Cardiovascular Inflammation Reduction Trial

Inclusion Criteria:

• Age ≥ 18 years at screening

• Documented past history of myocardial infarction OR past evidence of multivesselcoronary artery disease by angiography.

• To qualify on the basis of past history of myocardial infarction, the event mustbe documented either by hospital records or by evidence on current ECG of Q wavesin two contiguous leads and/or an imaging test demonstrating wall motionabnormality or scar. The patient must also have completed any planned coronaryrevascularization procedures associated with the qualifying event, and beclinically stable for at least 60 days prior to screening.

• To qualify on the basis of multivessel coronary disease, there must be pastangiographic evidence of atherosclerosis in at least 2 major epicardial vesselsdefined either as the presence of a stent, a coronary bypass graft, or anangiographic lesion of 60% or greater. Left main coronary artery disease that hasbeen revascularized with a stent or bypass graft will qualify as multivesseldisease, as will the presence of a 50% or greater isolated left main stenosis.The patient must also have completed any planned coronary revascularizationprocedures associated with the qualifying event, and be clinically stable for atleast 60 days prior to screening.

• History of type 2 diabetes or metabolic syndrome at time of study enrollment

• Willingness to participate as evidenced by signing the study informed consent

Exclusion Criteria:

• Prior history of chronic infectious disease, tuberculosis, or severe fungal disease;chronic hepatitis B or C infection; renal insufficiency; interstitial pneumonitis,bronchiectasis, or pulmonary fibrosis; known chronic pericardial effusion, pleuraleffusion, or ascites; chronic liver disease; myeloproliferative disorders in the past 5 years; non-basal cell malignancy or treated lymphoproliferative disease within thepast 5 years; known HIV positive; life expectancy of < 3 years;

• Chronic inflammatory condition such as lupus or rheumatoid arthritis, ulcerativecolitis or Crohn's disease

• White blood cell count < 3,500/ul, hematocrit < 32 percent, or platelet count < 75,000/ul

• Liver transaminase levels (AST or ALT) >upper limit of normal (ULN) or albumin < thelower limit of normal (LLN);

• Creatinine clearance < 40 ml/min as estimated with the Cockcroft-Gault equation;

• History of alcohol abuse or unwillingness to limit alcohol consumption to less than 4drinks per week

• Women of child bearing potential, even if they are currently using contraception, andwomen intending to breastfeed.

• Men who plan to father children during the study period or who are unwilling to useeffective forms of contraception.

• Requirement for use of drugs that alter folate metabolism (trimethoprim/sulfamethoxazol) or reduce tubular excretion (probenecid) or knownallergies to antibiotics making avoidance of trimethoprim impossible;

• Current indication for methotrexate therapy;

• Chronic use of oral steroid therapy or other immunosuppressive or biologic responsemodifiers. Eligible study participants will be encouraged to have up to datepneumococcal and influenza vaccinations as recommended based on their age andunderlying medical conditions.

• Chest X-ray evidence in the past 12 months of interstitial pneumonitis,bronchiectasis, or pulmonary fibrosis. For participants who do not have a chest X-rayin the prior 12 months, a chest X-ray will be obtained at baseline as part of thestudy protocol.

• New York Heart Association Class IV congestive heart failure.