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Vancouver, BC, Canada
The authors are affiliated with the James Hogg iCAPTURE Centre for Pulmonary and Cardiovascular Research, University of British Columbia.
Correspondence to: Stephen F. van Eeden, MD, PhD, iCAPTURE Centre, University of British Columbia, St. Paul’s Hospital, 1081 Burrard St, Vancouver, BC, V6Z 1Y6 Canada; e-mail: svaneeden{at}mrl.ubc.ca
The association between impaired lung function (reduction in FEV1 or FEV1) and cardiovascular morbidity and mortality is well established.12 In the last decade, similar associations have been shown between FEV1 and stroke incidence and mortality.234 The predominant risk factors for stroke are hypertension and preexisting vascular disease or atherosclerosis (and the risk factors leading to atherosclerosis, such as age, cigarette smoking, or diabetes). In a large 20-year follow-up study, Hart and colleagues4 showed a significant association between stroke mortality and BP (systolic and diastolic), smoking, blood glucose level, cardiothoracic ratio, height, preexisting coronary heart disease, and FEV1. The British Regional Heart Study,3 a large prospective cardiovascular risk assessment study, showed that stroke is inversely related to FEV1 in older hypertensive men with preexisting ischemic heart disease who are nonsmokers or ex-smokers. Several other studies have supported this inverse relationship between FEV1 and stroke, independent of other risk factors, including smoking,345 suggesting that impaired lung function is an independent risk factor for stroke mortality. In this issue of CHEST (see page 1642), Hozawa and colleagues,6 using data from the Atherosclerotic Risk in Communities study, showed an inverse relationship between FEV1 (and FVC) and ischemic stroke incidence in never-smokers, which is a novel finding that underlines the importance of impaired lung function as a independent risk factor for stroke. The biological mechanisms responsible for the association between reduced lung function and the incidence of ischemic stroke are still unclear.
Respiratory symptoms, specifically those that are indicative of infection, are well known to be associated with vascular events; Hozawa and colleagues6 postulate that an increase in BP with coughing or during episodes of hypoxemia could result in cerebral ischemia in regions with marginal blood flow due to arterial stenosis. However, they showed that even in subjects with no respiratory symptoms the inverse relationship between FEV1 and ischemic stroke was still present.6 If they had corrected for the presence of biomarkers that are known to predict vascular disease, such as circulating WBC count and fibrinogen levels, this relationship would have weakened, suggesting that systemic inflammation somehow influences the relationship between impaired lung function and vascular disease, leading to stroke.
In the general population, the predominant reason for impaired lung function (ie, reduced FEV1) is COPD, with smoking being the leading cause. COPD is a chronic inflammatory condition in the lung that is characterized by inflammation in both the airways and lung parenchyma.7 COPD is also associated with a significant systemic inflammatory response with increased circulating levels of acute-phase proteins (ie, C-reactive protein [CRP] and fibrinogen), stimulation of the bone marrow with elevated WBC and band cells counts, and increased circulating levels of cytokines (ie, interleukin [IL]-1ß, tumor necrosis factor-
, and IL-6) with the potential to activate the vascular endothelium.8 Several of these circulating biomarkers are known to be associated with the magnitude of atherosclerosis, and also to predict cardiovascular morbidity and mortality in population-based studies.
Exposure to ambient air pollution particles is also associated with a reduced FEV1, and cardiovascular and stroke morbidity and mortality.9 Recently, Kunzli and colleagues10 demonstrated a 4 to 5% increase in carotid intima-media wall thickness for every 10 µg/m3 increase in ambient particulate matter levels of < 2.5 µm in 798 participants who lived in the Los Angeles basin. These epidemiologic observations are supported by animal studies11 showing the progression of atherosclerosis in the coronary arteries and aortas of rabbits that naturally develop atherosclerosis and had received long-term exposure to ambient particulate matter levels of < 10 µm. In these studies, lung inflammation and the number of alveolar macrophages that have phagocytosed in particles correlate with the number of subjects with coronary atherosclerosis, suggesting that lung inflammation impacts the development of atherosclerosis. After the exposure of both animals11 and humans12 to air pollution, there is an increase in the circulating levels of biomarkers of inflammation, including elevation of leukocyte counts (with elevated band cell counts, signifying bone marrow stimulation), activation of the acute-phase response with increases in the levels of CRP and fibrinogen, and increases in the levels of circulating proinflammatory mediators (eg, IL-1ß, IL-6, and granulocyte macrophage colony-stimulating factor). This systemic inflammatory response has been postulated to be the link between lung inflammation and downstream vascular disease. Therefore, impaired lung function due to long-term exposure to particulate matter air pollution9 could explain the association between reduced FEV1 and stroke in never-smokers that is reported by Hozawa and colleagues.6 Similarly, other chronic inflammatory lung conditions resulting in reduced FEV1, such as bronchiectasis and interstitial lung disease, could also contribute to this association.
Discovery of the mechanisms by which the systemic inflammatory response produces vascular events remains an active area of research. A proposed cascade of events is shown in Figure 1
. It is known that circulating mediators such as cytokines and CRP are associated with endothelial dysfunction, which is a critically important step in the initiation and progression of atherosclerosis as well as the destabilization of existing atherosclerotic plaques. These mediators (eg, IL-1ß and tumor necrosis factor-) have the ability to activate the endothelium. This leads to a cascade of events that includes the following: up-regulation of the endothelial adhesion molecules (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) that are responsible for leukocyte recruitment; increases in endothelial permeability, which promotes the uptake of oxidized low-density lipoprotein into the plaques, thereby increasing lipid content in the plaque; and stimulation of the release of proteinases from tissue macrophages (eg, matrix metalloproteins 2 and 9) that degrade the subendothelial extracellular matrix. All of these events increase the vulnerability of plaque to rupture, resulting in thrombus formation and occlusion of the vessel.
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Footnotes
This work was supported by the BC Lung Association, Heart and Stroke Foundation, and the Churg Foundation. Dr. van Eeden is the recipient of a Career Investigators Award from the American Lung Association and the William Thurlbeck Distinguished Researcher Award.
The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
References
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