BADERC Welcome

Robert E. Gerszten M.D.

Biomarker discovery in Myocardial Injury

Coronary heart disease in all of its manifestations is the leading cause of death in the United States. Further improvements in survival from myocardial injury will, to a great degree, depend on more rapid diagnosis and treatment. A particular focus of our efforts in biomarker and pathway discovery is the diabetic population. For any given ischemic insult, diabetics are known to have worse clinical outcomes than non-diabetic patients. Furthermore, in light of the atypical presentations of diabetic patients with acute coronary syndromes, the mandate to develop biomarkers relevant to this population is most compelling. Two specific ongoing projects are:

Project 1: Identification of Novel Markers of Myocardial Ischemia

The cardiac stress test is commonly used to help confirm or rule-out the diagnosis of myocardial ischemia. Based on Medicare data, close to 2 million tests are ordered each year. Unfortunately, the standard exercise stress test has a sensitivity of only 60% (and less than 50% for single-vessel disease) and a specificity of only 70%. Although the addition of myocardial perfusion imaging with agents such as ²⁰¹thallium and ^99mTc-sestaMIBI improves the operating characteristics of the test, these modifications add over $2000 to the cost. No serum biomarkers are available to diagnose myocardial ischemia. Such markers would be of immense value, both as an adjunct to exercise testing and in a host of clinical management scenarios, especially in the diabetic population.

We are currently performing proteomic and metabolic profiling of blood from patients who have undergone cardiac stress testing. Samples are obtained at baseline, peak exercise, and after one hour of recovery. These samples are ideal for analysis, as each patient serves as his or her own biological control. Samples from over 200 patients have already been obtained. Results from the ECG and imaging portions of the tests confirm a spectrum of patients, from “no ischemia” to “severe ischemia”. A large percentage of the patients are diabetic, and findings will be compared to the general population of ischemic heart disease.

Project 2: Novel Markers of Myocardial Infarction (irreversible injury)

Although several well-characterized markers of myocardial infarction exist, available markers such as the cardiac troponins can detect myocardial injury/necrosis only 4-6 hours after its initiation; identification of new proteins that are elaborated sooner after injury would be of immense clinical utility. For this purpose, we take advantage of samples obtained during alcohol septal ablation, a “controlled myocardial infarction” performed on patients with hypertrophic cardiomyopathy. In this human model, blood is obtained just prior to and following the planned injury, and protein compositions can be compared—with each patient serving as his or her own biological control. Samples, obtained just prior to the onset of injury, and at 1, 2, 4 and 24 hours intervals following the procedure, have been obtained from over 50 patients and are currently being evaluated. Coronary sinus samples, likely to contain higher levels of the proteins of interest, are available from approximately ten of these patients. Although such “planned MI’s” are not performed in diabetic populations, the findings could be of considerable utility to the diabetic population.

Refernces

1. Tager AM, Bromley SK, Medoff BD, Islam SA, Bercury SD, Friedrich EB, Carafone AD, Gerszten RE, Luster AD. Leukotriene B4 receptor BLT1 mediates early effector T cell recruitment. Nat Immunol. 2003;4:982-90.

2. Friedrich EB, Tager AM, Liu E, Pettersson A, Owman C, Munn L, Luster AD, Gerszten RE. Mechanisms of leukotriene B4--triggered monocyte adhesion. Arterioscler Thromb Vasc Biol. 2003;23:1761-7.

3. Jaffer FA, Tung CH, Gerszten RE, Weissleder R. In vivo imaging of thrombin activity in experimental thrombi with thrombin-sensitive near-infrared molecular probe. Arterioscler Thromb Vasc Biol. 2002;22:1929-35.

4. Gerszten RE. Pleiotropic effects of chemokines in vascular lesion development. Arterioscler Thromb Vasc Biol. 2002;22:528-9

5. Tung CH, Gerszten RE, Jaffer FA, Weissleder R. A novel near-infrared fluorescence sensor for detection of thrombin activation in blood. Chembiochem. 2002;3:207-11.

6. Friedrich EB, Sinha S, Li L, Dedhar S, Force T, Rosenzweig A, Gerszten RE. Role of integrin-linked kinase in leukocyte recruitment. J Biol Chem. 2002;277:16371-5.

7. Yoshida M, Sawada T, Ishii H, Gerszten RE, Rosenzweig A, Gimbrone MA Jr, Yasukochi Y, Numano F. Hmg-CoA reductase inhibitor modulates monocyte-endothelial cell interaction under physiological flow conditions in vitro: involvement of Rho GTPase-dependent mechanism. Arterioscler Thromb Vasc Biol. 2001;21:1165-71.

8. Gerszten RE, Friedrich EB, Matsui T, Hung RR, Li L, Force T, Rosenzweig A. Role of phosphoinositide 3-kinase in monocyte recruitment under flow conditions. J Biol Chem. 2001;276:26846-51.

9. Gerszten RE, Mach F, Sauty A, Rosenzweig A, Luster AD. Chemokines, leukocytes, and atherosclerosis. J Lab Clin Med. 2000;136:87-92.

10. Gerszten RE, Garcia-Zepeda EA, Lim YC, Yoshida M, Ding HA, Gimbrone MA Jr, Luster AD, Luscinskas FW, Rosenzweig A. MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature. 1999;398:718-23.






			Robert E. Gerszten M.D. Biomarker discovery in Myocardial Injury Coronary heart disease in all of its manifestations is the leading cause of death in the United States. Further improvements in survival from myocardial injury will, to a great degree, depend on more rapid diagnosis and treatment. A particular focus of our efforts in biomarker and pathway discovery is the diabetic population. For any given ischemic insult, diabetics are known to have worse clinical outcomes than non-diabetic patients. Furthermore, in light of the atypical presentations of diabetic patients with acute coronary syndromes, the mandate to develop biomarkers relevant to this population is most compelling. Two specific ongoing projects are: Project 1: Identification of Novel Markers of Myocardial Ischemia The cardiac stress test is commonly used to help confirm or rule-out the diagnosis of myocardial ischemia. Based on Medicare data, close to 2 million tests are ordered each year. Unfortunately, the standard exercise stress test has a sensitivity of only 60% (and less than 50% for single-vessel disease) and a specificity of only 70%. Although the addition of myocardial perfusion imaging with agents such as ²⁰¹thallium and ^99mTc-sestaMIBI improves the operating characteristics of the test, these modifications add over $2000 to the cost. No serum biomarkers are available to diagnose myocardial ischemia. Such markers would be of immense value, both as an adjunct to exercise testing and in a host of clinical management scenarios, especially in the diabetic population. We are currently performing proteomic and metabolic profiling of blood from patients who have undergone cardiac stress testing. Samples are obtained at baseline, peak exercise, and after one hour of recovery. These samples are ideal for analysis, as each patient serves as his or her own biological control. Samples from over 200 patients have already been obtained. Results from the ECG and imaging portions of the tests confirm a spectrum of patients, from “no ischemia” to “severe ischemia”. A large percentage of the patients are diabetic, and findings will be compared to the general population of ischemic heart disease. Project 2: Novel Markers of Myocardial Infarction (irreversible injury) Although several well-characterized markers of myocardial infarction exist, available markers such as the cardiac troponins can detect myocardial injury/necrosis only 4-6 hours after its initiation; identification of new proteins that are elaborated sooner after injury would be of immense clinical utility. For this purpose, we take advantage of samples obtained during alcohol septal ablation, a “controlled myocardial infarction” performed on patients with hypertrophic cardiomyopathy. In this human model, blood is obtained just prior to and following the planned injury, and protein compositions can be compared—with each patient serving as his or her own biological control. Samples, obtained just prior to the onset of injury, and at 1, 2, 4 and 24 hours intervals following the procedure, have been obtained from over 50 patients and are currently being evaluated. Coronary sinus samples, likely to contain higher levels of the proteins of interest, are available from approximately ten of these patients. Although such “planned MI’s” are not performed in diabetic populations, the findings could be of considerable utility to the diabetic population. Refernces 1. Tager AM, Bromley SK, Medoff BD, Islam SA, Bercury SD, Friedrich EB, Carafone AD, Gerszten RE, Luster AD. Leukotriene B4 receptor BLT1 mediates early effector T cell recruitment. Nat Immunol. 2003;4:982-90. 2. Friedrich EB, Tager AM, Liu E, Pettersson A, Owman C, Munn L, Luster AD, Gerszten RE. Mechanisms of leukotriene B4--triggered monocyte adhesion. Arterioscler Thromb Vasc Biol. 2003;23:1761-7. 3. Jaffer FA, Tung CH, Gerszten RE, Weissleder R. In vivo imaging of thrombin activity in experimental thrombi with thrombin-sensitive near-infrared molecular probe. Arterioscler Thromb Vasc Biol. 2002;22:1929-35. 4. Gerszten RE. Pleiotropic effects of chemokines in vascular lesion development. Arterioscler Thromb Vasc Biol. 2002;22:528-9 5. Tung CH, Gerszten RE, Jaffer FA, Weissleder R. A novel near-infrared fluorescence sensor for detection of thrombin activation in blood. Chembiochem. 2002;3:207-11. 6. Friedrich EB, Sinha S, Li L, Dedhar S, Force T, Rosenzweig A, Gerszten RE. Role of integrin-linked kinase in leukocyte recruitment. J Biol Chem. 2002;277:16371-5. 7. Yoshida M, Sawada T, Ishii H, Gerszten RE, Rosenzweig A, Gimbrone MA Jr, Yasukochi Y, Numano F. Hmg-CoA reductase inhibitor modulates monocyte-endothelial cell interaction under physiological flow conditions in vitro: involvement of Rho GTPase-dependent mechanism. Arterioscler Thromb Vasc Biol. 2001;21:1165-71. 8. Gerszten RE, Friedrich EB, Matsui T, Hung RR, Li L, Force T, Rosenzweig A. Role of phosphoinositide 3-kinase in monocyte recruitment under flow conditions. J Biol Chem. 2001;276:26846-51. 9. Gerszten RE, Mach F, Sauty A, Rosenzweig A, Luster AD. Chemokines, leukocytes, and atherosclerosis. J Lab Clin Med. 2000;136:87-92. 10. Gerszten RE, Garcia-Zepeda EA, Lim YC, Yoshida M, Ding HA, Gimbrone MA Jr, Luster AD, Luscinskas FW, Rosenzweig A. MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature. 1999;398:718-23.