Coronary Artery Disease

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Coronary Artery Disease

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

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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

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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.

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Atherosclerosis- Hypothesized Risk factors
positive family history

• Hyperhomocystineuria (ala/val polymorphism of
  5,10, methylenetetra hydrofolate
  reductaseMTHFR)
• Elevated Fibrinogen level
• Increased Triglycerides
• Increased Lp(a) lipoprotein
• Increased C reactive protein
• Increased visceral fat
• Polymorphic PlA2 Allele platelet glycoprotein
  IIIa
• Spherocytosis

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Atherosclerosis-Risk factorsHypothesized

• 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

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Atherosclerosis-Risk factorsETOH

• 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.

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Atherosclerosis-ProtectiveHypothesized 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

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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.

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Atherogenesis Theories

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

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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.

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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

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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

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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

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WIZARD TRIAL Hypothesis

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

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WIZARD TRIALPatients

• 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.

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WIZARD TRIAL Randomization

• If a subjects titers for C. Pneumoniae are
  elevated, the subject will be enrolled and may
  receive
• 6 Months of 600mg azithromycin weekly
• 6 Months placebo

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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.

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Subject Selection CriteriaInclusion

• Out patients gt 18 years, males females
• Females must be without childbearing potential
• Must have had MI gt 6 weeks ago documented by EKG
  or one elevated CK-MB
• Must have IgG titer to C. pneumonia gt 116
• Must be expected to survive at least 6 months
• Must provide informed consent

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Subject Selection CriteriaExclusion

• 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

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WIZARD TRIALRisks

• 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

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WIZARD TRIALFinancial Considerations

• This study is being supported by Pfizer
  Pharmacuticals