Development and validation of techniques to measure myocardial efficiency by MRI and PET: Over the past few years we have devoted a significant effort to developing methodology that would permit measurements of both global and regional myocardial efficiency by combining MRI and PET techniques. This research was performed in close collaboration with the laboratory of Dr. Michael K. Pasque of the Division of Cardiothoracic Surgery in the Department of Surgery. Myocardial work was determined from the relationship between myocardial wall stress and strain. Circumferential wall stress was calculated using finite element analysis of cine MR images and left ventricular loads were determined from externally recorded calibrated carotid pressure tracings. Circumferential myocardial strain was determined from MRI tagged images. Myocardial strain was determined from the deformation of spines that were generated on the tagged images using computer methodology developed in Dr. Pasque’s laboratory. The measurements of myocardial work were validated in humans in the cardiac catheterization laboratory under a variety of loading conditions. Myocardial oxygen consumption was determined by PET using 11C-acetate. Knowledge of work and MVO2 permits measurements of efficiency. We have demonstrated that accurate measurements of regional myocardial efficiency can be obtained using this approach and have now begun to apply this technique in the study of both normal and abnormal cardiac conditions (see below). Validation of 1-11C-glucose as a tracer of myocardial glucose metabolism: Over the past two years we have developed a method to quantify myocardial glucose utilization by PET and glucose radiolabeled with 11C in the one carbon position. Unlike 18F-fluorodeoxyglucose, this tracer potentially permits the assessment of various aspects of myocardial glucose metabolism including glucose uptake, glycogen formation, further glucose metabolism via glycolytic and oxidative pathways. Moreover, rates of overall glucose utilization can be determined without the need for a lumped constant as is required when using 18F-fluorodeoxyglucose. We have demonstrated that the rates of myocardial glucose utilization determined from the myocardial kinetics of 11C-glucose measured by PET and described with a four-compartmental model correlate closely with the rates of myocardial glucose use measured directly in a well controlled canine model. In conjunction with the laboratory of Dr. Michael J. Welch, we have also developed techniques to measure the metabolites of 11C-glucose including 11CO2 and 11C-lactate, which is necessary to perform compartmental modeling. Furthermore, we have shown that the measurements of myocardial glucose utilization obtained with this tracer are more accurate than those obtained with 18F-flurodeoxyglucose. The decreased accuracy in measured myocardial utilization with 18F-flurodeoxyglucose appears to be related to a marked variability in the lump constant. In addition, we have also demonstrated that dephosphorylation of 18F-flurodeoxyglucose-6-phosphate occurs in canine myocardium under a variety of conditions. We are now using this tracer in a variety of studies (see below). Visualization of coronary arteries by cardiac MRI: Over the past few years we have been actively involved in evaluating techniques designed to noninvasively image the coronary arteries by cardiac MRI. Most recently these efforts have focused on the use of novel intravascular contrast agents with studies being performed in both experimental models of coronary artery stenoses and in humans with coronary artery disease. We have demonstrated that use of these intravascular contrast agents when performed in conjunction with 3-dimensional coronary MRI using navigator approaches to correct for respiratory motion, resolution significant improvement in contrast and signal to noise. Study of Normal and Abnormal Cardiac States: Measurement of myocardial energy transduction in ischemic myocardium: In patients with ischemic cardiomyopathy it appears that myocardial energy transduction is impaired as myocardial oxygen consumption is frequently within normal limits yet mechanical function is reduced. Using the techniques described above, we have measured the myocardial stress-strain relationship as it relates to myocardial oxygen consumption in patients with ischemic cardiomyopathy. We have demonstrated that there is a shift in the stress-strain relation in patients with ischemic cardiomyopathy (higher stress per given level of strain) compared to normal volunteers. Moreover, we have shown that this alteration of the stress-strain relationship is most pronounced during the administration of dobutamine. More recently, we have demonstrated that the shift in the stress-strain relationship appears to be secondary to impairment in myocardial perfusion reserve. Future studies will be directed towards delineating the impact of therapies designed to improve the balance between myocardial oxygen supply and demand which should hopefully have a salutary effect on the stress-strain relationship and myocardial energy transduction. Evaluation of the diabetic heart: There are numerous cardiac manifestations of diabetes mellitus including impairment of myocardial perfusion, alterations in intermediary metabolism with a greater reliance on fatty acid utilization, and impairment in mechanical function, to name a few. Recently, we have begun to investigate the interrelationship between myocardial perfusion metabolism and function in type 1 diabetics particularly as they related to changes in plasma levels of insulin, glucose, and fatty acids. In the past year we have begun to study the impact of hypoinsulinemia and hyperglycemia on myocardial perfusion and perfusion reserve as they relate to endothelial-independent mechanisms. Moreover, we are studying how the impairment in myocardial perfusion effects mechanical function as measured by MRI. Over the next few years we will be determining how alterations in plasma, insulin, fatty acids, glucose levels impact on myocardial substrate usage and how this relates to myocardial mechanical function. Measurements of myocardial metabolism are being performed by PET using 11C-acetate (to measure MVO2), 11C-palmatate (to measure myocardial fatty acid utilization) and 11C-glucose (to measure myocardial glucose utilization). Measurements are obtained at rest and during dobutamine administration. The information obtained from these studies should provide a basis for a more targeted studies designed to delineate the mechanisms responsible for the impairment in perfusion and metabolism in patients with type 1 diabetes. Moreover, we believe that demonstrating that intermediary metabolism can be modified by specific interventions with subsequent salutary effects of myocardial function will provide a therapeutic option designed to improve ventricular function or at least slow the progression of left ventricular dysfunction in patients with this disease. Evaluation of aging on the human heart: It is well known that with age there is a decline in mechanical function of the heart. However, the mechanisms responsible for this decline of function are not well understood. Recently, we have begun to delve into the impact of aging on myocardial perfusion, intermediary metabolism and mechanical function. We believe that impairment of the fatty acid oxidation that occurs with age (as observed in experimental animals) results in an increased reliance on glucose as a myocardial energy fuel and has detrimental effects on myocardial mechanical function. We initiated a set of experiments where we measure myocardial perfusion by PET with 15O-water under resting conditions and during vasodilatory stress using both intravenous adenosine (to assess endothelial-independent mechanisms) and during cold-pressor testing (to assess endothelial-dependent mechanisms). Myocardial intermediary metabolism is being assessed by PET using 11C-acetate, 11C-palmatate, and 11C-glucose at rest and during the administration of dobutamine. Myocardial mechanical function is being assessed by MRI at rest and during dobutamine. These measurements are being related to exercise capacity, maximal oxygen consumption and changes in cardiac output with exercise. Measurements are being compared between young (20-35 years) and moderately older (60-72 years) individuals. In the older subjects, measurements are being obtained both before and after one year of endurance exercise training as it is well known that myocardial mechanical function improves following exercise training. Studies in experimental animals suggest that the improvement in mechanical function with training may be related to changes in myocardial metabolism. We believe that the results of these studies will further our understanding of the effects of aging on myocardial perfusion and intermediary metabolism as it relates to myocardial mechanical function. Furthermore, demonstration that myocardial perfusion and metabolism can be modified by endurance exercise training with subsequent salutary effects on myocardial function will provide a therapeutic strategy designed to improve left ventricular function or at least slow the progression of left ventricular dysfunction that occurs with aging. Assessment of the effects of ACAT inhibition on myocardial perfusion: There is a new class of anit-hyperlipidemia agents called the ACAT inhibitors which appear to have salutary effects on myocardial vasodilatory capacity. We have recently become part of a multicenter trial sponsored by Parke-Davis entitled "Relative and Absolute Myocardial Perfusion Changes as Measured by Positron Emission of PET to assess the effects of ACAT inhibition: a double-blind randomized multicenter trial (RAMPART). In this study myocardial perfusion as measured by PET and 13N-ammonia both at rest and during the intravenous administration of adenosine are obtained both before and while patients with coronary artery disease are on this novel antihypolipdemic agent. The purpose of this study is to determine the extent to which this agent has salutary effects on myocardial vasodilatory capacity separate from its hypolipidemic effects. Studies of the effects of estrogen on myocardial perfusion: We have recently begun to study the effects of estrogen myocardial perfusion and perfusion reserve. Studies are underway where myocardial perfusion and perfusion reserve are being measured in both pre and postmenopausal women. Measurements of perfusion are being obtained at rest, during intravenous adenosine and during cold pressor testing. To further delineate the role of nitric oxide synthase on estrogen mediated effects on myocardial perfusion, measurements of myocardial perfusion at rest and cold-pressor testing are also being obtained during the intravenous administration of L-arginine. As a surrogate for changes in coronary artery diameter, brachial artery diameters are being measured by ultrasound both at rest and following hyperemia. Once these studies are complete we will determine the time course of improvement in myocardial perfusion reserve following estrogen replacement therapy. We will also assess the differential responses in myocardial perfusion to estrogen replacement alone compared with either estrogen-progesterone combinations or with the specific estrogen receptor modulator raloxifine. Collaborative Projects: Assessment of left ventricular hypertrophy in humans: It is well established that there are extensive abnormalities in myocardial perfusion, intermediary metabolism, and mechanical function in patients with left ventricular hypertrophy. We are working in close collaboration with Dr. Victor G. Davila-Roman, in the Cardiovascular Division, of the Department of Internal Medicine to determine the impact of left ventricular hypertrophy due to hypertensive heart disease on myocardial perfusion and perfusion reserve, intermediary metabolism, and mechanical function. The experiments being performed are nearly identical to those that were described in the study of the effects of aging on the heart. The difference is that the measurements are being performed both before and after the inititation of ACE inhibition. The rationale behind these studies is that with left hypertrophy there is a switch in myocardial metabolism to more of the fetal type pattern with a greater reliance on glucose utilization. This switch to a more fetal phenotype may well portend the transition from left ventricular hypertrophy to left ventricular failure commonly observed in these patients. These studies will help sort out the role of changes in metabolism on the continued impairment in mechanical function in these patients and the impact of ACE inhibition on slowing or reversing these changes. Evaluation of novel hypoxic markers to detect ischemic myocardium: We are working in collaboration with the laboratory of Dr. Michael J. Welch to evaluate the novel marker of myocardial hypoxia diacteyl-dis N4-methythiosemicarbazone (ATSM). This agent can be labeled with copper-62 and has shown significant promise in the visualization of hypoxic or ischemic myocardium. We are currently collaborating with Dr. Welch in the performance of the animal studies validating the use of this tracer and will shortly be starting human studies to test its feasibility identifying myocardial ischemia.
Validation of 1-11C-glucose as a tracer of myocardial glucose metabolism: Over the past two years we have developed a method to quantify myocardial glucose utilization by PET and glucose radiolabeled with 11C in the one carbon position. Unlike 18F-fluorodeoxyglucose, this tracer potentially permits the assessment of various aspects of myocardial glucose metabolism including glucose uptake, glycogen formation, further glucose metabolism via glycolytic and oxidative pathways. Moreover, rates of overall glucose utilization can be determined without the need for a lumped constant as is required when using 18F-fluorodeoxyglucose. We have demonstrated that the rates of myocardial glucose utilization determined from the myocardial kinetics of 11C-glucose measured by PET and described with a four-compartmental model correlate closely with the rates of myocardial glucose use measured directly in a well controlled canine model. In conjunction with the laboratory of Dr. Michael J. Welch, we have also developed techniques to measure the metabolites of 11C-glucose including 11CO2 and 11C-lactate, which is necessary to perform compartmental modeling. Furthermore, we have shown that the measurements of myocardial glucose utilization obtained with this tracer are more accurate than those obtained with 18F-flurodeoxyglucose. The decreased accuracy in measured myocardial utilization with 18F-flurodeoxyglucose appears to be related to a marked variability in the lump constant. In addition, we have also demonstrated that dephosphorylation of 18F-flurodeoxyglucose-6-phosphate occurs in canine myocardium under a variety of conditions. We are now using this tracer in a variety of studies (see below). Visualization of coronary arteries by cardiac MRI: Over the past few years we have been actively involved in evaluating techniques designed to noninvasively image the coronary arteries by cardiac MRI. Most recently these efforts have focused on the use of novel intravascular contrast agents with studies being performed in both experimental models of coronary artery stenoses and in humans with coronary artery disease. We have demonstrated that use of these intravascular contrast agents when performed in conjunction with 3-dimensional coronary MRI using navigator approaches to correct for respiratory motion, resolution significant improvement in contrast and signal to noise. Study of Normal and Abnormal Cardiac States: Measurement of myocardial energy transduction in ischemic myocardium: In patients with ischemic cardiomyopathy it appears that myocardial energy transduction is impaired as myocardial oxygen consumption is frequently within normal limits yet mechanical function is reduced. Using the techniques described above, we have measured the myocardial stress-strain relationship as it relates to myocardial oxygen consumption in patients with ischemic cardiomyopathy. We have demonstrated that there is a shift in the stress-strain relation in patients with ischemic cardiomyopathy (higher stress per given level of strain) compared to normal volunteers. Moreover, we have shown that this alteration of the stress-strain relationship is most pronounced during the administration of dobutamine. More recently, we have demonstrated that the shift in the stress-strain relationship appears to be secondary to impairment in myocardial perfusion reserve. Future studies will be directed towards delineating the impact of therapies designed to improve the balance between myocardial oxygen supply and demand which should hopefully have a salutary effect on the stress-strain relationship and myocardial energy transduction. Evaluation of the diabetic heart: There are numerous cardiac manifestations of diabetes mellitus including impairment of myocardial perfusion, alterations in intermediary metabolism with a greater reliance on fatty acid utilization, and impairment in mechanical function, to name a few. Recently, we have begun to investigate the interrelationship between myocardial perfusion metabolism and function in type 1 diabetics particularly as they related to changes in plasma levels of insulin, glucose, and fatty acids. In the past year we have begun to study the impact of hypoinsulinemia and hyperglycemia on myocardial perfusion and perfusion reserve as they relate to endothelial-independent mechanisms. Moreover, we are studying how the impairment in myocardial perfusion effects mechanical function as measured by MRI. Over the next few years we will be determining how alterations in plasma, insulin, fatty acids, glucose levels impact on myocardial substrate usage and how this relates to myocardial mechanical function. Measurements of myocardial metabolism are being performed by PET using 11C-acetate (to measure MVO2), 11C-palmatate (to measure myocardial fatty acid utilization) and 11C-glucose (to measure myocardial glucose utilization). Measurements are obtained at rest and during dobutamine administration. The information obtained from these studies should provide a basis for a more targeted studies designed to delineate the mechanisms responsible for the impairment in perfusion and metabolism in patients with type 1 diabetes. Moreover, we believe that demonstrating that intermediary metabolism can be modified by specific interventions with subsequent salutary effects of myocardial function will provide a therapeutic option designed to improve ventricular function or at least slow the progression of left ventricular dysfunction in patients with this disease. Evaluation of aging on the human heart: It is well known that with age there is a decline in mechanical function of the heart. However, the mechanisms responsible for this decline of function are not well understood. Recently, we have begun to delve into the impact of aging on myocardial perfusion, intermediary metabolism and mechanical function. We believe that impairment of the fatty acid oxidation that occurs with age (as observed in experimental animals) results in an increased reliance on glucose as a myocardial energy fuel and has detrimental effects on myocardial mechanical function. We initiated a set of experiments where we measure myocardial perfusion by PET with 15O-water under resting conditions and during vasodilatory stress using both intravenous adenosine (to assess endothelial-independent mechanisms) and during cold-pressor testing (to assess endothelial-dependent mechanisms). Myocardial intermediary metabolism is being assessed by PET using 11C-acetate, 11C-palmatate, and 11C-glucose at rest and during the administration of dobutamine. Myocardial mechanical function is being assessed by MRI at rest and during dobutamine. These measurements are being related to exercise capacity, maximal oxygen consumption and changes in cardiac output with exercise. Measurements are being compared between young (20-35 years) and moderately older (60-72 years) individuals. In the older subjects, measurements are being obtained both before and after one year of endurance exercise training as it is well known that myocardial mechanical function improves following exercise training. Studies in experimental animals suggest that the improvement in mechanical function with training may be related to changes in myocardial metabolism. We believe that the results of these studies will further our understanding of the effects of aging on myocardial perfusion and intermediary metabolism as it relates to myocardial mechanical function. Furthermore, demonstration that myocardial perfusion and metabolism can be modified by endurance exercise training with subsequent salutary effects on myocardial function will provide a therapeutic strategy designed to improve left ventricular function or at least slow the progression of left ventricular dysfunction that occurs with aging. Assessment of the effects of ACAT inhibition on myocardial perfusion: There is a new class of anit-hyperlipidemia agents called the ACAT inhibitors which appear to have salutary effects on myocardial vasodilatory capacity. We have recently become part of a multicenter trial sponsored by Parke-Davis entitled "Relative and Absolute Myocardial Perfusion Changes as Measured by Positron Emission of PET to assess the effects of ACAT inhibition: a double-blind randomized multicenter trial (RAMPART). In this study myocardial perfusion as measured by PET and 13N-ammonia both at rest and during the intravenous administration of adenosine are obtained both before and while patients with coronary artery disease are on this novel antihypolipdemic agent. The purpose of this study is to determine the extent to which this agent has salutary effects on myocardial vasodilatory capacity separate from its hypolipidemic effects. Studies of the effects of estrogen on myocardial perfusion: We have recently begun to study the effects of estrogen myocardial perfusion and perfusion reserve. Studies are underway where myocardial perfusion and perfusion reserve are being measured in both pre and postmenopausal women. Measurements of perfusion are being obtained at rest, during intravenous adenosine and during cold pressor testing. To further delineate the role of nitric oxide synthase on estrogen mediated effects on myocardial perfusion, measurements of myocardial perfusion at rest and cold-pressor testing are also being obtained during the intravenous administration of L-arginine. As a surrogate for changes in coronary artery diameter, brachial artery diameters are being measured by ultrasound both at rest and following hyperemia. Once these studies are complete we will determine the time course of improvement in myocardial perfusion reserve following estrogen replacement therapy. We will also assess the differential responses in myocardial perfusion to estrogen replacement alone compared with either estrogen-progesterone combinations or with the specific estrogen receptor modulator raloxifine. Collaborative Projects: Assessment of left ventricular hypertrophy in humans: It is well established that there are extensive abnormalities in myocardial perfusion, intermediary metabolism, and mechanical function in patients with left ventricular hypertrophy. We are working in close collaboration with Dr. Victor G. Davila-Roman, in the Cardiovascular Division, of the Department of Internal Medicine to determine the impact of left ventricular hypertrophy due to hypertensive heart disease on myocardial perfusion and perfusion reserve, intermediary metabolism, and mechanical function. The experiments being performed are nearly identical to those that were described in the study of the effects of aging on the heart. The difference is that the measurements are being performed both before and after the inititation of ACE inhibition. The rationale behind these studies is that with left hypertrophy there is a switch in myocardial metabolism to more of the fetal type pattern with a greater reliance on glucose utilization. This switch to a more fetal phenotype may well portend the transition from left ventricular hypertrophy to left ventricular failure commonly observed in these patients. These studies will help sort out the role of changes in metabolism on the continued impairment in mechanical function in these patients and the impact of ACE inhibition on slowing or reversing these changes. Evaluation of novel hypoxic markers to detect ischemic myocardium: We are working in collaboration with the laboratory of Dr. Michael J. Welch to evaluate the novel marker of myocardial hypoxia diacteyl-dis N4-methythiosemicarbazone (ATSM). This agent can be labeled with copper-62 and has shown significant promise in the visualization of hypoxic or ischemic myocardium. We are currently collaborating with Dr. Welch in the performance of the animal studies validating the use of this tracer and will shortly be starting human studies to test its feasibility identifying myocardial ischemia.
Visualization of coronary arteries by cardiac MRI: Over the past few years we have been actively involved in evaluating techniques designed to noninvasively image the coronary arteries by cardiac MRI. Most recently these efforts have focused on the use of novel intravascular contrast agents with studies being performed in both experimental models of coronary artery stenoses and in humans with coronary artery disease. We have demonstrated that use of these intravascular contrast agents when performed in conjunction with 3-dimensional coronary MRI using navigator approaches to correct for respiratory motion, resolution significant improvement in contrast and signal to noise. Study of Normal and Abnormal Cardiac States: Measurement of myocardial energy transduction in ischemic myocardium: In patients with ischemic cardiomyopathy it appears that myocardial energy transduction is impaired as myocardial oxygen consumption is frequently within normal limits yet mechanical function is reduced. Using the techniques described above, we have measured the myocardial stress-strain relationship as it relates to myocardial oxygen consumption in patients with ischemic cardiomyopathy. We have demonstrated that there is a shift in the stress-strain relation in patients with ischemic cardiomyopathy (higher stress per given level of strain) compared to normal volunteers. Moreover, we have shown that this alteration of the stress-strain relationship is most pronounced during the administration of dobutamine. More recently, we have demonstrated that the shift in the stress-strain relationship appears to be secondary to impairment in myocardial perfusion reserve. Future studies will be directed towards delineating the impact of therapies designed to improve the balance between myocardial oxygen supply and demand which should hopefully have a salutary effect on the stress-strain relationship and myocardial energy transduction. Evaluation of the diabetic heart: There are numerous cardiac manifestations of diabetes mellitus including impairment of myocardial perfusion, alterations in intermediary metabolism with a greater reliance on fatty acid utilization, and impairment in mechanical function, to name a few. Recently, we have begun to investigate the interrelationship between myocardial perfusion metabolism and function in type 1 diabetics particularly as they related to changes in plasma levels of insulin, glucose, and fatty acids. In the past year we have begun to study the impact of hypoinsulinemia and hyperglycemia on myocardial perfusion and perfusion reserve as they relate to endothelial-independent mechanisms. Moreover, we are studying how the impairment in myocardial perfusion effects mechanical function as measured by MRI. Over the next few years we will be determining how alterations in plasma, insulin, fatty acids, glucose levels impact on myocardial substrate usage and how this relates to myocardial mechanical function. Measurements of myocardial metabolism are being performed by PET using 11C-acetate (to measure MVO2), 11C-palmatate (to measure myocardial fatty acid utilization) and 11C-glucose (to measure myocardial glucose utilization). Measurements are obtained at rest and during dobutamine administration. The information obtained from these studies should provide a basis for a more targeted studies designed to delineate the mechanisms responsible for the impairment in perfusion and metabolism in patients with type 1 diabetes. Moreover, we believe that demonstrating that intermediary metabolism can be modified by specific interventions with subsequent salutary effects of myocardial function will provide a therapeutic option designed to improve ventricular function or at least slow the progression of left ventricular dysfunction in patients with this disease. Evaluation of aging on the human heart: It is well known that with age there is a decline in mechanical function of the heart. However, the mechanisms responsible for this decline of function are not well understood. Recently, we have begun to delve into the impact of aging on myocardial perfusion, intermediary metabolism and mechanical function. We believe that impairment of the fatty acid oxidation that occurs with age (as observed in experimental animals) results in an increased reliance on glucose as a myocardial energy fuel and has detrimental effects on myocardial mechanical function. We initiated a set of experiments where we measure myocardial perfusion by PET with 15O-water under resting conditions and during vasodilatory stress using both intravenous adenosine (to assess endothelial-independent mechanisms) and during cold-pressor testing (to assess endothelial-dependent mechanisms). Myocardial intermediary metabolism is being assessed by PET using 11C-acetate, 11C-palmatate, and 11C-glucose at rest and during the administration of dobutamine. Myocardial mechanical function is being assessed by MRI at rest and during dobutamine. These measurements are being related to exercise capacity, maximal oxygen consumption and changes in cardiac output with exercise. Measurements are being compared between young (20-35 years) and moderately older (60-72 years) individuals. In the older subjects, measurements are being obtained both before and after one year of endurance exercise training as it is well known that myocardial mechanical function improves following exercise training. Studies in experimental animals suggest that the improvement in mechanical function with training may be related to changes in myocardial metabolism. We believe that the results of these studies will further our understanding of the effects of aging on myocardial perfusion and intermediary metabolism as it relates to myocardial mechanical function. Furthermore, demonstration that myocardial perfusion and metabolism can be modified by endurance exercise training with subsequent salutary effects on myocardial function will provide a therapeutic strategy designed to improve left ventricular function or at least slow the progression of left ventricular dysfunction that occurs with aging. Assessment of the effects of ACAT inhibition on myocardial perfusion: There is a new class of anit-hyperlipidemia agents called the ACAT inhibitors which appear to have salutary effects on myocardial vasodilatory capacity. We have recently become part of a multicenter trial sponsored by Parke-Davis entitled "Relative and Absolute Myocardial Perfusion Changes as Measured by Positron Emission of PET to assess the effects of ACAT inhibition: a double-blind randomized multicenter trial (RAMPART). In this study myocardial perfusion as measured by PET and 13N-ammonia both at rest and during the intravenous administration of adenosine are obtained both before and while patients with coronary artery disease are on this novel antihypolipdemic agent. The purpose of this study is to determine the extent to which this agent has salutary effects on myocardial vasodilatory capacity separate from its hypolipidemic effects. Studies of the effects of estrogen on myocardial perfusion: We have recently begun to study the effects of estrogen myocardial perfusion and perfusion reserve. Studies are underway where myocardial perfusion and perfusion reserve are being measured in both pre and postmenopausal women. Measurements of perfusion are being obtained at rest, during intravenous adenosine and during cold pressor testing. To further delineate the role of nitric oxide synthase on estrogen mediated effects on myocardial perfusion, measurements of myocardial perfusion at rest and cold-pressor testing are also being obtained during the intravenous administration of L-arginine. As a surrogate for changes in coronary artery diameter, brachial artery diameters are being measured by ultrasound both at rest and following hyperemia. Once these studies are complete we will determine the time course of improvement in myocardial perfusion reserve following estrogen replacement therapy. We will also assess the differential responses in myocardial perfusion to estrogen replacement alone compared with either estrogen-progesterone combinations or with the specific estrogen receptor modulator raloxifine. Collaborative Projects: Assessment of left ventricular hypertrophy in humans: It is well established that there are extensive abnormalities in myocardial perfusion, intermediary metabolism, and mechanical function in patients with left ventricular hypertrophy. We are working in close collaboration with Dr. Victor G. Davila-Roman, in the Cardiovascular Division, of the Department of Internal Medicine to determine the impact of left ventricular hypertrophy due to hypertensive heart disease on myocardial perfusion and perfusion reserve, intermediary metabolism, and mechanical function. The experiments being performed are nearly identical to those that were described in the study of the effects of aging on the heart. The difference is that the measurements are being performed both before and after the inititation of ACE inhibition. The rationale behind these studies is that with left hypertrophy there is a switch in myocardial metabolism to more of the fetal type pattern with a greater reliance on glucose utilization. This switch to a more fetal phenotype may well portend the transition from left ventricular hypertrophy to left ventricular failure commonly observed in these patients. These studies will help sort out the role of changes in metabolism on the continued impairment in mechanical function in these patients and the impact of ACE inhibition on slowing or reversing these changes. Evaluation of novel hypoxic markers to detect ischemic myocardium: We are working in collaboration with the laboratory of Dr. Michael J. Welch to evaluate the novel marker of myocardial hypoxia diacteyl-dis N4-methythiosemicarbazone (ATSM). This agent can be labeled with copper-62 and has shown significant promise in the visualization of hypoxic or ischemic myocardium. We are currently collaborating with Dr. Welch in the performance of the animal studies validating the use of this tracer and will shortly be starting human studies to test its feasibility identifying myocardial ischemia.
Study of Normal and Abnormal Cardiac States:
Measurement of myocardial energy transduction in ischemic myocardium: In patients with ischemic cardiomyopathy it appears that myocardial energy transduction is impaired as myocardial oxygen consumption is frequently within normal limits yet mechanical function is reduced. Using the techniques described above, we have measured the myocardial stress-strain relationship as it relates to myocardial oxygen consumption in patients with ischemic cardiomyopathy. We have demonstrated that there is a shift in the stress-strain relation in patients with ischemic cardiomyopathy (higher stress per given level of strain) compared to normal volunteers. Moreover, we have shown that this alteration of the stress-strain relationship is most pronounced during the administration of dobutamine. More recently, we have demonstrated that the shift in the stress-strain relationship appears to be secondary to impairment in myocardial perfusion reserve. Future studies will be directed towards delineating the impact of therapies designed to improve the balance between myocardial oxygen supply and demand which should hopefully have a salutary effect on the stress-strain relationship and myocardial energy transduction. Evaluation of the diabetic heart: There are numerous cardiac manifestations of diabetes mellitus including impairment of myocardial perfusion, alterations in intermediary metabolism with a greater reliance on fatty acid utilization, and impairment in mechanical function, to name a few. Recently, we have begun to investigate the interrelationship between myocardial perfusion metabolism and function in type 1 diabetics particularly as they related to changes in plasma levels of insulin, glucose, and fatty acids. In the past year we have begun to study the impact of hypoinsulinemia and hyperglycemia on myocardial perfusion and perfusion reserve as they relate to endothelial-independent mechanisms. Moreover, we are studying how the impairment in myocardial perfusion effects mechanical function as measured by MRI. Over the next few years we will be determining how alterations in plasma, insulin, fatty acids, glucose levels impact on myocardial substrate usage and how this relates to myocardial mechanical function. Measurements of myocardial metabolism are being performed by PET using 11C-acetate (to measure MVO2), 11C-palmatate (to measure myocardial fatty acid utilization) and 11C-glucose (to measure myocardial glucose utilization). Measurements are obtained at rest and during dobutamine administration. The information obtained from these studies should provide a basis for a more targeted studies designed to delineate the mechanisms responsible for the impairment in perfusion and metabolism in patients with type 1 diabetes. Moreover, we believe that demonstrating that intermediary metabolism can be modified by specific interventions with subsequent salutary effects of myocardial function will provide a therapeutic option designed to improve ventricular function or at least slow the progression of left ventricular dysfunction in patients with this disease. Evaluation of aging on the human heart: It is well known that with age there is a decline in mechanical function of the heart. However, the mechanisms responsible for this decline of function are not well understood. Recently, we have begun to delve into the impact of aging on myocardial perfusion, intermediary metabolism and mechanical function. We believe that impairment of the fatty acid oxidation that occurs with age (as observed in experimental animals) results in an increased reliance on glucose as a myocardial energy fuel and has detrimental effects on myocardial mechanical function. We initiated a set of experiments where we measure myocardial perfusion by PET with 15O-water under resting conditions and during vasodilatory stress using both intravenous adenosine (to assess endothelial-independent mechanisms) and during cold-pressor testing (to assess endothelial-dependent mechanisms). Myocardial intermediary metabolism is being assessed by PET using 11C-acetate, 11C-palmatate, and 11C-glucose at rest and during the administration of dobutamine. Myocardial mechanical function is being assessed by MRI at rest and during dobutamine. These measurements are being related to exercise capacity, maximal oxygen consumption and changes in cardiac output with exercise. Measurements are being compared between young (20-35 years) and moderately older (60-72 years) individuals. In the older subjects, measurements are being obtained both before and after one year of endurance exercise training as it is well known that myocardial mechanical function improves following exercise training. Studies in experimental animals suggest that the improvement in mechanical function with training may be related to changes in myocardial metabolism. We believe that the results of these studies will further our understanding of the effects of aging on myocardial perfusion and intermediary metabolism as it relates to myocardial mechanical function. Furthermore, demonstration that myocardial perfusion and metabolism can be modified by endurance exercise training with subsequent salutary effects on myocardial function will provide a therapeutic strategy designed to improve left ventricular function or at least slow the progression of left ventricular dysfunction that occurs with aging. Assessment of the effects of ACAT inhibition on myocardial perfusion: There is a new class of anit-hyperlipidemia agents called the ACAT inhibitors which appear to have salutary effects on myocardial vasodilatory capacity. We have recently become part of a multicenter trial sponsored by Parke-Davis entitled "Relative and Absolute Myocardial Perfusion Changes as Measured by Positron Emission of PET to assess the effects of ACAT inhibition: a double-blind randomized multicenter trial (RAMPART). In this study myocardial perfusion as measured by PET and 13N-ammonia both at rest and during the intravenous administration of adenosine are obtained both before and while patients with coronary artery disease are on this novel antihypolipdemic agent. The purpose of this study is to determine the extent to which this agent has salutary effects on myocardial vasodilatory capacity separate from its hypolipidemic effects. Studies of the effects of estrogen on myocardial perfusion: We have recently begun to study the effects of estrogen myocardial perfusion and perfusion reserve. Studies are underway where myocardial perfusion and perfusion reserve are being measured in both pre and postmenopausal women. Measurements of perfusion are being obtained at rest, during intravenous adenosine and during cold pressor testing. To further delineate the role of nitric oxide synthase on estrogen mediated effects on myocardial perfusion, measurements of myocardial perfusion at rest and cold-pressor testing are also being obtained during the intravenous administration of L-arginine. As a surrogate for changes in coronary artery diameter, brachial artery diameters are being measured by ultrasound both at rest and following hyperemia. Once these studies are complete we will determine the time course of improvement in myocardial perfusion reserve following estrogen replacement therapy. We will also assess the differential responses in myocardial perfusion to estrogen replacement alone compared with either estrogen-progesterone combinations or with the specific estrogen receptor modulator raloxifine. Collaborative Projects: Assessment of left ventricular hypertrophy in humans: It is well established that there are extensive abnormalities in myocardial perfusion, intermediary metabolism, and mechanical function in patients with left ventricular hypertrophy. We are working in close collaboration with Dr. Victor G. Davila-Roman, in the Cardiovascular Division, of the Department of Internal Medicine to determine the impact of left ventricular hypertrophy due to hypertensive heart disease on myocardial perfusion and perfusion reserve, intermediary metabolism, and mechanical function. The experiments being performed are nearly identical to those that were described in the study of the effects of aging on the heart. The difference is that the measurements are being performed both before and after the inititation of ACE inhibition. The rationale behind these studies is that with left hypertrophy there is a switch in myocardial metabolism to more of the fetal type pattern with a greater reliance on glucose utilization. This switch to a more fetal phenotype may well portend the transition from left ventricular hypertrophy to left ventricular failure commonly observed in these patients. These studies will help sort out the role of changes in metabolism on the continued impairment in mechanical function in these patients and the impact of ACE inhibition on slowing or reversing these changes. Evaluation of novel hypoxic markers to detect ischemic myocardium: We are working in collaboration with the laboratory of Dr. Michael J. Welch to evaluate the novel marker of myocardial hypoxia diacteyl-dis N4-methythiosemicarbazone (ATSM). This agent can be labeled with copper-62 and has shown significant promise in the visualization of hypoxic or ischemic myocardium. We are currently collaborating with Dr. Welch in the performance of the animal studies validating the use of this tracer and will shortly be starting human studies to test its feasibility identifying myocardial ischemia.
Evaluation of the diabetic heart: There are numerous cardiac manifestations of diabetes mellitus including impairment of myocardial perfusion, alterations in intermediary metabolism with a greater reliance on fatty acid utilization, and impairment in mechanical function, to name a few. Recently, we have begun to investigate the interrelationship between myocardial perfusion metabolism and function in type 1 diabetics particularly as they related to changes in plasma levels of insulin, glucose, and fatty acids. In the past year we have begun to study the impact of hypoinsulinemia and hyperglycemia on myocardial perfusion and perfusion reserve as they relate to endothelial-independent mechanisms. Moreover, we are studying how the impairment in myocardial perfusion effects mechanical function as measured by MRI. Over the next few years we will be determining how alterations in plasma, insulin, fatty acids, glucose levels impact on myocardial substrate usage and how this relates to myocardial mechanical function. Measurements of myocardial metabolism are being performed by PET using 11C-acetate (to measure MVO2), 11C-palmatate (to measure myocardial fatty acid utilization) and 11C-glucose (to measure myocardial glucose utilization). Measurements are obtained at rest and during dobutamine administration. The information obtained from these studies should provide a basis for a more targeted studies designed to delineate the mechanisms responsible for the impairment in perfusion and metabolism in patients with type 1 diabetes. Moreover, we believe that demonstrating that intermediary metabolism can be modified by specific interventions with subsequent salutary effects of myocardial function will provide a therapeutic option designed to improve ventricular function or at least slow the progression of left ventricular dysfunction in patients with this disease. Evaluation of aging on the human heart: It is well known that with age there is a decline in mechanical function of the heart. However, the mechanisms responsible for this decline of function are not well understood. Recently, we have begun to delve into the impact of aging on myocardial perfusion, intermediary metabolism and mechanical function. We believe that impairment of the fatty acid oxidation that occurs with age (as observed in experimental animals) results in an increased reliance on glucose as a myocardial energy fuel and has detrimental effects on myocardial mechanical function. We initiated a set of experiments where we measure myocardial perfusion by PET with 15O-water under resting conditions and during vasodilatory stress using both intravenous adenosine (to assess endothelial-independent mechanisms) and during cold-pressor testing (to assess endothelial-dependent mechanisms). Myocardial intermediary metabolism is being assessed by PET using 11C-acetate, 11C-palmatate, and 11C-glucose at rest and during the administration of dobutamine. Myocardial mechanical function is being assessed by MRI at rest and during dobutamine. These measurements are being related to exercise capacity, maximal oxygen consumption and changes in cardiac output with exercise. Measurements are being compared between young (20-35 years) and moderately older (60-72 years) individuals. In the older subjects, measurements are being obtained both before and after one year of endurance exercise training as it is well known that myocardial mechanical function improves following exercise training. Studies in experimental animals suggest that the improvement in mechanical function with training may be related to changes in myocardial metabolism. We believe that the results of these studies will further our understanding of the effects of aging on myocardial perfusion and intermediary metabolism as it relates to myocardial mechanical function. Furthermore, demonstration that myocardial perfusion and metabolism can be modified by endurance exercise training with subsequent salutary effects on myocardial function will provide a therapeutic strategy designed to improve left ventricular function or at least slow the progression of left ventricular dysfunction that occurs with aging. Assessment of the effects of ACAT inhibition on myocardial perfusion: There is a new class of anit-hyperlipidemia agents called the ACAT inhibitors which appear to have salutary effects on myocardial vasodilatory capacity. We have recently become part of a multicenter trial sponsored by Parke-Davis entitled "Relative and Absolute Myocardial Perfusion Changes as Measured by Positron Emission of PET to assess the effects of ACAT inhibition: a double-blind randomized multicenter trial (RAMPART). In this study myocardial perfusion as measured by PET and 13N-ammonia both at rest and during the intravenous administration of adenosine are obtained both before and while patients with coronary artery disease are on this novel antihypolipdemic agent. The purpose of this study is to determine the extent to which this agent has salutary effects on myocardial vasodilatory capacity separate from its hypolipidemic effects. Studies of the effects of estrogen on myocardial perfusion: We have recently begun to study the effects of estrogen myocardial perfusion and perfusion reserve. Studies are underway where myocardial perfusion and perfusion reserve are being measured in both pre and postmenopausal women. Measurements of perfusion are being obtained at rest, during intravenous adenosine and during cold pressor testing. To further delineate the role of nitric oxide synthase on estrogen mediated effects on myocardial perfusion, measurements of myocardial perfusion at rest and cold-pressor testing are also being obtained during the intravenous administration of L-arginine. As a surrogate for changes in coronary artery diameter, brachial artery diameters are being measured by ultrasound both at rest and following hyperemia. Once these studies are complete we will determine the time course of improvement in myocardial perfusion reserve following estrogen replacement therapy. We will also assess the differential responses in myocardial perfusion to estrogen replacement alone compared with either estrogen-progesterone combinations or with the specific estrogen receptor modulator raloxifine. Collaborative Projects: Assessment of left ventricular hypertrophy in humans: It is well established that there are extensive abnormalities in myocardial perfusion, intermediary metabolism, and mechanical function in patients with left ventricular hypertrophy. We are working in close collaboration with Dr. Victor G. Davila-Roman, in the Cardiovascular Division, of the Department of Internal Medicine to determine the impact of left ventricular hypertrophy due to hypertensive heart disease on myocardial perfusion and perfusion reserve, intermediary metabolism, and mechanical function. The experiments being performed are nearly identical to those that were described in the study of the effects of aging on the heart. The difference is that the measurements are being performed both before and after the inititation of ACE inhibition. The rationale behind these studies is that with left hypertrophy there is a switch in myocardial metabolism to more of the fetal type pattern with a greater reliance on glucose utilization. This switch to a more fetal phenotype may well portend the transition from left ventricular hypertrophy to left ventricular failure commonly observed in these patients. These studies will help sort out the role of changes in metabolism on the continued impairment in mechanical function in these patients and the impact of ACE inhibition on slowing or reversing these changes. Evaluation of novel hypoxic markers to detect ischemic myocardium: We are working in collaboration with the laboratory of Dr. Michael J. Welch to evaluate the novel marker of myocardial hypoxia diacteyl-dis N4-methythiosemicarbazone (ATSM). This agent can be labeled with copper-62 and has shown significant promise in the visualization of hypoxic or ischemic myocardium. We are currently collaborating with Dr. Welch in the performance of the animal studies validating the use of this tracer and will shortly be starting human studies to test its feasibility identifying myocardial ischemia.
Evaluation of aging on the human heart: It is well known that with age there is a decline in mechanical function of the heart. However, the mechanisms responsible for this decline of function are not well understood. Recently, we have begun to delve into the impact of aging on myocardial perfusion, intermediary metabolism and mechanical function. We believe that impairment of the fatty acid oxidation that occurs with age (as observed in experimental animals) results in an increased reliance on glucose as a myocardial energy fuel and has detrimental effects on myocardial mechanical function. We initiated a set of experiments where we measure myocardial perfusion by PET with 15O-water under resting conditions and during vasodilatory stress using both intravenous adenosine (to assess endothelial-independent mechanisms) and during cold-pressor testing (to assess endothelial-dependent mechanisms). Myocardial intermediary metabolism is being assessed by PET using 11C-acetate, 11C-palmatate, and 11C-glucose at rest and during the administration of dobutamine. Myocardial mechanical function is being assessed by MRI at rest and during dobutamine. These measurements are being related to exercise capacity, maximal oxygen consumption and changes in cardiac output with exercise. Measurements are being compared between young (20-35 years) and moderately older (60-72 years) individuals. In the older subjects, measurements are being obtained both before and after one year of endurance exercise training as it is well known that myocardial mechanical function improves following exercise training. Studies in experimental animals suggest that the improvement in mechanical function with training may be related to changes in myocardial metabolism. We believe that the results of these studies will further our understanding of the effects of aging on myocardial perfusion and intermediary metabolism as it relates to myocardial mechanical function. Furthermore, demonstration that myocardial perfusion and metabolism can be modified by endurance exercise training with subsequent salutary effects on myocardial function will provide a therapeutic strategy designed to improve left ventricular function or at least slow the progression of left ventricular dysfunction that occurs with aging. Assessment of the effects of ACAT inhibition on myocardial perfusion: There is a new class of anit-hyperlipidemia agents called the ACAT inhibitors which appear to have salutary effects on myocardial vasodilatory capacity. We have recently become part of a multicenter trial sponsored by Parke-Davis entitled "Relative and Absolute Myocardial Perfusion Changes as Measured by Positron Emission of PET to assess the effects of ACAT inhibition: a double-blind randomized multicenter trial (RAMPART). In this study myocardial perfusion as measured by PET and 13N-ammonia both at rest and during the intravenous administration of adenosine are obtained both before and while patients with coronary artery disease are on this novel antihypolipdemic agent. The purpose of this study is to determine the extent to which this agent has salutary effects on myocardial vasodilatory capacity separate from its hypolipidemic effects. Studies of the effects of estrogen on myocardial perfusion: We have recently begun to study the effects of estrogen myocardial perfusion and perfusion reserve. Studies are underway where myocardial perfusion and perfusion reserve are being measured in both pre and postmenopausal women. Measurements of perfusion are being obtained at rest, during intravenous adenosine and during cold pressor testing. To further delineate the role of nitric oxide synthase on estrogen mediated effects on myocardial perfusion, measurements of myocardial perfusion at rest and cold-pressor testing are also being obtained during the intravenous administration of L-arginine. As a surrogate for changes in coronary artery diameter, brachial artery diameters are being measured by ultrasound both at rest and following hyperemia. Once these studies are complete we will determine the time course of improvement in myocardial perfusion reserve following estrogen replacement therapy. We will also assess the differential responses in myocardial perfusion to estrogen replacement alone compared with either estrogen-progesterone combinations or with the specific estrogen receptor modulator raloxifine. Collaborative Projects: Assessment of left ventricular hypertrophy in humans: It is well established that there are extensive abnormalities in myocardial perfusion, intermediary metabolism, and mechanical function in patients with left ventricular hypertrophy. We are working in close collaboration with Dr. Victor G. Davila-Roman, in the Cardiovascular Division, of the Department of Internal Medicine to determine the impact of left ventricular hypertrophy due to hypertensive heart disease on myocardial perfusion and perfusion reserve, intermediary metabolism, and mechanical function. The experiments being performed are nearly identical to those that were described in the study of the effects of aging on the heart. The difference is that the measurements are being performed both before and after the inititation of ACE inhibition. The rationale behind these studies is that with left hypertrophy there is a switch in myocardial metabolism to more of the fetal type pattern with a greater reliance on glucose utilization. This switch to a more fetal phenotype may well portend the transition from left ventricular hypertrophy to left ventricular failure commonly observed in these patients. These studies will help sort out the role of changes in metabolism on the continued impairment in mechanical function in these patients and the impact of ACE inhibition on slowing or reversing these changes. Evaluation of novel hypoxic markers to detect ischemic myocardium: We are working in collaboration with the laboratory of Dr. Michael J. Welch to evaluate the novel marker of myocardial hypoxia diacteyl-dis N4-methythiosemicarbazone (ATSM). This agent can be labeled with copper-62 and has shown significant promise in the visualization of hypoxic or ischemic myocardium. We are currently collaborating with Dr. Welch in the performance of the animal studies validating the use of this tracer and will shortly be starting human studies to test its feasibility identifying myocardial ischemia.
Assessment of the effects of ACAT inhibition on myocardial perfusion: There is a new class of anit-hyperlipidemia agents called the ACAT inhibitors which appear to have salutary effects on myocardial vasodilatory capacity. We have recently become part of a multicenter trial sponsored by Parke-Davis entitled "Relative and Absolute Myocardial Perfusion Changes as Measured by Positron Emission of PET to assess the effects of ACAT inhibition: a double-blind randomized multicenter trial (RAMPART). In this study myocardial perfusion as measured by PET and 13N-ammonia both at rest and during the intravenous administration of adenosine are obtained both before and while patients with coronary artery disease are on this novel antihypolipdemic agent. The purpose of this study is to determine the extent to which this agent has salutary effects on myocardial vasodilatory capacity separate from its hypolipidemic effects. Studies of the effects of estrogen on myocardial perfusion: We have recently begun to study the effects of estrogen myocardial perfusion and perfusion reserve. Studies are underway where myocardial perfusion and perfusion reserve are being measured in both pre and postmenopausal women. Measurements of perfusion are being obtained at rest, during intravenous adenosine and during cold pressor testing. To further delineate the role of nitric oxide synthase on estrogen mediated effects on myocardial perfusion, measurements of myocardial perfusion at rest and cold-pressor testing are also being obtained during the intravenous administration of L-arginine. As a surrogate for changes in coronary artery diameter, brachial artery diameters are being measured by ultrasound both at rest and following hyperemia. Once these studies are complete we will determine the time course of improvement in myocardial perfusion reserve following estrogen replacement therapy. We will also assess the differential responses in myocardial perfusion to estrogen replacement alone compared with either estrogen-progesterone combinations or with the specific estrogen receptor modulator raloxifine. Collaborative Projects: Assessment of left ventricular hypertrophy in humans: It is well established that there are extensive abnormalities in myocardial perfusion, intermediary metabolism, and mechanical function in patients with left ventricular hypertrophy. We are working in close collaboration with Dr. Victor G. Davila-Roman, in the Cardiovascular Division, of the Department of Internal Medicine to determine the impact of left ventricular hypertrophy due to hypertensive heart disease on myocardial perfusion and perfusion reserve, intermediary metabolism, and mechanical function. The experiments being performed are nearly identical to those that were described in the study of the effects of aging on the heart. The difference is that the measurements are being performed both before and after the inititation of ACE inhibition. The rationale behind these studies is that with left hypertrophy there is a switch in myocardial metabolism to more of the fetal type pattern with a greater reliance on glucose utilization. This switch to a more fetal phenotype may well portend the transition from left ventricular hypertrophy to left ventricular failure commonly observed in these patients. These studies will help sort out the role of changes in metabolism on the continued impairment in mechanical function in these patients and the impact of ACE inhibition on slowing or reversing these changes. Evaluation of novel hypoxic markers to detect ischemic myocardium: We are working in collaboration with the laboratory of Dr. Michael J. Welch to evaluate the novel marker of myocardial hypoxia diacteyl-dis N4-methythiosemicarbazone (ATSM). This agent can be labeled with copper-62 and has shown significant promise in the visualization of hypoxic or ischemic myocardium. We are currently collaborating with Dr. Welch in the performance of the animal studies validating the use of this tracer and will shortly be starting human studies to test its feasibility identifying myocardial ischemia.
Studies of the effects of estrogen on myocardial perfusion: We have recently begun to study the effects of estrogen myocardial perfusion and perfusion reserve. Studies are underway where myocardial perfusion and perfusion reserve are being measured in both pre and postmenopausal women. Measurements of perfusion are being obtained at rest, during intravenous adenosine and during cold pressor testing. To further delineate the role of nitric oxide synthase on estrogen mediated effects on myocardial perfusion, measurements of myocardial perfusion at rest and cold-pressor testing are also being obtained during the intravenous administration of L-arginine. As a surrogate for changes in coronary artery diameter, brachial artery diameters are being measured by ultrasound both at rest and following hyperemia. Once these studies are complete we will determine the time course of improvement in myocardial perfusion reserve following estrogen replacement therapy. We will also assess the differential responses in myocardial perfusion to estrogen replacement alone compared with either estrogen-progesterone combinations or with the specific estrogen receptor modulator raloxifine. Collaborative Projects: Assessment of left ventricular hypertrophy in humans: It is well established that there are extensive abnormalities in myocardial perfusion, intermediary metabolism, and mechanical function in patients with left ventricular hypertrophy. We are working in close collaboration with Dr. Victor G. Davila-Roman, in the Cardiovascular Division, of the Department of Internal Medicine to determine the impact of left ventricular hypertrophy due to hypertensive heart disease on myocardial perfusion and perfusion reserve, intermediary metabolism, and mechanical function. The experiments being performed are nearly identical to those that were described in the study of the effects of aging on the heart. The difference is that the measurements are being performed both before and after the inititation of ACE inhibition. The rationale behind these studies is that with left hypertrophy there is a switch in myocardial metabolism to more of the fetal type pattern with a greater reliance on glucose utilization. This switch to a more fetal phenotype may well portend the transition from left ventricular hypertrophy to left ventricular failure commonly observed in these patients. These studies will help sort out the role of changes in metabolism on the continued impairment in mechanical function in these patients and the impact of ACE inhibition on slowing or reversing these changes. Evaluation of novel hypoxic markers to detect ischemic myocardium: We are working in collaboration with the laboratory of Dr. Michael J. Welch to evaluate the novel marker of myocardial hypoxia diacteyl-dis N4-methythiosemicarbazone (ATSM). This agent can be labeled with copper-62 and has shown significant promise in the visualization of hypoxic or ischemic myocardium. We are currently collaborating with Dr. Welch in the performance of the animal studies validating the use of this tracer and will shortly be starting human studies to test its feasibility identifying myocardial ischemia.
Collaborative Projects:
Assessment of left ventricular hypertrophy in humans: It is well established that there are extensive abnormalities in myocardial perfusion, intermediary metabolism, and mechanical function in patients with left ventricular hypertrophy. We are working in close collaboration with Dr. Victor G. Davila-Roman, in the Cardiovascular Division, of the Department of Internal Medicine to determine the impact of left ventricular hypertrophy due to hypertensive heart disease on myocardial perfusion and perfusion reserve, intermediary metabolism, and mechanical function. The experiments being performed are nearly identical to those that were described in the study of the effects of aging on the heart. The difference is that the measurements are being performed both before and after the inititation of ACE inhibition. The rationale behind these studies is that with left hypertrophy there is a switch in myocardial metabolism to more of the fetal type pattern with a greater reliance on glucose utilization. This switch to a more fetal phenotype may well portend the transition from left ventricular hypertrophy to left ventricular failure commonly observed in these patients. These studies will help sort out the role of changes in metabolism on the continued impairment in mechanical function in these patients and the impact of ACE inhibition on slowing or reversing these changes. Evaluation of novel hypoxic markers to detect ischemic myocardium: We are working in collaboration with the laboratory of Dr. Michael J. Welch to evaluate the novel marker of myocardial hypoxia diacteyl-dis N4-methythiosemicarbazone (ATSM). This agent can be labeled with copper-62 and has shown significant promise in the visualization of hypoxic or ischemic myocardium. We are currently collaborating with Dr. Welch in the performance of the animal studies validating the use of this tracer and will shortly be starting human studies to test its feasibility identifying myocardial ischemia.
Evaluation of novel hypoxic markers to detect ischemic myocardium: We are working in collaboration with the laboratory of Dr. Michael J. Welch to evaluate the novel marker of myocardial hypoxia diacteyl-dis N4-methythiosemicarbazone (ATSM). This agent can be labeled with copper-62 and has shown significant promise in the visualization of hypoxic or ischemic myocardium. We are currently collaborating with Dr. Welch in the performance of the animal studies validating the use of this tracer and will shortly be starting human studies to test its feasibility identifying myocardial ischemia.
