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PARTICULATE AIR POLLUTION AND MYOCARDIAL INFARCTION: EXPLAINING THE CONNECTION

PARTICULATE AIR POLLUTION AND MYOCARDIAL INFARCTION: EXPLAINING THE CONNECTION. Howard M. Kipen, MD, MPH NJ Clean Air Council April 13, 2005. Thin, fibrous cap ruptures. Large, soft, fatty core. Coronary Artery. Clot. Unstable Plaque. Endothelial Function (eNOS) Structural – COL1, C0L3

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PARTICULATE AIR POLLUTION AND MYOCARDIAL INFARCTION: EXPLAINING THE CONNECTION

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  1. PARTICULATE AIR POLLUTION AND MYOCARDIAL INFARCTION: EXPLAINING THE CONNECTION Howard M. Kipen, MD, MPH NJ Clean Air Council April 13, 2005

  2. Thin, fibrous cap ruptures Large, soft, fatty core Coronary Artery Clot Unstable Plaque

  3. Endothelial Function (eNOS) Structural – COL1, C0L3 Paraoxonase – PON1 Homocysteine - MTHFR Inflammatory Mediators (IL6, TNF, CCR5, CCR2, CD18, CD14, MMP2, MMP3, MMP9, MMP12) GST Lipid metabolism Apoproteins – APOE Receptors – LDLR Enzymes -LPL Hyperlipidaemia Thrombolysis & Fibrinolysis, FIBB, FVII, PAI1, Lp(a) Platelet Glycoproteins, (GPllb/llla, Glycoprotein VI, GP1bX) Platelet adhesion molecules (E-selectin, P-selectin, PECAM I); Fibrinogen; FVII, Endothelial Function (eNOS) Atherosclerosis Plaquerupture Environment Smoking, diet Lack exercise Infection DIESEL EXHAUST Clotformation Myocardial infarction

  4. Epidemiologic Evidence of Heart Disease from Air Pollution • Air Pollution Episodes (London, Donora, Meuse Valley) • Daily changes in mortality or morbidity • Spatial differences (6 Cities) • Case Crossover

  5. Science 307:1857-1861, News Focus, March 2005

  6. Pope et al. Circulation. 2004 Jan 6;109(1):71-7

  7. Pope et al. Circulation. 2004 Jan 6;109(1):71-7

  8. Estimates of Daily Mortality Effects of Increases in PM: 60 studies in 35 cities

  9. Particles and MI • MI risk increased with PM2.5 elevations in 2 hours preceding onset of symptoms. • Multivariate OR= 1.48 (1.09-2.02) for 25 mcg/m3 increase in PM 2.5. (Peters, 2001) • OR=2.9 1-2 h after exposure to traffic (Peters, 2004) • UF particles increase thrombosis within one hour of instillation by platelet activation • Effects not explained by a mechanism dependent on lung inflammation because they occur too quickly for inflammation to manifest

  10. Brooks et al, Circulation 109:2655-2671, 2004

  11. Controlled Environmental Facility at EOHSI

  12. Endothelial Dysfunction • Physiological dysfunction of normal biochemical processes carried out by endothelial cells lining inner surface of all blood vessels, arteries and veins. • May compromise coagulation, platelet adhesion, immune function, control of volume and electrolyte content of the intravascular and extravascular spaces. • Characteristic of smokers, diabetics, heart disease

  13. Endothelial Function and ASCVD • Endothelial dysfunction precedes plaque formation and may acutely promote abnormal reactions between vessel walls, platelets & WBC • Can be assessed noninvasively by USG: brachial artery reactivity (flow mediated dilation) following ischemia • Acutely responds to ascorbic acid, tea, ETS, or 150mcg/m3 PM2.5 + 120ppb ozone

  14. Genetic Endothelial Susceptibility ? • Low concentrations of the intercellular messenger NO are important to endothelial function • Directly Inhibits platelet aggregation • Variant eNOS (Glu298Asp) variably increases risk of ASCVD; +/- decreases FMD • 10% homozygous SNP prevalence in UK and Italy

  15. RESTINGPLATELET ACTIVATED PLATELET PAC1 PAC1 Fibrinogen receptors granule P-selectin GP11b-IIIa complex GP11b-IIIa complex Thrombin P-selectin GPIV GP1b-IX complex GP1b-IX complex GPIV

  16. Schematic drawing of ultrasound imaging of the brachial artery with upper versus lower cuff placement and transducer position above the antecubital fossa. BP = blood pressure; FMD = flow-mediated vasodilation. Journal of the American College of Cardiology, Jan 2002.

  17. Ultrasound image of the brachial artery at (A) baseline and (B) 1 min after hyperemic stimulus. Journal of the American College of Cardiology, Jan 2002.

  18. Specific Aims of 4 Year EPA Study • 50 healthy, young, non-smoking volunteers • Two hour exposure to freshly generated aerosols (200 mcg/m3) • Measure endothelial function as brachial artery reactivity change • Measure platelet activation markers • independent of pulmonary inflammation • Determine if individuals with genetically increased risk for ASCVD and endothelial dysfunction exhibit enhanced sensitivity for above endpoints

  19. IMMEDIATELY (2h) Platelet Activation Vascular Reactivity Pulmonary / Systemic Inflammation Induced Sputum (WBC, IL-1, IL-6, TNF-a) Blood (WBC, IL-1, IL-6, TNF-a) Spirometry DELAYED (6h) Platelet Activation Pulmonary / Systemic Inflammation Induced Sputum (WBC, IL-1, IL-6, TNF-a) Blood (WBC, IL-1, IL-6, TNF-a) Spirometry Outcomes

  20. Costs of Myocardial Infarction • 2003: 22,439 inpatient MI’s (NJ CHS) • 1997: cost per MI (752 US Hospitals) • $15,631* (excludes MD fees, inflation, indirect) • $350,744,000 • 1% is $3,507,440 *Azoulay et al. Cardiovasc Rev Rep 24:555-560 2003

  21. EOHSI Studies of Diesel Health Effects • DE and Stress on Acute Phase Response: Fiedler & Laumbach (DOD) • DE Vessels, Coagulation: Kipen (EPA) • DE Biomarkers Validation: Zhang (EPA) • PM2.5, Crossing Guards, and HRV: Fan (EOHSI) • Nasal Resp to DE Particles: Laumbach (EOHSI) Strong support from Debra Laskin, Emmy Gordon, Alexander Kusnecov, Terri Kinzy, Omowunmi Osinubi, Kathy Kelly-McNeil, Kelechi Olejeme, Pamela Ohman-Strickland, Claire Philipp, Daniel Shindler

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