Research Concentrated Ambient Particles Alter Myocardial Blood Flow during Acute Ischemia in Conscious Canines Carlo R. Bartoli,1 Gregory A. Wellenius,1,2 Brent A. Coull,3 Ichiro Akiyama,1 Edgar A. Diaz,1 Joy Lawrence,1 Kazunori Okabe,4 Richard L. Verrier,2 and John J. Godleski1,5 1Molecular and Integrative Physiological Sciences Program, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA; 2Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; 3Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA; 4Sanyo National Hospital, Yamaguchi, Japan; 5Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA Background : Experimental and observational studies have demonstrated that short-term exposure to ambient particulate matter (PM) exacerbates myocardial ischemia. o Bjectivs : We conducted this study to investigate the effects of concentrated ambient particles (CAPs) on myocardial blood flow during myocardial ischemia in chronically instrumented conscious canines. Methods : Eleven canines were instrumented with a balloon occluder around the left anterior descending coronary artery and catheters for determination of myocardial blood flow using fluores- cent microspheres. Telemetric electrocardiographic and blood pressure monitoring was available for four of these animals. After recovery, we exposed animals by inhalation to 5 hr of either filtered air or CAPs (mean concentration ± SD, 349.0 ± 282.6 gμ/m 3) in a crossover protocol. We determined myocardial blood flow during a 5-min coronary artery occlusion immediately after each exposure. Data were analyzed using mixed models for repeated measures. The primary analysis was based on four canines that completed the protocol. r esult : CAPs exposure decreased total myocardial blood flow during coronary artery occlusion by 0.12 mL/min/g (p < 0.001) and was accompanied by a 13% (p < 0.001) increase in coronary vascular resistance. Rate–pressure product, an index of myocardial oxygen demand, did not differ by exposure (p = 0.90). CAPs effects on myocardial blood flow were significantly more pronounced in myocardium within or near the ischemic zone versus more remote myocardium (p interaction < 0.001). c onclusi owrds : These results suggest that PM exacerbates myocardial ischemia by increased coro- nary vascular resistance and decreased myocardial perfusion. Further studies are needed to elucidate the mechanism of these effects. k ey : coronary vasoconstriction, microspheres, myocardial blood flow, myocardial ischemia, particulate air pollution. Environ Health Perspect 117:333–337 (2009). doi:10.1289/ehp.11380 available via http://dx.doi.org/ [Online 10 September 2008] Transient elevations in ambient levels of par- ticulate matter (PM) have been linked to an increased risk of acute cardiovascular events, including myocardial infarction, decompensa- tion of heart failure patients, and stroke (Brook et al. 2004). Recent studies suggest that acute events that lead to hospitalization or death may represent only a small fraction of the acute cardiovascular effects of PM (Mittleman 2007). For example, studies in patients with implantable cardioverter defibrillators suggest an association between PM and the risk of life- threatening ventricular arrhythmias (Dockery et al. 2005; Rich et al. 2005). Similarly, although multiple studies have identified an association between short-term changes in PM and the risk of acute myocardial infarc- tion (D’Ippoliti et al. 2003; Peters et al. 2001; Zanobetti and Schwartz 2005), more recent studies suggest a potential link between PM and unstable angina (Pope et al. 2006). Several experimental (Godleski et al. 2000; Mills et al. 2007; Wellenius et al. 2003) and observational (Gold et al. 2005; Pekkanen et al. 2002) studies suggest that acute PM exposure may be associated with enhanced myocardial ischemia as determined by ST-segment changes on the electrocardio- gram. Two such studies from our group found that conscious dogs exposed to concentrated ambient particles (CAPs) experienced greater ST-segment changes during transient coronary artery occlusion compared with dogs exposed to filtered air (Godleski et al. 2000; Wellenius et al. 2003). The above studies suggest that PM-related changes in myocardial blood flow may be responsible for the observed effects, but this hypothesis has not been directly examined. Our objective in this study was to test the hypothesis that acute exposure to CAPs reduces myocardial blood flow during transient myocardial ischemia. We tested this hypothesis in chronically instrumented con- scious dogs exposed to either CAPs or filtered air, using fluorescent microspheres to directly measure myocardial blood flow. Materials and Methods Surgical preparation. Animals were treated humanely and with regard for alleviation of suffering using protocols approved by the Harvard Medical Area Standing Committee Environmental Health Perspectives • volume 117 | number 3 | March 2009 on Animals. We obtained adult female mixed- breed canines weighing 14–18 kg from Marshall Laboratories (North Rose, NY, USA) for use in this study. Anesthesia and instrumentation surgeries were performed as previously described (Bartoli et al. 2008b; Wellenius et al. 2003). Briefly, a left lateral thoracotomy was performed under inhala- tion anesthesia. A hydraulic balloon occluder was installed around the left anterior descend- ing (LAD) coronary artery. Silicone catheters (7 French; Access Technologies, Skokie, IL, USA) were chronically implanted in the left atrium and descending aorta, tunneled from the thoracotomy incision to the back, and attached to a subcutaneous vascular access port (Polysulfone GPVu; Access Technologies). In four animals, a radiotelemetry unit (D70-CCTP; Data Sciences International, St. Paul, MN, USA) capable of measuring femoral arterial blood pressure and electrocar- diogram was implanted in the left flank. In all animals, a permanent tracheostomy was surgi- cally created to facilitate inhalation exposure (Bartoli et al. 2008a). After surgery, animals recovered for a minimum of 3 weeks before participating in experiments. Each dog was gradually acclimated to the laboratory and exposure conditions to minimize any stress associated with the experiments. Eleven animals underwent surgery as described above. The hydraulic coronary occluder failed in three animals, and three additional animals developed a myocardial infarction; we excluded these six animals Address correspondence to J.J. Godleski, Department of Environmental Health, Harvard School of Public Health, 665 Huntington Ave., II-231, Boston, MA 02115 USA. Telephone: (617) 432-1252. Fax: (617) 432-0014. E-mail: jgodlesk@hsph.harvard.edu We thank S. Verrier, L. Lee, T. Katz, and J. Pettit for their assistance. This study was supported by grants RD831917, R827353, and R832416 from the U.S. Environmental Protection Agency (U.S. EPA), and grants ES012972 and ES00002 from the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH). The contents of this article are solely the responsi- bility of the authors and do not necessarily represent the official views of the NIEHS, NIH, or U.S. EPA. The authors declare they have no competing Received 15 February 2008; accepted 10 September financial interests. 2008. 333