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2. Edoxaban versus warfarin in patients with atrial fibrillation

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Robert P. Giugliano, Christian T. Ruff, Eugene Braunwald, Sabina A. Murphy, Stephen D. Wiviott, Jonathan L. Halperin, Albert L. Waldo, Michael D. Ezekowitz, Jeffrey I. Weitz, Jind?ich ?pinar, Witold Ruzyllo, Mikhail Ruda, Yukihiro Koretsune, Joshua Betcher, Minggao Shi, Laura T. Grip, Shirali P. Patel, Indravadan Patel, James J. Hanyok, Michele Mercuri, Elliott M. Antman, Braunwald E, Antman EM, Giugliano RP, Ruff CT, Morin SE, Hoffman EB, Murphy SA, Deenadayalu N, Grip L, Mercuri M, Lanz H, Patel I, Curt V, Duggal A, Hanyok J, Davé J, Morgan D, Choi Y, Shi M, Jin J, Xie J, Crerand W, Kappelhof J, Maxwell W, Skinner M, Patel S, Betcher J, Selicato G, Otto C. Jr, Reissner C, Smith K, Ostroske J, Ron A, Giugliano R, Connolly S, Camm J, Ezekowitz M, Halperin J, Waldo A, Paolasso E, Aylward P, Heidbuchel H, Nicolau JC, Goudev A, Roy D, Weitz J, Corbalán R, Yang Y, Botero R, Bergovec M, Ŝpinar J, Grande P, Hassager C, Voitk J, Huikuri H, Nieminen M, Blanc JJ, LeHeuzey JY, Mitrovic V, Alexopoulos D, Sotomora G, Kiss R, SomaRaju B, Lewis B, Merlini P, Metra M, Koretsune Y, Yamashita T, García Castillo A, Ophuis T, White H, Atar D, Horna M, Babilonia N, Ruzyllo W, Morais J, Dorobantu M, Ruda M, Ostojic M, Duris T, Dalby A, Chung N, Zamorano JL, Juul Möller S, Moccetti T, Chen SA, Sritara P, Oto A, Parkhomenko A, Senior R, Verheugt F, Skene A, Anderson J, Bauer K, Easton JD, Goto S, Wiviott S, Lowe C, Awtry E, Berger CJ, Croce K, Desai A, Gelfand E, Goessling W, Greenberger NJ, Ho C, Leeman DE, Link MS, Norden AD, Pande A, Rost N, Ruberg F, Silverman S, Singhal A, Vita JA, Vogelmann O, Gonzalez C, Ahuad Guerrero R, Rodriguez M, Albisu J, Rosales E, Allall O, Reguero M, Alvarez C, Garcia M, Ameriso S, Ameriso P, Amuchastegui M, Caceres M, Beloscar J, Petrucci J, Berli M, Budassi N, Valle M, Bustamante Labarta G, Saravia M, Caccavo A, Fracaro V, Cartasegna L, Novas V, Caruso O, Zarandon RS, Colombo H, Morandini M, Cuello J, Rosell M, Cuneo C, Bocanera M, D'Amico A, Cendali G, Dran R, Moreno V, Estol C, Davolos M, Facello A, Facello M, Falu E, Iriarte M, Femenia F, Arrieta M, Fuselli J, Zanotti A, Gant Lopez J, Meiller F, Garcia Duran R, Perlo D, Garrido M, Ceirano C, Giacomi G, Eden M, Giannaula R, Huerta M, Goicoechea R, von Wulffen M, Hominal M, Bianchini M, Jure H, Jure D, Kevorkian R, Monaco F, Lanternier G, Belcuore M, Liniado G, Iglesias M, Litvak B, Nigro A, Llanos J, Vignau S, Lorente C, Shatsky K, Lotti J, Raimondi G, Mackinnon I, Carne M, Manuale O, Calderon M, Marino J, Funes I, Muntaner J, Gandur H, Nul D, Verdini E, Piskorz D, Tommasi A, Povedano G, Casares E, Pozzer D, Fernandez E, Prado A, Venturini C, Ramos H, Navarrete S, Alvarez M, Sanchez A, Bowen L, Sanjurjo M, Codutti O, Saravia Toledo S, Formoso I, Schmidberg J, Goloboulicz A, Schygiel P, Buzzetti C, Severino P, Morara P, Sosa Liprandi M, Teves M, Vico M, Morell Y, Anderson C, Paraskevaidis T, Arstall M, Hoffmann B, Colquhoun D, Price Smith S, Crimmins D, Slattery A, Dart A, Kay S, Davis S, Silver G, Flecknoe Brown S, Roberts J, Gates P, Jones S, Lehman R, Morrison H, McKeirnan M, Li J, Paul V, Batta C, Purnell P, Perrett L, Szto G, O'Shea V, Capiau L, Banaeian F, De Bleecker J, de Koning K, De Tollenaere M, De Bruyne L, Desfontaines P, Tincani G, Meeusen K, Herzet J, Malmendier D, Mairesse G, Raepers M, Parqué J, Clinckemaille N, Scavée C, Huyberechts D, Stockman D, Jacobs C, Vandekerckhove Y, Derycker K, Vanwelden J, van Welden J, Vervoort G, Mestdagh I, Vrolix M, Beerts C, Wollaert B, Denie D, Amato Vincenzo de Paola A, Coutinho E, Andrade Lotufo P, de Melo RF, Atie J, Motta C, Augusto Alves da Costa F, Ferraz RF, Bertolim Precoma D, Sehnem E, Botelho R, Cunha S, Brondani R, Fleck N, Chaves Junior H, Silva J, Costantini C, Barroso D, De Patta M, Pereira V, Duda N, Laimer R, Dutra O, Morgado S, Faustino Saporito W, Seroqui M, Ferreira L, Araújo E, Finimundi H, Daitz C, Gagliardi R, Pereira G, Gomes M, Gomes A, Guimarães A, Ninho L, Jaeger C, Pereira L, Jorge J, Cury C, Kaiser S, Almeida A, Kalil C, Radaelli G, Kunz Sebba Barroso de Souza W, Morales K, Leaes P, Luiz RO, Pimenta Almeida J, Gozalo A, Reis G, Avellar K, Reis Katz Weiand L, Leipelt J, Rocha J, Barros R, Rodrigues L, Rocha MR, Rodrigues A, Rodrigues D, Rossi dos Santos F, Pagnan LG, Sampaio R, do Val R, Saraiva J, Vicente C, Simoes M, Carraro A, Sobral Filho D, Lustosa E, Villas Boas F, Almeida M, Zimmermann S, Zimmermann EB, Chompalova B, Parishev G, Denchev S, Milcheva N, Donova T, Gergova V, Georgiev B, Kostova E, Kinova E, Hergeldjieva V, Kamenova P, Manolova A, Vasilev I, Mihov A, Miteva B, Mincheva V, Stoyanovski V, Nikolov F, Vasilev D, Pencheva G, Kostov K, Petranov S, Milusheva T, Popov A, Staneva A, Momchilova Lozeva D, Todorov G, Nyagina M, Tumbev H, Tumbeva D, Tzekova M, Kitova M, Manoylov E, Archibald J, Antle S, Bhargava R, Stafford C, Bose S, Hundseth M, Cha J, Otis J, Chehayeb R, Lepage C, Chilvers M, Vansickle L, Cleveland D, Valley S, Constance C, Gauthier M, Costi P, Masson C, Coutu B, Denis I, du Preez M, Kubanska A, Dufresne M, Krider J, Eikelboom J, Zondag M, Fortin C, Viau C, Green M, Houbraken D, Hatheway R, Mabee J, Heath J, Scott L, Ho K, Ho V, Hoag G, Standring R, Huynh T, Perkins L, Kouz S, Roy M, Labonte R, Dewar C, Lainesse A, St Germain L, Lam S, Lam H, Lichtenstein T, Roberts P, Luton R, Douglas S, Ma P, Seib M, MacCallum C, Matthews J, Malette P, Vaillancourt T, Maranda C, Studenikow E, Mawji A, Morely A, Morrison D, Roth M, Mucha M, Najarali A, Lamoureux U, Nicholson R, O'Hara G, Banville P, O'Mahony W, Bolton R, Parkash R, Carroll L, Pesant Y, Sardin V, Polasek P, Turri L, Qureshi A, Nethercott C, Ricci J, Bozek B, Rupka D, Marchand C, Shu D, Silverio G, St Hilaire R, Morissette A, Sussman J, Kailey P, Syan G, Bobbie C, Talajic M, David D, Talbot P, Tremblay M, Teitelbaum I, Teitelbaum J, Velthuysen G, Giesbrecht L, Wahby R, Morley A, Wharton S, Caterini T, Woodford T, Balboa W, Matus LR, Bugueño C, Mondaca PM, Cobos J, Obreque C, Corbalan R, Parada A, Florenzano F, Diaz PA, Lopetegui M, Rebolledo C, Manriquez L, Silva LM, Martinez D, Llamas RR, Opazo M, Pérez MC, Pincetti C, Carrasco GT, Potthoff S, Staub JZ, Campisto Y, Stockins B, Lara CL, Yovaniniz P, Azua MG, Bai F, Xu GL, Chen JZ, Xie XD, Chen XP, Zhang X, Dong YG, Feng C, Fu GS, Zhang P, Hong K, You ZG, Hong L, Qiu Y, Jiang XJ, Qu Z, Li L, Liu H, Li TF, Kong YQ, Li WM, Liu B, Li ZQ, Liu Y, Liao DN, Gu XJ, Liu L, Lu ZH, Ma SM, Yang ZY, Wang DM, Qi SY, Wang GP, Shi XJ, Wei M, Huang D, Wu SL, Li YE, Xu JH, Gu JY, Xu YM, Liang YZ, Yang K, Li AY, Yang YJ, Zheng X, Zheng Y, Gao M, Yin YH, Xu YP, Yu B, Li LL, Yuan ZY, Qiang H, Zhang HQ, Lin YN, Zhang Z, Kang H, Zhao RP, Han RJ, Zhao XL, Wang JQ, Zheng ZQ, Li BG, Zhou SX, Zhang YL, Accini J, Accini M, Cano N, Pineda LL, Delgado Restrepo J, Arroyave C, Fernández Ruiz R, Diaz IA, Hernandez H, Delgado P, Jaramillo Muñoz C, Builes A, Manzur F, Rodriguez ER, Moncada Corredor M, Giraldo DL, Orozco Linares L, Fonseca J, Quintero A, Gonzales C, Sanchez Vallejo G, Mejia IP, Bagatin J, Carevic V, Car S, Jeric M, Ciglenecki N, Tusek S, Ferri Certic J, Romic I, Francetic I, Ausperger KM, Jelic V, Jurinjak SJ, Knezevic A, Buksa B, Samardzic P, Lukenda KC, Steiner R, Kirner D, Sutalo K, Bakliza Z, Vrazic H, Lucijanic T, Bar M, Brodova P, Berka L, Kunkelova V, Brtko M, Burianova H, Cermak O, Elbl L, Ferkl R, Florian J, Francek L, Golan L, Gregor P, Honkova M, Hubac J, Jandik J, Jarkovsky P, Jelinek Z, Jerabek O, Jirmar R, Kobza R, Kochrt M, Kostkova G, Kosek Z, Kovar P, Kuchar R, Kvasnicka J, Ludka O, Machova V, Krocova E, Melichar M, Nechanicky R, Olsr J, Peterka K, Petrova I, Havlova I, Pisova J, Podrazil P, Jirsova E, Reichert P, Slaby J, Spacek R, Spinar J, Labrova R, Vodnansky P, Samkova D, Zidkova E, Dodt K, Christensen H, Christensen L, Loof A, Ibsen H, Madsen H, Iversen H, Veng Olsen T, Nielsen H, Olsen R, Overgaard K, Petrovic V, Raymond I, Raae D, Sand N, Svenningsen A, Torp Pedersen C, Jakobsen U, Wiggers H, Serup Hansen K, Kaik J, Stern A, Kolk R, Laane E, Rivis L, Paumets M, Laheäär M, Rosenthal A, Rajasalu R, Vahula V, Ratnik E, Kaarleenkaski S, Hussi E, Valpas S, Jäkälä P, Lappalainen T, Mäenpää A, Viitaniemi J, Nyman K, Sankari T, Rasi H, Salminen O, Virtanen V, Nappila H, Le Heuzey J, Agraou B, El Jarroudi F, Amarenco P, Boursin P, Babuty D, Boyer M, Belhassane A, Berbari H, Blanc J, Dias P, Coisne D, Berger N, Decoulx E, El Jarroudi M, Dinanian S, Arfaoui M, Hermida J, Deruche E, Kacet S, Corbut S, Poulard J, Leparree S, Roudaut R, Duprat C, Al Zoebi A, Wurow A, Bernhardt P, Dichristin U, Berrouschot J, Vierbeck S, Beyer Westendorf J, Sehr B, Bouzo M, Schnelzer P, Braun R, Ladenburger K, Buhr M, Weihrauch D, Contzen C, Kara M, Daut W, Ayasse D, Degtyareva E, Kranz P, Drescher T, Herfurth B, Faghih M, Forck Boedeker K, Schneider K, Fuchs R, Manuela W, Grigat C, Otto A, Hartmann A, Peitz M, Heuer H, Dieckheuer U, Hoffmann U, Dorn S, Hoffmann S, Schuppe M, Horacek T, Fink P, Junggeburth J, Schmid S, Jungmair W, Schoen B, Kleinecke Pohl U, Meusel P, Koenig H, Bauch F, Lohrbaecher Kozak I, Grosse B, Lueders S, Venneklaas U, Luttermann M, Wulf M, Maus O, Hoefer K, Meissner G, Braemer U, Meyer Pannwitt U, Frahm E, Vogt S, Muegge A, Barbera S, Mueller Glamann M, Raddatz K, Piechatzek R, Lewinsky D, Pohl W, Proskynitopoulos N, Kuhlmann M, Rack K, Pilipenko H, Rinke A, Kühlenborg A, Schaefer A, Szymanowski N, Schellong S, Frommhold R, Schenkenberger I, Finsterbusch T, Dreykluft K, Schiewe C, Schmidt A, Schmidt M, Schreckenberg A, Hellmers J, Seibert H, Gold G, Sohn H, Baylacher M, Spitzer S, Bonin K, Stoehring R, Taggeselle J, Zarpentin C, Veltkamp R, Ludwig I, Voehringer, Buchholz M, Weyland K, Winkelmann B, Buelow Johansen B, Wolde C, Winter K, Mavronasiou E, Bourlios P, Tziortziotis A, Karamitsos C, Exarchou E, Kifnidis K, Daskalaki A, Moschos N, Dimitra K, Olympios C, Kartsagkoulis E, Pyrgakis V, Korantanis K, Ayau Milla O, Ramirez Vde L, Guzman Melgar I, Jimenez T, Ovando Lavagnino A, Guevara S, Rodas Estrada M, Sanchez M, Pozuelos JM, Sanchez Samayoa C, Guerra L, Velasquez Camas L, Almaraz SP, Dioszeghy P, Muskoczki E, Edes I, Szatmari J, Fiok J, Varga A, Kanakaridisz N, Kosztyu M, Kis E, Feil JF, Jakal A, Koczka M, Kovacs I, Baranyai M, Kovacs Z, Lupkovics G, Karakai HH, Matoltsy A, Kiss T, Medvegy M, Kiss K, Merkely B, Kolumban E, Nagy A, Palinkas A, Toth SR, Sayour A, Bognar A, Simor T, Ruzsa D, Sipos T, Szakal I, Tomcsanyi J, Marosi A, Vertes A, Kincses M, Malhan S, Abdullakutty J, Agarwal D, Ranka R, Arneja J, Memon A, Arora V, Shree R, Avvaru G, Shaikh A, Babu P, Rao B, Babu R, Reddy J, Banker D, Sheth T, Benjarge P, Surushe S, Bharani A, Solanki R, Bhargava V, Rathi A, Biniwale A, Bhuti M, Calambur N, Somaraju B, Karnwal N, Chopda M, Mali N, Goyal N, Saini A, Gupta J, Singh P, Hadan S, Savanth P, Hardas S, Thakor G, Hiremath J, Ghume A, Jain R, Pahuja M, Joseph S, Oommen D, Joseph J, Thomas R, Joshi H, Iby, Kale V, Raut N, Kandekar B, Kandekar S, Kishore R, Krishnan H, Kotiwale V, Kulkarni R, Deokar M, Kulkarni G, Lawande A, Kumar P, Karpuram M, Kumar A, Francis J, Kumbla M, Anthony A, Lavhe P, Kale M, Mardikar H, Bhaskarwar P, Mathur A, Sharma P, Menon J, Francis V, Namjoshi D, Shelke S, Narendra J, Natarajan S, Oomaan A, Gurusamy P, Angel J, Purayil MP, Shams S, Pandurangi U, Sababathi R, Parekh P, Jasani B, Patki N, Babbar A, Pinto B, Kharalkar H, Premchand R, Jambula H, Rao M, Vuriya A, Ravi Shankar A, Reddy R, Bekal S, Barai A, Saha D, Gadepalli R, Sant H, Jadhav D, Sarna M, Arora T, Sawhney J, Singh R, Sethi K, Bansal N, Sethia A, Sethia S, Shetty G, Sudheer R, Singh G, Gupta R, Srinivas A, Thankaraj L, Varma S, Kaur A, Vinod MV, Thakur B, Zanwar I, Dharmarao A, Atar S, Lasri E, Dicker D, Marcoviciu D, Elias M, Ron GA, Francis A, Ghantous R, Goldhaber A, Goldhaber M, Gottlieb S, Rouwaida S, Grossman E, Dagan T, Hasin Y, Roshrosh M, Hayek T, Majdoub A, Klainman E, Genin I, Lahav M, Gilat T, Ben Ari M, Lishner M, Karny M, Ouzan E, Givoni H, Rozenman Y, Logvinenko S, Schiff E, Sterlin J, Shochat M, Aloni I, Swissa M, Belatsky V, Tsalihin D, Kisos D, Zeltser D, Platner N, Berni A, Giovannelli F, Boriani G, Cervi E, Comi G, Peruzzotti L, Cuccia C, Forgione C, De Caterina R, De Pace D, De Servi S, Mariani M, Di Lenarda A, Mazzone C, Di Pasquale G, Di Niro M, Fattore L, Bosco B, Grassia V, Murena E, Laffi, Gaggioli G, Lo Pinto G, Raggi F, Marino P, Francalacci G, Babbolin M, Bulgari M, Penco M, Lioy E, Marciano C, Pirelli S, Paradiso G, Piseddu G, Fenu L, Raisaro A, Granzow K, Rasura M, Cannoni S, Severi S, Breschi M, Toschi V, Gagliano M, Zacà V, Furiozzi F, Hirahara T, Akihisa U, Masaki W, Ajioka M, Matsushita C, Anzai T, Mino K, Arakawa S, Tsukimine A, Endo H, Fujiwara M, Fujii K, Kozeni S, Fujii E, Kotera M, Fujimoto S, Omae K, Fujimoto K, Ichishita Y, Fujita T, Ito Y, Fukamizu S, Harada J, Fukuda N, Fujimoto C, Funazaki T, Yamaguchi A, Furukawa Y, Kamitake C, Hagiwara N, Naganuma M, Hara S, Kumagai S, Harada K, Fuki Y, Haruna T, Nakahara Y, Hashimoto Y, Shimazu Y, Hiasa Y, Oga Y, Higashikata T, Nakagawa Y, Hirayama A, Kawaguchi A, Iesaka Y, Miyamoto C, Iijima T, Higuchi K, Ino H, Noguchi H, Inomata T, Nakamura K, Ishibashi Y, Nozaki T, Ishii Y, Tomita H, Ishimaru S, Ise M, Itamoto K, Ito T, Onishi M, Iwade K, Sakuma Y, Iwasaki T, Nagatome H, Kakinoki S, Adachi C, Kamakura S, Nakahara F, Kamijo M, Iida S, Kamiyama K, Fujii R, Kato K, Ishida A, Kazatani Y, Ichikawa Y, Kitazawa H, Igarashi C, Kobayashi Y, Kikuchi R, Kohno M, Tamura S, Yumoto I, Kurabayashi M, Koya E, Masuyama T, Kaneno Y, Matsuda K, Ebina E, Meno H, Satake M, Mita T, Takeda M, Miyamoto N, Kimizu T, Miyauchi Y, Sakamoto S, Munemasa M, Murata J, Nagai Y, Sakata Y, Naito S, Oyama H, Nishi Y, Nagase T, Ochiai J, Junko H, Ogawa T, Sugeno M, Oguro H, Tanabe M, Okada K, Moriyama Y, Okajima K, Nakashima M, Okazaki O, Wada H, Okishige K, Kitani S, Okumura K, Narita Y, Onaka H, Moriyama H, Ozaki Y, Tanikawa I, Sakagami S, Nakano A, Sakuragi S, Hayashi N, Sakurai S, Ooki H, Sasaki T, Oosawa N, Satoh A, Fujimoto E, Seino Y, Narumi M, Shirai T, Shigenari M, Shoji Y, Ueda J, Sugi K, Miyazaki E, Sumii K, Asakura H, Takagi M, Mohri S, Takahashi W, Yoshida K, Takahashi A, Kishi N, Takahashi T, Sakurai Y, Takeda K, Yahata A, Takenaka T, Yamagishi K, Takeuchi S, Watanabe E, Tanaka K, Uchida M, Tanouchi J, Nishiya Y, Tsuboi H, Tsuboi N, Terakura K, Uematsu M, Yasumoto S, Ueyama Y, Usuda K, Sakai Y, Yagi M, Sato A, Yagi H, Kuroda T, Yamabe H, Sakamoto Y, Yamada T, Yamano R, Yamagishi T, Sasaki S, Yamamoto Y, Yamashina A, Takiguchi M, Yonehara T, Yoshino H, Nomura H, Yoshioka K, Fujiwara Y, Bayram Llamas E, Hurtado A, Calvo Vargas C, Limon MC, Cardona Muñoz E, Hernandez S, Carrillo J, Delgadillo T, Cásares Ramirez M, Valles JF, Garcia N, Colin MA, Garcia Castillo A, Jaramillo A, Leiva Pons J, de la Mora S, Llamas Esperón G, Grajales A, Mendez Machado G, Avila H, Ruiz LN, Magallanes G, Sánchez Díaz C, Ortiz A, Sánchez RV, Velazquez EM, Alhakim M, van Welsen I, Bruning T, Jones A, Buiks C, de Groot J, Radder I, de Vos R, Hazeleger R, Daniels R, Kietselaer B, Muijs L, Mannaerts H, Kooiman E, Mevissen H, van der Heijden D, Hofmeyer H, Anscombe R, O'Meeghan T, Kjentjes M, Benatar J, Borthwick L, Doughty R, Copley M, Fisher R, Monkley R, Green B, Scott D, Hamer A, Tomlinson J, Hart H, Turner A, Cammell R, Troughton R, Skelton L, Young C, Kennett K, Claussen H, Hofsøy K, Melbue R, Sandvik J, Thunhaug H, Tveit A, Enger S, Bustamante G, Guillen MT, Cabrera J, Mendoza RE, Chavez C, Luna C, Lema J, Carrion A, Llerena N, Bedregal SA, Medina Palomino F, Rodriguez J, Minchola J, Bautista C, Negron Miguel S, Armas BH, Rodriguez A, Romero N, Torres P, Rodriguez KF, Yanac Chavez P, Delgado S, Sambaz CM, Barcinas R, Zapanta M, Coching R, Vallenas M, Matiga G, Enad C, Rogelio G, Joaquin F, Roxas A. Jr, Gilo L, To R, Aquino M, Villamor L, Nario K, Adamus J, Korzeniowska Adamus J, Baszak J, Bronisz M, Cieslak B, Busz Papiez B, Krzystolik A, Cymerman K, Dabrowska M, Ptak A, Derlaga B, Laskowska Derlaga E, Domanska E, Guziewicz M, Gieroba A, Zajac E, Gniot J, Mroczkowski P, Januszewicz A, Makowiecka Ciesla M, Jazwinska Tarnawska E, Ciezak P, Jurowiecki J, Kaczmarek B, Pacholska A, Kaminski L, Kania G, Tymendorf K, Karczmarczyk A, Kaliszczak R, Konieczny M, Benicka E, Korzeniak R, Borowski W, Krzyzanowski W, Muzyk Osikowicz M, Kus W, Lesnik J, Wierzykowski T, Lewczuk J, Stopyra Poczatek M, Lubinski A, Szymanska K, Lysek R, Jaguszewska G, Matyszczak Toniak L, Sznajder R, Wnetrzak Michalska R, Kosmaczewska A, Mazur S, Chmielowski A, Miekus P, Kosmalska K, Mosiewicz J, Myslinski W, Napora P, Biniek D, Nessler J, Nessler B, Niezgoda K, Nej A, Nowak J, Olszewski M, Podjacka D, Janczewska D, Pogorzelska H, Polaszewska Pulkownik V, Bojanowska E, Raczak G, Zienciuk Krajka A, Rewinska H, Rozmyslowicz Szerminska W, Ronkowski R, Norwa Otto B, Sendrowski D, Spyra J, Szolkiewicz M, Malanska A, Turbak R, Wrobel W, Muzalewski P, Wysokinski A, Kudlicki J, Zarebinski M, Krauze R, Zielinski M, Nawrot M, Matias F, Correia J, Gil V, Lopes S, Madeira J, Maymone D, Martins D, Neves E, Monteiro P, Oliveira D, Marques AL, Castro C, Salgado A, Gonçalves A, Sao Marcos H, Santos O, Nunes LV, Sao Teotonio H, Santos J, Soares D, Albulescu P, Ciortea M, Apetrei E, Matei C, Bartos D, Badila E, Bengus C, Ochean V, Bobescu E, Doka B, Bolohan F, Ciobotaru G, Andor M, Coman I, Ghionea M, Constantinescu M, Creteanu M, Parasteac M, Cristea M, Anciu M, Crisu D, Jemna D, Dobre I, Voicu O, Dobreanu D, Sirbu I, Dragomir D, Jurca S, Iosipescu L, Costache L, Minescu B, Serban D, Pop C, Cozma M, Popescu M, Ardelean A, Sipciu D, Plosca P, Stamate S, Spinu C, Topolnitchi L, Topolnitchi O, Tudoran M, Tudoran C, Zhukova N, Arutyunov G, Chernyavskaya T, Ballyuzek M, Alexandrova L, Barbarash O, Bashkireva A, Bart B, Larina V, Belenky D, Kosolapov Y, Berns S, Yukhno E, Bokarev I, Khlevchuk T, Chumakova G, Pokutneva O, Demko A, Masin A, Dovgalevsky P, Puchinyan N, Drapkina O, Zyatenkova E, Egorova L, Esip V, Kirichek N, Filatov A, Soin I, Gilinskaya O, Valuyshkih E, Glezer M, Valovyeva S, Golitsyn S, Kratskina T, Goloshchekin B, Laptev I, Gratsiansky N, Mazovets O, Karpov Y, Buza V, Kosenko B, Khirmanov V, Kireenkov I, Khokhlov A, Sinitsina O, Khokhlov R, Tsareva E, Khrustalev O, Khrustalev A, Kostenko V, Karabalieva S, Koziolova N, Polyanskaya E, Kozyrev O, Kostenko O, Kuznetsov V, Rychkov A, Lavrova O, Tereschenko L, Levashov S, Volkova E, Libis R, Maslova A, Libov I, Moiseeva Y, Lila A, Belousova L, Lukyanov Y, Lamden D, Nikolaev K, Nikolaev A, Nikolskaya I, Khromova O, Novikova N, Patrusheva S, Panchenko E, Laguta P, Panov A, Nilk R, Polkanova E, Matveeva I, Poluyanova N, Pikalova N, Raskina T, Letaeva M, Rebrov A, Karoli N, Repin M, Rodina N, Shaposhnik I, Lebedev E, Shogenov Z, Agirov 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Pazier P, Riofrio K, Braun D, Robinson J, Cherrico M, Roehll W, Hollihan P, Rosado, Barnhorst M, Rosado J, Bamhorst M, Rosen R, Martin C, Ross S, Freeman R, Ruoff G, Nelson T, Sacco J, Ball E, Samal A, Schomburg J, Sandberg J, Lafave J, Savin V, Clifton R, Schaefer S, Fekete A, Schneider R, Schneider W, Schulman D, Mercer S, Seals A, Ullig T, Holt A, Seide H, Mather N, Shah G, Witt P, Shalaby A, Seese M, Shanes J, Fleets J, Shaoulian E, Hren A, Sheikh K, Hengerer T, Shih H, Browning J, Shoukfeh M, Stephenson L, Siler T, Champagne M, Simpson P, Meyer R, Singh N, Turner K, Singh V, Nelson M, Skierka R, Hughes B, Keene R, Smith R, Hodnett P, Spangenthal S, Thomason L, Sperling M, Vasquez E, Spivack E, McCartney P, Staniloae C, Liu M, Steljes A, Cox C, Struble R, Vittitow T, Suresh D, Frost J, Swerchowsky V, Freemyer D, Szulawski I, Herwehe S, Tahirkheli N, Springer K, Takata T, Bruton T, Talano J, Leo L, Tami L, Corchado D, Tatarko M, Swauger M, Tawney K, Dastoli K, Teague S, Young K, Tee H, Mitchell T, Teixeira J, Southam D, Torres M, Tucker P, Salas L, Updegrove J, Hanna K, Val Mejias J, Harrelson KG, Vemireddy D, Cardoza T, Verma S, Parsons T, Vicari R, Warren K, Vijay N, Washam M, Vossler M, Kilcup S, Walsh R, Renaud K, Ward S, Locklear T, Waxman F, Sanchez G, Weiss R, St Laurent B, Westcott J, Williams D, Gibson C, Williams R, Dowling C, Willis J, VonGerichten S, Wood K, Capasso Gulve E, Worley S, Pointer S, Yarows S, Sheehan T, Yasin M, Yi J, Dongas B, Yousuf K, Zakhary B, Curtis S, Zeig S, Mason T, Zellner C, Harden M, Roper E, Waseem M, Grammer M., PERRONE FILARDI, PASQUALE, Cardiovascular Division (SZG), Brigham and Women's Hospital [Boston], Mount Sinai Medical Center, Icahn School of Medicine at Mount Sinai [New York] (MSSM), University Hospitals Case Medical Center (CLEVELAND - UHCMC), University Hospitals Case Medical Center, Jefferson Medical College (JMC), Thomas Jefferson University Hospitals, Thrombosis and Atherosclerosis Research Institute (TARI), McMaster University [Hamilton, Ontario], University Hospital Brno, Institute of Cardiology (WARSAW - Cardiology), Institute of Cardiology, Cardiology Research Center (MOSCOU - CRC), Cardiology Research Center, National Hopital Organization (OSAKA - NHO), Osaka National Hospital, Université de Brest (UBO), Centre d'Investigation Clinique (CIC - Brest), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Graduate School, Endocrinology, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Nursing, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, General Internal Medicine, Giugliano, Rp, Ruff, Ct, Braunwald, E, Murphy, Sa, Wiviott, Sd, Halperin, Jl, Waldo, Al, Ezekowitz, Md, Weitz, Ji, Špinar, J, Ruzyllo, W, Ruda, M, Koretsune, Y, Betcher, J, Shi, M, Grip, Lt, Patel, Sp, Patel, I, Hanyok, Jj, Mercuri, M, Antman, Em, Comi, Giancarlo, ENGAGE AF TIMI 48, Investigators, Robert P., Giugliano, Christian T., Ruff, Eugene, Braunwald, Sabina A., Murphy, Stephen D., Wiviott, Jonathan L., Halperin, Albert L., Waldo, Michael D., Ezekowitz, Jeffrey I., Weitz, Jind?ich, ?pinar, Witold, Ruzyllo, Mikhail, Ruda, Yukihiro, Koretsune, Joshua, Betcher, Minggao, Shi, Laura T., Grip, Shirali P., Patel, Indravadan, Patel, James J., Hanyok, Michele, Mercuri, Elliott M., Antman, Morin, Se, Hoffman, Eb, Deenadayalu, N, Grip, L, Lanz, H, Curt, V, Duggal, A, Hanyok, J, Davé, J, Morgan, D, Choi, Y, Jin, J, Xie, J, Crerand, W, Kappelhof, J, Maxwell, W, Skinner, M, Patel, S, Selicato, G, Otto C., Jr, Reissner, C, Smith, K, Ostroske, J, Ron, A, Giugliano, R, Connolly, S, Camm, J, Ezekowitz, M, Halperin, J, Waldo, A, Paolasso, E, Aylward, P, Heidbuchel, H, Nicolau, Jc, Goudev, A, Roy, D, Weitz, J, Corbalán, R, Yang, Y, Botero, R, Bergovec, M, Ŝpinar, J, Grande, P, Hassager, C, Voitk, J, Huikuri, H, Nieminen, M, Blanc, Jj, Leheuzey, Jy, Mitrovic, V, Alexopoulos, D, Sotomora, G, Kiss, R, Somaraju, B, Lewis, B, Merlini, P, Metra, M, Yamashita, T, García 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Grammer, M.

Subjects
Male, Pyridines, [SDV]Life Sciences [q-bio], Embolism, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, chemistry.chemical_compound, 0302 clinical medicine, Edoxaban, Atrial Fibrillation, MESH: Double-Blind Method, 030212 general & internal medicine, MESH: Warfarin, Stroke, MESH: Aged, MESH: Middle Aged, Cardiovascular diseases [NCEBP 14], Hazard ratio, General Medicine, MESH: Follow-Up Studies, Middle Aged, 3. Good health, MESH: Atrial Fibrillation, Cardiovascular Diseases, Anesthesia, Cardiology, Female, Adult, Aged, Anticoagulants, Double-Blind Method, Follow-Up Studies, Hemorrhage, Humans, Thiazoles, Warfarin, MESH: Hemorrhage, Andexanet alfa, medicine.drug, medicine.medical_specialty, MESH: Enoxaparin, MESH: Anticoagulants, MESH: Stroke, Dabigatran, 03 medical and health sciences, Internal medicine, medicine, MESH: Kaplan-Meier Estimate, Rivaroxaban, MESH: Humans, business.industry, MESH: Cardiovascular Diseases, MESH: Adult, medicine.disease, Confidence interval, MESH: Male, chemistry, business, MESH: Female, MESH: Embolism
Abstract

Contains fulltext : 125374.pdf (Publisher’s version ) (Open Access) BACKGROUND: Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects. The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known. METHODS: We conducted a randomized, double-blind, double-dummy trial comparing two once-daily regimens of edoxaban with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation (median follow-up, 2.8 years). The primary efficacy end point was stroke or systemic embolism. Each edoxaban regimen was tested for noninferiority to warfarin during the treatment period. The principal safety end point was major bleeding. RESULTS: The annualized rate of the primary end point during treatment was 1.50% with warfarin (median time in the therapeutic range, 68.4%), as compared with 1.18% with high-dose edoxaban (hazard ratio, 0.79; 97.5% confidence interval [CI], 0.63 to 0.99; P

Published
2013

3. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes

Author

Tricoci, P, Huang, Z, Held, C, Moliterno, Dj, Armstrong, Pw, Van de Werf, F, White, Hd, Aylward, Pe, Wallentin, L, Chen, E, Lokhnygina, Y, Pei, J, Leonardi, S, Rorick, Tl, Kilian, Am, Jennings, Lh, Ambrosio, G, Bode, C, Cequier, A, Cornel, Jh, Diaz, R, Erkan, A, Huber, K, Hudson, Mp, Jiang, L, Jukema, Jw, Lewis, Bs, Lincoff, Am, Montalescot, G, Nicolau, Jc, Ogawa, H, Pfisterer, M, Prieto, Jc, Ruzyllo, W, Sinnaeve, Pr, Storey, Rf, Valgimigli, M, Whellan, Dj, Widimsky, P, Strony, J, Harrington, Ra, Mahaffey, Kw, Huo, Y, Lixin, J, Isaza, D, Grande, P, Laine, M, Wong, L, Ofner, P, Yamaguchi, T, Park, Sj, Nordrehaug, Je, Providencia, L, Cheem, Th, Dalby, A, Betriu, A, Chen, Mf, Verheugt, F, Frye, Rl, Hochman, J, Steg, Pg, Bailey, Kr, Easton, Jd, Lincoff, A, Underwood, Fd, Wrestler, J, Larson, D, Vandyne, B, Kilian, A, Harmelin-Kadouri, R, Layton, L, Lipka, L, Petrauskas, S, Qidwai, M, Sorochuck, C, Temple, T, Mason, D, Sydlowski, D, Gallagher, B, Villasin, A, Beernaert, A, Douglas, S, Garrett, J, Wiering, J, Adriaenssens, T, Ganame, J, Hulselmans, M, Katz, Jn, Kayaert, P, La Gerche, A, Onsea, K, Zalewski, J, Johnson, A, O'Briant, J, Smith, M, Akerblom, A, Armaganijan, L, Bertolami, A, Brennan, M, da Ponte Nacif SA, de Campos Gonzaga, C, Dequadros, A, Déry, Jp, Dev, S, Ducrocq, G, Eapen, Zp, Echenique, L, Eggers, K, Garcia, H, Guimaraes, Hp, Hagstrom, E, Hanet, C, James, S, Jonelid, B, Kolls, Bj, Leiria, T, Leite, R, Lombardi, C, Lopes, Rd, Malagutti, P, Mathews, R, Mehta, Rh, Melloni, C, Piccini, Jp, Rodriques Soares, P, Roe, Mt, Shah, Br, Stashenko, G, Szczech, La, Truffa, A, Varenhorst, C, Vranckx, P, Williams, J, Kilaru, R, White, Ja, Binkowitz, B, He, W, Ramos, Ms, Hasbani, E, Farras, Ha, Luz del Valle, L, Zapata, G, Centeno, Ep, Hominal, M, Beloscar, J, Panno, M, Berli, M, Carlevaro, O, Wasserman, T, Lembo, L, Diez, F, Bettinotti, M, Allall, O, Macin, S, Hii, C, Bett, N, Aroney, C, Roberts-Thomson, P, Arstall, M, Horowitz, J, Prasan, A, Farshid, A, Rankin, J, Duffy, S, Sinhal, A, Hendricks, R, Waites, J, Hill, A, French, J, Adams, M, Soward, A, Dick, R, Jepson, N, Nelson, G, Thompson, P, Neunteufl, T, Pachinger, O, Leisch, F, Siostrzonek, P, Roithinger, F, Pieske, B, Weber, H, Eber, B, Zenker, G, Sinnaeve, P, Roosen, J, Vervoort, G, Coussement, P, Striekwold, H, Boland, J, Van Dorpe, A, Dujardin, K, Mertens, D, Vanneste, L, Celen, H, Lesseliers, H, Vrolix, M, Leone, A, De Maeseneire, S, Hellemans, S, Silva, Fa, Franken, M, Moraes JB Jr, Mora, R, Michalaros, Y, Perin, M, Guimaraes, Ae, da Silva DG, Mattos, Ma, Alves AR Jr, Hernandes, Me, Golin, V, da Silva SA, Ardito, W, Dery, Jp, Mukherjee, A, Tanguay, Jf, Kornder, J, Lutchmedial, S, Degrace, M, Klinke, P, Constance, C, Nogareda, G, Wong, G, Macdonald, P, Senaratne, M, Rupka, D, Halperin, F, Ramanathan, K, Natarajan, M, Lai, C, Brossoit, R, Tymchak, W, Rose, B, Dupuis, R, Mansour, S, Bata, I, Zadra, R, Turek, M, Madan, M, Le May, M, Leon, L, Perez, L, Yovaniniz, P, Pedemonte, O, Campos, P, Pincetti, C, Sepulveda, P, Li, W, Zhao, R, Li, Z, Yang, Y, Chen, J, Li, H, Jiang, Y, Li, D, Qu, P, Sun, Y, Zheng, Y, Zhou, C, Zhang, F, Wei, M, Wang, D, Lemus, J, Fernandez, Rl, Jaramillo, C, Ochoa, J, Velez, S, Cano, N, Lutz, J, Botero, R, Jaramillo, M, Saaib, J, Sanchez, G, Hernandez, H, Mendoza, F, Rizcala, A, Urina, M, Polasek, R, Motovska, Z, Zemanek, D, Ostransky, J, Kettner, J, Spinar, J, Groch, L, Ramik, C, Stumar, J, Linhart, A, Pleva, L, Niedobova, E, Macha, J, Vojacek, J, Stipal, R, Galatius, S, Eggert, S, Mickley, H, Egstrup, K, Pedersen, O, Hvilsted, L, Sykulski, R, Skagen, K, Dodt, K, Klarlund, K, Husted, S, Jensen, G, Melchior, T, Sjoel, A, Steffensen, Fh, Airaksinen, Ke, Laukkanen, Ja, Syvanne, Ms, Kotila, Mj, Mikael, K, Naveri, Hk, Hekkala, Am, Mustonen, Jn, Halkosaari, M, Ohlmann, P, Khalife, K, Dibon, O, Hirsch, Jl, Furber, A, Nguyen-Khac, Jo, Delarche, N, Probst, V, Lim, P, Bayet, G, Dauphin, R, Levai, L, Galinier, M, Belhassane, A, Wiedemann, Jy, Fouche, R, Coisne, D, Henry, P, Schiele, F, Boueri, Z, Vaquette, B, Davy, Jm, Cottin, Y, D'Houdain, F, Danchin, N, Cassat, C, Messner, P, Elbaz, M, Coste, P, Zemour, G, Maupas, E, Feldman, L, Soto, Fx, Ferrari, E, Haltern, G, Heuer, H, Genth-Zotz, S, Loges, C, Stellbrink, C, Terres, W, Ferrar, M, Zeymer, U, Brachmann, J, Mudra, H, Vohringer, Hf, vom Dah, J, Kreuzer, J, Hill, S, Kleinertz, K, Kadel, C, Appel, Kf, Nienabe, C, Behrens, S, Frantz, S, Mehrhof, F, Krings, P, Hengstenberg, C, Lueders, S, Hanefel, C, Krulls-Munch, J, Dorse, T, Leschke, M, Nogai, K, Butter, C, Darius, H, Fichtlscherer, Hp, Schmitt, C, Kasisk, Hp, Dorr, M, Fran, N, Jereczek, M, Wiemer, M, Nickenig, G, Boudriot, E, Werner, G, Altila, T, Strasser, R, Baldus, S, Desaga, M, Buerke, M, Land, S, Schunkert, H, Schulze, Ho, Holmer, S, Sohn, Hy, Burkhardt, W, Lauer, B, Schwimmbeck, P, Schoeller, R, Lapp, H, Gross, M, Kindermann, I, Schuster, P, Yu, Cm, Lee, S, Merkely, B, Apro, D, Lupkovics, G, Edes, I, Ungi, I, Piroth, Z, Csapo, K, Dezsi, Ca, Herczeg, B, Sereg, M, Butnaru, A, Lewis, B, Rosenschein, U, Mosseri, M, Turgeman, Y, Pollak, A, Shotan, A, Hammerman, H, Rozenman, Y, Gottlieb, S, Atar, S, Weiss, A, Marmor, A, Iakobishvili, Z, Mascia, F, De Cesare, N, Piovaccari, G, Ceravolo, R, Fiscella, A, Salvioni, A, Silvestri, O, Moretti, L, Severi, S, Carmina, Mg, De Caterina, R, Fattore, L, Terrosu, P, Trimarco, B, Ardissino, D, Uguccioni, L, Auguadro, C, Gregorio, G, De Ferrari, G, Testa, R, Evola, R, De Servi, S, Sganzerla, P, Vassanelli, C, Brunelli, C, Scherillo, M, Tamburino, C, Limido, A, Luzza, F, Percoco, Gf, Sinagra, G, Volpe, M, Crea, F, Fedele, F, Rasetti, G, Cinelli, F, Merlini, P, Sisto, F, Biancoli, S, Fresco, C, Corrada, E, Casolo, G, Santini, M, D'Alessandro, B, Antoniucci, D, Tuccillo, B, Assennato, P, Puccioni, E, Pasquetto, G, Perna, Gp, Morgagni, G, Takizawa, K, Kato, K, Oshima, S, Yagi, M, Asai, T, Kamiya, H, Hirokami, M, Sakota, S, Sueyoshi, A, Shimomura, H, Hashimoto, T, Miyahara, M, Matsumura, T, Nakao, K, Kakuta, T, Nakamura, S, Nishi, Y, Kawajiri, K, Nagai, Y, Takahashi, A, Ikari, Y, Hara, K, Koga, T, Fujii, K, Tobaru, T, Tsunoda, R, Uchiyama, T, Hirayama, H, Fujimoto, K, Sakurai, S, Tanigawa, T, Ohno, M, Yamamoto, E, Ikuta, S, Kato, A, Kikuta, K, Takami, A, Chong, Wp, Ong, Tk, Yusof, A, Maskon, O, Kahar, A, Breedveld, Rw, Bendermacher, Pe, Hamer, Bj, Oude Ophuis AJ, Nierop, Pr, Westendorp, Ic, Beijerbacht, Hp, Herrman, Jp, van 't Hof AW, Troquay, Rp, van der Meer, P, Peters, Rh, van Rossum, P, Liem, A, Pieterse, Mg, van Eck JW, van der Zwaan, C, Pasupati, S, Elliott, J, Tisch, J, Hart, H, Luke, R, Scott, D, Ternouth, I, White, H, Hamer, A, Harding, S, Wilkins, G, O'Meeghan, T, Harrison, N, Nilsen, D, Thalamus, J, Aaberge, L, Brunvand, H, Lutterbey, G, Omland, Tm, Eritsland, J, Wiseth, R, Aase, O, Campos, C, Horna, M, Toce, L, Salazar, M, Przewlocki, T, Ponikowski, P, Kasprzak, J, Kopaczewski, J, Musial, W, Mazurek, W, Kawecka-Jaszcz, K, Pluta, W, Dobrzycki, S, Loboz-Grudzien, K, Lewczuk, J, Karwowski, D, Grajek, S, Dudek, D, Trusz-Gluza, M, Kornacewicz-Jach, Z, Gil, R, Ferreira, J, Gavina, C, Ferreira, R, Martins, D, Garcia-Rinaldi, R, Ufret, R, Vazquez-Tanus, J, Banchs, H, Wong, A, Tan, Hc, Guerra, M, Ebrahim, I, Roux, J, Blomerus, P, Saaiman, A, Corbett, C, Pillay, T, Freeman, V, Horak, A, Zambakides, C, Burgess, L, Yoon, Jh, Ahn, Th, Gwon, Hc, Seong, Iw, Kim, Hs, Jeong, Mh, Kim, Yd, Chae, Sc, Hernandez, Jm, Pique, M, Fernandez Portales, J, Paz, Ma, Lopez Palop, R, Iniguez, A, Diaz Fernandez, J, Alvarez, P, Sanz, E, Heras, M, Sala, J, Goicolea, J, Cruz Fernandez, J, Serra, A, Fernandez Ortiz, A, Calle, G, Barriales, V, Albarran, A, Curos, A, Molano Casimiro FJ, Suarez, Ma, Franco, Sn, Bayon, J, Suarez, J, Belchi, J, Moreu, J, San Martin, M, Melgares Moreno, R, Aguirre Salcedo, J, Gonzalez Juanatey JR, Martinez Romero, P, Galache Osuna JG, Albertsson, P, Diderholm, E, Lycksell, M, Rasmanis, G, Swahn, E, Cherfan, P, Christensen, K, Lundman, P, Larson, Le, Vasko, P, Pripp, Cm, Johansson, A, Moccetti, T, Corti, R, Pieper, M, Mach, F, Eberli, F, Jeger, R, Rickli, H, Vogt, P, Windecker, S, Wu, Cj, Kao, Hl, Charng, Mj, Chang, Kc, Chen, Zc, Tsa, Cd, Shyu, Kg, Lai, Wt, Hsieh, Ic, Hou, Jy, Yeh, Hi, Ueng, Kc, Yin, Wh, Timurkaynak, T, Yigit, Z, Yilmaz, M, Boyaci, A, Sahin, M, Goktekin, O, Bozkurt, E, Ercan, E, Yildirir, A, Muthusamy, R, Keeling, P, Levy, T, Zaman, A, Cohen, A, Gorog, D, Baumbach, A, Oldroyd, K, Kadr, H, Tait, G, Bellenger, N, Davis, G, Shakespeare, C, Senior, R, Bruce, D, Uren, N, Trouton, T, Ahsan, A, Hamed, A, Malik, I, Sarma, J, Millar-Craig, M, Robson, H, Kennon, S, Sprigings, D, Brodie, B, Kang, Gs, Thomas, G, Cheng, Sc, Espinoza, A, Kassas, S, Jafar, Z, Kumar, P, Izzo, M, Wiseman, A, Chandna, H, Felten, W, D'Urso, M, Gudipati, Cr, Coram, R, Gill, S, Bengtson, J, Chang, M, Raisinghani, A, Blankenship, J, Harbor, Wf, Kraft, P, Ashraf, R, Chambers, J, Albirini, A, Malik, A, Ziada, K, Slepian, M, Taussig, A, Vernon, H, Jetty, P, Islam, Ma, Canaday, D, Martin, T, Burchenal, Jj, Gencheff, N, Nygaard, T, Panchal, V, Merritt, R, Abrahams, L, Lambert, C, Reyes, P, Leimbach, W, Chhabra, A, Caputo, R, Imburgia, M, Erickson, B, Kleiman, N, Hunter, J, Dehning, M, Graham, B, Strain, J, White, Jk, Mcgarvey, J Jr, Henderson, D, Treasure, C 2nd, Mirro, M, Pancholy, S, Helmy, T, Westerhausen, D, Dib, N, Penny, W, Kim, H, Degregorio, M, Jay, D, Kmonicek, J, Berlowitz, M, Starling, M, Langevin, E, Nelson, R, Singer, A, Siachos, A, Gibson, G, Parrott, C, Held, J, Puleo, P, Wolford, T, Omar, B, Brilakis, E, Lewis, S, Heller, L, Brener, S, Addo, T, Lieberman, S, Eisenberg, D, Feldman, R, Waksman, R, Waltman, J, Schulman, S, Bounds, C, Voyce, S, Batchelor, W, Dobies, D, Pasnoori, V, Chandrashekhar, Y, Vetrovec, G, Azrin, M, Spriggs, D, Hirsch, C, Smucker, M, Chetcuti, S, Stella, R, Levite, H, Shoukfeh, M, Vidovich, M, Saucedo, J, Fintel, D, Low, R, Gellman, J, Ahsan, C, Unks, Dm, Tolleson, T, Ceccoli, H, Aggarwal, K, Bhaktaram, V, Olson, C, Decaro, M, Kaluski, E, Mehta, V, Puma, J, Singh, V, Fulmer, J, Lewis, D, Khadra, S, Staniloae, C, East, M, Sundram, Ps, Anderson, J, Wasserman, H, Guy, D, Brill, D, Kruse, K, Ebrahimi, R, Nguyen, T, Keating, F, Srivastava, R, Wassmer, P, Todd, J 3rd, Stein, M, Hamzeh, I, Laxson, D, Hodson, R, Puri, S, Vijayaraghavan, K, Gazmuri, R, Chu, A, Vijay, N, Rabinowitz, A, Block, T, Agarwal, H, Martin, J, Zetterlund, P, Fortuin, D, Macdonell, A 3rd, Zouzoulas, S, Chepuri, V, Schmalfuss, C, Karve, M, Aviles, R, Lieberman, E, Amlani, M, Murphy, S, Shapiro, T, Herzog, E, Ariani, K, Bhagwat, R, Hockstad, E, Kai, W, Saririan, M, Roth, R, Weiland, F, Atassi, K, Harjai, K, Muhlestein, J, Marsh, R, Shokooh, S, Nahhas, A, Labroo, A, Mayor, M, Koshy, S, Tariq, M, Rayos, G, Jones, S, Klugherz, B, Dewey, R, Rashid, Hu, Wohns, D, Feiring, A, Bowles, M, Rohrbeck, S, Monroe, Vs, De Gottlieb, A, Gumm, D, Brown, C 3rd, Chang, D, Kalaria, V, Minisi, A, Joumaa, M, Josephson, R, Kleczka, J, Silver, K, Coleman, P, Brachfeld, C, Saltiel, F, Reiner, J, Carell, E, Hanovich, G, Rosenberg, M, Das, G, Blick, D, and Universitat de Barcelona

Subjects
Male, Pyridines, medicine.medical_treatment, Kaplan-Meier Estimate, law.invention, Lactones, Randomized controlled trial, law, Thrombin receptor antagonist, clopidogrel, placebo, thienopyridine derivative, vorapaxar, antithrombocytic agent, lactone, proteinase activated receptor 1, pyridine derivative, Coronary Artery Bypass, Vorapaxar, Cardiovascular diseases [NCEBP 14], Drugs, General Medicine, Middle Aged, Combined Modality Therapy, Cardiovascular diseases, Cardiovascular Diseases, Cardiology, Platelet aggregation inhibitor, Drug Therapy, Combination, Female, Plaquetes sanguínies, Intracranial Hemorrhages, Major bleeding, Medicaments, medicine.drug, medicine.medical_specialty, Acute coronary syndrome, Bypass cardiopulmonary, Hemorrhage, Pharmacotherapy, Blood platelets, Double-Blind Method, Angioplasty, Internal medicine, medicine, Humans, Receptor, PAR-1, Acute Coronary Syndrome, Aged, business.industry, Malalties cardiovasculars, medicine.disease, Surgery, Bypass cardiopulmonar, business, Platelet Aggregation Inhibitors, Follow-Up Studies
Abstract

Item does not contain fulltext BACKGROUND: Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation. METHODS: In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization. RESULTS: Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan-Meier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P=0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P

Published
2012

6. Impact of circulating monocyte CD36 level on atrial fibrillation and subsequent catheter ablation.

Author

Hu YF, Yeh HI, Tsao HM, Tai CT, Lin YJ, Chang SL, Lo LW, Tuan TC, Tzeng CH, Huang SH, Lin YK, Chen SA, Hu, Yu-Feng, Yeh, Hung-I, Tsao, Hsuan-Ming, Tai, Ching-Tai, Lin, Yenn-Jiang, Chang, Shih-Lin, Lo, Li-Wei, and Tuan, Ta-Chuan

Abstract

Background: Inflammation, an important mechanism in the pathogenesis of atrial fibrillation (AF), can be regulated by CD36 in monocytes.Objective: The purpose of this study was to test the hypothesis that CD36 in monocytes contributes to the pathogenesis of AF.Methods: A prospective study that enrolled 87 patients with AF and 70 without AF was conducted.Results: Compared to patients without AF, patients with AF had monocytes with a lower level of CD36 protein, which correlated with left atrial diameter, left atrial emptying fraction, and left atrial mean voltage. In AF patients after catheter ablation, Kaplan-Meier analysis showed that the sinus rhythm maintenance rate was higher in patients with high CD36 levels. Low CD36 level was an independent predictor of recurrence. After successful ablation, the CD36 level increased by 57%, reaching that of control patients. CD36 level was not correlated with the level of high-sensitivity C-reactive protein. Analysis of mRNA levels from a buffy coat revealed that AF patients had lower CD36 and interleukin-10 levels and higher peroxisome proliferator-activated receptor-γ and tumor necrosis factor-α levels, with CD36 level positively correlated with interleukin-10 level but inversely correlated with peroxisome proliferator-activated receptor-γ and tumor necrosis factor-α levels.Conclusion: Low CD36 levels in circulating monocytes were associated with AF occurrence and predicted recurrence after catheter ablation. The link between CD36 and AF identified a novel AF-related inflammatory pathway. [ABSTRACT FROM AUTHOR]

Published
2011
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8. Fluorescent gold nanoclusters possess multiple actions against atherosclerosis.

Author

Lee YN, Wu YJ, Su CH, Wang BJ, Yang SH, Lee HI, Chou YH, Tien TY, Lin CF, Chan WH, Chung CH, Wang SW, and Yeh HI

Abstract

Atherosclerosis caused major morbidity and mortality worldwide. Molecules possessing lipid-lowering and/or anti-inflammatory properties are potential druggable targets against atherosclerosis. We examined the anti-atherosclerotic effects of fluorescent gold nanoclusters (FANC), which were dihydrolipoic acid (DHLA)-capped 2-nm gold nanoparticles. We evaluated the 8-week effects of FANC in Western-type diet-fed ApoE-deficient mice by either continuous intraperitoneal delivery (20 μM, 50 μl weekly) or via drinking water (300 nM). FANC reduced aortic atheroma burden, serum total cholesterol, and oxidative stress markers malondialdehyde and 4-hydroxynonenal levels. FANC attenuated hepatic lipid deposit, with changed expression of lipid homeostasis-related genes HMGCR, SREBP, PCSK9, and LDLR in a pattern similar to mice treated with ezetimibe. FANC also inhibited intestinal cholesterol absorption, resembling the action of ezetimibe. The lipid-lowering and anti-atherosclerotic effects of FANC reappeared in Western-type diet-fed LDLr-deficient mice. FANC bound insulin receptor β (IRβ) via DHLA, leading to AKT activation. However, unlike insulin, which also bound IRβ to activate AKT to induce HO-1, activation of AKT by FANC was independent of HO-1 expression in human aortic endothelial cells (HAECs). Alternatively, FANC up-regulated NRF2, interfered the binding of KEAP1 to NRF2, and promoted KEAP1 degradation to free NRF2 for nuclear entry to induce HO-1 that suppressed the expression of ICAM-1 and VCAM-1. Consistently, FANC suppressed ox-LDL-induced enhanced attachment of THP-derived macrophages onto HAECs. In macrophages, FANC up-regulated ABCA1, and reversed ox-LDL-induced suppression of cholesterol efflux. FANC effected in vitro at nano moles. In conclusion, our findings showed novel actions and multiple mechanisms of FANC worked coherently against atherosclerosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2024
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9. Functional and prognostic impacts of serum albumin with thoracic arterial calcification among asymptomatic individuals.

Author

Chien SC, Lan WR, Yun CH, Sung KT, Yeh HI, Tsai CT, Chien CY, and Hung CL

Subjects
Humans, Male, Female, Middle Aged, Prognosis, Aged, Aorta, Thoracic diagnostic imaging, Aorta, Thoracic pathology, Coronary Artery Disease blood, Coronary Artery Disease diagnostic imaging, Asymptomatic Diseases, Risk Factors, Vascular Calcification diagnostic imaging, Vascular Calcification blood, Vascular Calcification etiology, Serum Albumin metabolism, Serum Albumin analysis
Abstract

Although several studies have demonstrated the cardiovascular (CV) implication of hypoalbuminemia and arterial calcification among hemodialysis patients, little is known regarding their cardiac correlates and relevant CV outcomes in asymptomatic individuals. We assessed the potential CV interrelation between serum albumin (SA) and aortic calcification. Among 2,723 asymptomatic individuals underwent cardiovascular health check-up, we assessed serum albumin (SA) level, thoracic aortic calcification (TAC) and coronary artery calcification (CAC) by multi-detector computed tomography, and ultrasound-determined carotid plaque burden. We related these measures to cardiac structure/function and CV outcomes. Lower SA level was associated with higher TAC score and volume rather than carotid plaque or coronary calcification burden in fully adjusted models. By categorizing the study population into 4 groups by SA (>, ≤ 4.6 mg/dL) and presence of TAC, subjects classified into low SA/TAC(+) category were oldest with highest prevalent CV disease. Both lower SA and TAC(+) were independently associated with impaired myocardial systolic/diastolic mechanics and higher CV events during a median of 6.6 years (IQR: 5.1, 6.8 years) follow-up. Participants classified into low SA/TAC(+) category showed highest risk for CV events (adjusted HR: 3.78 [95% CI: 2.11, 6.77], high SA/TAC[-] as reference) in fully adjusted Cox model. Among symptom-free individuals, TAC was closely associated with low SA concentration in relation to unfavorable cardiac mechanics and may serve as a useful prognosticator for adverse CV events., (© 2024. The Author(s).)

Published
2024
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10. Recent trends of low-density lipoprotein cholesterol control and lipid-lowering therapy in patients with atherosclerotic cardiovascular disease in Taiwan: 2015-2020.

Author

Chen TY, Hsiao YC, Wu YW, Lin TH, Sheu WH, Lee TL, Hsieh IC, Li YH, Yin WH, Yeh HI, Chen JW, Lin FJ, and Wu CC

Abstract

Objective: This study aimd to assess recent trends in the control of low-density lipoprotein cholesterol (LDL-C) and the utilization of lipid-lowering drugs (LLD) among patients with atherosclerotic cardiovascular disease (ASCVD) in Taiwan., Methods: Patients with ASCVD and without a history of hemorrhagic stroke were identified from the Taiwanese Secondary Prevention for patients with AtheRosCLErotic disease (T-SPARCLE) Registry. ASCVD patients were stratified into four categories: those who ever had acute coronary syndrome (ACS), those who underwent percutaneous coronary intervention or coronary artery bypass grafting (PCI/CABG) without ACS, those who ever had an ischemic stroke (IS) without ACS or PCI/CABG, and other ASCVD cases. We assessed their latest recorded LDL-C levels for the periods 2015-16, 2017-18, and 2019-20. LLD therapy patterns were presented as monotherapy, dual therapy, or combination therapy of three or more drugs, with statin use classified by intensity., Results: We identified 3831 ASCVD patients in 2015-16, 3531 in 2017-18, and 1231 in 2019-20. LLD utilization rose from 58.4% in 2015-16 to 73.2% in 2019-20. The proportions of patients achieving LDL-C goals in 2015-16, 2017-18, and 2019-20 were 21.5%, 25.8%, and 33.3% in the ACS cohort (goal <70 mg/dL); 20.4%, 26.1%, and 39.0% in the PCI/CABG cohort (goal <70 mg/dL); 54.4%, 58.5%, and 58.9% in the IS cohort (goal <100 mg/dL); and 60.0%, 65.5%, and 67.0% in the other ASCVD cohort (goal <100 mg/dL), respectively. Over half of the patients were prescribed moderate-intensity statins. Statin use, age, history of diabetes mellitus, and hypertension were important factors for attaining LDL-C goal in ACS patients., Conclusion: Despite improvements in LDL-C management observed over recent years, significant gaps remain in guideline adherence, especially for patients with ACS or PCI/CABG in Taiwan, with over 60% not meeting LDL-C targets. Intensifying efforts to align clinical practice with guidelines are imperative., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Published
2024
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11. Long-term prognostic effect of serum albumin concentration in diabetic patients with stable coronary artery disease: A multicenter cohort study.

Author

Lu TW, Chien SC, Leu HB, Yin WH, Tseng WK, Wu YW, Lin TH, Chang KC, Wang JH, Wu CC, Yeh HI, and Chen JW

Abstract

Background: Diabetes and insulin resistance alter the physiological state of serum albumin (SA), which is a prognostic marker for stable coronary artery disease (CAD). However, whether the SA concentration is associated with long-term cardiovascular (CV) outcomes in diabetic patients with stable CAD remains unclear., Methods: In total, 1148 patients were retrospectively identified from a nationwide multicenter cohort study on patients with stable CAD. They were categorized into four groups according to their diabetes mellitus (DM) status and SA concentration (cutoff: 4 g/dL)., Results: The patients' mean age was 62.5 years, and 83.5% were male. Of the total patients, 405 were included in group 1 (SA ≥ 4/non-DM), 322 in group 2 (SA < 4/non-DM), 201 in group 3 (SA ≥ 4/ DM), and 220 in group 4 (SA < 4/DM). Group 4 had the oldest age and a higher prevalence of prior myocardial infarction and stroke. During the median 4.5-year follow up (interquartile range: 1.5-6.7 year), the highest and lowest survival rates in terms of all-cause and CV mortality were found in groups 1 and 4, respectively. However, no prognostic differences were noted in nonfatal stroke and myocardial infarction among the groups. The data were consistent after covariate adjustment. Using group 1 as the reference, HRs (95% CIs) for all-cause mortality in groups 2, 3, and 4 were 3.64 (1.22-10.83), 3.26 (0.95-11.33), and 5.74 (1.92-16.95), respectively, and those for CV mortality were 2.8 (0.57-13.67), 2.62 (0.40-17.28), and 6.15 (1.32-28.58), respectively., Conclusion: In diabetic patients with stable CAD, a low SA concentration (<4 g/dL) was associated with increased long-term mortality regardless of all-cause or CV reasons but not nonfatal CV events., Competing Interests: Conflicts of interest: Dr. Wei-Hsian Yin, an editorial board member at Journal of the Chinese Medical Association, had no role in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2024, the Chinese Medical Association.)

Published
2024
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12. Allosteric inhibition of CFTR gating by CFTRinh-172 binding in the pore.

Author

Gao X, Yeh HI, Yang Z, Fan C, Jiang F, Howard RJ, Lindahl E, Kappes JC, and Hwang TC

Subjects
Humans, Allosteric Regulation, Ion Channel Gating drug effects, Cystic Fibrosis metabolism, Cystic Fibrosis genetics, Cystic Fibrosis drug therapy, Animals, Protein Binding, Aminophenols pharmacology, Aminophenols chemistry, Aminophenols metabolism, Benzodioxoles pharmacology, Mutation, Cystic Fibrosis Transmembrane Conductance Regulator metabolism, Cystic Fibrosis Transmembrane Conductance Regulator chemistry, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Cryoelectron Microscopy
Abstract

Loss-of-function mutations of the CFTR gene cause the life-shortening genetic disease cystic fibrosis (CF), whereas overactivity of CFTR may lead to secretory diarrhea and polycystic kidney disease. While effective drugs targeting the CFTR protein have been developed for the treatment of CF, little progress has been made for diseases caused by hyper-activated CFTR. Here, we solve the cryo-EM structure of CFTR in complex with CFTRinh-172 (Inh-172), a CFTR gating inhibitor with promising potency and efficacy. We find that Inh-172 binds inside the pore of CFTR, interacting with amino acid residues from transmembrane segments (TMs) 1, 6, 8, 9, and 12 through mostly hydrophobic interactions and a salt bridge. Substitution of these residues lowers the apparent affinity of Inh-172. The inhibitor-bound structure reveals re-orientations of the extracellular segment of TMs 1, 8, and 12, supporting an allosteric modulation mechanism involving post-binding conformational changes. This allosteric inhibitory mechanism readily explains our observations that pig CFTR, which preserves all the amino acid residues involved in Inh-172 binding, exhibits a much-reduced sensitivity to Inh-172 and that the apparent affinity of Inh-172 is altered by the CF drug ivacaftor (i.e., VX-770) which enhances CFTR's activity through binding to a site also comprising TM8., (© 2024. The Author(s).)

Published
2024
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13. Transdermal Nicotine Patch Increases the Number and Function of Endothelial Progenitor Cells in Young Healthy Nonsmokers without Adverse Hemodynamic Effects.

Author

Liu YY, Tien TY, Hung CL, Wu YJ, Su CH, and Yeh HI

Subjects
Humans, Male, Adult, Female, Young Adult, Non-Smokers, Cells, Cultured, Pulse Wave Analysis, Tobacco Use Cessation Devices adverse effects, Administration, Cutaneous, Endothelial Progenitor Cells drug effects, Endothelial Progenitor Cells metabolism, Nicotine administration & dosage, Nicotine blood, Cotinine blood, Cell Movement drug effects, Hemodynamics drug effects, Transdermal Patch
Abstract

Transdermal nicotine patches (TNPs), administering nicotine into the bloodstream through skin, have been widely used as nicotine replacement therapy, and exposure to nicotine can be detected by measurement of plasma cotinine concentration. In animal studies, nicotine treatment could increase the number of endothelial progenitor cells (EPCs), but the effect of TNPs on circulating EPCs and their activity in humans remained unclear. This study aimed to explore the influence of TNPs on circulating EPCs with surface markers of CD34, CD133, and/or KDR, and colony-forming function plus migration activity of early EPCs derived from cultured peripheral blood mononuclear cells before and after TNP treatments in young healthy nonsmokers. In parallel, pulse wave analysis (PWA) was applied to evaluate the vascular effect of TNP treatments. Twenty-one participants (25.8 ± 3.6 years old, 10 males) used TNP (nicotine: 4.2 mg/day) for 7 consecutive days. During the treatment, the CD34 + EPCs progressively increased in number. In addition, the number of EPCs positive for CD34/KDR, CD133, and CD34/CD133 were also increased on day 7 of the treatment. Furthermore, the early EPC colony-forming function and migration activity were increased with the plasma cotinine level positively correlating with change in colony-forming unit number. PWA analyses on day 7, compared with pretreatment, did not show significant change except diastolic pressure time index, which was prolonged and implied potential vascular benefit. In conclusion, 7-day TNP treatments could be a practical strategy to enhance angiogenesis of circulating EPCs to alleviate tissue ischemia without any hemodynamic concern., (© 2024 The Authors. Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Published
2024
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14. Hsa-miR-134-5p predicts cardiovascular risk in circulating mononuclear cells and improves angiogenic action of senescent endothelial progenitor cells.

Author

Tien TY, Wu YJ, Chang CY, Hung CL, Lee YN, Lee HI, Chou YH, Lin CF, Lee CW, Su CH, and Yeh HI

Subjects
Humans, Middle Aged, Male, Female, Aged, Neovascularization, Physiologic genetics, Transforming Growth Factor beta1 metabolism, Transforming Growth Factor beta1 genetics, Adult, Risk Factors, MicroRNAs genetics, MicroRNAs metabolism, Endothelial Progenitor Cells metabolism, Cellular Senescence genetics, Leukocytes, Mononuclear metabolism, Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Cardiovascular Diseases genetics, Cardiovascular Diseases metabolism, Cardiovascular Diseases pathology, p38 Mitogen-Activated Protein Kinases metabolism, p38 Mitogen-Activated Protein Kinases genetics
Abstract

This research explores the role of microRNA in senescence of human endothelial progenitor cells (EPCs) induced by replication. Hsa-miR-134-5p was found up-regulated in senescent EPCs where overexpression improved angiogenic activity. Hsa-miR-134-5p, which targeted transforming growth factor β-activated kinase 1-binding protein 1 (TAB1) gene, down-regulated TAB1 protein, and inhibited phosphorylation of p38 mitogen-activated protein kinase (p38) in hsa-miR-134-5p-overexpressed senescent EPCs. Treatment with siRNA specific to TAB1 (TAB1si) down-regulated TAB1 protein and subsequently inhibited p38 activation in senescent EPCs. Treatment with TAB1si and p38 inhibitor, respectively, showed angiogenic improvement. In parallel, transforming growth factor Beta 1 (TGF-β1) was down-regulated in hsa-miR-134-5p-overexpressed senescent EPCs and addition of TGF-β1 suppressed the angiogenic improvement. Analysis of peripheral blood mononuclear cells (PBMCs) disclosed expression levels of hsa-miR-134-5p altered in adult life, reaching a peak before 65 years, and then falling in advanced age. Calculation of the Framingham risk score showed the score inversely correlates with the hsa-miR-134-5p expression level. In summary, hsa-miR-134-5p is involved in the regulation of senescence-related change of angiogenic activity via TAB1-p38 signalling and via TGF-β1 reduction. Hsa-miR-134-5p has a potential cellular rejuvenation effect in human senescent EPCs. Detection of human PBMC-derived hsa-miR-134-5p predicts cardiovascular risk., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Published
2024
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15. A risk stratification model modified from the U.S. guideline could be applied in an Asian population with or without ASCVD: Validation study.

Author

Hsiao YC, Lee TL, Lin FJ, Hsuan CF, Yeh CF, Chang WT, Kao HL, Jeng JS, Wu YW, Hsieh IC, Fang CC, Wang KY, Chang KC, Lin TH, Sheu WH, Li YH, Yin WH, Yeh HI, Chen JW, and Wu CC

Subjects
Humans, Female, Male, Middle Aged, Aged, Risk Assessment methods, Cardiovascular Diseases, Prospective Studies, United States, Risk Factors, Japan, Atherosclerosis, Asian People
Abstract

Background: This study aimed to evaluate the performance of a modified U.S. (MUS) model for risk prediction of cardiovascular (CV) events in Asian patients and compare it to European and Japanese models., Methods: The MUS model, based on the US ACC/AHA 2018 lipid treatment guideline, was employed to stratify patients under primary or secondary prevention. Two multi-center prospective observational registry cohorts, T-SPARCLE and T-PPARCLE, were used to validate the scoring system, and the primary outcome was the time to first occurrence/recurrence of major adverse cardiac events (MACEs). The MUS model's performance was compared to other models from Europe and Japan., Results: A total of 10,733 patients with the mean age of 64.2 (SD: 11.9) and 36.5% female were followed up for a median of 5.4 years. The MUS model was validated, with an AUC score of 0.73 (95% CI 0.68-0.78). The European and Japanese models had AUC scores ranging from 0.6 to 0.7. The MUS model categorized patients into four distinct CV risk groups, with hazard ratios (HRs) as follows: very high- vs. high-risk group (HR = 1.91, 95% CI 1.53-2.39), high- vs. moderate-risk group (HR = 2.08, 95% CI 1.60-2.69), and moderate- vs. low-risk group (HR = 3.14, 95% CI 1.63-6.03). After adjusting for the MUS model, a history of atherosclerotic vascular disease (ASCVD) was not a significant predictor of adverse cardiovascular outcomes within each risk group., Conclusion: The MUS model is an effective tool for risk stratification in Asian patients with and without ASCVD, accurately predicting MACEs and performing comparably or better than other established risk models. Our findings suggest that patient management should focus on background risk factors instead of solely on primary or secondary prevention., Competing Interests: Conflicts of interest The authors declared no conflicts of interest., (© 2023 The Authors. Published by Elsevier B.V. on behalf of Chang Gung University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Published
2024
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16. Senescence induces miR-409 to down-regulate CCL5 and impairs angiogenesis in endothelial progenitor cells.

Author

Chou YH, Lee YN, Su CH, Lee HI, Hsieh CL, Tien TY, Lin CF, Yeh HI, and Wu YJ

Subjects
Animals, Humans, Male, Mice, Angiogenesis, Cell Proliferation, Down-Regulation genetics, Ischemia metabolism, Ischemia pathology, Ischemia genetics, Receptors, CCR5 metabolism, Receptors, CCR5 genetics, Signal Transduction, Vascular Endothelial Growth Factor A metabolism, Vascular Endothelial Growth Factor A genetics, Cellular Senescence, Chemokine CCL5 metabolism, Chemokine CCL5 genetics, Endothelial Progenitor Cells metabolism, Endothelial Progenitor Cells cytology, MicroRNAs genetics, MicroRNAs metabolism, Neovascularization, Physiologic genetics
Abstract

This study explores the impact of senescence on autocrine C-C motif chemokine ligand 5 (CCL5) in human endothelial progenitor cell (EPCs), addressing the poorly understood decline in number and function of EPCs during ageing. We examined the effects of replication-induced senescence on CCL5/CCL5 receptor (CCR5) signalling and angiogenic activity of EPCs in vitro and in vivo. We also explored microRNAs controlling CCL5 secretion in senescent EPCs, its impact on EPC angiogenic activity, and validated our findings in humans. CCL5 secretion and CCR5 levels in senescent EPCs were reduced, leading to attenuated angiogenic activity. CCL5 enhanced EPC proliferation via the CCR5/AKT/P70S6K axis and increased vascular endothelial growth factor (VEGF) secretion. Up-regulation of miR-409 in senescent EPCs resulted in decreased CCL5 secretion, inhibiting the angiogenic activity, though these negative effects were counteracted by the addition of CCL5 and VEGF. In a mouse hind limb ischemia model, CCL5 improved the angiogenic activity of senescent EPCs. Analysis involving 62 healthy donors revealed a negative association between CCL5 levels, age and Framingham Risk Score. These findings propose CCL5 as a potential biomarker for detection of EPC senescence and cardiovascular risk assessment, suggesting its therapeutic potential for age-related cardiovascular disorders., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Published
2024
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17. Novel prognostic impact and cell specific role of endocan in patients with coronary artery disease.

Author

Lin LY, Chang TT, Leu HB, Huang CC, Wu TC, Chou RH, Huang PH, Yin WH, Tseng WK, Wu YW, Lin TH, Yeh HI, Chang KC, Wang JH, Wu CC, and Chen JW

Abstract

Background: Both the clinical and mechanistic impacts of endocan were not well elucidated especially in coronary artery disease (CAD)., Objective: This study aimed to investigate the prognostic and potential pathological role of endocan for cardiovascular (CV) events in stable CAD patients., Methods: A total of 1,071 stable CAD patients with previous percutaneous coronary intervention (PCI) were enrolled prospectively in a nationwide Biosignature study. Another cohort of 76 CAD patients with or without PCI were enrolled for validation. Baseline biomarkers including endocan level was measured and total CV events especially hard CV events (including CV mortality, non-fatal myocardial infection and stroke) during follow-up were identified. Circulating endothelial progenitor cells (EPCs) as an in vivo biological contributor to vascular repairment from CAD patients were used for the in vitro functional study., Results: After 24 months, there were 42 patients (3.92%) with hard CV events and 207 (19.3%) with total CV events in the study group. The incidence of both events was increased with the tertiles of baseline endocan level (hard events: 1.7%,3.4%, and 6.7% in 1st,2nd, and 3rd tertile respectively, p = 0.002; total events: 13.8%vs.16.2%vs.28.0%, p < 0.0001). Multivariate regression analysis revealed the independent association of endocan level with total and hard CV events. These findings were validated in another cohort with a 5-year follow-up. Furthermore, in vitro inhibition of endocan improved cell migration and tube formation capacities, and reduced cell adhesiveness of EPCs from CAD patients., Conclusions: Endocan might be a novel prognostic indicator, mechanistic mediator, and potential therapeutic target for clinical CAD., (© 2024. The Author(s).)

Published
2024
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18. ELUCIDATE Trial: A Single-Center Randomized Controlled Study.

Author

Lin JL, Liu SC, Liu TF, Chuang SM, Huang CT, Chen YJ, Lee CC, Chien MN, Hou CJ, Yeh HI, Chiang CE, and Hung CL

Subjects
Humans, Male, Female, Middle Aged, Prospective Studies, Aged, Treatment Outcome, Echocardiography, Natriuretic Peptide, Brain blood, Time Factors, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 complications, Benzhydryl Compounds therapeutic use, Glucosides therapeutic use, Sodium-Glucose Transporter 2 Inhibitors therapeutic use, Ventricular Remodeling drug effects, Ventricular Function, Left drug effects, Stroke Volume drug effects, Peptide Fragments
Abstract

Background: Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, is an epochal oral antidiabetic drug that improves cardiorenal outcomes. However, the effect of early dapagliflozin intervention on left ventricular (LV) remodeling in patients with type 2 diabetes free from cardiovascular disease remains unclear., Methods and Results: The ELUCIDATE trial was a prospective, open-label, randomized, active-controlled study that enrolled 76 patients with asymptomatic type 2 diabetes with LV ejection fraction ≥50%, randomized to the dapagliflozin 10 mg/day add-on or standard-of-care group. Speckle-tracking echocardiography-based measurements of the cardiac global longitudinal strain were performed at baseline and 24 weeks after treatment initiation. Patients who received dapagliflozin had a greater reduction in LV dimension (1.68 mm [95% CI, 0.53-2.84]; P =0.005), LV end-systolic volume (5.51 mL [95% CI, 0.86-10.17]; P =0.021), and LV mass index (4.25 g/m 2.7 [95% CI, 2.42-6.09]; P <0.0001) compared with standard of care in absolute mean differences. Dapagliflozin add-on therapy led to a significant LV global longitudinal strain increment (0.74% [95% CI, 1.00-0.49]; P <0.0001) and improved LV systolic and early diastolic strain rates (0.27/s [95% CI, 0.17-0.60]; and 0.11/s [95% CI, 0.06-0.16], respectively; both P <0.0001) but not in global circumferential strain. No significant changes were found in insulin resistance, NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, or other biomarkers at 6 months after the dapagliflozin administration., Conclusions: Dapagliflozin add-on therapy could lead to more favorable cardiac remodeling accompanied by enhanced cardiac mechanical function among patients with asymptomatic type 2 diabetes. Our findings provide evidence of the efficacy of dapagliflozin use for the primary prevention of diabetic cardiomyopathy., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03871621.

Published
2024
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19. Effect of Standardized Bundle Care and Bundle Compliance on Reducing Surgical Site Infections: A Pragmatic Retrospective Cohort Study.

Author

Chien YS, Chen HT, Chiang HT, Luo TS, Yeh HI, Sheu JC, and Li JY

Subjects
Humans, Retrospective Studies, Anti-Bacterial Agents, Infection Control methods, Surgical Wound Infection epidemiology, Surgical Wound Infection prevention & control, Surgical Wound Infection etiology, Patient Care Bundles adverse effects, Patient Care Bundles methods
Abstract

BACKGROUND Care bundles for infection control consist of a set of evidence-based measures to prevent infections. This retrospective study aimed to compare surgical site infections (SSIs) from a single hospital surveillance system between 2017 and 2020, before and after implementing a standardized care bundle across specialties in 2019. It also aimed to assess whether bundle compliance affects the rate of SSIs. MATERIAL AND METHODS A care bundle consisting of 4 components (peri-operative antibiotics use, peri-operative glycemic control, pre-operative skin preparation, and maintaining intra-operative body temperature) was launched in 2019. We compared the incidence rates of SSIs, standardized infection ratio (SIR), and clinical outcomes of surgical procedures enrolled in the surveillance system before and after introducing the bundle care. The level of bundle compliance, defined as the number of fully implemented bundle components, was evaluated. RESULTS We included 6059 procedures, with 2010 in the pre-bundle group and 4049 in the post-bundle group. Incidence rates of SSIs (1.7% vs 1.0%, P=0.013) and SIR (0.8 vs 1.48, P<0.01) were significantly lower in the post-bundle group. The incidence of SSIs was significantly lower when all bundle components were fully adhered to, compared with when only half of the components were adhered to (0.3% vs 4.0%, P<0.01). CONCLUSIONS SSIs decreased significantly after the application of a standardized care bundle for surgical procedures across specialties. Full adherence to all bundle components was the key to effectively reducing the risk of surgical site infections.

Published
2024
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20. Preclinical systolic dysfunction relating to ankle-brachial index among high-risk PAD population with preserved left ventricular ejection fraction.

Author

Lin YH, Sung KT, Tsai CT, Lai YH, Lo CI, Yu FC, Lan WR, Hung TC, Kuo JY, Hou CJ, Yen CH, Peng MC, Yeh HI, Wu MT, and Hung CL

Subjects
Humans, Stroke Volume, Ventricular Function, Left, Retrospective Studies, Ankle Brachial Index, Risk Factors, Prognosis, Heart Failure, Peripheral Arterial Disease, Ventricular Dysfunction, Left
Abstract

Peripheral artery disease (PAD) shares common clinical risk factors, for example, endothelial dysfunction, with preserved ejection fraction (LVEF) heart failure (HFpEF). Whether PAD is associated with preclinical systolic dysfunction and higher HF risk among individuals presenting preserved LVEF remains uncertain. We retrospectively included outpatients with at least one known or established cardiovascular (CV) risk factor with LVEF ≥ 50%. Patients were categorized into high risk and low risk of developing PAD (PAD vs Non-PAD) by ankle-brachial index (ABI) (≤ 0.90 or > 1.4) and further stratified based on their history of HFpEF (HFpEF vs. Non-HFpEF), resulting in the formation of four distinct strata. Preclinical systolic dysfunction was defined using dedicated speckle-tracking algorithm. A total of 2130 consecutive patients were enrolled in the study, with a median follow-up of 4.4 years. The analysis revealed a higher prevalence of high risk of developing PAD in patients with HFpEF compared to those without HFpEF (25.1% vs. 9.4%). Both high risk of developing PAD and HFpEF were independently associated with preclinical systolic dysfunction (global longitudinal strain, GLS ≥ - 18%) (odds ratio, OR: 1.38; 95% confidence interval, CI: 1.03-1.86). In comparison to patients at low risk of developing PAD without HFpEF (Non-PAD/Non-HFpEF group), those categorized as having a high risk of developing PAD with HFpEF (PAD/HFpEF group) exhibited the most impaired GLS and a heightened susceptibility to heart failure hospitalization (hazard ratio, HR: 6.51; 95% CI: 4.43-9.55), a twofold increased risk of all-cause mortality (HR: 2.01; 95% CI: 1.17-3.38), cardiovascular mortality (HR: 2.44; 95% CI: 1.08-5.51), and non-cardiovascular mortality (HR: 1.78; 95% CI: 0.82-3.84). A high risk of developing PAD was strongly linked to impaired preclinical systolic function and an increased likelihood for subsequent hospitalization for HF, all-cause mortality, CV mortality and non-CV mortality. There is a clear need for preventive strategies aimed at reducing hospitalizations for HF and mortality in this high-risk population., (© 2024. The Author(s).)

Published
2024
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21. Fatty acid-binding protein-3 and renal function decline in patients with chronic coronary syndrome.

Author

Yeh JT, Huang CC, Leu HB, Yin WH, Tseng WK, Wu YW, Lin TH, Yeh HI, Chang KC, Wang JH, Wu CC, and Chen JW

Subjects
Humans, Heart, Kidney, Prospective Studies, Syndrome, Coronary Artery Disease, Renal Insufficiency, Chronic complications, Renal Insufficiency, Chronic diagnosis, Fatty Acid Binding Protein 3
Abstract

Background: Renal dysfunction is common in patients with coronary artery disease. Due to the shared vascular pathogenesis between the two conditions, novel biomarkers such as the fatty acid-binding protein-3 (FABP-3) have been proposed for diagnosis and prognosis prediction. This multicentre prospective cohort study investigates the association between FABP-3 and renal dysfunction., Hypothesis: We hypothesized that higher FABP-3 levels are correlated to worse renal outcome., Methods: Patients with chronic coronary syndrome were classified into three groups based on the initial serum FABP-3 levels. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used to estimate the patient's renal function. Renal events were defined as >25% and >50% decline in estimated glomerular filtration rate (eGFR). Cox multivariable regression was employed to delineate the correlation between FABP-3 and renal dysfunction., Results: A total of 1606 subjects were included. During a mean follow-up of 35.9 months, there were 239 patients with eGFR >25% reduction and 60 patients with >50% reduction. In the Kaplan-Meier survival curve and log-rank test, increased levels of FABP-3 were significantly correlated with eGFR >25% reduction (p < .001) and >50% reduction (p < .001). Multivariate Cox regression model revealed that subjects with higher FABP-3 exhibited a greater risk of eGFR >25% reduction (Group 2: hazard ratio [HR] = 2.328, 95% confidence interval [CI] = 1.521-3.562, p < .001; Group 3: HR = 3.054, 95% CI = 1.952-4.776, p < .001) and >50% reduction (Group 3: HR = 4.838, 95% CI = 1.722-13.591, p = .003)., Conclusions: Serum FABP-3 may serve as a novel biomarker to predict eGFR decline in patients with chronic coronary syndrome., (© 2024 The Authors. Clinical Cardiology published by Wiley Periodicals, LLC.)

Published
2024
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22. CFTR Modulators: From Mechanism to Targeted Therapeutics.

Author

Yeh HI, Sutcliffe KJ, Sheppard DN, and Hwang TC

Subjects
Humans, Mutation, Signal Transduction, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Cystic Fibrosis Transmembrane Conductance Regulator metabolism, Cystic Fibrosis drug therapy, Cystic Fibrosis genetics
Abstract

People with cystic fibrosis (CF) suffer from a multi-organ disorder caused by loss-of-function variants in the gene encoding the epithelial anion channel cystic fibrosis transmembrane conductance regulator (CFTR). Tremendous progress has been made in both basic and clinical sciences over the past three decades since the identification of the CFTR gene. Over 90% of people with CF now have access to therapies targeting dysfunctional CFTR. This success was made possible by numerous studies in the field that incrementally paved the way for the development of small molecules known as CFTR modulators. The advent of CFTR modulators transformed this life-threatening illness into a treatable disease by directly binding to the CFTR protein and correcting defects induced by pathogenic variants. In this chapter, we trace the trajectory of structural and functional studies that brought CF therapies from bench to bedside, with an emphasis on mechanistic understanding of CFTR modulators., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Published
2024
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23. Serum Albumin was Associated with a Long Term Cardiovascular Mortality among Elderly Patients with Stable Coronary Artery Disease.

Author

Cheng CW, Lee CW, Chien SC, Yeh HI, and Chen CY

Abstract

Background: Serum albumin (SA), a multifunction protein, contributes to maintaining a variety of physiological functions. Studies have linked SA to atherosclerosis with possible mechanisms including a response to inflammation. The contribution of albumin to cardiovascular (CV) mortality in elderly patients with stable coronary artery disease (CAD) remains unclear., Methods: We investigated 321 elderly patients with stable CAD undergoing coronary angiography between 2003 and 2006. CV mortality data were obtained from the National Registry of Deaths in Taiwan. CV mortality included deaths attributable to ischemic heart disease, congestive heart disease, and stroke. The association between baseline SA and CV mortality was assessed using a Cox model and Fine-Gray model when non-CV mortality was considered a competing event., Results: During a median follow-up of 97 months, 39 (12.1%) participants died from CV disease and 76 (23.7%) died from non-CV diseases. After adjusting for covariates, patients in the SA ≥ 3.75 g/dL group had a lower frequency of CV mortality compared with those in the SA < 3.75 g/dL group [hazard ratio (HR): 0.20; 95% confidence interval (CI): 0.08-0.49; p < 0.001]. Similarly, compared to the participants with non-CV mortality, the SA ≥ 3.75 g/dL group had a lower frequency of CV mortality compared with the SA < 3.75 g/dL group (subdistribution HR: 0.27; 95% CI: 0.11-0.65; p < 0.001) in adjusted competing risk models., Conclusions: A SA level ≥ 3.75 g/dL at admission was associated with decreased long-term CV mortality and may be useful for risk prediction in elderly patients with stable CAD., Competing Interests: The authors have no conflicts of interest to declare.

Published
2024
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24. Discriminative Ability of Left Ventricular Strain in Mildly Reduced Ejection Fraction Heart Failure.

Author

Chung FP, Chao TF, Lee AS, Sung KT, Huang WH, Hsiao CC, Su CH, Yang LT, Chen YJ, Chen YY, Liao JN, Jia-Yin Hou C, Yeh HI, and Hung CL

Abstract

Background: Left ventricular (LV) systolic strain is presumably a more sensitive myocardial indicator than LV ejection fraction (LVEF). Data regarding the use of LV strain in clinical risk stratification and in identifying angiotensin receptor-neprilysin inhibitor (ARNi) responders remain scarce in heart failure with mildly reduced ejection fraction (HFmrEF)., Objectives: The authors aimed to examine whether assessing LV strain may provide prognostic insight beyond LVEF and help discriminate the therapeutic efficacy of ARNi in HFmrEF patients., Methods: LVEF and LV strain were quantified among 1,075 first-time hospitalized HFmrEF patients (mean age: 68.1 ± 15.1 years, 40% female). The MAGGIC (Meta-analysis Global Group in Chronic Heart Failure) risk score and its components were calculated. A Cox proportional hazard model was constructed for time-to-event analysis. Restrictive cubic spline curves were used to model the therapeutic effects of ARNi against renin-angiotensin system inhibitor according to baseline LVEF or LV strain., Results: LV strain showed a statistically significant inverse association with MAGGIC cardiac risk (coefficient: -0.14, P  < 0.001). LV strain was independently associated with clinical outcomes after accounting for LVEF. MAGGIC-LV strain strata outperformed MAGGIC-LVEF strata in overall survival (Harrell's C-index: 0.71 and 0.56, P for difference <0.001; category-free net reclassification index: 0.44, P  < 0.001). Lower LV strain but not LVEF consistently showed the beneficial therapeutic effects of ARNi against renin-angiotensin system inhibitor by Cox models and restrictive cubic spline (all P interaction  <0.05)., Conclusions: Among HFmrEF patients, LV strain may serve as an attractive systolic marker and provide a better prognostic and therapeutic discriminative measure for ARNi treatment than conventional LVEF., Competing Interests: This research was supported by the Ministry of Science and Technology (Taiwan) (MOST 109-2314-B-715-008, and MOST 110-2314-B-715-009-MY1, 110-2314-B-195-020, 111-2314-B-038-087, 111-2314-B-715-013, 111-2622-8-002-024-SB, 112-2314-B-715-008-MY3). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.PERSPECTIVESCOMPETENCY IN CLINICAL KNOWLEDGE: HFmrEF (LVEF 40%-50%), a HF phenotype with intermediate clinical features between HFrEF and HFpEF, remains an underexplored clinical HF phenotype with poorly defined myocardial characterization. According to contemporary HF management guideline, ARNi along with most guideline recommended medications for HFrEF were given Class IIb recommendations for HFmrEF except for sodium-glucose cotransporter-2 inhibitors (as a Class IIa recommendation). TRANSLATIONAL OUTLOOK: LV strain likely provides better insights on clinical comorbid conditions and outperforms LVEF in risk stratification as potentially new “morphofunctional phenotypes” defined by LV strain measure. Additionally, the clinical implementation of LV strain also supplements the current knowledge gap on sacubitril/valsartan use within a HFmrEF in clinical practice., (© 2023 The Authors.)

Published
2023
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25. Inflammation and renal function decline in chronic coronary syndrome: a prospective multicenter cohort study.

Author

Kao TW, Huang CC, Leu HB, Yin WH, Tseng WK, Wu YW, Lin TH, Yeh HI, Chang KC, Wang JH, Wu CC, and Chen JW

Subjects
Humans, Adiponectin, Prospective Studies, Tumor Necrosis Factor-alpha, Inflammation diagnosis, Biomarkers, Kidney physiology, C-Reactive Protein metabolism, Coronary Artery Disease
Abstract

Background: Renal function decline is a frequently encountered complication in patients with chronic coronary syndrome. Aside from traditional cardiovascular risk factors, the inflammatory burden emerged as the novel phenotype that compromised renal prognosis in such population., Methods: A cohort with chronic coronary syndrome was enrolled to investigate the association between inflammatory status and renal dysfunction. Levels of inflammatory markers, including high-sensitivity C-reactive protein (hs-CRP), tumour necrosis factor-α (TNF-α), adiponectin, matrix metalloproteinase-9, interleukin-6, lipoprotein-associated phospholipase A2, were assessed. Renal event was defined as > 25% decline in estimated glomerular filtration rate (eGFR). Inflammatory scores were calculated based on the aggregate of hs-CRP, TNF-α, and adiponectin levels., Results: Among the 850 enrolled subjects, 145 patients sustained a renal event during an averaged 3.5 years follow-up. Multivariate analysis with Cox regression suggested elevations in hs-CRP, TNF-α, and adiponectin levels were independent risk factors for the occurrence of a renal event. Whereas, Kaplan-Meier curve illustrated significant correlation between high TNF-α (P = 0.005), adiponectin (P < 0.001), but not hs-CRP (P = 0.092), and eGFR decline. The aggregative effect of these biomarkers was also distinctly correlated with renal events (score 2: P = 0.042; score 3: P < 0.001)., Conclusions: Inflammatory burden was associated with eGFR decline in patients with chronic coronary syndrome., (© 2023. The Author(s).)

Published
2023
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26. Machine Learning Models for ASCVD Risk Prediction in an Asian Population - How to Validate the Model is Important.

Author

Hsiao YC, Kuo CY, Lin FJ, Wu YW, Lin TH, Yeh HI, Chen JW, and Wu CC

Abstract

Introduction: Atherosclerotic cardiovascular disease (ASCVD) is prevalent worldwide including Taiwan, however widely accepted tools to assess the risk of ASCVD are lacking in Taiwan. Machine learning models are potentially useful for risk evaluation. In this study we used two cohorts to test the feasibility of machine learning with transfer learning for developing an ASCVD risk prediction model in Taiwan., Methods: Two multi-center observational registry cohorts, T-SPARCLE and T-PPARCLE were used in this study. The variables selected were based on European, U.S. and Asian guidelines. Both registries recorded the ASCVD outcomes of the patients. Ten-fold validation and temporal validation methods were used to evaluate the performance of the binary classification analysis [prediction of major adverse cardiovascular (CV) events in one year]. Time-to-event analyses were also performed., Results: In the binary classification analysis, eXtreme Gradient Boosting (XGBoost) and random forest had the best performance, with areas under the receiver operating characteristic curve (AUC-ROC) of 0.72 (0.68-0.76) and 0.73 (0.69-0.77), respectively, although it was not significantly better than other models. Temporal validation was also performed, and the data showed significant differences in the distribution of various features and event rate. The AUC-ROC of XGBoost dropped to 0.66 (0.59-0.73), while that of random forest dropped to 0.69 (0.62-0.76) in the temporal validation method, and the performance also became numerically worse than that of the logistic regression model. In the time-to-event analysis, most models had a concordance index of around 0.70., Conclusions: Machine learning models with appropriate transfer learning may be a useful tool for the development of CV risk prediction models and may help improve patient care in the future., Competing Interests: All the authors declare no conflict of interest.

Published
2023
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27. Pannexin 1 Modulates Angiogenic Activities of Human Endothelial Colony-Forming Cells Through IGF-1 Mechanism and Is a Marker of Senescence.

Author

Tien TY, Wu YJ, Su CH, Hsieh CL, Wang BJ, Lee YN, Su Y, and Yeh HI

Subjects
Animals, Humans, Mice, Calcium metabolism, Cells, Cultured, Cellular Senescence, Connexins genetics, Connexins metabolism, Cyclin-Dependent Kinases metabolism, Cyclin-Dependent Kinases pharmacology, Ischemia metabolism, Nerve Tissue Proteins metabolism, Insulin-Like Growth Factor I, Tumor Suppressor Protein p53 genetics
Abstract

Background: We examined the role of Panxs (pannexins) in human endothelial progenitor cell (EPC) senescence., Methods: Young and replication-induced senescent endothelial colony-forming cells (ECFCs) derived from human circulating EPCs were used to examine cellular activities and senescence-associated indicators after transfection of short interference RNA specific to Panx1 or lentivirus-mediated Panx1 overexpression. Hind limb ischemia mice were used as in vivo angiogenesis model. Protein and phospho-kinase arrays were used to determine underlying mechanisms., Results: Panx1 was the predominant Panx isoform in human ECFCs and upregulated in both replication-induced senescent ECFCs and circulating EPCs from aged mice and humans. Cellular activities of the young ECFCs were enhanced by Panx1 downregulation but attenuated by its upregulation. In addition, reduction of Panx1 in the senescent ECFCs could rejuvenate cellular activities with reduced senescence-associated indicators, including senescence-associated β-galactosidase activity, p16 INK4a (cyclin-dependent kinase inhibitor 2A), p21 (cyclin-dependent kinase inhibitor 1), acetyl-p53 (tumor protein P53), and phospho-histone H2A.X (histone family member X). In mouse ischemic hind limbs injected senescent ECFCs, blood perfusion ratio, salvaged limb outcome, and capillary density were all improved by Panx1 knockdown. IGF-1 (insulin-like growth factor 1) was significantly increased in the supernatant from senescent ECFCs after Panx1 knockdown. The enhanced activities and paracrine effects of Panx1 knockdown senescent ECFCs were completely inhibited by anti-IGF-1 antibodies. FAK (focal adhesion kinase), ERK (extracellular signal-regulated kinase), and STAT3 (signal transducer and activator of transcription 3) were activated in senescent ECFCs with Panx1 knockdown, in which the intracellular calcium level was reduced, and the activation was inhibited by supplemented calcium. The increased IGF-1 in Panx1-knockdown ECFCs was abrogated, respectively, by inhibitors of FAK (PF562271), ERK (U0126), and STAT3 (NSC74859) and supplemented calcium., Conclusions: Panx1 expression is upregulated in human ECFCs/EPCs with replication-induced senescence and during aging. Angiogenic potential of senescent ECFCs is improved by Panx1 reduction through increased IGF-1 production via activation of the FAK-ERK axis following calcium influx reduction. Our findings provide new strategies to evaluate EPC activities and rejuvenate senescent EPCs for therapeutic angiogenesis., Competing Interests: Disclosures None.

Published
2023
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28. Penalized Model-Based Unsupervised Phenomapping Unravels Distinctive HFrEF Phenotypes With Improved Outcomes Discrimination From Sacubitril/Valsartan Treatment Independent of MAGGIC Score.

Author

Sung KT, Chang HY, Hsu NW, Huang WH, Lin YH, Yun CH, Hsiao CC, Hsu CY, Tsai SY, Chen YJ, Tsai CT, Su CH, Hung TC, Hou CJ, Yeh HI, and Hung CL

Subjects
Humans, Antihypertensive Agents, Stroke Volume, Valsartan therapeutic use, Ventricular Function, Left, Male, Female, Heart Failure drug therapy
Abstract

Background The angiotensin receptor-neprilysin inhibitor (LCZ696) has emerged as a promising pharmacological intervention against renin-angiotensin system inhibitor in reduced ejection fraction heart failure (HFrEF). Whether the therapeutic benefits may vary among heterogeneous HFrEF subgroups remains unknown. Methods and Results This study comprised a pooled 2-center analysis including 1103 patients with symptomatic HFrEF with LCZ696 use and another 1103 independent HFrEF control cohort (with renin-angiotensin system inhibitor use) matched for age, sex, left ventricular ejection fraction, and comorbidity conditions. Three main distinct phenogroup clusterings were identified from unsupervised machine learning using 29 clinical variables: phenogroup 1 (youngest, relatively lower diabetes prevalence, highest glomerular filtration rate with largest left ventricular size and left ventricular wall stress); phenogroup 2 (oldest, lean, highest diabetes and vascular diseases prevalence, lowest highest glomerular filtration rate with smallest left ventricular size and mass), and phenogroup 3 (lowest clinical comorbidity with largest left ventricular mass and highest hypertrophy prevalence). During the median 1.74-year follow-up, phenogroup assignment provided improved prognostic discrimination beyond Meta-Analysis Global Group in Chronic Heart Failure risk score risk score (all net reclassification index P <0.05) with overall good calibrations. While phenogroup 1 showed overall best clinical outcomes, phenogroup 2 demonstrated highest cardiovascular death and worst renal end point, with phenogroup 3 having the highest all-cause death rate and HF hospitalization among groups, respectively. These findings were broadly consistent when compared with the renin-angiotensin system inhibitor control as reference group. Conclusions Phenomapping provided novel insights on unique characteristics and cardiac features among patients with HFrEF with sacubitril/valsartan treatment. These findings further showed potentiality in identifying potential sacubitril/valsartan responders and nonresponders with improved outcome discrimination among patients with HFrEF beyond clinical scoring.

Published
2023
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29. Real-World Analyses of the Treatment Conditions in Patients Initiating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitor in Taiwan.

Author

Lin PL, Wu YW, Lin CF, Yeh HI, Chang WT, Charng MJ, Huang PH, Lin CC, Lin TH, Lin WW, Hsieh IC, Kuo FY, Chen CP, and Li YH

Subjects
Humans, Male, Adult, Middle Aged, Aged, Cholesterol, LDL, Antibodies, Monoclonal therapeutic use, Retrospective Studies, Taiwan epidemiology, Subtilisins, Proprotein Convertase 9, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use
Abstract

Aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor is a powerful low density lipoprotein cholesterol (LDL-C)-lowering therapy, but this drug is expensive. This study aimed to describe the real-world treatment conditions in patients initiating PCSK9 inhibitor in Taiwan., Methods: This was a multicenter, retrospective, and observational study. The clinical characteristics, baseline lipid-lowering therapy, and changes in the lipid profile of patients receiving PCSK9 inhibitor treatment were obtained from 11 major teaching hospitals in Taiwan., Results: A total of 296 patients (age 57±13 years, male 73%) who received PCSK9 inhibitor treatments (73.3% alirocumab and 26.7% evolocumab) from 2017 to 2021 were included. Among the patients, 62.8% had history of coronary artery disease, and 27.7% had myocardial infarction. High intensity statin (HIS) monotherapy or HIS＋ezetimibe treatment was used in 32.5% when initiating PCSK9 inhibitor treatment. Among alirocumab users, 21.2% received 75 mg every 3 to 4 weeks, whereas among evolocumab users, 8.9% received 140 mg every 3 to 4 weeks. Almost all the non-standard-dosing PCSK9 inhibitors were paid by the patients themselves but were not reimbursed by the Taiwan National Health Insurance. Overall, the LDL-C levels at baseline and 12 weeks after treatment were 147.4±67.4 and 69.7±58.2 mg/dL (p＜0.01), corresponding to a 49.6%±31.8% LDL-C reduction., Conclusions: In the real-world practice in Taiwan, the LDL-C reduction efficacy of PCSK9 inhibitors was slightly lower than that reported in the clinical trials. The use of non-standard-dosing PCSK9 inhibitors was not uncommon in Taiwan.

Published
2023
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30. Rationale and Study Design of the TSOC-Fully Organized Registry for the Management of Symptomatic ACS Study (T-FORMOSA Study).

Author

Chao TH, Yeh HI, Shyu KG, Lai CH, Lee JK, Huang CC, Wang JH, Hsieh IC, Tsai CT, Lee WL, Liu PY, Wang TD, Chen WJ, and Hou CJ

Abstract

Background: Successful implementation of practice guidelines has been challenging in the treatment of acute coronary syndrome (ACS), leaving room for improvement. A nationwide registry can provide more information than that recorded in the National Health Insurance Research Database (NHIRD)., Methods: We conducted a prospective, nationwide, multi-center ACS full spectrum registry involving 3600 patients admitted to hospitals within 24 hours of the onset of myocardial infarction with ST-segment elevation or ACS without ST-segment elevation. In total, 41 sites including medical centers and regional hospitals were selected across Taiwan. The data for each patient are collected at 3 time points for the main study: during hospitalization, 6 months, and 12 months after the discharge. The milestone for first patient in was reached on January 7, 2022, and complete enrollment is expected before October 2023. The primary aims of the main study are to determine the degree of guideline-directed medical therapies and to identify prognostic predictors associated with 1-year composite outcomes, including death, myocardial infarction, stroke, and unplanned coronary revascularization in ACS patients. Thereafter, the patient data will be analyzed every 3 to 5 years for up to 20 years after discharge using the NHIRD in the extended study., Conclusions: We hypothesized that a greater increase in the implementation of guideline-directed medical therapies can be observed. The results of the current study will add new and important information regarding a broad spectrum of ACS to drive further investigations., Competing Interests: Ting-Hsing Chao have been on the speaker bureau for AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Novartis, Pfizer, Sanofi, Tanabe, Orient EuroPharma, and TSH biopharm. Tzung-Dau Wang has been on the speaker bureau for AstraZeneca, Daiichi-Sankyo, Medtronic, Novartis, Pfizer, and Omron. All other authors declare no potential conflict of interest in relation to this work.

Published
2023
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32. A Common East Asian aldehyde dehydrogenase 2*2 variant promotes ventricular arrhythmia with chronic light-to-moderate alcohol use in mice.

Author

Lee AS, Sung YL, Pan SH, Sung KT, Su CH, Ding SL, Lu YJ, Hsieh CL, Chen YF, Liu CC, Chen WY, Chen XR, Chung FP, Wang SW, Chen CH, Mochly-Rosen D, Hung CL, Yeh HI, and Lin SF

Subjects
Animals, Humans, Mice, Arrhythmias, Cardiac genetics, East Asian People, Mice, Transgenic, Aldehyde Dehydrogenase, Mitochondrial genetics, Ethanol toxicity, Long QT Syndrome chemically induced
Abstract

Chronic heavy alcohol use is associated with lethal arrhythmias. Whether common East Asian-specific aldehyde dehydrogenase deficiency (ALDH2*2) contributes to arrhythmogenesis caused by low level alcohol use remains unclear. Here we show 59 habitual alcohol users carrying ALDH2 rs671 have longer QT interval (corrected) and higher ventricular tachyarrhythmia events compared with 137 ALDH2 wild-type (Wt) habitual alcohol users and 57 alcohol non-users. Notably, we observe QT prolongation and a higher risk of premature ventricular contractions among human ALDH2 variants showing habitual light-to-moderate alcohol consumption. We recapitulate a human electrophysiological QT prolongation phenotype using a mouse ALDH2*2 knock-in (KI) model treated with 4% ethanol, which shows markedly reduced total amount of connexin43 albeit increased lateralization accompanied by markedly downregulated sarcolemmal Nav1.5, Kv1.4 and Kv4.2 expressions compared to EtOH-treated Wt mice. Whole-cell patch-clamps reveal a more pronounced action potential prolongation in EtOH-treated ALDH2*2 KI mice. By programmed electrical stimulation, rotors are only provokable in EtOH-treated ALDH2*2 KI mice along with higher number and duration of ventricular arrhythmia episodes. The present research helps formulate safe alcohol drinking guideline for ALDH2 deficient population and develop novel protective agents for these subjects., (© 2023. The Author(s).)

Published
2023
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33. Relation of early-stage renal insufficiency and cardiac structure and function in a large population of asymptomatic Asians: a cross-sectional cohort analysis.

Author

Wu PC, Sung KT, Lin JL, Hung TC, Lai YH, Su CH, Yeh HI, Wu CJ, and Hung CL

Abstract

Background: Few studies have addressed early-stage kidney disease and preclinical cardiac structural and functional abnormalities from a large-scale Asian population. Further, the extent to which measures of myocardial function and whether these associations may vary by testing various formulas of renal insufficiency remains largely unexplored., Objective: To explore the associations among renal function, proteinuria, and left ventricular (LV) structural and diastolic functional alterations., Design: A cross-sectional, retrospective cohort study., Setting: Registered data from a cardiovascular health screening program at MacKay Memorial Hospital from June 2009 to December 2012., Participants: Asymptomatic individuals., Measurements: Renal function was evaluated in terms of estimated glomerular filtration rate (eGFR) by both MDRD and CKD-EPI formulas and severity of proteinuria, which were further related to cardiac structure, diastolic function (including LV e' by tissue Doppler), and circulating N-terminal pro-brain natriuretic peptide (NT-proBNP) level., Results: Among 4942 participants (65.8% men, mean age 49.4 ± 11.2 years), the mean CKD-EPI/MDRD eGFR was 90.6 ± 15.7 and 88.5 ± 16.9 ml/min/1.73m 2 , respectively. Lower eGFR, estimated either by the MDRD or CKD-EPI method, and higher proteinuria were significantly associated with lower LV e' and higher NT-proBNP (all p<0.05) even after adjusting for clinical covariates. In general, lower eGFR estimated by CKD-EPI and MDRD displayed similar impacts on worsening e' and NT-proBNP, rather than E/e', in multivariate models. Finally, lower LV e' or higher composite diastolic score, rather than E/e', demonstrated remarkable interaction with eGFR level estimated by either CKD-EPI or MDRD on circulating NT-proBNP level (p interaction < 0.05)., Limitations: Proteinuria was estimated using a urine dipstick rather than more accurately by the urine protein-to-creatinine ratio. Also, pertaining drug history and clinical hard outcomes were lacking., Conclusion: Both clinical estimate of renal insufficiency by eGFR or proteinuria, even in a relatively early clinical stage, were tightly linked to impaired cardiac diastolic relaxation and circulating NT-proBNP level. Elevation of NT-proBNP with worsening renal function may be influenced by impaired myocardial relaxation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer Y-WW declared a past co-authorship with the authors H-IY, C-JW, and C-LH to the handling editor., (Copyright © 2023 Wu, Sung, Lin, Hung, Lai, Su, Yeh, Wu and Hung.)

Published
2023
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34. 2023 Consensus of Taiwan Society of Cardiology on the Pharmacological Treatment of Chronic Heart Failure.

Author

Chiang CE, Hung CL, Wu YW, Lin TH, Ueng KC, Sung SH, Wu CK, Chao TH, Lin HJ, Lin YH, Huang JL, Chen MYC, Lin PL, Chao TF, Cheng HM, Liu ME, Wang TD, Yeh HI, Li YH, Liu PY, Yin WH, Hsieh IC, Wang CC, Chen CH, Chu PH, Lin SJ, Yeh SJ, Lin JL, Hwang JJ, Hung HF, Chen WJ, and Hou CJ

Abstract

The prevalence of heart failure is increasing, causing a tremendous burden on health care systems around the world. Although mortality rate of heart failure has been significantly reduced by several effective agents in the past 3 decades, yet it remains high in observational studies. More recently, several new classes of drugs emerged with significant efficacy in reducing mortality and hospitalization in chronic heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). To integrate these effective therapies and prioritize them in the management of Asian patients, Taiwan Society of Cardiology has recently appointed a working group to formulate a consensus of pharmacological treatment in patients with chronic heart failure. Based on most updated information, this consensus provides rationales for prioritization, rapid sequencing, and in-hospital initiation of both foundational and additional therapies for patients with chronic heart failure., Competing Interests: Dr. C.-E. Chiang has received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Menarini, MSD, Novartis, Pfizer, and Sanofi. Dr. C.-L. Hung has received honorarium from Astrazeneca, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Pfizer, and Sanofi. Dr. Y.-W. Wu has received honorarium from AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, MSD, Novartis, Pfizer, Sanofi, and Takeda. Dr. T.-H. Lin has received honorarium from Astrazeneca, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, MSD, Novartis, Pfizer, Sanofi, Bayer, Viatris, Menariri, Tanabe, and Takeda. Dr. K.-C. Ueng has received honorarium from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, Merck Sharp and Dohme, Novartis, Pfizer, and Sanofi. Dr. S.-H. Sung has received honorarium from Astrazeneca, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, Novartis, Pfizer, Sanofi, Abbott, and Edward. Dr. C.-K. Wu has received honorarium from AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, Novartis, Pfizer, Sanofi, and Abbott. Dr. T.-H. Chao has received honorarium from Bayer, AstraZeneca, Eli Lilly, Boehringer Ingelheim, Daiichi-Sankyo, Tanabe Taiwan, and Novartis. Dr. Y.-H. Lin has received honorarium from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, MSD, Novartis, Pfizer, and Sanofi. Dr. M. YC Chen has received honorarium from AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, and Pfizer. Dr. P.-L. Lin has received honorarium from AstraZeneca, Abbott, Boehringer Ingelheim, Bayer, Daiichi-Sankyo, Eli Lilly, Novartis, Novo Nordisk, Pfizer, and Sanofi. Dr. T.-F. Chao has received speaker honorarium from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, Novartis, Pfizer, and Sanofi. Dr. H.-M. Cheng has received honorarium from AstraZeneca, Pfizer, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Novartis, SERVIER, Sanofi, Takeda, and Eli Lilly. Dr. M.-E. Liu has received honorarium from Abbott, AstraZeneca, Bayer, Biotronik, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, Medtronic, MSD, Novartis, Pfizer, and Sanofi. Dr. H.-I. Yeh has received honorarium from AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, MSD, Novartis, Novo Nordisk, Pfizer, and Sanofi. Dr. Y.-H. Li has received honorarium from AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, Novartis, Pfizer, and Sanofi. Dr. I.-C. Hsieh has received honorarium from AstraZeneca, Boehringer Ingelheim, Novartis, Bayer, MSD, Sanofi, Daiichi Sankyo, Pfizer, and Eli Lilly. Dr. C.-C. Wang has received honorarium from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Novartis, and Pfizer. Dr. C.-H. Chen reports honoraria from Novartis and Daiichi Sankyo. Dr. P.-H. Chu has received honorarium from AstraZeneca. Dr. S.-J. Yeh has received honorarium from Tanabe. Dr. W.-J. Chen has received honorarium from Astrazeneca, Boehringer Ingelheim, Daiichi-Sankyo, MSD, Novartis, Pfizer, and Sanofi. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Published
2023
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35. Personalized Management for Heart Failure with Preserved Ejection Fraction.

Author

Lin CY, Sung HY, Chen YJ, Yeh HI, Hou CJ, Tsai CT, and Hung CL

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome with multiple underlying mechanisms and comorbidities that leads to a variety of clinical phenotypes. The identification and characterization of these phenotypes are essential for better understanding the precise pathophysiology of HFpEF, identifying appropriate treatment strategies, and improving patient outcomes. Despite accumulating data showing the potentiality of artificial intelligence (AI)-based phenotyping using clinical, biomarker, and imaging information from multiple dimensions in HFpEF management, contemporary guidelines and consensus do not incorporate these in daily practice. In the future, further studies are required to authenticate and substantiate these findings in order to establish a more standardized approach for clinical implementation.

Published
2023
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36. Epicardial electrical heterogeneity after amiodarone treatment increases vulnerability to ventricular arrhythmias under therapeutic hypothermia.

Author

Lin CY, Chang TY, Hu YF, Hsieh YC, Chen YJ, Yeh HI, Lin YJ, Chang SL, Lo LW, Chao TF, Chung FP, Liao JN, Tuan TC, and Chen SA

Subjects
Animals, Swine, Connexin 43 metabolism, Arrhythmias, Cardiac, Heart Ventricles, Amiodarone adverse effects, Hypothermia, Induced adverse effects
Abstract

Background: Amiodarone is commonly used during therapeutic hypothermia (TH) following cardiac arrest due to ventricular arrhythmias. However, electrophysiological changes and proarrhythmic risk after amiodarone treatment have not yet been explored in TH., Methods: Epicardial high-density bi-ventricular mapping was performed in pigs under baseline temperature (BT), TH (32-34°C), and amiodarone treatment during TH. The total activation time (TAT), conduction velocity (CV), local electrogram (LE) duration, and wavefront propagation from pre-specified segments were analyzed during sinus rhythm (SR) or right ventricular (RV) pacing (RVP), along with tissue expression of connexin 43. The vulnerability to ventricular arrhythmias was assessed., Results: Compared to BT, TH increased the global TAT, decreased the CV, and generated heterogeneous electrical substrate during SR and RVP. During TH, the CV reduction and LE duration prolongation were greater in the anterior mid RV than in the other areas, which changed the wavefront propagation in all animals. Compared to TH alone, amiodarone treatment during TH further increased the TAT and LE duration and decreased the CV. Heterogeneous conduction was partially attenuated after amiodarone treatment. After TH and amiodarone treatment, the connexin 43 expression in the anterior mid RV was lower than that in the other areas, compatible with the heterogeneous CV reduction. The animals under TH and amiodarone treatment had a higher incidence of inducible ventricular arrhythmias than those under BT or TH without amiodarone., Conclusion: Electrical heterogeneity during amiodarone treatment and TH was associated with vulnerability to ventricular arrhythmias., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Lin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Published
2023
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37. The clinical significance of osteopontin on the cardiovascular outcomes in patients with stable coronary artery disease.

Author

Cheong KI, Leu HB, Wu CC, Yin WH, Wang JH, Lin TH, Tseng WK, Chang KC, Chu SH, Yeh HI, Chen JW, and Wu YW

Subjects
Humans, Osteopontin, C-Reactive Protein analysis, Prospective Studies, Clinical Relevance, Risk Factors, Treatment Outcome, Coronary Artery Disease therapy, Percutaneous Coronary Intervention, Myocardial Infarction therapy, Heart Failure
Abstract

Background: Osteopontin (OPN) is a noncollagenous matricellular protein which is mainly present in bone matrix. A high OPN level has been associated with heart failure and acute coronary syndrome, however data on patients with chronic coronary syndrome (CCS) are lacking. The present study aimed to evaluate the association between OPN and the prognosis of Taiwanese patients with CCS., Methods: We enrolled participants from the Biosignature Registry, a nationwide prospective cohort study conducted at nine different medical centers throughout Taiwan. The inclusion criteria were participants who had received successful percutaneous coronary intervention at least once previously, and stable under medical therapy for at least 1 month before enrollment. They were followed for at least 72 months. Logistic regression and Cox proportional hazard model were used to investigate the association between OPN and clinical outcomes. The outcomes of this study were the first occurrence of hard cardiovascular events and composite cardiovascular outcomes including cardiovascular mortality, revascularization, hospitalization for acute myocardial infarction (AMI) or heart failure., Results: A total of 666 patients with both hs-CRP and osteopontin measurements were enrolled and followed for 72 months. OPN was correlated positively with AMI-related hospitalization, where the highest tertile (Tertile 3) of baseline OPN had the highest risk of AMI-related hospitalization, which remained significant after multivariate adjustments (HR 3.20, p = 0.017). In contrast, combining OPN and hs-CRP did not improve the prediction of CV outcomes., Conclusion: OPN may be a potentially valuable biomarker in predicting CV outcomes. During 6 years of follow-up period, an OPN level >4810 pg/ml was associated with a significantly higher incidence of AMI-related hospitalization in CCS patients who received successful PCI before the enrollment., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Published
2023
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38. QRS Fragmentation in Preserved Ejection Fraction Heart Failure: Functional Insights, Pathological Correlates, and Prognosis.

Author

Sung KT, Chang SH, Chi PC, Chien SC, Lo CI, Lin CF, Huang WH, Yun CH, Tsai CT, Su CH, Hou CJ, Yeh HI, Tsao CH, Kuo JY, and Hung CL

Subjects
Male, Humans, Electrocardiography methods, Stroke Volume, Prognosis, Heart Failure etiology, Heart Failure, Diastolic, Heart Failure, Systolic
Abstract

Background Fragmented QRS (fQRS) morphology as a surrogate marker of the possible presence of myocardial scarring has been shown to confer a higher risk in patients with reduced ejection fraction heart failure. We aimed to investigate the pathophysiological correlates and prognostic implications of fQRS in patients with heart failure with preserved ejection fraction (HFpEF). Methods and Results We consecutively studied 960 patients with HFpEF (76.4±12.7 years, men: 37.2%). fQRS was assessed using a body surface ECG during hospitalization. QRS morphology was available and classified into 3 categories among 960 subjects with HFpEF as non-fQRS, inferior fQRS, and anterior/lateral fQRS groups. Despite comparable clinical features in most baseline demographics among the 3 fQRS categories, anterior/lateral fQRS showed significantly higher B-type natriuretic peptide/troponin levels (both P <0.001), with both the inferior and anterior/lateral fQRS HFpEF groups demonstrating a higher degree of unfavorable cardiac remodeling, greater extent of myocardial perfusion defect, and slower coronary flow phenomenon (all P <0.05). Patients with anterior/lateral fQRS HFpEF exhibited significantly altered cardiac structure/function and more impaired diastolic indices (all P <0.05). During a median of 657 days follow-up, the presence of anterior/lateral fQRS conferred a doubled HF re-admission risk (adjusted hazard ratio 1.90, P <0.001), with both inferior and anterior/lateral fQRS having a higher risk of cardiovascular and all-cause death (all P <0.05) by using Cox regression models. Conclusions The presence of fQRS in HFpEF was associated with more extensive myocardial perfusion defects and worsened mechanics, which possibly denotes a more severe involvement of cardiac damage. Early recognition in such patients with HFpEF likely benefits from targeted therapeutic interventions.

Published
2023
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39. Association of Major Adverse Cardiac Events and Beta-Blockers in Patients with and without Atherosclerotic Cardiovascular Disease: Long-Term Follow-Up Results of the T-SPARCLE and T-PPARCLE Registry in Taiwan.

Author

Liu PY, Lin FJ, Yeh CF, Hsiao YC, Hsuan CF, Chang WT, Kao HL, Jeng JS, Wu YW, Hsieh IC, Fang CC, Wang KY, Chang KC, Lin TH, Sheu WH, Li YH, Yin WH, Yeh HI, Chen JW, and Wu CC

Abstract

Beta-blockers are widely used, but the benefit is now challenged in patients at risk of atherosclerotic cardiovascular disease (ASCVD) in the present coronary reperfusion era. We aimed to identify the risk factors of a major adverse cardiac event (MACE) and the long-term effect of beta-blockers in two large cohorts in Taiwan. Two prospective observational cohorts, including patients with known atherosclerosis cardiovascular disease (T-SPARCLE) and patients with at least one risk factor of ASCVD but without clinically evident ASCVD (T-PPARCLE), were conducted in Taiwan. The primary endpoint is the time of first occurrence of a MACE (cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, and cardiac arrest with resuscitation). Between December 2009 and November 2014, with a median 2.4 years follow-up, 11,747 eligible patients (6921 and 4826 in T-SPARCLE and T-PPARCLE, respectively) were enrolled. Among them, 273 patients (2.3%) met the primary endpoint. With multivariate Cox PH model analysis, usage of beta-blocker was lower in patients with MACE (42.9% vs. 52.4%, p < 0.01). In patients with ASCVD, beta-blocker usage was associated with lower MACEs (hazard ratio 0.72; p < 0.001), but not in patients without ASCVD. The event-free survival of beta-blocker users remained higher during the follow-up period ( p < 0.005) of ASCVD patients. In conclusion, in ASCVD patients, reduced MACE was associated with beta-blocker usage, and the effect was maintained during a six-year follow-up. Prescribing beta-blockers as secondary prevention is reasonable in the Taiwanese population.

Published
2023
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40. Pulse Wave Analysis Predicts Invasive Hemodynamics in Pre-Capillary Pulmonary Hypertension.

Author

Liu YY, Wu SH, Tsai CT, Sun FJ, Hou CJ, Yeh HI, and Wu YJ

Abstract

Background: We tested the hypothesis that non-invasive pulse wave analysis (PWA)-derived systemic circulation variables can predict invasive hemodynamics of pulmonary circulation and the indicator of right heart function, N-terminal pro-brain natriuretic peptide (NT-proBNP), in patients with precapillary pulmonary hypertension (PH)., Methods: This prospective study enrolled patients with group 1 and 4 PH who had complete PWA, NT-proBNP, and hemodynamics data. Risk assessment-based "hemodynamic score (HS)" and principal component analysis-based PWA variable grouping were determined/performed. Models of hierarchical multiple linear regression (HMLR) and receiver operating characteristic (ROC) curves were used to determine the relationships of PWA variables with HS and NT-proBNP and to predict the latter parameters., Results: Fifty-three PWAs were included. PWA variables were classified into 4 eigenvalue principal components (representing 90% configuration). Univariate analysis showed that left ventricular ejection time (LVET) was significantly negatively associated with HS and NT-proBNP levels. HMLR analysis showed that LVET was still significantly, negatively, and independently associated with HS (B = -0.006 [-0.010~-0.001]) and NT-proBNP (B = -13.47 [-21.20~-5.73]). ROC curve analysis showed that LVET > 306.9 msec and > 313.2 msec predicted the low-risk group of HS (AUC: 0.802; p = 0.001; sensitivity: 100%; and specificity: 59%) and low-to-intermediate risk levels of NT-proBNP (AUC: 0.831; p < 0.001; sensitivity: 100%; and specificity: 59%)., Conclusions: The non-invasive PWA parameter, LVET, is an independent predictor of invasive right heart HS and NT-proBNP levels; it may serve as a novel biomarker of right ventricular function in patients with pre-capillary PH.

Published
2023
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41. Hsa-miR-409-3p regulates endothelial progenitor senescence via PP2A-P38 and is a potential ageing marker in humans.

Author

Lee YN, Wu YJ, Lee HI, Wang HH, Hung CL, Chang CY, Chou YH, Tien TY, Lee CW, Lin CF, Su CH, and Yeh HI

Subjects
Humans, Aging genetics, Leukocytes, Mononuclear metabolism, Protein Phosphatase 2 genetics, p38 Mitogen-Activated Protein Kinases, Endothelial Progenitor Cells metabolism, MicroRNAs metabolism
Abstract

We explored the roles of hsa-microRNA (miR)-409-3p in senescence and signalling mechanism of human endothelial progenitor cells (EPCs). Hsa-miR-409-3p was found upregulated in senescent EPCs. Overexpression of miRNA mimics in young EPCs inhibited angiogenesis. In senescent EPCs, compared to young EPCs, protein phosphatase 2A (PP2A) was downregulated, with activation of p38/JNK by phosphorylation. Young EPCs treated with siPP2A caused inhibited angiogenesis with activation of p38/JNK, similar to findings in senescent EPCs. Time series analysis showed, in young EPCs treated with hsa-miR-409-3p mimics, PP2A was steadily downregulated for 72 h, while p38/JNK was activated with a peak at 48 hours. The inhibited angiogenesis of young EPCs after miRNA-409-3p mimics treatment was reversed by the p38 inhibitor. The effect of hsa-miR-409-3p on PP2A signalling was attenuated by exogenous VEGF. Analysis of human peripheral blood mononuclear cells (PBMCs) obtained from healthy people revealed hsa-miR-409-3p expression was higher in those older than 65 years, compared to those younger than 30 years, regardless of gender. In summary, hsa-miR-409-3p was upregulated in senescent EPCs and acted as a negative modulator of angiogenesis via targeting protein phosphatase 2 catalytic subunit alpha (PPP2CA) gene and regulating PP2A/p38 signalling. Data from human PBMCs suggested hsa-miR-409-3p a potential biomarker for human ageing., (© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Published
2023
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42. Referral, Diagnosis, and Pharmacological Management of Peripheral Artery Disease: Perspectives from Taiwan.

Author

Lee JK, Hsieh IC, Su CH, Huang HL, Lei MH, Chiu KM, Huang CL, Chen CC, Hsu PC, Hsu CH, Huang CY, Lee CH, Chang WC, Lee HF, Liu JC, and Yeh HI

Abstract

Peripheral artery disease (PAD) imposes a heavy burden of major adverse cardiovascular events that are associated with considerable mortality and morbidity, and major adverse limb events (e.g., thrombectomy, revascularization, amputation) that can substantially impact patients' daily functioning and quality of life. Global registry data have indicated that PAD is an underdiagnosed disease in Taiwan, and its associated risk factors remain inadequately controlled. This review discusses the burden of PAD in Taiwan, major guidelines on PAD management, and the latest clinical trial outcomes. Practical experience, opinions, and the latest trial data were integrated to derive a series of clinical algorithms - patient referral, PAD diagnosis, and the antithrombotic management of PAD. These algorithms can be adapted not only by physicians in Taiwan involved in the clinical management of patients with PAD but also by general practitioners in local clinics and regional hospital settings, with the ultimate aim of improving the totality of PAD patient care in Taiwan.

Published
2023
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43. Management of Patients with Type V Hyperlipoproteinemia: An Uncommon Phenotype of Dyslipidemia with Chylomicronemia and Severe Hypertriglyceridemia.

Author

Chang YH, Lin DY, Tsai CL, Liang CH, Yu YT, Hsieh YL, Chuang JY, Chen YH, Yeh HI, and Lin CF

Abstract

Hypertriglyceridemia (HTG) remains a risk-enhancing factor of atherosclerotic cardiovascular disease. We aimed to report real-world data on the management of patients with type V hyperlipoproteinemia (HLP5), an uncommon phenotype of dyslipidemia characterized by fasting chylomicronemia and severe HTG. Between July 2018 and May 2021, 90 patients with HTG, including 83 patients with type IV hyperlipoproteinemia (HLP4) and 7 patients with HLP5, were identified by plasma apolipoprotein B (apoB) and lipoprotein electrophoresis. Patients with HLP5 were younger, had higher total cholesterol (TC) (264.9 ± 26.7 mg/dL vs. 183.9 ± 26.1 mg/dL; p < 0.01) and higher triglyceride (TG) (1296.7 ± 380.5 mg/dL vs. 247.6 ± 96.1 mg/dL; p < 0.01), and had lower high-density lipoprotein cholesterol (HDL-C) (30.6 ± 4.8 mg/dL vs. 40.5 ± 8.7 mg/dL; p < 0.01) and lower low-density lipoprotein cholesterol (LDL-C) (62.9 ± 16.4 vs. 103.0 ± 21.1 mg/dL; p < 0.01) compared with patients with HLP4. Despite an aggressive use of statin and fenofibrate with greater reductions in TG (-65.9 ± 13.7% vs. -27.9 ± 30.5%; p < 0.01) following 6 months of treatment, patients with HLP5 had persistent HTG (440.1 ± 239.0 mg/dL vs. 173.9 ± 94.8 mg/dL; p < 0.01) and an increase in LDL-C (28.3 ± 57.2% vs. -19.5 ± 32.0%; p < 0.01) compared with patients with HLP4. Our findings highlight that the lack of novel TG-lowering medications and management guidelines remains an unmet medical need in patients with HLP5. Closely monitoring lipid profiles, full assessment of individual’s risk of cardiovascular disease, and emphasis on medication adherence are of clinical importance.

Published
2022
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44. 2022 Taiwan lipid guidelines for primary prevention.

Author

Huang PH, Lu YW, Tsai YL, Wu YW, Li HY, Chang HY, Wu CH, Yang CY, Tarng DC, Huang CC, Ho LT, Lin CF, Chien SC, Wu YJ, Yeh HI, Pan WH, and Li YH

Subjects
Humans, Cholesterol, LDL, Taiwan, Risk Factors, Primary Prevention, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Dyslipidemias, Atherosclerosis prevention & control, Cardiovascular Diseases prevention & control, Cardiovascular Diseases complications
Abstract

Elevated circulating low-density lipoprotein cholesterol (LDL-C) is a major risk factor of atherosclerotic cardiovascular disease (ASCVD). Early control of LDL-C to prevent ASCVD later in life is important. The Taiwan Society of Lipids and Atherosclerosis in association with the other seven societies developed this new lipid guideline focusing on subjects without clinically significant ASCVD. In this guideline for primary prevention, the recommended LDL-C target is based on risk stratification. A healthy lifestyle with recommendations for foods, dietary supplements and alcohol drinking are described. The pharmacological therapies for LDL-C reduction are recommended. The aim of this guideline is to decrease the risk of ASCVD through adequate control of dyslipidemia in Taiwan., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2022 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Published
2022
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45. Real-World Data on Comparison of Lipid-Lowering Effects between Alirocumab and Evolocumab in Patients with Hypercholesterolemia.

Author

Lin DY, Tsai CL, Chang YH, Liang CH, Chuang JY, Chen YH, Yeh HI, and Lin CF

Abstract

Background: Even though the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, alirocumab and evolocumab, have been approved to reduce plasma low-density lipoprotein cholesterol (LDL-C) and the risk of atherosclerotic cardiovascular disease in high-risk patients, real-world data showing comparisons of the lipid-lowering effects between alirocumab and evolocumab are scarce because of the low prescription rates of PCSK9 inhibitors in clinical practice., Methods: Between Feb 2018 and Sep 2021, 22 patients who received alirocumab and 22 patients who received evolocumab at a tertiary medical center were enrolled. The patients' baseline characteristics, prescribed medications, plasma LDL-C levels, and percentages of reduction in LDL-C were compared between alirocumab users and evolocumab users., Results: The alirocumab users more frequently received ezetimibe treatment (72.7% vs. 40.9%, p = 0.03) and had higher baseline LDL-C (165.6 ± 63.2 mg/dL vs. 130.8 ± 56.3 mg/dL, p = 0.04) compared with the evolocumab users. At 6 months of follow-up, the plasma LDL-C levels in the alirocumab users were similar to those in the evolocumab users (79.3 ± 64.0 mg/dL vs. 63.5 ± 44.1 mg/dL, p = 0.48). Additionally, the percentages of LDL-C reduction following treatment were similar between the alirocumab users and evolocumab users (-47.0% ± 45.0% vs. -49.8 ± 24.9%, p = 0.66)., Conclusions: The LDL-C lowering effects of alirocumab are similar to those of evolocumab in clinical practice.

Published
2022
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46. Fluctuating Cutaneous Varices as a Diagnostic Clue for a Huge Right Atrial Mass in a Dialysis Patient.

Author

Chen TY, Hung CL, Lin CJ, Yeh HI, and Liu YY

Subjects
Aged, Humans, Male, Renal Dialysis adverse effects, Subclavian Vein, Vena Cava, Superior, Kidney Failure, Chronic complications, Kidney Failure, Chronic diagnosis, Kidney Failure, Chronic therapy, Varicose Veins complications, Varicose Veins diagnosis, Varicose Veins therapy
Abstract

A 72-year-old man presented with altered consciousness. His past medical history included left renal cell carcinoma status post nephrectomy 3 years earlier, end-stage renal disease with regular hemodialysis, and central venous obstruction with stenting at the right subclavian vein and superior vena cava 8 months earlier. He was intubated and placed on a mechanical ventilator and inotropes for managing respiratory failure and shock. After numerous tests, it was evident that a right atrial mass was hindering blood flow into the right ventricle and causing blood to flow back into the peripheral venous system. This could cause obstructive cardiogenic shock and fluctuating cutaneous varices. The patient refused further intervention and died from multiple organ failure. This unusual phenomenon can provide a clue for the discovery of atrial masses in dialysis patients.

Published
2022
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47. The prognostic significance of the presence of tenascin-C in patients with stable coronary heart disease.

Author

Kong Ho S, Leu HB, Wu CC, Yeh HI, Yin WH, Lin TH, Chang KC, Wang JH, Tseng WK, Chen JW, and Wu YW

Subjects
Humans, Heart Failure blood, Heart Failure etiology, Myocardial Infarction blood, Myocardial Infarction etiology, Prognosis, Heart Disease Risk Factors, Predictive Value of Tests, Coronary Disease blood, Coronary Disease complications, Coronary Disease mortality, Tenascin blood
Abstract

Background: We investigated the prognostic value of tenascin-C in patients with stable coronary heart disease., Methods: A total of 666 patients were enrolled and followed for 72 months. The primary outcome was a composite of cardiac events. The secondary outcomes were all-cause death, cardiovascular death, acute myocardial infarction (AMI), and heart failure hospitalization., Results: The area under the curve of tenascin-C to discriminate the occurrence of composite cardiac events was 70 % (95 % CI: 64.2 % to 75.8 %), and the corresponding optimal cutoff value was 19.91 ng/ml. A higher concentration of tenascin-C was associated with a greater risk of composite cardiac events (P trend < 0.001). Similar results were observed in all-cause death, AMI, and heart failure hospitalization., Conclusion: Tenascin-C was found to be an independent predictor of total cardiovascular events in patients with stable coronary heart disease at 72 months, and also for all-cause death, AMI, and heart failure hospitalization., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Published
2022
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48. Both epicardial and peri-aortic adipose tissue blunt heart rate recovery beyond body fat mass.

Author

Chang SH, Chu PH, Tsai CT, Kuo JY, Tsai JP, Hung TC, Hou CJ, Lai YH, Liu CY, Huang WM, Yun CH, Yeh HI, and Hung CL

Abstract

Background: Epicardial adipose tissue (EAT) as a marker of metabolic disorders has been shown to be closely associated with a variety of unfavorable cardiovascular events and cardiac arrhythmias. Data on regional-specific visceral adiposity outside the heart and its modulation on autonomic dysfunction, particularly heart rate recovery after exercise, remain obscure., Methods: We studied 156 consecutive subjects (mean age: 49.3 ± 8.0 years) who underwent annual health surveys and completed treadmill tests. Multi-detector computed tomography-based visceral adiposity, including EAT and peri-aortic fat (PAF) tissue, was quantified using dedicated software (Aquarius 3D Workstation, TeraRecon, San Mateo, CA, USA). We further correlated EAT and PAF with blood pressure and heart rate (HR) recovery information from an exercise treadmill test. Metabolic abnormalities were scored by anthropometrics in combination with biochemical data., Results: Increased EAT and PAF were both associated with a smaller reduction in systolic blood pressure during the hyperventilation stage before exercise compared to supine status (β-coefficient (coef.): -0.19 and -0.23, respectively, both p < 0.05). Both visceral adipose tissue mediated an inverted relationship with heart rate recovery at 3 (EAT: β-coef.: -0.3; PAF: β-coef.: -0.36) and 6 min (EAT: β-coef.: -0.32; PAF: β-coef.: -0.34) after peak exercise, even after adjusting for baseline clinical variables and body fat composition (all p < 0.05)., Conclusion: Excessive visceral adiposity, whether proximal or distal to the heart, may modulate the autonomic response by lowering the rate of HR recovery from exercise after accounting for clinical metabolic index. Cardiac autonomic dysfunction may partly explain the increase in cardiovascular morbidity and mortality related to both visceral fats., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chang, Chu, Tsai, Kuo, Tsai, Hung, Hou, Lai, Liu, Huang, Yun, Yeh and Hung.)

Published
2022
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49. Real-world data on the prescription of proprotein convertase subtilisin/kexin type 9 inhibitors in high-risk patients in a tertiary medical center.

Author

Tsai CL, Chang YH, Su CH, Wu YJ, Yeh HI, and Lin CF

Subjects
Antibodies, Monoclonal, Cholesterol, LDL, Ezetimibe, Humans, PCSK9 Inhibitors, Prescriptions, Proprotein Convertase 9, Subtilisins, Anticholesteremic Agents, Hydroxymethylglutaryl-CoA Reductase Inhibitors
Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, alirocumab and evolocumab, are currently approved for clinical use by Taiwan National Health Insurance (NHI) in patients who had a recent atherosclerotic cardiovascular disease with persistent LDL-C levels >135 mg/dL despite high-intensity statin (HIS) or maximally tolerated statin in combination with ezetimibe treatment. Since January 2020 to July 2020, total of 10 patients who had received coronary revascularization received NHI-approved alirocumab or evolocumab in our institution. The mean reduction of LDL-C following PCSK9 inhibitors treatment at 6-month and 12-month were respectively 62.5% and 60.2%. The patients in our study were younger, had more frequently received HIS/ezetimibe, and had higher baseline LDL-C levels with a greater LDL-C reduction following PCSK9 inhibitors treatment compared with those patients in previously studies. Our findings highlight that the NHI's regulation of PCSK9 inhibitors application should be re-evaluation to increase the use of NHI-approved PCSK9 inhibitors in high-risk patients., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Published
2022
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50. Alcohol patch test with hue-saturation-value model analysis predicts ALDH2 genetic polymorphism.

Author

Hu CY, Hung CL, Huang YC, Huang PH, Tseng DY, Lin YH, Sun FJ, Kao FJ, Yeh HI, and Liu YY

Subjects
Aldehyde Dehydrogenase, Mitochondrial genetics, Ethanol, Female, Genotype, Humans, Male, Patch Tests, Alcohol Dehydrogenase genetics, Polymorphism, Genetic
Abstract

Background: The alcohol patch test (APT) can detect aldehyde dehydrogenase (ALDH) genetic polymorphisms used to diagnose cutaneous erythema. However, the subjective results can vary owing to confounding factors. The hue-saturation-value (HSV) model provides an objective means of image analysis with APT., Methods: This study enrolled 57 participants (27.7 ± 9.0 years, 52.6% females) with ALDH2*1/*1, ALDH2*1/*2, and ALDH2*2/*2 percentages of 50.9%, 43.8%, and 5.3%, respectively. In total, 56 APT protocols were applied and analyzed employing both visual inspection and the HSV model. The value of the delta standard deviation (SD) of the hue histogram, which manifests the difference between the APT reaction and the baseline skin color, was obtained using the HSV model. The receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) were used to predict the ALDH2*2 allele with the HSV model., Results: Upon visual inspection, a maximal Youden index with a sensitivity of 82.1% and a specificity of 96.6% was determined for the ALDH2 genetic mutation. Using the delta SD of hue obtained in the HSV model, a maximal Youden index with 85.7% sensitivity and 96.6% specificity was determined using the ROC curve analysis (AUC = 0.948, p < 0.001). Thus, the use of the HSV model analysis with APT resulted in equal specificity, but better sensitivity, compared to those obtained upon visual inspection., Conclusion: The HSV model took into account the potential confounding factors, and thus, could help in the prediction of ALDH2 genetic polymorphisms., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Published
2022
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