Air pollution and plaque healing in acute coronary syndromes

Abstract

Plaque healing plays a key role in coronary atherosclerosis1 and represents ‘the second hit’ required to cause an acute coronary syndrome (ACS) after plaque destabilization, this latter being the ‘first hit’.1–3 Moreover, an impaired plaque healing has been found in patients with recurrent ACS, suggesting its importance in preventing repeated symptomatic coronary thrombosis.3 Nonetheless, mechanisms modulating plaque healing are unknown. Air pollution is an important yet overlooked cardiovascular risk factor.4–6 We recently demonstrated that increased long-term particulate matter 2.5 (PM2.5) exposure was associated with coronary plaque inflammation, vulnerability and rupture at optical coherence tomography (OCT) analysis in ACS patients.4 However, the relationship between plaque healing and air pollution has not been yet determined. We investigated the association between air pollution and healed plaques in patients with ACS, stratified by first or recurrent ACS, and whether the previous observation that PM2.5 exposure is associated with coronary plaque vulnerability is valid also in patients with recurrent ACS.5 Consecutive ACS patients undergoing coronary angiography and OCT imaging of the culprit vessel from January 2015 to December 2020 were enrolled in the Gemelli Hospital OCT registry, a prospective observational registry at Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome, Italy. Detailed information on the study protocol and definitions has been previously published.4 From an original population of 383 ACS patients, we excluded 169 patients for stent-related thrombosis/restenosis or no clear culprit lesion; 40 patients for poor OCT imaging quality, post-percutaneous coronary intervention OCT imaging only, and other causes of ACS; and 38 patients for home address unavailability. Optical coherence tomography images were analysed as previously described.7 Detailed methods about air pollutant data collection have been previously published.4,5 Particularly, air pollution data were obtained from air quality monitor stations located in the Rome area. Clinical and air pollutant data were compared between patients with and without healed plaque, macrophage infiltration (MØI), or thin-cap fibroatheroma (TCFA) in the culprit lesion (Figure 1), stratified by first and recurrent ACS. Recurrent ACS was defined as the occurrence of more than or equal to one episode of ACS prior to current admission. First ACS was defined as the absence of ACS events prior to current admission. Patients admitted with first ACS event experiencing recurrence of ACS at follow-up were excluded (n = 3 patients). Univariate logistic regression was performed to study the association between OCT findings (healed plaques, MØI, and TCFA) in separate analyses and clinical [age, sex, body mass index, hypertension, diabetes mellitus, current smoking, hypercholesterolemia, obesity, family history of coronary artery disease, peripheral artery disease (PAD), history of malignancies, ST-elevation myocardial infarction (STEMI), aspirin, thienopyridines, anticoagulants, and statins on admission, laboratory data on admission] and air pollutant data [PM2.5, PM10, ozone, nitric dioxide, carbon monoxide (CO), benzene, and sulfur dioxide] in recurrent and first ACS patients. Only variables showing a P-value of <0.05 in univariate logistic regression were entered in multivariate logistic regression models. The study was approved by the local ethics committee, and all participants gave their written informed consent to be included in this study. Difference in particulate matter 2.5 chronic exposure levels in recurrent and first acute coronary syndrome patients according to healed plaque, macrophage infiltration, and thin-cap fibroatheroma at the culprit lesion. Among recurrent acute coronary syndrome patients, particulate matter 2.5 chronic exposure levels were lower in those with healed plaque in the culprit lesion and higher when macrophage infiltration and thin-cap fibroatheroma were present at the culprit plaque. In first acute coronary syndrome patients, particulate matter 2.5 chronic exposure levels were similar between patients with and without healed plaques in the culprit lesion, while particulate matter 2.5 was higher in those with macrophage infiltration and thin-cap fibroatheroma at the culprit plaque. ACS, acute coronary syndrome; MØI, macrophage infiltration; PM, particulate matter; TCFA, thin-cap fibroatheroma. We enrolled 133 ACS patients [mean age 66.2 ± 12.5 years; 102 (76.7%) males], of which 29 (21.8%) had STEMI. Twenty-nine (21.8%) patients presented with recurrent ACS and 104 (78.2%) with first ACS. Recurrent ACS patients were older, more frequently had PAD, and were more frequently on aspirin, thienopyridines, and statin therapy on admission than first ACS ones. Mean PM2.5 exposure in the total population was 14.8 ± 3.8 µg/m3, and no differences were found between recurrent and first ACS patients (14.5 ± 3.8 vs. 14.9 ± 3.8 µg/m3, P = 0.681). The time interval between previous ACS and index admission was 32 months [interquartile range (IQR) 13.0; 86.3] for recurrent ACS patients. Median clinical follow-up after discharge for first ACS patients was 49 months (IQR: 24.0; 61.0). Healed plaques were found in the culprit lesion of 11 (37.9%) patients with recurrent ACS and 44 (42.3%) with first ACS (P = 0.672). Among patients with recurrent ACS, those with healed plaques, compared to those without, had lower PM2.5 exposure levels (12.6 ± 3.1 vs. 15.7 ± 3.8 µg/m3, P = 0.026) (Figure 1), and PM2.5 was the only variable associated with healed plaque at univariate analysis [odds ratio (OR) 0.753, 95% confidence interval (CI) 0.569–0.997; P = 0.048]. Among patients with first ACS, there were no significant differences in PM2.5 exposure levels between patients with and without healed plaques (15.0 ± 3.5 vs. 14.8 ± 4.0 µg/m3, P = 0.630, P for interaction = 0.043). Among recurrent ACS patients, MØI at the culprit lesion was found in 18 (62.1%) patients. Particulate matter 2.5 levels were significantly higher in patients with MØI compared to those without (15.7 ± 3.9 vs. 12.5 ± 2.9 µg/m3, P = 0.017) (Figure 1), and PM2.5 was the only variable associated with MØI at univariate analysis (OR 1.359, 95% CI 1.017–1.817; P = 0.038). Among first ACS patients, 65 (62.5%) had MØI, and these patients had higher PM2.5 exposure levels compared to those without (16.2 ± 3.4 vs. 12.5 ± 3.2 µg/m3, P < 0.001). Furthermore, although PM2.5 and CO were associated with MØI at univariate analysis, PM2.5 only independently predicted MØI at multivariate analysis (OR 1.417, 95% CI 1.196–1.678; P < 0.001). Among recurrent ACS patients, 6 patients (20.7%) had TCFA at the culprit lesion, and these patients had higher PM2.5 (17.9 ± 3.6 vs. 13.6 ± 3.4 µg/m3, P = 0.030) and PM10 (28.8 ± 3.2 vs. 24.2 ± 3.9 µg/m3, P = 0.014) exposure levels compared to those without TCFA. Both PM2.5 and PM10 were significantly associated with TCFA at univariate analysis, although these associations were not significant at multivariate analysis. Among first ACS patients, 30 (28.8%) had TCFA. Patients with TCFA had higher exposure to PM2.5 (16.5 ± 4.0 vs. 14.2 ± 3.5 µg/m3, P = 0.008) and PM10 (27.4 ± 4.7 vs. 24.9 ± 5.7 µg/m3, P = 0.026) compared to those without. PM2.5, PM10, and CO were associated with TCFA at univariate analysis, although only CO was independently associated with TCFA at multivariate analysis (OR 13.831, 95% CI 1.577–121.331; P = 0.018). We show for the first time that, among patients with recurrent ACS, a higher long-term PM2.5 exposure is associated with an impaired plaque healing along with the presence of more vulnerable plaque features at the culprit lesion. Several mechanisms may explain this association, including PM2.5-mediated vascular inflammation, oxidative stress, endothelial dysfunction, prothrombotic pathways, and vascular smooth muscle cell dysfunction.6,8–10 Although the relatively small sample size of our study subgroups makes larger studies necessary to confirm our hypothesis-generating results, our findings suggest as acting on air pollution may have a deep impact on the natural history of atherosclerosis. Not applicable. The study protocol complied with the Declaration of Helsinki, and the study was approved by Local Institutional Review Committee. The data underlying this article will be shared on reasonable request to the corresponding author. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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