Degree(s): MS, MD
Graduate School: University of Virginia; Medical University of South Carolina
Primary Appointment: Associate Professor, Medicine, Cardiovascular Medicine
Diabetic cardiovascular disease - early diagnosis and prevention; Women's heart disease.
Email Address: email@example.com
Project 1: Early Noninvasive Detection of Myocardial Microvascualr Dysfunction in Diabetes Brief Description: Type 2 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. Microvascular reactivity can be measured invasively at the time of cardiac catheterization by measuring myocardial blood flow and calculating the coronary flow reserve (CFR). Commonly used noninvasive tools may not be adequate to evaluate microvascular function in the heart at baseline or in response to therapy. The American Diabetes Association has recently released a consensus statement stating that better approaches are needed to screen for and identify coronary artery disease in patients with diabetes. 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 significant 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 CMR will predict invasive findings on CFR and IVUS providing a noninvasive mechanism to diagnose microvascular dysfunciton and thus early coronary disease. Secondary objectives will include demonstrating that CMR can be used to follow microvascular function noninvasively over time and that risk factors for the metabolic syndrome will predict disease burden using invasive and noninvasive meaasurements contrary to recent literature using standard noninvasive diagnostic methods. 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 CMR will predict invasive findings with CFR and IVUS. The hypothesis is that MRI will predict findings on IVUS and CFR, providing a novel noninvasive mechanism for direct detection of early coronary artery disease. 2.) To assess whether changes in microvascular flow over time, and thus early coronary disease, can be followed noninvasively by CMR. The hypothesis is that changes in microvascular function measured noninvasively with CMR will predict invasive measurements using CFR and that improvements in microvascular function will predict plaque stabilization and/or regression as measured by IVUS. 3.) 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 and CFR. 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 disease burden on IVUS as well as CMR and CFR and that improvements in risk factors will predict improvements on invasive and noninvasive measurements. Project 2: Mechanism of Acute Coronary Syndromes in Premenopausal Women Brief Description: The prevalence of cardiovascular disease and myocardial infarction is higher in men compared to women for every age group. Despite this, women have a 2-fold increase in cardiovascular mortality compared to men. This increase in mortality cannot be explained by age, comorbidities, therapy, or revascularization. Further, women are more likely to have a larger symptom burden for a given amount of angiographically detectable disease ( 1) ( 2) ( 3). Many women without angiographically detectable disease have demonstrable ischemia and an increase in adverse cardiovascular events. It has been suggested that this may be due to microvascular dysfunction, a composite of endothelial dysfunction, abnormal blood cell rheology, and abnormal blood cell viscosity. It has been demonstrated in women by intravascular ultrasound (IVUS) that large amounts of plaque can be stored in the artery wall prior to overt stenosis formation and that this plaque may contribute to dysfunction in the microvasculature measured invasively during cardiac catheterization. It has been suggested that this process may be more active in cardiovascular disease in women, particularly in the presence of the metabolic syndrome ( 4). It has further been suggested that women often develop acute coronary syndromes in mostly fibrous areas via plaque erosion as opposed to plaque rupture in lipid rich areas. This appears to be particularly true in premenopausal women. It is not completely understand what differences exist between men and women in terms of plaque composition and intimal changes during acute coronary syndromes that drive the increased morbidity and mortality in women. In order to initiate proper therapy in women, a better understanding is needed of the pathophysiology of coronary artery disease in the female gender. Technology now exists that will allow both visualization of the artery composition and the luminal surface. Intravascular ultrasound (IVUS-VH) with virtual histology capabilities allows in vivo characterization of plaque type. Optical coherence tomography (OCT) further allows a more detailed view of the luminal surface of the artery and can identify areas of plaque erosion and white thrombus. Together, these tools represent a powerful method whereby to fully examine differences in plaque characteristics between men and women, potentially redirecting therapy. Further, populations in studies of drug therapy and risk factor modification in the arena of cardiovascular disease have been predominantly male. Further study is needed to determine if current therapy for cardiovascular risk factor reduction is as affective in women as compared to men at the level of the plaque. The overall hypothesis of this study is that plaque morphology in acute coronary syndromes will differ significantly between premenopausal women and age-matched men and that measurement of traditional cardiovascular risk factors will be less predictive of findings on IVUS and OCT in premenopausal women compared to men. Specific Aims: 1. To demonstrate that IVUS and OCT, used together, can successfully differentiate plaque characteristics in men and premenopausal women with acute coronary syndromes. 2. To assess whether traditional risk factors predict quantitative and qualitative findings on IVUS and OCT in men and women. 3. To investigate if novel risk factors may be linked to acute coronary syndromes in women.
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