Less Invasive Detection and Treatment of Very Early Coronary Artery Disease in Patients With Diabetes Mellitus
Less Invasive Detection and Treatment of Very Early Coronary Artery Disease in Patients With Diabetes Mellitus
This protocol focuses on the development of a noninvasive method of early coronary artery
 disease detection in diabetes. The overall hypothesis is that risk factors for the metabolic
 syndrome will predict invasive findings on intravascular ultrasound (IVUS) and noninvasive
 findings on cardiac magnetic resonance (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.

 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.

 3. To assess which risk factors are most predictive early in disease and to demonstrate
 which risk factors, when treated, provide the most benefit.

 4. To assess whether findings on CMR predict findings on IVUS, thus, providing a
 noninvasive method of early disease detection.
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