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

PARTICULATE AIR
POLLUTION AND
MYOCARDIAL INFARCTION:
EXPLAINING THE
CONNECTION
Howard M. Kipen, MD, MPH
NJ Clean Air Council
April 13, 2005
Coronary Artery
Thin, fibrous cap ruptures
Large, soft,
fatty core
Clot
Unstable Plaque
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
Atherosclerosis
Plaque rupture
Environment
Smoking, diet
Lack exercise
Infection
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)
Clot formation
DIESEL EXHAUST
Myocardial infarction
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
RESTING PLATELET
ACTIVATED PLATELET
PAC1
PAC1
Fibrinogen
receptors
granul
e
P-selectin
GP11b-IIIa
complex
Thrombin
P-selectin
GPIV
GP11b-IIIa
complex
GP1b-IX
complex
GPIV
GP1b-IX
complex
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)
 DELAYED (6h)
 Platelet Activation
 Platelet Activation
 Vascular Reactivity
 Pulmonary / Systemic
 Pulmonary / Systemic
Inflammation
Induced Sputum (WBC, IL1, IL-6, TNF-a)
 Blood
(WBC, IL-1, IL-6, TNF-a)
Spirometry

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