Coronary Flow Reserve to Assess Cardiovascular Inflammation (CIRT-CFR)

Randomization and double-blind study treatment period to either placebo or LDM (1:1) of
willing and eligible patients will occur at the end of the open label run-in phase per the
parent CIRT protocol, and will be stratified by time since the qualifying event (< 6 or ≥ 6
months from the date of MI or most recent angiogram), type of event (MI or multivessel CAD),
presence of either type 2 DM or metabolic syndrome, and site, which will ensure balance in
the proposed study. Patients willing to participate in CIRT will be asked to enroll into the
sub-study and may sign the CIRT-CFR informed consent at any point between signing the parent
CIRT informed consent and completing the parent CIRT randomization visit (Visit 4). After
giving informed consent for the ancillary CIRT-CFR, patients will undergo the baseline PET
scan along with echocardiography at any point between the parent CIRT post run-in visit
(Visit 3) and up to 4 weeks after randomization (Visit 4).

Imaging will be performed at the 3 imaging centers (BWH, OHI, and UAB). To minimize
participant and site burden, only a baseline and single follow-up imaging time point will be
pursued. Imaging tests (PET and echo) will be scheduled on the same day for patient
convenience if possible, and no more than one week apart. "Baseline" study visit imaging will
follow the open label run-in period of the parent trial to enhance long-term compliance and
eliminate risk of radiation exposure for any individuals with immediate intolerance to the
LDM study protocol. The imaging tests proposed are non-invasive, routinely performed, and
historically well tolerated by patients.

Inclusion Criteria:

1. Age ≥18 years at screening;

2. Documented past history of MI OR past evidence of multivessel CAD by angiography,
completed any planned coronary revascularization associated with a qualifying event at
least 60 days prior to enrollment, and clinically stable for ≥60 days prior to
enrollment; qualifying prior MI must be documented either by hospital records,
evidence on current ECG of Q waves in 2 contiguous leads, and/or an imaging test
demonstrating wall motion abnormality or scar; qualifying evidence of multivessel CAD
by angiography must be documented by CAD in at least two major epicardial vessels
defined either as the presence of a stent, a coronary artery bypass graft, or an
angiographic lesion of 60% or greater (left main CAD that has been revascularized with
a stent or bypass graft will qualify as multivessel disease, as will the presence of a
50% or greater isolated left main stenosis);

3. History of type 2 DM or metabolic syndrome (meeting 2004 AHA/NHLBI definition*) at
time of study enrollment; *includes any 3 of the following 5 diagnostic criteria:
waist circumference ≥ 102 cm in men or 88 cm in women; triglycerides ≥ 150 mg/dl or on
drug treatment for elevated triglycerides; high-density lipoprotein cholesterol
(HDL-C)< 40 mg/dL in men or < 50 mg/dL in women or on drug treatment for reduced
HDL-C; systolic blood pressure ≥ 130 mm Hg or diastolic blood pressure ≥ 85 mm Hg or
on drug treatment for hypertension; and elevated fasting glucose ≥ 100 mg/dL or on
drug treatment for elevated glucose.

4. Willingness to participate as evidenced by signing the CIRT and CIRT-CFR informed
consent.

Exclusion criteria:

1. 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, pleural
effusion, or ascites; chronic liver disease; myeloproliferative disorders in the past
5 years; non-basal cell malignancy or treated lymphoproliferative disease within the
past 5 years; known HIV positive; life expectancy of <3 years;

2. Chronic inflammatory condition such as lupus or rheumatoid arthritis, ulcerative
colitis or Crohn's disease

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

4. Liver transaminase levels (AST or ALT) >upper limit of normal (ULN) or albumin < the
lower limit of normal (LLN);

5. Creatinine clearance < 40 ml/min as estimated with the Cockroft-Gault equation;

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

7. Women of child bearing potential, even if they are currently using contraception, and
women intending to breastfeed.

8. Men who plan to father children during the study period or who are unwilling to use
effective forms of contraception.

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

10. Current indication for methotrexate therapy;

11. Chronic use of oral steroid therapy or other immunosuppressive or biologic response
modifiers (see Exclusionary Medication List in Manual of Operations). Eligible study
participants will be encouraged to have up to date pneumococcal and influenza
vaccinations as recommended based on their age and underlying medical conditions.

12. 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-ray
in the prior 12 months, a chest X-ray will be obtained at baseline as part of the
study protocol.

13. New York Heart Association Class IV congestive heart failure.