Association Between Cigarette Smoking and Subclinical Markers of Cardiovascular Harm

Background: Cigarette smoking is a strong risk factor for cardiovascular harm. Objective: To explore the detailed relationships between smoking intensity, pack-years, and time since cessation on inflammation, thrombosis, and subclinical atherosclerosis markers of cardiovascular harm remain undefined. Methods: We included 182,364 participants (mean age: 58.2 years, 69.0% female) from 22 cohorts of the Cross Cohort Collaboration with self-reported smoking status, including smoking intensity and/or pack-years, and concurrent subclinical marker measurements. Markers were categorized into three domains: inflammation (hs-CRP, IL-6, GlycA), thrombosis (fibrinogen, D-dimer), and subclinical atherosclerosis (coronary artery calcium (CAC), carotid intima-media thickness (cIMT), carotid plaque, and ankle-brachial index). Utilizing multivariate regression models and restricted cubic splines, we assessed associations of smoking status, intensity, pack-years, time since cessation and subclinical markers. Results: 15.3% of participants currently smoke (mean cigarettes use per day: 16.7, mean pack-years: 30.0), and 34.6% of participants formerly smoked (median time since quitting: 19.0 years, mean pack-years: 22.4). Participants with a history of smoking showed higher levels of all subclinical markers compared to those who have never smoked, with stronger associations observed in those currently smoke. Among participants who currently smoke, smoking intensity showed a clear dose-response relationship with all markers, except for D-dimer, specifically with incremental 1%–9% higher levels of subclinical markers per 10 cigarettes. After 20 cigarettes, the patterns appeared to plateau for blood markers, while it continued to increase for atherosclerosis markers. Among those who have ever smoked, robust dose-response relationships were observed for pack-years with all subclinical markers, with incremental 1%–9% higher levels per 10 pack-years. The dose-response effects persisted after 20 pack-years for all markers, though with a milder slope. Among participants who smoked formerly, there were substantially lower levels of biomarkers with longer time since quitting, and most markers became non-significant compared to those who have never smoked by 30 years, except for the CAC score, which remained 19% higher even beyond quitting after 30 years. Conclusions: Smoking-relevant parameters all show strong and dose-response relationships across three domains of subclinical markers of cardiovascular harm. The sensitivity of the tested subclinical markers to small increments in cigarette exposure suggests potential value of these markers in the regulation of new and existing tobacco products.