046 respiratory infection of apoe ko mice and plaque inflammation
TRANSCRIPT
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Respiratory Infection of Apo E KO Mice Causes Excessive
Plaque Inflammation
Implication for triggering effect of flu in human heart attack
Adeeba Akhtar MD, Silvio Litovsky, MD, Philip Wyde PhD, Mohammad Madjid MD, Ward Casscells MD, James
Willerson MD, Morteza Naghavi MD.
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Background
• The role of infection in atherosclerosis has been known for years.
• A number of pathogens such as C. pneumonia, HSV, CMV have been reported to be present in the plaque and moreover related to CHD
• Other chronic infections such as H. pylori, and dental infection were also found to increase likelihood of chronic coronary heart disease.
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Background
• However, acute effect of infection in triggering coronary events has not received as much attention.
• A number of retrospective epidemiological studies have shown the relationship between acute upper respiratory infection and myocardial infarction.
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Background
• The role of inflammation and inflammatory cytokines in the development of vulnerable plaque and plaque rupture is now well established.
• Increased circulating cytokines was shown to accelerate plaque formation in Apo E mice.
• Influenza infection can increase thrombogenecity of blood by increasing platelet aggregation.
• We have previously shown in a case-control study that flu vaccination is associated with reduced recurrence of MI.
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Background
Therefore we have hypothesized :• 1) Acute influenza infection of old Apo E
deficient mice may cause acute coronary event and heart attack.
• 2) Acute influenza infection can increase plaque inflammation and macrophage infiltration, with or without rupture/erosion.
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Study Design42 ApoE Mice
Controls infected with Influenza virus Hong Kong P9 LD50
9 Direct infection 24 Intranasal inoculation
933
6 sacrificed 3died
11sacrificed 13died
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Procedure:
• We measured the baseline weight , heart rate, pulse oximetry of all the infected mice and measured these parameters again before sacrificing.
• This was a short term (15 days) study and the mice were sacrificed at 3, 5, 10, 15 days.
• After sacrifice we took the heart and aorta in formalin and cut 5 sections for each aorta and one mid-transverse ventricular section of the heart.
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Examinations
• Weight (substitute for Temp)• Oxygen sat.• Pulse• Lung virus titration.• rtPCR for influenza virus.• CBC and Hb.• Blood smear.• Multiple aorta and heart specimens for pathology
examinations, H&E, Movat, CD68, TUNEL, actin, CD3 staining.
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General Findings
• - As expected based on LD 50%, old mice were prompted to die mainly due to overwhelming lung infection . But we sacrificed most of them at their maximum load of infection.
• Significant weight loss occurred in all infected mice but not in control mice.
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Specific Findings
• Hot and ground-breaking !!!
…
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Control mice 1(power10)
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Control mice 1(Power40)
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Control mice 2(power 40)
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Control mice 3(power 10)
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Control mice 3(power40)
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Infected Mice 1(Intra nasal group)Power 10
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Power 40
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Power100
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Infected mice2( Intranasal group) power10
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Power 40
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Power100
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Infected mice3(Intranasal group) power4
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power10
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Power40
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power100
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Infected mice4(Intranasal Group) Power 10
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Power 40
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Power100
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Infected Mice5 (Intranasalgroup) power 4
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Power10
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Power40
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Infected Mice6 (Intranasal group)power4
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Power10
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Power40a
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Power40b
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Power100
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Infected Mice 7( Direct group) Power10
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Power40
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Infected Mice8 (Intranasal Group) Power 10
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power40
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Power100
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Infected Mice 1(Intranasal Group) Power10
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Power40
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InfectedMice2(Intranasal GroupPower4)
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Power10
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Power40
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Infected mice 6(Intransal Group)Power4
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Power 10
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Power 40
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Actin staining 1power40
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Actin staining2 power100
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CD3staining Power 40
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CD3staining power 100
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KP-1 staining (Power 40)
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Conclusion:
• One third of the infected mice developed this inflammatory infiltrate associated with clusters of platelets and occasionally fibrin overlying the infiltrate.
• The infiltrate is polymorphic (macrophages, smooth muscle cells, T-lymphocytes). Next set of stainings will be done on frozen tissue to improve antigenicity.
• Upregulation of inflammatory and procoagulant cytokines and receptors will be investigated.
• Longer-term studies will investigate the possible acceleration of the plaque burden in infected ApoE mice compared to non-infected mice.
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Adeeba !
Mitra !
Mort !
Khawar !
Tania !
Birendra !Mohammad !
Silvio !
Moein !
Sadaf !Reza !