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Coronary Artery Disease by jianghongl

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									        Coronary Artery Disease

             John Hakim, M.D.
             Cardiology Fellow
           West Virginia University
           Division of Cardiology


11/98                                 1
           Atherosclerosis
 One of the most common diseases in U.S.A.
 50% of U.S. Deaths are attributed to MI
 Atherosclerosis is the Principal cause of
  Death in Western World (Braunwald)
 Atherosclerosis begins in childhood and
  advances throughout life


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  Atherogenesis-Progression to an
        Advanced Lesion
   Accumulation of lipid, principally in the form of
    cholesterol esters and free cholesterol in the cell
    walls & surrounding tissue.
   Accumulation of smooth muscle cells, along with
    infiltration with macrophages and T-lymphocytes.
   formation by proliferation of smooth muscle cells
    + matrix + collagen + proteogylcans



11/98                                                     3
        Atherosclerosis-Risk factors

   Proven Risk factors for Atherosclerosis:
    Cigarette Smoking, Hypertension, Diabetes,
    Increased body mass index, Age, Male
    gender, the previous occurrence of CAD,
    and increased plasma Cholesterol
    (principally LDL and Triglycerides)



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        Atherosclerosis-Risk factors

   Presence of risk factors does not imply a
    causal relationship.

    Risk factor may be causative but is not
    necessarily causative.




11/98                                           5
Atherosclerosis- Hypothesized Risk factors
         “positive family history”
   Hyperhomocystineuria (ala/val polymorphism of 5,10,
    methylenetetra hydrofolate reductase[MTHFR])
   Elevated Fibrinogen level
   Increased Triglycerides
   Increased Lp(a) lipoprotein
   Increased C reactive protein
   Increased visceral fat
   Polymorphic PlA2 Allele platelet glycoprotein IIIa
   Spherocytosis


11/98                                                     6
        Atherosclerosis-Risk factors
              Hypothesized
   Lifestyle (illiteracy, crowded housing, sedentary)
   Urban living
   Nuclear family with more than 4 children
   Lower employment grade or chronic work stress
   Women married to Men with MI are at increased
    risk of CAD
   Women who have low birth weight full term baby
   African American race

11/98                                                    7
        Atherosclerosis-Risk factors
                  ETOH
 May be a U shaped curve for men
 Women who drink more than 28 drinks a
  week have an increased risk of CAD
 There may be a minor benefit to moderate
  beer or wine use
 It is hypothesized red wine has a favorable
  effect on platelets, definitive effect on CAD
  are inconclusive.
11/98                                             8
        Atherosclerosis-Protective
          Hypothesized factors
   Rural life
   Increased aerobic exercise
   mono and poly unsaturated fats
   Fish oils (omega 3 fatty acids)
   Iron and antioxidants
   Increased dietary fiber
   Increased Job control
   Increased educational level
   Estrogen replacement

11/98                                 9
         Atherogenesis Theories

1 “Reaction to Injury”-
    Endothelial injury exposes underlying cells
    to circulating factors.
    This stimulates smooth muscle cells to
    proliferate, deposit connective tissue matrix,
    and attracts monocytes to migrate into the
    area and accumulate lipid.

11/98                                           10
        Atherogenesis Theories

2 Monoclonal Hypothesis-
  Smooth muscle proliferation is a single cell
  dividing unchecked.




11/98                                            11
        Atherogenesis Theories

3 Lysosomal Theory-
  A relative deficiency of lysosomal cholesterol
  ester hydrolase may allow for accumulation of
  lipid within cells, subsequent cell death, and
  ultimately an increase in concentration of locally
  deposited lipid.
  This accounts for the minority of patients who do
  not have lipid droplets in the cytoplasms of foam
  cells.

11/98                                              12
        Atherosclerotic Progression

   Involves the immune process (T cells and
    macrophages)
   An inflammatory signal is presumably driving
    immunologic activity. ( From a local or distant
    site of inflammation.)
   Candidate antigens- modified LDL, Intracellular
    CMV, intracellular Chlamydia pneumonia



11/98                                                 13
        Chlamydia Pneumonia

 In 1988 a serologic association was reported
  between CAD and Antibodies to C.
  Pneumonia.
 12 studies have found evidence of it in
  plaques by PCR, Culture or special stains.
 Animal models in mouse and rabbit confirm
  development of atheroscerosis after URI
  from Chlamydia Pneumonia
11/98                                       14
            WIZARD TRIAL

   Title: A Randomized, Double Blind,
    Placebo Controlled Trial of Weekly
    Azithromycin on the Incidence of Coronary
    Artery Disease in Subjects with Evidence of
    Exposure to Chlamydia Pneumoniae




11/98                                         15
    WIZARD TRIAL: Hypothesis

   Chlamydia Pneumoniae is an infective
    agent that exacerbates the progression of
    coronary artery disease and leads to
    premature artery closure.




11/98                                           16
        WIZARD TRIAL:Patients

 This study is a Phase 3 study designed to
  assess the efficacy of Azithromycin in
  preventing the progression of clinical
  coronary artery disease in subjects who are
  6 weeks or more post MI.
 Subjects will be enrolled at multiple centers
  looking for those who have antibodies to C.
  Pneumoniae.
11/98                                         17
          WIZARD TRIAL:
           Randomization
 If a subject’s titers for C. Pneumoniae are
  elevated, the subject will be enrolled and
  may receive:
 6 Months of 600mg azithromycin weekly
 6 Months placebo




11/98                                           18
        WIZARD TRIAL: Blinding

 All subjects and staff will be blinded to the
  three treatment arms.
 Subjects will be seen at 3 months intervals
  to assess for possible side effects.
 Safety labs will be drawn pre and post
  study.
 Extra blood will be banked.


11/98                                             19
        Subject Selection Criteria
                Inclusion
   Out patients > 18 years, males & females
   Females must be without childbearing potential
   Must have had MI > 6 weeks ago documented by
    EKG or one elevated CK-MB
   Must have IgG titer to C. pneumonia > 1:16
   Must be expected to survive at least 6 months
   Must provide informed consent


11/98                                                20
        Subject Selection Criteria
                Exclusion
   Subjects who expected to require revascularization within
    90 days (CABG/PTCA)
   Hypersensitivity to macrolides or azithromycin
   condition doesn't allow them to complete trial
   Underlying condition requires them to take abx in study
    period
   CABG or PTCA in last 6 months
   Systemic Abx in last 6 months
   in another investigational trial


11/98                                                           21
          WIZARD TRIAL
              Risks
 Side effects of Azithromycin (0.7%
  discontinue therapy due to adverse effects)
 Most common problems GI upset (N/D)
 Vomiting and Vaginitis at higher doses
 High doses associated with hearing loss
 Discomfort from blood draws
 Rare allergic symptoms

11/98                                           22
           WIZARD TRIAL
        Financial Considerations
   This study is being supported by Pfizer
    Pharmacuticals




11/98                                         23

								
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