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Comparative Progression of Comparative Progression of Atherosclerosis in ApoE-/- Mice Atherosclerosis in ApoE-/- Mice
Exposed to ETS and CAPsExposed to ETS and CAPs
Lung Chi Chen, Ph. D.Lung Chi Chen, Ph. D.Department of Environmental MedicineDepartment of Environmental Medicine
NYU School of MedicineNYU School of Medicine
7th ICCAD, Venice Italy7th ICCAD, Venice ItalyOct. 10, 2007Oct. 10, 2007
SCHOOL OFMEDICINE
NEW YORK UNIVERSITY
Health Risks of Environmental Health Risks of Environmental Tobacco Smoke (ETS) ExposureTobacco Smoke (ETS) Exposure
ETS increases coronary heart disease (CHD) ETS increases coronary heart disease (CHD) in non-smokers by a factor of 1.3.in non-smokers by a factor of 1.3.
Long term exposure to ETS caused 40,000 - Long term exposure to ETS caused 40,000 - 60,000 excess heart disease deaths in the 60,000 excess heart disease deaths in the US.US.
Smoking produces atherogenic serum lipid Smoking produces atherogenic serum lipid profileprofile
Smoking increases intima-media thickness Smoking increases intima-media thickness coronary progressioncoronary progression
When Pollution Gets High, Deaths Increase:When Pollution Gets High, Deaths Increase:1952 London Fog Episode Deaths vs. PM1952 London Fog Episode Deaths vs. PM
(Pope, Burnett, Thun, Calle, Krewski, Ito , and Thurston) (Pope, Burnett, Thun, Calle, Krewski, Ito , and Thurston) ((JAMAJAMA, 2002), 2002)
Association between Ambient Particle Pollution and Atherosclerosis
Künzli et al, EHP 113, 201-206, 2005In Los AngelesCIMT: carotid intima-media thickness
Schematic of the evolution of the Schematic of the evolution of the atherosclerotic plaqueatherosclerotic plaque
Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 7th ed
Common Mechanisms of Ambient Particles and Tobacco Smoke Induced Atherosclerosis
Ambient ParticlesCigarette Smoke
Oxidative Stress(O2
-, H2O2, ONOO-)
Vascular Dysfunction, Prothrombotic Factors,Leukocyte, Platelet Activation, Lipid PeroxidationAdhesion Molecules, Smooth Muscle Proliferation
Initiation and Progression ofAtherothrombotic Diseases
InflammatoryGene Activation
NO Regulation
EXPERIMENTAL DESIGNEXPERIMENTAL DESIGNEXPERIMENTAL DESIGNEXPERIMENTAL DESIGN ApoEApoE-/--/- mice mice
Normal Chow (Normal Chow (4% fat, w/w, 8% calories from fat)4% fat, w/w, 8% calories from fat) High Fat Chow (High Fat Chow (21% fat, w/w, 42% calories from fat)21% fat, w/w, 42% calories from fat)
Exposed, whole body, to fine CAPs or filtered air for 6 hours/day, 5 days per Exposed, whole body, to fine CAPs or filtered air for 6 hours/day, 5 days per weekweek May 29, - Dec. 7, 2007.May 29, - Dec. 7, 2007. Average 6 hr Concentration: 165 µg/mAverage 6 hr Concentration: 165 µg/m33
equivalent to 30 ug/mequivalent to 30 ug/m33 annual average. annual average. Exposed, whole body, to side stream (SS) smoke or filtered air for 6 hours/day, Exposed, whole body, to side stream (SS) smoke or filtered air for 6 hours/day,
5 days per week, for 6 months5 days per week, for 6 months Average 6 hr Concentration: 450 µg/mAverage 6 hr Concentration: 450 µg/m33
Approximately equivalent to living with a smoker who smoke 3 cigarettes/day.Approximately equivalent to living with a smoker who smoke 3 cigarettes/day.
Ambient Particle Concentrating and Exposure SystemsAmbient Particle Concentrating and Exposure SystemsAmbient Particle Concentrating and Exposure SystemsAmbient Particle Concentrating and Exposure Systems
Animal Exposure Chambers
VACES
Modified DataScience ECG Receivers
Inside of the exposure chambers
ETS ExposureETS ExposureSide-Stream Smoking MachineSide-Stream Smoking Machine
(CSM 2070, CH Tech)(CSM 2070, CH Tech)
2R4F, 2 sec 35 ml puff/min, 12 puffs/cigarette2R4F, 2 sec 35 ml puff/min, 12 puffs/cigarette Whole-body exposure chamberWhole-body exposure chamber
EXPERIMENTAL DESIGNEXPERIMENTAL DESIGNEXPERIMENTAL DESIGNEXPERIMENTAL DESIGN
ECG tracing monitored continuously for daily ECG tracing monitored continuously for daily changes in heart rate (HR) and heart rate changes in heart rate (HR) and heart rate variability (HRV)variability (HRV)
At 2, 4, 6 months of ETS exposure or at 3 and 6 At 2, 4, 6 months of ETS exposure or at 3 and 6 months of CAPs exposuremonths of CAPs exposure
Ultrasound Biomicroscopy (UBM)Ultrasound Biomicroscopy (UBM)
Vascular ReactivityVascular Reactivity
HistopathologyHistopathology
H&EH&E
ImmunohistostainingImmunohistostaining
Ultrasound Biomicroscopy (UBM)Ultrasound Biomicroscopy (UBM)Ultrasound Biomicroscopy (UBM)Ultrasound Biomicroscopy (UBM)
Vevo 660, VisualSonics, Toronto, OntarioVevo 660, VisualSonics, Toronto, Ontario single-crystal mechanical transducersingle-crystal mechanical transducer central frequency: 40 MHz central frequency: 40 MHz focal length: 6 mmfocal length: 6 mm frame rate: 30 Hzframe rate: 30 Hz maximum field of view of 2D imaging: 10x10 mmmaximum field of view of 2D imaging: 10x10 mm spatial resolution: spatial resolution: ~60 µm (lateral) by ~30 µm (axial) ~60 µm (lateral) by ~30 µm (axial) Doppler pulse repetition frequency: up to 96 kHz, maximum Doppler pulse repetition frequency: up to 96 kHz, maximum
unaliased velocity of 120 cm/sunaliased velocity of 120 cm/s
Mice were anesthetized using 1.5% isofluraneMice were anesthetized using 1.5% isoflurane Total scan time: 30 min/mouseTotal scan time: 30 min/mouse Advantage:Advantage: Non-invasive, Progression Non-invasive, Progression
Ultrasound Scan ProcedureUltrasound Scan Procedure
Anesthetized: continuous 1.5% isoflurane
Total scan time: 30min/mice
Ultrasound Images of Aorta Plaques
Ascending Aorta Aorta Arch
LeftCommonCorotidartery
Brachio-Cephalicartery
RightCommonCorotidartery
UBM Quantification ProcedureUBM Quantification Procedure
330um
Atherosclerosis Progression inNaïve ApoE-/-
At baseline, Young: 1.5 month old; Old: 10.5 month old
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Percent Plaque Volume
Baseline 2-month4-month6-month9-month
Young NCYoung HFC
Old NCOld HFC
Left Common Carotid Artery
Young NCYoung HFCOld NCOld HFC
Longevity of the ApoELongevity of the ApoE-/--/- mice mice reduced by SS but not by CAPsreduced by SS but not by CAPs
No death occurred in ApoE-/- mice in CAPs exposed group.
CAPs Study in 2003
SS Enhanced Atherogenesis (UBM)
4 Month--Brachiocephalic Artery
Air ETS0
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Exposure
4 Month--Carotid Artery
Air ETS0
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Exposure
6 Month -- Brachiocephalic Artery
Air ETS0
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Exposure
6 Month--Carotid Artery
Air ETS0
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Exposure
Normal Chow
High Fat Chow
*
SS Enhanced Atherogenesis(within the same animals)
CAPs exposure enhanced atherogenesis in ApoE-/-
mice, with accompanied increases in lipid content
H&EH&E
OROORO
AirAir CAPsCAPs AirAir CAPsCAPs
Normal ChowNormal Chow High Fat ChowHigh Fat ChowSun et al, JAMA, 2005
Comparative Atherogenic Effects of Comparative Atherogenic Effects of CAPs vs SS (UBM)CAPs vs SS (UBM)
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Percentage Increase
Over Control
Normal Chow High Fat Chow
SSCAPs (85 µg/m3)CAPs (165µg/m3)
CAPs: Aortic Arch and Bachiocephalic Artery; SS: Carotid Artery
SummarySummary UBM is a useful imaging technique to follow lesion UBM is a useful imaging technique to follow lesion
progression in atherosclerotic mice.progression in atherosclerotic mice.
Carotid artery appears to be the optimal location to Carotid artery appears to be the optimal location to evaluate atherosclerosis progression.evaluate atherosclerosis progression.
SS, but not CAPs, reduced longevity in ApoESS, but not CAPs, reduced longevity in ApoE-/--/-..
CAPs and SS exposures promote similar magnitude of CAPs and SS exposures promote similar magnitude of change in animals susceptible to atherosclerosis, change in animals susceptible to atherosclerosis, regardless of the diet. regardless of the diet.
Exacerbation of atherosclerosis is evident after 4 months Exacerbation of atherosclerosis is evident after 4 months of low level SS exposure or after 3 months of CAPs of low level SS exposure or after 3 months of CAPs exposure.exposure.
Acknowledgements:
Qinghua Sun (Ohio State University) Sanjay Rajagopalan (Ohio State University) Chunli Quan Mianhua Zhong Ximei Jin Qiang Li
Thank You !!!Thank You !!!
Contact Information:Tel: (845) 731-3560
E-mail: LCC4@nyu.edu