Less Invasive Detection and Treatment of Very Early Coronary Artery Disease in Patients With Diabetes Mellitus

Type II Diabetes has become an epidemic in the United States. Cardiovascular disease is the
most common cause of death in this population and is two to four fold higher than the
general population. This increased risk is at least partially attributable to the high
prevalence of the metabolic syndrome with its multiple coronary heart disease risk factors
including central obesity, hypertension, glucose intolerance, chronic inflammation, and
dyslipidemia. However, recent trials have demonstrated that traditional risk factors alone
are not completely predictive of disease burden particularly early in the disease process
prior to the development of flow-limiting coronary stenoses. Diagnosis and prevention of
cardiovascular disease development has, thus, been elusive in this high risk population. It
is not entirely clear which factors, known or novel, contribute the most in very early
disease and which therapies may be most beneficial.

It has been suggested that microvascular dysfunction, a composite of endothelial
dysfunction, abnormal blood cell rheology, and abnormal blood viscosity, precedes the
development of overt coronary stenoses and contributes to increased cardiovascular risk very
early in disease development. Microvascular reactivity is affected by many aspects of the
metabolic syndrome. Commonly used tools may not be adequate to evaluate microvascular
function in the heart at baseline or in response to therapy. Myocardial contrast
echocardiography (MCE) and cardiac magnetic resonance imaging (CMR) provide noninvasive
technology capable of directly measuring microvascular function within the heart. Our
preliminary data with these modalities shows significantly reduced microvascular function in
diabetes in the absence of distinct coronary stenoses.

Prior to development of stenoses in the coronary arteries, plaque accumulates via positive
remodeling preserving the lumen. This can be detected invasively through the use of
intravascular ultrasound (IVUS). Coronary CT is a potential noninvasive modality able to
assess this early remodeling process, but it requires a substantial radiation dose and
iodinated contrast dye. In addition, CT requires calcification to have occurred within the
plaque, a finding believed to occur well into the life of the plaque. It is unclear how
early plaque development is related to microvascular function and if stabilization or
regression of plaque with available therapies improves microvascular function.

The overall hypothesis is that risk factors for the metabolic syndrome will predict invasive
findings on IVUS and noninvasive findings on CMR perfusion imaging. Secondary objectives
will include demonstrating the relative importance of individual risk factors early in
disease, demonstrating the positive effects of aggressive risk factor modification on
disease, demonstrating the relative importance of treatment of individual risk factors on
disease progression or stabilization, and that invasive findings on IVUS will predict
noninvasive findings with CMR. Such techniques may allow earlier noninvasive detection of
disease as well as tailor treatment early in the disease process making prevention more cost
effective.

The specific aims of this proposal are as follows:

1. To assess whether risk factors for coronary artery disease, both known and novel,
predict quantitative and qualitative plaque characteristics on IVUS and alterations in
myocardial blood flow on CMR. This will be accomplished by performing IVUS during
cardiac catheterization followed by CMR perfusion imaging in subjects at baseline. Risk
factors will be assessed by the following methods: history, physical exam, and
laboratory testing. As CMR has the ability to detect global dysfunction, as opposed to
current commonly used noninvasive techniques, the hypothesis is that risk factors for
cardiovascular disease will predict findings on IVUS as well as CMR.

2. To assess whether improvements in risk factors through aggressive treatment improve
microvascular function as measured by CMR and plaque stabilization and/or regression as
measured by IVUS. Subjects will be treated aggressively according to current American
College of Cardiology and American Diabetes Association recommendations in the Diabetes
Cardiovascular Clinic and will be reassessed at one year. The hypothesis is that
improvement in risk factors will predict improvements in measurements by IVUS and MRI.

3. To assess which risk factors are most predictive early in disease and to demonstrate
which risk factors, when treated, provide the most benefit. As the metabolic syndrome
is present for as many as 10 years prior to the development of diabetes, the hypothesis
is that risk factors associated directly with the metabolic syndrome will be most
predictive of disease and disease improvement.

4. To assess whether findings on CMR predict findings on IVUS, thus, providing a
noninvasive method of early disease detection. The hypothesis is that MRI will predict
findings on IVUS, providing a novel noninvasive mechanism for direct detection of early
coronary artery disease.

Inclusion Criteria:

- Type 2 Diabetes

- Metabolic Syndrome

- Not all risk factors at goal

- Willingness to attend frequent clinic visits

- No coronary stenosis greater than 50% found on catheterization

Exclusion Criteria:

- Type 1 diabetes

- GFR less than 60ml/min/1.73m2

- Females who are pregnant, lactating, not using reliable contraceptive method

- Known coronary stenosis greater than 50%

- Subjects in which stress testing would be contraindicated

- Prior heart transplantation

- Expected survival less than one year

- HIV infection

- Hepatorenal syndrome or history of liver transplant

- Contraindication to MRI

- Significant pulmonary hypertension