Developed and validated methods by which biochemical quantification of the extent of myocardial infarction could be accomplished in vivo based on sequential analyses of concentration in plasma of macromolecules (CK, MB CK isoenzymes, and other moieties) and applied them to determine whether the extent of infarction was an important determinant of prognosis after myocardial infarction and furthermore, whether the extent of infarction could 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;
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;
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. Sobel played a leadership role that demonstrated 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 delineated altered fibrinolysis in blood and myocardium 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 and heart failure 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.
Representative Publications from a Total of More Than 975
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.
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.
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.
Kruszynska Y, Yu JG, Sobel BE, Olefsky JM: Effects of troglitazone on blood concentrations of plasminogen activator inhibitor 1 in patients with type 2 diabetes mellitus and in lean and obese normal subjects. Diabetes 49:633-639, 2000.
Schneider DJ, Hayes M, Wadsworth M, Taatjes H, Rincon M, Taatjes DJ, Sobel BE: Attenuation of neointimal vascular smooth muscle cellularity in atheroma by plasminogen activator inhibitor type-1 (PAI-1). J Histochem Cytochem 52:1091-1099, 2004.
Brooks MM, Frye RL, Genuth S, Detre KM, Nesto R, Sobel BE, Kelsey SF, Orchard TJ, for the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial Investigators: Hypothesis, design, and methods for the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial. Am J Cardiol 97(Suppl.):9G-19G, 2006.
Zaman AKMT, Fujii S, Schneider DJ, Taatjes DJ, Lijnen HR, Sobel BE: Deleterious effects of lack of cardiac PAI-1 after coronary occlusion in mice and their pathophysiologic determinants. Histochem Cell Biol. 128:135-145, 2007.
McBane RD II, Hardison RM, Sobel BE and the BARI 2D Study Group: Comparison of plasminogen activator inhibitor-1, tissue-type plasminogen activator antigen, fibrinogen, and D-dimer levels in various age decades in patients with type-2 diabetes mellitus and stable coronary artery disease (From the Bypass Angioplasty Revascularization Investigation 2 Diabetes Trial). Am J Cardiol 105:17-24, 2010.
French CJ,* Zaman AKMT,* Kelm RJ, Sobel BE (* co-first authors): Vascular rhexis: Loss of integrity of coronary vasculature in mice subjected to myocardial infarction. Exp Biol Med 235:966-973, 2010.
Binbrek AS, Rao KN, Van de Werf F, Sobel BE: Meta-analysis of studies of patients in the United Arab Emirates with ST elevation myocardial infarction treated with thrombolytic agents. Am J Cardiol 106:1692-1695, 2010.
French CJ, Zaman TAKM, Sobel BE: The angiotensin receptor blocker, Azilsartan medoxomil (TAK-491), suppresses vascular wall expression of plasminogen activator inhibitor type-1 (PAI-1) protein potentially facilitating the stabilization of atherosclerotic plaques. J Cardiovasc Pharm 58:143-148, 2011.
Zaman AK, French CJ, Spees JL, Binbrek AS, Sobel BE: Vascular rhexis in mice subjected to non-sustained myocardial ischemia and its therapeutic implications. Exp Biol Med 236:598-603, 2011.
Sobel BE, Hardison RM, Genuth S, Brooks MM, McBane RD III, Schneider DJ, Pratley RE, Huber K, Wolk R, Krishnaswami A, Frye RL for the BARI 2D Investigators. Profibrinolytic, anti-thrombotic, and anti-inflammatory effects of an insulin sensitizing strategy in patients in the BARI 2D trial. Circulation 124:695-703, 2011.
Schneider DJ and Sobel BE: PAI-1 and diabetes: A journey from the bench to the bedside. Diabetes Care 35, 2012 in press.
Sobel BE. Diabetes and heart disease. In: Cardiovascular Medicine. Edited by James T. Willerson, MD, Paul W. Armstrong, MD, and David Holmes, MD. Springer-Verlag London, 2013, in press.