PARTICULATE AIR POLLUTION AND MYOCARDIAL INFARCTION: EXPLAINING THE CONNECTION

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
Plaque rupture
Environment Smoking, diet Lack exercise Infection
DIESEL EXHAUST
Clot formation
Myocardial infarction
4
(No Transcript)
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 3071857-1861, News Focus, March 2005
7
Pope et al. Circulation. 2004 Jan 6109(1)71-7
8
Pope et al. Circulation. 2004 Jan 6109(1)71-7
9
Estimates of Daily Mortality Effects of
Increases in PM 60 studies in 35 cities
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)
• OR2.9 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 1092655-2671, 2004
12
(No Transcript)
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

17
(No Transcript)
18
(No Transcript)
19
RESTING PLATELET 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
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 24555-560
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