A leucopoietic-arterial axis underlying the link between ambient air pollution and cardiovascular disease in humans

Abstract

Aims: Air pollution [i.e. particulate matter with diameter <2.5 μm (PM2.5)] is a risk factor for major adverse cardiovascular events (MACE). While PM2.5 promotes leucopoiesis and atherosclerotic inflammation in experimental models, it is unknown whether this occurs in humans. We tested in humans (a) whether PM2.5 associates with higher leucopoietic tissue activity and arterial inflammation (ArtI), (ii) whether these associations persist after accounting for the effects of potential confounders including socioeconomics, traffic noise, and risk factors, and (iii) whether these tissue effects mediate the association between air pollution and MACE.

Methods and results: Individuals (N = 503) without cardiovascular disease (CVD) or active malignancy underwent 18 F-fluorodeoxyglucose positron emission tomography/computed tomography. Major adverse cardiovascular event was adjudicated over 5 years of follow-up. Leucopoietic tissue activity (in bone marrow and spleen) as well as ArtI were measured. Annual PM2.5 levels were assessed at each individual's home address. At baseline, higher PM2.5 associated with increased leucopoietic activity [standardized (95% CI): 0.129 (0.042, 0.215), P = 0.004] as well as ArtI [0.088 (0.006, 0.171), P = 0.036] after adjusting for CVD risk factors. Over a median 4.1 years, 40 individuals experienced MACE. PM2.5 exposure associated with MACE [Cox HR (95% CI): 1.404 (1.135, 1.737), P = 0.002], remaining significant after adjustment for CVD risk factors and other potential confounders. Mediation analysis demonstrated that increased leucopoietic activity and ArtI serially mediate the link between PM2.5 exposure and MACE.

Conclusions: Higher air pollution exposure associates with heightened leucopoietic activity and ArtI and independently predicts MACE through a biological pathway that includes higher leucopoietic activity and ArtI in series.

Keywords: 18F-FDG-PET/CT; Air pollution; Arterial inflammation; Cardiovascular disease; Leucopoietic activity.

The hypothesized mechanism linking air pollution exposure to major adverse cardiovascular disease events through an up-regulated leucopoietic-arterial axis (solid red arrows).

Figure 1

Subject selection. CT, computed tomography; CVD, cardiovascular disease; FDG, fluorodeoxyglucose; MACE, major adverse cardiovascular event; MGH, Massachusetts General Hospital; PET, positron emission tomography.

Figure 2

Tissue activities on ¹⁸F-FDG-PET/CT by PM_2.5 exposure (≥ vs. < population median). Axial views of the spleen (middle) and coronal views of the bone marrow (top) and aorta (bottom) are shown. Tissue ¹⁸F-FDG uptake was increased in individual with increased PM_2.5 exposure and major adverse cardiovascular event (left) vs. an individual with lower PM_2.5 and no major adverse cardiovascular event (right). MACE, major adverse cardiovascular event; PM, particulate matter.

Figure 3

Air pollution exposure (as quartiles) vs. bone marrow activity (A), splenic activity (B), and arterial inflammation (C). Models were adjusted for cardiovascular disease risk factors (i.e. age, sex, current smoking, diabetes, hyperlipidaemia, hypertension), race, body mass index, and statin use. Z-values for tissue activities are shown, wherein each unit change indicates a standard deviation difference in absolute values. Error bars represent standard error of the mean. CVD, cardiovascular disease.

Figure 4

Kaplan–Meier major adverse cardiovascular event-free survival curves for individuals with (≥ vs. < population median) of annual PM_2.5 exposure. The log-rank P-value is shown. MACE, major adverse cardiovascular event; PM, particulate matter.

Figure 5

Mediation analyses for hypothesized pathways linking PM_2.5 exposure and major adverse cardiovascular event. Serial three-mediator analyses testing the hypothesized indirect pathways (red, blue, and green arrows) and the direct effect (black arrow) of PM_2.5 on major adverse cardiovascular event. CI, confidence interval; MACE, major adverse cardiovascular event; PM, particulate matter.