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

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Presentation on theme: "PARTICULATE AIR POLLUTION AND MYOCARDIAL INFARCTION: EXPLAINING THE CONNECTION Howard M. Kipen, MD, MPH NJ Clean Air Council April 13, 2005."— Presentation transcript:

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

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

3 Lipid metabolism Apoproteins – APOE Receptors – LDLR Enzymes -LPL Hyperlipidaemia Atherosclerosis Clot formation Myocardial infarction Environment Smoking, diet Lack exercise Infection DIESEL EXHAUST Endothelial Function (eNOS) Structural – COL1, C0L3 Paraoxonase – PON1 Homocysteine - MTHFR Inflammatory Mediators (IL6, TNF, CCR5, CCR2, CD18, CD14, MMP2, MMP3, MMP9, MMP12) GST 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) Plaque rupture

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5 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

6 Science 307:1857-1861, News Focus, March 2005

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

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9 Estimates of Daily Mortality Effects of Increases in PM: 60 studies in 35 cities Cause of deathPercent of total deaths Cause-specific % increase / 50mcg inc in PM2.5 % of excess deaths due to PM exposure All Causes1007.0100 Respiratory 825.028 Cardiovascular 4511.069 Other Disease 470.4 3

10 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

11 Brooks et al, Circulation 109:2655-2671, 2004

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13 Controlled Environmental Facility at EOHSI

14 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

15 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

16 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

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19 PAC1 granul e Thrombin GPIV P-selectin GP1b-IX complex P-selectin GP11b-IIIa complex GP11b-IIIa complex GPIV GP1b-IX complex Fibrinogen receptors PAC1 RESTING PLATELET ACTIVATED PLATELET

20 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.

21 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.

22 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

23 Outcomes 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

24 Costs of Myocardial Infarction 2003: 22,439 inpatient MIs (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

25 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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