), hypertension (OR 3.10), and premature family history of pASCVD (OR 3.26). Elevated lipoprotein(a) ≥50 mg/dL (≥125 nmol/L) (OR 3.93) and LDL-C ≥160 mg/dL (≥4.1 mmol/L) (OR 3.22) showed the largest biomarker-related size effects.Interpretation: Premature ASCVD reflects early exposure to adverse cardiometabolic risk as well as genetic susceptibility. Major determinants include male sex, smoking, dyslipidemia, hypertension, obesity, and diabetes, with inflammatory biomarkers and genetic variants contributing incremental risk. Early identification of persons at risk and the initiation of intensive, life-course prevention strategies are essential to reduce the global burden of premature ASCVD.

BACKGROUND: In general, women have lower aortic valve calcium (AVC) scores compared with men of similar age, and the AVC score threshold for diagnosing severe aortic stenosis (AS) is lower for women. We examined whether the association of AVC with the long-term risk of clinically significant AS differed for women compared with men. METHODS: AVC was measured using cardiac computed tomography among 6810 MESA (Multi-Ethnic Study of Atherosclerosis) participants. We examined AVC as a continuous (ln [AVC+1]) and categorical variable (0, 1–99, 100–299, ≥300 AU). Incident moderate or severe AS was adjudicated using standard clinical criteria with a median follow-up of 16 years. The association between AVC and AS was examined using multivariable-adjusted Cox proportional hazards regression. RESULTS: Women comprised 52.9% of participants, with AVC >0 present among 10.1% of women and 17.0% of men. There were 65 cases of incident AS in women and 75 in men. AVC as a continuous variable was associated with a higher risk of incident AS for women (hazard ratio, 1.91 [95% CI, 1.68–2.16]) and men (hazard ratio, 2.13 [95% CI, 1.88–2.41]). There was no interaction between AVC and sex ( P =0.31) for their association with AS. Women and men had similar adjusted hazards for incident AS across AVC categories, and for those with AVC ≥300, the hazard ratio was 134.9 (95% CI, 45.1–403.9) for women and 132.8 (95% CI, 6.2–274.9) for men. CONCLUSIONS: The association of AVC with the long-term risk of incident AS was similar for women and men, further supporting the utility of AVC as a prognostic marker for incident AS.