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1. Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome

Author

Bittner, V. A. (Vera A.), Szarek, M. (Michael), Aylward, P. E. (Philip E.), Bhatt, D. L. (Deepak L.), Diaz, R. (Rafael), Edelberg, J. M. (Jay M.), Fras, Z. (Zlatko), Goodman, S. G. (Shaun G.), Halvorsen, S. (Sigrun), Hanotin, C. (Corinne), Harrington, R. A. (Robert A.), Jukema, W. (Wouter), Loizeau, V. (Virginie), Moriarty, P. M. (Patrick M.), Moryusef, A. (Angèle), Pordy, R. (Robert), Roe, M. T. (Matthew T.), Sinnaeve, P. (Peter), Tsimikas, S. (Sotirios), Vogel, R. (Robert), White, H. D. (Harvey D.), Zahger, D. (Doron), Zeiher, A. M. (Andreas M.), Steg, G. (Gabriel), Schwartz, G. G. (Gregory G.), and Huikuri, H. (Heikki)

Subjects
low-density lipoprotein cholesterol, proprotein convertase subtilisin/kexin type 9 inhibition, lipids (amino acids, peptides, and proteins), acute coronary syndromes, alirocumab, cardiovascular diseases, major adverse cardiovascular events
Abstract

Background: Lipoprotein(a) concentration is associated with cardiovascular events. Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, lowers lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C). Objectives: A pre-specified analysis of the placebo-controlled ODYSSEY Outcomes trial in patients with recent acute coronary syndrome (ACS) determined whether alirocumab-induced changes in lipoprotein(a) and LDL-C independently predicted major adverse cardiovascular events (MACE). Methods: One to 12 months after ACS, 18,924 patients on high-intensity statin therapy were randomized to alirocumab or placebo and followed for 2.8 years (median). Lipoprotein(a) was measured at randomization and 4 and 12 months thereafter. The primary MACE outcome was coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina. Results: Baseline lipoprotein(a) levels (median: 21.2 mg/dl; interquartile range [IQR]: 6.7 to 59.6 mg/dl) and LDL-C [corrected for cholesterol content in lipoprotein(a)] predicted MACE. Alirocumab reduced lipoprotein(a) by 5.0 mg/dl (IQR: 0 to 13.5 mg/dl), corrected LDL-C by 51.1 mg/dl (IQR: 33.7 to 67.2 mg/dl), and reduced the risk of MACE (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.78 to 0.93). Alirocumab-induced reductions of lipoprotein(a) and corrected LDL-C independently predicted lower risk of MACE, after adjustment for baseline concentrations of both lipoproteins and demographic and clinical characteristics. A 1-mg/dl reduction in lipoprotein(a) with alirocumab was associated with a HR of 0.994 (95% CI: 0.990 to 0.999; p = 0.0081). Conclusions: Baseline lipoprotein(a) and corrected LDL-C levels and their reductions by alirocumab predicted the risk of MACE after recent ACS. Lipoprotein(a) lowering by alirocumab is an independent contributor to MACE reduction, which suggests that lipoprotein(a) should be an independent treatment target after ACS. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402)

Published
2020

4. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome

Author

Schwartz, G. G., Steg, P. G., Szarek, M., Bhatt, D. L., Bittner, V. A., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J. W., Lecorps, G., Mahaffey, K. W., Moryusef, A., Pordy, R., Quintero, K., Roe, M. T., Sasiela, W. J., Tamby, J. -F., Tricoci, P., White, H. D., Zeiher, A. M., Aylward, Philip E., Drexel, Heinz, Sinnaeve, Peter, Dilic, Mirza, Lopes, Renato D., Gotcheva, Nina N., Goodman, Shaun G., Prieto, Juan-Carlos, Yong, Huo, Lopez-Jaramillo, Patricio, Pecin, Ivan, Reiner, Zeljko, Ostadal, Petr, Poulsen, Steen Hvitfeldt, Viigimaa, Margus, Nieminen, Markku S., Danchin, Nicolas, Chumburidze, Vakhtang, Marx, Nikolaus, Liberopoulos, Evangelos, Montenegro Valdovinos, Pablo Carlos, Tse, Hung-Fat, Kiss, Robert Gabor, Xavier, Denis, Zahger, Doron, Valgimigli, Marco, Kimura, Takeshi, Kim, Hyo Soo, Kim, Sang-Hyun, Erglis, Andrejs, Laucevicius, Aleksandras, Kedev, Sasko, Yusoff, Khalid, Ramos Lopez, Gabriel Arturo, Alings, Marco, Halvorsen, Sigrun, Correa Flores, Roger M., Sy, Rody G., Budaj, Andrzej, Morais, Joao, Dorobantu, Maria, Karpov, Yuri, Ristic, Arsen D., Chua, Terrance, Murin, Jan, Fras, Zlatko, Dalby, Anthony J., Tunon, Jose, de Silva, H. Asita, Hagstrom, Emil, Muller, Christian, Chiang, Chern-En, Sritara, Piyamitr, Guneri, Sema, Parkhomenko, Alexander, Ray, Kausik K., Moriarty, Patrick M., Vogel, Robert, Chaitman, Bernard, Kelsey, Sheryl F., Olsson, Anders G., Rouleau, Jean-Lucien, Simoons, Maarten L., Alexander, Karen, Meloni, Chiara, Rosenson, Robert, Sijbrands, Eric J. G., Alexander, John H., Armaganijan, Luciana, Bagai, Akshay, Bahit, Maria Cecilia, Brennan, J. Matthew, Clifton, Shaun, DeVore, Adam D., Deloatch, Shalonda, Dickey, Sheila, Dombrowski, Keith, Ducrocq, Gregory, Eapen, Zubin, Endsley, Patricia, Eppinger, Arleen, Hess, Connie Ng, Hlatky, Mark A., Jordan, Joseph Dedrick, Knowles, Joshua W., Kolls, Bradley J., Kong, David F., Leonardi, Sergio, Lillis, Linda, Maron, David J., Marcus, Jill, Mathews, Robin, Mehta, Rajendra H., Mentz, Robert J., Moreira, Humberto Graner, Patel, Chetan B., Pereira, Sabrina Bernardez, Perkins, Lynn, Povsic, Thomas J., Puymirat, Etienne, Jones, William Schuyler, Shah, Bimal R., Sherwood, Matthew W., Stringfellow, Kenya, Sujjavanich, Darin, Toma, Mustafa, Trotter, Charlene, van Diepen, Sean F. P., Wilson, Matthew D., Yan, Andrew Tze-Kay, Schiavi, Lilia B., Garrido, Marcelo, Alvarisqueta, Andres F., Sassone, Sonia A., Bordonava, Anselmo P., Alves De Lima, Alberto E., Schmidberg, Jorge M., Duronto, Ernesto A., Caruso, Orlando C., Novaretto, Leonardo P., Angel Hominal, Miguel, Montana, Oscar R., Caccavo, Alberto, Gomez Vilamajo, Oscar A., Lorenzatti, Alberto J., Cartasegna, Luis R., Paterlini, Gustavo A., Mackinnon, Ignacio J., Caime, Guillermo D., Amuchastegui, Marcos, Codutti, Oscar R., Jure, Horacio O., Bono, Julio O. E., Hrabar, Adrian D., Vallejos, Julio A., Ahuad Guerrero, Rodolfo A., Novoa, Federico, Patocchi, Cristian A., Zaidman, Cesar J., Giuliano, Maria E., Dran, Ricardo D., Vico, Marisa L., Carnero, Gabriela S., Guzman, Pablo N., Medrano Allende, Juan C., Garcia Brasca, Daniela F., Bustamante Labarta, Miguel H., Nani, Sebastian, Blumberg, Eduardo D. S., Colombo, Hugo R., Liberman, Alberto, Luciardi, Hector L., Waisman, Gabriel D., Berli, Mario A., Garcia Duran, Ruben O., Cestari, Horacio G., Luquez, Hugo A., Giordano, Jorge A., Saavedra, Silvia S., Waites, Jonathon H., Collins, Nicholas, Soward, Allan, Hii, Chris L. S., Shaw, James, Arstall, Margaret A., Horowitz, John, Rogers, James F., Colquhoun, David, Flores, Romulo E. Oqueli, Roberts-Thomson, Philip, Raffel, Owen, Lehman, Sam J., Coverdale, Steven G. M., Garrahy, Paul J., Starmer, Gregory, Sader, Mark, Carroll, Patrick A., Zweiker, Robert, Hoppe, Uta, Huber, Kurt, Berger, Rudolf, Weidinger, Franz, Faes, Dirk, Hermans, Kurt, Pirenne, Bruno, Leone, Attilio, Hoffer, Etienne, Vrolix, Mathias C. M., De Wolf, Luc, Wollaert, Bart, Castadot, Marc, Dujardin, Karl, Beauloye, Christophe, Vervoort, Geert, Striekwold, Harry, Convens, Carl, Roosen, John, Barbato, Emanuele, Claeys, Marc J., Cools, Frank, Terzic, Ibrahim, Barakovic, Fahir, Midzic, Zlatko, Pojskic, Belma, Fazlibegovic, Emir, Durak-Nalbantic, Azra, Vulic, Dusko, Muslibegovic, Adis, Reis, Gilmar, Sousa, Luciano, Nicolau, Jose C., Giorgeto, Flavio E., Silva, Ricardo P., Maia, Lilia Nigro, Rech, Rafael, Rossi, Paulo R. F., Cerqueira, Maria Jose A. G., Duda, Norberto, Kalil, Renato, Kormann, Adrian, Abrantes, Jose Antonio M., Pimentel Filho, Pedro, Soggia, Ana Priscila, de Santos, Mayler O. N., Neuenschwander, Fernando, Bodanese, Luiz C., Michalaros, Yorghos L., Eliaschewitz, Freddy G., Vidotti, Maria H., Leaes, Paulo E., Botelho, Roberto V., Kaiser, Sergio, Fernandes Manenti, Euler Roberto F., Precoma, Dalton B., Moura Jorge, Jose C., de Silva, Pedro G. M. B., Silveira, Jose A., Saporito, Wladimir, Marin Neto, Jose A., Feitosa, Gilson S., Ritt, Luiz Eduardo F., de Souza, Juliana A., Costa, Fernando, Souza, Weimar K. S. B., Reis, Helder J. L., Machado, Leandro, Aidar Ayoub, Jose Carlos, Todorov, Georgi V., Nikolov, Fedya P., Velcheva, Elena S., Tzekova, Maria L., Benov, Haralambi O., Petranov, Stanislav L., Tumbev, Haralin S., Shehova-Yankova, Nina S., Markov, Dimitar T., Raev, Dimitar H., Mollov, Mihail N., Kichukov, Kostadin N., Ilieva-Pandeva, Katya A., Ivanova, Raya, Mincheva, Valentina M., Lazov, Petar V., Dimov, Bojidar I., Senaratne, Manohara, Stone, James, Kornder, Jan, Pearce, Stephen, Dion, Danielle, Savard, Daniel, Pesant, Yves, Pandey, Amritanshu, Robinson, Simon, Gosselin, Gilbert, Vizel, Saul, Hoag, Gordon, Bourgeois, Ronald, Morisset, Anne, Sabbah, Eric, Sussex, Bruce, Kouz, Simon, MacDonald, Paul, Diaz, Ariel, Michaud, Nicolas, Fell, David, Leung, Raymond, Vuurmans, Tycho, Lai, Christopher, Nigro, Frank, Davies, Richard, Nogareda, Gustavo, Vijayaraghavan, Ram, Ducas, John, Lepage, Serge, Mehta, Shamir, Cha, James, Dupuis, Robert, Fong, Peter, Rodes-Cabau, Josep, Fadlallah, Hussein, Cleveland, David, Huynh, Thao, Bata, Iqbal, Hameed, Adnan, Pincetti, Cristian, Potthoff, Sergio, Acevedo, Monica, Aguirre, Arnoldo, Vejar, Margarita, Yanez, Mario, Araneda, Guillermo, Fernandez, Mauricio, Perez, Luis, Varleta, Paola, Florenzano, Fernando, Huidobro, Laura, Raffo, Carlos A., Olivares, Claudia, Chen, Jiyan, Dong, Yugang, Huang, Weijian, Wang, Jianzhong, Huang, Shi'An, Yao, Zhuhua, Cui, Lan, Lin, Wenhua, Sun, Yuemin, Wang, Jingfeng, Li, Jianping, Zhang, Xuelian, Zhu, Hong, Chen, Dandan, Huang, Lan, Dong, Shaohong, Su, Guohai, Xu, Biao, Su, Xi, Cheng, Xiaoshu, Lin, Jinxiu, Zong, Wenxia, Li, Huanming, Feng, Yi, Xu, Dingli, Yang, Xinchun, Ke, Yuannan, Lin, Xuefeng, Zhang, Zheng, Zheng, Zeqi, Luo, Zhurong, Chen, Yundai, Ding, Chunhua, Zheng, Yang, Li, Xiaodong, Peng, Daoquan, Li, Ying, Wei, Meng, Liu, Shaowen, Yu, Yihua, Qu, Baiming, Jiang, Weihong, Zhou, Yujie, Zhao, Xingsheng, Yuan, Zuyi, Guo, Ying, Xu, Xiping, Shi, Xubo, Ge, Junbo, Fu, Guosheng, Bai, Feng, Fang, Weiyi, Shou, Xiling, Yang, Xiangjun, Wang, Jian'An, Jaramillo, Nicolas, Vallejo, Gregorio Sanchez, Botia, Diana C. Luna, Lopez, Rodrigo Botero, De Salazar, Dora I. Molina, Bonfanti, Alberto J. Cadena, Higuera, Juan Diego, Silva, Sandra I. Barrera, Lozada, Henry J. Garcia, Arroyo, Julian A. Coronel, Mendoza, Jose L. Accini, Ruiz, Ricardo L. Fernandez, Fernandez, Angela M., Jatin, Fernando G. Manzur, Herazo, Aristides Sotomayor, Parada, Jeffrey Castellanos, Triana, Miguel A. Urina, Spinar, Jindrich, Horak, David, Stasek, Josef, Alan, David, Machova, Vilma, Linhart, Ales, Novotny, Vojtech, Kaucak, Vladimir, Rokyta, Richard, Naplava, Robert, Coufal, Zdenek, Adamkova, Vera, Podpera, Ivo, Zizka, Jiri, Motovska, Zuzana, Marusincova, Ivana, Svab, Premysl, Heinc, Petr, Kuchar, Jiri, Povolny, Petr, Raungaard, Bent, Clemmensen, Peter, Bang, Lia E., May, Ole, Bottcher, Morten, Hove, Jens D., Frost, Lars, Gislason, Gunnar, Larsen, John, Johansen, Peter Betton, Hald, Flemming, Jeppesen, Jorgen, Nielsen, Tonny, Kristensen, Kjeld S., Walichiewicz, Piotr Maria, Lomholdt, Jens D., Klausen, Ib C., Nielsen, Peter Kaiser, Davidsen, Flemming, Videbaek, Lars, Soots, Mai, Vahula, Veiko, Hedman, Anu, Soopold, sllar, Martsin, Kaja, Taskinen, Marja-Riitta, Porthan, Kimmo, Airaksinen, Juhani K., Juonala, Markus, Kiviniemi, Tuomas, Vikman, Saila, Posio, Pirjo, Taurio, Jyrki, Huikuri, Heikki, Kaikkonen, Kari, Coste, Pierre, Ferrari, Emile, Morel, Olivier, Montalescot, Gilles, Barone-Rochette, Gilles, Mansourati, Jacques, Cottin, Yves, Steg, Philippe Gabriel, Leclercq, Florence, Belhassane, Abdelkader, Delarche, Nicolas, Boccara, Franck, Paganelli, Franck, Clerc, Jerome, Schiele, Francois, Aboyans, Victor, Probst, Vincent, Berland, Jacques, Lefevre, Thierry, Khintibidze, Irakli, Shaburishvili, Tamaz, Pagava, Zurab, Ghlonti, Ramaz, Lominadze, Zaza, Khabeishvili, George, Hemetsberger, Rayyan, Rauch-Kroehnert, Ursula, Stratmann, Matthias, Appel, Karl-Friedrich, Schmidt, Ekkehard, Omran, Heyder, Stellbrink, Christoph, Dorsel, Thomas, Lianopoulos, Emmanouil, Marx, Roger, Zirlik, Andreas, Schellenberg, Detlev, Heitzer, Thomas, Laufs, Ulrich, Gielen, Stephan, Winkelmann, Bernhard, Behrens, Steffen, Sydow, Karsten, Simonis, Gregor, Muenzel, Thomas, Werner, Nikos, Leggewie, Stefan, Boecker, Dirk, Braun-Dullaeus, Ruediger, Toursarkissian, Nicole, Jeserich, Michael, Weissbrodt, Matthias, Schaeufele, Tim, Weil, Joachim, Voeller, Heinz, Waltenberger, Johannes, Natour, Mohammed, Steiner, Stephan, Heidenreich, Lothar, Gremmler, Uwe, Killat, Holger, Patsilinakos, Sotiris, Kartalis, Athanasios, Manolis, Athanassios, Sionis, Dimitrios, Skoumas, Ioannis, Athyros, Vasilios, Parthenakis, P. I. Frangkiskos, Hahalis, P. I. Georgios, Lekakis, John, Xatzitolios, Apostolos, Fausto Ovando, Sergio R., Arango Benecke, Juan L., Rodriguez De Leon, Edgar R., Yan, Bryan P. Y., Siu, David C. W., Turi, Tibor, Merkely, Bela, Ungi, Imre, Lupkovics, Geza, Nagy, Lajos, Katona, Andras, Edes, Istvan, Muller, Gabor, Horvath, Ivan, Kapin, Tibor, Falukozy, Jozsef, Kumbla, Mukund, Sandhu, Manjinder, Annam, Sharath, Proddutur, Naveen Reddy, Premchand, Rajendra K., Mahajan, Ajaykumar, Abhyanakar, Atul D., Kerkar, Prafulla, Govinda, Ravishankar A., Oomman, Abraham, Sinha, Dhurjati, Patil, Sachin N., Kahali, Dhiman, Sawhney, Jitendra, Joshi, Abhijeet B., Chaudhary, Sanjeev, Harkut, Pankaj, Guha, Santanu, Porwal, Sanjay, Jujjuru, Srimannarayana, Pothineni, Ramesh B., Monteiro, Minguel R., Khan, Aziz, Iyengar, Shamanna S., Grewal, Jasprakash Singh, Chopda, Manoj, Fulwani, Mahesh C., Patange, Aparna, Chopra, Vijay K., Goyal, Naresh K., Shinde, Rituparna, Manakshe, Gajendra V., Patki, Nitin, Sethi, Sumeet, Munusamy, Vengatesh, Karna, Sunil, Adhyapak, Srilakshmi, Pandurangi, Ulhas, Mathur, Rishabh, Kalashetti, Suhas, Bhagwat, Ajit, Raghuraman, Bagirath, Yerra, Shiv Kumar, Bhansali, Prasant, Borse, Rohidas, Das, Srihari, Abdullakutty, Jabir, Saathe, Shireesh, Palimkar, Priya, Atar, Shaul, Shechter, Michael, Mosseri, Morris, Arbel, Yaron, Lotan, Chaim, Rosenschein, Uri, Katz, Amos, Henkin, Yaakov, Francis, Adi, Klutstein, Marc, Nikolsky, Eugenia, Turgeman, Yoav, Halabi, Majdi, Kornowski, Ran, Jonas, Michael, Amir, Offer, Rozenman, Yoseph, Fuchs, Shmuel, Hussein, Osamah, Gavish, Dov, Vered, Zvi, Caraco, Yoseph, Elias, Mazen, Tov, Naveh, Piovaccari, Giancarlo, De Pellegrin, Annamaria, Guardigli, Gabriele, Licciardello, Giovanni, Auguadro, Carla, Cuccia, Claudio, Salvioni, Alessandro, Musumeci, Giuseppe, Calabro, Paolo, Novo, Salvatore, Faggiano, Pompilio, De Cesare, Nicoletta B., Berti, Sergio, Cavallini, Claudio, Puccioni, Enrico, Galvani, Marcello, Tespili, Maurizio, Piatti, Piermarco, Palvarini, Michela, De Luca, Giuseppe, Violini, Roberto, De Leo, Alessandro, Filardi, Pasquale Perrone, Ferratini, Maurizio, Dai, Kazuoki, Kamiya, Haruo, Ando, Kenji, Takeda, Yoshihiro, Morino, Yoshihiro, Hata, Yoshiki, Kimura, Kazuo, Kishi, Koichi, Michishita, Ichiro, Uehara, Hiroki, Higashikata, Toshinori, Hirayama, Atsushi, Hirooka, Keiji, Sakagami, Satoru, Taguchi, Shuichi, Koike, Akihiro, Fujinaga, Hiroyuki, Koba, Shinji, Kozuma, Ken, Kawasaki, Tomohiro, Ono, Yujiro, Shimizu, Masatoshi, Katsuda, Yousuke, Wada, Atsuyuki, Shinke, Toshiro, Ako, Junya, Fujii, Kenshi, Takahashi, Toshiyuki, Sakamoto, Tomohiro, Furukawa, Yutaka, Sugino, Hiroshi, Mano, Toshiaki, Utsu, Noriaki, Ito, Kashima, Haraguchi, Takuya, Ueda, Yasunori, Nishibe, Akira, Fujimoto, Kazuteru, Yoon, Jung Han, Park, Hun Sik, Chae, In-Ho, Kim, Moo Hyun, Jeong, Myung Ho, Rha, Seungwoon, Kim, Chongjin, Hong, Taekjong, Busmane, Arija, Pontaga, Natalija, Strelnieks, Aldis, Mintale, Iveta, Sime, Iveta, Petrulioniene, Zaneta, Kavaliauskiene, Roma, Jurgaitiene, Ruta, Sakalyte, Gintare, Slapikas, Rimvydas, Norkiene, Sigute, Misonis, Nerijus, Kibarskis, Aleksandras, Kubilius, Raimondas, Bojovski, Stojko, Lozance, Nensi, Kjovkaroski, Aleksandar, Doncovska, Snezana, Ong, Tiong Kiam, Kasim, Sazzli, Maskon, Oteh, Kandasamy, Balachandran, Liew, Houng B., Mohamed, Wan Mohd Izani Wan, Garcia Castillo, Armando, Carrillo Calvillo, Jorge, Fajardo Campos, Pedro, Nunez Fragoso, Juan Carlos, Bayram Llamas, Edmundo Alfredo, Alcocer Gamba, Marco Antonio, Carranza Madrigal, Jaime, Gonzalez Salas, Luis Gerardo, Lopez Rosas, Enrique, Gonzalez Diaz, Belinda, Salcido Vazquez, Eduardo, Nacoud Ackar, Alfredo, Llamas Esperon, Guillermo Antonio, Martinez Sanchez, Carlos Rodolfo, Guerrero De Leon, Maria, Suarez Otero, Rodrigo, Fanghanel Salmon, Guillermo, Perez Rios, Jesus Antonio, Garza Ruiz, Jose Angel, Breedveld, Robert W., Hoogslag, Pieter A. M., Suryapranata, Harry, Oomen, Antonius, Wiersma, Jacobijne J., Van Der Wal, Ruud M. A., Van Huysduynen-Monraats, Pascalle S. Hooft, Karalis, Ioannis, Verdel, Gerardus J. E., Brueren, Bart R. G., Troquay, Roland P. Th, Viergever, Eric P., Al-Windy, Nadea Y. Y., Bartels, Gerard L., Cornel, Jan H., Hermans, Walter R. M., Herrman, Johannes P. R., Bos, Robert J., Groutars, Reginald G. E. J., Van Der Zwaan, Coenraad C., Kaplan, Refik, Ronner, Eelko, Groenemeijer, Bjorn E., Bronzwaer, Patrick N. A., Liem, Anho A. H., Rensing, Bernard J. W. M., Bokern, Marcel J. J. A., Nijmeijer, Remco, Hersbach, Ferry M. R. J., Willems, Frank F., Gosselink, Antonius T. M., Elliott, John, Wilkins, Gerard, Fisher, Raewyn, Scott, Douglas, Hart, Hamish, Stewart, Ralph, Harding, Scott, Ternouth, Ian, Fisher, Nicholas, Aitken, Denise, Anscombe, Russell, Tomala, Tadeusz, Nygard, Ottar, Sparby, Jon Arne, Andersen, Kjell, Gullestad, Lars, Jortveit, Jarle, Munk, Peter S., Hurtig, Ulf, Ticona, Jorge R. Calderon, Velasquez, Julio R. Durand, Miguel, Sandra A. Negron, Perez, Enrique S. Sanabria, Chambilla, Jesus M. Carrion, Ayala, Carlos A. Chavez, Leon, Reynaldo P. Castillo, Gonzales, Rolando J. Vargas, Zuniga, Jose D. Hernandez, Cosavalente, Luis A. Camacho, Mannucci, Jorge E. Bravo, Navarro, Nassip C. Llerena, Concha, Yudy M. Roldan, Chavez, Victor E. Rodriguez, Hernandez, Henry A. Anchante, Nunez, Carlos A. Zea, Ferrolino, Arthur, Sy, Rosa Allyn G., Tirador, Louie, Matiga, Generoso, Coching, Raul Martin, Bernan, Alisa, Rogelio, Gregorio, Morales, Dante D., Tan, Edgar, Wlodarczak, Adrian, Jaworska, Krystyna, Skonieczny, Grzegorz, Pawlowicz, Lidia, Wojewoda, Pawel, Busz-Papiez, Benita, Bednarski, Janusz, Goch, Aleksander, Staneta, Pawel, Dulak, Elzbieta, Saminski, Krzysztof, Krasowski, Wlodzimierz, Sudnik, Wanda, Zurakowski, Aleksander, Skorski, Marcin, Lysek, Roman, Miklaszewicz, Beata, Kubica, Jacek, Lipko, Jan Andrzej, Kostarska-Srokosz, Edyta, Piepiorka, Marek, Drzewiecka, Anna, Sciborski, Ryszard, Stasiewski, Arkadiusz, Blicharski, Tomasz, Bystryk, Leszek, Szpajer, Michal, Korol, Marek, Czerski, Tomasz, Mirek-Bryniarska, Ewa, Gniot, Jacek, Lubinski, Andrzej, Gorny, Jerzy, Franek, Edward, Monteiro, Pedro, Bastos, Jose Mesquita, Pereira, Helder H., Martins, Dinis, Seixo, Filipe, Mendonca, Carlos, Botelho, Ana, Minescu, Bogdan, Istratoaie, Octavian, Tesloianu, Dan N., Cristian, Gabriel, Podoleanu, Cristian G. C., Constantinescu, Mircea C. A., Bengus, Cristina M., Militaru, Constantin, Rosu, Doina, Parepa, Irinel R., Matei, Adrian V., Alexandru, Tom M., Shvarts, Yury, Orlikova, Olga, Kobalava, Zhanna, Barbarash, Olga L., Markov, Valentin, Lyamina, Nadezhda, Gordienko, Alexander, Zrazhevsky, Konstantin, Vishnevsky, Alexander Y., Gurevich, Victor, Stryuk, Raisa, Lomakin, Nikita V., Bokarev, Igor, Shalaev, Sergey, Khaisheva, Larisa, Chizhov, Petr, Viktorova, Inna, Osokina, Natalya, Akatova, Evgenia, Chumakova, Galina, Libov, Igor, Voevoda, Mikhail I., Tretyakova, Tatyana V., Baranov, Evgeny, Shustov, Sergey, Yakushin, Sergey, Gordeev, Ivan, Khasanov, Niiaz, Reshetko, Olga, Sotnikova, Tatiana, Molchanova, Olga, Nikolaev, Konstantin, Gapon, Liudmila, Baranova, Elena, Shogenov, Zaur, Kosmachova, Elena, Karpov, Yuriy, Povzun, Anton, Egorova, Liudmila, Tyrenko, Vadim V., Ivanov, Igor G., Simic, Dragan, Ivanovic, Nikola, Davidovic, Goran, Tasic, Nebojsa, Asanin, Milika R., Stojic, Stevo, Apostolovic, Svetlana R., Ilic, Stevan, Putnikovic, Biljana, Stankovic, Aleksandar, Arandjelovic, Aleksandra, Radovanovic, Slavica, Balinovac, Jovan, Dincic, Dragan V., Seferovic, Petar, Dodic, Slobodan, Dimkovic, Sinisa, Poh, Kian-Keong, Ong, Hean Yee, Micko, Karol, Nociar, Jan, Pella, Daniel, Fulop, Peter, Hranai, Marian, Palka, Juraj, Mazur, Juraj, Majercak, Ivan, Dzupina, Andrej, Fazekas, Frantisek, Gonsorcik, Jozef, Bugan, Viliam, Selecky, Juraj, Kamensky, Gabriel, Strbova, Jaroslava, Smik, Rudolf, Dukat, Andrej, Zuran, Ivan, Oklukar, Janez, Suligoj, Natasa Cernic, Cevc, Matija, Lipar, Luka, Cyster, Henry P., Ranjith, Naresh, Corbett, Clive, Bayat, Junaid, Makotoko, Ellen Makoali, Kapp, Ilse E., de Basson, Matthys M. V., Lottering, Hanlie, Van Zyl, Louis J., Sebastian, Peter J., Pillay, Thayabran, Saaiman, Jan A., Commerford, Patrick J., Cassimjee, Soraya, Ebrahim, Iftikhar O., Sarvan, Mahomed, Mynhardt, Joseph H., Reuter, Helmuth, Moodley, Rajendran, Vida, Manuel, Cequier Fillat, Angel R., Bodi Peris, Vicente, Fuentes Jimenez, Francisco, Marin, Francisco, Cruz Fernandez, Jose M., Gil-Extremera, Blas, Worner Diz, Fernando, Garcia-Dorado, David, Iniguez, Andres, Tunon Fernandez, Jose, Gonzalez-Juanatey, Jose R., Fernandez Portales, Javier, Civeira Murillo, Fernando, Matas Pericas, Laia, Luis Zamorano, Jose, De Mora Martin, Manuel, Bruguera Cortada, Jordi, Alonso Martin, Joaquin J., De Berrazueta Fernandez, Jose R., Diaz Fernandez, Jose Francisco, Garcia Lledo, Jose Alberto, Cosin Sales, Juan, Botas Rodriguez, Javier, Gusi Tragant, Gabriel, Benedicto, Amparo, Gonzalez-Juanatey, Carlos, Camprubi Potau, Mercedes, Plaza Perez, Ignacio, Moris De La Tassa, Cesar, Loma-Osorio Rincon, Pablo, Balaguer Recena, Javier, M Escudier, Juan, Constantine, Godwin, Haniffa, Ruvaiz, Tissera, Nirmali, Amarasekera, Stanley, Fernando, Nimali, Jayawardena, Jayanthimala, Santharaj, Wijeyasingam, Ekanayaka, Ruvan, Mendis, Sepalika, Senaratne, Vajira, Mayurathan, Gnanamoorthy, Sirisena, Thilak, Rajapaksha, Ajantha, Herath, Jagath I., Amarasena, Naomali, Berglund, Stefan, Rasmanis, Gundars, Witt, Nils, Mourtzinis, Georgios, Nicol, Peter, Hansen, Ole, Romeo, Stefano, Jensen, Steen Agergaard, Torstensson, Ingemar, Ahremark, Ulf, Sundelin, Torbjorn, Moccetti, Tiziano, Mueller, Christian, Mach, Francois, Binder, Ronald, Tsai, Wei-Chuan, Ueng, Kwo-Chang, Lai, Wen-Ter, Liu, Ming-En, Hwang, Juey-Jen, Yin, Wei-Hsian, Hsieh, I-Chang, Lin, Wei Hsiang, Kuo, Jen-Yuan, Huang, Tsuei-Yuan, Fang, Chih-Yuan, Kaewsuwanna, Pinij, Soonfuang, Wasant, Jintapakorn, Woravut, Sukonthasarn, Apichard, Wongpraparut, Nattawut, Sastravaha, Krisada, Sansanayudh, Nakarin, Kehasukcharoen, Wirash, Piyayotai, Dilok, Camsari, Ahmet, Kultursay, Hakan, Mutlu, Bulent, Ersanli, Murat, Demirtas, Mustafa, Kirma, Cevat, Ural, Ertan, Koldas, Lale, Karpenko, Oleksandr, Prokhorov, Alexander, Vakaluyk, Ihor, Myshanych, Halyna, Reshotko, Dmytro, Batushkin, Valeriy, Rudenko, Leonid, Kovalskyi, Ihor, Kushnir, Mykola, Tseluyko, Vira, Mostovoy, Yuriy, Stanislavchuk, Mykola, Kyiak, Yulian, Karpenko, Yuriy, Malynovsky, Yaroslav, Klantsa, Andriy, Kutniy, Oles, Amosova, Ekaterina, Tashchuk, Viktor, Leshchuk, Oleh, Rishko, Mykola, Kopytsya, Mykola, Yagensky, Andriy, Vatutin, Mykola, Bagriy, Andriy, Barna, Olga M., Ushakov, Olexiy, Dzyak, Georgiy, Goloborodko, Borys, Rudenko, Anatolii, Trevelyan, Jasper, Zaman, Azfar, Lee, Kaeng, Moriarty, Andrew, Aggarwal, Rajesh K., Clifford, Piers, Wong, Yuk-Ki, Iqbal, Syed M. R., Subkovas, Eduardas, Braganza, Denise, Sarkar, David, Storey, Robert, Griffiths, Huw, Mcclure, Sam, Muthusamy, Rangasamy, Kurian, John, Levy, Terry, Barr, Craig, Kadr, Honer, Gerber, Robert, Simaitis, Audrius, Soran, Handrean, Mathur, Anthony, Brodison, Adrian, Oliver, Richard, Mudawi, Telal, Reynolds, Timothy, Sharman, David, Butler, Rob, Wilkinson, Peter, Lip, Gregory Y. H., Halcox, Julian, Vardi, Gil, Baldari, Duccio, Brabham, David, Treasure, Charles, II, Dahl, Charles, Palmer, Bruce, Wiseman, Alan, Khan, Abul, Puri, Sanjeev, Mohart, Ann Elizabeth, Ince, Carlos, Flores, Enrique, Wright, Scott, Cheng, Shi-Chi, Rosenberg, Michael, Rogers, William, Jr., Kosinski, Edward, Forgosh, Les, Waltman, Jonathan, Khan, Misal, Shoukfeh, Mohammad, Dagher, Georges, Lieber, Ira, Kumar, Priya, East, Cara, Krichmar, Perry, White, Lindsey, Knickelbine, Thomas, Haldis, Thomas, Gillespie, Eve, Suh, David, Arif, Imran, Akhter, Faiq, Carlson, Eric, D'Urso, Michael, El-Ahdab, Fadi, Nelson, William, Harris, Barry, Cohen, Steven, Carter, Luther, Sabatino, Kenneth, Haddad, Tariq, Malik, Amir, Rao, Sunder, Mulkay, Angel, Jovin, Ion, Klancke, Kim, Malhotra, Vinay, Devarapalli, Sai K., Koren, Michael, Chandna, Harish, Dodds, George, III, Janik, Matthew, Moran, Joseph, Sumner, Andrew, Kobayashi, John, Davis, William, Yazdani, Shahram, Pasquini, John, Thakkar, Maitreya, Vedere, Amarnath, Leimbach, Wayne, Rider, James, Singh, Narendra, Shah, Anil V., Janosik, Denise, Pepine, Carl, Berman, Brett, Gelormini, Joseph, Daniels, Christopher, Keating, Friederike, Kondo, Nicholas I., Shetty, Sanjay, Waider, Winfried, Takata, Theodore, Abu-Fadel, Mazen, Shah, Vipul, Aggarwal, Rahul, Izzo, Mark, Kumar, Anil, Hattler, Brack, Link, Chad, Bortnick, Anna, Kinzfogl, George, III, Ghitis, Arnold, Larry, John, Teufel, Edward, Kuhlman, Peter, Mclaurin, Brent, Zhang, Wenwu, Thew, Stephen, Abbas, Jalal, White, Matthew, Ranadive, Nandkishore, Gring, Christian, Henderson, David, Schuchard, Timothy, Farhat, Naim, Kline, Geoffrey, Mahal, Sharan, Whitaker, Jack, Speirs, Shawn, Andersen, Rolf, Daboul, Nizar, Horwitz, Phillip, Jafar, Zubair, Mcgarvey, Joseph, Jr., Panchal, Vipul, Voyce, Stephen, Blok, Thomas, Sheldon, William, Azizad, Masoud M., Schmalfuss, Carsten, Picone, Mark, Herzog, William, Jr., Lindsey, Jason, Nowins, Rosemary, Lepor, Norman, El Shahawy, Mahfouz, Weintraub, Howard, Irimpen, Anand, May, Wade, Galski, Thomas, Chu, Alan, Mody, Freny, Hodes, Zachary, Fairlamb, James, Lambert, Charles, Jr., Raisinghani, Ajit, Abbate, Antonio, King, Marilyn, Carey, Charles, Gerber, Jaime, Younis, Liwa, Park, Hyeun (Tom), Vidovich, Mladen, Knutson, Thomas, Friedman, Dennis, Chaleff, Fred, Loussararian, Arthur, Kimmelstiel, Carey, Silver, Kevin, Foster, Malcolm, Tonnessen, Glen, Amlani, Mohamadali, Wali, Andreas, Malozzi, Christopher, Wattanakit, Keattiyoat, O'Donnell, Philip J., Singal, Dinesh, Jaffrani, Naseem, Banuru, Sridhar, Fisher, Daniel, Xenakis, Mark, Perlmutter, Neal, Bhagwat, Ravi, Strader, James, Jr., Akyea-Djamson, Ayim, Labroo, Ajay, Lee, Kwan, Marais, H. John, Claxton, Edmund, Jr., Berk, Martin, Rossi, Peter, Joshi, Parag, Khaira, Ajit S., Kumkumian, Greg, Lupovitch, Steven, Purow, Joshua, Welka, Stephen, Hoffman, David, Fischer, Stuart, Soroka, Eugene, Eagerton, Donald, Pancholy, Samir, Ray, Michael, Farrar, Michael, Pollock, Stewart, French, William J., Diamantis, Steve, Gimple, Lawrence, Schwartz, Steven, Pereira, Edward, Spriggs, Douglas, Strain, Janet, Vo, Anthony, Chane, Majed, Hall, Jason, Vijay, Nampalli, Lotun, Kapildeo, Lester, F. Martin, Nahhas, Ahed, Pope, Theodore, Nager, Paul, Vohra, Rakesh, Bashir, Riyaz, Ahmed, Hinan, Berlowitz, Michael, Fishberg, Robert, Barrucco, Robert, Yang, Eric, Radin, Michael, Sporn, Daniel, Eisenberg, Steven, Landzberg, Joel, Mcgough, Martin, Turk, Samir, Schwartz, Michael, Sundram, P. Sandy, Jain, Diwakar, Zainea, Mark, Bayron, Carlos, Karlsberg, Ronald, Lui, Henry, Keen, William, Westerhausen, Donald, Jr., Khurana, Sandeep, Agarwal, Himanshu, Birchem, Jessica, Penny, William, Jr., Chang, Mark, Gilbert, John M., Chalavarya, Gopal, Eaton, Charles, Schmedtje, John F., Jr., Christenson, Stuart, Denham, Douglas, Macdonell, Alexander, Gibson, Paul, Rahman, Aref, Al Joundi, Tammam, Conrad, Gary, Kotha, Purushotham, Love, Michael, Giesler, Gregory, Rubenstein, Howard, Akright, Laura, Schifferdecker, Branislav, Krawczyk, Justine, Wells, Terry, Welker, James, Foster, Robert, Gilmore, Richard, Anderson, Jay, Jacoby, Douglas, Harris, Bill, Gardner, Geraldine, Dandillaya, Ramprasad, Vora, Kishor, Kostis, John, Hunter, John, Laxson, David, Ball, Eric, Internal Medicine, ODYSSEY OUTCOMES Comm Inv, VA Boston Healthcare System, Department of General Surgery. Surgical Oncology Unit, Reina Sofía University Hospital, Metacohorts Consortium, Sanofi [Vitry-sur-Seine], SANOFI Recherche, CIC Brest, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche, University of Zurich, and Schwartz, Gregory G

Subjects
Adult, Male, medicine.medical_specialty, Acute coronary syndrome, Evinacumab, [SDV]Life Sciences [q-bio], Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Hypercholesterolemia, 610 Medicine & health, 2700 General Medicine, 030204 cardiovascular system & hematology, Antibodies, Monoclonal, Humanized, Placebo, 11171 Cardiocentro Ticino, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Humans, Medicine, 03.02. Klinikai orvostan, 030212 general & internal medicine, Myocardial infarction, Acute Coronary Syndrome, ComputingMilieux_MISCELLANEOUS, Aged, Alirocumab, business.industry, Unstable angina, Anticholesteremic Agents, PCSK9, PCSK9 Inhibitors, Hazard ratio, Antibodies, Monoclonal, Cholesterol, LDL, General Medicine, Middle Aged, ta3121, medicine.disease, 3. Good health, Cardiovascular Diseases, Cardiology, Female, Human medicine, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract

PubMed: 30403574, 2-s2.0-85057337718, BACKGROUND Patients who have had an acute coronary syndrome are at high risk for recurrent ischemic cardiovascular events. We sought to determine whether alirocumab, a human monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9), would improve cardiovascular outcomes after an acute coronary syndrome in patients receiving high-intensity statin therapy. METHODS We conducted a multicenter, randomized, double-blind, placebo-controlled trial involving 18,924 patients who had an acute coronary syndrome 1 to 12 months earlier, had a low-density lipoprotein (LDL) cholesterol level of at least 70 mg per deciliter (1.8 mmol per liter), a non-highdensity lipoprotein cholesterol level of at least 100 mg per deciliter (2.6 mmol per liter), or an apolipoprotein B level of at least 80 mg per deciliter, and were receiving statin therapy at a high-intensity dose or at the maximum tolerated dose. Patients were randomly assigned to receive alirocumab subcutaneously at a dose of 75 mg (9462 patients) or matching placebo (9462 patients) every 2 weeks. The dose of alirocumab was adjusted under blinded conditions to target an LDL cholesterol level of 25 to 50 mg per deciliter (0.6 to 1.3 mmol per liter). The primary end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. RESULTS The median duration of follow-up was 2.8 years. A composite primary end-point event occurred in 903 patients (9.5%) in the alirocumab group and in 1052 patients (11.1%) in the placebo group (hazard ratio, 0.85; 95% confidence interval [CI], 0.78 to 0.93; P

Published
2018

14. Purification of heparan sulfate D-glucosaminyl 3-O-sulfotransferase.

Author

Liu, J, Shworak, N W, Fritze, L M, Edelberg, J M, and Rosenberg, R D

Abstract

The cellular generation of proteoglycans with anticoagulant heparan sulfate (HSPGact) is determined by microsomal "HSact conversion activity" that functions in concert with the sulfate donor 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to convert nonanticoagulant heparan sulfate (HSinact) to anticoagulant heparan sulfate (HSact) (Shworak, N. W., Fritze, L. M. S., Liu, J., Butler, L. D., and Rosenberg, R. D. (1996) J. Biol. Chem. 271, 27063-27071). Suspension cultures of L-33(+) cells in serum-free medium produce HSPGact and secrete HSact conversion activity. The secreted protein exhibiting HSact conversion activity was isolated by subjecting large volumes of conditioned suspension culture medium to heparin-AF Toyopearl affinity chromatography, Mono Q-FPLC, TSK SW3000-HPLC, and 3',5'-ADP-agarose affinity chromatography. The final product was purified approximately 700,000-fold relative to cellular material with a 5% overall recovery of HSact conversion activity. The isolated protein migrated on SDS-polyacrylamide gel electrophoresis as a broad band of Mr = 46,000 and co-migrated on nondenaturing acidic pH gel electrophoresis with HSact conversion activity. The purified component was identified as heparan sulfate D-glucosaminyl 3-O-sulfotransferase because it transferred sulfate from [35S]PAPS to the 3-O-position of D-glucosamine and D-glucosamine 6-O-sulfate of HSact precursor and HSinact precursor to produce nearly equivalent amounts of labeled HSact and HSinact. The exhaustive modification of wild-type LTA cell [35S]HS with either microsomal HSact conversion activity or purified enzyme increased HSact content from 9 to approximately 36%, which indicates that microsomal HSact conversion activity predominantly reflects the level of a 3-O-sulfotransferase that converts HSact precursor into HSact. The kinetic parameters of purified 3-O-sulfotransferase were determined for modification of HSact precursor and HSinact precursor. The apparent KM* and Vmax* with respect to PAPS concentration for sulfation of HSact precursor and HSinact precursor were 2.4 microM and 23 fmol of sulfate/min/ng of enzyme and 2.1 microM and 38 fmol of sulfate/min/ng of enzyme, respectively. There was substrate inhibition of the sulfation reaction at elevated HS concentration. The apparent KM* and Vmax* with respect to GAG concentration for sulfation of HSact precursor and HSinact precursor were 16 nM and 120 fmol of sulfate/min/ng of enzyme and 17 nM and 240 fmol of sulfate/min/ng of enzyme, respectively. The observation that purified 3-O-sulfotransferase catalyzes sulfation of HSact precursor and HSinact precursor in conjunction with a documented discordant regulation of 3-O-sulfate content in HSinact and HSact suggests that two discrete forms of the enzyme may exist.

Published
1996

15. Aging-associated changes in vascular activity: a potential link to geriatric cardiovascular disease.

Author

Weinsaft JW and Edelberg JM

Subjects
Age Factors, Aged, Cardiovascular Diseases physiopathology, Geriatric Assessment, Humans, United States epidemiology, Aging physiology, Blood Vessels physiology
Abstract

Ischemic cardiovascular disease is a common cause of morbidity and mortality in the United States population over the age of 65. Prior clinical studies have demonstrated that the severity of cardiovascular pathophysiology is increased in older individuals. Both in vitro and in vivo experimental studies have shown that age-associated clinical events parallel changes in vascular function. Aging is associated with systemic as well as cardiac alterations in three basic vascular regulatory functions: vascular tone, hemostasis, and vascular repair/angiogenesis. This article reviews the molecular and cellular events that may contribute to senescent cardiac pathology. Indeed, a better understanding of the biology of aging-associated vascular dysfunction is fundamental for the development of therapeutics targeted for the treatment of cardiovascular disease in older individuals.

Published
2001
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16. Regulation of vascular bed-specific prothrombotic potential.

Author

Edelberg JM, Christie PD, and Rosenberg RD

Subjects
Animals, Endothelium, Vascular metabolism, Hemostasis, Humans, Models, Biological, Anticoagulants metabolism, Blood Vessels metabolism
Abstract

Hemostasis is the result of interdependent and complex systemic and local endothelial pathways that govern vascular integrity and rheology. A striking feature of hypercoagulable conditions is the focal nature of the resultant thrombotic pathology. Such disorders in hemostasis may be associated with distinct vascular beds, thus implying that the relative combined contribution of individual regulatory pathways may be specific and/or unique to a particular locale in the vasculature. Systemic factors and platelets mediate the formation of fibrin deposition; however, it is the diverse interrelationships in the interaction of these systemic elements with the local endothelial components that dictate vascular bed-specific hemostatic regulation. Indeed, the local activation of coagulation cascades, rather than increases in systemic thrombotic potential, is what leads to fibrin formation in different vascular beds. Hence, the propensity for congenital or acquired disorders to result in local thrombotic pathology is based on the relative contribution of the various hemostatic regulatory pathways in individual vascular beds. The present review highlights the role of local endothelial regulation in the interaction between local and systemic elements that contribute to vascular bed-specific prothrombotic potential.

Published
2001
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17. Direct biologically based biosensing of dynamic physiological function.

Author

Christini DJ, Walden J, and Edelberg JM

Subjects
Animals, Biological Clocks physiology, Catecholamines blood, Ear, External surgery, Mice, Mice, Inbred Strains, Biosensing Techniques methods, Heart Rate physiology, Heart Transplantation
Abstract

Dynamic regulation of biological systems requires real-time assessment of relevant physiological needs. Biosensors, which transduce biological actions or reactions into signals amenable to processing, are well suited for such monitoring. Typically, in vivo biosensors approximate physiological function via the measurement of surrogate signals. The alternative approach presented here would be to use biologically based biosensors for the direct measurement of physiological activity via functional integration of relevant governing inputs. We show that an implanted excitable-tissue biosensor (excitable cardiac tissue) can be used as a real-time, integrated bioprocessor to analyze the complex inputs regulating a dynamic physiological variable (heart rate). This approach offers the potential for long-term biologically tuned quantification of endogenous physiological function.

Published
2001
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18. A murine model of myocardial microvascular thrombosis.

Author

Christie PD, Edelberg JM, Picard MH, Foulkes AS, Mamuya W, Weiler-Guettler H, Rubin RH, Gilbert P, and Rosenberg RD

Subjects
Animals, Cells, Cultured, Coronary Thrombosis genetics, Coronary Thrombosis pathology, Endothelium, Vascular metabolism, Endothelium, Vascular pathology, Fibrosis, Genetic Predisposition to Disease, Genotype, Hemostasis, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Microcirculation, Thrombomodulin deficiency, Thrombomodulin genetics, Tissue Plasminogen Activator deficiency, Tissue Plasminogen Activator genetics, Ultrasonography, Urokinase-Type Plasminogen Activator deficiency, Urokinase-Type Plasminogen Activator genetics, Ventricular Dysfunction, Left diagnostic imaging, Ventricular Dysfunction, Left genetics, Coronary Thrombosis metabolism, Disease Models, Animal, Fibrin biosynthesis, Myocardium pathology, Thrombomodulin physiology, Tissue Plasminogen Activator physiology, Urokinase-Type Plasminogen Activator physiology
Abstract

Disorders of hemostasis lead to vascular pathology. Endothelium-derived gene products play a critical role in the formation and degradation of fibrin. We sought to characterize the importance of these locally produced factors in the formation of fibrin in the cardiac macrovasculature and microvasculature. This study used mice with modifications of the thrombomodulin (TM) gene, the tissue-type plasminogen activator (tPA) gene, and the urokinase-type plasminogen activator (uPA) gene. The results revealed that tPA played the most important role in local regulation of fibrin deposition in the heart, with lesser contributions by TM and uPA (least significant). Moreover, a synergistic relationship in fibrin formation existed in mice with concomitant modifications of tPA and TM, resulting in myocardial necrosis and depressed cardiac function. The data were fit to a statistical model that may offer a foundation for examination of hemostasis-regulating gene interactions.

Published
1999
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19. Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation.

Author

Enjyoji K, Sévigny J, Lin Y, Frenette PS, Christie PD, Esch JS 2nd, Imai M, Edelberg JM, Rayburn H, Lech M, Beeler DL, Csizmadia E, Wagner DD, Robson SC, and Rosenberg RD

Subjects
Animals, Antigens, CD genetics, Apyrase deficiency, Apyrase genetics, Arterioles pathology, Bleeding Time, Blood Platelets cytology, Blood Platelets pathology, Cells, Cultured, Endothelium, Vascular cytology, Endothelium, Vascular enzymology, Endothelium, Vascular metabolism, Female, Fibrin metabolism, Graft Rejection immunology, Graft Rejection pathology, Heart Transplantation immunology, Heart Transplantation pathology, Male, Mesentery blood supply, Mice, Mice, Knockout, Platelet Aggregation, Rats, Receptors, Purinergic P2 physiology, Receptors, Purinergic P2Y1, Thromboplastin metabolism, Thrombosis pathology, Adenosine Triphosphatases, Antigens, CD metabolism, Apyrase metabolism, Blood Coagulation, Blood Platelets physiology, Gene Deletion, Hemostasis
Abstract

CD39, or vascular adenosine triphosphate diphosphohydrolase, has been considered an important inhibitor of platelet activation. Unexpectedly, cd39-deficient mice had prolonged bleeding times with minimally perturbed coagulation parameters. Platelet interactions with injured mesenteric vasculature were considerably reduced in vivo and purified mutant platelets failed to aggregate to standard agonists in vitro. This platelet hypofunction was reversible and associated with purinergic type P2Y1 receptor desensitization. In keeping with deficient vascular protective mechanisms, fibrin deposition was found at multiple organ sites in cd39-deficient mice and in transplanted cardiac grafts. Our data indicate a dual role for adenosine triphosphate diphosphohydrolase in modulating hemostasis and thrombotic reactions.

Published
1999
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20. Vascular bed-specific expression of an endothelial cell gene is programmed by the tissue microenvironment.

Author

Aird WC, Edelberg JM, Weiler-Guettler H, Simmons WW, Smith TW, and Rosenberg RD

Subjects
Animals, Animals, Newborn, Cerebrovascular Circulation, Coculture Techniques, Coronary Circulation, DNA Primers, Endothelium, Vascular cytology, Exons, Genes, Reporter, Heart, Mice, Mice, Transgenic, Microcirculation physiology, Muscle, Skeletal blood supply, Myocardium cytology, Organ Specificity, Polymerase Chain Reaction, Thrombomodulin biosynthesis, beta-Galactosidase biosynthesis, Endothelium, Vascular metabolism, Gene Expression Regulation, Heart Transplantation physiology, Lung Transplantation physiology, von Willebrand Factor biosynthesis, von Willebrand Factor genetics
Abstract

The endothelium is morphologically and functionally adapted to meet the unique demands of the underlying tissue. At the present time, little is known about the molecular basis of endothelial cell diversity. As one approach to this problem, we have chosen to study the mechanisms that govern differential expression of the endothelial cell-restricted von Willebrand factor (vWF) gene. Transgenic mice were generated with a fragment of the vWF gene containing 2,182 bp of 5' flanking sequence, the first exon and first intron coupled to the LacZ reporter gene. In multiple independent lines of mice, beta-galactosidase expression was detected within endothelial cells in the brain, heart, and skeletal muscle. In isogeneic transplantation models, LacZ expression in host-derived auricular blood vessels was specifically induced by the microenvironment of the heart. In in vitro coculture assays, expression of both the transgene and the endogenous vWF gene in cardiac microvascular endothelial cells (CMEC) was upregulated in the presence of cardiac myocytes. In contrast, endothelial cell levels of thrombomodulin protein and mRNA were unchanged by the addition of ventricular myocytes. Moreover, CMEC expression of vWF was not influenced by the addition of 3T3 fibroblasts or mouse hepatocytes. Taken together, the results suggest that the vWF gene is regulated by vascular bed-specific pathways in response to signals derived from the local microenvironment.

Published
1997
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21. Lipoprotein (a) in the regulation of fibrinolysis.

Author

Edelberg JM and Pizzo SV

Subjects
Animals, Arteriosclerosis blood, Humans, Arteriosclerosis physiopathology, Fibrinolysis, Lipoprotein(a) physiology
Abstract

Elevated plasma levels of lipoprotein(a) [LP(a)] are associated with increased an risk of developing atherosclerosis. This increased risk may be due to an Lp(a)-mediated depression of fibrinolytic activity. Lp(a) regulates fibrinolysis by controlling the activity of plasminogen activators. Lp(a) is a low density lipoprotein with an apoprotein(a) subunit which has a high degree of homology with the fibrinolytic zymogen plasminogen. The apoprotein(a) subunit contains up to thirty seven copies of a domain homologous to the plasminogen kringle 4 domain, which enables Lp(a) to bind to fibrin. The subunit also has a zymogen domain, but it is not activated by plasminogen activators. Lp(a) inhibits plasminogen activation by competing with plasminogen for access to plasminogen activators bound to vascular surfaces. Lp(a) also competes with the irreversible inhibitor of plasminogen activators, plasminogen activator inhibitor-1. Therefore increases in Lp(a) concentration may decrease fibrinolytic activity by preventing activation of plasminogen, but Lp(a) may also prolong plasminogen activation by preventing the irreversible inhibition of the activators. At elevated levels of Lp(a) the decreased rate of plasmin generation may not be offset by the prolongation in plasminogen activation, and fibrinolysis will be inhibited.

Published
1995
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23. Lipoprotein (a): purification and kinetic analysis.

Author

Edelberg JM, Lee YJ, Young TN, and Pizzo SV

Subjects
Amino Acid Sequence, Chromatography, Affinity methods, Chromatography, Gel methods, Electrophoresis, Polyacrylamide Gel methods, Enzyme Activation, Fibrinolysin metabolism, Humans, Indicators and Reagents, Kinetics, Lipoprotein(a) blood, Mathematics, Models, Theoretical, Molecular Sequence Data, Plasminogen analysis, Plasminogen metabolism, Plasminogen Activators metabolism, Substrate Specificity, Triglycerides analysis, Fibrinolysis, Lipoprotein(a) isolation & purification, Lipoprotein(a) metabolism
Published
1993
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24. Lipoprotein (a) promotes plasmin inhibition by alpha 2-antiplasmin.

Author

Edelberg JM and Pizzo SV

Subjects
Aminocaproic Acid pharmacology, Cyanogen Bromide, Fibrin Fibrinogen Degradation Products pharmacology, Humans, Kinetics, Lipoprotein(a), Fibrinolysin antagonists & inhibitors, Fibrinolysin pharmacology, Lipoproteins pharmacology, alpha-2-Antiplasmin pharmacology, alpha-Macroglobulins pharmacology
Abstract

Plasmin inhibition by alpha 2-antiplasmin (alpha 2AP) is regulated by the vascular components fibrin(ogen) fragments, plasminogen and lipoprotein (a). Kinetic analysis demonstrates that CNBr-derived fibrinogen fragments completely protect plasmin from alpha 2AP. Plasminogen and 6-aminohexanoic acid decrease the rate of inhibition by 5- and 10-fold respectively. These studies show that CNBr-derived fibrinogen fragments and 6-aminohexanoic acid bind plasmin kringle(s) with binding constants of 2 micrograms/ml and 120 microM respectively, and that plasminogen binds to alpha 2AP with an affinity of 0.5 nM. The unmodulated inhibition is not effected by the presence of lipoprotein (a), but in the presence of protective CNBr-derived fibrinogen fragments the rate of inhibition is increased by the presence of the lipoprotein. The kinetics demonstrate that lipoprotein (a) binds to CNBr-derived fibrinogen fragments with an affinity of 4 nM, displacing plasmin from the protective surface. In addition, tissue-type plasminogen activator and trypsin inhibition by alpha 2AP is not slowed by the presence of CNBr-derived fibrinogen fragments or plasminogen (Pg), respectively. These kinetics suggest that the initial reversible interaction between plasmin and alpha 2AP is mediated by binding of the inhibitor to the kringle 1 domain of plasmin, with a reversible inhibition constant (Ki) of 5.0 x 10(-10) M. Under conditions where this kringle-inhibitor interaction is blocked, the reversible inhibition still occurs between the plasmin and alpha 2AP, but the initial Ki is increased to 5.0 x 10(-9) M. These data suggest that, in the circulation, plasmin inhibition by alpha 2AP may be down-regulated by fibrin, fibrin(ogen) fragments and Pg, but up-regulated by lipoprotein (a) in the presence of fibrin or fibrin(ogen) fragments. The lipoprotein (a)-mediated promotion of plasmin inhibition may provide an additional mechanism by which the lipoprotein impairs fibrinolysis and promotes atherosclerosis.

Published
1992
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25. Ionic modulation of the effects of heparin on plasminogen activation by tissue plasminogen activator: the effects of ionic strength, divalent cations, and chloride.

Author

Young TN, Edelberg JM, Stack S, and Pizzo SV

Subjects
Binding, Competitive, Calcium pharmacology, Cations, Divalent, Fibrinolysin metabolism, Glycosaminoglycans pharmacology, Humans, Kinetics, Magnesium pharmacology, Osmolar Concentration, Chlorides pharmacology, Heparin pharmacology, Plasminogen metabolism, Tissue Plasminogen Activator pharmacology
Abstract

Ionic strength, divalent cations, and Cl- modulate the ability of the glycosaminoglycan heparin to stimulate the activation of human plasminogen (Pg) by tissue-type Pg activator. Kinetic analysis of Pg activation indicates that heparin is inhibitory, stimulatory, or nonstimulatory as a function of ionic strength. While increasing ionic strength inhibits Pg activation in the absence of heparin, in it presence an activation phase followed by an inhibitory phase is observed. Divalent cations, inhibitors of activation in the absence of heparin, increase the rate of activation in its presence. Kinetic analysis demonstrates that divalent cations augment the heparin stimulatory effect a maximum of 60-fold due to increases in kcat without changes in Km of the reaction. This effect is heparin-specific, since activation is not affected by Ca2+ in the presence of heparan sulfate or de-N-sulfated heparin. Also, Cl- inhibits Pg activation in the presence of heparin by acting as a competitive inhibitor (Kic of 100 mM). Furthermore, inhibition by Cl- reduces the overall magnitude of heparin stimulation of Pg activation. These results suggest that physiologic ions in combination with heparin may be significant effectors of Pg activation in the vascular microenvironment.

Published
1992
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26. Heparin oligosaccharides enhance tissue-type plasminogen activator: a correlation between oligosaccharide length and stimulation of plasminogen activation.

Author

Edelberg JM, Conrad HE, and Pizzo SV

Subjects
Amino Acid Sequence, Enzyme Activation, Humans, Kinetics, Molecular Sequence Data, Oligopeptides, Structure-Activity Relationship, Heparin pharmacology, Oligosaccharides pharmacology, Plasminogen metabolism, Tissue Plasminogen Activator metabolism
Abstract

The rate of plasminogen (Pg) activation by tissue-type Pg activator (t-PA) is enhanced by heparin-derived oligosaccharides. Kinetic analysis of the effects of heparin oligosaccharides, ranging in size from di- to dodecasaccharides, on Pg activation demonstrates that stimulation of the reaction is dependent on the size of the heparin oligosaccharides. Di- and tetrasaccharides enhance the activation through 2-fold increases in kcat and 4-fold decreases in Km. Hexasaccharide and larger oligosaccharides stimulate the reaction by increasing the kcat by as much as 4-fold, but do not affect the Km. Previous experiments have shown that lipoprotein(a) [Lp(a)] inhibits Pg activation by t-PA, but only in the presence of a template which enhances t-PA activity such as fibrinogen fragments or intact heparin. Similiarly, Lp(a) inhibits the enhancement of t-PA activity by the larger heparin oligosaccharides but has no effect on t-PA activity in the presence of di- and tetrasaccharides. The results of this study when considered with our previous observations (Edelberg & Pizzo, 1990) suggest that the enhancement in Pg activation by the smaller oligosaccharides is mediated exclusively via binding to t-PA while the larger oligosaccharides may interact with both t-PA and Pg. Furthermore, studies of Pg activation in the presence of both heparin oligosaccharides and fibrinogen fragments demonstrate that t-PA is stimulated preferentially by fibrinogen fragments.

Published
1991
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27. Kinetic analysis of the effects of heparin and lipoproteins on tissue plasminogen activator mediated plasminogen activation.

Author

Edelberg JM and Pizzo SV

Subjects
Heparitin Sulfate pharmacology, Humans, Kinetics, Lipoprotein(a), Lipoproteins, LDL pharmacology, Tissue Plasminogen Activator antagonists & inhibitors, Heparin pharmacology, Lipoproteins pharmacology, Plasminogen pharmacology, Tissue Plasminogen Activator physiology
Abstract

Heparin sulfate and the less sulfated glycosaminoglycan heparan sulfate enhance human plasminogen (Pg) conversion to plasmin by tissue-type plasminogen activator (t-PA). Kinetic studies indicate that both heparin and heparan increase the kcat of t-PA-mediated Pg activation by 25- and 3.5-fold, respectively. The Km of plasmin formation is unaltered by the presence of either heparin or heparan. Both heparin and heparan stimulate the activity of t-PA by interacting with the finger domain of t-PA, with association constants of 1 microM and 200 nM, respectively. Additionally, the lipoproteins lipoprotein(a) [Lp(a)] and low-density lipoprotein (LDL) inhibit the heparin enhancement of Pg activation. Lp(a) is a competitive inhibitor and LDL is a mixed inhibitor of t-PA-mediated Pg activation, with inhibition constants of 30 and 70 nM, respectively. The inhibition constants correspond to physiologic concentrations of these lipoproteins. These data suggest that heparin, heparan, and lipoproteins may play an important in vivo role in regulating cell surface associated activation of the fibrinolytic system.

Published
1990
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29. Further characterization of the cellular plasminogen binding site: evidence that plasminogen 2 and lipoprotein a compete for the same site.

Author

Gonzalez-Gronow M, Edelberg JM, and Pizzo SV

Subjects
Binding Sites, Binding, Competitive, Cell Line, Fibrinolysis, Humans, Lipoprotein(a), Plasminogen isolation & purification, Receptors, Urokinase Plasminogen Activator, Lipoproteins metabolism, Plasminogen metabolism, Receptors, Cell Surface metabolism
Abstract

Specific cell surface receptors for plasminogen (Pg) are expressed by a wide variety of cell types and serve to promote fibrinolysis and local Pg proteolysis. Pg types 1 and 2, separated by chromatography on concanavalin A-Sepharose, were utilized to determine their binding to the monocytoid U937 cell line. Both forms bind in a dose-dependent manner. However, Pg 2 binds to the cellular receptor considerably better than Pg 1 and at equilibrium demonstrates approximately 10-fold greater binding. Lipoprotein a [Lp(a)], which possesses a subunit showing considerable homology to Pg, competes with Pg 2 for the Pg receptor in U937 cells. Moreover, Pg 1 is not able to displace Pg 2 from the receptor. These studies suggest that high levels of Lp(a) may alter the profibrinolytic activity at the cell surface and increase the risks of atherosclerosis and thrombosis. This hypothesis is in accord with the 2-5-fold increased risk of atherosclerosis in patients having high levels of Lp(a).

Published
1989
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30. Lipoprotein a inhibits streptokinase-mediated activation of human plasminogen.

Author

Edelberg JM, Gonzalez-Gronow M, and Pizzo SV

Subjects
Chromatography, Gel, Humans, Kinetics, Lipoprotein(a), Lipoproteins isolation & purification, Protein Binding, Streptokinase isolation & purification, Lipoproteins metabolism, Plasminogen metabolism, Plasminogen Activators, Streptokinase antagonists & inhibitors
Abstract

Lipoprotein a [Lp(a)] inhibits human plasminogen (Pg) conversion to plasmin (Pm) by streptokinase- (SK-) mediated activation. Kinetic and binding studies indicate that Lp(a) inhibits Pg activation by competitive and uncompetitive inhibition. Lp(a) competes with Pg for SK and forms a stable complex. Lp(a) does not, however, inhibit Pg activation by the proteolytic SK-Pm complex. The SK-Pg and SK-Pg(act) intermediate complexes are possible targets of the Lp(a) uncompetitive inhibition. The competitive inhibition constant (Kic) is 45 nM or 14 mg/dL, and the uncompetitive inhibition constant (Kiu) is 140 nM or 42 mg/dL, corresponding to physiologic and pathophysiologic Lp(a) concentrations, respectively.

Published
1989
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