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1. ANGPTL3 deficiency impairs lipoprotein production and produces adaptive changes in hepatic lipid metabolism

Author

Kendall H. Burks, Yan Xie, Michael Gildea, In-Hyuk Jung, Sandip Mukherjee, Paul Lee, Upasana Pudupakkam, Ryan Wagoner, Ved Patel, Katherine Santana, Arturo Alisio, Ira J. Goldberg, Brian N. Finck, Edward A. Fisher, Nicholas O. Davidson, and Nathan O. Stitziel

Subjects
apolipoproteins, dyslipidemias, LDL/metabolism, lipase/endothelial, PPARs, triglycerides, Biochemistry, QD415-436
Abstract

Angiopoietin-like protein 3 (ANGPTL3) is a hepatically secreted protein and therapeutic target for reducing plasma triglyceride-rich lipoproteins and low-density lipoprotein (LDL) cholesterol. Although ANGPTL3 modulates the metabolism of circulating lipoproteins, its role in triglyceride-rich lipoprotein assembly and secretion remains unknown. CRISPR-associated protein 9 (CRISPR/Cas9) was used to target ANGPTL3 in HepG2 cells (ANGPTL3−/−) whereupon we observed ∼50% reduction of apolipoprotein B100 (ApoB100) secretion, accompanied by an increase in ApoB100 early presecretory degradation via a predominantly lysosomal mechanism. Despite defective particle secretion in ANGPTL3−/− cells, targeted lipidomic analysis did not reveal neutral lipid accumulation in ANGPTL3−/− cells; rather ANGPTL3−/− cells demonstrated decreased secretion of newly synthesized triglycerides and increased fatty acid oxidation. Furthermore, RNA sequencing demonstrated significantly altered expression of key lipid metabolism genes, including targets of peroxisome proliferator-activated receptor α, consistent with decreased lipid anabolism and increased lipid catabolism. In contrast, CRISPR/Cas9 LDL receptor (LDLR) deletion in ANGPTL3−/− cells did not result in a secretion defect at baseline, but proteasomal inhibition strongly induced compensatory late presecretory degradation of ApoB100 and impaired its secretion. Additionally, these ANGPTL3−/−;LDLR−/− cells rescued the deficient LDL clearance of LDLR−/− cells. In summary, ANGPTL3 deficiency in the presence of functional LDLR leads to the production of fewer lipoprotein particles due to early presecretory defects in particle assembly that are associated with adaptive changes in intrahepatic lipid metabolism. In contrast, when LDLR is absent, ANGPTL3 deficiency is associated with late presecretory regulation of ApoB100 degradation without impaired secretion. Our findings therefore suggest an unanticipated intrahepatic role for ANGPTL3, whose function varies with LDLR status.

Published
2024
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2. SVEP1 is an endogenous ligand for the orphan receptor PEAR1

Author

Jared S. Elenbaas, Upasana Pudupakkam, Katrina J. Ashworth, Chul Joo Kang, Ved Patel, Katherine Santana, In-Hyuk Jung, Paul C. Lee, Kendall H. Burks, Junedh M. Amrute, Robert P. Mecham, Carmen M. Halabi, Arturo Alisio, Jorge Di Paola, and Nathan O. Stitziel

Subjects
Science
Abstract

SVEP1 is linked to numerous human diseases, though its disease-promoting mechanism has remained unclear. Here, the authors identify SVEP1 as a ligand for the orphan receptor PEAR1 and provide insight into the role of this interaction in cardiovascular disease.

Published
2023
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4. Association of Time of Day With Outcomes Among Patients Triaged for a Suspected Severe Stroke in Nonurban Catalonia

Author

Álvaro García-Tornel, Alan Flores, Mikel Terceño, Pedro Cardona, Sergi Amaro, Meritxell Gomis, Josep Zaragoza, Jerzy Krupinski, Manuel Gómez-Choco, Natalia Mas, Dolores Cocho, Esther Catena, Francesc Purroy, Matias Deck, Marta Rubiera, Jorge Pagola, David Rodriguez-Luna, Jesús Juega, Noelia Rodríguez-Villatoro, Carlos A. Molina, Cristina Soro, Xavier Jimenez, Mercè Salvat-Plana, Antoni Dávalos, Tudor G Jovin, Sonia Abilleira, Natalia Pérez de la Ossa, Marc Ribó, Estela Sanjuan, Katherine Santana, Olga Maisterra, Estevo Santamarina, Marian Muchada, Sandra Boned, Antonio Palasi Franco, Marta Olivé Gadea, Matías Deck, Manuel Requena, Victoria Sala, Lucía Muñoz, Mónica Millán, Elena López-Cancio, Laura Dorado, María Hernández-Pérez, Jordi Ciurans, Daniela Samaniego, Tamara Canento, Lorena Martin, Anna Planas, Joaquin Broto, Agustín Sorrentino, Martí Paré, Nuole Zhu, Alicia Garrido, Laia Grau, Ane Miren Crespo, Silvia Presas, Miriam Almendrote, Alba Ramos, Giuseppe Lucente, Lourdes Ispierto, Manuel Lozano, Juan Luis Becerra, Marta Jiménez, Dolores Vilas Rolán, Nicolas Guanyabens, Josep Sanchez-Ojanguren, Alicia Martínez-Piñeiro, Sara Forcén, Mireia Gea, Marta Álvarez, Anna Ramos, Manuel Domínguez Lizarbe, Rubio Guerra, Irene Bragado, Andrea Arbex, Luis Rodríguez, Alejandro Bustamante, Pere Cardona Portela, Helena Quesada García, Blanca Lara Rodríguez, Nuria Cayuela, Julia Miró, Clara Marzal, Andrés Paipa, Sergio Campoy, Ana Núñez, Pablo Arroyo, Sarah Besora, Vanessa Adell, Jaume Campdelacreu, Montse Alemany Martí, Belén González, Laura Bau Vila, Marta Fiter Crespo, Anna Berbel, Ma. Cristina Villaescusa Urbaneja, Núria Guillen, Nuria Vidal, Patricia Valentina Vérez Santamaria, Diego Herrero Navarro, Marta Simó, Mercedes Falip, Elisabeth Matas, Neus Mongay Ochoa, Ariadna Gifreu, Albert Muñoz, Lucía Romero, Eduard Portell, Guillermo Hernández Perez, F. Ruiz Esteve, Silvia Teixidor, Augusto Salazar Talavera, Roser Gómez, Xabier Urra Nuin, Martha Vargas, Ángel Chamorro, Laura Llull, Arturo Renú, Salvatore Rudilosso, Raquel Sánchez del Valle, Helena Ariño, Nuria Solà, Delón la Puma, Francisco Gil, Juan Bernardo Gómez, Nuria Matos, Neus Falgàs, Sergi Borrego, Almudena Sánchez, Mircea Balasa, Carmen Montejo, Mar Guasp, David Reyes, Pablo Sánchez Cervilla, Jose Miguel Contador, Victor Augusto Vera Monge, Oscar Ramos, Alejandro Rodríguez, Ana Rodríguez Campello, Gemma Romeral Ballester, Mireia Llop Trujillano, Eva Giralt Steinhauer, Elisa Cuadrado Godia, Angel Javier Ois Santiago, Jordi Jimenez Conde, Joan Martí Fábregas, Daniel Guisado, Luís Prats, Pol Camps, Raquel Delgado, Alejandro Martínez Domeño, Rebeca Marín, David Cànovas, Jordi Estela, Marta Ros, Sonsoles Aranceta, Jordi Espinosa, Marta Rubio, Cristina Lafuente, Oriol Barrachina, Alicia Anguita, Anna Reverter, Carmen García, Gemma Sansa, Mariona Hervas, Monica Crosas, Tania Delgado, Dra Sonia Huertas Folch, Gemma Muñoz Gamito, Josep Trenado Alvarez, Teresa Subirana, Jessica Molina, Laura Comes Romero, Gemma Guardia Valls, Miriam Jover, Javier Joaquín Sotova, Sonia Mª García Sánchez, Sebastian Valenzuela, Juan José Mengual, M. Àngels Font, Mª Isabel Gómez Ruiz, Irati Zubizarreta, Susana Fernández González, Laura Gubieras, Carmen E. Cobos, Luis Mena Romo, Nuria Caballol, Luis Cano, Joaquín Serena Leal, Yolanda Silva Blas, Irene Bragado Trigo, Saima Bashir Viturro, Laura Pardo Albiñana, Montserrat Reina Garrido, Carla Marco Cazcarra, Karol Enrique Uscamaita, Fabian Márquez, Cristina Coll, Mar Irida Lloret Villlas, Berta Solano Vila, Berta Alemany Perna, Daniel López Domínguezl, Mercedes de Lera, Anna Cots Foraster, Urszula Bojaryn, Ikram Benabdelhak, Gerard Mauri Capdevila, Jordi Sanahuja Montesinos, Daniel Vázquez, José Vicente Hervás, Cristina González, Alejandro Quílez, Mikel Vicente Pascual, María Ruiz, Yolanda Riba, M. Pilar Gil Villar, Cristina García, Xavier Ustrell Roig, Mònica Baldrich Mora, Anna Pellisé Guinjoan, Judit Borras, Alba Mañé Martínez, Rafael Marés, Jaume Viñas i Gaya, Laia Seró, Paula Rodríguez, Gislaine Castilho, Angela Monterde Ortega, Silvia Reverté, Joan Josep Baiges, Gisela Martín Ozaeta, Sonia Escalante, Patricia Esteve Belloch, Iago Payo, Júlia Saura Salvado, Josep M Soler Insa, Ester Tio Vilamala, Josep Abos Navarro, Héctor Cruz Tabuenca, Tamara Canento Sánchez, Elisabet Roldán, Elsa Puiggrós Rubiol, Elisabet Franquet, Lidia Fuentes, Javier Donaire, Elena Martí, Laura Giménez, Junior Gil Vázquez, Eloisa Nieto Clara Gris Ambrós, Puri Rodríguez, José Félix Oletta, Pilar Pons Mellado, Bárbara Gómez, Vergilin Raileau, Oscar Pardina, Jordi Mercadal, María López-Diéguez, Pilar Pérez, Lourdes Gabarró, María Orriols, José Carlos Molina, Joan Josep Canet, Mireia Roca, Muriel Álvaro, Francesc Boneu, Georgina Giménez, Jaume Albà, Francesc Gibert, Jéssica Garcia, Patricia Barragan, Gustavo Jurado, Vanesa Pascual_Medicina Interna, Josep Sabaté Ortega, Joan Amaurys Martínez Solano, Víctor Fernández, Mónica Torres, Ana Belén Montero Alvaredo, Laura Redondo Parejo, Josep Maria Aragonés, Anna Bullón, Cora Loste, Paula González, Neker Bejarano, Francisco Sanchez, Gianni Lucchetti, Xavier Pla, Dr Javier Gimeno, Esteban Reynaga, Montse Barcons, Gabriel Celedón, Juan Ortiz, Dr Goran Anastasovski, Dr Oscar Mascaró, Dr Javier Diez de los Ríos, Meritxell Feliu, Anna Ribera, Cristhian Ruiz, Gerard Corominas, Dra Daniella Nunes, Claudia Roca, Nadina Latorre, Lizbeth Yataco, Maricelys Cruz, Nerea Blanco, Santiago Castejón, Claustre Pont Sunyer, Jordi Espinosa Garcia, Rodrigo Paz Martin, Albert de Luis Sanchez, Dolores Espinosa Vivas, Juan Valencia Molina, Planels Palome, Laia Tomas Chaume, Ares Villagrasa Vilella, Marco Bustamante, Anunciación Boltes, Fernando Rodríguez, Itziar Arrieta, Jordi Ciurans Molist, Barnés Andreu, Ernest Palomeras Soler, Nicolau Guanyabens Buscà, Manuel Daza López, Jordi Bigas Farreres, Virginia Casado Ruiz, Desiree Muriana Batiste, Mª Pilar Sanz Cartagena, Eulalia Cabot de Vega, Josep Bassa Real, Hector Pelaez Roman, César Socolich, Josep Mª Alonso Camp, Antonio Tomás Cano Orgaz, Mª Pilar Fossas Felip, Nicolás Morón, Sandra Bacca, Mauricio Molina, Francesc Casarramona, Lorena Elias, Muhammad Zidane Bukaei, Jose Antonio Martos Gutierrez, Judith Lopez Escuin, Cristina Olaizola, Yolexis López Vargas, Juan Jiménez Oyonarte, Rashida Soultana, Eduardo Sanjurjo Golpe, Esther Salvador, Guillem Vila, Marcos Serrano, Matilde Nuria López Claverol, Marian Lamolla, Miquel Amate, Adriana Rodriguez, Ruth Romero, Montgomery del Carpio, Ana Isabel Hernandez, Julián Martín, M Carmen Rosas, Antonio Nogueroles, Sorilandy Encarnación, Augusto Robles, Jose Antonio Herrera, Roger Gavilán, Toghrol Mameghani, Gastón Araujo, M.Angeles Garrido Morales, Enric Ramon Albert Segui, Eva Fernandez Climent, Francesc Paris Pujol, Mireia Judit Garrofé Seira, Lucía Gómez Pía, Fernando Salleres Nuñez, Cristina Aguar Peñalver, Cristina Vaz Lopes, Elisenda Ribera Tasa, Carmen Repullo Vilchez, Modesto Sánchez Zambrana, Beatriu Suescun Ribas, Inés Vilà Panés, Montserrat Vila Planavila, Alicia Vaqueiro Lorenzo, Meritxell Sabartés Guixes, Jorge Medina, David Sambrano, Javi Zamarreño, Carmen Pirela, Paola Vélez, Luis Cajamarca, Honey Pérez, Yarles Martínez, Jesus Alexander Gonçalves, Carles Regordosa, Claudia Mormeneo, Laura Griu, Maria Francia Colina, Enric Farik, Dolors Carrión Duch, Carles Badenas, Oscar Bernal, Núria Agramunt, Shyrlei Morales, Victoria Reynoso, Miguel Guerrero, Primitivo Romera Cid, Mònica Folqué, Claudia Pedroza, Adnan Hachem, Íñigo Soteras Martínez, Xavier Verdera García, Mercè López Amorós, Xavier Costa Subirós, Marta Cufí Benet, Cecile Van Eendenburg, Teresa Osuna, Dra Gina Santos, Dra Mireia Pallisera, Dr Lluís Gonzalo Oliva, Dra Gemma Sanchez, Dr Xavier Basurto, Dr Ludgi Vivoda, Dr Richard Van der Kleyn, Dra Laura Robles, Ana Cabanelas Barranco, Mª Cruz Almendros, Marc Pérez Oliveras, Amelia Fernández Álvarez, Maria Rybyeva, Antoni Viñas, Maria Barcons, Joaquim Danès Alberto Tavera, Pablo Burbano, Cintie López, David Cruz, Paula Bisbe, Nora Fernández, Juan Carlos Palacio, Eduardo Fraiz, Oriol Aguiló, Rollmy Amorodjo, John Velázquez, Elena Sánchez, Jaume Español, Judit Perez de Celis, Anna Coll, Glòria Díaz, Margarida Vergés i Sala, Mª Ángels Casas Capdevila, Yosmairy Yoselin Ferrini, Aitor Gorriz, Diego-Javier Cucurell Navarro, Dulce Velásquez, Jaume Pla Soler, Josep González, Julian David Higuera, Lina Cuellar, Liza Margarita Miniello, Lluis Pujol, Sorin Cracan, Mora Vives, M Angela, Lopez Lopez, Montse Gorchs Molist, Delofeu Anna, Silvia Solà Muñoz, Ferreres Yolanda, Carol Pujalte, Elisabeth Téllez Marín, Yolanda Font Casas, Sara Hernández Luque, Joaquim Mejias Sendra, Francesca Mellado Valero, Campos Escala, Galup De Lacanal, Lopez Diaz, Castillo Paramio, Català Estopà, Español Moreda, Calafell Majo, Carballo Almeida, Castro Naval, M Elena, Cregut Ruiz, Pere Lluis, Deulofeu Font, Fabregat Sanjuan, Joan Pere, Fontquerni Gorchs, Forés Bellés, Joan Antoni, Gomez Herrera, Juan Carlos, Hijazo Prades, Itzaina Torvisco, Marti Rovira, Obiols Gonzalez, Olive Cavero, Querol Gil, M Soledad, Rico Rodriguez, Rios Sambernardo, Ropero Molina, Jose Ramon, Sanchez Valero, Santos Arevalo, Maria Jose, Soto Garcia, Maria Angeles, Tebar Escribano, Torres Garcia, Pedro José, Verdes Carrion, M Isabel, Verge Lopez, Juan Jose, Lopez Canela, M Angeles, Lucas Guarque, Morales Alvarez, Jorge Arnulfo, Morell Fornieles, Subirats Gomez, Maria Teresa, Torello Masa, Miquel, Val Lopez, Maria Mercedes, Palmero Reyes, Juan Manuel, Rodriguez Forne, Ruana Turiel, Sanchez Gonzalez, Sebastia Gornals, Abrio Rico, Albert Gual Falip, Aznar Oliveros, Brugues Perotti, Calvet Molinero, Catells Franco, Corrales Medina, Daroca Miro, Duran Marquez, Feliu Pradas, Figueras Casanova, Garcia Tortajada, Grajera Gallego, Azahara del Mar, Las Arroyo, Dulcenombre de Jesus, Laserreta Sanz, Llambrich Vidal, Monllao Corral, Morales de la Cruz, Moreno Blanco, Orejuela Orgaz, Piñana Suazo, Pons Minguillon, Rodríguez Gómez, José Carlos, Rodriguez Pereira, Sedo Porcel, Anna, Sevil Villar, Sierra Lopez, Torres Romero, Trepat Calveres, Anna, Ventura Arnella, Acera Gil, M Teresa, Biesot Vico, Castro Galea, Rosa Maria, Escorcia Chafer, Juan Antonio, Gil Faure, Hernandez Luque, Jimenez Delgado, Mallafre Gay, M. Angel, Olivares Sanzo, Pubill Fondevila, Sabate Fort, Segovia Agámez, Antonio Carlos, Turata Longaretti, Valle Hernandez, Trayner Guixens, Aguilar Valor, Aguirre Alvarez, Alastrue Naval, Alferez Baquero, Alonso Marne, Aloy Orozco, Alvarez Colino, Alvarez Peñuela, Ameller Cirilo, Maria Vanessa, Andujar Guerrero, Estefania Remedios, Auladell Sillero, Azcarate Sorbet, Basany Genesca, Benavent Barduena, Benito Tudela, Blanch Pardo, Boluda Pla, Bonilla Gonzalez, Bru Serramalera, Burnat Andreu, Caballero Calvo-Rayo, Calvo Casellas, Camps Mombiela, Cano Bresme, Carcelen Fernandez, Caro Solà, Casasas Matavacas, Castanedo Bolado, Cerdeña Cortina, Abella Jane, Laia Collado Borrego, Colom Orri, Comellas Vilanova, Conillera Sole, Cots Torres, Cuchi Estepa, Marc de Sostoa Graell, Laura del Rio Lopez, Delgado Compte, Diaz Bueno, Diaz Maneiro, Andrea Lucia, Domenech Palau, M. Carme, Duran Carasso, Pablo Javier, El Abidi, Escoda Martin, Esteve Casanovas, Fernandez Perez, Ferre Quintero, Flores Escobar, Fontcuberta Abad, Fortes del Valle, Mª Luisa, Franco Quesada, Sara Maria, Franco Romero, Gallego Francisco, Gamiz Gala, Garcia Castañeda, Garcia Rodriguez, Casajuana Gemma, Gomez Arroyo, Gomez Girbau, Gonzalez Fernandez, Gonzalez Gonzalez, Gonzalez Lopez, Gual Obeso, Guerrero Blanco, Guillemas Roca, Guillermo Eudaldo, Sebastia Hernandez, Homar Covas, Hostench Alvarez, Huerta Royo, Ibañez Barcelo, Izquiero Cruz, Jaione Urdangarin Etxetxikia, Juárez Gimenez, Khlifi Alami, Laparra Gasco, Lara Moreales, Lasaosa Medina, Maria Lourdes, Lazaro Cava, Leon Berrar, López Maturana, Lopez Ramirez, López Romero, Lorente Marco, Lorenzo Martin, Lozano Casals, Lujan Nicola, Madrid Diaz, Jose Antonio, Maria Teresa Peris Morales, Marti Clemente, Martinez Castaño, David Natanael, Martinez Gamez, Martinez Gonzalez, Martinez Quesada, Maria de la Cabeza, Marzà Fusté, Melendo Lasheras, Miralles Mestre, Montserrat Puig Pastalle, Montserrate Vidal, Mora Mellado, Morales Ponce, Morera Cabre, Morera Vivet, Mundi Souza, Muñoz Quiles, Navea Rosa, Neira Iglesias, M Asuncion, Nuñez Manrique, Mª Pilar, Obiols Martinez, Pallares Reig, Partegas Torres, Pascual Berengueras, Perez Gamez, Perez Oset, Perez Restrepo, Maria Alejandra, Planas Yeste, Planells Mangado, Puertas Carbonell, Quinteiro Blanco, Rebollar Benavente, Recasens Fernandez, Reyes Gomez, Maria del Carmen, Roca Pou, Rodriguez Ferrer, Rodriguez Franco, Rodriguez Fuertes, Rodriguez Muñoz, Rodriguez Navarro, Roig Iniesta, Romero Gracia, Rovira Brunet, Rovira de Eugenio, Rubio Baena, Ruiz Llorens, Sala Llamazares, San Juan Alaez, Sanchez Segura, Santasusana Soldevilla, Sanz Salmeron, Segura Perez, Serra Balcells, Sorina Dumitras, Teixidor Montoya, Tena Vicente, Tierno Salinas, Ester Ines, Toledo Testa, Tomàs Figueras, Tomas Ruperez, Torrano Garcia-Penche, Torres Esparza, Vazquez Blanco, Vazquez De la Paz, Vazquez Gil, Vazquez Gonzalez, Vidal Meler, Vilalta Cots, Vilches Jimenez, Visser Fernandez, Viu Gavin, Vives Vives, Carmona Jimenez, Francisco Jose, Galobardes Vilches, Gonzalez Gomez, Jodar Manzanera, Marimon Cortes, Marrodan Orive, Martin Bosch, Martorell Lopez, Millares Roca, M Jesus, Miralles Guri, Muliterno Hernandez, Muñoz Oliva, Pons Pujol, Postius Conde, Prieto Arruñada, Quintana Mathé, Rosell Mata, Alvarin Alvarez, Arrufat Flores, Bañuelos Pago, Campo Vilar, Cardus Hidalgo, Castello Gil, Maria Gloria, Castrillo Montsesinos, Clave Garces, Comes Sanroma, Descalzo Sequi, Errando Ricol, Escudero Campillo, Maria del Mar, Fernandez Alvarez, Fernandez Gomez, Franch Espinosa, Freixes Graells, Garcia Plaza, Garcia-Marron Gallego, Hernandez Simancas, Jaraba Armas, Jimenez Ramos, Lopez Oganissian, Madrona Romero, M Rosa, Martinez Millan, Martínez Morón, Merchan Encinas, Moreno Jimenez, Muñoz Rico, Navarro Rodriguez, Nogales Ibañez, Rita Maria, Novillo Viera, Parella Torrabadella, Mari Alba, Pera Villar, Carla Montserrat, Rabella Miralles, Ramis Trilles, Ribera Ortiz, Sastre Perez, Soro Borrega, Tapia Fores, Tellez Bernad, Trenado Alvarez, Felix Martin, Herrero Perez, Lanau Fuster, Lopez Gomariz, Pardo Lozano, Quintana Altimiras, Ventosa Lopez, Almodovar Damian, Alvarez Monterroso, Arambudo Comas, Boullon Garzon, Burgos Capella, Campuzano Garcia, Maria Del Mar, Capdevila Olivas, Carre Marti, Clara Isabel, Carretero Bacaicoa, Cazorla Calderon, Chacon Osuna, Cortes Planas, Cortit Olio, Delhomme Estany, Fructuos Martinez, Garcia Lopez, Pascual Luis, Genis Amill Vallve, Gonzalez Muñoz, Hernaez Ventura, Lavernia Gimenez, Martin Rojo, Martínez Medina, Mayol Barrera, Mercader Pi, Merino Dalmau, Miguel Campodarbe, Moreno Sanchez, Francisco Javier, Penela Barrameda, Prieto Ajenjo, Rodriguez Pareja, Rodríguez Piñar, Rodriguez Tello, Romero Pereda, Sainz Saborido, Santacana Martin, Santos Martinez, Sierra Chavez, Turbau Torres, Vicente Domenech, Villena Esteo, Vives Pertegaz, Baena Gonzalez, Bagaria Pont, Beltran Sanchez, Bonet Alarcon, Borch Ballescà, Buhils Clanchet, Closa Garcia, Colomina Carril, Cristina Fernandez Sanchez, Edurne Judith Fernandez Toledo, Espases Rodriguez, Espert Resa, F Xavier, Fernández Sol, Gonzalez Lugo, Gracia Llesera, Herrada Lendinez, Juliench Liesa, Sandra Alicia, Lopez Ortega, Lopez Yuste, Lozano Villanueva, Lucia Sola Soto, Madrid Castellano, Megias Cano, Daniel Jesus, Montasell Ponce, Montesinos Sospedra, Moya Martinez, Muñoz Herrera, Ocaña Fernandez, Palau Bernal, Perez Sole, Ramon Carbonell, Ribas Lop, Rubio López, Rueda Lopez, Sabat Castaño, Sabata Lara, Salmerón Ramírez, Serra Creus, Serrano Dalmau, Sumasi Mainero, Gonzalo Gabriel, Torello Masa, Valencia Primo, Ana Maria Viñuales Muñoz, Josep Roig, and Verònica Hidalgo

Subjects
Advanced and Specialized Nursing, Neurology (clinical), Cardiology and Cardiovascular Medicine
Abstract

Background: We aim to assess whether time of day modified the treatment effect in the RACECAT trial (Direct Transfer to an Endovascular Center Compared to Transfer to the Closest Stroke Center in Acute Stroke Patients With Suspected Large Vessel Occlusion Trial), a cluster-randomized trial that did not demonstrate the benefit of direct transportation to a thrombectomy-capable center versus nearest local stroke center for patients with a suspected large vessel stroke triaged in nonurban Catalonia between March 2017 and June 2020. Methods: We performed a post hoc analysis of RACECAT to evaluate if the association between initial transport routing and functional outcome differed according to trial enrollment time: daytime (8:00 am –8:59 pm ) and nighttime (9:00 pm –7:59 am ). Primary outcome was disability at 90 days, as assessed by the shift analysis on the modified Rankin Scale score, in patients with ischemic stroke. Subgroup analyses according to stroke subtype were evaluated. Results: We included 949 patients with an ischemic stroke, of whom 258 patients(27%) were enrolled during nighttime. Among patients enrolled during nighttime, direct transport to a thrombectomy-capable center was associated with lower degrees of disability at 90 days (adjusted common odds ratio [acOR], 1.620 [95% CI, 1.020–2.551]); no significant difference between trial groups was present during daytime (acOR, 0.890 [95% CI, 0.680–1.163]; P interaction =0.014). Influence of nighttime on the treatment effect was only evident in patients with large vessel occlusion(daytime, acOR 0.766 [95% CI, 0.548–1.072]; nighttime, acOR, 1.785 [95% CI, 1.024–3.112] ; P interaction P interaction >0.1 for all comparisons). We observed longer delays in alteplase administration, interhospital transfers, and mechanical thrombectomy initiation during nighttime in patients allocated to local stroke centers. Conclusions: Among patients evaluated during nighttime for a suspected acute severe stroke in non-urban areas of Catalonia, direct transport to a thrombectomy-capable center was associated with lower degrees of disability at 90 days. This association was only evident in patients with confirmed large vessel occlusion on vascular imaging. Time delays in alteplase administration and interhospital transfers might mediate the observed differences in clinical outcome. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02795962.

Published
2023

5. Workflows and Outcomes in Patients With Suspected Large Vessel Occlusion Stroke Triaged in Urban and Nonurban Areas

Author

Alvaro Garcia-Tornel, Monica Millan, Marta Rubiera, Alejandro Bustamante, Manuel Requena, Laura Dorado, Marta Olivé-Gadea, Xavier Jiménez, Angels Soto, Marisol Querol, Maria Hernández-Pérez, Meritxell Gomis, Pere Cardona, Xabier Urra, Francesc Purroy, Yolanda Silva, Xavier Ustrell, Patricia Esteve, Mercè Salvat-Plana, Miquel Gallofré, Carlos Molina, Antoni Dávalos, Tudor Jovin, Sonia Abilleira, Marc Ribo, Natalia Pérez de la Ossa, Marc Ribó Jacobi, Estela Sanjuan, Katherine Santana, Noelia Rodríguez, Jorge Pagola, David Rodriguez-Luna, Olga Maisterra, Estevo Santamarina, Marian Muchada, Jesús Juega, Sandra Boned, Antonio Palasi Franco, Álvaro García -Tornel, Matías Deck, Victoria Sala, Lucía Muñoz, Mónica Millán, Elena López-Cancio, María Hernández-Pérez, Jordi Ciurans, Daniela Samaniego, Tamara Canento, Lorena Martin, Anna Planas, Joaquin Broto, Agustín Sorrentino, Martí Paré, Nuole Zhu, Alicia Garrido, Laia Grau, Ane Miren Crespo, Silvia Presas, Miriam Almendrote, Alba Ramos, Giuseppe Lucente, Lourdes Ispierto, Manuel Lozano, Juan Luis Becerra, Marta Jiménez, Dolores Vilas Rolán, Nicolas Guanyabens, Josep Sanchez-Ojanguren, Alicia Martínez-Piñeiro, Sara Forcén, Mireia Gea, Marta Álvarez, Anna Ramos, Manuel Domínguez Lizarbe, Sara, Rubio Guerra, Irene Bragado, Andrea Arbex, Luis Rodríguez, Pere Cardona Portela, Helena Quesada García, Blanca Lara Rodríguez, Nuria Cayuela, Julia Miró, Clara Marzal, Andrés Paipa, Sergio Campoy, Ana Núñez, Pablo Arroyo, Sarah Besora, Vanessa Adell, Jaume Campdelacreu, Montse Alemany Martí, Belén González, Laura Bau Vila, Marta Fiter Crespo, Anna Berbel, Ma. Cristina Villaescusa Urbaneja, Núria Guillen, Nuria Vidal, Patricia Valentina Vérez Santamaria, Diego Herrero Navarro, Marta Simó, Mercedes Falip, Elisabeth Matas, Neus Mongay Ochoa, Ariadna Gifreu, Albert Muñoz, Lucía Romero, Eduard Portell, Guillermo Hernández Perez, F. Ruiz Esteve, Silvia Teixidor, Augusto Salazar Talavera, Roser Gómez, Xabier Urra Nuin, Martha Vargas, Ángel Chamorro, Sergio Amaro, Laura Llull, Arturo Renú, Salvatore Rudilosso, Raquel Sánchez del Valle, Helena Ariño, Nuria Solà, Delón la Puma, Francisco Gil, Juan Bernardo Gómez, Nuria Matos, Neus Falgàs, Sergi Borrego, Almudena Sánchez, Mircea Balasa, Carmen Montejo, Mar Guasp, David Reyes, Pablo Sánchez Cervilla, Jose Miguel Contador, Victor Augusto Vera Monge, Oscar Ramos, Alejandro Rodríguez, Ana Rodríguez Campello, Gemma Romeral Ballester, Mireia Llop Trujillano, Eva Giralt Steinhauer, Elisa Cuadrado Godia, Angel Javier Ois Santiago, Jordi Jimenez Conde, Joan Martí Fábregas, Daniel Guisado, Luís Prats, Pol Camps, Raquel Delgado, Alejandro Martínez Domeño, Rebeca Marín, David Cànovas, Jordi Estela, Marta Ros, Sonsoles Aranceta, Jordi Espinosa, Marta Rubio, Cristina Lafuente, Oriol Barrachina, Alicia Anguita, Anna Reverter, Carmen García, Gemma Sansa, Mariona Hervas, Monica Crosas, Tania Delgado, Jerzy Krupinski, Sonia Huertas Folch, Gemma Muñoz Gamito, Josep Trenado Alvarez, Teresa Subirana, Jessica Molina, Laura Comes Romero, Gemma Guardia Valls, Miriam Jover, Javier Joaquín Sotova, Sonia Mª García Sánchez, Sebastian Valenzuela (intensivista), Manuel Gómez-Choco, Juan José Mengual, M. Àngels Font, Mª Isabel Gómez Ruiz, Irati Zubizarreta, Susana Fernández González, Laura Gubieras, Carmen E. Cobos, Luis Mena Romo, Nuria Caballol, Luis Cano, Joaquín Serena Leal, Mikel Terceño Izarra, Irene Bragado Trigo, Saima Bashir Viturro, Laura Pardo Albiñana, Montserrat Reina Garrido, Carla Marco Cazcarra, Karol Enrique Uscamaita, Fabian Márquez, Cristina Coll, Mar Irida Lloret Villlas, Berta Solano Vila, Berta Alemany Perna, Daniel López Domínguezl, Mercedes de Lera, Anna Cots Foraster, Urszula Bojaryn, Ikram Benabdelhak, Gerard Mauri Capdevila, Jordi Sanahuja Montesinos, Daniel Vázquez, José Vicente Hervás, Cristina González, Alejandro Quílez, Mikel Vicente Pascual, María Ruiz, Yolanda Riba, M. Pilar Gil Villar, Cristina García, Xavier Ustrell Roig, Mònica Baldrich Mora, Anna Pellisé Guinjoan, Judit Borras, Alba Mañé Martínez, Rafael Marés, Jaume Viñas i Gaya, Laia Seró, Alan Flores, Paula Rodríguez, Gislaine Castilho, Angela Monterde Ortega, Silvia Reverté, Josep Zaragoza, Joan Josep Baiges, Gisela Martín Ozaeta, Sonia Escalante, Iago Payo, Júlia Saura Salvado, Natalia Mas Sala, Josep M Soler Insa, Ester Tio Vilamala, Josep Abos Navarro, Héctor Cruz Tabuenca, Tamara Canento Sánchez, Elisabet Roldán, Elsa Puiggrós Rubiol, Elisabet Franquet, Lidia Fuentes, Javier Donaire, Elena Martí, Laura Giménez, Junior Gil Vázquez, Eloisa Nieto Clara Gris Ambrós, Puri Rodríguez, José Félix Oletta, Pilar Pons Mellado, Catena, Bárbara Gómez, Vergilin Raileau, Esther Catena Ruíz, Oscar Pardina, Jordi Mercadal, María López-Diéguez, Pilar Pérez, Lourdes Gabarró, María Orriols, Joan Josep Canet, Mireia Roca, Muriel Álvaro, Francesc Boneu, Georgina Giménez, Jaume Albà, Francesc Gibert, Jéssica Garcia, Patricia Barragan, Gustavo Jurado, Josep Sabaté Ortega, Joan Amaurys Martínez Solano, Víctor Fernández, Mónica Torres, Ana Belén Montero Alvaredo, Laura Redondo Parejo, Josep Maria Aragonés, Anna Bullón, Cora Loste, Paula González, Neker Bejarano, Francisco Sanchez, Gianni Lucchetti, Xavier Pla, Javier Gimeno, Esteban Reynaga, Montse Barcons, Gabriel Celedón, Juan Ortiz, Goran Anastasovski, Oscar Mascaró, Javier Diez de los Ríos, Meritxell Feliu, Anna Ribera, Cristhian Ruiz, Gerard Corominas, Daniella Nunes, Claudia Roca, Nadina Latorre, Lizbeth Yataco, Maricelys Cruz, Nerea Blanco, Santiago Castejón, Dolores Cocho Calderón, Claustre Pont Sunyer, Jordi Espinosa Garcia, Rodrigo Paz Martin, Albert de Luis Sanchez, Dolores Espinosa Vivas, Juan Valencia Molina, Gemma, Planels Palome, Laia Tomas Chaume, Ares Villagrasa Vilella, Marco Bustamante, Anunciación Boltes, Fernando Rodríguez, Itziar Arrieta, Jordi Ciurans Molist, Barnés Andreu, Ernest Palomeras Soler, Nicolau Guanyabens Buscà, Manuel Daza López, Jordi Bigas Farreres, Virginia Casado Ruiz, Desiree Muriana Batiste, Mª Pilar Sanz Cartagena, Eulalia Cabot de Vega, Josep Bassa Real, Hector Pelaez Roman, César Socolich, Josep Mª Alonso Camp, Antonio Tomás Cano Orgaz, Mª Pilar Fossas Felip, Nicolás Morón, Sandra Bacca, Mauricio Molina, Francesc Casarramona, Lorena Elias, Muhammad Zidane Bukaei, Jose Antonio Martos Gutierrez, Judith Lopez Escuin, Cristina Olaizola, Yolexis López Vargas, Juan Jiménez Oyonarte, Rashida Soultana, Eduardo Sanjurjo Golpe, Esther Salvador, Guillem Vila, Marcos Serrano, Matilde Nuria López Claverol, Marian Lamolla, Miquel Amate, Adriana Rodriguez, Ruth Romero, Montgomery del Carpio, Ana Isabel Hernandez, Julián Martín, M Carmen Rosas, Antonio Nogueroles, Sorilandy Encarnación, Augusto Robles, Jose Antonio Herrera, Roger Gavilán, Toghrol Mameghani, Gastón Araujo, M.Angeles Garrido Morales, Enric Ramon Albert Segui, Eva Fernandez Climent, Francesc Paris Pujol, Mireia Judit Garrofé Seira, Lucía Gómez Pía, Fernando Salleres Nuñez, Cristina Aguar Peñalver, Cristina Vaz Lopes, Elisenda Ribera Tasa, Carmen Repullo Vilchez, Modesto Sánchez Zambrana, Beatriu Suescun Ribas, Inés Vilà Panés, Montserrat Vila Planavila, Alicia Vaqueiro Lorenzo, Meritxell Sabartés Guixes, Jorge Medina, David Sambrano, Javi Zamarreño, Carmen Pirela, Paola Vélez, Luis Cajamarca, Honey Pérez, Yarles Martínez, Jesus Alexander Gonçalves, Carles Regordosa, Claudia Mormeneo, Laura Griu, Maria Francia Colina, Enric Farik, Dolors Carrión Duch, Carles Badenas, Oscar Bernal, Núria Agramunt, Shyrlei Morales, Victoria Reynoso, Miguel Guerrero, Primitivo Romera Cid, Mònica Folqué, Claudia Pedroza, Adnan Hachem, Íñigo Soteras Martínez, Xavier Verdera García, Mercè López Amorós, Xavier Costa Subirós, Marta Cufí Benet, Cecile Van Eendenburg, Teresa Osuna, Dra Gina Santos, Mireia Pallisera, Lluís Gonzalo Oliva, Gemma Sanchez, Xavier Basurto, Ludgi Vivoda, Richard Van der Kleyn, Laura Robles, Ana Cabanelas Barranco, Mª Cruz Almendros, Marc Pérez Oliveras, Amelia Fernández Álvarez, Maria Rybyeva, Antoni Viñas, Maria Barcons, Joaquim Danès Alberto Tavera, Pablo Burbano, Cintie López, David Cruz, Paula Bisbe, Nora Fernández, Juan Carlos Palacio, Eduardo Fraiz, Oriol Aguiló, Rollmy Amorodjo, John Velázquez, Elena Sánchez, Jaume Español, Judit Perez de Celis, Anna Coll, Glòria Díaz, Margarida Vergés i Sala, Mª Ángels Casas Capdevila, Yosmairy Yoselin Ferrini, Aitor Gorriz, Diego-Javier Cucurell Navarro, Dulce Velásquez, Jaume Pla Soler, Josep González, Julian David Higuera, Lina Cuellar, Liza Margarita Miniello, Lluis Pujol, Sorin Cracan, Mora Vives, M Angela, Lopez Lopez, null Anabel, Montse Gorchs Molist, Delofeu Anna, Silvia Solà Muñoz, Ferreres Yolanda, Carol Pujalte, Elisabeth Téllez Marín, Yolanda Font Casas, Sara Hernández Luque, Joaquim Mejias Sendra, Francesca Mellado Valero, Campos Escala, Galup De Lacanal, Lopez Diaz, Castillo Paramio, Català Estopà, Español Moreda, Calafell Majo, Carballo Almeida, Castro Naval, M Elena, Cregut Ruiz, Pere Lluis, Deulofeu Font, Fabregat Sanjuan, Joan Pere, Fontquerni Gorchs, Forés Bellés, Joan Antoni, Gomez Herrera, Juan Carlos, Hijazo Prades, Itzaina Torvisco, Marti Rovira, Obiols Gonzalez, Olive Cavero, Querol Gil, M Soledad, Rico Rodriguez, Rios Sambernardo, Ropero Molina, Jose Ramon, Sanchez Valero, Santos Arevalo, Maria Jose, Soto Garcia, Maria Angeles, Tebar Escribano, Torres Garcia, Pedro José, Verdes Carrion, M Isabel, Verge Lopez, Juan Jose, Lopez Canela, M Angeles, Lucas Guarque, Morales Alvarez, Jorge Arnulfo, Morell Fornieles, Subirats Gomez, Maria Teresa, Torello Masa, Val Lopez, Maria Mercedes, Palmero Reyes, Juan Manuel, Rodriguez Forne, Ruana Turiel, Sanchez Gonzalez, Sebastia Gornals, Abrio Rico, Albert Gual Falip, Aznar Oliveros, Brugues Perotti, Calvet Molinero, Catells Franco, Corrales Medina, Daroca Miro, Duran Marquez, Feliu Pradas, Figueras Casanova, Garcia Tortajada, Grajera Gallego, Azahara del Mar, Las Arroyo, Dulcenombre de Jesus, Laserreta Sanz, Llambrich Vidal, Monllao Corral, Morales de la Cruz, Moreno Blanco, Orejuela Orgaz, Piñana Suazo, Pons Minguillon, Rodríguez Gómez, José Carlos, Rodriguez Pereira, Sedo Porcel, Sevil Villar, Sierra Lopez, Torres Romero, Trepat Calveres, Ventura Arnella, Acera Gil, M Teresa, Biesot Vico, Castro Galea, Rosa Maria, Escorcia Chafer, Juan Antonio, Gil Faure, Hernandez Luque, Jimenez Delgado, Mallafre Gay, M. Angel, Olivares Sanzo, Pubill Fondevila, Sabate Fort, Segovia Agámez, Antonio Carlos, Turata Longaretti, Valle Hernandez, Trayner Guixens, Aguilar Valor, Aguirre Alvarez, Alastrue Naval, Alferez Baquero, Alonso Marne, Cristina, Aloy Orozco, Alvarez Colino, Alvarez Peñuela, Ameller Cirilo, Maria Vanessa, Andujar Guerrero, Estefania Remedios, Auladell Sillero, Azcarate Sorbet, Basany Genesca, Benavent Barduena, Benito Tudela, Blanch Pardo, Boluda Pla, Bonilla Gonzalez, Bru Serramalera, Burnat Andreu, Caballero Calvo-Rayo, Calvo Casellas, Camps Mombiela, Cano Bresme, Carcelen Fernandez, Caro Solà, Casasas Matavacas, Castanedo Bolado, Cerdeña Cortina, Abella Jane, Laia Collado Borrego, Colom Orri, Comellas Vilanova, Conillera Sole, Cots Torres, Cuchi Estepa, de Sostoa Graell, del Rio Lopez, Delgado Compte, Diaz Bueno, Diaz Maneiro, Andrea Lucia, Domenech Palau, M. Carme, Duran Carasso, Pablo Javier, El Abidi, Escoda Martin, Esteve Casanovas, Fernandez Perez, Ferre Quintero, Flores Escobar, Fontcuberta Abad, Fortes del Valle, Mª Luisa, Franco Quesada, Sara Maria, Franco Romero, Gallego Francisco, Gamiz Gala, Alicia, Garcia Castañeda, Garcia Rodriguez, Casajuana Gemma, Gomez Arroyo, Gomez Girbau, Gonzalez Fernandez, Gonzalez Gonzalez, Gonzalez Lopez, Gual Obeso, Guerrero Blanco, Guillemas Roca, Guillermo Eudaldo, Hernandez Sebastia, Homar Covas, Hostench Alvarez, Huerta Royo, Ibañez Barcelo, Izquiero Cruz, Jaione Urdangarin Etxetxikia, Juárez Gimenez, Khlifi Alami, Laparra Gasco, Lara Moreales, Lasaosa Medina, Maria Lourdes, Lazaro Cava, Leon Berrar, López Maturana, Lopez Ramirez, López Romero, Lorente Marco, Lorenzo Martin, Lozano Casals, Lujan Nicola, Madrid Diaz, Jose Antonio, Maria Teresa Peris Morales, Marti Clemente, Martinez Castaño, David Natanael, Martinez Gamez, Martinez Gonzalez, Martinez Quesada, Maria de la Cabeza, Marzà Fusté, Mireia, M Conillera, Melendo Lasheras, Miralles Mestre, Montserrat Puig Pastalle, Montserrate Vidal, Mora Mellado, Morales Ponce, Morera Cabre, Morera Vivet, Mundi Souza, Muñoz Quiles, Navea Rosa, Neira Iglesias, M Asuncion, Nuñez Manrique, Mª Pilar, Obiols Martinez, Pallares Reig, Partegas Torres, Pascual Berengueras, Perez Gamez, Perez Oset, Perez Restrepo, Maria Alejandra, Planas Yeste, Planells Mangado, Puertas Carbonell, Quinteiro Blanco, Rebollar Benavente, Recasens Fernandez, Reyes Gomez, Maria del Carmen, Roca Pou, Rodriguez Ferrer, Rodriguez Franco, Rodriguez Fuertes, Rodriguez Muñoz, Rodriguez Navarro, Roig Iniesta, Romero Gracia, Rovira Brunet, Rovira de Eugenio, Rubio Baena, Ruiz Llorens, Sala Llamazares, San Juan Alaez, Sanchez Segura, Santasusana Soldevilla, Sanz Salmeron, Segura Perez, Serra Balcells, Sorina Dumitras, Teixidor Montoya, Tena Vicente, Tierno Salinas, Ester Ines, Toledo Testa, Tomàs Figueras, Tomas Ruperez, Torrano Garcia-Penche, Torres Esparza, Florenc Uku, Vazquez Blanco, Vazquez De la Paz, Vazquez Gil, Vazquez Gonzalez, Vidal Meler, Vilalta Cots, Vilches Jimenez, Visser Fernandez, Viu Gavin, Vives Vives, Carmona Jimenez, Francisco Jose, Galobardes Vilches, Gonzalez Gomez, Jodar Manzanera, Marimon Cortes, Marrodan Orive, Martin Bosch, Martorell Lopez, Millares Roca, M Jesus, Miralles Guri, Muliterno Hernandez, Muñoz Oliva, Pons Pujol, Postius Conde, Prieto Arruñada, Quintana Mathé, Rosell Mata, Alvarin Alvarez, Arrufat Flores, Bañuelos Pago, Campo Vilar, Cardus Hidalgo, Castello Gil, Maria Gloria, Castrillo Montsesinos, Clave Garces, Comes Sanroma, Descalzo Sequi, Errando Ricol, Escudero Campillo, Maria del Mar, Fernandez Alvarez, Fernandez Gomez, Franch Espinosa, Freixes Graells, Garcia Plaza, Garcia-Marron Gallego, Hernandez Simancas, Jaraba Armas, Jimenez Ramos, Lopez Oganissian, Madrona Romero, M Rosa, Martinez Millan, Martínez Morón, Merchan Encinas, Moreno Jimenez, Muñoz Rico, Navarro Rodriguez, Nogales Ibañez, Rita Maria, Novillo Viera, Parella Torrabadella, Mari Alba, Pera Villar, Carla Montserrat, Rabella Miralles, Ramis Trilles, Ribera Ortiz, Sastre Perez, Soro Borrega, Tapia Fores, Tellez Bernad, Trenado Alvarez, Felix Martin, Herrero Perez, Lanau Fuster, Lopez Gomariz, Pardo Lozano, Quintana Altimiras, Ventosa Lopez, Almodovar Damian, Alvarez Monterroso, Arambudo Comas, Boullon Garzon, Burgos Capella, Campuzano Garcia, Maria Del Mar, Capdevila Olivas, Carre Marti, Clara Isabel, Carretero Bacaicoa, Cazorla Calderon, Chacon Osuna, Cortes Planas, Cortit Olio, Delhomme Estany, Fructuos Martinez, Garcia Lopez, Pascual Luis, Genis Amill Vallve, Gonzalez Muñoz, Hernaez Ventura, Lavernia Gimenez, Martin Rojo, Martínez Medina, Mayol Barrera, Mercader Pi, Merino Dalmau, Miguel Campodarbe, Moreno Sanchez, Francisco Javier, Alba Mari, Penela Barrameda, Prieto Ajenjo, Rodriguez Pareja, Rodríguez Piñar, Javier Francisco, Rodriguez Tello, Romero Pereda, Sainz Saborido, Santacana Martin, Santos Martinez, Sierra Chavez, Turbau Torres, Vicente Domenech, Villena Esteo, Vives Pertegaz, Baena Gonzalez, Bagaria Pont, Beltran Sanchez, Bonet Alarcon, Borch Ballescà, Buhils Clanchet, Closa Garcia, Colomina Carril, Cristina Fernandez Sanchez, Fernandez Toledo Edurne Judith, Espases Rodriguez, Espert Resa, F Xavier, Fernández Sol, Gonzalez Lugo, Gracia Llesera, Herrada Lendinez, Juliench Liesa, Sandra Alicia, Lopez Ortega, Lopez Yuste, Lozano Villanueva, Lucia Sola Soto, Madrid Castellano, Megias Cano, Daniel Jesus, Montasell Ponce, Montesinos Sospedra, Moya Martinez, Muñoz Herrera, Ocaña Fernandez, Palau Bernal, Perez Sole, Ramon Carbonell, Ribas Lop, Rubio López, Rueda Lopez, Sabat Castaño, Sabata Lara, Salmerón Ramírez, Serra Creus, Serrano Dalmau, Sumasi Mainero, Gonzalo Gabriel, Valencia Primo, Ana Maria Viñuales Muñoz, Josep Roig, and Verònica Hidalgo.

Subjects
Stroke, Advanced and Specialized Nursing, Treatment Outcome, Endovascular Procedures, Humans, Neurology (clinical), Cardiology and Cardiovascular Medicine, Brain Ischemia, Ischemic Stroke, Thrombectomy, Workflow
Abstract

Background: We aim to compare the outcome of patients from urban areas, where the referral center is able to perform thrombectomy, with patients from nonurban areas enrolled in the RACECAT trial (Direct Transfer to an Endovascular Center Compared to Transfer to the Closest Stroke Center in Acute Stroke Patients With Suspected Large Vessel Occlusion). Methods: Patients with suspected large vessel occlusion stroke, as evaluated by a Rapid Arterial Occlusion Evaluation score of ≥5, from urban catchment areas of thrombectomy-capable centers during RACECAT trial enrollment period were included in the Stroke Code Registry of Catalonia. Primary outcome was disability at 90 days, as assessed by the shift analysis on the modified Rankin Scale score, in patients with an ischemic stroke. Secondary outcomes included mortality at 90 days, rate of thrombolysis and thrombectomy, time from onset to thrombolysis, and thrombectomy initiation. Propensity score matching was used to assemble a cohort of patients with similar characteristics. Results: The analysis included 1369 patients from nonurban areas and 2502 patients from urban areas. We matched 920 patients with an ischemic stroke from urban areas and nonurban areas based on their propensity scores. Patients with ischemic stroke from nonurban areas had higher degrees of disability at 90 days (median [interquartle range] modified Rankin Scale score, 3 [2–5] versus 3 [1–5], common odds ratio, 1.25 [95% CI, 1.06–1.48]); the observed average effect was only significant in patients with large vessel stroke (common odds ratio, 1.36 [95% CI, 1.08–1.65]). Mortality rate was similar between groups(odds ratio, 1.02 [95% CI, 0.81–1.28]). Patients from nonurban areas had higher odds of receiving thrombolysis (odds ratio, 1.36 [95% CI, 1.16–1.67]), lower odds of receiving thrombectomy(odds ratio, 0.61 [95% CI, 0.51–0.75]), and longer time from stroke onset to thrombolysis (mean difference 38 minutes [95% CI, 25–52]) and thrombectomy(mean difference 66 minutes [95% CI, 37–95]). Conclusions: In Catalonia, Spain, patients with large vessel occlusion stroke triaged in nonurban areas had worse neurological outcomes than patients from urban areas, where the referral center was able to perform thrombectomy. Interventions aimed at improving organizational practices and the development of thrombectomy capabilities in centers located in remote areas should be pursued. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02795962.

Published
2022

6. Abstract 496: The Cardiometabolic Disease Risk Protein SVEP1 Activates AKT/mTOR By Signaling Through The Orphan Receptor PEAR1

Author

Jared S Elenbaas, Upasana Pudupakkam, Ved Patel, Katrina Ashworth, Chul Joo Kang, In-Hyuk Jung, Katherine Santana, Arturo Alisio, Jorge Di Paola, and Nathan Stitziel

Subjects
Cardiology and Cardiovascular Medicine
Abstract

Background: Sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1 (SVEP1) is an extracellular matrix protein that circulates in plasma and is causally related to cardiovascular disease, hypertension, and type 2 diabetes. A recent genome wide association study (GWAS) also implicates SVEP1 in platelet reactivity. The gene most strongly associated with platelet reactivity in the GWAS is Platelet and Endothelial Cell Receptor 1 ( PEAR1 ), a gene that encodes an orphan receptor tyrosine kinase-like protein that also associates with cardiovascular disease. Little is known about the molecular interactions and disease mechanisms of these proteins, despite their associations with cardiovascular disease and platelet reactivity. Methods: We used Mendelian Randomization (MR) and phenome-wide association studies to identify candidate SVEP1 protein interactions. We tested candidate interactions using recombinant proteins with molecular, cellular, and ex vivo assays. Results: A coding variant within the ectodomain of PEAR1 alters plasma levels of SVEP1 in humans (p=1.7x10^-17), suggesting these proteins may interact. MR demonstrates that genetically determined, increased plasma PEAR1 levels causally associate with decreased plasma SVEP1 (p=1.3x10^-11), further supporting an interaction. PEAR1 co-immunoprecipitates with SVEP1. Exposure to SVEP1 induces PEAR1 phosphorylation and activation of AKT/mTOR signaling in endothelial cells, vascular smooth muscle cells, and platelets. siRNA knockdown of PEAR1 abrogates this signaling. Endothelial cells adhere and proliferate in response to immobilized SVEP1. Platelets isolated from mice lacking SVEP1 have lower activation relative to controls and phenocopy platelets from mice lacking PEAR1. Conclusions: Despite robust evidence for the role of SVEP1 and PEAR1 in cardiovascular disease, critical gaps remain in our understanding of their disease mechanisms. Here, we identify SVEP1 as the first biological ligand of PEAR1 and a potent activator of AKT/mTOR signaling. The interaction between SVEP1 and PEAR1 is particularly intriguing, given the prominent role of AKT/mTOR in cardiovascular disease, and disrupting the interaction may be therapeutically beneficial.

Published
2022

7. SVEP1 is a human coronary artery disease locus that promotes atherosclerosis

Author

Erica P. Young, Robert P. Mecham, Puja Kachroo, In Hyuk Jung, Katherine Santana, Arturo Alisio, Jared S. Elenbaas, Kory J. Lavine, Babak Razani, Chul Joo Kang, and Nathan O. Stitziel

Subjects
0301 basic medicine, Vascular smooth muscle, Myocytes, Smooth Muscle, Integrin, Notch signaling pathway, Inflammation, Coronary Artery Disease, 030204 cardiovascular system & hematology, Muscle, Smooth, Vascular, Article, Coronary artery disease, Extracellular matrix, Mice, 03 medical and health sciences, 0302 clinical medicine, Von Willebrand factor, Animals, Humans, Medicine, Cells, Cultured, Cell Proliferation, biology, business.industry, General Medicine, Atherosclerosis, medicine.disease, Plaque, Atherosclerotic, Mice, Inbred C57BL, 030104 developmental biology, Fibroblast growth factor receptor, biology.protein, Cancer research, medicine.symptom, business, Cell Adhesion Molecules
Abstract

A low-frequency variant of sushi, von Willebrand factor type A, EGF and pentraxin domain containing protein 1 (SVEP1), an extracellular matrix protein, is associated with risk of coronary disease in humans independent of plasma lipids. Despite a robust statistical association, if and how SVEP1 might contribute to atherosclerosis remained unclear. Here, using Mendelian randomization and complementary mouse models, we provide evidence that SVEP1 promotes atherosclerosis in humans and mice and is expressed by vascular smooth muscle cells (VSMCs) within the atherosclerotic plaque. VSMCs also interact with SVEP1, causing proliferation and dysregulation of key differentiation pathways, including integrin and Notch signaling. Fibroblast growth factor receptor transcription increases in VSMCs interacting with SVEP1, and is further increased by the coronary disease-associated SVEP1 variant p.D2702G. These effects ultimately drive inflammation and promote atherosclerosis. Taken together, our results suggest that VSMC-derived SVEP1 is a pro-atherogenic factor, and support the concept that pharmacological inhibition of SVEP1 should protect against atherosclerosis in humans.

Published
2021

8. SVEP1, a novel human coronary artery disease locus, promotes atherosclerosis

Author

Arturo Alisio, In-Hyuk Jung, Nathan O. Stitziel, Puja Kachroo, Robert P. Mecham, Erica P. Young, Jared S. Elenbaas, Kory J. Lavine, Babak Razani, Katherine Santana, and Chul Joo Kang

Subjects
Vascular smooth muscle, biology, business.industry, Integrin, Notch signaling pathway, Inflammation, medicine.disease, Extracellular matrix, Coronary artery disease, Fibroblast growth factor receptor, Mendelian randomization, Cancer research, biology.protein, Medicine, medicine.symptom, business
Abstract

SummaryA low-frequency variant of SVEP1, an extracellular matrix protein, is associated with risk of coronary disease in humans independent of plasma lipids. Despite a robust statistical association, however, it was unclear if and how SVEP1 might contribute to atherosclerosis. Here, using Mendelian randomization and complementary mouse models, we provide evidence that SVEP1 promotes atherosclerosis in humans and mice. We find that SVEP1 is expressed by vascular smooth muscle cells (VSMCs) within the atherosclerotic plaque. VSMCs also interact with SVEP1, causing proliferation and dysregulation of key differentiation pathways, including integrin and Notch signaling. Fibroblast growth factor receptor transcription increases in VSMCs interacting with SVEP1, and is further increased by the coronary disease-associated SVEP1 variant. These effects ultimately drive inflammation and promote atherosclerosis. Taken together, our results suggest that VSMC-derived SVEP1 is a pro-atherogenic factor, and support the concept that pharmacological inhibition of SVEP1 should protect against atherosclerosis in humans.

Published
2020

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