According to a new study published in JACC, there is a strong dose-response relationship between cigarette smoking and three different domains of subclinical cardiovascular markers: inflammation, thrombosis and subclinical atherosclerosis. Moreover, this association can last for decades after quitting smoking.

Study authors Zhiqi Yao, MD, ScM, et al., compiled data from 182,364 participants (mean age 58.2 years, 69.0% women, 27.2% Black, 10.8% Hispanic/Latino) in the U.S. and Brazil, across 22 cohorts of the Cross-Cohort Collaboration, categorized into currently smoking (15.3%; mean 16.7 cigarettes/day, mean 30.0 pack-years), formerly smoked (34.6%; median 19.0 years since quitting, mean 22.4 pack-years) and never smoked (50.1%).

Smoking was measured as self-reported smoking intensity, historical smoking pack-years and time since quitting. Participants who currently smoked were more likely to be younger non-White men. They were less likely to be hypertensive or using antihypertensive or lipid-lowering medications.

Subclinical cardiovascular harm was measured using nine markers: high-sensitivity C-reactive protein (hs-CRP), interleukin-6 and glycoprotein acetylation for inflammation; fibrinogen and D-dimer for thrombosis; and coronary artery calcium (CAC), carotid intima-media thickness, carotid plaque and ankle-brachial index (ABI) for subclinical atherosclerosis.

Results showed that participants who currently smoked had the strongest association between cigarette smoking and biomarkers of cardiovascular disease risk. Study authors observed a clear dose-response relationship between smoking frequency and all markers except for D-dimer. Those eight markers rose at a 1%-9% increment per 10 cigarettes/day.

The association was strongest for subclinical atherosclerosis and inflammation, as measured by CAC, carotid plaque, ABI and hs-CRP.

Participants who currently or formerly smoked also had a clear dose-response relationship between pack-years and all markers, which rose at a 1%-9% increment per 10 pack-years. These effects lowered in relation to longer time since quitting, with little difference in any marker except for CAC in those who had quit ≥30 years ago; CAC remained 19% higher in former smokers after 30 years. Notably, markers of cardiovascular harm were seen even in participants who smoked less than five cigarettes a day.

The study authors call these biomarkers a tool for public health organizations to show patients "the adverse 'hidden' effects of cigarette use before they become clinically evident manifestations," and visualize a campaign with "explicit and transparent dose-response adverse effect information on cigarette packaging and advertisements."

In an accompanying editorial comment, Oisin Galvin, MB BC_H BAO; Khurram Nasir, MD, MPH, FACC; and John W. McEvoy, MB BC_H BAO, MHS, PhD, wrote: "Without doubt, this is the one of the largest and most detailed reports on the contemporary epidemiology of cigarette smoking in relation to cardiovascular disease."

While they call for additional studies focused on more objective smoking measurements beyond self-reported use, such as cotinine levels, Galvin, et al., write, "this study shows a path forward to a rethink. A revamp of future smoking investigations based on subclinical disease biomarkers such as those highlighted in the current study could play a role in guiding contemporary clinical practice, public health strategies, and regulatory policies in a more timely and pragmatic fashion."