Author + information
- David S. Celermajer, MBBS, DSc, FAA, FRACP⁎ ( and )
- Martin K.C. Ng, MBBS, PhD, FRACP
- ↵⁎Reprint requests and correspondence:
Dr. David S. Celermajer, Department of Cardiology, Royal Prince Alfred Hospital, Missenden Road, Camperdown, Sydney, NSW 2050, Australia.
Environmental tobacco smoke (ETS) contains nicotine, particulate matter, and a wide variety of potential biological toxins, which epidemiological and mechanistic studies now coherently suggest can be responsible for increased cardiovascular risk. Although many are surprised that the effects of ETS on cardiovascular risk rates are not too dissimilar from the magnitude of risk conferred by active cigarette smoking, ETS is neither filtered nor burnt at as high temperatures as mainstream smoke inhaled by the active smoker, and thus plausibly has a different and potentially more hazardous chemical composition, balancing the fact that the mass dose of smoke experienced by passive compared to active smokers is manifold lower.
Indeed, published epidemiologic studies are remarkably consistent in documenting cardiovascular event rates 20% to 50% higher in ETS-exposed versus nonexposed adults, with the risk applying whether such exposure occurs in the home or at work (1,2). In a remarkable recent study, Kallio et al. (3) even showed that tobacco smoke exposure was associated with impaired arterial endothelial function in healthy 11-year-old children.
A number of putative mechanisms have been studied to explain the link between ETS exposure and atherothrombotic risk. These include increased sympathetic activity, enhanced platelet aggravation, and increased uptake of oxidatively damaged lipoprotein particles by foam cell macrophages (4). Perhaps the most consistently observed vascular consequence of ETS exposure is impairment of arterial endothelial function, measured as flow-mediated dilation (FMD) of the systemic arteries, a phenomenon in large part caused by diminished nitric oxide release by the arterial endothelium. Endothelial dysfunction has now been shown in a large number of prospective studies to predispose to clinical cardiovascular events (5).
In recent years, it has become appreciated that endothelial dysfunction is reversible by a number of potential interventions, including physical exercise and lipid lowering. The mechanisms that underlie endothelial damage and repair are now being investigated with a new urgency, stimulated by a recent literature linking endothelial progenitor cells to restoration of normal endothelial function (6) and to the role of endothelial progenitor cell (EPC) therapy in improving clinical outcomes in a variety of cardiovascular disorders. The biology of EPCs, however, is complex, with a lack of clarity currently surrounding the definition of an EPC, how to characterize EPCs ex vivo, and the different physiological functions of different types of EPCs in health and disease (7,8).
In this context, the current findings of Heiss et al. (9) concerning a profound and sustained effect of brief exposure to ETS on EPC numbers and function are disturbing. In their study reported in this issue of the Journal, the investigators report that real-world levels of ETS exposure for just 30 min result in profound changes in vascular biology over the subsequent 24 h. There is a marked increase in EPC numbers, but these EPCs have importantly impaired ability to migrate toward vascular endothelial growth factor (VEGF), a key signaling molecule in vascular growth and repair. This impairment of EPC chemotaxis seems to be mediated by a plasma factor, as yet unidentified, which decreases VEGF-stimulated nitric oxide production by the EPCs. The investigators also document an increase in endothelial microparticles circulating after ETS exposure and a significant decrease in flow-mediated dilation of the brachial artery. Thus ETS exposure seems to result in a double hit: acute endothelial injury as evidenced by the decrease in FMD and increase in endothelial microparticle release, and an impairment in the repair mechanism of endothelial damage, as the EPCs rapidly mobilized after ETS exposure are dysfunctional and possibly incapable of restoring normal endothelial function.
Emerging data suggest that nicotine may play a key role in some of the observed effects of ETS. Nicotine is known to stimulate angiogenesis and to participate in tumor angiogenesis and atherosclerotic plaque neovascularization via stimulation of endothelial nicotinic acetylcholine receptors (nAChR) (10). Recent data suggest that EPCs participate in nicotine-mediated angiogenesis. In mice, nicotine administration increases EPC proliferation, mobilization, and incorporation into sites of ischemia-induced neovascularization (11). Interestingly, nAChR stimulation also plays an important role in VEGF-mediated endothelial cell migration and specific nAChR blockade substantially attenuates the migragenic effects of VEGF (12). It is therefore plausible that the observed ETS-mediated EPC mobilization is, in part, mediated by nicotine via nAChR activation. Because nicotine improves EPC incorporation into new vessels in vivo, the observed effects of ETS on impairment of EPC chemotaxis may be mediated by the additive effects of cotinine and other compounds rather than by nicotine. Nevertheless, as acute nicotine exposure markedly downregulates nAChR (12), the activation of which is a key signaling event in VEGF-mediated migration, acute ETS exposure may lead to impairment of the nAChR-dependent mechanisms for VEGF-dependent migration.
There are some excellent features in the study by Heiss et al. (9), including the documentation that the ETS exposure obtained in the custom-built glass chamber described does indeed result in similar levels of nicotine and particulate matter compared with those observed in bars and restaurants where smoking is permitted, and resulted in similar cotinine levels in the nonsmokers compared with those observed in passive smokers in real-world situations. The experiment was well controlled with the use of a smoke-free air control situation. Given current debate and uncertainty over EPC definitions (7), the investigators are to be commended for corroborating their cell surface antigen expression-derived (CD133+/KDR+ and CD34+/KDR+) EPC counts with culture-based EPC assessment to confirm an increase in monocytic cells showing an endothelial cell-like phenotype, because there is evidence to suggest that EPCs identified by flow cytometry are not the same as the EPC subpopulations identified in culture.
Some limitations should also be noted. The number of subjects was very small (10 subjects attended for a first visit, and only 7 completed the schedule of 2 visits); because 5 key end points were measured (FMD, EPC numbers, EPC function, endothelial microparticles, and VEGF levels), confidence in the conclusions should be tempered by the relatively small sample size. Furthermore, the pathophysiological relevance of endothelial microparticles remains uncertain, as noted by the investigators, and only 1 measure of EPC dysfunction has been provided (chemotaxis toward VEGF); further studies might examine other EPC functions, such as ability to repair endothelial damage and angiogenic potential.
The current study has evaluated the acute effects of ETS on EPC mobilization and function. However, the cumulative effects of ETS might be different from the acute effects, as has been noted in the case of mainstream smoke exposure (13). Although a study of 519 coronary artery disease patients found that smoking was associated with increased circulating CD34+/KDR+ EPCs but impaired EPC function as determined by colony-forming assay (14), another recent study of 574 subjects from the general population found that neither smoking status nor dose of smoking exposure had any significant association with culture-derived EPC counts or EPC function using a similar functional assay (15). The discrepancy between these large studies may reflect, in part, different sensitivities to ETS effects in coronary artery disease versus healthy populations. Because different EPC definitions were used for counting in the 2 studies, it is likely that inherent differences in cell populations studied also played a role in the heterogeneity of these study findings. Further studies, using more robust EPC definitions, are required to elaborate the effects of chronic ETS exposure on EPC function.
Thus, there seem to be 2 key “take-home messages” from the current study. The first is that exposure to commonly encountered levels of ETS for short periods of time can have profound and sustained effects on several aspects of endothelial cell biology and thus arterial health, including microparticle release, nitric oxide release, and dysfunction of EPCs, some or all of which may contribute to the important cardiovascular risk of ETS exposure.
The second and perhaps more provocative message is the importance of measuring EPC function, as well as simple EPC numbers, in assessing reparative or therapeutic capabilities of EPCs in pathophysiological situations. The majority of published studies on EPCs to date have simply used EPC numbers as indicators of effective cardiovascular repair and therapeutic potential. Nevertheless, ETS exposure provides a significant lesson in this regard; EPC numbers may be high but their function may be poor, and this may lead to adverse (or neutral) rather than beneficial consequences.
Some recent articles have started to examine the factors associated with dysfunctional EPCs, and these include cardiovascular risk factors in general (16) and the effects of age and coronary disease in particular. It is also unclear what the process of ex vivo culture does to the ability to measure EPC function accurately, and this will be particularly important in subsequent studies that examine the putative therapeutic potential of EPCs.
Epidemiological and mechanistic studies concerning the adverse cardiovascular effects of passive smoking have now resulted in public health and legislative changes that have protected countless individuals from cardiovascular events; this constitutes one of the great efforts of preventive medicine of the last decade. Studies such as those by Heiss et al. (9) have shown that where there's smoke, there is indeed fire, a sustained and complex adverse response that threatens cardiovascular homeostasis with potentially important health consequences. Among these, the concept that EPC dysfunction, rather than simply number, may be a particularly maladaptive cardiovascular response is an exciting and provocative one, worthy of much further investigation.
↵⁎ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
- American College of Cardiology Foundation
- Steenland K.,
- Thun M.,
- Lally C.,
- Health C.J.
- Kawachi I.,
- Kolditz G.A.,
- Speizer F.E.,
- et al.
- Kallio K.,
- Jokinen E.,
- Raitakari O.T.,
- et al.
- Valkonen M.,
- Kuusi T.
- Lerman A.,
- Zeiher A.M.
- Sieveking D.P.,
- Buckle A.,
- Celermajer D.S.,
- Ng M.K.C.
- Yoder M.C.,
- Mead L.E.,
- Prater D.,
- et al.
- Heiss C.,
- Amabile N.,
- Lee A.C.,
- et al.
- Heeschen C.,
- Chang E.,
- Aicher A.,
- Cooke J.P.
- Ng M.K.,
- Wu J.,
- Chang E.,
- et al.