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1. Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes: a randomized trial

Author

Tardif, Jean-Claude, Ballantyne, Christie M, Barter, Philip, Dasseux, Jean-Louis, Fayad, Zahi A, Guertin, Marie-Claude, Kastelein, John JP, Keyserling, Constance, Klepp, Heather, Koenig, Wolfgang, L'Allier, Philippe L, Lespérance, Jacques, Lüscher, Thomas F, Paolini, John F, Tawakol, Ahmed, Waters, David D, Pfeffer, M, Brown, V, Rouleau, J, Watkins, P, Wei, LJ, Gosselin, G, Chayer, C, Lanthier, S, Pelletier, GB, Racine, N, Agarwal, H, Brilakis, E, Cannon, L, Carrié, D, Corbelli, J, Coste, P, de Winter, R, Diaz, A, Eisenberg, S, Ennis, B, Fajadet, J, Fam, N, Fortuin, D, Gessler, C, Grines, C, Guerra, D, Gum, H, Haldis, T, Heestermans, T, Herrman, JP, Huynh, T, Kedhi, E, Koren, M, Kouz, S, Krolick, M, Kumkumian, G, Lavi, S, Li, RJ, Masud, ARZ, McAlhany, C, McGrew, FA, O'Shaughnessy, C, Ophuis, AJM Oude, Parr, K, Penny, W, Pesant, Y, Post, H, Robinson, S, Rodes-Cabau, J, Roy, A, Schulman, S, Spence, F, Stouffer, G, Stys, T, Sussex, B, Tahirkheli, N, Tardif, J-C, Grégoire, J, Berg, J ten, van Boven, AJ, von Birgelen, C, and Weinstein, D

Subjects
Aging, Clinical Trials and Supportive Activities, Atherosclerosis, Clinical Research, Cardiovascular, Heart Disease - Coronary Heart Disease, Heart Disease, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Acute Coronary Syndrome, Adult, Aged, Aged, 80 and over, Apolipoprotein A-I, Cardiovascular Agents, Coronary Angiography, Coronary Artery Disease, Female, Humans, Infusions, Intravenous, Male, Middle Aged, Phospholipids, Prospective Studies, Recombinant Proteins, Treatment Outcome, Ultrasonography, Coronary disease, High-density lipoproteins, Clinical trial, Can HDL Infusions Significantly QUicken Atherosclerosis REgression (CHI-SQUARE) Investigators, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Cardiovascular System & Hematology
Abstract

AimHigh-density lipoproteins (HDLs) have several potentially protective vascular effects. Most clinical studies of therapies targeting HDL have failed to show benefits vs. placebo.ObjectiveTo investigate the effects of an HDL-mimetic agent on atherosclerosis by intravascular ultrasonography (IVUS) and quantitative coronary angiography (QCA).Design and settingA prospective, double-blinded, randomized trial was conducted at 51 centres in the USA, the Netherlands, Canada, and France. Intravascular ultrasonography and QCA were performed to assess coronary atherosclerosis at baseline and 3 (2-5) weeks after the last study infusion.PatientsFive hundred and seven patients were randomized; 417 and 461 had paired IVUS and QCA measurements, respectively.InterventionPatients were randomized to receive 6 weekly infusions of placebo, 3 mg/kg, 6 mg/kg, or 12 mg/kg CER-001.Main outcome measuresThe primary efficacy parameter was the nominal change in the total atheroma volume. Nominal changes in per cent atheroma volume on IVUS and coronary scores on QCA were also pre-specified endpoints.ResultsThe nominal change in the total atheroma volume (adjusted means) was -2.71, -3.13, -1.50, and -3.05 mm(3) with placebo, CER-001 3 mg/kg, 6 mg/kg, and 12 mg/kg, respectively (primary analysis of 12 mg/kg vs. placebo: P = 0.81). There was also no difference among groups for the nominal change in per cent atheroma volume (0.02, -0.02, 0.01, and 0.19%; nominal P = 0.53 for 12 mg/kg vs. placebo). Change in the coronary artery score was -0.022, -0.036, -0.022, and -0.015 mm (nominal P = 0.25, 0.99, 0.55), and change in the cumulative coronary stenosis score was -0.51, 2.65, 0.71, and -0.77% (compared with placebo, nominal P = 0.85 for 12 mg/kg and nominal P = 0.01 for 3 mg/kg). The number of patients with major cardiovascular events was 10 (8.3%), 16 (13.3%), 17 (13.7%), and 12 (9.8%) in the four groups.ConclusionCER-001 infusions did not reduce coronary atherosclerosis on IVUS and QCA when compared with placebo. Whether CER-001 administered in other regimens or to other populations could favourably affect atherosclerosis must await further study. Name of the trial registry: Clinicaltrials.gov; Registry's URL: http://clinicaltrials.gov/ct2/show/NCT01201837?term=cer-001&rank=2;Trial registration numberNCT01201837.

Published
2014

13. Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes: a randomized trial†

Author

Tardif, Jean-Claude, Ballantyne, Christie M., Barter, Philip, Dasseux, Jean-Louis, Fayad, Zahi A., Guertin, Marie-Claude, Kastelein, John J. P., Keyserling, Constance, Klepp, Heather, Koenig, Wolfgang, L'Allier, Philippe L., Lespérance, Jacques, Lüscher, Thomas F., Paolini, John F., Tawakol, Ahmed, Waters, David D., Pfeffer, M., Brown, V., Rouleau, J., Watkins, P., Wei, L.J., Gosselin, G., Chayer, C., Lanthier, S., Pelletier, G.B., Racine, N., Agarwal, H., Brilakis, E., Cannon, L., Carrié, D., Corbelli, J., Coste, P., de Winter, R., Diaz, A., Eisenberg, S., Ennis, B., Fajadet, J., Fam, N., Fortuin, D., Gessler, C., Grines, C., Guerra, D., Gum, H., Haldis, T., Heestermans, T., Herrman, J.P., Huynh, T., Kedhi, E., Koren, M., Kouz, S., Krolick, M., Kumkumian, G., Lavi, S., Li, R.J., Masud, ARZ, McAlhany, C., McGrew, F.A., O'Shaughnessy, C., Oude Ophuis, A.J.M., Parr, K., Penny, W., Pesant, Y., Post, H., Robinson, S., Rodes-Cabau, J., Roy, A., Schulman, S., Spence, F., Stouffer, G., Stys, T., Sussex, B., Tahirkheli, N., Tardif, J-C, Grégoire, J., ten Berg, J., van Boven, A.J., von Birgelen, C., and Weinstein, D.

Abstract

Aim High-density lipoproteins (HDLs) have several potentially protective vascular effects. Most clinical studies of therapies targeting HDL have failed to show benefits vs. placebo. Objective To investigate the effects of an HDL-mimetic agent on atherosclerosis by intravascular ultrasonography (IVUS) and quantitative coronary angiography (QCA). Design and setting A prospective, double-blinded, randomized trial was conducted at 51 centres in the USA, the Netherlands, Canada, and France. Intravascular ultrasonography and QCA were performed to assess coronary atherosclerosis at baseline and 3 (2-5) weeks after the last study infusion. Patients Five hundred and seven patients were randomized; 417 and 461 had paired IVUS and QCA measurements, respectively. Intervention Patients were randomized to receive 6 weekly infusions of placebo, 3 mg/kg, 6 mg/kg, or 12 mg/kg CER-001. Main outcome measures The primary efficacy parameter was the nominal change in the total atheroma volume. Nominal changes in per cent atheroma volume on IVUS and coronary scores on QCA were also pre-specified endpoints. Results The nominal change in the total atheroma volume (adjusted means) was −2.71, −3.13, −1.50, and −3.05 mm3 with placebo, CER-001 3 mg/kg, 6 mg/kg, and 12 mg/kg, respectively (primary analysis of 12 mg/kg vs. placebo: P = 0.81). There was also no difference among groups for the nominal change in per cent atheroma volume (0.02, −0.02, 0.01, and 0.19%; nominal P = 0.53 for 12 mg/kg vs. placebo). Change in the coronary artery score was −0.022, −0.036, −0.022, and −0.015 mm (nominal P = 0.25, 0.99, 0.55), and change in the cumulative coronary stenosis score was −0.51, 2.65, 0.71, and −0.77% (compared with placebo, nominal P = 0.85 for 12 mg/kg and nominal P = 0.01 for 3 mg/kg). The number of patients with major cardiovascular events was 10 (8.3%), 16 (13.3%), 17 (13.7%), and 12 (9.8%) in the four groups. Conclusion CER-001 infusions did not reduce coronary atherosclerosis on IVUS and QCA when compared with placebo. Whether CER-001 administered in other regimens or to other populations could favourably affect atherosclerosis must await further study. Name of the trial registry: Clinicaltrials.gov; Registry's URL: http://clinicaltrials.gov/ct2/show/NCT01201837?term=cer-001&rank=2; Trial registration number: NCT01201837

Published
2017

14. Acute ST-Elevation Myocardial Infarction in Patients Hospitalized for Noncardiac Conditions

Author

Bumgarner, J., Spangler, A., Smith, S. C., Meredith, D., Dai, X., and Stouffer, G. A.

Subjects
surgical procedures, operative, cardiovascular diseases
Abstract

BackgroundMajor advances have been made in the treatment of ST‐elevation myocardial infarction (STEMI) in outpatients. In contrast, little is known about outcomes in STEMI that occur in patients hospitalized for a noncardiac condition.Methods and ResultsThis was a retrospective, single‐center study of inpatient STEMIs from January 1, 2007, to July 31, 2011. Forty‐eight cases were confirmed to be inpatient STEMIs of a total of 139 410 adult discharges. These patients were older and more often female and had higher rates of chronic kidney disease and prior cerebrovascular events compared with 227 patients with outpatient STEMIs treated during the same period. Onset of inpatient STEMI was heralded most frequently by a change in clinical status (60%) and less commonly by patient complaints (33%) or changes on telemetry. Coronary angiography and percutaneous coronary intervention were performed in 71% and 56% of patients, respectively. The median time to obtain ECG (41 [10, 600] versus 5 [2, 10] minutes; P

Published
2013
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15. Mitochondrial Oxidative Stress in Aortic Stiffening With Age: The Role of Smooth Muscle Cell Function

Author

Molnar, K. C., Zhou, R.-H., Rojas, M., Tong, H., Runge, M. S., Vendrov, A. E., Madamanchi, N. R., Carter, J. D., Stouffer, G. A., Niu, X.-L., and Tchivilev, I.

Subjects
cardiovascular system, musculoskeletal system
Abstract

Age-related aortic stiffness is an independent risk factor for cardiovascular diseases. Although oxidative stress is implicated in aortic stiffness, the underlying molecular mechanisms remain unelucidated. Here, we examined the source of oxidative stress in aging and its effect on smooth muscle cell (SMC) function and aortic compliance using mutant mouse models.

Published
2012
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17. Dominant-Negative Loss of PPAR Function Enhances Smooth Muscle Cell Proliferation, Migration, and Vascular Remodeling

Author

Stouffer, G. A., Panchatcharam, M., Miriyala, S., Smyth, S. S., Tsai, Y.-S., Meredith, D., Maeda, N., and Morris, A. J.

Subjects
endocrine system diseases
Abstract

The Peroxisome Proliferator Activated Receptor-gamma (PPARγ) protein is a nuclear transcriptional activator with importance in diabetes management as the molecular target for the thiazolidinedione (TZD) family of drugs. Substantial evidence indicates that the TZD family of PPARγ agonists may retard the development of atherosclerosis. However, recent clinical data has suggested that at least one TZD may increase the risk of myocardial infarction and death from cardiovascular disease. In this study, we used a genetic approach to disrupt PPARγ signaling to probe the protein's role in smooth muscle cell (SMC) responses that are important for atherosclerosis.

Published
2009
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18. Intravenous NPA for the treatment of infarcting myocardium early; InTIME-II, a double-blind comparison of single-bolus lanoteplase vs accelerated alteplase for the treatment of patients with acute myocardial infarction

Author

Braunwald, E., Neuhaus, K. -L., Antman, E., Chew, P., Skene, A., Wilcox, R., Ambrosioni, E., Anderson, J., Apetrei, E., Bata, I., Carrageta, M., Col, J., Dalby, A., Davies, R., Deckers, J., Eichman, D., Grande, P., Greene, R., Gurfinkel, E., Heikkilä, J., Henry, T., Hillis, D., Hochman, J., Huber, K., Kostis, J., Klinke, P., López-Sendón, J., Mckendall, G., Móller, B., Moore, P., Morris, A., Mueller, H., Östör, E., Oto, A., Ruda, M., Sadowski, Z., Schweiger, M., Sequeira, R., Shah, P., Shannon, R., Smith, B., Sobel, B., Steingart, R., Tebbe, U., Toman, J., Traboulsi, M., Vahanian, A., Warnica, J. W., Willerson, J., Deitchman, D., Davidson, L., Folgia, T., Foxley, A., Goodman, J., Hauck, C., Henry, D., Mccabe, C., Pangerl, A., Thomson, A., Wagner, M., Kennedy, J. W., Cairns, J., Demets, D., Julian, D., Simoons, M., Charlesworth, A., Easton, J. D., Ferbert, A., Feske, S., Kuhn, P., Moseley, J., Rogg, J. M., Reichmann, H., Sloan, M., von Kummer, R., Zamani, A., Coulter, S., Giugliano, R., Skene, A. M., Ardill, R., Ince, Y., Peters, A., Ward, K., Wolf, L., Curtis, N., De Brés, J., Stead, S., Watson, S., Cutler, S., Friedman, J., Helfrick, R., Williams, S., Klimovsky, J., Kumagai, S., Adams, E., Anderson, C., Bauhuber, I., Bennett, L., Biro, E., Boyce, E., Bregman, B., Carvalho, P., Ciganovic, D., Csukas, M., Cuenca, P., De Cuyper, S., Diez, P., Dijkhuizen, M., Dille-Amo, C., Gonzalez-Santis, A., Gursoy, M., Hammarstrom, K., Harasta, E., Ingman, E., Kelemen, B., Keulen, I., Koren, A., Langthaler, G., Lemaire, F., Little, I., Montalban, C., Nijssen, K., Neumueller, I., Palander, M., Pekuri, T., Persson, U., Pilz, J., Oudotova, S., Pisklakov, V., Proinov, F., Ptaszynska, A., Read, J., Retei, S., Romeyer, F., Romanini, M., Saar, L., Salein, D., Samsonov, M., Simeon-Dubach, D., Simmonds, J., Skaza, M., Skvortsova, N., Smidlova, Z., Spitzerova, H., Strijdveen, I., Szajewski, T., Ugurnal, B., Valcarce, M., van Rompaey, I., Walker, A., Zak, E., Zimova, N., Barrero, C., Beck, E., Bruno, M. L., Caccavo, A., Cagide, A., Campo, A., Cermesoni, R., Chahin, M., Dutra, O., Estrada, J., Falu, E. A., Gagliardi, J., Garre, L. E., Liprandi, A. S., Luciardi, H., Mautner, B., Muntaner, J., Nau, G., Salzberg, S., Santopinto, J., Sinisi, A., Torres, H., Eber, B., Elliott, P., Hiemetsberger, H., Juhasz, M., Kühn, P., Leisch, F., Niktardjam, M., Reisinger, J., Schmalix, G., Schuster, R., Sihorsch, K., Silberhauer, K., Slany, J., Steinbach, K., Tragl, K. H., Valentin, A., Al Shwafi, K., Dasnoy, P., De Clippel, M., de Meester, A., De Raedt, H. J. L. P., Emonts, M., Evrard, P., Eycken, M., Geboers, M., Heyndrickx, G., Lauwers, K., Mitrie, K., Pirenne, B., Renard, M., Somers, Y., Timmermans, P., Van Kuyk, M., Van Mieghem, W., Vermeulen, J., Verrostte, J. M., Albuquerque, D., Ayoub, J. C. A., Carvalho, A., Cesar, L., Gebara, O., Golin, V., Knobel, E., Leaes, P., Neto, J. A. M., Nicolau, J. C., Piegas, L. S., Rabelo, A., Rassi, A., Sila, L., Simao, A. F., Ashton, T., Baillie, H., Bhargava, R., Bota, G., Cameron, W., Chan, N., Chan, Y. K., Daly, P. A., Darcel, I., Davies, E., Desjardin, L., Dhingra, S., Ducas, J., Ervin, F. L., Fortin, C., Fowlis, R., Fulop, J., Furey, M., Gagnon, S., Gebhardt, V., Giannaccro, P., Gosselin, G., Graham, J., Grondin, F., Heath, J. W., Henderson, M., Hilton, D. R., Hiscock, J., Hui, W., Kaza, L., Kesselman, T., Kouz, S., Kucerak, M., Lahoude, N., Lamothe, M., Lebouthillier, P., Lenis, J., Levesque, P., Lopez, J. F., Lubelsky, B., Macritchie, D., Mayer, J. -P., Mcdowell, J. D., Montigny, M., Orestien-Lyall, T., Parekh, P., Pistawka, K., Price, J. B., Pruneau, G., Quinn, B., Reid, B. R., Richmond, M., Rose, B., Schuld, R., Sharma, N. K., Shetty, P., Stanton, E., Strauss, H. D., Sussex, B., Theroux, P., Turabian, M., Turner, C., Vizel, S., Walker, M., Weeks, A., Winkler, L., Zacharias, G., Zimmerman, R., Bartolucci, J., Castro, P., Diaz, M. A., Illanes, G., Potthoff, S., Sanchez, E. C., Silva, L. M., Yovanovich, J., Zanetti, F. L., Alan, D., Balázová, K., Boček, P., Cerny, J., Fischerova, B., Holub, M., Hradec, J., Janota, T., Janský, P., Kasper, J., Klimsa, Z., Motovská, Z., Pleva, L., Pluhacek, L., Pšenčka, M., Semrád, B., Spinar, J., Staněk, V., Štípal, R., Suítil, P., Vítovec, J., Wichterie, D., Widimský, P., Zeman, K., Andersen, C. B., Kriegbaum, J., Nielsen, N., Nielsen, P. E., Schou, J. B., Teesalu, R., Voitk, J., Haapamäki, H. V. H., Halkosaari, M., Härkönen, M., Jägerholm, S., Kärjä-Koskenkari, P., Karthunen, P., Kesäniemi, Y. A., Koskivirta, H., Lehto, P., Lilja, M., Paakkinen, S., Palomäki, A. K., Pietilä, K., Tuominen, J., Viopio-Pulkki, L., Ylönen, H., Adi, I., Admant, P., Akadirik, A., Alagha, Z., Alhabaj, S., Amat, G., Andre, A. A., Apffel, F., Aswad, K., Baradat, G., Bareiss, P., Barthers, F. B., Baudet, M., Baudouy, M., Bearez, E. M., Berthou, J. D., Berzin, B., Bessede, G., Blanc, J. J., Bocara, A., Bonneau, A., Bourdad, C., Bouvier, J. M., Cassagnes, J., Cassat, A., Cazaux, P., Charbonnier, B., Clementy, J., Cohen, A., Coisne, D., Colin, P., Croizier, O., D’Hautefeuille, B., D’Ivernois, C., Daumas, P. L., Dauphin, C. L., Deforet, M. F., Degand, B., Dequeker, J. L., Dickele, M. C., Dugrand, P., Durand, S., Ebagosti, A., Elharrar, C., Equine, O., Fichter, E., Flork, L., Fouche, R., Fourchard, V., Fourme, T., Fournier, P. Y., Funck, F., Galley, D., Garbarz, E., Ghadban, W., Gladin, M., Grall, J. Y., Grand, A., Gryman, R., Guillard, N., Guillo, P., Haftel, Y., Hannebicque, G., Henry, R., Huret, J. F., Janin-Magnificat, L., Jarnier, J., Joly, A., Kamal, H., Khalife, A., Roynard, J. L., Lang, M., Lapeyssonnie, A., Ledain, L., Lejeune, P., Lemetayer, L., Lepori, R., Lombart, A., Lusson, J. R., Magnin, O., Marquand, A., Martelet, M. M., Martelli, A., Mathurin, C., Mentre, B., Messager, D., Morizot, M., Mouallem, M. J., Mouhoub, O., Mycimski, C., Nallet, O., Olive, T., Pacouret, G., Palcoux, M. C., Poulard, J. E., Pruvost, A., Quiret, J. C., Richard, C., Richard, P., Rickaud, P., Riehl-Aleil, V., Rifai, A., Rocher, R., Rotreff, P., Segrestin, B., Slama, M. S., Sultan, P., Tabone, X., Talbodec, A., Tissot, M. T., Toussaint, C., Veyrat, A., Zerrouk, Z., Adamczak, M., Altmann, E., Altybernd, B., Andreassen, G., Andresen, D., Appenrodt, H., Bachmann, S., Bäcker, U., Beckert, U., Behr, H. M., Beier, W., Beier, T., Berger, D., Bernsmeier, R., Beythien, R. D., Biechl, E., Biedermann, G., Bischoff, K. O., Blerich, J., Boch, H. B., Bonzel, T., Both, A. R., Breidenbach, K., Breuer, M., Breuer, H. W. M., Brunkhorst, F. B., Bruns, A., Bundschu, H. D., Burkhardt, W., Busse, H. J., Caesar, K., Cailloud, J., Chlosta, A., Chorlanopoulos, E., Consemüller, S., Decker, W., Dichgans, M., Dick, R., Diederich, K. W., Dienst, C., Dietz, A., Dißmann, R., Ditter, H., Doering, W., Drost, H., Dundalek, E. D., Eckardt, D., Edelmann, A., Eggeling, T., Eggert, G., Eichner, R., Endres, C., Engberding, R., Engel, H. J., Faehnrich, A., Fischer, J. L., Flor, A., Forycki, F. Z. F., Froböse, H. J., Fruehauf, T., Fuchs, M., Geiser, R., Geletneky, J., Gerdes, H., Gerecke, B., Gesing, S., Gieser, H., Girth, E., Glogner, P., Glover, M., Goetz, J., Goetz, H., Göttfert, G., Gottwik, M., Gregori, B., Grieshaber, M., Großmann, C., Gruber, G., Gunold, H., Häßler, W. H., Hackenjos, B., Hader, O., Hamer, H., Harmjanz, D., Hasst, G., Haun, H., Hauptmann, K. E., Hegge, F. J., Heinze, A., Heinze, R., Henrichs, K. J., Hergenröther, H., Herrmann, F., Herzig, C., Hey, D., Hill, S., Hinzmann, S., Hoffmann, S., Höfs, T., Höhler, H., Holle, G., Höltman, B. J., Horacek, T., Hossmann, V., Hübner, F. S., Hülskamp, C., Hunecke, R., Hust, M., Jaeckh, G., Jebens, C., Jennen, E., Jost, M., Justiz, R., Kallmann, L., Kalscheur, F., Kaschner, W., Kaspar, W., Kauder, E., Keitel, B., Keller, H., Kemkes, T., Kerler, N., Kester, M., Kettner, W., Kilp, M., Kirklies, A., Klaus, A., Klein, H. H., Klenböck, J. R., Kley, H. K., Klingenbeck, R., Koch, H., Kohler, B., Kohler, J., Kolloch, R., Konermann, M., Körber, H. G., Kother, T. K., Kötter, V., Kottwitz, B., Kozariszcsuk, G., Kracht, T., Kratzsch, G., Kreft, H. U., Kreuter, G., Krönert, H., Krönig, B., Krueger, E., Krülls-Münch, J., Kuckuk, H., Kuelschbach, M., Kuhrt-Lassay, O. W., Kummerhoff, P. W., Kunevt, R., Kurth, C. U., Lang, C., Lange, C., Langhoff, R., Laskus, A., Lazarus, P., Lehmann, H. U., Lenga, P., Lengfelder, W., Leupolz, W., Limbourg, P., Loos, U., Lucanus, W., Machill, K., Mäckel, P., Mackes, K. G., Maier, S., Makowski, B., Mandok, J., Manz, M., Mäurer, W., Meier, F., Meier, J., Menges, M., Merx, W., Meurers, G., Michels, U., Mickeler, C. H., Mons, D., Moos, E., Mueller, R., Müller, G., Nast, H. P., Naumann, G., Nebelsieck, H., Neubaur, J., Niederer, W., Nitsch, J., Noack, J., Nogai, K. F. W., Oberheiden, A., Obst, R., Ochs, H. R., Odemar, F., Odenthal, H. J. B., Offers, E., Öhl, S., Ohlmeier, H. A. R. M., Patzer, P., Pech, A., Peters, U., Petry, U., Pietschmann, G. J., Pistner, W., Plappert, B., Pohlmann, W. K., Pollock, B., Presser, H. J., Przytarski, K., Puerner, K. L., Raouf, N., Reike, N., Reil, G. H., Reinhard, U., Riebeling, V., Ritzmann, M., Rödder, J., Roth, E., Rüdelstein, R., Saborowski, F., Sauter, B., Sceffler, N., Schartl, A., Schifferdecker, E., Schlotterbeck, K. P., Schmidt, J., Schmidt-Dannert, D. R., Schmidt-Klewitz, H., Schmitz, H. J., Schnebelt, T., Schneider, H. L., Schneider, F. J., Schoeller, R., Scholz, D., Schoppe, W. D., Schreiner, G., Schroeder, J., Schuh, N., Schulte, K. L., Schulze, H., Schulze, H. D., Schuster, P., Schuster, H. P., Schweizer, P., Sechtem, U., Sedlmaier, H. P., Segel, S., Sehnert, W., Seidel, F., Siedentopf, K., Simon, H., Sodomann, C. P., Solbach, C., Sorges, E., Stabenow, S., Stadler, K. P., Stammwitz, E., Stein, U., Sternberg, H., Stiepak, C., Stockmann, M., Straus, W., Striegel, H., Struch, E., Strupp, G., Taubert, T. B. T., Thoeming, B., Thoß, A., Tinnappel, J., Tomsik, H., Topp, H., Troost, S., Öberreiter, A., Uebis, R., Ungler, T., Urbaszek, W., Vöhringer, H. F., von Arnim, T., von Leitner, E. R., von Löwis of Menar, A., von Mengden, H. J., von Smekal, P., Voss, W., Wacker, P., Warning, A., Warzecha, A., Wefers, U., Wehr, M., Weigel, H., Weissthanner, F., Weller, P., Werner, M., Wette, A., Wichert, H., Wielage, T., Wiese, U., Wilbrand, T. B., Wilhelms, E., Wilmsmann, G., Wolf, F. H., Wolf, T., Wonhas, F. C. M., Zastrow, B., Zeymer, U., Ziruler, S., Ziss, W., Zölch, K. A., Zwirner, K., Becker, D., Bosko, M., Csillag, I., Ermenyi, A., Fogas, J., Heltai, K., Jánosi, A., Katona, A., Kiraly, C., Kiss, B., Kutor, G., Mizik, R., Molnar, T., Mühl, M., Nagy, D., Palacti, I., Rudas, L., Sárosi, I., Simon, K., Sitkel, E., Sydó, T., Szaboki, F., Szikla, K., Szönyi, T., Timar, S., Vándor, L., Zamolyl, K., Walsh, M., Caspi, A., Swissa, M., Badano, L., Baldacci, G., Balli, E., Banda, D., Baretta, G., Boccalatte, A., Borgatti, M. L., Branzi, A., Burelli, C., Capelletti, D., Capucci, A., Caragiulo, D., Carbonieri, E., Cassin, M., Ceci, V., Cocchieri, M., Coletta, C., Conte, E., Contini, G. M., Corsini, G., D’Annunzio, E., De Blasi, M., De Luca, I., Delciterna, F., Di Pasquale, G., Diguardo, G., Fattore, L., Ferraiuulo, G., Finardi, A., Fioretti, P. M., Giunta, G., Guiducci, U., Guzzardi, G., Horando, G., Ignone, G., Lazzaroli, A., Levantesi, D., Liberati, R., Losi, E., Macor, F., Mangiameli, S., Martines, C., Meinardi, F., Morgera, T., Morozzi, L., Mostacci, M., Naccarella, F. F., Ottani, F., Palamara, A., Pani, A., Paperini, L., Pes, R., Pesola, A., Porzio, A., Raviele, A., Ricci, S., Rosi, A., Rossi, R., Rotiroti, D., Rusconi, L., Sabino, G., Saccone, V., Sanna, A., Scaramuzzino, G., Scorcu, G. P., Semprini, F., Severini, D., Staniscia, D., Tantalo, L., Tartagni, F., Terrosu, P., Tondelli, S., Trichero, R., Uslenghi, E., Vajola, S. F., Vetrano, A., Violi, E., Zardini, P., Zingarini, G. L., Zobbi, G., Zuin, G., Kalnins, U., Cârvekülg, A., Laanoca, J., Iacis, J., Lankiene, L., Laucevicius, A., Lukoseviciute, A., Palsauskaite, R., Petrauskiene, B., Soopóld, W., Uuetoa, H., Vilks, J., Vitonyte, R., Zakke, I., Dorantes, J., Hernández, H., Jerjes, C., Leva Garza, J. L., Martinez, C., Anneveldt, A., Baars, H. F., Baldew, S. C., Bendermacher, P. E. F., Boersma, L. V. A., Bos, R. J., Breedveld, R. W., Bruggink, P. W. F., Ciampricotti, R., Darmanata, J. I., de Porto, A. E., de Weerd, G. J., Deckers, J. W., Freericks, M. P., Hillebrand, F. A., Kerker, J. P., Koenen, J. C., Kofflard, M. G. M., Liem, K. L., Liem, A. H., Linssen, G. C. M., Lionarons, R. J., Peters, J. R. M., Posma, J. P., Saat, E. W. M., Savalle, L. H., Smits, W. C. G., Suttorp, M. J., Tans, A. C., Troquay, R. P. Th., van Beek, G. J., van Boven, A. J., Van der Heijden, R., Van Hessen, A., van Langeveld, R. A. M., van Lier, T. A. R., van Loo, L. W. H., van Wijngaarden, J., van Ziejl, L. G. P. M., Veerhoek, M. J., Vermer, F., Werner, H. A., Graven, T., Klykken, B., Meyerdieks, O., Omland, T. M., Otterstad, J. E., Pedersen, T., Rød, R., Banaszewski, M., Bednarkiewicz, Z., Bojarski, G., Ceremuzyñski, L., Czestochowska, E., Gajewski, M., Galewicz, M., Gorski, J., Grabczewska, Z. S., Gruchaka, M., Janicki, K., Janion, M., Jaworska, K., Jezewska, M., Kakol, J., Kizciuk, M., Kleinrok, A., Kolodziej, P., Komorowski, P., Konopka, A., Kopaczewski, J., Korecki, J., Kornacewicz-Jach, Z., Kowalewski, M., Kratochwil, D., Krolczyk, J., Krzminska-Pakula, M., Kurek, P., Kurowski, M., Kurpesa, M., Kurzawski, J., Kwiecien, R., Lenartowski, L., Lewandowski, M., Loboz-Grudzieñ, K., Luczak, G., Maliñski, A., Michalski, M., Musial, W., Nartowicz, E., Nowicka, A., Odyniec, A., Pasyk, S., Prastowski, W., Przybylski, A., Raczynska, A., Rodzik, J., Romanowski, M., Rynkiewicz, A., Rzyman, M., Sidorowicz, A., Sledziona, M., Sobiczewski, W., Sobkowicz, B., Sobolewska, J., Sokalski, L., Stepinska, J., Sterlinski, M., Stopinski, M., Świątecka, G., Szpernal, Z., Tarnowska, H., Trzos, E., Ujda, M., Wierzchowiecki, M., Wodynska, T., Wojciechowski, D., Wrabec, K., Wrzesinski, K., Zuk, P., Albuquergue, A., Costa, A., Cunha, D., Ferreira, D., Ferreira, R., Gaog Leiria, J. M., Pimenta, A., Rufino, E., Vasconcelos, J., Aldica, M., Balanescu, S., Bruckner, I. V., Capalneanu, R., Florescu, N., Georgescu, C. S., Cherasim, L., Ginshina, C., Merenta, A., Parvu, O., Radutiu, S., Savulescu, I., Vita, I., Averkov, O., Bokarev, I. N., Gratsiansky, N., Grigoriev, Y., Gruzdev, A., Kakhnovsky, I., Kheevehuk, T. V., Khrustalev, O., Kobalava, Y., Konoratieva, T. B., Koukline, Vladimir, Martiouchov, S., Pavlikova, E., Poskotinov, I., Rogalev, K., Sinopainikov, A., Syrkin, A., Tereschenko, S. T., Yavelov, I., Zavolghin, S., Čurilla, E., Kohn, R., Kovář, F., Murín, J., Poliačik, P., Drinovec, I., Horvat, M., Krivec, B., Markež, J., Pareznik, R., Pehnec, Z., Resman, J., Sifrer, F., Skale, R., Trinkaus, D., Voga, G., Baig, M. M. E., Blomerus, P., Botha, B. P., Burgess, L., Duncan, D., Duncan, D. I., Gillmer, D., Govender, N., Jardine, R. J., Kok, A., Manga, P., Naidu, R. K., Rajput, M. C., Ranjith, N., Roos, J. S., Snyders, F. A., Steingo, L., Stern, A., Tayob, F. Z., Vythilingum, S., Alonso-Orcajo, N., Arribas Jimenez, A., Ayestaran, J. I., Balsera, B. B. G., Barras, C., Castro, A., Cobo, N., Duque, A., Garcia, M. J., Goiriena, P., Gonzalez-Valdayo, M., Gulias Lopez, J. M., Jimenez Gomez, P., Lopez Garanda, V., Martín Santos, F., Nogueira, R., Pabon Osuna, P., Ponce De Leon, E., Quesada Dorador, A., Paya Serrano, R., Rodriguez, L., Rodriguez, M., Rubio, F., Ruiz-Salmeron, R., Solar, J., Toquero, J., Velasco, J., Vilar Herrero, V., Vizcaino, M., Wancisidor, X., Basilier, E., Birgersdotter, V., Björnsdotter, E., Bjurman, A., Hagström, D., Hallin, I., Hansen, O., Hemmingson, L. O., Lundkvist, L., Lycksell, M., Möller, B., Nolgard, P., Sjölund, G., Stjerna, A., Angehrn, W., de Benedetti, E., Diethelm, M., Gallino, A., Plebani, G., Vögelin, H. P., Wojtyna, W., Akgöz, H., Akgün, G., Akyürek, O., Batur, M. K., Bayata, S., Deger, N., Emel, O., Gürgün, C., Korkmaz, M. E., Kozan, O., Kumbasar, D., Muderrisoglu, H., Nisanci, Y., Ozin, B., Ozsaruhan, O., Payzin, S., Postaci, N., Sozcuer, H., Tamci, B., Topuzoglu, F., Türkoglu, C., Tutar, E., Ulucam, M., Ulusoy, T., Umman, B., Yalçinkaya, S., Yesil, M., Zoghi, M., Adams, P. C., Ahir, S., Ahsan, A. J., Akhtar, J., Albers, C. J., Al-Khafaji, M. N., Anderson, N., Bailey, R. J., Bain, R. J. I., Basu, A., Beal, A., Boyle, R. M., Brown, N., Campbell, S., Card, D., Cross, S. J., Davies, P., Davis, E. T. L., Dean, J. W., Deaner, A., Devine, M. A., Dhawan, J., Doig, J. C., Dubrey, S., Dunn, P. G., Dwight, J., Ecob, R., Fitzpatrick, H., Fletcher, S., Francis, C. M., Gershlick, A. H., Glennon, P. E., Goodfield, N. E., Grabau, W. J., Gray, M., Gray, K. E., Heath, J., Hendry, W. G., Highland, J., Hogg, K., Irving, J. B., James, M. A., Jennings, K., Joy, M., Kadr, H. H., Kahn, S., Keeling, P. J., Keir, P. M., Kemp, T. M., Kinaird, J., Kinsey, C., Knowles, K., Kooner, J. S., Lahiri, A., Lawson, C., Lewis, R., Macdermott, A. F. N., Mackay, A., Macleod, D. C., Mccance, A. J., Morrison, A., Mortimer, M., Mulvey, D., Murphy, J. J., Murray, S., Muthusamy, R., Myers, A., Nicolson, V. G., Northridge, D., Odemuyiwa, S., Oldroyd, K. G., Oliver, R. M., Pell, A. C. H., Pohl, J. E. F., Price, B., Quereshi, N., Rae, A. P., Reader, S., Reid, D. S., Reynolds, G. W., Robinson, A., Robson, R. H., Rodger, J. C., Rodrigues, E., Rose, E. L., Rowlands, D. B., Rowley, J. M., Rozkovec, A., Shreeve, J., Siklos, P., Smith, R. H., Sneddon, J. F., Somasundram, U., Squire, I., Stephens, J. D., Stephens-Lloyd, A., Strand, J. M., Stuart, J., Sutaria, N., Swan, J., Tait, G. W., Thomas, R. D., Thompson, M. A., Tildesley, G., Travill, C. M., Treadgold, J. A., Trelawney, J. M. S., Turner, D., Vallance, B. D., Wallbridge, D., Weissberg, P. L., White, E., Wicks, M., Wilcox, R. G., Wilkinson, P., Wiltshire, J. E., Wright, A., Andrea, B., Attassi, K., Bahr, R., Banas, J., Baran, K., Belknap, M., Bensman, M., Bertolet, B., Besley, D., Bethala, V., Betzu, R., Bhalla, R., Bhargava, M., Binder, A., Birkhead, R., Bodine, K., Brewer, D., Carey, S., Chengot, M., Coppola, J., Cragg, D., D’Arcy, B., Denny, D. M., Dilorenzo, P., Dixon, E., Doorey, A., Doty, D., Doty, W., Drossner, M., Eisenberg, P., Falco, T., Feldman, R., Freman, I., Frey, M., Garcia, J., Glassman, J., Goldman, S., Gomez, M., Gonzalez, M., Goodfield, P., Gottlieb, S., Grech, D., Hack, T., Haffey, T., Hanson, J., Havranek, E., Hermany, P., Hernandez, H., Herron, R., Hession, W., Hines, J., Hundley, R., Jacobs, W. C., Jerjes-Sanchez, C., Jerome, S., Josephson, R., Kalan, J., Kawalsky, D., Khan, A., Kmetzo, K., Kraemer, M., Lader, E., Landis, J., Lash, J., Leber, R., Leimbach, W., Leiva Garza, J. -L., Maddox, W., Magorien, R., Mahapatra, S., Mantecon, I., Mendelson, R., Miklin, J., Milas, J., Miller, R., Molk, B., Monrad, E. S., Morrison, J., Morse, H., Neustel, M., Nichols, D., Niederman, A., Nygaard, T., O’Connor, R., O’Riordan, W., Obermueller, S., Palmeri, S., Patel, R., Paul, T., Phiambolis, T., Piana, R., Polansky, B., Polinski, W., Ponce, G., Ribeiro, P., Roccario, E., Rogers, C. P., Rogers, W., Rosenblatt, A., Runyon, J. P., Scheel, F., Schmidt, P., Schneider, R., Schwartz, H., Shelhamer, L., Sheridan, F., Shine, W., Shook, T., Siskind, S., Slama, R., Spear, E., Stouffer, G., Strunk, B., Thadani, U., Timmis, G., Trautloff, R., Tse, A., Wohl, B., Zarren, H., Zucker, R., Kuster, F., and Pardie, J. P.

Subjects
Male, Risk, Infusions, medicine.medical_treatment, Myocardial Infarction, Bolus lytic therapy, Acute myocardial infarction, Tissue plasminogen activator, Thrombolytic drug, Double-Blind Method, Fibrinolytic Agents, medicine, Humans, Thrombolytic Therapy, Myocardial infarction, Infusions, Intravenous, Stroke, Aged, business.industry, ST elevation, Lanoteplase, Emergency department, Middle Aged, medicine.disease, Survival Analysis, Regimen, Relative risk, Anesthesia, Tissue Plasminogen Activator, Female, Intracranial Hemorrhages, Cardiology and Cardiovascular Medicine, business, Intravenous, medicine.drug
Abstract

AIMS To compare the efficacy and safety of lanoteplase, a single-bolus thrombolytic drug derived from alteplase tissue plasminogen activator, with the established accelerated alteplase regimen in patients presenting within 6 h of onset of ST elevation acute myocardial infarction. METHODS AND RESULTS 15,078 patients were recruited from 855 hospitals worldwide and randomized in a 2:1 ratio to receive either lanoteplase 120 KU. kg(-1)as a single intravenous bolus, or up to 100 mg accelerated alteplase given over 90 min. The primary end-point was all-cause mortality at 30 days and the hypothesis was that the two treatments would be equivalent. By 30 days, 6.61% of alteplase-treated patients and 6.75% lanoteplase-treated patients had died (relative risk 1.02). Total stroke occurred in 1.53% alteplase- and 1.87% lanoteplase-treated patients (ns); haemorrhagic stroke rates were 0.64% alteplase and 1.12% lanoteplase (P=0.004). The net clinical deficit of 30-day death or non-fatal disabling stroke was 7.0% and 7.2%, respectively. By 6 months, 8.8% of alteplase-treated patients and 8.7% of lanoteplase-treated patients had died. CONCLUSION Single-bolus weight-adjusted lanoteplase is an effective thrombolytic agent, equivalent to alteplase in terms of its impact on survival and with a comparable risk-benefit profile. The single-bolus regimen should shorten symptoms to treatment times and be especially convenient for emergency department or out-of-hospital administration.

Published
2000

27. Vascular expression of integrin-associated protein and thrombospondin increase after mechanical injury.

Author

Sajid, Mansoor, Hu, Zhaoyong, Guo, Huiping, Li, Husong, Stouffer, George A., Sajid, M, Hu, Z, Guo, H, Li, H, and Stouffer, G A

Subjects
BLOOD vessels, ANIMAL experimentation, ANTIGENS, CARRIER proteins, CELL culture, CELL division, GLYCOPROTEINS, PRIMATES, SMOOTH muscle, WOUND healing, WOUNDS & injuries
Abstract

Background: Integrin-associated protein (IAP) is a thrombospondin (TSP)-binding, Gi protein-coupled cell surface receptor. The vascular function of IAP has not been defined, and it is not known whether TSP and IAP are expressed at the same time in injured arteries.Methods: Left brachial arteries of baboons were injured using balloon withdrawal technique. Arteries were harvested 1 week after injury, and immunohistochemistry and in situ hybridization were performed using standard techniques. Uninjured right brachial arteries served as a control. Proliferation studies were performed using cultured human aortic smooth muscle cells (SMC).Results: We found significant IAP expression in the media and neointima 7 days after injury using BRIC-126, an immunoglobulin (Ig) G2b monoclonal antibody that recognizes IAP with high specificity. In contrast, IAP staining in the uninjured vessel was only observed in the endothelium. Concurrent with IAP expression, TSP mRNA and protein expression in the neointima and media was enhanced 1 week after injury. In cultured SMC, activation of IAP was sufficient to elicit a proliferative response. TSP-induced proliferation was inhibited by antibodies that block TSP binding to IAP and mimicked by 4N1K, a 10-amino acid peptide derived from the IAP binding site within the carboxyl terminus of TSP.Conclusions: Vascular expression of IAP and TSP increased after mechanical injury and activation of IAP elicited a proliferative response in cultured SMC. These findings support the hypothesis that IAP participates in vascular healing responses. [ABSTRACT FROM AUTHOR]

Published
2001
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29. Queuing for coronary angiography during severe supply-demand mismatch in a US public hospital: analysis of a waiting list registry.

Author

Rosanio, Salvatore, Tocchi, Monica, Cutler, David, Uretsky, Barry F., Stouffer, George A., DeFilippi, Christopher R., MacInerney, Edward J., Runge, Susan R., Aaron, Joann, Otero, Javier, Garg, Sandeep, Runge, Marschall S., Rosanio, S, Tocchi, M, Cutler, D, Uretsky, B F, Stouffer, G A, deFilippi, C R, MacInerney, E J, and Runge, S R

Subjects
CORONARY arterial radiography, MEDICAL radiography, CARDIOVASCULAR disease diagnosis, HOSPITAL waiting lists
Abstract

Context: Adverse cardiac events have been reported in patients waiting for either coronary surgery or angioplasty. However, data on the risk of adverse events while awaiting coronary angiography are limited, and none are available from a US population.Objective: To quantify cardiac outcomes in patients waiting for elective coronary angiography.Design, Setting, and Participants: Observational cohort study of 381 adult outpatients (mean [SD] age, 55 [12] years; 64% male; 61% white) on a waiting list for coronary angiography at a US tertiary care public teaching hospital during 1993-1994.Main Outcome Measures: Rates of cardiac death, nonfatal myocardial infarction, and hospitalizations for unstable angina or heart failure as a function of amount of time spent on a waiting list.Results: Sixty-six patients were dropped from the waiting list but were included in the study analysis. During a mean (SD) follow-up of 8.4 (6.5) months, cardiac death, myocardial infarction, and hospitalization occurred in 6 (1.6%), 4 (1.0%), and 26 (6.8%) patients, respectively. The probability of events was minimal in the first 2 weeks and increased steadily between 3 and 13 weeks. By Cox multivariate analysis, 2 variables independently identified an increased risk of adverse events: a strongly positive treadmill exercise electrocardiogram or positive stress imaging result at referral (odds ratio [OR], 2.32; 95% confidence interval [CI], 1.22-4.16; P=.01) and the use of 2 to 3 anti-ischemic medications (OR, 1.98; 95% CI, 1.19-3.96; P=.04). Among 311 patients who ultimately underwent angiography, those with adverse events had a higher prevalence of coronary disease (96% vs 60%; P<.001), more frequently required revascularization (93% vs 53%; P<.001), and had longer hospital stays (mean [SD], 6.2 [4.3] vs 1.3 [0.7] days; P=.001).Conclusion: Our data suggest that in a cohort referred for coronary angiography, delaying the procedure places some patients at risk for death, myocardial infarction, unplanned hospitalization, a longer hospital stay, and, potentially, a poorer prognosis. Waits longer than 2 weeks should be avoided, and patients with strongly positive stress test results and those who require 2 to 3 anti-ischemic medications should be prioritized for early intervention. [ABSTRACT FROM AUTHOR]

Published
1999
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32. Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes: a randomized trial†

Author

Tardif, Jean-Claude, Ballantyne, Christie M., Barter, Philip, Dasseux, Jean-Louis, Fayad, Zahi A., Guertin, Marie-Claude, Kastelein, John J. P., Keyserling, Constance, Klepp, Heather, Koenig, Wolfgang, L'Allier, Philippe L., Lespérance, Jacques, Lüscher, Thomas F., Paolini, John F., Tawakol, Ahmed, Waters, David D., Pfeffer, M., Brown, V., Rouleau, J., Watkins, P., Wei, L.J., Gosselin, G., Chayer, C., Lanthier, S., Pelletier, G.B., Racine, N., Agarwal, H., Brilakis, E., Cannon, L., Carrié, D., Corbelli, J., Coste, P., de Winter, R., Diaz, A., Eisenberg, S., Ennis, B., Fajadet, J., Fam, N., Fortuin, D., Gessler, C., Grines, C., Guerra, D., Gum, H., Haldis, T., Heestermans, T., Herrman, J.P., Huynh, T., Kedhi, E., Koren, M., Kouz, S., Krolick, M., Kumkumian, G., Lavi, S., Li, R.J., Masud, ARZ, McAlhany, C., McGrew, F.A., O'Shaughnessy, C., Oude Ophuis, A.J.M., Parr, K., Penny, W., Pesant, Y., Post, H., Robinson, S., Rodes-Cabau, J., Roy, A., Schulman, S., Spence, F., Stouffer, G., Stys, T., Sussex, B., Tahirkheli, N., Tardif, J-C, Grégoire, J., ten Berg, J., van Boven, A.J., von Birgelen, C., Weinstein, D., Tardif, Jean-Claude, Ballantyne, Christie M., Barter, Philip, Dasseux, Jean-Louis, Fayad, Zahi A., Guertin, Marie-Claude, Kastelein, John J. P., Keyserling, Constance, Klepp, Heather, Koenig, Wolfgang, L'Allier, Philippe L., Lespérance, Jacques, Lüscher, Thomas F., Paolini, John F., Tawakol, Ahmed, Waters, David D., Pfeffer, M., Brown, V., Rouleau, J., Watkins, P., Wei, L.J., Gosselin, G., Chayer, C., Lanthier, S., Pelletier, G.B., Racine, N., Agarwal, H., Brilakis, E., Cannon, L., Carrié, D., Corbelli, J., Coste, P., de Winter, R., Diaz, A., Eisenberg, S., Ennis, B., Fajadet, J., Fam, N., Fortuin, D., Gessler, C., Grines, C., Guerra, D., Gum, H., Haldis, T., Heestermans, T., Herrman, J.P., Huynh, T., Kedhi, E., Koren, M., Kouz, S., Krolick, M., Kumkumian, G., Lavi, S., Li, R.J., Masud, ARZ, McAlhany, C., McGrew, F.A., O'Shaughnessy, C., Oude Ophuis, A.J.M., Parr, K., Penny, W., Pesant, Y., Post, H., Robinson, S., Rodes-Cabau, J., Roy, A., Schulman, S., Spence, F., Stouffer, G., Stys, T., Sussex, B., Tahirkheli, N., Tardif, J-C, Grégoire, J., ten Berg, J., van Boven, A.J., von Birgelen, C., and Weinstein, D.

Abstract

Aim High-density lipoproteins (HDLs) have several potentially protective vascular effects. Most clinical studies of therapies targeting HDL have failed to show benefits vs. placebo. Objective To investigate the effects of an HDL-mimetic agent on atherosclerosis by intravascular ultrasonography (IVUS) and quantitative coronary angiography (QCA). Design and setting A prospective, double-blinded, randomized trial was conducted at 51 centres in the USA, the Netherlands, Canada, and France. Intravascular ultrasonography and QCA were performed to assess coronary atherosclerosis at baseline and 3 (2-5) weeks after the last study infusion. Patients Five hundred and seven patients were randomized; 417 and 461 had paired IVUS and QCA measurements, respectively. Intervention Patients were randomized to receive 6 weekly infusions of placebo, 3 mg/kg, 6 mg/kg, or 12 mg/kg CER-001. Main outcome measures The primary efficacy parameter was the nominal change in the total atheroma volume. Nominal changes in per cent atheroma volume on IVUS and coronary scores on QCA were also pre-specified endpoints. Results The nominal change in the total atheroma volume (adjusted means) was −2.71, −3.13, −1.50, and −3.05 mm3 with placebo, CER-001 3 mg/kg, 6 mg/kg, and 12 mg/kg, respectively (primary analysis of 12 mg/kg vs. placebo: P = 0.81). There was also no difference among groups for the nominal change in per cent atheroma volume (0.02, −0.02, 0.01, and 0.19%; nominal P = 0.53 for 12 mg/kg vs. placebo). Change in the coronary artery score was −0.022, −0.036, −0.022, and −0.015 mm (nominal P = 0.25, 0.99, 0.55), and change in the cumulative coronary stenosis score was −0.51, 2.65, 0.71, and −0.77% (compared with placebo, nominal P = 0.85 for 12 mg/kg and nominal P = 0.01 for 3 mg/kg). The number of patients with major cardiovascular events was 10 (8.3%), 16 (13.3%), 17 (13.7%), and 12 (9.8%) in the four groups. Conclusion CER-001 infusions did not reduce coronary atherosclerosis on IVUS and QC

38. Catheter-based renal denervation in the treatment of resistant hypertension.

Author

Stouffer GA, Dibona GF, Patel A, Kaul P, and Hinderliter AL

Subjects
Animals, Blood Pressure physiology, Humans, Catheter Ablation methods, Denervation methods, Hypertension therapy, Kidney innervation
Abstract

Clinical trials have shown that catheter-based renal denervation (RD), i.e. interruption of afferent and efferent sympathetic nerves supplying the kidney, can reduce systolic blood pressure (BP) by approximately 30 mm Hg. This technology is currently being tested as a therapeutic option for patients with resistant hypertension, a condition in which BP remains elevated despite adherence to a rational medication regimen. This novel treatment approach was developed on the basis of a wealth of animal and human research demonstrating the importance of the sympathorenal axis in the pathogenesis of hypertension. Sympathetic efferent signals to the kidneys raise BP by stimulating sodium retention and renin release, and the kidneys influence central sympathetic drive via afferent nerves. But as is true with many therapeutic advances, RD has shown benefit in clinical studies long before the mechanisms are fully understood. Additional research is needed to understand the contribution of afferent sympathetic nerve interruption to BP reductions observed with RD; to examine the degree and significance of re-innervation following RD; to elucidate factors that may lead to a lack of response to RD in some patients; to determine whether the modulation of the sympathetic nervous system via RD can have beneficial effects independent of BP reduction; and to develop methods to measure the effectiveness of RD in real time., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Published
2013
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39. Unilateral renal artery stenosis causes a chronic vascular inflammatory response in ApoE-/- mice.

Author

Stouffer GA, Pathak A, and Rojas M

Subjects
Animals, Aorta, Abdominal metabolism, Aorta, Abdominal pathology, Apolipoproteins E genetics, Carotid Arteries metabolism, Carotid Arteries pathology, Chemokine CCL2 metabolism, Disease Models, Animal, Hypertension, Renovascular etiology, Hypertension, Renovascular physiopathology, Inflammation etiology, Inflammation metabolism, Inflammation pathology, Ligation, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle, Smooth, Vascular pathology, Myosin Heavy Chains metabolism, Plaque, Atherosclerotic etiology, Plaque, Atherosclerotic metabolism, Plaque, Atherosclerotic pathology, Vasculitis metabolism, Vasculitis pathology, Apolipoproteins E deficiency, Renal Artery Obstruction complications, Vasculitis etiology
Abstract

Unlabelled: Unilateral renal artery ligation (RAL) causes a short-term vascular inflammatory reaction in ApoE-/- mice, but whether this persists is unknown. Partial constriction of the right renal artery resulted in a mild, sustained increase in systolic blood pressure over the 90 days of the study, whereas there was no change in blood pressure in mice that underwent sham-surgery. Atheroma was present in the abdominal aorta, with pronounced staining for macrophages (39% +/- 9% of area of atheroma) and monocyte chemoattractant-1 (MCP-1; 40%+/-15%) in mice with unilateral RAL. Atheroma was also present in the carotid arteries, with pronounced staining for macrophages (56%+/-15%) and MCP-1 (53%+/-21%). Non-muscle myosin-A, a marker of smooth muscle cell dedifferentiation, was observed in atheroma within the abdominal aorta and carotid arteries in mice that underwent unilateral RAL. There were no atheroma and minimal staining for macrophages, MCP-1 or non-muscle myosin A in carotid arteries or abdominal aorta of mice that underwent sham surgery., Conclusions: Chronic unilateral partial RAL results in the formation of atheroma in the aorta and carotid arteries of ApoE-/- mice that is characterized by chronic inflammation and dedifferentiation of smooth muscle cells.

Published
2010

41. Effect of rosiglitazone on restenosis after coronary stenting in patients with type 2 diabetes.

Author

Osman A, Otero J, Brizolara A, Waxman S, Stouffer G, Fitzgerald P, and Uretsky BF

Subjects
Administration, Oral, Adult, Aged, Coronary Angiography, Coronary Restenosis blood, Coronary Restenosis surgery, Diabetes Mellitus, Type 2 blood, Diabetes Mellitus, Type 2 drug therapy, Diabetic Angiopathies surgery, Double-Blind Method, Female, Glycated Hemoglobin analysis, Humans, Male, Middle Aged, Rosiglitazone, Cardiovascular Agents therapeutic use, Coronary Restenosis prevention & control, Diabetes Mellitus, Type 2 complications, Diabetic Angiopathies prevention & control, Hypoglycemic Agents therapeutic use, Plasminogen Activator Inhibitor 1 blood, Stents, Thiazolidinediones therapeutic use
Abstract

Background: Thiazolidinediones have been shown to have an antiproliferative vascular effect in experimental models. We sought to study the effect of rosiglitazone on in-stent restenosis in patients with established type 2 diabetes., Methods: Patients with treated type 2 diabetes (mean duration 5.5 +/- 7.5 years) referred for coronary stenting were randomized in a double-blind fashion to receive oral rosiglitazone or placebo for 6 months. Quantitative coronary angiography and intravascular ultrasound data were obtained at baseline and follow-up. Plasma plasminogen activator inhibitor-1 levels were prospectively measured., Results: Sixteen patients were enrolled. There were no significant differences in follow-up in-stent luminal diameter stenosis measured by quantitative coronary angiography or in-stent luminal area stenosis and neointimal volume index obtained by intravascular ultrasound, nor were there any differences in plasma plasminogen activator inhibitor-1 levels after long-term use despite improvement in diabetes control and insulin sensitivity., Conclusions: Rosiglitazone, given at the time of stent implantation in treated diabetics, did not reduce in-stent restenosis in this small series. The vascular biological effects of this agent await further clarification in humans and evaluation in larger clinical trials.

Published
2004
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42. Effects of thrombin on interactions between beta3-integrins and extracellular matrix in platelets and vascular cells.

Author

Stouffer GA and Smyth SS

Subjects
Animals, Blood Coagulation physiology, Humans, Platelet Activation physiology, Signal Transduction physiology, Blood Platelets metabolism, Endothelial Cells metabolism, Extracellular Matrix metabolism, Integrin beta3 metabolism, Thrombin physiology
Abstract

The beta3-integrin family consists of alphaIIbbeta3 (also known as glycoprotein IIb/IIIa) and alpha(v)beta3. alphaIIbbeta3 is found on platelets and megakaryocytes and has an essential role in hemostasis. alpha(v)beta3 has a broader distribution, and it functions in angiogenesis, neointimal formation after vascular injury, and leukocyte trafficking. There are important interactions between thrombin and beta3-integrins relative to both "inside-out" (integrin activation) and "outside-in" (modification of cellular events by ligand binding to integrins) signaling. Thrombin, by binding to G protein-coupled, protease-activated receptors, is a potent activator of alphaIIbbeta3. Conversely, outside-in signaling through alphaIIbbeta3 amplifies events initiated by thrombin and is necessary for full platelet spreading, platelet aggregation, granule secretion, and the formation of a stable platelet thrombus. In smooth muscle cells, alpha(v)beta3-integrins influence various responses to thrombin, including proliferation, c-Jun NH2-terminal kinase-1 activation, and focal adhesion formation. Other interactions between beta3-integrins and thrombin include beta3-integrin promotion of the generation of thrombin by localizing prothrombin to cellular surfaces and/or enhancing the formation of procoagulant microparticles and the requirement of beta3-integrin function for platelet-dependent clot retraction. In summary, there is increasing evidence that interactions between beta3-integrins and thrombin play important roles in the regulation of hemostatic and vascular functions.

Published
2003
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43. Alphavbeta3-integrin antagonists inhibit thrombin-induced proliferation and focal adhesion formation in smooth muscle cells.

Author

Sajid M, Zhao R, Pathak A, Smyth SS, and Stouffer GA

Subjects
Animals, Aorta cytology, Aorta drug effects, Aorta physiology, Cell Division drug effects, Cell Division physiology, Cells, Cultured, Focal Adhesions physiology, Integrin alphaVbeta3 metabolism, Myocytes, Smooth Muscle physiology, Rats, Rats, Sprague-Dawley, Thrombin antagonists & inhibitors, Focal Adhesions drug effects, Integrin alphaVbeta3 antagonists & inhibitors, Integrin alphaVbeta3 physiology, Myocytes, Smooth Muscle cytology, Myocytes, Smooth Muscle drug effects, Thrombin pharmacology
Abstract

Alphavbeta3-integrin antagonists reduced neointimal formation following vascular injury in eight different animal models. Because alpha-thrombin contributes to neointimal formation, we examined the hypothesis that alphavbeta3-integrins influence alpha-thrombin-induced signaling. Cultured rat aortic smooth muscle cells (RASMC) expressed alphavbeta3-integrins as demonstrated by immunofluorescence microscopy and fluorescence-activated cell sorting analysis. Proliferative responses to alpha-thrombin were partially inhibited by anti-beta3-integrin monoclonal antibody F11 and by cyclic RGD peptides. Immunofluorescence microscopy showed that alpha-thrombin stimulated a rapid increase in the formation of focal adhesions as identified by vinculin staining and that this effect was partially inhibited by alphavbeta3 antagonists. Beta3-integrin staining was diffuse in quiescent RASMC and did not concentrate at sites of focal adhesions following thrombin treatment. Alpha-thrombin elicited a time-dependent increase in activation of c-Jun NH2-terminal kinase-1 (JNK1) and in tyrosine phosphorylation of focal adhesion kinase (FAK). Alphavbeta3-integrin antagonists partially inhibited increases in JNK1 activity but had no effect on FAK phosphorylation. In SMC isolated from beta3-integrin-deficient mice, focal adhesion formation was impaired in response to thrombin but not sphingosine-1-phosphate, a potent activator of Rho. In summary, alphavbeta3-integrins play an important role in alpha-thrombin-induced proliferation and focal adhesion formation in RASMC.

Published
2003
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46. Vascular expression of integrin-associated protein and thrombospondin increase after mechanical injury.

Author

Sajid M, Hu Z, Guo H, Li H, and Stouffer GA

Subjects
Animals, CD47 Antigen, Cell Division drug effects, Cells, Cultured, Humans, Male, Muscle, Smooth, Vascular cytology, Muscle, Smooth, Vascular drug effects, Papio, Wound Healing, Antigens, CD biosynthesis, Blood Vessels injuries, CD36 Antigens biosynthesis, Carrier Proteins biosynthesis, Muscle, Smooth, Vascular metabolism, Thrombospondins biosynthesis
Abstract

Background: Integrin-associated protein (IAP) is a thrombospondin (TSP)-binding, Gi protein-coupled cell surface receptor. The vascular function of IAP has not been defined, and it is not known whether TSP and IAP are expressed at the same time in injured arteries., Methods: Left brachial arteries of baboons were injured using balloon withdrawal technique. Arteries were harvested 1 week after injury, and immunohistochemistry and in situ hybridization were performed using standard techniques. Uninjured right brachial arteries served as a control. Proliferation studies were performed using cultured human aortic smooth muscle cells (SMC)., Results: We found significant IAP expression in the media and neointima 7 days after injury using BRIC-126, an immunoglobulin (Ig) G2b monoclonal antibody that recognizes IAP with high specificity. In contrast, IAP staining in the uninjured vessel was only observed in the endothelium. Concurrent with IAP expression, TSP mRNA and protein expression in the neointima and media was enhanced 1 week after injury. In cultured SMC, activation of IAP was sufficient to elicit a proliferative response. TSP-induced proliferation was inhibited by antibodies that block TSP binding to IAP and mimicked by 4N1K, a 10-amino acid peptide derived from the IAP binding site within the carboxyl terminus of TSP., Conclusions: Vascular expression of IAP and TSP increased after mechanical injury and activation of IAP elicited a proliferative response in cultured SMC. These findings support the hypothesis that IAP participates in vascular healing responses.

Published
2001
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47. MTHFR 677 C-->T mutation: a predictor of early-onset coronary artery disease risk.

Author

Payne DA, Chamoun AJ, Seifert SL, and Stouffer GA

Subjects
Adult, Age of Onset, Chi-Square Distribution, Coronary Artery Disease complications, Coronary Artery Disease diagnosis, Diabetes Complications, Diabetes Mellitus genetics, Female, Humans, Male, Methylenetetrahydrofolate Reductase (NADPH2), Middle Aged, Pilot Projects, Prognosis, Risk Factors, Texas epidemiology, Coronary Artery Disease genetics, Oxidoreductases Acting on CH-NH Group Donors genetics
Abstract

The atherosclerotic potential of the methyenetetrahydrofolate reductase (MTHFR) gene mutation 677 C --> T substitution remains controversial. In this study, we describe the association of this mutation in a Southern Texan patient population of multiracial ethnic background with risk and extent of coronary artery disease (CAD) as measured by luminal narrowing. Sixty nine patients who were 50 years or younger composed our population. Chi-square analysis was used to analyze the data and found a significant association between CAD and this mutation (P value=0.03). In addition, in the small number of patients in this study who had diabetes, those who had mutation have more severe disease than those without the mutation. This study highlights the potential cardiovascular prognostic significance of the MTHFR 677 C --> T in the studied population.

Published
2001
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48. Mitral valve prolapse: a review of the literature.

Author

Jacobs W, Chamoun A, and Stouffer GA

Subjects
Adrenergic beta-Antagonists therapeutic use, Echocardiography, Electrocardiography, Endocarditis, Bacterial etiology, Female, Humans, Intracranial Embolism etiology, Male, Mitral Valve surgery, Mitral Valve Insufficiency etiology, Mitral Valve Prolapse classification, Mitral Valve Prolapse complications, Mitral Valve Prolapse diagnosis, Mitral Valve Prolapse therapy
Published
2001
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49. New tricks for old dogs: nonthrombotic effects of thrombin in vessel wall biology.

Author

Patterson C, Stouffer GA, Madamanchi N, and Runge MS

Subjects
Animals, Apoptosis, Blood Vessels drug effects, Cell Division drug effects, Cell Movement drug effects, Endothelium, Vascular drug effects, Endothelium, Vascular physiology, Enzyme Activation physiology, Humans, Muscle, Smooth, Vascular drug effects, Neovascularization, Physiologic drug effects, Plasminogen Activator Inhibitor 1 metabolism, Receptor, PAR-1, Receptors, Thrombin metabolism, Signal Transduction drug effects, Signal Transduction physiology, Thrombin antagonists & inhibitors, Thrombin pharmacology, Blood Vessels metabolism, Muscle, Smooth, Vascular metabolism, Thrombin metabolism
Abstract

Thrombin is a serine protease that potently activates platelets and catalyzes the conversion of fibrinogen to fibrin. Thrombin also exerts direct effects on vascular cells, such as smooth muscle cells, via interactions with members of the protease-activated receptor family. Evidence in several animal models implicates thrombin-mediated signaling events in the response to injury that typifies vascular lesion formation in atherosclerosis and restenosis. In this review, we examine the activation of protease-activated receptors by thrombin, the downstream signaling events mediated by these receptors, and the physiological role of thrombin in vascular cells and vascular disease.

Published
2001
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50. Role of reactive oxygen species in angiotensin ii signaling : the plot thickens.

Author

Stouffer GA, Patterson C, Madamanchi N, and Runge MS

Subjects
Cardiovascular Diseases physiopathology, Humans, Muscle, Smooth, Vascular cytology, Muscle, Smooth, Vascular physiopathology, Receptors, Angiotensin drug effects, Receptors, Angiotensin physiology, Angiotensin II physiology, Muscle, Smooth, Vascular physiology, Reactive Oxygen Species physiology, Signal Transduction physiology
Published
2001
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