Long-Term Nitrogen Dioxide Exposure as a Possible 5-Year Mortality Risk Factor in Diabetic Patients Treated Using Off-Pump Surgical Revascularization—A Retrospective Analysis

Background: There is mounting evidence that diabetic-related cardiac metabolism abnormalities with oxidative stress and inflammatory mechanism activation align with the functional impairments that result in atherosclerotic lesion formation. Among the possible non-traditional coronary lesion risk factors, environmental exposure may be significant, especially in diabetic patients. Methods: A total of 140 diabetic patients (115 (82%) males and 25 (18%) females) with a mean age of 65 (60–71) underwent surgical revascularization due to multivessel coronary disease. The possible all-cause mortality risk factors, including demographical and clinical factors followed by chronic air pollution exposure, were identified. Results: All patients were operated on using the off-pump technique and followed for 5.6 (5–6.1) years. The multivariable model for 5-year mortality prediction presented the nitrogen dioxide chronic exposure (HR: 3.99, 95% CI: 1.16–13.71, p = 0.028) and completeness of revascularization (HR: 0.19, 95% CI: 0.04–0.86, p = 0.031) as significant all-cause mortality risk factors. Conclusions: Ambient air pollutants such as an excessive chronic nitrogen dioxide concentration (>15 µg/m3) may increase 5-year all-cause mortality in diabetic patients following surgical revascularization.


Introduction
The current trend of an increasing population age is giving rise to the co-existence of coronary artery disease.As the intricacies of cardiovascular disease (CVD) unfold, identifying proper risk factors is of utmost importance.Multivessel coronary artery disease represents the advanced epicardial atherosclerotic involvement that requires intervention to improve patients' life expectancy.Percutaneous interventions and the surgical approach are the optimal therapeutic approaches that improve long-term life expectancy [1].
The growing prevalence of diabetes mellitus has been observed in recent years [2], encompassing atherosclerosis risk.Chronic exposure to hyperglycemia leads to multiorgan dysfunction through interference with microvasculopathic degeneration and possesses a high impact on overall life expectancy.
There is mounting evidence that diabetic-related cardiac metabolism abnormalities with oxidative stress and inflammatory mechanism activation align with the functional impairments that result in atherosclerotic lesions formation [3].The genetic background of diabetes and epicardial atherosclerosis represent different genetic architectures but are characterized by pleiotropy [4].Patients presenting with chronic coronary syndrome and concomitant diseases such as diabetes mellitus are believed to benefit most from surgical revascularization [5].More importantly, the clinically hidden earlier involvement of coronary arteries by atherosclerosis lesions is postulated in diabetic patients [6].
The components of air pollution constitute over 40 toxic substances from natural and human-made sources.Chronic or excessive exposure to ambient pollutants may result in increased mortality or mortality.The relationship between lung cancer and air pollutants, including nitrogen dioxide, has already been presented in prospective studies [7].Wu et al. [8] revealed the association between nitrogen dioxide exposure and an increased risk of multimorbidity.Epidemiological studies included in Huang et al.'s meta-analysis [9] pointed out the increased cardiovascular mortality related to chronic exposure to nitrogen dioxide independently of other common air components.Nitrogen dioxide (NO 2 ) is a common traffic tracer, and the relationship with acute coronary syndrome risk was revealed in Shearston et al.'s analysis [10].
The air pollution-related risk for coronary artery disease is believed to account for increasing the risk of myocardial infarction, arrhythmia, or stroke by up to 5-10% [11].Recent studies based on epidemiological data have focused on short-term air pollution exposure and its positive association with acute cardiovascular events [12,13].In their review, Kulik et al. [14] related the risk of stroke incidence and outcomes to either short-or long-term exposure to ambient pollutants.In animal models [15], chronic exposure to air pollutants promoted atherosclerosis development via inflammatory activation.According to Braunwald [16], up to 20% of cardiovascular deaths are claimed to be air pollution-related.
This study aimed to present a possible relationship between chronic exposure to air pollutants (particulate matter with a diameter of 2.5 microns or less (PM2.5),fine particles with maximal diameter of 10 µm (PM10), or nitrogen dioxide (NO) exposure) and long-term survival in diabetic patients after surgical revascularization.

Patients and Methods
A total of 140 consecutive diabetic patients (115 (82%) males and 25 (18%) females) with a mean age of 65 (60-71) referred for surgical revascularization due to multivessel coronary disease presenting with chronic coronary syndrome were enrolled in the analysis.The exclusion criteria included patients operated on in an unplanned manner, requiring combined procedures, or patients operated on using cardiopulmonary bypass.This study did not include patients with severe left ventricular dysfunction or an oncological history.The detailed characteristics are presented in Table 1.

Statistical Analysis
The normality of the distribution of variables was tested with the Shapiro-Wilk test.The t-test, Cochran-Cox test, Mann-Whitney test, and Fisher's exact test were used where applicable to compare the variables between the two groups.Logistic regression was performed to analyze the predictors of long-term mortality.Statistical analysis was performed using Statistica 13 by TIBCO.p < 0.05 was considered statistically significant.

Air Pollution Exposure Personalized Analysis
The basis for assessing the level of individual exposure to air pollution including particulate matter (PM) with diameters of ≤2.5 (PM2.5) and ≤10 µm (PM10) and nitrogen dioxide (NO 2 ) for each of the patients was the spatial distribution of air concentration fields for Poland provided by the Chief Inspectorate of Environmental Protection [17].The maps were based on the results of the national air quality modeling system elaborated by the Institute of Environmental Protection-National Research Institute in Poland (IEP-NRI) based on the legal obligation set out in the Environmental Protection Act in Poland (Art 66, paragraph 6).

Bioethics Committee
Informed consent was obtained from all participants.This study was conducted by the Declaration of Helsinki and approved by the Institutional Review Board (or Ethics Committee) of Poznan University of Medical Sciences, Poznan, Poland (protocol code 55/20 from 16 January 2020) for studies involving humans.

Results
A total of 140 diabetic patients were operated on using the off-pump technique due to multivessel coronary disease.No perioperative death were noted, and the overall mortality rate was 21 (15%) within 5.5 (5.0-6.1) years of follow-up.The number of grafts performed was 2.4 (0.8), reaching a 86% rate of complete revascularization of 86%.The detailed information is presented in Table 2.

Air Pollution Exposure
The chronic exposure to air pollutants was individually calculated for each patient enrolled in the analysis.The mean values of PM2.5, PM10, and nitrogen dioxide were analyzed.The detailed information is presented in Table 3.

Regression Model
The uni-and multivariable models were created for all-cause mortality risk prediction in the 5-year follow-up, as presented in Table 4.

Discussion
Our analysis demonstrates the predictive value of air pollutants on all-cause mortality in diabetic patients requiring surgical revascularization.We observed the negative impact of chronic exposure to air nitric oxide concentration above 15 µg/m 3 on diabetic patients' survival.In the multivariable model, we also pointed out the protective effect of the completeness of revascularization on 5-year survival.
Diabetes mellitus is a metabolic disorder that implicates inflammatory activation and lipid disturbances in metabolism, causing atherosclerosis formation and propagation.This group of patients is reported to be at higher risk for complications and inferior long-term results, while interventional procedures are proposed.
The multivessel disease represents the advanced stage of coronary atherosclerosis, which can be treated via percutaneous or surgical revascularization to achieve survival benefits.Our multivariable model for 5-year mortality prediction revealed the protective effect of revascularization completeness on patient outcomes.The benefit of complete revascularization (CR) was presented in numerous studies demonstrating its association with mortality reduction [18].As the minimalization of residual ischemia is the primary target of surgical revascularization, the priority in decision-making was based on the extent of revascularization.The completeness of revascularization can be regarded in the anatomical or viability-guided spectrum [19].The Syntax Extended Survival Study confirmed the primary role of revascularization completeness achieved by percutaneous or surgical techniques [20].In Li et al.'s [21] meta-analysis, complete revascularization in acute coronary syndromes significantly reduced the risk for future adverse events compared to culprit-only strategies.
A previous study by Alexeeff et al. [22] suggested the relationship between trafficrelated air pollution and increased cardiovascular risk even within neighborhood differences.Boogaard et al.'s [22] meta-analysis demonstrated a moderate association between air pollutants and adverse health outcomes, including increased risk for ischemic heart disease and lung cancer mortality, followed by acute respiratory tract and chronic morbidities.The pathophysiological basis of chronic exposure to air pollutants is linked to enhanced calcium deposition in the vasculature, leading to inflammatory reactions followed by endothelial dysfunction, leading to coronary artery calcification (CAC) [23].
The utility of nitrogen dioxide as a potential coronary artery disease progression factor was presented in our previous analysis [24].Although air pollutants enter the airways directly, their damaging effect involves other organs, primarily caused by oxidative mediators and inflammatory activations.Among patients exposed to an increased risk of air pollution-induced cardiovascular morbidities, crowded city inhabitants, elderly patients, and those with asthma, chronic obstructive pulmonary disease, and diabetes mellitus are mentioned [25].The unequivocal evidence of the causative role of air pollutants in cardiovascular diseases has presented the necessity of personalized approaches to minimize devastating health effects [26].

Study Limitation
This retrospective analysis presents all causes of mortality in diabetic patients operated on due to chronic coronary syndrome using the off-pump technique.

Conclusions
Chronic exposure to air pollution and arterial revascularization can be regarded as possible long-term survival factors in diabetic patients.Ambient air exposure to nitrogen dioxide above 15 µg/m 3 may increase the 5-year mortality risk in diabetic patients following surgical revascularization.The personalized approach to optimize long-term results, including the interplay between ambient air pollution and certain co-morbidities, should be considered after surgical revascularization.

Table 1 .
Demographical and clinical characteristics of diabetic groups.

Table 2 .
Perioperative characteristics of diabetic groups.

Table 3 .
Air pollution exposure in the presented groups.

Table 4 .
Uni-and multivariable models for mortality prediction in diabetic patients.