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1. Genetic Disorders of Lipoprotein Metabolism

Author: Cupido, A. J., Stoekenbroek, R. M., Kastelein, J. J. P., Graduate School, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, ACS - Amsterdam Cardiovascular Sciences, APH - Personalized Medicine, and ACS - Pulmonary hypertension & thrombosis
Abstract: Disorders of lipoprotein metabolism are major contributors to cardiovascular disease (CVD). Dyslipidemia refers to elevated LDL-C levels, triglycerides, or remnant cholesterol, and decreased HDL-C. Most cases of CVD are multifactorial and/or polygenic in origin. However, (mono)genic causes can be suspected in individuals with early-onset CVD or with specific clinical hallmarks. The first step in the diagnostic workup of dyslipidemias is to exclude secondary dyslipidemias by obtaining a medical history and through biochemical testing. Specialized biochemical tests or genetic tests can often help in establishing a definite diagnosis. Treatment consists of lifestyle modifications, usually in combination with pharmacological agents such as statins. However, advances in gene technologies have enabled a rapid increase in the repertoire of available treatment options. This chapter provides an extensive overview of lipoprotein metabolism, followed by an overview of mono- and polygenic disorders of lipoprotein metabolism, including underlying causes, clinical and diagnostic characteristics, and available treatment options.
Published: 2020

2. Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients

Author: Ridker, P. M., Revkin, J., Amarenco, P., Brunell, R., Civeira, F., Flather, M., Glynn, R. J., Gregoire, J., Jukema, J. W., Karpov, Y., Kastelein, J. J. P., Koenig, W., Lorenzatti, A., Manga, P., Masiukiewicz, U., Miller, M., Mosterd, A., Murin, J., Nicolau, J. C., Nissen, S., Ponikowski, P., Santos, R. D., Schwartz, P. F., Soran, H., White, H., Wright, R. S., Vrablik, M., Yunis, C., Shear, C. L., Tardif, Conde D, J. -C., Colquhoun, D, Missault, L, Grégoire, J, Gao, R, Urina, M, Solar, M, Jensen, Hk, Grobbee, D, Savolainen, M, Schiele, Fn, Montalescot, G, Edes, I, Blake, G, Lotan, C, Maggioni, A, Savonitto, S, Lee, Cw, Leiva Pons JL, Dan, Ga, Cortada, Jb, Mellbin, L, Kahan, T, Noble, S, Hwang, Jj, Sritara, P, Tökgozoğlu, L, Tarasenko, L, Borer, Js, Black, H, Carmena, R, Furie, Kl, Mcmurray, J, Neaton, J, Zannad, F, O’Neill, B, Welty, F, Mcnamara, R, Chun, H, Abbott, Jd, Jacoby, D, Mcpherson, C, Jadbabaie, F, Pinto, D, Mccullough, L, Silverman, Ie, Sansing, Lh, Dearborn-Tomazos, J, Foody, J, Schindler, J, Piazza, G, Chakrabarti, A, Pride, Y, Gelfand, E, Baultrukonis, D, Chaudhuri, S, Frederich, R, Johnson, M, Mridha, K, Powell, C, Wang, E, Wei, C, Anderson, P, Buonanno, M, Epsley, C, Evans, B, Frolova, M, Goetsch, M, Hessinger, D, Ikehara, E, Ivanac, K, Kizko, J, Le, K, McNally-Dufort, C, Morocco, T, Nadkarni, S, Nissen, T, Nye, R, Pak, R, Pence, D, Redifer, P, Schwartz, W, Sattler, C, Schade, R, Sullivan, B, Wegner, J, Alvarez, Ca, Budassi, N, Vogel, Dr, Avaca, H, Conde, Dg, Estol, Cc, Gelersztein, E, Glenny, Ja, Hershson, Ar, Bruno, Rl, Maffei, Le, Soler, Jm, Zaidman, Cj, Carnero, Gs, Colombo, Hr, Jure, Ho, Luquez, Ha, Ramos, Hr, Resk, Jh, Rusculleda, Mm, Ulla, Mr, Caccavo, A, Farias, Ef, Wenetz, Lm, Cabella, Pr, Cuadrado, Ja, Chahin, M, Mackinnon, Ij, Zarandon, Rb, Schmidberg, J, Fernandez, Aa, Montana, O, Codutti, Or, Gorosito, Vm, Maldonado, N, Sala, J, De La Fuente RA, Casabella, Te, Di Gennaro JP, Guerrero, Ra, Alvarez, Ms, Berli, M, Botta, Ce, Montenegro, Ee, Vico, Ml, Begg, A, Lehman, R, Gilfillan, Cp, D'Emden, M, Markovic, Tp, Sullivan, D, Aroney, C, Stranks, Sn, Crimmins, Ds, Arstall, M, Van Gaal, W, Davis, T, Aylward, Pe, Amerena, J, William, M, Proietto, J, Purnell, Pw, Singh, B, Arya, Kw, Dart, Am, Thompson, P, Davis, Sm, Carroll, Pa, De Looze, F, Jayasinghe, R, Bhindi, R, Buysschaert, I, Sarens, T, van de Borne, P, Scott, Bp, Roosen, J, Cools, F, Missault, Lh, Debroye, C, Schoors, Df, Hollanders, G, Schroe, Hh, De Sutter, J, Hermans, K, Carlier, M, van Landegem, P, Verwerft, J, Mulleners, T, Delforge, Md, Soufflet, V, Elegeert, I, Descamps, Os, Janssens, S, Lemmens, Rc, Desfontaines, P, Scheen, A, Heijmans, S, Capiau, L, Vervoort, G, Carlier, Sg, Faes, D, Alzand, B, Keuleers, S, De Wolf, L, Thoeng, J, De Bruyne, L, de Santos MO, Felicio, Js, Areas, Ca, Figueiredo, El, Michalaros, Yl, Neuenschwander, Fc, Reis, G, Saad, Ja, Kormann, Ap, Nascimento, Cv, Precoma, Db, Abib, E Jr, dos Santos FR, Mello, Yg, Saraiva, Jf, Rech, Rl, Cerci, R, Fortes, Ja, Rossi, Pr, de Lima, e Silva FA, Hissa, M, Silva, Rp, de Souza WK, Guimarães Filho FV, Mangili, Oc, de Oliveira Paiva MS, Tumelero, R, Abrantes, Ja, Caramori, Pr, Dutra, Op, Leaes, Pe, Manenti, Er, Polanczyk, Ca, Bandeira, e Farias FA, de Moraes Junior JB, Russo, La, Alves AR Jr, Dracoulakis, Md, Ritt, Le, Saporito, Wf, Herdy, Ah, Maia, Ln, Sternieri, Mv, Ayoub, Jc, Bianco, Ht, da Costa FA, Eliaschewitz, Fg, Fonseca, Fa, Nakandakare, Er, Bonansea, Tc, Castro, Nm, de Barros, e Silva PG, Smith, P, Botelho, Rv, Resende, Es, Barbieri, Ds, Hernandes, Me, Bajaj, H, Beaudry, P, Berlingieri, Jc, Salter, Tj, Ajala, B, Anderson, Tj, Nanji, A, Ross, S, Pandey, S, Desrosiers, D, Gaudet, D, Moran, G, Csanadi, Ma, St-Amour, E, Cusimano, S, Halperin, Fa, Babapulle, M, Vizel, S, Petrella, J, Spence, Jd, Gupta, N, Tellier, G, Bourgeois, R, Gregóire, Jc, Wesson, T, Zadra, R, Twum-Barima, Dy, Cha, Jy, Hartleib, Mc, Bergeron, J, Chouinard, G, Mcpherson, Tp, Searles, G, Peterson, Sr, Mukherjee, A, Lepage, S, Conway, Jr, Kouz, Sm, Dion, D, Pesant, Y, Cheung, Ss, Goldenberg, Rm, Aronson, R, Gupta, Ak, O’Mahoney, M, Pliamm, L, Teitelbaum, I, Hoag, Gn, Nadra, Ij, Yared, Z, Yao, Lc, Nguyen, T, Saunders, Kk, Potthoff, S, Varleta, P, Assef, V, Godoy, Jg, Olivares, C, Roman, O, Vejar, M, Montecinos, H, Pincetti, C, Li, Y, Wang, D, Li, J, Yang, X, Du, Y, Wang, G, Yang, P, Zhang, X, Xu, P, Zhao, Y, Chen, J, Li, S, Li, W, Zhang, L, Zhu, Y, Zhang, Y, Zhou, C, Wang, Y, Liu, F, Ma, Y, Ti, Z, Zeng, X, Zhou, Y, Cui, G, Li, D, Xue, L, Jiang, J, Lian, Y, He, Y, Mendoza, Ja, Bonfanti, Ja, Dada, Fa, Urina-Triana, Ma, Rodriguez, Wr, Sanchez, Ml, Lozno, Hy, Triana, Eh, Arambula, Rm, Rico-Carrillo, Ae, Gallo, Hj, Catano, Js, Jattin, Fg, Plazas, Ja, Gomez, Je, Botero-Lopez, R, Gomez, Ni, Munoz, Cf, Pelaez, Sv, Eraso, Am, Goyes, Ar, Elbl, L, Fiserova, N, Vesely, J, Wasserburger, B, Blaha, V, Vojacek, J, Maskova, P, Hutyra, M, Vrkoc, J, Hala, T, Vodnansky, P, Bocek, P, Cifkova, R, Bufka, V, Ceska, R, Machkova, M, Zidkova, E, Lukac, M, Mikusova, T, Kellnerova, I, Kuchar, L, Ferkl, R, Cech, V, Zemek, S, Monhart, Z, Davidsen, F, Joensen, A, Lihn, As, Rasmussen, Tk, Wiggers, H, Lindgren, Lm, Schmidt, U, Galatius, S, Sillesen, H, Bronnum Schou, J, Thomsen, Kk, Urhammer, S, Jeppensen, J, Schou, M, May, O, Steffensen, R, Nielsen, Wb, Nielesen, T, Jepsen, Jm, Rai, A, Sykulski, R, Andersen, Lt, Rickers, H, Frost, L, Lomholdt, J, Egstrup, K, Wermuth, S, Klausen, L, Lassus, J, Palomaki, A, Khari, J, Tatlisumak, T, Kekki, S, Vanttinen, E, Strandberg, A, Valtonen, M, Sia, Sm, Nerg, O, Puhakka, M, Strand, J, Timonen, M, Levola, J, Arstila, L, Taurio, J, Kantola, I, Suomi, J, Humaloja, K, Askonen, K, Schiele, F, Sibon, I, Zemour, G, Goube, P, Petit, C, Chati, Z, Range, G, Rabahi, F, Rihani, R, Bergerot, C, Roubille, F, Boye, A, Probst, V, Ferrari, E, Cayla, G, Thouvenot, E, Delarche, N, Couffinhal, T, Coisne, D, Paillard, F, Elbaz, M, Decoulx, E, Angoulvant, D, Agraou, B, Caudmont, S, Berrouschot, J, Lauer, B, Schoell, I, Trenk, D, Derwahl, Km, Khariouzov, A, Proepper, F, Stawowy, P, Da Stephan, U, Stoessel, J, Voehringer, Hf, Dorsel, T, Stellbrink, C, Rinke, A, Northroff, J, Bourhaial, H, Stratmann, M, Wetzel, T, Axthelm, C, Guenzel, A, Weigmann, I, Faghih, M, Hagemann, D, Schaefer, A, Weber, D, Luedemann, J, Contzen, C, Kornmann, Mo, Winkelmann, B, Simon, J, Felix, S, Brauer, C, Laufs, U, Schmidt, E, Marten, I, Licka, M, Heisters, J, Appel, Kf, Kleinecke-Pohl, U, Klein, C, von Hodenberg EF, Maus, O, Sigal, H, Taeschner, H, Schwimmbeck, P, Lemke, B, Perings, C, Illies, G, Pfuetzner, A, Salbach, P, Hengstenberg, C, Kohler, A, Mudra, H, Behnke, T, Baar, M, Jeserich, M, Scholz, G, Naudts, I, Voller, H, Herrmann, Hj, von Engelhardt CB, Gerke, S, Pohlmeier, L, Schaufele, T, Woehrle, J, Al-Zoebi, A, Horacek, T, Peterfai, E, Kemeny, V, Lakatos, F, Bod, E, Andrassy, P, Andreka, P, Balo, T, Davidovits, Z, Laszlo, Z, Nagy, K, Papp, A, Somogyi, A, Toldy-Schedel, E, Vertes, A, Voros, P, Paragh, G, Martyin, T, Hajdu, C, Deak, L, Farago, K, Nagy, A, Kirschner, R, Koszegi, Z, Zilahi, Z, Toth, K, Wittmann, I, Bajcsi, D, Reiber, I, Toth, L, Benczur, B, Nagy, L, Sydo, T, Lupkovics, G, Oroszlan, T, Crean, P, Mahon, Ng, Mcadam, B, Macneill, B, Katz, A, Tsalihin, D, Vazan, A, Eitan, A, Lewis, Bs, Gavish, D, Wainstein, J, Mosenzon, O, Mosseri, M, Vishlitzky, V, Atar, S, Nseir, Wb, Brenner, H, Elis, A, Fuchs, S, Shimon, I, Solodky, A, Goldhaber, A, Tanne, D, Knobler, H, Kracoff, Oh, Hussein, O, Auriel, E, Chorin, E, Sharir, T, Bitzur, R, Shechter, M, Antonicelli, R, Franceschini, E, Porcu, M, Sesti, G, Maggiolini, S, Salvioni, A, Filardi, Pp, Trimarco, B, Averna, M, Pasqualini, L, Pirro, M, Pantaleoni, M, Piovaccari, G, Arca, M, Fedele, Francesco, Roncon, L, Anselmi, M, Sganzerla, P, Morocutti, G, Bonora, E, Dimas, Al, Esperon, Ga, Morales-Villegas, E, Isunza, Jm, Beltran, Lg, Molina, Ca, Garcia, Dk, Ruiz, La, Reyna, Ls, De los Rios Ibarra MO, Soto, Jr, Gonzalez-Ortiz, M, Herrera-Marmolejo, M, Ramos, Sa, Ramos-Lopez, Ga, Stobschinski, Ca, Aguilarsalinas, Ca, Alpizar-Salazar, M, Jimenez-Sanchez, M, Sanchez Mijangos JH, Elizondo Moreno ER, Garcia Castillo, A, Garcia Hernandez PA, Gonzalez-Gonzalez, Jg, Riojas Charles CM, Valdez Lopez HG, Nuriulu Escobar PL, Lechuga Martin del Campo, A, Castro Montes BE, Mendez Bucio, A, Rodriguez-Briones, I, Torre Amione, G, Violante Ortiz, R, Luna Ceballos RI, Lopez Rosas, E, Bax, Wa, Alhakim, M, van de Wiel, A, Liem, Ss, Groutars, Rg, Herrman, Jp, Hovingh, Gk, van de Wetering ML, van Royen, N, Groenemeijer, Be, Hoedemaker, G, Schaap, J, Ronner, E, Angun, M, Mairuhu, At, Van Alem AP, Martens, Fm, Heijmeriks, Ja, van Hal JM, Schoofs, Mw, den Hartog FR, Kentgens, S, Post, Jc, Louwerenburg, Jw, van Rossum, P, Viergever, Ep, Donders, Sh, Kamphuisen, Pw, van Beek, E, Nijmeijer, R, Lenderink, T, Schreuder, T, Kuijper, Af, The, Sh, Van het Hof-Wiersma JJ, Tichelaar, P, Westerndorp, I, Breedveld, Rw, Karalis, I, Romer, Tj, Bogaard, K, Van Koningsbruggen, P, Kroon, Aa, Hoogslag, Pa, Rensing, Bj, Cramer, E, Remmen, Jj, Riksen, Np, Bokern, Mj, Cabezas, Mc, Mulder, H, Nierop, Pr, van Kempen WW, Zoet-Nugteren, Sk, van Daele ME, Swart, Hp, van der Zwaan CT, Hermans, Wr, Magro, M, van de Wal RM, Hassink, Rj, Visseren, F, Veenendaal, A, De Nooijer, C, Troquay, Rp, Imholz, Bp, van der Meer, P, Visser, Rp, van Leendert RJ, Gosselink, Ma, Baker, J, Benatar, Jr, Kerr, J, Pryke, Jr, Scott, Rs, Millar-Corte, Gd, Williams, M, Montgomery, B, Venter, Dj, Ternouth, If, Decaigney, Sc, Hart, Hh, Corin, A, Garden, Pi, Sheahan, D, Harding, Sa, Korecki, J, Supronik, J, Styczkiewicz, M, Bijata-Bronisz, R, Rusicka, T, Walczak, M, Krolikowski, Z, Ostrowski, J, Lukaszewicz, M, Przekwas-Jaruchowska, M, Zieba, B, Miekus, P, Orkwiszewska-Nalewajko, A, Piepiorka, M, Kubalski, P, Wychota, K, Blach, E, Ochala, A, Okopien, B, Wronska, D, Janion, M, Czarnecka, D, Kolodziejczyk, J, Konieczynska, M, Landa, K, Mirek-Bryniarska, E, Necki, M, Pasternak, Da, Rozpondek, P, Trebacz, J, Walczewska, J, Sidor, M, Broncel, M, Drozdz, J, Kosmider, M, Saryusz-Wolska, M, Kucharska, D, Opalinska, E, Pijanowski, Z, Wozniak, I, Banaszkiewicz, K, Klecha, A, Horodecki, M, Piskorz-Wapinska, J, Kobielusz-Gembala, I, Kim, Mh, Kim, Dk, Cho, Br, Kim, Ks, Her, Sh, Lee, Sy, Rhee, My, Kim, K, Kang, Wc, Kim, Dh, Cho, Ys, Kim, Sh, Rim, Sj, Tahk, Sj, Jeon, Hk, Yoon, J, Mociran, M, Pop, Cf, Minescu, B, Andrei, Ld, Radoi, M, Calin, A, Ciomag, Rm, Copaci, I, Fruntelata, Ag, Popescu, M, Tivadar, S, Roman, G, Avram, Ri, Mistodie, Cv, Morosanu, M, Popa, Ar, Popescu, Ml, Popoviciu, Ms, Tase, A, Busegeanu, M, Popescu, A, Szilagyi, I, Sitterli-Natea, Cn, Maximov, Dm, Munteanu, M, Negrisanu, Gd, Kuzin, A, Popov, D, Shapovalova, J, Vishneva, E, Shutemova, E, Pasechnik, E, Bogdanov, E, Khasanov, N, Barbarash, Ol, Shangina, Oa, Tarasov, N, Solonev, O, Kosmacheva, E, Chernyatina, Ma, Ginzburg, M, Blokhin, A, Bulanova, N, Drapkina, Om, Gordeev, Ig, Libov, Ia, Lomakin, N, Panchenko, E, Shogenov, Zs, Zateyshchikov, D, Klein, G, Motylev, I, Belenkiy, Di, Demin, A, Nikolaev, Ky, Oleynikov, V, Zrazhevskiy, K, Katelnitskiy, I, Khaisheva, L, Aksentiev, S, Nedoshivin, A, Popova, Vb, Agafina, As, Ballyuzek, M, Baranova, E, Burova, N, Eryshev, S, Filippov, A, Goloshchekin, Bm, Konstantinov, V, Kostenko, Va, Simanenkov, Vi, Volkova, A, Duplyakov, D, Reshetko, O, Shvarts, Y, Kuznetsov, Va, Samoylova, Yg, Tolkacheva, V, Shalaev, Sv, Khokhlov, Al, Malygin, A, Shilkina, Np, Yakusevich, Vv, Margoczy, R, Zubek, V, Dzupina, A, Dubrava, J, Dulkova, K, Fabryova, L, Gaspar, L, Kamensky, G, Kokles, M, Raslova, K, Soosova, I, Stevlik, J, Strbova, J, Sumbal, J, Uhliar, R, Micik, J, Truban, J, Fedacko, J, Pastrnakova, E, Pella, D, Fazekas, F, Ambrovicova, V, Kycina, P, Martinka, E, Nociar, J, Belicova, M, Banik, M, Kanderkova, D, Hranai, M, Duris, T, Krahulec, B, Benacka, J, Vinanska, D, Roskova, E, Skripova, D, Macek, V, Vohnout, B, Buganova, I, Engelbrecht, Jm, Pretorius, Mm, Ebrahim, Io, Bayat, J, Ganesh, S, Ranjith, N, Coetzer, Tf, Jacovides, A, Distiller, La, Hellig, Fs, Engelbrecht, Iv, Mahomed, Aa, Blignault, Sc, Burgess, Lj, Kotze, Hj, van Nieuwenhuizen, E, Musungaie, Db, Emanuel, S, van der Walt, E, Pretorius, Ce, Roos, Js, Roux, Sm, Badat, Ae, Fouche, L, Vahed, Ya, Jansen van Resburg, D, van Zyl LJ, Soto Gonzalez, A, Diaz, Jl, Segura, T, Botella Serrano, M, Botas Rodrigues, J, Molto-Jorda, Jm, Dominguez Escribano JR, Sogorb Garri, F, Blanco Coronado JL, Gaztambide Saenz MS, Brotons Cuixart, C, Bruguera Cortada, J, Garcia-Moll Marimon, X, Gonzalbez Morgaez JD, Maisterra Santos, O, Roquer Gonzalez, J, Sobrino-Martinez, J, Chueca Fernandez JE, Narejos, S, Suarez Garcia, S, Perez Martinez, P, Figueras Camos, R, Medrano Martinez, V, Bellido Guerrero, D, Martinez Deben, F, Vila Belmonte, A, Mediavilla Garcia JD, Romero Hinojosa JA, Martorell Mateu, E, Cequier Fillat AR, Pinto Sala, X, Adroer Martori, R, Bueno Diez, M, Lopez Cano, C, Worner Diz, F, Gonzalez Juanatey, C, Alvarez-Sala Walther LA, De Dios Garcia Diaz, J, Garcia Puig, J, Jodar Gimeno, E, Plaza Perez, I, Suarez-Fernandez, C, Tunon, J, Zamorano Gomez JL, Brito Sanfiel MA, Escudier Villa JM, de Mora Martin, M, Dominguez Lopez, M, Hernandez Garcia JM, Tinahones Madueno FJ, Perez Paredes, M, Aracil Villar, J, Barreda Gonzalez MJ, Ripoll Vera TV, Tofe Povedano, S, Sanchez Alvarez, J, Martinez Via, L, Robles Iniesta, A, Masana, L, Vinyoles Bargallo, E, Calvo Gomez, C, Gonzalez Juanatey JR, Cruz Fernandez JM, De La Cuesta Mayor, C, Duran Garcia, S, Jimenez Hernandez MD, Morales Portillo, C, Muniz Grijalvo, O, De Castro, R, Taverna Llaurado, E, Pons Amate JM, Terns Riera, M, Civeira Murillo, F, Linderfalk, C, Curiac, D, Saldeen-Nilehn, K, Koskinen, P, Khalili, P, Tortensson, I, Lindholm, Cj, Luts, A, Koskinen, Pt, Gottsater, A, Persson, Be, Mooe, T, Larnefeldt, H, Boman, K, Crisby, M, Rasmanis, G, Tengmark, Bo, Witt, N, Hagstrom, E, Viklund, J, Muller, C, Mach, F, Burnier, M, Nanchen, D, Wuerzner, G, Banyai, M, Moccetti, T, Miserez, Ar, Bilz, S, Weber, K, Lai, Wt, Chang, Kc, Ueng, Kc, Tsai, Wc, Chiang, Ce, Hou, C, Pei, D, Krittayaphong, R, Kiatchoosakun, S, Srimahachota, S, Boonyavarakul, A, Jintapakorn, W, Gullu, H, Onrat, E, Erkan, Af, Demirci, D, Sari, R, Ceyhan, C, Ari, H, Araz, M, Degertekin, M, Goktekin, O, Uresin, Ay, Yigit, Z, Akdeniz, B, Comlekci, A, Kayikcioglu, M, Sahin, T, Ozcan, T, Durakoglugil, E, Asamoah-Owusu, N, Reed, R, Bakhai, A, Dixon, L, Sharma, R, Avornyo, Aa, Jones, Af, Lip, G, Clark, R, Banerjee, M, Wakeling, J, Arden, C, Blagden, Md, Walukiewica, P, Marshall, A, Maxwell, Tg, Gunstone, Ae, Kadr, Hh, Patle, R, Arif, I, Jhund, Ps, Mckaig, G, Douglas, F, Mierzejewski, L, Turner, W, Sathyapalan, T, Ivan, P, Manoj, A, Rice, S, Collier, Dj, Nair, Dr, Thom, S, Fiore, G, De Belder, M, Price, D, Sobolewska, J, Martin, S, Takhar, A, Moriarty, A, Kondagunta, V, Myhill, T, Gibson, Jm, Cecil, Jt, Halcox, J, Annamalai, N, Gorog, Da, Mccormack, T, Pegge, N, Field, A, Adams, F, Klein, Jj, Busch, Rs, Bretton, Em, Jaffrani, N, Salacata, A, Assadourian, A, Gogia, Hs, Dyke, Ck, Rubenfire, M, Essandoh, Lk, Welker, Ja, Ledesma, G, Lupovitch, S, Delgado, Jp, Hendrix, El, Quyyumi, Aa, Riesenberg, Ra, Robertson, Dg, Weinstein, Dl, Weiss, R, Casaubon, L, Gammon, Rs, Brar, Hs, Bittar, Gd, Guarnieri, Tt, Ince CS Jr, Jrquraishi, Am, Saeed, S, Albert, M, Sotolongo, Rp, Bernard, Jv, Karlsbergg, Rp, Lepor, Ne, Kirby, We, Mclean, B, Miller, Ap, Ovalle, F, Townsend, Jc, Beckett, Pl, Eaves, Wb, West, Sh, Kosinski, Ej, Zarich, Sw, Mahal, Ss, Maw, K, Maynard, Km, Chen, Jc, Gelormini, J, Gottlieb, Dw, Gabra, Nw, Narayan, P, Sparks, J, Field, Jc, Willits, Vl, O’Steen, Mb, Pasquini, Ja, Sensebrenner, Jw, Yarows, Sa, Hiotis, L, Jagielo, Tj, Levinson, Dj, Diller, Pm, Kereiakes, Dj, Turner, Ta, Vincent, S, Camp, Ad, Denker, Ps, Manning, Mb, Rocco, Mb, Stamps, Hb, Strader, Jr, Uusinarkaus, Kt, Kennett, Jd, Leichter, Sb, Mcneil, Dl, Schumacher, Dr, Chang, Ar, Ellison, Hs, Updegrove, Jd, Hamroff, Gs, Kay, Js, Marar, Ie, Flores, E, Saini, S, Abdullah, S, Berk, Mr, Fordan, S, Joshi, Ph, Mccullough, Pa, Reynolds, Rd, Rosenstock, J, Sachson, Ra, Shammas, N, Fishbein, Gj, Randall, Wj, Henderson, Da, Nash, Ml, Barker, Ba, Cohen, Ss, Seidman, B, Odekirk, Ll, Grillo, Rs, Martinez, Lm, Multani, P, Alwine, Lk, Mcgarvey, Jf, Mollerus, Me, Miller, Ab, Kotek, Lw, Changlani, M, Zavaro, Sh, Munoz, F, Mehta, Pm, Helm, Rj, Farhat, Nz, Farsad, R, Raoof, Tj, Shultz, Jh, Geohas, Jg, Allaw, Ma, Dela Llana, A, Gutmann, Je, Inzerello, At, Alappat, P, George, Ar, Haddad, Tm, Lillestol, Mj, Grodman, R, Peniston, Jh, Wadud, K, Garcia, B, Hamilton, Me, Lerman, S, Perloff, De, Graff, A, Saxena, S, Alvarado, Op, Malik, A, Reddy, Rd, Kinzfogl, G, Cornett, Gm, Norwood, Pc, Gilbert, Jm, Willis, Jg, Mcgrew, F, Sharma, S, Castro, Ma, Cucher, Fh, Altafullah, Im, Khurana, S, Knutson, Tj, Kinnaman, Sj, Stuckey, T, Pudi, Kk, Mayfield, Rk, Funk, Gs, Nixon, Wa, Dor, I, Boyett, Be, Srivastava, S, Elosegui, Am, Isserman, Sm, Cheek, Hb, Promisloff, Sd, Tami, Lf, Zeig, S, fitz-Patrick, D, Dave, Kn, Ahmad, A, Arain, S, Ballantyne, Cm, Doshi, A, El Hafi SE, Feldman, J, Fragoso, Vg, Gilford, T, Hoffman, As, Pouzar, Je, Vivekananthan, K, Ansari, Sh, Strzinek, Ra, Crater, Ta, Robinson, Jg, Fulmer, Jj, Patel, Am, Pereira, Es, Stich, Ma, Sultan, S, Geskin, G, Ruoff, Ge, Gillespie, E, Bybee, Ka, Moriarty, Pm, Savin, V, Agaiby, Jm, Melucci, Mb, Jantzi, Cm, Davidson, E, Smith, Wb, Treasure, Cb, Wakefield, Ph, Deck, K, Edris, Ma, Gilmore, Rm, Seep, Mk, Andersen, Jl, Detweiler, Ro, Rosenfeld, Jc, Strobl, Dj, Steinhoff, Jp, Adams, A, Estevez, R, Molin, Cj, Kim, Cy, Dy, J, Fox, Ke, Farris, Nr, Wayne, Jd, Whitney, Rt, Randhawa, Pm, Mego, Dm, Macdolnald, L, Caputo, Rp, Rigolosi, R, Vannatta, B, Pacheco, Tr, El-Shahawy, M, Gonzalez, Ej, Guice, Mj, Cherlin, Rs, Bays, He, Shoukfeh, M, Morris, Fh, Loy, J, Vora, Sk, Staab, Pk, Frisoli, A, Kimmel, Ma, Cohen, Aj, Green, Cb, Whitlock, L, Butuk, Dj, Mccartney, Mj, Ables, Lr, Acosta, R, Alvarez, Jg, Barrera, Cm, Benitez, O, Berenguer, Ra, Breton, Cf, Chiong, R, Delgado, Mi, Dufreny, A, Fialkow, Ja, Franczek, S, Frias, Jj, Iglesias, C, Landron-Garcia, L, Llerena, Sn, Martinez, Rf, Miranda, Aa, Morytko, Ja, Rodriguez, Ij, Sotolongo, R, Suarez-Sarmiento, A, Terrelonge, Ae, Vaca, Ce, Venereo, Jm, Verdeza, C, Zeno, Ml, Chilka, S, Felten, Wr, Hartman, An, Shayani, Ss, Duprez, D, Knickelbine, T, Chambers, Jd, Cone, Cl, Broughton, R, Napoli, Mc, Seaton, Bl, Smith, Sk, Reedy, Ma, Kesani, Mk, Nicol, Pr, Stringam, So, Talano, Jv, Barnum, O, Desai, V, Montero, M, Jacks, Rk, Kostis, Jb, Owen, Jg, Makam, Sk, Grosman, I, Underberg, Ja, Masri, Be, Peters, Ss, Serje, J, Lenhard, Mj, Glover, R, Paraboschi, Cf, Lim, Eh, Connery, L, Kipgen, W, Bravo, P, Digiovanna, Mj, Tayoum, H, Gabriel, Jd, Ariani, Mk, Robinson, Mf, Clemens, Pc, Corder, Cn, Schifferdecker, B, Tahirkheli, Nk, Hurling, Rt, Rendell, Ms, Shivaswamy, V, Madu, Ij, Dahl, Cf, Ayesu, K, Kim, C, Barettella, Mb, Jamidar, Ha, Bloom, Sa, Vora, Kn, Ong, St, Aggarwala, G, Sack, G, Blaze, K, Krichmar, P, Murcia, A, Teltser, M, Villaman-Bencosme, Y, Fahdi, Ie, Williams, Dg, Lain, El, Garcia, Hl, Karim, Sn, Francyk, Dm, Gordon, Mb, Palchick, Ba, Mckenzie, Me, Gimness, Mp, Greiff, J, Ruiz-R, L, Vazquez-Tanus, Jb, Schlager, D, Connelly, T, Soroka, E, Hastings, Wl, O’Dea, Dj, Purdy, Da, Jackson, B, Arcanese, Ml, Strain, Je, Schmedtje JF Jr, Jrdavis, Mg, A, A, Prasada, S, Scott, Dl, Vukotic, G, Akhtar, N, Larsen, Dc, Rhudy, Jm, Zebrack, Js, Bailey, Sr, Grant, Dc, Mora, A, Perez, Ja, Reyes, Rg, Sutton, Jc, Brandon, Dm, First, Bp, Risser, Ja, Claudio, J, Figueroa-Cruz, Wl, Sosa-Padilla, Ma, Tan, Ae, Traboulssi, Ma, Morcos, Nc, Glaser, La, Bredlau, Ce, El Shahawy, M, Ramos, Mj, Kandath, Dd, Kaluski, E, Akright, L, Rictor, Kw, Pluto, Tm, Hermany, Pr, Bellingar, B, Clark, Gb, Herrod, Jn, Goisse, M, Hook, M, Barrington, P, Lentz, Jd, Singal, Dk, Gleason, Gp, Lipetz, Rs, Schuchard, Tn, Bonner, Jh, Forgosh, Lb, Lefebvre, Gc, Pierpoint, Be, Radin, Dm, Stoller, Sr, Segall, N, Shah, Sa, Ramstad, Ds, Nisnisan, Jm, Trippett, Jm, Benjamin, Sa, Labissiere, Jc, Nashed, An, Maaieh, M, Aslam, Aa, Mandviwala, M, Budoff, Mj, French, Wj, Vlach, Jj, Destefano, P, Bayron, Cj, Fraser, Nj, Sandberg, Jh, Fagan, Tc, Peart, Bc, Suryanarayana, Pg, Gupta, Dk, Lee, Mw, Bertolet, Bd, Hartley, Pa, Kelberman, M, Behmanesh, B, Buynak, Rj, Chochinov, Rh, Steinberg, Aa, Chandna, H, Bjasker, Kr, Perlman, Rl, Ball, Em, Pock, J, Singh, S, Baldari, D, Kaster, S, Lovell, Jp, Horowitz, Bs, Gorman, Ta, Pham, Dn, Landzberg, Js, Mootoo, Ki, Moon, E, Krawczyk, J, Alfieri, Ad, Janik, Mj, Herrington, Dm, Koilpillai, Rn, Waxler, Ar, Hoffman, Da, Sahul, Zh, Gumbiner, B, Cropp, A, Fujita, K, Garzone, P, Imai, K, Levisetti, M, Plowchalk, D, Sasson, S, Skaggs, J, Sweeney, K, Vincent, J., Curto, M, Ridker, P., Revkin, J., Amarenco, P., Brunell, R., Curto, M., Civeira, F., Flather, M., Glynn, R., Gregoire, J., Jukema, J., Karpov, Y., Kastelein, J., Koenig, W., Lorenzatti, A., Manga, P., Masiukiewicz, U., Miller, M., Mosterd, A., Murin, J., Nicolau, J., Nissen, S., Ponikowski, P., Santos, R., Schwartz, P., Soran, H., White, H., Wright, R., Vrablik, M., Yunis, C., Shear, C., Tardif, J., SPIRE Cardiovascular Outcome Investigators, Averna, M., Brigham and Women's Hospital [Boston], Université Paris Diderot - Paris 7 (UPD7), Université Sorbonne Paris Cité (USPC), RS: CARIM - R3.02 - Hypertension and target organ damage, MUMC+: MA Alg Interne Geneeskunde (9), Interne Geneeskunde, Ridker, P. M., Glynn, R. J., Jukema, J. W., Kastelein, J. J. P., Nicolau, J. C., Santos, R. D., Schwartz, P. F., Wright, R. S., Shear, C. L., Tardif, J. -C., SPIRE Cardiovascular Outcome Investigator, Perrone, Filardi, P, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, ACS - Pulmonary hypertension & thrombosis, and ACS - Atherosclerosis & ischemic syndromes
Subjects: Male, STATIN THERAPY, Anticholesteremic Agents/adverse effects, Antibodie, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Injections, Subcutaneous/adverse effects, 030204 cardiovascular system & hematology, Bococizumab, law.invention, PCSK9, 0302 clinical medicine, Randomized controlled trial, law, Risk Factors, GENETIC-VARIANTS, Cardiovascular Disease, Monoclonal, Anticholesteremic Agent, 030212 general & internal medicine, Myocardial infarction, Treatment Failure, Humanized, Proprotein Convertase 9/antagonists & inhibitors, Medicine(all), Antibodies, Antibodies, Monoclonal, Humanized, Anticholesteremic Agents, Cardiovascular Diseases, Cholesterol, LDL, Double-Blind Method, Female, Follow-Up Studies, Humans, Hypercholesterolemia, Injections, Subcutaneous, Lipids, Middle Aged, Proprotein Convertase 9, Medicine (all), PCSK9 Inhibitors, antibodies monoclonal humanized, anticholesteremic agents, cardiovascular diseases, cholesterol, LDL, double-blind method, female, follow-up studies, humans, hypercholesterolemia, injections, subcutaneous, lipids, male, middle aged, proprotein convertase 9, risk factors, treatment failure, medicine (all), Vascular damage Radboud Institute for Molecular Life Sciences [Radboudumc 16], General Medicine, Lipid, 3. Good health, LDL/blood, Multicenter Study, Cholesterol, TRIALS, Cholesterol, LDL/blood, Antibodies, Monoclonal, Humanized/adverse effects, Randomized Controlled Trial, subcutaneous, lipids (amino acids, peptides, and proteins), Cardiovascular Diseases/prevention & control, REDUCING LIPIDS, Human, medicine.medical_specialty, animal structures, Hypercholesterolemia/drug therapy, Placebo, Injections, Subcutaneou, LDL, Injections, Follow-Up Studie, EVENTS, 03 medical and health sciences, Internal medicine, medicine, Journal Article, Comparative Study, METAANALYSIS, Alirocumab, business.industry, Unstable angina, Lipids/blood, Risk Factor, fungi, Antibodies/blood, ta3121, medicine.disease, Surgery, Evolocumab, REDUCTION, Humanized/adverse effects, Subcutaneous/adverse effects, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Item does not contain fulltext BACKGROUND: Bococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and reduces levels of low-density lipoprotein (LDL) cholesterol. We sought to evaluate the efficacy of bococizumab in patients at high cardiovascular risk. METHODS: In two parallel, multinational trials with different entry criteria for LDL cholesterol levels, we randomly assigned the 27,438 patients in the combined trials to receive bococizumab (at a dose of 150 mg) subcutaneously every 2 weeks or placebo. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death; 93% of the patients were receiving statin therapy at baseline. The trials were stopped early after the sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies, as seen in data from other studies in the program. The median follow-up was 10 months. RESULTS: At 14 weeks, patients in the combined trials had a mean change from baseline in LDL cholesterol levels of -56.0% in the bococizumab group and +2.9% in the placebo group, for a between-group difference of -59.0 percentage points (P/=70 mg per deciliter [1.8 mmol per liter] and the median follow-up was 7 months), major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group (hazard ratio, 0.99; 95% confidence interval [CI], 0.80 to 1.22; P=0.94). In the higher-risk, longer-duration trial (in which the patients had a baseline LDL cholesterol level of >/=100 mg per deciliter [2.6 mmol per liter] and the median follow-up was 12 months), major cardiovascular events occurred in 179 and 224 patients, respectively (hazard ratio, 0.79; 95% CI, 0.65 to 0.97; P=0.02). The hazard ratio for the primary end point in the combined trials was 0.88 (95% CI, 0.76 to 1.02; P=0.08). Injection-site reactions were more common in the bococizumab group than in the placebo group (10.4% vs. 1.3%, P
Published: 2017
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3. Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events

Author: Robinson, J. G., Farnier, M., Krempf, M., Bergeron, J., Luc, G., Averna, M., Stroes, E. S., Langslet, G., Raal, F. J., El Shahawy, M., Koren, M. J., Lepor, N. E., Lorenzato, C., Pordy, R., Chaudhari, U., Kastelein, J. J., ODYSSEY LONG TERM Investigators, Lembo, Giuseppe, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Robinson, J., Farnier, M., Krempf, M., Bergeron, J., Luc, G., Averna, M., Stroes, E., Langslet, G., Raal, F., El Shahawy, M., Koren, M., Lepor, N., Lorenzato, C., Pordy, R., Chaudhari, U., Kastelein, J., University of Iowa [Iowa City], Le point, Centre hospitalier universitaire de Nantes (CHU Nantes), Clinique des Maladies Lipidiques de Québec, Partenaires INRAE, Université de Lille, Università degli studi di Palermo - University of Palermo, University of Amsterdam [Amsterdam] (UvA), University of Oslo (UiO), University of the Witwatersrand [Johannesburg] (WITS), Cardiovascular Center Sarasota, Jacksonville Center for Clinical Research, Westside Medical Associates L A, Sanofi, Regeneron Pharmaceuticals [Tarrytown], Sanofi Bridgewater, Università degli Studi di Palermo, and Regeneron Pharmaceuticals Inc.
Subjects: Male, medicine.medical_specialty, Settore MED/09 - Medicina Interna, Intention to Treat Analysi, Hypercholesterolemia, Urology, alirocumab, Bococizumab, Pharmacology, Placebo, Aged, Antibodies, Monoclonal, Anticholesteremic Agents, Cardiovascular Diseases, Cholesterol, LDL, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Intention to Treat Analysis, Middle Aged, Medicine (all), law.invention, chemistry.chemical_compound, cardiovascular events, Randomized controlled trial, law, Cardiovascular Disease, Anticholesteremic Agent, Medicine, proprotein convertase subtilisin–kexin type 9 (PCSK9), High Cardiovascular Risk Patients, Alirocumab, cholesterol, Cholesterol, business.industry, PCSK9, General Medicine, Lomitapide, Evolocumab, chemistry, low-density lipoprotein (LDL) cholesterol, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, lipids (amino acids, peptides, and proteins), Hydroxymethylglutaryl-CoA Reductase Inhibitor, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Human
Abstract: BACKGROUND: Alirocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), has been shown to reduce low-density lipoprotein (LDL) cholesterol levels in patients who are receiving statin therapy. Larger and longer-term studies are needed to establish safety and efficacy.METHODS: We conducted a randomized trial involving 2341 patients at high risk for cardiovascular events who had LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or more and were receiving treatment with statins at the maximum tolerated dose (the highest dose associated with an acceptable side-effect profile), with or without other lipid-lowering therapy. Patients were randomly assigned in a 2:1 ratio to receive alirocumab (150 mg) or placebo as a 1-ml subcutaneous injection every 2 weeks for 78 weeks. The primary efficacy end point was the percentage change in calculated LDL cholesterol level from baseline to week 24.RESULTS: At week 24, the difference between the alirocumab and placebo groups in the mean percentage change from baseline in calculated LDL cholesterol level was -62 percentage points (PCONCLUSIONS: Over a period of 78 weeks, alirocumab, when added to statin therapy at the maximum tolerated dose, significantly reduced LDL cholesterol levels. In a post hoc analysis, there was evidence of a reduction in the rate of cardiovascular events with alirocumab. (Funded by Sanofi and Regeneron Pharmaceuticals; ODYSSEY LONG TERM ClinicalTrials.gov number, NCT01507831.).
Published: 2015
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4. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials

Author: Fulcher, J, Mihaylova, B, O'Connell, R, Emberson, J, Blackwell, L, Reith, C, Koren, M, Tonkin, A, Ridker, P, Barnes, E, Ford, I, Kean, S, Trompet, S, Macfarlane, P, Cannon, C, Pedersen, TR, Wilhelmsen, L, LaRosa, J, Packard, C, Robertson, M, Young, R, Tobert, J, Flather, M, Goto, S, Kastelein, J, Newman, C, Shear, C, Varigos, J, White, H, Armitage, J, Davies, K, Halls, H, Harper, C, Herrington, W, Holland, L, Kirby, A, Oconnell, R, Preiss, D, Spata, E, Wilson, K, Lonn, E, Wanner, C, Koenig, W, Gotto, A, Kjekshus, J, Yusuf, S, Collins, R, Simes, J, Baigent, C, Keech, A, De Lemos, J, Braunwald, E, Blazing, M, Murphy, S, Downs, JR, Clearfield, M, Holdaas, H, Gordon, D, Davis, B, Dahlof, B, Poulter, N, Sever, P, Knopp, RH, Fellstrom, B, Jardine, A, Schmieder, R, Zannad, F, Colhoun, HM, Betteridge, DJ, Durrington, PN, Hitman, GA, Fuller, J, Neil, A, Sacks, F, Moye, L, Pfeffer, M, Hawkins, CM, Wedel, H, Wikstrand, J, Krane, V, Tavazzi, L, Maggioni, A, Marchioli, R, Tognoni, G, Franzosi, MG, Bowman, L, Landray, MJ, Parish, S, Peto, R, Sleight, P, Ridker, PM, Macmahon, S, Marschner, I, Shaw, J, Serruys, PW, Nakamura, H, Knatterud, G, Furberg, C, Byington, R, Sattar, N, and Jukema, JW
Subjects: medicine.medical_specialty, Statin, medicine.drug_class, Atorvastatin, 030204 cardiovascular system & hematology, ATORVASTATIN, PURLs®, Rate ratio, Article, 03 medical and health sciences, 0302 clinical medicine, Medicine, General & Internal, Risk Factors, Internal medicine, General & Internal Medicine, medicine, Humans, Rosuvastatin, CORONARY-HEART-DISEASE, 030212 general & internal medicine, Myocardial infarction, ROSUVASTATIN, Stroke, ELDERLY-PATIENTS, Aged, Randomized Controlled Trials as Topic, Aged, 80 and over, RISK, Science & Technology, Cholesterol Treatment Trialists' Collaboration, Vascular disease, business.industry, CHOLESTEROL, Age Factors, General Medicine, 11 Medical And Health Sciences, medicine.disease, R1, 3. Good health, LOWERING THERAPY, Regimen, MYOCARDIAL-INFARCTION, Cardiovascular Diseases, CARDIOVASCULAR-DISEASE, Hydroxymethylglutaryl-CoA Reductase Inhibitors, business, PRIMARY PREVENTION, Life Sciences & Biomedicine, medicine.drug
Abstract: Background: Statin therapy has been shown to reduce major vascular events and vascular mortality in a wide range of individuals, but there is uncertainty about its efficacy and safety among older people. We undertook a meta-analysis of data from all large statin trials to compare the effects of statin therapy at different ages.Methods: In this meta-analysis, randomised trials of statin therapy were eligible if they aimed to recruit at least 1000 participants with a scheduled treatment duration of at least 2 years. We analysed individual participant data from 22 trials (n=134 537) and detailed summary data from one trial (n=12 705) of statin therapy versus control, plus individual participant data from five trials of more intensive versus less intensive statin therapy (n=39 612). We subdivided participants into six age groups (55 years or younger, 56–60 years, 61–65 years, 66–70 years, 71–75 years, and older than 75 years). We estimated effects on major vascular events (ie, major coronary events, strokes, and coronary revascularisations), cause-specific mortality, and cancer incidence as the rate ratio (RR) per 1·0 mmol/L reduction in LDL cholesterol. We compared proportional risk reductions in different age subgroups by use of standard χ2 tests for heterogeneity when there were two groups, or trend when there were more than two groups.Findings: 14 483 (8%) of 186 854 participants in the 28 trials were older than 75 years at randomisation, and the median follow-up duration was 4·9 years. Overall, statin therapy or a more intensive statin regimen produced a 21% (RR 0·79, 95% CI 0·77–0·81) proportional reduction in major vascular events per 1·0 mmol/L reduction in LDL cholesterol. We observed a significant reduction in major vascular events in all age groups. Although proportional reductions in major vascular events diminished slightly with age, this trend was not statistically significant (ptrend=0·06). Overall, statin or more intensive therapy yielded a 24% (RR 0·76, 95% CI 0·73–0·79) proportional reduction in major coronary events per 1·0 mmol/L reduction in LDL cholesterol, and with increasing age, we observed a trend towards smaller proportional risk reductions in major coronary events (ptrend=0·009). We observed a 25% (RR 0·75, 95% CI 0·73–0·78) proportional reduction in the risk of coronary revascularisation procedures with statin therapy or a more intensive statin regimen per 1·0 mmol/L lower LDL cholesterol, which did not differ significantly across age groups (ptrend=0·6). Similarly, the proportional reductions in stroke of any type (RR 0·84, 95% CI 0·80–0·89) did not differ significantly across age groups (ptrend=0·7). After exclusion of four trials which enrolled only patients with heart failure or undergoing renal dialysis (among whom statin therapy has not been shown to be effective), the trend to smaller proportional risk reductions with increasing age persisted for major coronary events (ptrend=0·01), and remained non-significant for major vascular events (ptrend=0·3). The proportional reduction in major vascular events was similar, irrespective of age, among patients with pre-existing vascular disease (ptrend=0·2), but appeared smaller among older than among younger individuals not known to have vascular disease (ptrend=0·05). We found a 12% (RR 0·88, 95% CI 0·85–0·91) proportional reduction in vascular mortality per 1·0 mmol/L reduction in LDL cholesterol, with a trend towards smaller proportional reductions with older age (ptrend=0·004), but this trend did not persist after exclusion of the heart failure or dialysis trials (ptrend=0·2). Statin therapy had no effect at any age on non-vascular mortality, cancer death, or cancer incidence.Interpretation: Statin therapy produces significant reductions in major vascular events irrespective of age, but there is less direct evidence of benefit among patients older than 75 years who do not already have evidence of occlusive vascular disease. This limitation is now being addressed by further trials.Funding: Australian National Health and Medical Research Council, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, and British Heart Foundation.
Published: 2019
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5. Large scale association analysis of novel genetic loci for coronary artery disease

Author: Amouyel, P., Arveiler, D., Boekholdt, S. M., Braund, P., Bruse, P., Bumpstead, S. J., Bugert, P., Cambien, F., Danesh, J., Deloukas, P., Doering, A., Ducimetiere, P., Dunn, R. M., El Mokhtari, N. E., Erdmann, J., Evans, A., Ewels, P., Ferrieres, J., Fischer, Matthias, Frossard, P., Garner, S., Gieger, C., Gohri, M. J. R., Goodall, A. H., Grosshennig, A., Hall, A., Hardwick, R., Haukijarvi, A., Hengstenberg, C., Illig, T., Karvanen, J., Kastelein, J., Kee, F., Khaw, K. T., Kluter, H., Konig, I. R., Kuulasmaa, K., Laiho, P., Luc, G., Marz, W., McGinnis, R., McLaren, W., Meisinger, C., Morrison, C., Ou, X., Ouwehand, W. H., Preuss, M., Proust, C., Ravindrarajah, R., Renner, W., Rice, K., Ruidavets, J. B., Saleheen, D., Salomaa, V., Samani, N. J., Sandhu, M. S., Schafer, A. S., Scholz, M., Schreiber, Stefan, Schunkert, H., Silander, K., Singh, R., Soranzo, N., Stark, K., Stegmayr, B., Stephens, J., Thompson, J., Tiret, L., Trip, M. D., van der Schoot, E., Virtamo, J., Wareham, N. J., Wichmann, H. E., Wiklund, P. G., Wright, B., Ziegler, A., Zwaginga, J. J., Amsterdam Cardiovascular Sciences, and Cardiology
Subjects: Male, Risk, Single-nucleotide polymorphism, Locus (genetics), Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, White People, Article, Coronary artery disease, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Odds Ratio, medicine, Humans, Genetic Predisposition to Disease, Family history, Aged, 030304 developmental biology, Genetic association, Genetics, 0303 health sciences, business.industry, Case-control study, Odds ratio, Middle Aged, medicine.disease, Case-Control Studies, Female, business, Cardiology and Cardiovascular Medicine, Genome-Wide Association Study
Abstract: Background— Combined analysis of 2 genome-wide association studies in cases enriched for family history recently identified 7 loci (on 1p13.3, 1q41, 2q36.3, 6q25.1, 9p21, 10q11.21, and 15q22.33) that may affect risk of coronary artery disease (CAD). Apart from the 9p21 locus, the other loci await substantive replication. Furthermore, the effect of these loci on CAD risk in a broader range of individuals remains to be determined. Methods and Results— We undertook association analysis of single nucleotide polymorphisms at each locus with CAD risk in 11 550 cases and 11 205 controls from 9 European studies. The 9p21.3 locus showed unequivocal association (rs1333049, combined odds ratio [OR]=1.20, 95% CI [1.16 to 1.25], probability value=2.81×10 −21 ). We also confirmed association signals at 1p13.3 (rs599839, OR=1.13 [1.08 to 1.19], P =1.44×10 −7 ), 1q41 (rs3008621, OR=1.10 [1.04 to 1.17], P =1.02×10 −3 ), and 10q11.21 (rs501120, OR=1.11 [1.05 to 1.18], P =4.34×10 −4 ). The associations with 6q25.1 (rs6922269, P =0.020) and 2q36.3 (rs2943634, P =0.032) were borderline and not statistically significant after correction for multiple testing. The 15q22.33 locus did not replicate. The 10q11.21 locus showed a possible sex interaction ( P =0.015), with a significant effect in women (OR=1.29 [1.15 to 1.45], P =1.86×10 −5 ) but not men (OR=1.03 [0.96 to 1.11], P =0.387). There were no other strong interactions of any of the loci with other traditional risk factors. The loci at 9p21, 1p13.3, 2q36.3, and 10q11.21 acted independently and cumulatively increased CAD risk by 15% (12% to 18%), per additional risk allele. Conclusions The findings provide strong evidence for association between at least 4 genetic loci and CAD risk. Cumulatively, these novel loci have a significant impact on risk of CAD at least in European populations.
Published: 2009
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6. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus

Author: Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I, Desai N, Abrahamsen T, Grossman M, Morin S, Im K, Hoffman E, Gabovitch D, Pricken A, Buskila A, Stahre C, Price D, Billing-Clason S, Sabel K, Monyak J, Sjostrand M, Wei C, Lu J, Miller E, Raichlen J, Fitt S, Iqbal N, Donovan M, Davidson JA, Aguilar-Salinas C, Alvarsson M, Amerena J, Ardissino D, Averkov O, Avogaro A, Barnett A, Bretzel R, Chiang CE, Codoceo V, Corbalan R, Dalby A, Darius H, Deerochanawong C, Dellborg M, Eliaschewitz F, Garcia-Castillo A, Gomis R, Henry P, Hoekstra J, Jermendy G, Kastelein J, Keech A, Kiss R, Krempf M, Laakso M, Leiter L, Leitersdorf E, Lewis B, Litwak L, Lopez-Sendon J, Ma R, McGuire D, Medina F, Moses R, Nicolau JC, Opolski G, Ophuis TO, Paolasso E, Ruda M, Kumar KMP, Shestakova M, Sheu WHH, Smahelova A, Bhupathiraju BSR, Spinar J, Sritata P, Strojeck K, Villena-Chavez JE, Jia WP, Huo Y, Lowe C, Awtry E, Berger C, Desai AS, Gelfand E, Leeman D, Link M, Ruberg F, Vita J, Rost N, Silverman S, Greenberger NJ, Lerch MM, Gersh B, Nesto R, Del Prato S, Tuomilehto J, Kelsey S, Alvarisqueta A, Cuadrado J, Rista L, Hermida S, Baccaro C, Luquez C, Lagrutta M, Maffei L, Bartolacci I, Montana O, Cutuli H, Berli M, Lorenzatti A, Frechtel G, La Greca R, Fretes O, Diaz M, Papini NR, Farias E, Issa C, Elbert A, Lehman R, Arya M, Singh B, Colquhoun D, Jayasinghe R, de Looze F, Blombery P, Ward G, Szto G, Abhayaratna W, Borges J, Russo L, Felicio J, Santos F, Guimaraes F, Castro ML, Rossi P, Armaganijan D, Leaes P, Bandeira F, Franken M, Rassi N, Rea R, Zanella M, Amodeo C, Cesar L, Betti R, Chacra A, Schmid H, Bell A, Syan G, Zadra R, Conter H, Dumas R, Borts D, Dattani I, Poirier P, Cha J, Dzongowski P, Labonte R, St Pierre B, Gaudet D, Kouz S, Lamy A, Tishler S, Chehayeb R, Bedard J, Hramiak I, Teitelbaum I, Fortin C, Woo V, Conway J, Mehta P, Robinson S, Sussex B, Chiasson J, Muirhead N, Bose S, Ouellet A, Yale J, Bhargava R, Lau D, Tobe S, Perron P, Sigalas J, Bilodeau L, Tytus R, Achyuthan G, Pearce M, Steele A, Bailey G, Ma P, St-Maurice F, Rupka D, Houlden R, Bailey A, Rewa G, Sohal P, Ting R, Prieto J, Rodriguez M, Godoy G, Larenas G, Pincetti C, Cobos L, Saavedra V, Varleta P, Lucero F, Kuzmanic O, Acevedo M, Aguirre M, Florenzano F, Ma J, Bao Y, Jiang M, Xu W, Shi Y, Zheng M, Li Y, Dong Y, Zhao W, Sun M, Lei M, Wang J, Pistek Z, Rihacek I, Kucera D, Brada M, Naplava R, Karasova J, Vlasicova H, Skopecek J, Spinarova L, Raclavska L, Sarbochova R, Okenka L, Racicka E, Urbancova K, Oznerova M, Lorenc Z, Wasserburger B, Zahumensky E, Grunfeldova H, Hradec J, Lukac M, Svacina S, Podzimek J, Hemzsky L, Mikulkova I, Pavlickova J, Brychta T, Chochola J, Couffinhal T, Elbaz M, Petit C, Faller B, Marechaud R, Moulin P, Fendri S, Nazeyrollas P, Wendisch U, Busch K, Klausmann G, Duengen H, Appel K, Toursarkissian N, Jung T, Ott P, Schenkenberger I, Kuesters D, Landers B, Nischik R, Fischer H, Tschoepe D, Paschen B, Krause K, Derwahl K, Wenzl-Bauer V, Hamann A, Strotmann H, Milek K, Mueller S, Chu D, Tan K, Kung K, Tsang C, Tomlinson B, Koranyi L, Kerenyi Z, Benczur B, Illyes L, Hidvegi T, Somogyi A, Valco J, Ferenczi S, Rapi J, Voros P, Winkler G, Sydo T, Hetey M, Simon K, Penzes J, Kempler P, Bako B, Lengyel Z, Witmann I, Dudas M, Vandorfi G, Takacs J, Matoltsy A, Ladanyi E, Gyimesi A, Sadikot S, Parikh K, Jain S, Yajnik C, Sosale A, Shamanna P, Srikanta S, Shah S, Srinivas A, Banker D, Shah P, Sharda A, Makkar B, Rais N, Mardikar H, Mishra A, Bhupati S, Menon J, Sathe S, Gupta R, Sharma V, Darawsha M, Herskovits T, Hamoud S, Nikolsky E, Adawi F, Zimlichman R, Tsalihin D, Wainstein J, Klainman E, Mosseri M, Yerushalmi Y, Karnieli E, Knobler H, Benchetrit S, Tsur A, Yagil Y, Atar S, Beberashvili I, Fuchs S, Stern N, Pollak A, Chajek-Shaul T, Rozenman Y, Biton A, Bramucci E, Fiscella A, Grassia V, Piatti P, De Cosmo S, Di Lorenzo L, Merlini P, Mannucci E, Frontoni S, Trevisan R, Zenari L, Lambiase C, Salvioni A, Silvestri O, Ambrosio G, Di Bartolo P, Fattore L, Presbitero P, Calabrese M, Evola R, Gamba MA, Ibarra MOD, Munoz EC, Sanchez DR, Herrera CH, Rios JP, Llamas EB, Esperon GL, Cantu EG, Fragoso JN, Gonzalez JG, Martinez GR, Padilla FP, Mier GM, Marmolejo DH, Ruiz JG, Portilla NC, Rosas EL, Machado GM, Ramos JC, Briones IR, van Hessen MWJ, Strikwerda S, The SHK, Kooy A, Ronner E, Nierop PR, Remmen JJ, Groenemeijer BE, Hamer BJB, Basart DCG, van Lennep HWOR, Nieuwdorp M, van Dijk MPM, Kentgens S, van Kempen WW, Hoogendijk J, Spiering W, Voors-Pette C, Kose V, de Waard DEP, Gonkel F, Kaasjager HAH, Lingan GMR, Agous I, Kruik HJ, Imholz BPM, Pieterse M, Manrique H, Villena J, Leon L, Kundert K, Minchola J, Pinto M, Heredia J, Rodriguez A, Guerreros C, Berrospi P, Zubiate C, Allemant A, Arbanil H, Ponciano W, Calderon J, Lisson R, Segura L, Sidorowicz-Bialynicka A, Sciborski R, Fares I, Mader P, Skierkowska J, Stasinska T, Pomiecko W, Skorski M, Krzyzagorska E, Polaszewska-Muszynska M, Sowinski D, Strojek K, Rosinska-Migda J, Romanczuk P, Golebiowski G, Kubica J, Mazurek T, Wojnowski L, Pasternak D, Stachlewski P, Trzepla E, Bogdanowicz G, Uzunow A, Potakowska I, Miszczyszyn Z, Waszyrowski T, Smolenskaya O, Lukyanov Y, Vorokhobina N, Khalimov Y, Orlikova O, Rebrov A, Kukharchuk V, Boldueva S, Arkhipov M, Zhelninova T, Pavlysh E, Antsiferov M, Panov A, Pavlova M, Shustov S, Demchenko E, Galyavich A, Malakhina E, Semenova O, Kobalava Z, Kotova S, Gavrisheva I, Oschepkova E, Karpov Y, Sidorenko B, Kislyak O, Ametov A, Dreval A, Grineva E, Mkrtumyan A, Tyurina T, Sazonova O, Bonnici F, Ranjith N, Burgess L, Nortje H, Distiller L, Mitha I, Moore R, Conradie M, Horak A, Pillay S, Wellmann H, Berg E, Pillai P, Padayachee T, Corbett C, Makan H, Wing J, Vawda Z, Ebrahim I, Mitha E, Bhorat A, Fernandez JC, Munoz C, Cortada JB, Conde AC, Calvo C, Extremera BG, Delgado E, Masmiquel L, Puig JG, Parreno LD, Mauricio D, Redon J, Brito M, Lopez C, de la Morera JS, Linderfalk C, Larnefeldt H, Olsson A, Lonneborg L, Ekelund M, Samad B, Borgencrantz B, Nilsson J, Berglund O, Svensson M, Mooe T, Curiac D, Albin J, Angesjo E, Lannemyr O, Chiang C, Sheu W, Chen J, Tien K, Ueng K, Lai W, Yin W, Hung Y, Shyu K, Hou J, Lam H, Laothavorn P, Kuanprasert S, Khovidhunkit W, Benjasuratwong Y, Chotinaiwattarakul C, Mamanasiri S, Suraamornkul S, Pratipanawatr T, Nitiyanant W, Heller S, Ray K, Pieters R, Strang C, Bodalia B, Middleton A, Hall T, Chapman G, Calvert J, Reed R, Tam D, Butcher G, Jones N, Takhar A, Turner W, McNally D, Corey O, Chapman J, Mohr S, Edwards S, Bhatt D, Ocampo A, Kandath D, Aude Y, Ervin W, Savin V, Anderson R, Littlefield R, Oberoi M, Platt GE, Yazdani S, Mangoo-Karim R, Walder J, Gogia H, Chandrashekhar Y, Boccalandro F, Rogers W, Bilazarian S, Zieve F, Siage Y, O'Connor T, Mudaliar S, Nikas A, Giusti R, Glover R, Chilka S, French W, Roth E, Singh N, Christofferson R, Stich M, Dagogo-Jack S, Allison J, Zengotita GA, Ison R, Iteld B, Sulistio M, Gonzalez E, Gorman T, Hage-Korban E, Reddy R, Byars W, Antonishen M, Benjamin S, First B, Rosado J, Bruschetta H, Poling T, Rosendorff C, Kerstein HJ, Saba F, Willis J, Adams K, Vazquez EC, Ellison H, Kahn B, Kereiakes D, Powell S, Raskin P, Smith K, Varma S, Whittier F, Casanova R, Isserman S, Kaye W, McGuinn W, Bartkowiak A, Dworkin L, Labrador CA, Podlecki D, Popovtzer M, Aronoff S, Ballantyne C, Ortiz EG, Mora A, Pitts T, Reinhardt S, Soucie G, Wainwright W, Henson B, Sklaver N, Arakaki R, Brown J, Chalavarya G, Chochinov R, Dixon T, Kutner M, Perlman R, Raisinghani A, Salacata A, Awasty V, Elinoff V, George W, LaRochelle-Gryseels A, Mercado A, Miller G, Qureshi M, Steljes A, Wefald F, Wilson J, Chinn J, Chuang RB, Comulada-Rivera A, Hartman I, Narayan P, Pacheco T, Weiss R, Beavins J, Creevy J, Hamroff G, Hodson R, Kosinski E, Krichmar P, Patel R, Schneider R, Shapiro J, Sharp D, Speer J, Stegemoller R, Waxman F, Chang FY, Braun E, Eder F, Minor S, Albert M, Carr KW, Diaczok B, Gastman I, Gupta V, Longshaw K, Gonzalez-Campoy JM, Raikhel M, Thomas J, Wood K, Diab I, Furda J, Gelernt M, Halter M, House B, Kaster S, Raad G, Stamatin R, Barker B, Blonder R, Bloomberg RJ, Calderon RB, Carrol A, Comerota A, Feinglos M, Henderson D, Kastelic R, Stonesifer LD, Talano J, Lee PV, Brosseau J, Clark W, Cohen E, Fialkow J, Horton K, Kozman H, McGill J, Mihills C, Poonawala R, Shore K, Tejada L, Torres R, Wright W, Calatayud G, Chandna H, Drozdiak R, Fink R, Gill R, Glandt M, Gottlieb DW, Hack T, Kay J, Mansouri V, McKnight T, Mostel E, Schmidt L, Seide H, Sonel E, Taylor R, Velasquez M, Bretton E, Feldman R, Hartman A, Hershon K, Leach CR, Martin E, Mohiuddin F, Naygandhi Y, Riske T, Schima S, Uzoaga ER, Ward H, Weinstock R, Williams T, Altschuller A, Aoki T, Blumenthal S, Cash A, Eisner G, Gutmann J, Hagan M, Kabour A, Markus T, McKenzie W, Moursi M, Mystkowski P, Ovalle F, Perkins R, Popeil L, Saniuk R, Sierra Y, Alvarado O, Anderson J, Bajaj M, Blank R, Chu A, Levinsky L, Levy P, Osborne J, Pavon H, Sanderlin D, Schaer G, Zarich S, Atassi K, Bayron C, Casagrande M, Das D, Gimness M, Handel F, Kinstrey T, Leu S, Osei K, Nouel JS, Soltani Z, Sussman H, Chiu K, Duda R, Farnsworth K, Lano M, Lee F, Levin P, Pratt S, Richwine R, Ruiz-Rivera L, Turner J, Wood J, Zigrang WD, Baquerizo HR, Colon CB, Demattia J, Desai V, Fitz-Patrick D, Goral S, Odhav A, Prentiss A, Ruff C, Wu W, Wyne K, Abbott LG, Applegate R, Cabral J, Kotha P, Ortega P, Simmons D, General Internal Medicine, Vascular Medicine, Other departments, Scirica, B, Bhatt, D, Braunwald, E, Steg, P, Davidson, J, Hirshberg, B, Ohman, P, Frederich, R, Wiviott, S, Hoffman, E, Cavender, M, Udell, J, Desai, N, Mosenzon, O, Mcguire, D, Ray, K, Leiter, L, Raz, I, Abrahamsen, T, Grossman, M, Morin, S, Im, K, Gabovitch, D, Pricken, A, Buskila, A, Stahre, C, Price, D, Billing-Clason, S, Sabel, K, Monyak, J, Sjostrand, M, Wei, C, Lu, J, Miller, E, Raichlen, J, Fitt, S, Iqbal, N, Donovan, M, Aguilar-Salinas, C, Alvarsson, M, Amerena, J, Ardissino, D, Averkov, O, Avogaro, A, Barnett, A, Bretzel, R, Chiang, C, Codoceo, V, Corbalan, R, Dalby, A, Darius, H, Deerochanawong, C, Dellborg, M, Eliaschewitz, F, Garcia-Castillo, A, Gomis, R, Henry, P, Hoekstra, J, Jermendy, G, Kastelein, J, Keech, A, Kiss, R, Krempf, M, Laakso, M, Leitersdorf, E, Lewis, B, Litwak, L, Lopez-Sendon, J, Ma, R, Medina, F, Moses, R, Nicolau, J, Opolski, G, Ophuis, T, Paolasso, E, Ruda, M, Kumar, K, Shestakova, M, Sheu, W, Smahelova, A, Bhupathiraju, B, Spinar, J, Sritata, P, Strojeck, K, Villena-Chavez, J, Jia, W, Huo, Y, Lowe, C, Awtry, E, Berger, C, Desai, A, Gelfand, E, Leeman, D, Link, M, Ruberg, F, Vita, J, Rost, N, Silverman, S, Greenberger, N, Lerch, M, Gersh, B, Nesto, R, Del Prato, S, Tuomilehto, J, Kelsey, S, Alvarisqueta, A, Cuadrado, J, Rista, L, Hermida, S, Baccaro, C, Luquez, C, Lagrutta, M, Maffei, L, Bartolacci, I, Montana, O, Cutuli, H, Berli, M, Lorenzatti, A, Frechtel, G, La Greca, R, Fretes, O, Diaz, M, Papini, N, Farias, E, Issa, C, Elbert, A, Lehman, R, Arya, M, Singh, B, Colquhoun, D, Jayasinghe, R, de Looze, F, Blombery, P, Ward, G, Szto, G, Abhayaratna, W, Borges, J, Russo, L, Felicio, J, Santos, F, Guimaraes, F, Castro, M, Rossi, P, Armaganijan, D, Leaes, P, Bandeira, F, Franken, M, Rassi, N, Rea, R, Zanella, M, Amodeo, C, Cesar, L, Betti, R, Chacra, A, Schmid, H, Bell, A, Syan, G, Zadra, R, Conter, H, Dumas, R, Borts, D, Dattani, I, Poirier, P, Cha, J, Dzongowski, P, Labonte, R, St Pierre, B, Gaudet, D, Kouz, S, Lamy, A, Tishler, S, Chehayeb, R, Bedard, J, Hramiak, I, Teitelbaum, I, Fortin, C, Woo, V, Conway, J, Mehta, P, Robinson, S, Sussex, B, Chiasson, J, Muirhead, N, Bose, S, Ouellet, A, Yale, J, Bhargava, R, Lau, D, Tobe, S, Perron, P, Sigalas, J, Bilodeau, L, Tytus, R, Achyuthan, G, Pearce, M, Steele, A, Bailey, G, Ma, P, St-Maurice, F, Rupka, D, Houlden, R, Bailey, A, Rewa, G, Sohal, P, Ting, R, Prieto, J, Rodriguez, M, Godoy, G, Larenas, G, Pincetti, C, Cobos, L, Saavedra, V, Varleta, P, Lucero, F, Kuzmanic, O, Acevedo, M, Aguirre, M, Florenzano, F, Ma, J, Bao, Y, Jiang, M, Xu, W, Shi, Y, Zheng, M, Li, Y, Dong, Y, Zhao, W, Sun, M, Lei, M, Wang, J, Pistek, Z, Rihacek, I, Kucera, D, Brada, M, Naplava, R, Karasova, J, Vlasicova, H, Skopecek, J, Spinarova, L, Raclavska, L, Sarbochova, R, Okenka, L, Racicka, E, Urbancova, K, Oznerova, M, Lorenc, Z, Wasserburger, B, Zahumensky, E, Grunfeldova, H, Hradec, J, Lukac, M, Svacina, S, Podzimek, J, Hemzsky, L, Mikulkova, I, Pavlickova, J, Brychta, T, Chochola, J, Couffinhal, T, Elbaz, M, Petit, C, Faller, B, Marechaud, R, Moulin, P, Fendri, S, Nazeyrollas, P, Wendisch, U, Busch, K, Klausmann, G, Duengen, H, Appel, K, Toursarkissian, N, Jung, T, Ott, P, Schenkenberger, I, Kuesters, D, Landers, B, Nischik, R, Fischer, H, Tschoepe, D, Paschen, B, Krause, K, Derwahl, K, Wenzl-Bauer, V, Hamann, A, Strotmann, H, Milek, K, Mueller, S, Chu, D, Tan, K, Kung, K, Tsang, C, Tomlinson, B, Koranyi, L, Kerenyi, Z, Benczur, B, Illyes, L, Hidvegi, T, Somogyi, A, Valco, J, Ferenczi, S, Rapi, J, Voros, P, Winkler, G, Sydo, T, Hetey, M, Simon, K, Penzes, J, Kempler, P, Bako, B, Lengyel, Z, Witmann, I, Dudas, M, Vandorfi, G, Takacs, J, Matoltsy, A, Ladanyi, E, Gyimesi, A, Sadikot, S, Parikh, K, Jain, S, Yajnik, C, Sosale, A, Shamanna, P, Srikanta, S, Shah, S, Srinivas, A, Banker, D, Shah, P, Sharda, A, Makkar, B, Rais, N, Mardikar, H, Mishra, A, Bhupati, S, Menon, J, Sathe, S, Gupta, R, Sharma, V, Darawsha, M, Herskovits, T, Hamoud, S, Nikolsky, E, Adawi, F, Zimlichman, R, Tsalihin, D, Wainstein, J, Klainman, E, Mosseri, M, Yerushalmi, Y, Karnieli, E, Knobler, H, Benchetrit, S, Tsur, A, Yagil, Y, Atar, S, Beberashvili, I, Fuchs, S, Stern, N, Pollak, A, Chajek-Shaul, T, Rozenman, Y, Biton, A, Bramucci, E, Fiscella, A, Grassia, V, Piatti, P, De Cosmo, S, Di Lorenzo, L, Merlini, P, Mannucci, E, Frontoni, S, Trevisan, R, Zenari, L, Lambiase, C, Salvioni, A, Silvestri, O, Ambrosio, G, Di Bartolo, P, Fattore, L, Presbitero, P, Calabrese, M, Evola, R, Gamba, M, Ibarra, M, Munoz, E, Sanchez, D, Herrera, C, Rios, J, Llamas, E, Esperon, G, Cantu, E, Fragoso, J, Gonzalez, J, Martinez, G, Padilla, F, Mier, G, Marmolejo, D, Ruiz, J, Portilla, N, Rosas, E, Machado, G, Ramos, J, Briones, I, van Hessen, M, Strikwerda, S, The, S, Kooy, A, Ronner, E, Nierop, P, Remmen, J, Groenemeijer, B, Hamer, B, Basart, D, van Lennep, H, Nieuwdorp, M, van Dijk, M, Kentgens, S, van Kempen, W, Hoogendijk, J, Spiering, W, Voors-Pette, C, Kose, V, de Waard, D, Gonkel, F, Kaasjager, H, Lingan, G, Agous, I, Kruik, H, Imholz, B, Pieterse, M, Manrique, H, Villena, J, Leon, L, Kundert, K, Minchola, J, Pinto, M, Heredia, J, Rodriguez, A, Guerreros, C, Berrospi, P, Zubiate, C, Allemant, A, Arbanil, H, Ponciano, W, Calderon, J, Lisson, R, Segura, L, Sidorowicz-Bialynicka, A, Sciborski, R, Fares, I, Mader, P, Skierkowska, J, Stasinska, T, Pomiecko, W, Skorski, M, Krzyzagorska, E, Polaszewska-Muszynska, M, Sowinski, D, Strojek, K, Rosinska-Migda, J, Romanczuk, P, Golebiowski, G, Kubica, J, Mazurek, T, Wojnowski, L, Pasternak, D, Stachlewski, P, Trzepla, E, Bogdanowicz, G, Uzunow, A, Potakowska, I, Miszczyszyn, Z, Waszyrowski, T, Smolenskaya, O, Lukyanov, Y, Vorokhobina, N, Khalimov, Y, Orlikova, O, Rebrov, A, Kukharchuk, V, Boldueva, S, Arkhipov, M, Zhelninova, T, Pavlysh, E, Antsiferov, M, Panov, A, Pavlova, M, Shustov, S, Demchenko, E, Galyavich, A, Malakhina, E, Semenova, O, Kobalava, Z, Kotova, S, Gavrisheva, I, Oschepkova, E, Karpov, Y, Sidorenko, B, Kislyak, O, Ametov, A, Dreval, A, Grineva, E, Mkrtumyan, A, Tyurina, T, Sazonova, O, Bonnici, F, Ranjith, N, Burgess, L, Nortje, H, Distiller, L, Mitha, I, Moore, R, Conradie, M, Horak, A, Pillay, S, Wellmann, H, Berg, E, Pillai, P, Padayachee, T, Corbett, C, Makan, H, Wing, J, Vawda, Z, Ebrahim, I, Mitha, E, Bhorat, A, Fernandez, J, Munoz, C, Cortada, J, Conde, A, Calvo, C, Extremera, B, Delgado, E, Masmiquel, L, Puig, J, Parreno, L, Mauricio, D, Redon, J, Brito, M, Lopez, C, de la Morera, J, Linderfalk, C, Larnefeldt, H, Olsson, A, Lonneborg, L, Ekelund, M, Samad, B, Borgencrantz, B, Nilsson, J, Berglund, O, Svensson, M, Mooe, T, Curiac, D, Albin, J, Angesjo, E, Lannemyr, O, Chen, J, Tien, K, Ueng, K, Lai, W, Yin, W, Hung, Y, Shyu, K, Hou, J, Lam, H, Laothavorn, P, Kuanprasert, S, Khovidhunkit, W, Benjasuratwong, Y, Chotinaiwattarakul, C, Mamanasiri, S, Suraamornkul, S, Pratipanawatr, T, Nitiyanant, W, Heller, S, Pieters, R, Strang, C, Bodalia, B, Middleton, A, Hall, T, Chapman, G, Calvert, J, Reed, R, Tam, D, Butcher, G, Jones, N, Takhar, A, Turner, W, Mcnally, D, Corey, O, Chapman, J, Mohr, S, Edwards, S, Ocampo, A, Kandath, D, Aude, Y, Ervin, W, Savin, V, Anderson, R, Littlefield, R, Oberoi, M, Platt, G, Yazdani, S, Mangoo-Karim, R, Walder, J, Gogia, H, Chandrashekhar, Y, Boccalandro, F, Rogers, W, Bilazarian, S, Zieve, F, Siage, Y, O'Connor, T, Mudaliar, S, Nikas, A, Giusti, R, Glover, R, Chilka, S, French, W, Roth, E, Singh, N, Christofferson, R, Stich, M, Dagogo-Jack, S, Allison, J, Zengotita, G, Ison, R, Iteld, B, Sulistio, M, Gonzalez, E, Gorman, T, Hage-Korban, E, Reddy, R, Byars, W, Antonishen, M, Benjamin, S, First, B, Rosado, J, Bruschetta, H, Poling, T, Rosendorff, C, Kerstein, H, Saba, F, Willis, J, Adams, K, Vazquez, E, Ellison, H, Kahn, B, Kereiakes, D, Powell, S, Raskin, P, Smith, K, Varma, S, Whittier, F, Casanova, R, Isserman, S, Kaye, W, Mcguinn, W, Bartkowiak, A, Dworkin, L, Labrador, C, Podlecki, D, Popovtzer, M, Aronoff, S, Ballantyne, C, Ortiz, E, Mora, A, Pitts, T, Reinhardt, S, Soucie, G, Wainwright, W, Henson, B, Sklaver, N, Arakaki, R, Brown, J, Chalavarya, G, Chochinov, R, Dixon, T, Kutner, M, Perlman, R, Raisinghani, A, Salacata, A, Awasty, V, Elinoff, V, George, W, LaRochelle-Gryseels, A, Mercado, A, Miller, G, Qureshi, M, Steljes, A, Wefald, F, Wilson, J, Chinn, J, Chuang, R, Comulada-Rivera, A, Hartman, I, Narayan, P, Pacheco, T, Weiss, R, Beavins, J, Creevy, J, Hamroff, G, Hodson, R, Kosinski, E, Krichmar, P, Patel, R, Schneider, R, Shapiro, J, Sharp, D, Speer, J, Stegemoller, R, Waxman, F, Chang, F, Braun, E, Eder, F, Minor, S, Albert, M, Carr, K, Diaczok, B, Gastman, I, Gupta, V, Longshaw, K, Gonzalez-Campoy, J, Raikhel, M, Thomas, J, Wood, K, Diab, I, Furda, J, Gelernt, M, Halter, M, House, B, Kaster, S, Raad, G, Stamatin, R, Barker, B, Blonder, R, Bloomberg, R, Calderon, R, Carrol, A, Comerota, A, Feinglos, M, Henderson, D, Kastelic, R, Stonesifer, L, Talano, J, Lee, P, Brosseau, J, Clark, W, Cohen, E, Fialkow, J, Horton, K, Kozman, H, Mcgill, J, Mihills, C, Poonawala, R, Shore, K, Tejada, L, Torres, R, Wright, W, Calatayud, G, Chandna, H, Drozdiak, R, Fink, R, Gill, R, Glandt, M, Gottlieb, D, Hack, T, Kay, J, Mansouri, V, Mcknight, T, Mostel, E, Schmidt, L, Seide, H, Sonel, E, Taylor, R, Velasquez, M, Bretton, E, Feldman, R, Hartman, A, Hershon, K, Leach, C, Martin, E, Mohiuddin, F, Naygandhi, Y, Riske, T, Schima, S, Uzoaga, E, Ward, H, Weinstock, R, Williams, T, Altschuller, A, Aoki, T, Blumenthal, S, Cash, A, Eisner, G, Gutmann, J, Hagan, M, Kabour, A, Markus, T, Mckenzie, W, Moursi, M, Mystkowski, P, Ovalle, F, Perkins, R, Popeil, L, Saniuk, R, Sierra, Y, Alvarado, O, Anderson, J, Bajaj, M, Blank, R, Chu, A, Levinsky, L, Levy, P, Osborne, J, Pavon, H, Sanderlin, D, Schaer, G, Zarich, S, Atassi, K, Bayron, C, Casagrande, M, Das, D, Gimness, M, Handel, F, Kinstrey, T, Leu, S, Osei, K, Nouel, J, Soltani, Z, Sussman, H, Chiu, K, Duda, R, Farnsworth, K, Lano, M, Lee, F, Levin, P, Pratt, S, Richwine, R, Ruiz-Rivera, L, Turner, J, Wood, J, Zigrang, W, Baquerizo, H, Colon, C, Demattia, J, Desai, V, Fitz-Patrick, D, Goral, S, Odhav, A, Prentiss, A, Ruff, C, Wu, W, Wyne, K, Abbott, L, Applegate, R, Cabral, J, Kotha, P, Ortega, P, and Simmons, D
Subjects: Male, Adamantane, Dipeptidyl peptidase-4 inhibitor, Type 2 diabetes, Kaplan-Meier Estimate, Saxagliptin, chemistry.chemical_compound, 80 and over, glucose, saxagliptin, Aged, 80 and over, Medicine (all), Hazard ratio, 11 Medical And Health Sciences, General Medicine, Dipeptides, Middle Aged, Hospitalization, Cardiovascular Diseases, Female, Aged, Diabetes Mellitus, Type 2, Dipeptidyl-Peptidase IV Inhibitors, Double-Blind Method, Heart Failure, Humans, Hypoglycemia, Hypoglycemic Agents, Pancreatitis, Alogliptin, Type 2, medicine.drug, insulin, medicine.medical_specialty, General & Internal Medicine, Internal medicine, Diabetes mellitus, medicine, Empagliflozin, Diabetes Mellitus, Intensive care medicine, glycosylated hemoglobin, business.industry, Semaglutide, SAVOR-TIMI 53 Steering Committee and Investigators, medicine.disease, chemistry, placebo, business
Abstract: BACKGROUND: The cardiovascular safety and efficacy of many current antihyperglycemic agents, including saxagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, are unclear. METHODS: We randomly assigned 16,492 patients with type 2 diabetes who had a history of, or were at risk for, cardiovascular events to receive saxagliptin or placebo and followed them for a median of 2.1 years. Physicians were permitted to adjust other medications, including antihyperglycemic agents. The primary end point was a composite of cardiovascular death, myocardial infarction, or ischemic stroke. RESULTS: A primary end-point event occurred in 613 patients in the saxagliptin group and in 609 patients in the placebo group (7.3% and 7.2%, respectively, according to 2-year Kaplan-Meier estimates; hazard ratio with saxagliptin, 1.00; 95% confidence interval [CI], 0.89 to 1.12; P=0.99 for superiority; P
Published: 2013

7. The Asn9 variant of lipoprotein lipase is associated with the -93G promoter mutation and an increased risk of coronary artery disease. The Regress Study Group

Author: Kastelein, J. J., Groenemeyer, B. E., Hallman, D. M., Henderson, H., Reymer, P. W. A., Gagné, S. E., Jansen, H., jacob Seidell, Kromhout, D., Wouter Jukema, J., Bruschke, A. V. G., Boerwinkle, E., Hayden, M. R., Other departments, Organic Chemistry, and Youth and Lifestyle
Subjects: Male, Research Support, Non-U.S. Gov't, Glycine, Genetic Variation, Coronary Disease, Middle Aged, Research Support, Promoter Regions, Genetic Heterogeneity, Lipoprotein Lipase, Genetic, SDG 3 - Good Health and Well-being, Risk Factors, Journal Article, Humans, Point Mutation, Asparagine, Promoter Regions, Genetic, Non-U.S. Gov't
Abstract: Two mutations in the lipoprotein lipase (LPL) gene, a T to G transition at position -93 of the proximal promoter region and an Asp9Asn substitution in exon 2, were examined in 762 Dutch males with angiographically-diagnosed coronary artery disease (CAD) and 296 healthy normolipidemic Dutch males. The two mutations exhibited strong linkage disequilibrium (D' = 0.975). A significantly higher proportion of cases (4.86%) than controls (1.37%) carried the -93G/Asn9 allele (p = 0.008). In the combined sample of cases and controls, adjusted mean plasma total cholesterol (TC) levels were significantly higher in -93G/Asn9 carriers (6.20+/-0.13 mmol/l) than in non-carriers (5.93+/-0.03 mmol/l; p = 0.048), while mean high-density lipoprotein cholesterol (HDL-C) levels were lower in carriers (0.88+/-0.03 mmol/l) than in non-carriers (0.98+/-0.01 mmol/l; p = 0.002). There was a trend towards higher triglyceride (TG) levels in carriers (1.96+/-0.14 mmol/l) compared with non-carriers (1.73+/-0.03 mmol/l) (p = 0.08). Additionally, carrier frequencies in tertiles of TC, HDL-C, TG, and LPL activity, suggested an association of the -93G/Asn9 variant with higher TC and TG levels, and with lower HDL-C and LPL activity levels. Logistic regression revealed a significant odds ratio (OR) for the combined -93G/Asn9 genotype in CAD cases relative to controls (OR: 5.36; 95% CI: 1.57-18.24), with age, body mass index (BMI), smoking, and plasma total- and HDL-cholesterol levels included in the model. In conclusion, we show that the LPL Asp9Asn mutation is in non-random association with a T G substitution at position -93 of the proximal promoter region and that the combined -93G/Asn9 genotype predisposes to decreased HDL-C levels and an increased risk of CAD.
Published: 1998

8. Two novel mutations in apolipoprotein C3 underlie atheroprotective lipid profiles in families

Author: Bochem, A. E., van Capelleveen, J. C., Dallinga-Thie, G. M., Schimmel, A. W. M., Motazacker, M. M., Tietjen, I., Singaraja, R. R., Hayden, M. R., Kastelein, J. J. P., Stroes, E. S. G., Hovingh, G. K., Other departments, Vascular Medicine, Graduate School, Amsterdam Cardiovascular Sciences, Experimental Vascular Medicine, and Human Genetics
Subjects: lipids (amino acids, peptides, and proteins)
Abstract: Apolipoprotein C3 (APOC3) mutations carriers typically display high plasma high-density lipoprotein cholesterol (HDL-C) and low triglycerides (TGs). We set out to investigate the prevalence and clinical consequences of APOC3 mutations in individuals with hyperalphalipoproteinemia. Two novel mutations (c.-13-2A>G and c.55+1G>A) and one known mutation (c.127G>A;p.Ala43Thr) were found. Lipid profiles and apoCIII isoform distributions were measured. c.55+1G>A mutation carriers displayed higher HDL-C percentiles (35.6 ± 35.8 vs 99.0 ± 0, p = 0.002) and lower TGs (0.51 (0.37-0.61) vs 1.42 (1.12-1.81) mmol/l, p = 0.007) and apoCIII levels (4.24 ± 1.57 vs 7.33 ± 3.61 mg/dl, p = 0.18). c.-13-2A>G mutation carriers did not display significantly different HDL-C levels (84.0 ± 30.0 vs 63.7 ± 45.7, p = 0.50), a trend towards lower TGs [0.71 (0.54 to 0.78) vs 0.85 (0.85 to -) mmol/l, p = 0.06] and significantly lower apoCIII levels (3.09 ± 1.08 vs 11.45 ± 1.06 mg/dl, p = 0.003). p.Ala43Thr mutation carriers displayed a trend towards higher HDL-C percentiles (91.2 ± 31.8 vs 41.0 ± 29.7 mmol/l, p = 0.06) and significantly lower TGs [0.58 (0.36-0.63) vs 0.95 (0.71-1.20) mmol/l, p = 0.02] and apoCIII levels (4.92 ± 2.33 vs 6.60 ± 1.60, p = 0.25). Heterozygosity for APOC3 mutations results in high HDL-C and low TGs and apoCIII levels. This favourable lipid profile in patients with genetically low apoCIII levels holds promise for current studies investigating the potential of apoCIII inhibition as a novel therapeutic in cardiovascular disease prevention
Published: 2014

9. Einfluss des Prionen-Sterilisationszyklus auf die bakterielle Barrierewirkung von Sterilisationsvlies im Endverpackungstest [Influence of prion sterilisation cycle on the bacterial barrier performance of sterilisation wrap according to the final pack test]

Author: Kastelein, J. and Vossen, J.M.B.M. van der
Subjects: Barrier properties, Temperature measurement, Latex, Airflow, Prion steam sterilisation cycle, Ethylene oxide, Kimguard One-Step, Humidity, Flow rate, Microbial contamination, Final pack, Microbial barrier, Packaging material, Instrument sterilization, Packaging, Sterilisation wrap, Prion, Polypropylene, Biology, Environmental temperature, Medical device, Netherlands
Abstract: Kimguard One-Step sterilisation wrap has regulatory approval as a Class I medical device suitable for packaging terminally sterilised medical items. In this study, we evaluated the performance of five different grades of Kimguard One-Step sterilisation wrap after prion sterilisation cycle (134 °C for 18 minutes) using the final pack test method. Kimguard One-Step grades KC100, KC200, KC300, KC400 and KC500 were used to wrap a 1/1 DIN steel wire instrument tray (internal volume of 7.2 L) and each wrapped test pack was challenged with 100,000 1 μm latex particles delivered at an air flow rate of 250 mL/min during a 25-minute test period. For each grade of wrap, particle filtration efficiency measurements were carried out sixfold after sterilisation and repeated after test pack storage for three months. At both time points, particle counts within the wrapped test packs were negligible and yielded mean particle retention rates for all five grades of sterilisation wrap of ≥ 99.99%. From these results, we conclude that the microbial barrier effectiveness of Kimguard One-Step sterilisation wraps KC100, KC200, KC300, KC400 and KC500 remains unaffected by prevacuum steam sterilisation at 134 °C for 18 minutes, or by subsequent storage for three months with regular movement of packs during storage.
Published: 2013

10. Gene-centric meta-analyses of 108 912 individuals confirm known body mass index loci and reveal three novel signals

Author: Guo, Y., Lanktree, M. B., Taylor, K. C., Hakonarson, H., Lange, L. A., Keating, B. J., Fairfax, B. P., Elbers, C. C., Barnard, J., Farrall, M., Padmanabhan, S., Baumert, J., Castillo, B. A., Gaunt, T. R., Gong, Y., Rajagopalan, R., Romaine, S. P., Kumari, M., Rafelt, S., Smith, E. N., Li, Y. R., Sivapalaratnam, S., van Iperen, E. P., Speliotes, E. K., Toskala, E., Zhang, L., Ochs-Balcom, H. M., Bhangale, T. R., Chandrupatla, H. R., Drenos, F., Gieger, C., Gupta, J., Johnson, T., Kleber, M. E., Makino, S., Mangino, M., Meng, Y., Nelson, C. P., Pankow, J. S., Pankratz, N., Price, T. S., Shaffer, J., Shen, H., Tischfield, S., Tomaszewski, M., Atwood, L. D., Bailey, K. M., Balasubramanyam, A., Baldwin, C. T., Basart, H., Bauer, F., Behr, E. R., Beitelshees, A. L., Berenson, G. S., Beresford, S. A., Bezzina, C. R., Bhatt, D. L., Boer, J. M., Braund, P. S., Burke, G. L., Burkley, B., Carty, C., Chen, W., Clarke, R., Cooper-DeHoff, R. M., Curtis, S. P., de Bakker, P. I., de Jong, J. S., Delles, C., Dominiczak, A. F., Duggan, D., Feldman, H. I., Furlong, C. E., Gorski, M. M., Gums, J. G., Hardwick, R., Hastie, C., Heid, I. M., Huang, G.-H., Huggins, G. S., Humphries, S. E., Kirkland, S. A., Kivimaki, M., Klein, R., Klein, B. E., Knowler, W. C., Kottke-Marchant, K., LaCroix, A. Z., Langaee, T. Y., Li, M., Lyon, H. N., Maiwald, S., Marshall, J. K., Mehta, A., Meijs, M. F., Melander, O., Meyer, N., Mitra, N., Molony, C. M., Morrow, D. A., Murugesan, G., Newhouse, S. J., Nieto, J. F., Onland-Moret, N. C., Ouwehand, W. H., Palmen, J., Pepine, C. J., Ranchalis, J., Rosas, S. E., Rosenthal, E. A., Scharnagl, H., Schork, N. J., Schreiner, P. J., Shah, T., Shashaty, M., Shimbo, D., Srinivasan, S. R., Thomas, F., Tobin, M. D., Tsai, M. Y., Verschuren, W. M. M., Wagenknecht, L. E., Winkelmann, B. R., Young, T., Yusuf, S., Zafarmand, M. H., Zmuda, J. M., Zwinderman, A. H., Anand, S. S., Balmforth, A. J., Boehm, B. O., Boerwinkle, E., Burton, P. R., Cappola, T. P., Casas, J. P., Caulfield, M. J., Christiani, D. C., Christie, J., Cruickshanks, K. J., Davey-Smith, G., Davidson, K. W., Day, I. N., Doevendans, P. A., Dorn, G. W., FitzGerald, G. A., Hall, A. S., Hingorani, A. D., Hirschhorn, J. N., Hofker, M. H., Hovingh, K. G., Illig, T., Jamshidi, Y., Jarvik, G. P., Johnson, J. A., Kanetsky, P. A., Kastelein, J. J., Koenig, W., Lawlor, D. A., Marz, W., McCaffery, J., Mega, J. L., Mitchell, B. D., Murray, S. S., O'Connell, J. R., Patel, S. R., Peters, A., Pettinger, M., Rader, D. J., Redline, S., Reilly, M. P., Sabatine, M. S., Schadt, E. E., Shuldiner, A. R., Silverstein, R. L., Spector, T. D., Taylor, H. A., Thorand, B., Trip, M. D., Watkins, H., Wichmann, H.- E., Fox, C. S., Grant, S. F., Peter, I., Talmud, P. J., Munroe, P. B., Wilson, J. G., Knight, J. C., Samani, N. J., Hegele, R. A., Asselbergs, F. W., Monda, K. L., van der Schouw, Y. T., Demerath, E. W., Wijmenga, C., Timpson, N. J., Reiner, A. P., North, K. E., Papanicolaou, G. J., Lange , L. A., Keating , B. J., Vascular Medicine, Amsterdam Public Health, Epidemiology and Data Science, Graduate School, Other departments, Amsterdam Cardiovascular Sciences, Cardiology, Other Research, and Public and occupational health
Subjects: Population, Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Body Mass Index, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, SH2B1, Genotype, Ethnicity, Genetics, Humans, education, Molecular Biology, Gene, Genetics (clinical), 030304 developmental biology, Genetic association, 0303 health sciences, education.field_of_study, Association Studies Articles, General Medicine, Melanocortin 4 receptor, 030217 neurology & neurosurgery
Abstract: Recent genetic association studies have made progress in uncovering components of the genetic architecture of the body mass index (BMI). We used the ITMAT-Broad-Candidate Gene Association Resource (CARe) (IBC) array comprising up to 49 320 single nucleotide polymorphisms (SNPs) across ~2100 metabolic and cardiovascular-related loci to genotype up to 108 912 individuals of European ancestry (EA), African-Americans, Hispanics and East Asians, from 46 studies, to provide additional insight into SNPs underpinning BMI. We used a five-phase study design: Phase I focused on meta-analysis of EA studies providing individual level genotype data; Phase II performed a replication of cohorts providing summary level EA data; Phase III meta-analyzed results from the first two phases; associated SNPs from Phase III were used for replication in Phase IV; finally in Phase V, a multi-ethnic meta-analysis of all samples from four ethnicities was performed. At an array-wide significance (P < 2.40E-06), we identify novel BMI associations in loci translocase of outer mitochondrial membrane 40 homolog (yeast) - apolipoprotein E - apolipoprotein C-I (TOMM40-APOE-APOC1) (rs2075650, P = 2.95E-10), sterol regulatory element binding transcription factor 2 (SREBF2, rs5996074, P = 9.43E-07) and neurotrophic tyrosine kinase, receptor, type 2 [NTRK2, a brain-derived neurotrophic factor (BDNF) receptor gene, rs1211166, P = 1.04E-06] in the Phase IV meta-analysis. Of 10 loci with previous evidence for BMI association represented on the IBC array, eight were replicated, with the remaining two showing nominal significance. Conditional analyses revealed two independent BMI-associated signals in BDNF and melanocortin 4 receptor (MC4R) regions. Of the 11 array-wide significant SNPs, three are associated with gene expression levels in both primary B-cells and monocytes; with rs4788099 in SH2B adaptor protein 1 (SH2B1) notably being associated with the expression of multiple genes in cis. These multi-ethnic meta-analyses expand our knowledge of BMI genetics.
Published: 2013

11. Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia

Author: Surendran, R. P., Visser, M. E., Heemelaar, S., Wang, J., Peter, J., Defesche, J. C., Kuivenhoven, J. A., Hosseini, M., Péterfy, M., Kastelein, J. J. P., Johansen, C. T., Hegele, R. A., Stroes, E. S. G., Dallinga-Thie, G. M., Cardiovascular Centre (CVC), Lifestyle Medicine (LM), Vascular Ageing Programme (VAP), Center for Liver, Digestive and Metabolic Diseases (CLDM), Graduate School, Vascular Medicine, Other departments, ACS - Amsterdam Cardiovascular Sciences, and Experimental Vascular Medicine
Subjects: Adult, Hypertriglyceridemia, Male, LMF1, Molecular Epidemiology, APOC2, GPIHBP1, Mutation, Missense, Membrane Proteins, lipoprotein lipase, APOA5, Severity of Illness Index, Prevalence, Humans, Apolipoprotein C-II, Female, Genetic Testing, Carrier Proteins, triglycerides, Apolipoproteins A, Netherlands, Receptors, Lipoprotein
Abstract: Surendran RP, Visser ME, Heemelaar S, Wang J, Peter J, Defesche JC, Kuivenhoven JA, Hosseini M, Peterfy M, Kastelein JJP, Johansen CT, Hegele RA, Stroes ESG, Dallinga-Thie GM (Academic Medical Center, Amsterdam, the Netherlands; Robarts Research Institute, University of Western Ontario, London, Ontario, Canada; UCLA, University of California; Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA). Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia. J Intern Med 2012; 272: 185196. Objectives. The severe forms of hypertriglyceridaemia (HTG) are caused by mutations in genes that lead to the loss of function of lipoprotein lipase (LPL). In most patients with severe HTG (TG > 10 mmol L-1), it is a challenge to define the underlying cause. We investigated the molecular basis of severe HTG in patients referred to the Lipid Clinic at the Academic Medical Center Amsterdam. Methods. The coding regions of LPL, APOC2, APOA5 and two novel genes, lipase maturation factor 1 (LMF1) and GPI-anchored high-density lipoprotein (HDL)-binding protein 1 (GPIHBP1), were sequenced in 86 patients with type 1 and type 5 HTG and 327 controls. Results. In 46 patients (54%), rare DNA sequence variants were identified, comprising variants in LPL (n = 19), APOC2 (n = 1), APOA5 (n = 2), GPIHBP1 (n = 3) and LMF1 (n = 8). In 22 patients (26%), only common variants in LPL (p.Asp36Asn, p.Asn318Ser and p.Ser474Ter) and APOA5 (p.Ser19Trp) could be identified, whereas no mutations were found in 18 patients (21%). In vitro validation revealed that the mutations in LMF1 were not associated with compromised LPL function. Consistent with this, five of the eight LMF1 variants were also found in controls and therefore cannot account for the observed phenotype. Conclusions. The prevalence of mutations in LPL was 34% and mostly restricted to patients with type 1 HTG. Mutations in GPIHBP1 (n = 3), APOC2 (n = 1) and APOA5 (n = 2) were rare but the associated clinical phenotype was severe. Routine sequencing of candidate genes in severe HTG has improved our understanding of the molecular basis of this phenotype associated with acute pancreatitis and may help to guide future individualized therapeutic strategies
Published: 2012

12. Assessment of atherosclerosis: the role of flow-mediated dilatation

Author: Charakida, M, Masi, S, Luscher, T F, Kastelein, J J P, Deanfield, J E, and University of Zurich
Subjects: 570 Life sciences, biology, 610 Medicine & health, 142-005 142-005, 2705 Cardiology and Cardiovascular Medicine
Published: 2010

13. DAL-VESSEL - A RANDOMISED, PLACEBO-CONTROLLED STUDY OF DALCETRAPIB ON ENDOTHELIAL FUNCTION, AS MEASURED BY FLOW MEDIATED DILATATION, IN HIGH-RISK PATIENTS

Author: Luescher, T., Taddei, S., Thomas Muenzel, Jukema, J. W., Kastelein, J., Kaski, J. -C, Lehnert, V., Burgess, T., Kallend, D., and Deanfield, J.
Published: 2010

14. Cardiovascular outcomes and their relationships to lipoprotein components in patients with and without chronic kidney disease: results from the IDEAL trial

Author: Holme, I, Fayyad, R, Færgeman, Ole, Kastelein, J J P, Olsson, A G, Tikkanen, M J, Larsen, M L, Lindahl, C, Holdaas, H, Pedersen, T R, ACS - Amsterdam Cardiovascular Sciences, and Vascular Medicine
Abstract: Udgivelsesdato: 2009-Oct-13 Objectives. In Incremental Decrease in Endpoints through Aggressive Lipid-lowering (IDEAL), we compared cardiovascular outcomes in patients with and without chronic kidney disease (CKD) (estimated glomerular filtration rate
Published: 2010
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15. Particulate air pollution, coronary heart disease and individual risk assessment: a general overview

Author: Hassing, C., Twickler, M., Brunekreef, B., Cassee, F.R., Doevendans, P.A., Kastelein, J., Cramer, M.J.M., Risk Assessment of Toxic and Immunomodulatory Agents, and Dep IRAS
Abstract: Both long-term and short-term exposure to air pollution is associated with a marked increase in cardiovascular morbidity and mortality because of the coronary syndrome and its complications. The exact molecular mechanism that is responsible for these acute and chronic effects is not elucidated yet. Potential pathophysiological pathways, however, include vascular dysfunction, inflammation, and oxidative stress and altered cardiac autonomic dysfunction. Actually, the cardiovascular risk assessment for individual patients with regard to air pollution is still complicated. To support decision-making in clinic, we propose a risk model, named 'CardioVascular and AIR pollution' risk table, composed of acknowledged factors in the relationship of cardiovascular disease and air pollution.
Published: 2009

16. Van lipidenmetabolisme naar behandeling

Author: Bredie, Sebastian J. H., Stroes, E. S. G., Kastelein, J. J. P., Jukema, J. W., van der Wall, E. E., Van de Werf, F., Zijlstra, F., Amsterdam Cardiovascular Sciences, and Vascular Medicine
Published: 2008

17. Simvastatin with or without ezetimibe in familial hypercholesterolemia (vol 358, pg 1431, 2008)

Author: Kastelein, J. J. P., Akdim, F., Stroes, E. S. G., Zwinderman, A. H., Bots, M. L., Stalenhoef, A. F. H., Visseren, F. L. J., Sijbrands, E. J. G., Trip, M. D., Stein, E. A., Gaudet, D., Raphael Duivenvoorden, Veltri, E. P., Marais, A. D., Groot, E., Vascular Medicine, Epidemiology and Data Science, and Cardiology
Published: 2008

18. Premature hart- en vaatziekten

Author: Trip, M. D., Büller, H. R., Kastelein, J. J. P., Stroes, E. S. G., Amsterdam Cardiovascular Sciences, Cardiology, and Vascular Medicine
Published: 2007

19. Differential leucocyte count and the risk of future coronary artery disease in healthy men and women: the EPIC-Norfolk Prospective Population Study

Author: Rana, J. S., Boekholdt, S. M., Ridker, P. M., Jukema, J. W., Luben, R., Bingham, S. A., Day, N. E., Wareham, N. J., Kastelein, J. J. P., Khaw, K.-T., Amsterdam Cardiovascular Sciences, Cardiology, and Vascular Medicine
Subjects: cardiovascular diseases
Abstract: Background: We examined the relationship between granulocyte, lymphocyte and monocyte counts and risk of coronary heart disease (CHD) and cardiovascular disease (CVD) in men and women. There is paucity of data on the differential leucocyte count and its relationship with the risk of CHD and CVD. Methods: This prospective study comprised 7073 men and 9035 women who were 45-79 years of age and were residents of Norfolk. United Kingdom. Results: During an average of 8 years of follow-up we identified 857 incident CHD events and 2581 CVD incident events. Increased total leucocyte count was associated with increased risk for both CHD and CVD. The highest quartile of granulocyte count was associated with increased risk when compared to lowest quartile for CHD (men HR 1.70 95% CI: 1.30-2.21; women HR 1.24 95% CI: 0.91-1.69) and for CVD (men HR 1.46 95% CI: 1.24-1.71; women HR 1.20 95% CI: 1.02-1.42). The association remained unchanged when the analyses were restricted to nonsmokers and when risk was assessed for every 1000 cells L-1 increase in cell count. In multivariable models, despite adjusting for C-reactive protein (CRP), the granulocyte count remained an independent predictor of CHD and CVD risk, especially amongst men. Lymphocyte or monocyte counts were not significantly associated with increased risk. In all analyses, additionally adjusting for CRP did not affect the results materially. Conclusions: In conclusion, we found that the higher risk for CHD and CVD associated with increased total leucocyte count seems to be accounted for by the increased granulocyte count
Published: 2007

20. Flow-gemedieerde arteriële dilatatie en intima-mediadikte van de carotis als surrogate eindpunten voor vaatwandfunctionaliteit, cardiovasculaire ziekte en ziekterisico

Author: Stroes, E. S. G., de Groot, E., Büller, H. R., Kastelein, J. J. P., Amsterdam Cardiovascular Sciences, and Vascular Medicine
Published: 2007

21. Imaging modalities as tools for the investigation of atherosclerosis and atherosclerotic disease

Author: Duivenvoorden, Raphael, Kastelein, J. J. P., de Groot, E., Assmann, G., Vascular Medicine, and Amsterdam Cardiovascular Sciences
Published: 2007

22. Metingen van de intima-mediadikte van de arteria carotis

Author: de Groot, Eric, Büller, H. R., Kastelein, J. J. P., Stroes, E. S. G., and Vascular Medicine
Published: 2007

23. Bloedstolling en stollingsstoornissen

Author: Levi, M. [=Marcel M.], Büller, H. R., Kastelein, J. J. P., Stroes, E. S. G., and Vascular Medicine
Published: 2007

24. Essentiële hypertensie

Author: de Leeuw, P. W., van Montfrans, G. A., Büller, H. R., Kastelein, J. J. P., Stroes, E. S. G., Amsterdam Cardiovascular Sciences, General Internal Medicine, and Vascular Medicine
Published: 2007

25. Vasculaire Geneeskunde, 3e herziene druk

Author: Büller, H. R., Kastelein, J. J. P., Stroes, E. S. G., Amsterdam Cardiovascular Sciences, and Vascular Medicine
Published: 2007

26. Dyslipidemie

Author: van der Steeg, W. A., Kastelein, J. J. P., Hovingh, G. K., Somsen, G. A., Amsterdam Cardiovascular Sciences, and Vascular Medicine
Published: 2007

27. Common variants of multiple genes that control reverse cholesterol transport together explain only a minor part of the variation of HDL cholesterol levels

Author: Boekholdt, S. M., Souverein, O. W., Tanck, M. W. T., Hovingh, G. K., Kuivenhoven, J. A., Peters, R. I. G., Jansen, H., Schiffers, P. M. H., van der Wall, E. E., Doevendans, P. A., Reitsma, P. H., Zwinderman, A. H., Kastelein, J. J. P., Jukema, J. W., Cardiovascular Centre (CVC), Lifestyle Medicine (LM), Vascular Ageing Programme (VAP), Center for Liver, Digestive and Metabolic Diseases (CLDM), Clinical Chemistry, Cardiology, Vascular Medicine, APH - Amsterdam Public Health, Epidemiology and Data Science, ACS - Amsterdam Cardiovascular Sciences, Pulmonology, Experimental Vascular Medicine, AII - Amsterdam institute for Infection and Immunity, and General Internal Medicine
Subjects: Male, Apolipoprotein A-I, Genotype, Cholesterol, HDL, Biological Transport, Active, Genetic Variation, Coronary Artery Disease, Lipase, Middle Aged, Scavenger Receptors, Class B, Models, Biological, Cholesterol Ester Transfer Proteins, Cohort Studies, Phosphatidylcholine-Sterol O-Acyltransferase, Lipoprotein Lipase, Apolipoproteins E, Cholesterol, Humans, lipids (amino acids, peptides, and proteins), ATP-Binding Cassette Transporters, Carrier Proteins, Alleles, ATP Binding Cassette Transporter 1, Glycoproteins
Abstract: It is assumed that the combined effects of multiple common genetic variants explain a large part of variation of high-density lipoprotein cholesterol (HDL-C) plasma levels, but little evidence exists to corroborate this assumption. It was our objective to study the contribution of multiple common genetic variants of HDL-C-related genes to variation of HDL-C plasma levels. A well-characterized cohort of 546 Caucasian men with documented coronary artery disease was genotyped for common functional variants in genes that control reverse cholesterol transport: ATP-binding cassette transporter A1, apolipoprotein A-I and apolipoprotein-E, cholesteryl ester transfer protein, hepatic lipase, lecithin : cholesterol-acyl transferase, lipoprotein lipase, and scavenger receptor class B type 1. Multivariate linear regression showed that these variants, in conjunction, explain 12.4% (95% confidence interval: 6.9-17.9%) of variation in HDL-C plasma levels. When the covariates smoking and body mass index were taken into account, the explained variation increased to 15.3% (9.4-21.2%), and when 10 two-way interactions were incorporated, this percentage rose to 25.2% (18.9-31.5%). This study supports the hypothesis that multiple, mildly penetrant, but highly prevalent genetic variants explain part of the variation of HDL-C plasma levels, albeit to a very modest extent. Multiple environmental and genetic influences on HDL-C plasma levels still have to be elucidated.
Published: 2006

28. Gene therapy with lipoprotein lipase variant S447X - Response

Author: Ross, C. J. D., Twisk, J., Kuivenhoven, J. A., Rip, J., Kastelein, J. J., Hayden, M. R., Amsterdam Cardiovascular Sciences, Experimental Vascular Medicine, and Vascular Medicine
Published: 2006

29. De rol van het 'high-density'-lipoproteine (HDL)-partikel in de atherogenese en de mogelijkheden om de concentratie daarvan te verhogen

Author: Birjmohun, R. S., van der Steeg, W. A., Stroes, E. S. G., Kastelein, J. J. P., Other departments, Amsterdam Cardiovascular Sciences, and Vascular Medicine
Subjects: nutritional and metabolic diseases, lipids (amino acids, peptides, and proteins)
Abstract: The concentration of high-density lipoprotein (HDL) cholesterol has a strong inverse relationship to the incidence of cardiovascular disease. The protective effect of HDL cholesterol is due not only to its promotion of reverse cholesterol transport from the vascular wall to the liver, but also to its anti-inflammatory, antioxidative and antithrombotic effects. Patients with low HDL cholesterol concentrations are at increased risk for cardiovascular disease and may be considered for treatment with lipid-lowering drugs, such as statins, niacin and fibrates. Currently, only a limited number of HDL-increasing agents have demonstrated beneficial effects of increasing HDL in studies with intermediary endpoints. Among these drugs are apolipoprotein A-1 variants, inhibitors of the cholesterol ester transfer protein JTT-705 and torcetrapib
Published: 2006

30. Ezetimibe/simvastatin (INEGY) in the treatment of hyperlipidaemia

Author: Kastelein, J. J. P., Sankatsing, R. R., Amsterdam Cardiovascular Sciences, and Vascular Medicine
Subjects: nutritional and metabolic diseases, lipids (amino acids, peptides, and proteins), cardiovascular diseases
Abstract: Ezetimibe/simvastatin (INEGY), a dual inhibitor of both cholesterol production and absorption, is a new approach to the management of hyperlipidaemia. Recent studies have shown that it produces greater reductions in low-density lipoprotein (LDL) cholesterol than the single inhibition of statin therapy, enabling many more patients to achieve their LDL cholesterol treatment goals. With ezetimibe/simvastatin therapy, reductions of up to 61% from baseline have been seen in LDL cholesterol, with clear improvements in other associated lipid fractions. It has been well tolerated across all studies, with a safety profile similar to that of statin therapy. This article will review clinical experience to date with ezetimibe/simvastatin, commenting upon its place and potential value in the prevention of cardiovascular disease
Published: 2005

31. Achieving lipid goals in real life: the Dutch DISCOVERY Study

Author: Bots, A. F. E., Kastelein, J. J. P., ACS - Amsterdam Cardiovascular Sciences, and Vascular Medicine
Subjects: nutritional and metabolic diseases, lipids (amino acids, peptides, and proteins), cardiovascular diseases
Abstract: DISCOVERY Netherlands was an open-label, randomised, multicentre study (D3560/L00003) designed to compare the effects of rosuvastatin with those of atorvastatin, simvastatin or pravastatin on low-density lipoprotein cholesterol (LDL-C) goal achievement in a primary care setting. Patients (n = 1215) with type IIa or type IIb hypercholesterolaemia and cardiovascular risk of > 20% or a history of coronary heart or other atherosclerotic vascular disease were randomised to receive treatment with rosuvastatin 10 mg (n = 621), atorvastatin 10 mg (n = 189), simvastatin 20 mg (n = 194) or pravastatin 40 mg (n = 211) for 12 weeks. Significantly, more patients achieved 1998 and 2003 European LDL-C goals with rosuvastatin than with other statins after 12 weeks (p
Published: 2005

32. Statinen: voorlopig niet als regel maximaal doseren

Author: van der Harst, P., Kastelein, J. J. P., van Gilst, W. H., Amsterdam Cardiovascular Sciences, and Vascular Medicine
Published: 2005

33. Future strategies in the management of dyslipidemia

Author: Birjmohun, R. M., Stroes, E. S. G., Kastelein, J. J. P., Amsterdam Cardiovascular Sciences, and Vascular Medicine
Published: 2005

34. The basis for a common approach

Author: Jensen, B.B.B., Cnossen, H., Kastelein, J., Cocker, R., and TNO Kwaliteit van Leven
Subjects: Nutrition Chemistry, Biotechnology
Published: 2005

35. High-dose atorvastatin vs usual simvastatin for secondary prevention after myocardial infarction: the IDEAL study: A randomized controlled trial

Author: Pedersen, T. R., Færgeman, Ole, Kastelein, J. J., Olsson, A. G., Tikkanen, M. J., Holme, I., Larsen, Mogens Lytken, Bendiksen, F. S., Lindahl, C., Szarek, M., Tsai, J., and Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group
Published: 2005

36. Data density curves of B-mode ultrasound arterial wall thickness measurements in unaffected control and at-risk populations

Author: Groot, E., Hovingh, G. K., Zwinderman, A. H., Albert Wiegman, Smit, A. J., Kastelein, J. J. P., Vascular Medicine, Amsterdam Public Health, Epidemiology and Data Science, Paediatric Metabolic Diseases, Amsterdam Cardiovascular Sciences, Groningen Kidney Center (GKC), and Vascular Ageing Programme (VAP)
Subjects: COMMON CAROTID-ARTERY, MYOCARDIAL-INFARCTION, ATHEROSCLEROSIS, GROWTH EVALUATION STATIN, PRAVASTATIN, CHOLESTEROL, COMPONENTS, artery, risk factors, PROGRESSION, ultrasonography, CORONARY HEART-DISEASE, INTIMA-MEDIA THICKNESS
Abstract: Aim. Atherosclerosis is a slow disease process of arterial walls with onset decades prior to its clinical manifestations. Lifelong follow-up data may help to identify and understand the pathophysiology of this process. These longitudinal data are scarce. Using a standardized imaging and image analysis protocol, we acquired cross-sectional data of carotid and femoral arterial wall segments in populations at different cardiovascular disease risk. Methods. B-mode ultrasound intima-media thickness (IMT) data of carotid and femoral arteries were acquired in individuals at high cardiovascular disease risk: 44 young adolescents with familial hypercholesterolemia (1711), 248 adult FH patients and 184 patients with coronary artery disease (CAD), as well as in disease free unaffected individuals, 44 young adolescents, 26 middle-aged adults and 48 senior adults. Results. Per patient combined average IMT (SD) and % of lesions in the high risk populations were 0.55 (0.05) mm, 0.1%, 0.86 (0.18) mm, 15%, and 0.9 (0.18) nun, 18%, respectively. In the unaffected groups these values were 0.53 (0.03) nun, 0%, 0.59 (0.07) mm, 0%, and 0.77 (0.12) nun, 8%. Of all arterial segments, the far wall of the common femoral artery (CIA) of the 1711 patients exhibited the highest absolute BIT (1.12 [0.61] mm), the most rapid estimated IMT increase since adolescence (+0.58 mm) and the highest percentage of lesions (39% of CIA measurements). Conclusion. Regardless of location, carotid and femoral arterial walls increase in thickness with age and cardiovascular disease risk. This increase in thickness and prevalence of lesions is not similarly distributed among anatomical segments. The strong preponderance in arterial wall segments with the highest estimated atherosclerosis progression indicates the existence of a threshold value beyond which plaque formation is greatly increased. In the set of arterial locations we studied, this process might be best represented by the far wall of the CIA.
Published: 2005

37. A symposium: Statin Therapy: Setting New Standards in the Management of Dyslipidaemia - Foreword

Author: Cobbe, S. M., Kastelein, J. J. P., Amsterdam Cardiovascular Sciences, and Vascular Medicine
Published: 2005

38. Clinical, diagnostic and therapeutic aspects of (inherited) hypercholesterolemia

Author: van Aalst-Cohen, E. S., Trip, M. D., Vissers, M. N., Rodenburg, J., Kastelein, J. J. P., Amsterdam Cardiovascular Sciences, Cardiology, Other departments, and Vascular Medicine
Published: 2004

39. A boy with autosomal recessive hypercholesterolaemia

Author: Rodenburg, J., Albert Wiegman, Vissers, M. N., Kastelein, J. J. P., Stalenhoef, A. F. H., Paediatric Metabolic Diseases, Other departments, Amsterdam Cardiovascular Sciences, and Vascular Medicine
Subjects: lipids (amino acids, peptides, and proteins), cardiovascular diseases, Vascular medicine and diabetes [UMCN 2.2]
Abstract: Contains fulltext : 57340.pdf (Publisher’s version ) (Closed access) We describe a 9-year-old Iranian boy with tuberous xanthomas, elevated LDL-cholesterol levels of 15.5 mmol/l, and vague complaints of chest pain while playing soccer. The consanguineous parents of the boy had normal cholesterol concentrations, which indicated an autosomal recessive disorder rather than autosomal dominant familial hypercholesterolaemia. The diagnosis of autosomal recessive hypercholesterolaemia (ARH) was confirmed by the presence of a mutation in the phosphotyrosine binding domain of a putative adaptor protein, which prevents normal internalisation of the LDL receptor (LDLR) in the liver. The clinical phenotype of ARH is similar to that of classical homozygous familial hypercholesterolaemia caused by defects in the LDLR gene, but it is more variable, generally less severe, and more responsive to lipid-lowering therapy. The patient's complaints of chest pain were not caused by ischaemia as was tested by an exercise and 24-hour electrocardiogram and by a myocardial perfusion scan. His LDL-C dropped by about 6o% after being treated with a combination of 40 mg atorvastatin and 10 mg ezetimibe.
Published: 2004

40. Flow-gemedieerde arteriële dilatatie en carotis-intima-mediadikte als surrogate eindpunten voor vaatwandfunctionaliteit, cardiovasculiare ziekte en ziekterisico

Author: Stroes, E. S. G., de Groot, E., Büller, H. R., Kastelein, J. J. P., Amsterdam Cardiovascular Sciences, and Vascular Medicine
Published: 2004

41. Familial hypercholesterolemia

Author: van Bellen, A., Defesche, J. C., Kastelein, J. J. P., Wiegman, A., Poortman, Y., Steegers, R., Kluft, C., Amsterdam Cardiovascular Sciences, Experimental Vascular Medicine, Vascular Medicine, and Paediatric Metabolic Diseases
Published: 2004

42. Vasculaire geneeskunde

Author: Büller, H. R., Kastelein, J. J. P., Stroes, E. S. G., Vascular Medicine, and Amsterdam Cardiovascular Sciences
Published: 2004

43. Carotid and femoral B-mode ultrasound intima-media thickness measurements in adult post-coarctectomy patients

Author: Vriend, J. J. W., de Groot, E., Kastelein, J. J. P., Mulder, B. J. M., Vascular Medicine, Amsterdam Cardiovascular Sciences, and Cardiology
Subjects: cardiovascular system
Abstract: Aim. Cardiovascular and cerebrovascular morbidity and mortality in adult post-coarctectomy patients is increased even after successful surgical repair of the aorta. B-mode ultrasound intima-media thickness (IMT), a validated marker for atherosclerosis and vascular disease risk, was used to measure pre-coarctatial carotid and post-coarctatial femoral arterial wall changes in these patients. Methods. Measurements were done in 131 patients (mean age 31.6 y [SD 11.3 y]; 78 were normotensive, 53 were hypertensive) and in 26 controls (30.9 y [SD 9.4 y]). Results. Age, serum lipids and smoking history were similar in patients and controls. Overall, IMT in patients and controls were similar (0.59 mm, [SD 0.14 mm] and 0.59 mm [SD 0.08 mm]. In patients, carotid IMT was increased (0.67 mm, [SD 0.12 mm] vs 0.61 mm [SD 0.08 mm] in controls: p=0.01); femoral IMT was decreased (0.48 mm [SD 0.09 mm] vs 0.57 mm [SD 0.07 mm]: p=0.001). In normotensive patients carotid IMT was not increased (0.64 mm [SD 0.12 mm] vs 0.61 mm [SD 0.08 mm]: p=0.2), but patients showed a higher SD. Carotid IMT in hypertensive patients was increased (0.72 mm [SD 0.12 mm] vs 0.64 mm [SD 0.11 mm] in normotensive patients: p
Published: 2004

44. Metingen van de intima-media-dikte van de arteria carotis

Author: de Groot, E., Büller, H. R., Kastelein, J. J. P., Stroes, E. S. G., and Vascular Medicine
Published: 2004

45. Polymorphisms, practicalities and pleiotropism

Author: Kastelein, J., Amsterdam Cardiovascular Sciences, and Vascular Medicine
Published: 2004

46. Lipodystrophy associated with treatment of HIV-1 infection

Author: van der Valk, M., Sauerwein, H. P., Kastelein, J. J. P., Reiss, P., Infectious diseases, Other departments, Amsterdam Cardiovascular Sciences, Vascular Medicine, and Global Health
Published: 2003

47. Hygiene : awareness leads to improvement

Author: Cnossen, H., Kastelein, J., Barendsz, T., and TNO Voeding
Subjects: Health, Biotechnology
Published: 2003

48. Hygiëne : bewustwording leidt tot verbeteringen

Author: Cnossen, H., Kastelein, J., Barendsz, T., and TNO Voeding
Subjects: Health, Biotechnology
Published: 2003

49. The outcome of angiography in patients with Raynaud's phenomenon: an unexpected role for atherosclerosis and hypercholesterolemia

Author: van Vugt, R. M., Kater, L., Dijkstra, P. F., Schardijn, G. H., Kastelein, J. J., Bijlsma, J. W., Amsterdam Cardiovascular Sciences, Vascular Medicine, and Other departments
Abstract: Upper extremity angiography can make an important contribution to the diagnosis in vasculopathy. The present study was designed to assess the diagnostic role of upper extremity angiography in patients with disturbed circulation of the hand, according to a standardised protocol. The study was carried out in an outpatient setting in 103 patients suffering from bilateral Raynaud's phenomenon without any obvious underlying disease and who were unresponsive to nifedipine and aspirin. All patients had angiographies taken according to a standardized technique using vasodilating medication, and reviewed according to a standardised protocol that covered all the known characteristics of angiopathy such as diminished flow, stops, tortuosity, irregularity of the wall, tapering, collaterals and blushing. Standardised angiograms showed vasculopathy compatible with primary vasospasm in 42 patients [all women; mean age 35.1 years], atherosclerotic vascular disease in 44 patients [M/F 9/35; mean age 46.7 years], peripheral embolism in 8 patients [M/F 4/4; mean age 38.4 years], vasculitis in 3 patients [3 women; mean age 38 years] and Buerger's disease in 3 patients [3 men; mean age 47 years]. Inter-observer differences were present in 4 cases, but consensus could be reached through open discussion. An unexpected 47% of patients with atherosclerotic vascular disease had dyslipidemia, frequently of familial origin. The standardised angiography protocol proved to be helpful in the assessment of upper extremity angiography. Surprisingly, a high prevalence of angiographic abnormalities compatible with atherosclerotic vascular disease could already be diagnosed in relatively young patients with Raynaud's phenomenon, of whom 47% showed hypercholesterolemia
Published: 2003

50. The future of lipid-lowering therapy: the big picture

Author: Kastelein, J. J. P., Amsterdam Cardiovascular Sciences, and Vascular Medicine
Subjects: lipids (amino acids, peptides, and proteins)
Abstract: Several lipid-lowering intervention studies published in 2002 shed light on the current status and the future of cardiovascular risk reduction by drug therapy. The Heart Protection Study has demonstrated that simvastatin reduces heart attack, stroke and revascularisation risk by about one-third irrespective of total cholesterol, LDL cholesterol, patient's age or sex, or the nature of pre-existing cardiovascular disease. Coronary heart disease death and myocardial infarction risk reduction in elderly patients by pravastatin in the PROSPER study was similar to the benefit of statins in middle-aged populations in other studies. The ALLHAT-LLT study has failed to demonstrate a benefit of pravastatin on all-cause mortality, CHD death or nonfatal myocardial infarction, illustrating that too modest cholesterol lowering does not result in clinical benefit under all circumstances. The cholesterol absorption inhibitor ezetimibe has demonstrated significant LDL and total cholesterol lowering, and induced an additional 21% LDL cholesterol lowering when added to ongoing statin therapy. The cholesteryl ester transfer protein inhibitor JJT-705 produced a dose-dependent increase in HDL cholesterol concentrations of up to 34% and improved the total cholesterol/HDL cholesterol ratio in healthy individuals while having very mild side effects. Cholesterol absorption inhibitors and HDL cholesterol enhancers may become useful tools to achieve further improvements in cardiovascular risk reduction in the future
Published: 2003

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