PARTICULATE AIR POLLUTION AND

MYOCARDIAL INFARCTION: EXPLAINING THE

CONNECTION Howard M. Kipen, MD, MPHNJ Clean Air CouncilApril 13, 2005

Co

ron

ary

Art

ery

Thin, fibrous cap ruptures

Unstable Plaque

Large, soft,fatty core

Clot

Lipid metabolismApoproteins – APOE

Receptors – LDLREnzymes -LPL

Hyperlipidaemia

Atherosclerosis

Clot formation

Myocardial infarction

EnvironmentSmoking, dietLack exercise

InfectionDIESEL EXHAUST

Endothelial Function (eNOS)Structural – COL1, C0L3

Paraoxonase – PON1Homocysteine - 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

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

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

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

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

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

Cause of death Percent of total deaths

Cause-specific % increase / 50mcg inc in PM2.5

% of excess deaths due to PM exposure

All Causes 100 7.0 100

Respiratory 8 25.0 28

Cardiovascular 45 11.0 69

Other Disease 47 0.4 3

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

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

Controlled Environmental

Facility at EOHSI

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

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

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

PAC1

granule

Thrombin

GPIV

P-selectin

GP1b-IXcomplex

P-selectin

GP11b-IIIacomplex

GP11b-IIIacomplex

GPIV

GP1b-IXcomplex

Fibrinogenreceptors

PAC1

RESTING PLATELET ACTIVATED PLATELET

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.

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.

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

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

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

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