Department of Internal Medicine
Cardiovascular Division
Research Opportunities

Noninvasive Imaging of Myocardial Perfusion, Viability and Molecular Targets - Dr. George Beller

The major thrust of this laboratory is the investigation of the ability of various radionuclide agents to assess regional myocardial blood flow and myocardial viability. Several animal models of experimental myocardial ischemia and infarction are employed to study the effects of sustained or partial coronary occlusion and reperfusion on radioisotope tracer kinetics. A new microSPECT camera is used for SPECT imaging in mice and rats. There is a particular interest in this laboratory to develop approaches for distinguishing viable myocardium from myocardial necrosis utilizing radionuclide imaging agents. An isolated, perfused rat heart model is also being used for quantifying tracer kinetics of new imaging agents. Work is also being performed to evaluate the effectiveness of new adenosine A2A agonists for their use as vasodilator stress agents. Additionally, our laboratory has recently begun investigating the injurious role that inflammation plays following coronary reperfusion in animal models of myocardial stunning or infarction. Highly potent and selective adenosine receptor agonists and antagonists are being evaluated for their cardioprotective anti-inflammatory properties in these models.

Parallel clinical investigative studies are undertaken in this multidisciplinary research effort to develop and evaluate radionuclide-imaging techniques to quantitate myocardial ischemia and infarction and identify "hibernating" myocardium. In recent years, efforts have been directed at developing better tomographic techniques to identify zones of myocardial jeopardy with technetium-99m sestamibi administration. 
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Heart Failure and Transplant Programs- Dr. James Bergin

The heart failure and transplant programs are actively involved in several research projects. We are involved with phase III studies of a number of medications and device applications. We have also performed several studies involving hemodynamic studies in both the coronary care unit and cardiac catheterization laboratories.

We have an active ventricular assist device program utilizing the HeartMate Vented Electric device, and can assist the right ventricle as needed with the Abiomed system. We also have ECMO capabilities.

The transplant program has been active clinically in the areas of heart size, the impact of brain death on ventricular function, and the use of non-traditional donors. back to top

Cardiac Magnetic Resonance: From Mouse to Man - Dr. Christopher Kramer

The main focus of our laboratory is the further development of cardiac magnetic resonance imaging (CMR) for research and clinical applications. The goal is to make CMR the one-stop shop for imaging myocardial function perfusion, viability, coronary lumen and blood flow, and atherosclerotic plaque in animal models and man. Dedicated research clinical and small animal MR systems are available for use. Collaborating MR physicists in the Department of Radiology include Fred Epstein PhD (fast imaging) and Stuart Berr PhD (small animal imaging), and Craig Meyer PhD (coronary imaging) in the Department of Biomededical Engineering.

Ongoing animal projects include 1) the application of CMR techniques to evaluate the cardiac and vascular phenotypes of genetic models of cardiac and vascular disease in the mouse, including murine models of myocardial infarction; 2) the role of the beta adrenergic and angiotensin II receptor systems in the progression of left ventricular remodeling after MI in an ovine model; and 3) the development of intravascular MRI with catheter-based imaging.

Ongoing clinical projects include 1) the combination of MR techniques of delayed enhancement and dobutamine-induced contractile reserve to predict recovery of function after revascularization 2) the development of real time cine and tagged MR dobutamine stress testing; 3) atherosclerotic plaque imaging in abdominal aortic aneurysms and carotid arteries; 4) the development of faster MR perfusion imaging; 5) the differentiation of nonischemic and ischemic cardiomyopathy using MR techniques; 6) assessing the success of thrombolytic therapy for acute MI by MRI and the need for subsequent angiography and; 7) atherosclerotic coronary artery plaque imaging comparing intravascular ultrasound to multi-detector CT scanning and MRI.
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Protecting Tissues from Ischemic Injury by Targeting Adenosine Receptors - Dr. Joel Linden

Receptors for the purine nucleoside adenosine have been found on all mammalian tissues. Activation of these receptors regulates cardiac and vascular functions. Recently we have been interested in investigating the effects of adenosine receptors on inflammatory cells. We have found that activation of A2A adenosine receptors is profoundly inhibitory to mast cells, neutrophils, platelets and macrophages. Activation of these receptors following ischemia can reduce damage that occurs in heart, lung and kidney during reperfusion following ischemia. Activation of another adenosine receptor subtype, A2B, has a pro-inflammatory effect to facilitate allergen and ischemia-induced mast cell degranulation which results in the release of histamine and other allergic mediators. Blockage of A2B receptors reduces allergic and inflammatory responses.

We are characterizing adenosine receptors through a multi-faceted approach involving the study of wild-type and recombinant adenosine receptors by radioligand binding and various cellular assays. We are using reconstitution techniques to investigate the interactions of receptors with Guanine nucleotide binding proteins (G proteins). We have developed procedures to isolate human mast cells, monocytes and neutrophils to investigate their regulation by adenosine receptors. In collaboration with Drs. George Beller, Mark Okusa and Irving Kron, respectively, we are evaluating the effects of activating A2A receptors to reduce tissue damage in heart, kidney and lung. We are studying the effects on mice of either tissue-specific or whole animal receptor knock outs. We are developing and evaluating new drug candidates that may be useful to treat reperfusion injury, asthma and allergy.
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Molecular Mechanisms of Vascular Lesion Formation - Dr. Coleen McNamara

A major interest of my laboratory is to understand the molecular mechanisms involved in modulating the phenotype and growth of smooth muscle cells (SMC) in response to vascular injury. We have determined that the helix-loop-helix (HLH) class of transcription factors regulate p21 expression, and growth in vascular SMC and are expressed both in animal models of vascular lesion formation and in human disease. Additionally, our data implicate the HLH factors as important mediators of the accelerated SMC growth in diabetic states. Our current studies focus on further characterization of the role of these factors in regulating vascular lesion formation as well as developing gene delivery strategies for HLH-mediated inhibition of the vascular response to injury in both diabetic and non-diabetic states. We utilize the rat and mouse carotid injury models and molecular and cellular biology techniques such as mutagenesis, transfection of DNA into vascular cells, proliferation assays, migration assays, apoptosis assays, FACS, Northern analysis, Western analysis, in situ hybridization, immunohistochemistry, cloning, reporter assays, and the two-hybrid system.
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The Molecular Basis of Cardiac Excitability - Dr. J. Randall Moorman

The focus is on regulation of cardiac rhythm and of molecular mechanisms of membrane excitability. Three sets of projects are underway. First, we are investigating the physiological role of phospholemman, a major membrane substrate for protein kinases in heart and other excitable tissue. We have found that it forms ion channels selective for the osmolyte taurine, and that it plays a role in the regulation of cell volume. Second, we are studying the modulation of cardiac, brain, and skeletal muscle Na channels by protein kinases, particularly the kinase that is abnormal in the human illness myotonic muscular dystrophy. Third, we are testing the hypothesis that monitoring of heart rate variability leads to the early diagnosis of infectious illnesses in newborn infants. The techniques in the laboratory include molecular cloning, patch clamping of cultured cells and cells from transgenic mouse models, novel measurements of cell volume, and mathematical analysis of time series. 

Regulation of Smooth Muscle Contraction - Dr. Christopher Rembold

Christopher M. Rembold's laboratory is interested in the mechanisms regulating in contraction and relaxation of intact arterial smooth muscle. Currently, we are mainly interested in the mechanism involved in nitroglycerin induced arterial relaxation. Nitroglycerin is metabolized to nitric oxide which activates G cyclase and increases [cGMP]. We found that the increase in [cGMP] induces phosphorylation of HSP20. We have HSP20 cloned and are studying its effects on skinned smooth muscle and isolated thin filaments. A second area of interest is the role of the Ca2+ store in regulating contraction. We measure [Ca2+] in various cellular compartments (e.g. sarcoplasmic reticulum, nuclear, and cytosolic) with genetically targeted apoaequorin that is delivered by recombinant adenoviruses. back to top

Adenosine-induced Mechanisms of Angiogenesis, Cellular Proliferation, and Tissue Protection in the Cardiovascular System- Dr. Amy Tucker

  Adenosine modulates a number of important functions in cardiovascular physiology. In addition to its well-known antiarrhythmic properties, adenosine is also a mediator in coronary vasodilation, ischemic preconditioning, angiogenesis, and cellular proliferation. My laboratory studies the pharmacologic and signal transduction properties of adenosine receptors using combined pharmacologic and molecular biology techniques including chimeric receptor DNA construction, expression in mammalian tissue culture cells, radioligand binding assays, and cAMP second messenger assays.

We also study the properties of compounds that act as enhancers of adenosine actions at the A1 receptor. This receptor, in addition to having antiarrhythmic properties, is probably involved in protection of brain and heart tissues during ischemia. Drugs that would augment the tissue-sparing effects of adenosine during ischemia could be very important therapeutically. We use a chicken chorioallantoic membrane model for investigations into the pharmacology and cellular mechanisms of adenosine-induced angiogenesis and are using yeast two-hybrid cloning and tissue culture techniques to study the role of adenosine in cellular proliferation. My laboratory is also using sophisticated genetic techniques to engineer a knockout mouse involving the deletion of a small channel, the phosphorylation of which is modulated by adenosine. The channel is postulated to be important in cell volume regulation, cellular proliferation, and cardiac contractility. back to top


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