Please cite this article in press as: Reboul, C., et al., Carbon monoxide exposure in the urban environment: An insidious foe for the heart? Respir. Physiol. Neurobiol. (2012), http://dx.doi.org/10.1016/j.resp.2012.06.010 ARTICLE IN PRESS G Model RESPNB-1851; No. of Pages 9 Respiratory Physiology & Neurobiology xxx (2012) xxx–xxx Contents lists available at SciVerse ScienceDirect Respiratory Physiology & Neurobiology j our nal ho me p age: www.elsevier.com/locate/resphysiol Review Carbon monoxide exposure in the urban environment: An insidious foe for the heart?  C. Reboul a , J. Thireau b , G. Meyer a , L. André b , P. Obert a , O. Cazorla b , S. Richard b,∗ a EA-4278, Université Avignon et des Pays de Vaucluse, F-84000 Avignon, France b INSERM U1046, Université Montpellier1, Université Montpellier2, F-34295 Montpellier, France a r t i c l e i n f o Article history: Received 15 March 2012 Received in revised form 5 June 2012 Accepted 6 June 2012 Keywords: Excitation-contraction coupling ECG Arrhythmia Cardiac remodelling Ca 2+ handling a b s t r a c t Since Claude Bernard first demonstrated in the 19th century that carbon monoxide (CO) poisoning occurs through hemoglobin binding, CO has proven to be more than simply a toxic gas, and to possess complex biological properties. In this review, we highlight the dual nature of CO in cardiovascular function, from endogenous and therapeutic properties to harmful aspects. Focussing on exposure to low environmental CO levels, the most common but least studied form of exposure, we summarize the pathophysiological effects of CO in vivo and in vitro, from cardiac disorders to phenotypic remodelling of cardiomyocytes, based on clinical observations and experimental studies. While acute exposure to low CO levels is consid- ered beneficial and cardioprotective, prolonged exposure appears deleterious, mainly due to alterations in redox status, ion homeostasis, intracellular Ca 2+ handling, and sympathovagal balance. We empha- size that, despite its fascinating therapeutic potential at low levels, regular exposure to CO may have significant consequences on cardiovascular health and must be considered a cardiovascular risk factor. © 2012 Elsevier B.V. All rights reserved. 1. Introduction During the past few decades, carbon monoxide (CO) has received a great deal of scientific attention because of its biological proper- ties as a signalling molecule. The endogenous production of CO, resulting from the breakdown of heme proteins by the enzyme heme oxygenase (HO), has been described, notably in the res- piratory and cardiovascular systems (Durante et al., 2006; Olson et al., 2012; Peers and Steele, 2012). Organisms are also exposed to exogenous CO from various sources including second-hand smoke, vehicular exhaust, industrial emissions, etc. which can be deadly at high concentrations (Soslow and Woolf, 1992). Toxicity occurs mainly through the inhalation of this colourless and odourless gas. Since CO has a high affinity for hemoglobin, forming carboxy- hemoglobin (Hb CO ) in the blood, it can promote tissue hypoxia resulting from the inhibition of oxygen intake (Hlastala et al., 1976). The respiratory and cardiovascular effects of CO poisoning, induced by acute exposure to high CO levels (1000–10,000 ppm; 4.16 × 10 -5 –4.16 × 10 -4 mol L -1 ), have been widely studied and recognized to result primarily from tissue hypoxia (Anderson  This paper is part of a special issue entitled “Gasotransmitters and Respiration: Consequences in Health and Disease”, guest-edited by Prem Kumar and Chris S. Peers. ∗ Corresponding author at: Inserm U1046 Physiopathologie Cardiovasculaire, CHU Arnaud de Villeneuve, 34295 Montpellier, France. Tel.: +33 467 41 52 41; fax: +33 467 41 52 42. E-mail address: sylvain.richard@inserm.fr (S. Richard). et al., 1967; Kolarzyk, 1994). Recent studies have also highlighted the biological effects of low CO concentrations in these systems, although the consequences of prolonged exposure to low CO levels have been less studied and are more controversial. How- ever, the APHEA-2 study (Air Pollution and Health: A European Approach) examining the relationship between air pollution and total cardiovascular mortality in 19 European cities shows a signif- icant association between ambient CO and cardiovascular mortality (Samoli et al., 2007). Environmental CO pollution also has an impact on hospital admissions for respiratory and cardiovascular disor- ders (Bener et al., 2009; Morris and Naumova, 1998). In urban environments, average CO levels typically vary from 2 to 40 ppm (8 × 10 -8 to 1.8 × 10 -6 mol L -1 ), but may be as high as 500 ppm (2 × 10 -5 mol L -1 ) during heavy traffic or when individuals are exposed to second-hand cigarette smoke (Bevan et al., 1991; Stern et al., 1988; Waller et al., 1961; Wright et al., 1975). Interestingly, at low environmental CO levels, the Hb CO concentrations seen in humans are so low (4–6%) that direct hypoxic stress seems unlikely. In this review, we focus on the toxic effects and the cardiac risks associated with CO exposure with special emphasis on its effect following prolonged inhalation of environmental CO. 2. CO, a double-edged sword: from harmful effects to therapy Claude Bernard first proposed in 1865 that CO toxicity results from the formation of Hb CO . Indeed, the affinity of hemoglobin for CO is 200–250 times greater than its affinity for oxygen 1569-9048/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.resp.2012.06.010