Particle toxicity and pollutant gas/particle interactions in a rat model of acute myocardial infarction John Godleski, MD Harvard School of Public Health Rat Model of Acute MI • Perform left thoracotomy to expose heart. • Cauterize left main coronary artery to induce MI. • Close chest. Surgical Outcomes Wellenius et al. , 2004 Sample ECG QRS Normal Sinus Rhythm P T Ventricular Premature Beats VPB Atrioventricular Block Block 250 ms Wellenius et al. , 2002 Experimental Design Surgery & Recovery (12-18 hr) Diazepam (IP, 12 mg/kg) Room Air Exposure to Room Air (1 hr) Carbon Black Exposure to Room Air (1 hr) ROFA Change in VPB Frequency During Exposures as Compared to Room Air Exposure %∆ 95% CI p ROFA ↑ 566.7% 185.4, 1457.2 <0.0001 Carbon Black ↓ 52.3 -90.6, 140.5 0.37 Wellenius et al. , 2002 Study Hypotheses 1. Exposure to CAPs will increase arrhythmia incidence 2. Exposure to low levels of CO will increase arrhythmia incidence 3. Exposure to a combination of CAPs and CO will synergistically increase arrhythmia incidence Experimental Design Surgery & Recovery (12-18 hr) Diazepam (IP, 12 mg/kg) Air Only Exposure to Filtered Air (1 hr) Air+CO CAPs Only Exposure to Filtered Air (1 hr) CAPs+CO Harvard Ambient Particle Concentrator CAPs: • PM2.5 • Concentration is ~30x ambient • Composition is same as ambient Exposure Characterization Sampling Airstream Sample Type Parameter Mass Concentration Sulfate Ambient Air Integrated Ammonium Particles Particle Size Distribution Continuous Carbon Monoxide Mass Concentration Sulfate Elemental/Organic Carbon Integrated Trace Metals Endotoxins Concentrated Air Particles Non-Volatile Fine Mass Concentration Continuous Black Carbon Particle Number Concentration Analytic Method Gravimetric Analysis Ion Chromatography Ion Chromatography Gravimetric Analysis Non-Dispersive Infrared Gravimetric Analysis Ion Chromatography Thermal/Optical Reflectance X-Ray Fluorescence KLARE Limulus Ameobocyte Assay Tapered Element Oscillating Microbalance Aethalometer Condensation Particle Counter Godleski et al. HEI 2000 Change in VPB Frequency During CAPs and CO Exposures as Compared to Filtered Air Exposures %∆ 95% CI p CAPs ↑64.2% -17.7, 227.6 0.16 CO ↓60.4% -80.7, -18.8 0.012 CAPs/CO* ↓35.0% -53.6, 246.6 ns *: In a model assuming no interaction between CAPs and CO Wellenius et al. , 2004 Effects on Arrhythmia Frequency 400 350 CO Effect CAPs Effect 250 200 150 100 50 0 -50 ll Tra Su nsm be pic ural ar d ial Ov era Tra Su nsm be pic ural ar d ial ll -100 Ov era % Change 300 Wellenius et al. , 2004 Key Findings • Animal model for studying arrhythmias is available • Frequency ventricular arrhythmias – – – – Significantly increased by ROFA Tendency towards increase by CAPs Significantly decreased by CO No interaction was observed between the effects of CAPs and CO. Magnitude of Effect by Exposure Exposure %∆ 95% CI p ROFA ↑ 566.7% 185.4, 1457.2 <0.0001 CAPs ↑ 64.2% -17.7, 227.6 CO ↓ 60.4% -80.7, -18.8 0.16 0.012 Gurgueira SA, et al. Rapid Increases in the Steady-State Concentration of Reactive Oxygen Species in the Lungs and Heart after Particulate Air Pollution Inhalation. Environ. Health Perspect. 110:749-755 (2002) Summary • Particle / Gaseous pollutant effects can be disentangled in laboratory studies. • Particles and environmentally relevant levels of CO have opposite effects on arrhythmias in a model of acute MI. • Similar exposure protocols yield similar results in measurements of in vivo chemiluminescence in the heart and arrhythmias in the MI studies. • ROFA has greater toxicity than CAPs.