Absence of significant coronary artery disease does not eliminate smoking-related cardiovascular risk: insights from the PROMISE trial.

Authors

Nóra M Kerkovits, Thomas Mayrhofer, Isabel L Langenbach, Jan M Brendel, Michelle D Kelsey, Maros Ferencik, Michael T Lu, Neha Pagidipati, Svati H Shah, Pamela S Douglas, Borek Foldyna

Published in

American journal of preventive cardiology. Volume 31. Pages 101740. Epub Jul 11, 2026.

Abstract

Although the relationship between smoking and cardiovascular events is well established, it remains uncertain whether the outcomes of noninvasive testing (NIT) influence this relationship and how systemic biomarkers may aid risk stratification in patients presenting with chest pain.
This study included PROMISE participants with stable chest pain and available smoking status (current, ever, or never) and NIT results (Positive NIT: ≥70% coronary stenosis on CT angiography or inducible ischemia on stress testing). Smoking was associated with systemic biomarkers (e.g., hsCRP, IL-6, MMP-9), NIT results, and major adverse cardiovascular events (MACE: cardiovascular death, myocardial infarction, unstable angina), using regression and mediation models adjusted for traditional cardiovascular risk factors (median follow-up 24.4 months).
Among 9100 individuals (mean age 61±8 years; 53% female), 51% were ever-smokers, including 18% current smokers. Smoking was independently associated with MACE, with positive NIT mediating this relationship (current: 16%; ever: 12%, p ≤ 0.006). Compared with never-smokers, smoking was associated with MACE despite negative NIT (current: aHR 2.41, 95%CI 1.49-3.89; ever: aHR 1.80, 95%CI 1.25-2.59), with the most pronounced differences seen in men vs. women and CV death/MI (sex interaction p = 0.047). Smoking was associated with high levels of inflammatory biomarkers, particularly MMP-9 (+51%; current vs. never-smokers), which partially mediated the smoking-MACE association (current: 25%; ever: 8%, ≤0.05).
Negative NIT does not reduce smoking-associated MACE risk in patients with stable chest pain. Particularly, current smoking confers substantial residual cardiovascular risk, potentially mediated by MMP-9-related matrix remodeling not captured by standard testing, supporting aggressive smoking cessation irrespective of NIT results.

PMID:
42893174
Bibliographic data and abstract were imported from PubMed on 18 Oct 2026.

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