Ischemic Heart Disease
Ischemic Heart Disease
We have developed and validated methods by which biochemical quantification of the extent of myocardial infarction can be accomplished in vivo based on sequential analyses of concentration in plasma of macromolecules (CK, MB CK isoenzymes, and other moieties such as troponin I and troponin T) and applied them to determine the extent of infarction is an important determinant of prognosis after myocardial infarction and furthermore, whether the extent of infarction can be modified by interventions that reduce myocardial oxygen requirements or increase myocardial oxygen supply. This work has had a major impact on how patients with acute myocardial infarction are treated and led to a reduction of mortality secondary to treatments, such as thrombolysis that were validated initially with the methods developed.
We have contributed to the initial development of cardiac positron emission tomography with the use of positron-emitting radionuclides including carbon-11 labeled palmitate, the physiological fuel of myocardium, and applied it to further delineate the nature of evolution of infarction and its interdiction with interventions salvaging ischemic myocardium including coronary thrombolysis with clot-selective fibrinolytic agents.
We have pioneered coronary thrombolysis with the use of the clot-selective plasminogen activator, tissue-type plasminogen activator (t-PA), in studies of cells in culture, experimental animals, and mechanistic clinical studies in patients with acute myocardial infarction with quantification of the extent of infarction by positron emission tomography and analysis of time activity-curves in blood of enzymes liberated from myocardium. This work provided a foundation for subsequent large-scale, multicenter clinical trials in which Dr. Burton Sobel helped to demonstrate the efficacy of coronary thrombolysis with clot-selective agents, heparin, and aspirin in the reduction of death associated with coronary artery disease and acute myocardial infarction.
Recently we delineated altered fibrinolysis in blood and altered proteolytic activity in vessel walls as mediators of deleterious effects of hyperinsulinemia associated with insulin resistance, impaired glucose tolerance, and type 2 diabetes thereby helping to elucidate the pathophysiology of macrovascular angiopathy in type 2 diabetes. This work, coupled with results of studies demonstrating that insulin sensitizers normalize fibrinolysis in patients with type 2 diabetes, is changing the approach to their treatment directed at reducing the risk of heart attack and cardiac death.
Recent Grant Support
Grant Title: Hemostasis & Thrombosis Program for Trainees
Sponsor: National Institutes of Health
Co-Investigator: Dr. Burton E. Sobel; Dr. Kenneth G. Mann (PI)
Grant Title: Postdoctoral Cardiovascular Research Training Program
Sponsor: National Institutes of Health
Co-Investigator: Dr. Burton E. Sobel; Dr. Martin M. LeWinter (PI)
Grant Title: TNK – t-PA
Sponsor: Genentech, Inc.
Principal Investigator: Dr. Burton E. Sobel
Grant Title: Translational Research in Lung Biology and Disease
Sponsor: National Institutes of Health
Co-Investigator: Dr. Burton E. Sobel; Dr. Charles G. Irvin (PI)
Grant Title: Cardiomyopathy in Diabetes
Sponsor: National Institutes of Health
Co-Investigator: Dr. Burton E. Sobel; Dr. Martin M. LeWinter (PI)
Grant Title: BARI 2D – Fibrinolysis and Coagulation Core
Sponsor: National Institutes of Health
Principal Investigator: Dr. Burton E. Sobel
Grant Title: Inflammation, Procoagulation, & Plaque Vulnerability
Sponsor: National Institutes of Health
Principal Investigator: Dr. Burton E. Sobel
Representative Publications
Kjekshus JK, Sobel BE: Depressed myocardial creatine phosphokinase activity following experimental myocardial infarction in rabbit. Circ. Res. 27:403-414, 1970.
Shell WE, Kjekshus JK, Sobel BE: Quantitative assessment of the extent of myocardial infarction in the conscious dog by means of analysis of serial changes in serum creatine phosphokinase activity. J. Clin. Invest. 50:2614-2626, 1971.
Shell WE, Sobel BE: Protection of jeopardized ischemic myocardium by reduction of ventricular afterload. N. Engl. J. Med. 291:481-486, 1974.
Sobel BE, Weiss ES, Welch MJ, Siegel BA, Ter-Pogossian MM: Detection of remote myocardial infarction in patients with positron emission transaxial tomography and intravenous 11C-palmitate. Circulation 55:853-857, 1977.
Bergmann SR, Fox KAA, Ter-Pogossian MM, Sobel BE (Washington University), Collen D (University of Leuven): Clot-selective coronary thrombolysis with tissue-type plasminogen activator. Science 220:1181-1183, 1983.
Van de Werf F, Ludbrook PA, Bergmann SR, Tiefenbrunn AJ, Fox KAA, de Geest H, Verstraete M, Collen D, Sobel BE: Coronary thrombolysis with tissue-type plasminogen activator in patients with evolving myocardial infarction. N. Engl. J. Med. 310:609-613, 1984.
Schneider DJ, Sobel BE: Augmentation of synthesis of plasminogen activator inhibitor type-1 by insulin and insulin-like growth factor type-1 and its pathogenetic implications for diabetic vascular disease. Proc. Natl. Acad. Sci. USA 88:9959-9963, 1991.
McGill JB, Schneider DJ, Arfken CL, Lucore CL, Sobel BE: Factors responsible for impaired fibrinolysis in obese subjects and NIDDM patients. Diabetes 43:104-109, 1994.
Sobel BE, Woodcock-Mitchell J, Schneider DJ, Holt RE, Marutsuka K, Gold H: Increased plasminogen activator inhibitor type-1 in coronary artery atherectomy specimens from type 2 diabetic compared with nondiabetic patients: A potential factor predisposing to thrombosis and its persistence. Circulation 97:2213-2221,1998.
Sobel BE, Frye R, Detre KM: Burgeoning dilemmas in the management of diabetes and cardiovascular disease: Rationale for the BARI 2D trial. Circulation, in press.
