Cigarette smoking and release of the inflammatory chemokine CXCL10 (IP-10) after ST-elevation myocardial infarction

Abstract Background Excessive inflammation after ST-elevation myocardial infarction (STEMI) is associated with adverse outcomes. Cigarette smoking is controversially associated with improved short-term outcomes after MI, but its effect on post-MI inflammation is unknown. Purpose Investigate the relationship between cigarette smoking, the inflammatory chemokine CXCL10 (IP-10), and short-term clinical outcomes. Methods We measured serum CXCL10 level in archived blood samples from 354 patients with STEMI, who were enrolled in A Trial of Low-Dose Adjunctive Alteplase During Primary PCI (T-TIME). Patients underwent immediate percutaneous coronary intervention, and infarct size was assessed with cardiovascular magnetic resonance (CMR) imaging in the first week post-PCI. Rates of major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal MI, or hospitalization for heart failure, were assessed at 3 months. CXCL10 expression was assessed in human coronary artery endothelial cells (HCAECs) cultured under oscillatory, normal laminar or elevated flow with treatment with tumour necrosis factor-alpha (5ng/ml TNF-α) and/or cigarette smoke extract (10% CSE) for 48 hours. Results Of the STEMI patients, 118 were never smokers, 64 were ex-smokers and 172 were current smokers. Current smokers compared to never smokers were younger (56.9 vs 63.8yrs, p0.001) with lower rates of hypertension (21.1 vs 40.8%, p0.0001), but were similar with regards to sex (13.9 vs 16.3% female, p=0.55), diabetes (14.4 vs 11.6%, p=0.53), hypercholesterolaemia (19.1 vs 21.8%), and infarct size (26.5 vs 28.0% of LV, p=0.69). The median CXCL10 value was lower in current smokers than never smokers (59 IQR 34 – 125 vs 160pg/mL IQR 67 – 344, p0.001). After adjustment for age, sex, infarct location and traditional risk factors, current smoking was strongly associated with a lower CXCL10 level (adjusted OR for highest tertile CXCL10 vs never smokers: 0.26 0.16 – 0.42, p0.001). A MACE event occurred in 19.5% of patients in the highest CXCL10 tertile, compared to 9.1% in the lowest (OR 0.41, p=0.026). CXCL10 expression was strongly induced by TNFα treatment in HCAECs under all flow conditions, but was abrogated by the addition of CSE. Conclusion In STEMI patients, current smoking is associated with markedly lower circulating levels of CXCL10, an inflammatory chemokine. In HCAECs, cigarette smoke extract treatment suppressed CXCL10 gene expression, supporting a direct mechanistic association. At 3 months after STEMI, lower CXCL10 level was associated with a reduced incidence of MACE. These data suggest cigarette smoke modulates inflammation, which in the context of infarct expansion may result in beneficial outcomes. Further exploration of this mechanism is warranted.