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3. Aortic Valve Calcium Measured Via Cardiac Computed Tomography And Lipoprotein(a) For The Long-term Prediction Of Severe Aortic Stenosis

Author

Marrero, N., primary, Jha, K., additional, Razavi, A., additional, Boakye, E., additional, Anchouche, K., additional, Dzaye, O., additional, Budoff, M., additional, Tsai, M., additional, Shah, S., additional, Rotter, J., additional, Blumenthal, R., additional, Thanassoulis, G., additional, Post, W., additional, Blaha, M., additional, and Whelton, S., additional

Published
2023
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10. Apolipoprotein B Particles and Cardiovascular Disease: A Narrative Review.

Author

Thanassoulis G., Ference B.A., Catapano A., Glavinovic T., Sniderman A.D., Pencina M., Navar A.M., Thanassoulis G., Ference B.A., Catapano A., Glavinovic T., Sniderman A.D., Pencina M., and Navar A.M.

Abstract

Importance: The conventional model of atherosclerosis presumes that the mass of cholesterol within very low-density lipoprotein particles, low-density lipoprotein particles, chylomicron, and lipoprotein (a) particles in plasma is the principal determinant of the mass of cholesterol that will be deposited within the arterial wall and will drive atherogenesis. However, each of these particles contains one molecule of apolipoprotein B (apoB) and there is now substantial evidence that apoB more accurately measures the atherogenic risk owing to the apoB lipoproteins than does low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol. Observations: Cholesterol can only enter the arterial wall within apoB particles. However, the mass of cholesterol per apoB particle is variable. Therefore, the mass of cholesterol that will be deposited within the arterial wall is determined by the number of apoB particles that are trapped within the arterial wall. The number of apoB particles that enter the arterial wall is determined primarily by the number of apoB particles within the arterial lumen. However, once within the arterial wall, smaller cholesterol-depleted apoB particles have a greater tendency to be trapped than larger cholesterol-enriched apoB particles because they bind more avidly to the glycosaminoglycans within the subintimal space of the arterial wall. Thus, a cholesterol-enriched particle would deposit more cholesterol than a cholesterol-depleted apoB particle whereas more, smaller apoB particles that enter the arterial wall will be trapped than larger apoB particles. The net result is, with the exceptions of the abnormal chylomicron remnants in type III hyperlipoproteinemia and lipoprotein (a), all apoB particles are equally atherogenic. Conclusions and Relevance: Apolipoprotein B unifies, amplifies, and simplifies the information from the conventional lipid markers as to the atherogenic risk attributable to the apoB lipoproteins..Copyright © 20

Published
2020

11. Genome-wide association meta-analysis in 652,134 participants identifies 9 novel susceptibility loci for aortic stenosis

Author

Chen, H. Y., Small, A. M., Dina, C., Cairns, B. J., Whitmer, R. A., Lathrop, M., Smith, J. G., Holm, H., Wells, Q. S., Rader, D. J., Söderberg, S., Schott, J. J., Engert, J. C., Thanassoulis, G., Chen, H. Y., Small, A. M., Dina, C., Cairns, B. J., Whitmer, R. A., Lathrop, M., Smith, J. G., Holm, H., Wells, Q. S., Rader, D. J., Söderberg, S., Schott, J. J., Engert, J. C., and Thanassoulis, G.

Abstract

Background: Aortic stenosis (AS) is the most common form of incident valvular heart disease. While valve replacement is effective, the absence of an approved medical therapy provides no alternatives to patients with contraindications or mild disease. An improved understanding of the genetics of AS could identify targets for pharmacological intervention. Methods: An inverse variance-weighted, fixed effects meta-analysis of the association of 11,591,806 variants with AS was undertaken using data from 10 European cohorts totalling 652,134 participants (13,758 cases of AS). We queried publicly available datasets to characterize the functional consequences of genome-wide significant variants, conducted a phenome-wide association study to assess their association with other outcomes, and constructed polygenic risk scores to examine their association with AS. We also performed gene- and gene-set enrichment analyses, estimated genetic correlation with cardiovascular traits, and assessed whether five lipid or immunological biomarkers were causally associated with AS using Mendelian randomization. Results: Eighteen independent variants at 16 loci attained genome-wide significance in the meta-analysis, including variants at all seven previously reported loci. Many of the significant variants were intronic or intergenic, and the phenome-wide association study revealed extensive pleiotropy with apolipoprotein B, C-reactive protein, and other cardiovascular and immunological traits. A weighted polygenic risk score composed of the 18 variants was strongly associated with AS (adjusted OR per SD, 1.38; 95% CI, 1.33 to 1.44; p=4.6×10–57), and improved the discriminatory ability for AS when added to a model that contained clinical risk factors (difference in the area under the curve p=2.0×10–11). Gene-based approaches indicated higher IL6R expression in the blood among AS cases compared to controls (p=3.1×10–6), and the association of LDLR with AS (p=2.3×10–10). Gene set analyses reve

Published
2020
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12. Genome-wide association meta-analysis in 652,134 participants identifies 9 novel susceptibility loci for aortic stenosis

Author

Chen, H.Y, primary, Small, A.M, additional, Dina, C, additional, Cairns, B.J, additional, Whitmer, R.A, additional, Lathrop, M, additional, Smith, J.G, additional, Holm, H, additional, Wells, Q.S, additional, Rader, D.J, additional, Soderberg, S, additional, Schott, J.J, additional, Engert, J.C, additional, and Thanassoulis, G, additional

Published
2020
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15. Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events A GENIUS-CHD Study of Individual Participant Data

Author

Patel, R.S., Schmidt, A.F., Tragante, V., McCubrey, R.O., Holmes, M.V., Howe, L.J., Direk, K., Akerblom, A., Leander, K., Virani, S.S., Kaminski, K.A., Muehlschlegel, J.D., Dube, M.P., Allayee, H., Almgren, P., Alver, M., Baranova, E.V., Behlouli, H., Boeckx, B., Braund, P.S., Breitling, L.P., Delgado, G., Duarte, N.E., Dufresne, L., Eriksson, N., Foco, L., Gijsberts, C.M., Gong, Y., Hartiala, J., Heydarpour, M., Hubacek, J.A., Kleber, M., Kofink, D., Kuukasjarvi, P., Lee, V.V., Leiherer, A., Lenzini, P.A., Levin, D., Lyytikainen, L.P., Martinelli, N., Mons, U., Nelson, C.P., Nikus, K., Pilbrow, A.P., Ploski, R., Sun, Y.V., Tanck, M.W.T., Tang, W.H.W., Trompet, S., Laan, S.W. van der, Setten, J. van, Vilmundarson, R.O., Anselmi, C.V., Vlachopoulou, E., Boerwinkle, E., Briguori, C., Carlquist, J.F., Carruthers, K.F., Casu, G., Deanfield, J., Deloukas, P., Dudbridge, F., Fitzpatrick, N., Gigante, B., James, S., Lokki, M.L., Lotufo, P.A., Marziliano, N., Mordi, I.R., Muhlestein, J.B., Cheh, C.N., Pitha, J., Saely, C.H., Samman-Tahhan, A., Sandesara, P.B., Teren, A., Timmis, A., Werf, F. van de, Wauters, E., Wilde, A.A.M., Ford, I., Stott, D.J., Algra, A., Andreassi, M.G., Ardissino, D., Arsenault, B.J., Ballantyne, C.M., Bergmeijer, T.O., Bezzina, C.R., Body, S.C., Bogaty, P., Borst, G.J. de, Brenner, H., Burkhardt, R., Carpeggiani, C., Condorelli, G., Cooper-DeHoff, R.M., Cresci, S., Faire, U. de, Doughty, R.N., Drexel, H., Engert, J.C., Fox, K.A.A., Girelli, D., Hagstrom, E., Hazen, S.L., Held, C., Hemingway, H., Hoefer, I.E., Hovingh, G.K., Johnson, J.A., Jong, P.A. de, Jukema, J.W., Kaczor, M.P., Kahonen, M., Kettner, J., Kiliszek, M., Klungel, O.H., Lagerqvist, B., Lambrechts, D., Laurikka, J.O., Lehtimaki, T., Lindholm, D., Mahmoodi, B.K., Maitland-van der Zee, A.H., McPherson, R., Melander, O., Metspalu, A., Pepinski, W., Olivieri, O., Opolski, G., Palmer, C.N., Pasterkamp, G., Pepine, C.J., Pereira, A.C., Note, L., Quyyumi, A.A., Richards, A.M., Sanak, M., Scholz, M., Siegbahn, A., Sinisalo, J., Smith, J.G., Spertus, J.A., Stewart, A.F.R., Szczeklik, W., Szpakowicz, A., Berg, J.M. ten, Thanassoulis, G., Thieiy, J., Graaf, Y. van der, Visseren, F.L.J., Waltenberger, J., Harst, P. van der, Tardif, J.C., Sattar, N., Lang, C.C., Pare, G., Brophy, J.M., Anderson, J.L., Marz, W., Wallentin, L., Cameron, V.A., Horne, B.D., Samani, N.J., Hingorani, A.D., Asselbergs, F.W., and CARDIo-GRAMPlusC4D Consortium

Subjects
myocardial infarction, risk factor, cardiovascular diseases, chromosome, genetic, variation, secondary prevention
Abstract

BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUSCHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction < 0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).CONCLUSIONS: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

Published
2019

16. Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events

Author

Patel, RS, Schmidt, AF, Tragante, V, McCubrey, RO, Holmes, MV, Howe, LJ, Direk, K, Åkerblom, A, Leander, K, Virani, SS, Kaminski, KA, Muehlschlegel, JD, Dubé, M-P, Allayee, H, Almgren, P, Alver, M, Baranova, EV, Behlouli, H, Boeckx, B, Braund, PS, Breitling, LP, Delgado, G, Duarte, NE, Dufresne, L, Eriksson, N, Foco, L, Gijsberts, CM, Gong, Y, Hartiala, J, Heydarpour, M, Hubacek, JA, Kleber, M, Kofink, D, Kuukasjärvi, P, Lee, V-V, Leiherer, A, Lenzini, PA, Levin, D, Lyytikäinen, L-P, Martinelli, N, Mons, U, Nelson, CP, Nikus, K, Pilbrow, AP, Ploski, R, Sun, YV, Tanck, MWT, Tang, WHW, Trompet, S, Van Der Laan, SW, Van Setten, J, Vilmundarson, RO, Anselmi, C, Vlachopoulou, E, Boerwinkle, E, Briguori, C, Carlquist, JF, Carruthers, KF, Casu, G, Deanfield, J, Deloukas, P, Dudbridge, F, Fitzpatrick, N, Gigante, B, James, S, Lokki, M-L, Lotufo, PA, Marziliano, N, Mordi, IR, Muhlestein, JB, Newton-Cheh, C, Pitha, J, Saely, CH, Samman-Tahhan, A, Sandesara, PB, Teren, A, Timmis, A, Van De Werf, F, Wauters, E, Wilde, AAM, Ford, I, Stott, DJ, Algra, A, Andreassi, MG, Ardissino, D, Arsenault, BJ, Ballantyne, CM, Bergmeijer, TO, Bezzina, CR, Body, SC, Bogaty, P, De Borst, GJ, Brenner, H, Burkhardt, R, Carpeggiani, C, Condorelli, G, Cooper-Dehoff, RM, Cresci, S, De Faire, U, Doughty, RN, Drexel, H, Engert, JC, Fox, KAA, Girelli, D, Hagström, E, Hazen, SL, Held, C, Hemingway, H, Hoefer, IE, Hovingh, GK, Johnson, JA, De Jong, PA, Jukema, JW, Kaczor, MP, Kähönen, M, Kettner, J, Kiliszek, M, Klungel, OH, Lagerqvist, B, Lambrechts, D, Laurikka, JO, Lehtimäki, T, Lindholm, D, Mahmoodi, BK, Der Zee, AH, McPherson, R, Melander, O, Metspalu, A, Pepinski, W, Olivieri, O, Opolski, G, Palmer, CN, Pasterkamp, G, Pepine, CJ, Pereira, AC, Pilote, L, Quyyumi, AA, Richards, AM, Sanak, M, Scholz, M, Siegbahn, A, Sinisalo, J, Smith, JG, Spertus, JA, Stewart, AFR, Szczeklik, W, Szpakowicz, A, Berg, JM, Thanassoulis, G, Thiery, J, Van Der Graaf, Y, Visseren, FLJ, Waltenberger, J, Van Der Harst, P, Tardif, J-C, Sattar, N, Lang, CC, Paré, G, Brophy, JM, Anderson, JL, März, W, Wallentin, L, Cameron, VA, Horne, BD, Samani, NJ, Hingorani, AD, and Asselbergs, FW

Subjects
Male, Myocardial Infarction, genetic risk factor, Coronary Artery Disease, Middle Aged, Article, chromosome 9p21, Gene Frequency, Risk Factors, Case-Control Studies, Odds Ratio, Humans, Female, Genetic Predisposition to Disease, cardiovascular diseases, Chromosomes, Human, Pair 9, secondary prevention
Abstract

Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

Published
2019

17. Subsequent Event Risk in Individuals With Established Coronary Heart Disease

Author

Patel, R.S. (Riyaz), Tragante, V. (Vinicius), Schmidt, A.F. (Amand), McCubrey, R.O. (Raymond O.), Holmes, M.V. (Michael), Howe, L.J. (Laurence J.), Direk, K. (Kenan), Åkerblom, A. (Axel), Leander, K. (Karin), Virani, S.S. (Salim), Kaminski, K.A. (Karol A.), Muehlschlegel, J.D. (Jochen), Allayee, H. (Hooman), Almgren, P. (Peter), Alver, M. (Maris), Baranova, E.V. (Ekaterina V.), Behloui, H. (Hassan), Boeckx, B. (Bram), Braund, P.S. (Peter), Breitling, L.P. (Lutz), Delgado, G., Duarte, N.E. (Nubia E.), Dubé, G.P. (Gregory), Dufresne, L. (Line), Eriksson, N. (Niclas), Foco, L. (Luisa), Scholz, M. (Markus), Gijsberts, C.M. (Crystel M.), Glinge, C. (Charlotte), Gong, Y. (Yan), Hartiala, J. (Jaana), Heydarpour, M. (Mahyar), Hubacek, J.A. (Jaroslav A.), Kleber, M.E. (Marcus), Kofink, D. (Daniel), Kotti, S. (Salma), Kuukasjärvi, P. (Pekka), Lee, V.-V. (Vei-Vei), Leiherer, A. (Andreas), Lenzini, P.A. (Petra A.), Levin, D. (Daniel), Lyytikäinen, L.-P. (Leo-Pekka), Martinelli, N. (Nicola), Mons, U. (Ute), Nelson, C.P. (Christopher P.), Nikus, K. (Kjell), Pilbrow, A.P. (Anna P.), Ploski, R. (Rafal), Sun, Y.V. (Yan V.), Tanck, M.W.T. (Michael), Tang, W. (W.), Trompet, S. (Stella), van der Laan, S.W. (Sander W.), Setten, J. (Jessica) van, Vilmundarson, R.O. (Ragnar O.), Viviani Anselmi, C. (Chiara), Vlachopoulou, E. (Efthymia), Al Ali, L. (Lawien), Boerwinkle, E.A. (Eric), Briguori, C. (Carlo), Carlquist, J.F. (John), Carruthers, K.F. (Kathryn), Casu, G. (Gavino), Deanfield, J. (John), Deloukas, P. (Panos), Dudbridge, F. (Frank), Engstrøm, T. (Thomas), Fitzpatrick, N. (Natalie), Fox, K.M. (Kim), Gigante, B. (Bruna), James, S.K. (Stefan), Lokki, M.-L. (Marja-Liisa), Lotufo, P.A. (Paulo A.), Marziliano, N. (Nicola), Mordi, I.R. (Ify R.), Muhlestein, J.B. (Joseph), Newton-Cheh, C. (Christopher), Pitha, J. (Jan), Saely, C.H. (Christoph H.), Samman-Tahhan, A. (Ayman), Sandesara, P.B. (Pratik B.), Teren, A. (Andrej), Timmis, A. (Adam), Van de Werf, F. (Frans), Wilde, A.A.M. (Arthur), Ford, I. (Ian), Stott, D.J. (David. J.), Algra, A. (Ale), Andreassi, M.G. (Maria G.), Ardissino, D. (Diego), Arsenault, B.J. (Benoit J.), Ballantyne, C. (Christie), Bergmeijer, T.O. (Thomas O.), Bezzina, C.R. (Connie R.), Body, S.C. (Simon C.), Boersma, E.H. (Eric H.), Bogaty, P. (Peter), Bots, M.L. (Michiel), Brenner, H. (Hermann), Brugts, J.J. (Jasper), Burkhardt, R. (Ralph), Carpeggiani, C. (Clara), Condorelli, G. (Gianluigi), Cooper-Dehoff, R.M. (Rhonda), Cresci, S. (Sharon), Danchin, N. (Nicolas), Faire, U. (Ulf) de, Doughty, R.N. (Robert N.), Drexel, H. (Heinz), Engert, J.C. (James C.), Fox, K.A.A. (Keith), Girelli, D. (Domenico), Grobbee, D.E. (Diederick E.), Hagström, E. (Emil), Hazen, S.L. (Stanley), Held, C. (Claes), Hemingway, H., Hoefer, I.E. (Imo), Hovingh, G.K. (G Kees), Jabbari, R. (Reza), Johnson, J.A. (Jennifer ), Jukema, J.W. (Jan Wouter), Kaczor, M.P. (Marcin P.), Kähönen, M. (Mika), Kettner, J. (Jiri), Kiliszek, M. (Marek), Klungel, O.H. (Olaf), Lagerqvist, B. (Bo), Lambrechts, D. (Diether), Laurikka, J.O. (Jari O.), Lehtimäki, T. (Terho), Lindholm, D. (Daniel), Mahmoodi, B.K. (Bakhtawar K.), Maitland-van der Zee, A-H. (Anke-Hilse), McPherson, R. (Ruth), Melander, O. (Olle), Metspalu, A. (Andres), Niemcunowicz-Janica, A. (Anna), Olivieri, O. (Oliviero), Opolski, G. (Grzegorz), Palmer, C.N.A. (Colin), Pasterkamp, G. (Gerard), Pepine, C.J. (Carl), Pereira, A. (A.), Pilote, L. (Louise), Erdmann, J. (Jeanette), Richards, A.M. (A Mark), Sanak, M. (Marek), Siegbahn, A. (Agneta), Simon, T. (Tabassome), Sinisalo, J. (Juha), Smith, J.G. (J Gustav), Schwartz, S.M. (Stephen), Stender, S. (Steen), Stewart, A.F. (Alexandre F.), Szczeklik, W. (Wojciech), Szpakowicz, A. (Anna), Tardif, J.-C. (Jean-Claude), Berg, J.M. (Jurrien) ten, Tfelt-Hansen, J. (Jacob), Thanassoulis, G. (George), Thiery, J.P. (Joachim), Torp-Pedersen, C. (Christian Tobias), Graaf, Y. (Yolanda) van der, Visseren, F.L.J. (Frank), Waltenberger, J. (Johannes), Weeke, P.E. (Peter E.), Harst, P. (Pim) van der, Lang, C.C. (Chim C.), Sattar, N. (Naveed), Cameron, V.A. (Vicky A.), Anderson, J.L. (Jeffrey), Brophy, J.M. (James M.), Pare, G. (Guillame), Horne, B.D. (Benjamin), Ye, S. (Shu), Wallentin, L. (Lars), Wauters, E. (Els), Samani, N.J. (Nilesh), Hingorani, A. (Aroon), Asselbergs, F.W. (Folkert), Patel, R.S. (Riyaz), Tragante, V. (Vinicius), Schmidt, A.F. (Amand), McCubrey, R.O. (Raymond O.), Holmes, M.V. (Michael), Howe, L.J. (Laurence J.), Direk, K. (Kenan), Åkerblom, A. (Axel), Leander, K. (Karin), Virani, S.S. (Salim), Kaminski, K.A. (Karol A.), Muehlschlegel, J.D. (Jochen), Allayee, H. (Hooman), Almgren, P. (Peter), Alver, M. (Maris), Baranova, E.V. (Ekaterina V.), Behloui, H. (Hassan), Boeckx, B. (Bram), Braund, P.S. (Peter), Breitling, L.P. (Lutz), Delgado, G., Duarte, N.E. (Nubia E.), Dubé, G.P. (Gregory), Dufresne, L. (Line), Eriksson, N. (Niclas), Foco, L. (Luisa), Scholz, M. (Markus), Gijsberts, C.M. (Crystel M.), Glinge, C. (Charlotte), Gong, Y. (Yan), Hartiala, J. (Jaana), Heydarpour, M. (Mahyar), Hubacek, J.A. (Jaroslav A.), Kleber, M.E. (Marcus), Kofink, D. (Daniel), Kotti, S. (Salma), Kuukasjärvi, P. (Pekka), Lee, V.-V. (Vei-Vei), Leiherer, A. (Andreas), Lenzini, P.A. (Petra A.), Levin, D. (Daniel), Lyytikäinen, L.-P. (Leo-Pekka), Martinelli, N. (Nicola), Mons, U. (Ute), Nelson, C.P. (Christopher P.), Nikus, K. (Kjell), Pilbrow, A.P. (Anna P.), Ploski, R. (Rafal), Sun, Y.V. (Yan V.), Tanck, M.W.T. (Michael), Tang, W. (W.), Trompet, S. (Stella), van der Laan, S.W. (Sander W.), Setten, J. (Jessica) van, Vilmundarson, R.O. (Ragnar O.), Viviani Anselmi, C. (Chiara), Vlachopoulou, E. (Efthymia), Al Ali, L. (Lawien), Boerwinkle, E.A. (Eric), Briguori, C. (Carlo), Carlquist, J.F. (John), Carruthers, K.F. (Kathryn), Casu, G. (Gavino), Deanfield, J. (John), Deloukas, P. (Panos), Dudbridge, F. (Frank), Engstrøm, T. (Thomas), Fitzpatrick, N. (Natalie), Fox, K.M. (Kim), Gigante, B. (Bruna), James, S.K. (Stefan), Lokki, M.-L. (Marja-Liisa), Lotufo, P.A. (Paulo A.), Marziliano, N. (Nicola), Mordi, I.R. (Ify R.), Muhlestein, J.B. (Joseph), Newton-Cheh, C. (Christopher), Pitha, J. (Jan), Saely, C.H. (Christoph H.), Samman-Tahhan, A. (Ayman), Sandesara, P.B. (Pratik B.), Teren, A. (Andrej), Timmis, A. (Adam), Van de Werf, F. (Frans), Wilde, A.A.M. (Arthur), Ford, I. (Ian), Stott, D.J. (David. J.), Algra, A. (Ale), Andreassi, M.G. (Maria G.), Ardissino, D. (Diego), Arsenault, B.J. (Benoit J.), Ballantyne, C. (Christie), Bergmeijer, T.O. (Thomas O.), Bezzina, C.R. (Connie R.), Body, S.C. (Simon C.), Boersma, E.H. (Eric H.), Bogaty, P. (Peter), Bots, M.L. (Michiel), Brenner, H. (Hermann), Brugts, J.J. (Jasper), Burkhardt, R. (Ralph), Carpeggiani, C. (Clara), Condorelli, G. (Gianluigi), Cooper-Dehoff, R.M. (Rhonda), Cresci, S. (Sharon), Danchin, N. (Nicolas), Faire, U. (Ulf) de, Doughty, R.N. (Robert N.), Drexel, H. (Heinz), Engert, J.C. (James C.), Fox, K.A.A. (Keith), Girelli, D. (Domenico), Grobbee, D.E. (Diederick E.), Hagström, E. (Emil), Hazen, S.L. (Stanley), Held, C. (Claes), Hemingway, H., Hoefer, I.E. (Imo), Hovingh, G.K. (G Kees), Jabbari, R. (Reza), Johnson, J.A. (Jennifer ), Jukema, J.W. (Jan Wouter), Kaczor, M.P. (Marcin P.), Kähönen, M. (Mika), Kettner, J. (Jiri), Kiliszek, M. (Marek), Klungel, O.H. (Olaf), Lagerqvist, B. (Bo), Lambrechts, D. (Diether), Laurikka, J.O. (Jari O.), Lehtimäki, T. (Terho), Lindholm, D. (Daniel), Mahmoodi, B.K. (Bakhtawar K.), Maitland-van der Zee, A-H. (Anke-Hilse), McPherson, R. (Ruth), Melander, O. (Olle), Metspalu, A. (Andres), Niemcunowicz-Janica, A. (Anna), Olivieri, O. (Oliviero), Opolski, G. (Grzegorz), Palmer, C.N.A. (Colin), Pasterkamp, G. (Gerard), Pepine, C.J. (Carl), Pereira, A. (A.), Pilote, L. (Louise), Erdmann, J. (Jeanette), Richards, A.M. (A Mark), Sanak, M. (Marek), Siegbahn, A. (Agneta), Simon, T. (Tabassome), Sinisalo, J. (Juha), Smith, J.G. (J Gustav), Schwartz, S.M. (Stephen), Stender, S. (Steen), Stewart, A.F. (Alexandre F.), Szczeklik, W. (Wojciech), Szpakowicz, A. (Anna), Tardif, J.-C. (Jean-Claude), Berg, J.M. (Jurrien) ten, Tfelt-Hansen, J. (Jacob), Thanassoulis, G. (George), Thiery, J.P. (Joachim), Torp-Pedersen, C. (Christian Tobias), Graaf, Y. (Yolanda) van der, Visseren, F.L.J. (Frank), Waltenberger, J. (Johannes), Weeke, P.E. (Peter E.), Harst, P. (Pim) van der, Lang, C.C. (Chim C.), Sattar, N. (Naveed), Cameron, V.A. (Vicky A.), Anderson, J.L. (Jeffrey), Brophy, J.M. (James M.), Pare, G. (Guillame), Horne, B.D. (Benjamin), Ye, S. (Shu), Wallentin, L. (Lars), Wauters, E. (Els), Samani, N.J. (Nilesh), Hingorani, A. (Aroon), and Asselbergs, F.W. (Folkert)

Abstract

BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants a

Published
2019
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18. Variation In Lpa And Calcific Aortic Valve Stenosis In Patients Undergoing Cardiac Surgery And Familial Risk Of Aortic Valve Microcalcification

Author

Perrot, N., primary, Thériault, S., additional, Dina, C., additional, Chen, H.Y., additional, Boekholdt, M., additional, Rigade, S., additional, Després, A.A., additional, Poulin, A., additional, Capoulade, R., additional, Le Tourneau, T., additional, Messika-Zeitoun, D., additional, Engert, J., additional, Dweck, M., additional, Mathieu, P., additional, Pibarot, P., additional, Schott, J.J., additional, Thanassoulis, G., additional, Clavel, M.A., additional, Bossé, Y., additional, and Benoit, A., additional

Published
2019
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19. Lipoprotein(A), Oxidized Phospholipids, And Aortic Valve Microcalcification Assessed By 18f-Naf Pet/Ct

Author

Després, A.A., primary, Perrot, N., additional, Tastet, L., additional, Pouliot, A., additional, Shen, M., additional, Chen, H.Y., additional, Bourgeois, R., additional, Trottier, M., additional, Guimond, J., additional, Tessier, M., additional, Nadeau, M., additional, Sebastien, T., additional, Couture, P., additional, Dweck, M., additional, Tsimikas, S., additional, Thanassoulis, G., additional, Pibarot, P., additional, Marie-Annick Clavel, M.A.C., additional, and Arsenault, B., additional

Published
2019
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20. The spectrum of type III hyperlipoproteinemia

Author

Sniderman, A.D., Graaf, J. de, Thanassoulis, G., Tremblay, A.J., Martin, S.S., Couture, P., Sniderman, A.D., Graaf, J. de, Thanassoulis, G., Tremblay, A.J., Martin, S.S., and Couture, P.

Abstract

Item does not contain fulltext, BACKGROUND: Type III hyperlipoproteinemia is a highly atherogenic dyslipoproteinemia characterized by hypercholesterolemia and hypertriglyceridemia due to markedly increased numbers of cholesterol-enriched chylomicron and very-low-density lipoprotein (VLDL) remnant lipoprotein particles. Type III can be distinguished from mixed hyperlipidemia based on a simple diagnostic algorithm, which involves total cholesterol, triglycerides, and apolipoprotein B (apoB). However, apoB is not measured routinely. OBJECTIVE: The objective of the present study was to determine if patients with type III could be distinguished from mixed hyperlipidemia based on lipoprotein lipids. METHODS: Classification was based first on total cholesterol and triglyceride and then on the apoB diagnostic algorithm using apoB plus total cholesterol plus triglycerides, and validated by sequential ultracentrifugation. Four hundred and forty normals, 637 patients with hypertriglyceridemia, and 714 with hypertriglyceridemia and hypercholesterolemia were studied. Plasma lipoproteins were separated by sequential ultracentrifugation and heparin-manganese precipitation. Cholesterol, triglyceride, and apoB were measured in plasma and isolated lipoprotein fractions. RESULTS: Of the 1351 patients with hypertriglyceridemia, 49 had type III hyperlipoproteinemia, as diagnosed by the apoB algorithm and validated by ultracentrifugation. Plasma triglycerides were higher in the type III subjects: 4.16 mmol/L (3.35-6.08, 25th-75th percentile), but there was considerable overlap with the hypertriglyceridemic subjects 2.65 mmol/L (1.91-4.20, 25th-75th percentile) and the combined hyperlipidemic subjects 3.02 mmol/L (2.07-5.32, 25th-75th percentile). Similarly, total cholesterol was 4.79 mmol/L (4.31-5.58, 25th-75th percentile) for type III vs 5.5 mmol/L (4.64-5.78, 25th-75th percentile) and 7.02 mmol/L (6.39-7.96, 25th-75th percentile), respectively. By contrast, as identified by the apoB algorithm, the VLDL-C/TG, VLDL-C

Published
2018

21. Association of Triglyceride-Related Genetic Variants With Mitral Annular Calcification

Author

Afshar, M, Luk, K, Do, R, Dufresnse, L, Owens, DS, Harris, TB, Peloso, GM, Kerr, KF, Wong, Q, Smith, AV, Budoff, MJ, Rotter, JI, Cupples, LA, Rich, SS, Engert, JC, Gudnason, V, O'Donnell, CJ, Post, WS, Thanassoulis, G, and Worki, CHARGEEC

Subjects
lipids, mitral valve, prevention, single nucleotide polymorphism, Mendelian randomization
Published
2017

25. Association of low-density lipoprotein cholesterol - Related genetic variants with aortic valve calcium and incident aortic stenosis

Author

Smith, JG, Luk, K, Schulz, CA, Engert, JC, Do, R, Hindy, G, Rukh, G, Dufresne, L, Almgren, P, Owens, DS, Harris, TB, Peloso, GM, Kerr, KF, Wong, Q, Smith, AV, Budoff, MJ, Rotter, JI, Cupples, LA, Rich, S, Kathiresan, S, Orho-Melander, M, Gudnason, V, O'Donnell, CJ, Post, WS, and Thanassoulis, G

Abstract

IMPORTANCE Plasma low-density lipoprotein cholesterol (LDL-C) has been associated with aortic stenosis in observational studies; however, randomized trials with cholesterol-lowering therapies in individuals with established valve disease have failed to demonstrate reduced disease progression. Copyright 2014 American Medical Association. All rights reserved.OBJECTIVE To evaluate whether genetic data are consistent with an association between LDL-C, high-density lipoprotein cholesterol (HDL-C), or triglycerides (TG) and aortic valve disease.DESIGN, SETTING, AND PARTICIPANTS Using a Mendelian randomization study design, we evaluated whether weighted genetic risk scores (GRSs), a measure of the genetic predisposition to elevations in plasma lipids, constructed using single-nucleotide polymorphisms identified in genome-wide association studies for plasma lipids, were associated with aortic valve disease. We included community-based cohorts participating in the CHARGE consortium (n = 6942), including the Framingham Heart Study (cohort inception to last follow-up: 1971-2013; n = 1295), Multi-Ethnic Study of Atherosclerosis (2000-2012; n = 2527), Age Gene/Environment Study-Reykjavik (2000-2012; n = 3120), and the Malmö Diet and Cancer Study (MDCS, 1991-2010; n = 28 461).MAIN OUTCOMES AND MEASURES Aortic valve calcium quantified by computed tomography in CHARGE and incident aortic stenosis in the MDCS.RESULTS The prevalence of aortic valve calcium across the 3 CHARGE cohorts was 32% (n = 2245). In the MDCS, over a median follow-up time of 16.1 years, aortic stenosis developed in 17 per 1000 participants (n = 473) and aortic valve replacement for aortic stenosis occurred in 7 per 1000 (n = 205). Plasma LDL-C, but not HDL-C or TG, was significantly associated with incident aortic stenosis (hazard ratio [HR] per mmol/L, 1.28; 95% CI, 1.04-1.57; P =.02; aortic stenosis incidence: 1.3% and 2.4% in lowest and highest LDL-C quartiles, respectively). The LDL-C GRS, but not HDL-C or TG GRS, was significantly associated with presence of aortic valve calcium in CHARGE (odds ratio [OR] per GRS increment, 1.38; 95% CI, 1.09-1.74; P =.007) and with incident aortic stenosis in MDCS (HR per GRS increment, 2.78; 95% CI, 1.22-6.37; P=.02; aortic stenosis incidence: 1.9% and 2.6% in lowest and highest GRS quartiles, respectively). In sensitivity analyses excluding variants weakly associated with HDL-C or TG, the LDL-C GRS remained associated with aortic valve calcium (P =.03) and aortic stenosis (P =.009). In instrumental variable analysis, LDL-C was associated with an increase in the risk of incident aortic stenosis (HR per mmol/L, 1.51; 95% CI, 1.07-2.14; P =.02).CONCLUSIONS AND RELEVANCE Genetic predisposition to elevated LDL-C was associated with presence of aortic valve calcium and incidence of aortic stenosis, providing evidence supportive of a causal association between LDL-C and aortic valve disease. Whether earlier intervention to reduce LDL-C could prevent aortic valve disease merits further investigation.

Published
2014

31. Relations of change in plasma levels of LDL-C, non-HDL-C and apoB with risk reduction from statin therapy: a meta-analysis of randomized trials

Author

Thanassoulis, G., Williams, K., Ye, K., Brook, R., Couture, P., Lawler, P.R., Graaf, J. de, Furberg, C.D., Sniderman, A., Thanassoulis, G., Williams, K., Ye, K., Brook, R., Couture, P., Lawler, P.R., Graaf, J. de, Furberg, C.D., and Sniderman, A.

Abstract

Contains fulltext : 136688.pdf (publisher's version ) (Open Access), BACKGROUND: Identifying the best markers to judge the adequacy of lipid-lowering treatment is increasingly important for coronary heart disease (CHD) prevention given that several novel, potent lipid-lowering therapies are in development. Reductions in LDL-C, non-HDL-C, or apoB can all be used but which most closely relates to benefit, as defined by the reduction in events on statin treatment, is not established. METHODS AND RESULTS: We performed a random-effects frequentist and Bayesian meta-analysis of 7 placebo-controlled statin trials in which LDL-C, non-HDL-C, and apoB values were available at baseline and at 1-year follow-up. Summary level data for change in LDL-C, non-HDL-C, and apoB were related to the relative risk reduction from statin therapy in each trial. In frequentist meta-analyses, the mean CHD risk reduction (95% CI) per standard deviation decrease in each marker across these 7 trials were 20.1% (15.6%, 24.3%) for LDL-C; 20.0% (15.2%, 24.7%) for non-HDL-C; and 24.4% (19.2%, 29.2%) for apoB. Compared within each trial, risk reduction per change in apoB averaged 21.6% (12.0%, 31.2%) greater than changes in LDL-C (P<0.001) and 24.3% (22.4%, 26.2%) greater than changes in non-HDL-C (P<0.001). Similarly, in Bayesian meta-analyses using various prior distributions, Bayes factors (BFs) favored reduction in apoB as more closely related to risk reduction from statins compared with LDL-C or non-HDL-C (BFs ranging from 484 to 2380). CONCLUSIONS: Using both a frequentist and Bayesian approach, relative risk reduction across 7 major placebo-controlled statin trials was more closely related to reductions in apoB than to reductions in either non-HDL-C or LDL-C.

Published
2014

34. BARRIERS TO IMPROVEMENTS IN FRUIT AND VEGETABLE INTAKE AFTER PREMATURE ACUTE CORONARY SYNDROME: WHAT IS THE ROLE OF DIETARY COUNSELLING AND PATIENT CHARACTERISTICS?

Author

Yinko, SS Leung, primary, Pelletier, R., additional, Behlouli, H., additional, Lavoie, K.L., additional, Bacon, S.L., additional, Daskalopoulou, S.S., additional, Thanassoulis, G., additional, Karp, I., additional, Eisenberg, M.J., additional, Pilote, L., additional, and Investigators, G.E.N.E.S.I.S.-P.R.A.X.Y., additional

Published
2014
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36. GENETICALLY ELEVATED LOW-DENSITY LIPOPROTEIN CHOLESTEROL IS ASSOCIATED WITH AORTIC VALVE CALCIFICATION AND INCIDENT AORTIC STENOSIS: A MENDELIAN RANDOMIZATION STUDY

Author

Thanassoulis, G., primary, Luk, K., additional, Schulz, C., additional, Engert, J., additional, Do, R., additional, Hindy, G., additional, Rukh, G., additional, Dufresne, L., additional, Almgren, P., additional, Owens, D., additional, Harris, T., additional, Peloso, G.M., additional, Kerr, K., additional, Wong, Q., additional, Smith, A.V., additional, Budoff, M.J., additional, Rotter, J.I., additional, Cupples, L., additional, Rich, S.S., additional, Kathiresan, S., additional, Orho-Melander, M., additional, Gudnason, V., additional, O'Donnell, C.J., additional, Post, W., additional, and Smith, J., additional

Published
2014
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39. The causal exposure model of vascular disease.

Author

Sniderman, A.D., Lawler, P.R., Williams, K., Thanassoulis, G., Graaf, J. de, Furberg, C.D., Sniderman, A.D., Lawler, P.R., Williams, K., Thanassoulis, G., Graaf, J. de, and Furberg, C.D.

Abstract

1 april 2012, Item does not contain fulltext, Primary prevention of cardiovascular disease is governed at present by the risk factor model for cardiovascular events, a model which is widely accepted by physicians and professional associations, but which has important limitations: most critically, that effective treatment to reduce arterial damage is often delayed until the age at which cardiovascular events become common. This delay means that many of the early victims of vascular disease will not be identified in time. This delay also allows atherosclerosis to develop and progress unchecked within the arterial tree with the result that the absolute effectiveness of preventive therapy is limited by the time it is eventually initiated. The causal exposure model of vascular disease is an alternative to the risk factor model for cardiovascular events. Whereas the risk factor model aims to identify and treat those at markedly increased risk of vascular events within the next decade, the causal exposure model of vascular disease aims to prevent events by treating the causes of the disease when they are identified. In the risk factor model, age is an independent non-modifiable risk factor and the predictive power of age far outweighs that of the other risk factors. In the causal exposure model, age is the duration of time the arterial wall is exposed to the causes of atherosclerosis: apoB (apolipoprotein B) lipoproteins, hypertension, diabetes and smoking. Preventing the development of advanced atherosclerotic lesions by treating the causes of vascular disease is the simplest, surest and most effective way to prevent clinical events.

Published
2012

45. Distinct Genetic Risk Profile in Aortic Stenosis Compared With Coronary Artery Disease.

Author

Trenkwalder T, Maj C, Al-Kassou B, Debiec R, Doppler SA, Musameh MD, Nelson CP, Dasmeh P, Grover S, Knoll K, Naamanka J, Mordi IR, Braund PS, Dreßen M, Lahm H, Wirth F, Baldus S, Kelm M, von Scheidt M, Krefting J, Ellinghaus D, Small AM, Peloso GM, Natarajan P, Thanassoulis G, Engert JC, Dufresne L, Franke A, Görg S, Laudes M, Nowak-Göttl U, Vaht M, Metspalu A, Stoll M, Berger K, Pellegrini C, Kastrati A, Hengstenberg C, Lang CC, Kessler T, Hovatta I, Nickenig G, Nöthen MM, Krane M, Schunkert H, Samani NJ, Schumacher J, Kals M, Reigo A, Teder-Laving M, Gehlen J, Webb TR, Giel AS, Koebbe LL, Feirer N, Billmann M, Srinivasan S, Zimmer S, Palmer CNA, Li L, Yang C, Borisov O, Adam M, Veulemans V, Joner M, and Xhepa E

Abstract

Importance: Aortic stenosis (AS) and coronary artery disease (CAD) frequently coexist. However, it is unknown which genetic and cardiovascular risk factors might be AS-specific and which could be shared between AS and CAD., Objective: To identify genetic risk loci and cardiovascular risk factors with AS-specific associations., Design, Setting, and Participants: This was a genomewide association study (GWAS) of AS adjusted for CAD with participants from the European Consortium for the Genetics of Aortic Stenosis (EGAS) (recruited 2000-2020), UK Biobank (recruited 2006-2010), Estonian Biobank (recruited 1997-2019), and FinnGen (recruited 1964-2019). EGAS participants were collected from 7 sites across Europe. All participants were of European ancestry, and information on comorbid CAD was available for all participants. Follow-up analyses with GWAS data on cardiovascular traits and tissue transcriptome data were also performed. Data were analyzed from October 2022 to July 2023., Exposures: Genetic variants., Main Outcomes and Measures: Cardiovascular traits associated with AS adjusted for CAD. Replication was performed in 2 independent AS GWAS cohorts., Results: A total of 18 792 participants with AS and 434 249 control participants were included in this GWAS adjusted for CAD. The analysis found 17 AS risk loci, including 5 loci with novel and independently replicated associations (RNF114A, AFAP1, PDGFRA, ADAMTS7, HAO1). Of all 17 associated loci, 11 were associated with risk specifically for AS and were not associated with CAD (ALPL, PALMD, PRRX1, RNF144A, MECOM, AFAP1, PDGFRA, IL6, TPCN2, NLRP6, HAO1). Concordantly, this study revealed only a moderate genetic correlation of 0.15 (SE, 0.05) between AS and CAD (P = 1.60 × 10-3). Mendelian randomization revealed that serum phosphate was an AS-specific risk factor that was absent in CAD (AS: odds ratio [OR], 1.20; 95% CI, 1.11-1.31; P = 1.27 × 10-5; CAD: OR, 0.97; 95% CI 0.94-1.00; P = .04). Mendelian randomization also found that blood pressure, body mass index, and cholesterol metabolism had substantially lesser associations with AS compared with CAD. Pathway and transcriptome enrichment analyses revealed biological processes and tissues relevant for AS development., Conclusions and Relevance: This GWAS adjusted for CAD found a distinct genetic risk profile for AS at the single-marker and polygenic level. These findings provide new targets for future AS research.

Published
2024
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46. Discordance Analysis of VLDL-C and ApoB in UK Biobank and Framingham Study: A Prospective Observational Study.

Author

Bilgic S, Pencina KM, Pencina MJ, Cole J, Dufresne L, Thanassoulis G, and Sniderman AD

Subjects
Humans, Male, Middle Aged, Female, Prospective Studies, United Kingdom epidemiology, Biomarkers blood, Risk Assessment, Aged, Adult, Cardiovascular Diseases epidemiology, Cardiovascular Diseases blood, Cardiovascular Diseases diagnosis, Incidence, Apolipoproteins B blood, Risk Factors, Heart Disease Risk Factors, UK Biobank, Cholesterol, VLDL blood, Apolipoprotein B-100 blood, Cholesterol, HDL blood, Biological Specimen Banks
Abstract

Background: Recent observational and Mendelian randomization analyses have reported significant effects of VLDL-C (very-low density lipoprotein cholesterol) on risk that is independent of ApoB (apolipoprotein B). We aim to determine the independent association of VLDL-C and ApoB with the risk of new onset cardiovascular events in the UK Biobank and Framingham Heart Study cohorts., Methods: We included 294 289 UK Biobank participants with a median age of 56 years, 42% men, and 2865 Framingham Heart Study participants (median age, 53 years; 47% men). The residual resulting from regressing VLDL-C on ApoB expresses the portion of VLDL-C not explained by ApoB, while the residual from regressing ApoB on VLDL-C expresses the portion of ApoB not explained by VLDL-C. Cox proportional hazards models for atherosclerotic cardiovascular disease incidence were created for residual VLDL-C and residual ApoB. Models were analyzed with and without high-density lipoprotein cholesterol (HDL-C). Furthermore, we investigated the independent effects of VLDL-C after accounting for ApoB and HDL-C and of HDL-C after accounting for ApoB and VLDL-C., Results: In the UK Biobank, ApoB was highly correlated with VLDL-C (r=0.70; P <0.001) but weakly negatively correlated with HDL-C (r=-0.11; P <0.001). The ApoB residual and the VLDL-C residual were significantly associated with new-onset atherosclerotic cardiovascular disease (hazard ratio [HR], 1.08 and 1.05, respectively; P <0.001). After adjusting for HDL-C, the ApoB residual remained similar in magnitude (HR, 1.10; P <0.001), whereas the effect size of the VLDL-C residual was reduced (HR, 1.02; P =0.029). The independent effect of HDL-C (after accounting for ApoB and VLDL-C) remained robust (HR, 0.86; P <0.0001), while the independent effect of VLDL-C (after accounting for ApoB and HDL-C) was modest (HR, 1.02; P =0.029). All results were consistent in the Framingham cohort., Conclusions: When adjusted for HDL-C, the association of VLDL-C with cardiovascular risk was no longer clinically meaningful. Our residual discordance analysis suggests that adjustment for HDL-C cannot be ignored., Competing Interests: M.J. Pencina reports funding from the nonprofit Doggone Foundation, consulting fees from Cleerly, Inc, and advisory board fees from Eli Lilly and Janssen. K.M. Pencina reports funding from the nonprofit Doggone Foundation. G. Thanassoulis has participated in advisory boards or speaker bureaus for Amgen, Regeneron/Sanofi, HLS Therapeutics, Ionis, Servier, and Novartis and has received grant funding from Servier and Ionis. The other authors report no conflicts.

Published
2024
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47. Association of aortic valve calcium with dementia and stroke: The Multi-Ethnic Study of Atherosclerosis.

Author

Marrero N, Jha K, Hughes TM, Razavi AC, Grant JK, Boakye E, Anchouche K, Dzaye O, Budoff MJ, Rotter JI, Guo X, Yao J, Wood AC, Blumenthal RS, Michos ED, Thanassoulis G, Post WS, Blaha MJ, Ibeh C, and Whelton SP

Subjects
Humans, Female, Male, Aged, Middle Aged, Risk Factors, Aged, 80 and over, Incidence, United States epidemiology, Proportional Hazards Models, Risk Assessment, Time Factors, Prospective Studies, Atherosclerosis ethnology, Multivariate Analysis, Tomography, X-Ray Computed, Aortic Valve diagnostic imaging, Aortic Valve pathology, Stroke epidemiology, Stroke ethnology, Dementia epidemiology, Dementia ethnology, Calcinosis ethnology, Aortic Valve Stenosis ethnology, Aortic Valve Stenosis diagnostic imaging, Aortic Valve Stenosis epidemiology
Abstract

Background and Aims: Calcific aortic valve disease is associated with increased thrombin formation, platelet activation, decreased fibrinolysis, and subclinical brain infarcts. We examined the long-term association of aortic valve calcification (AVC) with newly diagnosed dementia and incident stroke in the Multi-Ethnic Study of Atherosclerosis (MESA)., Methods: AVC was measured using non-contrast cardiac CT at Visit 1. We examined AVC as a continuous (log-transformed) and categorical variable (0, 1-99, 100-299, ≥300). Newly diagnosed dementia was adjudicated using International Classification of Disease codes. Stroke was adjudicated from medical records. We calculated absolute event rates (per 1000 person-years) and multivariable adjusted Cox proportional hazards ratios (HR)., Results: Overall, 6812 participants had AVC quantified with a mean age of 62.1 years old, 52.9 % were women, and the median 10-year estimated atherosclerotic cardiovascular disease (ASCVD) risk was 13.5 %. Participants with AVC >0 were older and less likely to be women compared to those with AVC=0. Over a median 16-year follow-up, there were 535 cases of dementia and 376 cases of stroke. The absolute risk of newly diagnosed dementia increased in a stepwise pattern with higher AVC scores, and stroke increased in a logarithmic pattern. In multivariable analyses, AVC was significantly associated with newly diagnosed dementia as a log-transformed continuous variable (HR 1.09; 95 % CI 1.04-1.14) and persons with AVC ≥300 had nearly a two-fold higher risk (HR 1.77; 95 % CI 1.14-2.76) compared to those with AVC=0. AVC was associated with an increased risk of stroke after adjustment for age, sex, and race/ethnicity, but not after adjustment for ASCVD risk factors., Conclusions: After multivariable adjustment, AVC >0 was significantly associated with an increased risk of newly diagnosed dementia, but not incident stroke. This suggests that AVC may be an important risk factor for the long-term risk of dementia beyond traditional ASCVD risk factors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Published
2024
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48. Role of apolipoprotein B in the clinical management of cardiovascular risk in adults: An expert clinical consensus from the national lipid association.

Author

Soffer DE, Marston NA, Maki KC, Jacobson TA, Bittner VA, Peña JM, Thanassoulis G, Martin SS, Kirkpatrick CF, Virani SS, Dixon DL, Ballantyne CM, and Remaley AT

Abstract

This National Lipid Association (NLA) Expert Clinical Consensus provides an overview of the physiologic and clinical considerations regarding the role of apolipoprotein B (apoB) measurement to guide clinical care based on the available scientific evidence and expert opinion. ApoB represents the total concentration of atherogenic lipoprotein particles in the circulation and more accurately reflects the atherogenic burden of lipoproteins when compared to low-density lipoprotein cholesterol (LDL-C). ApoB is a validated clinical measurement that augments the information found in a standard lipoprotein lipid panel; therefore, there is clinical value in using apoB in conjunction with a standard lipoprotein lipid profile when assessing risk and managing lipid-lowering therapy (LLT). ApoB has been shown to be superior to LDL-C in risk assessment both before and during treatment with LLT. In individuals, there can be discordance between levels of LDL-C and apoB, as well as LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C), despite high levels of population-wide correlation. When there is discordance between LDL-C and apoB, or LDL-C and non-HDL-C, atherosclerotic cardiovascular disease risk generally aligns better with apoB or non-HDL-C. Additionally, apoB can be used in tandem with standard lipoprotein lipid measurements to diagnose distinct lipoprotein phenotypes. ApoB testing can inform clinical prognosis and care, as well as enable family cascade screening, when an inherited lipoprotein syndrome is identified. The NLA and other organizations will continue to educate clinicians about the role of apoB measurement in improving clinical risk assessment and dyslipidemia management. An urgent need exists to improve access and reimbursement for apoB testing., (Copyright © 2024. Published by Elsevier Inc.)

Published
2024
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49. Plasma Proteomic Biomarkers of Aortic Stenosis: A Mendelian Randomization Study.

Author

Yang TY, Small AM, Dufresne L, Peloso GM, Natarajan P, Engert JC, and Thanassoulis G

Subjects
Humans, Female, Male, Aortic Valve Stenosis blood, Aortic Valve Stenosis genetics, Aortic Valve Stenosis diagnosis, Mendelian Randomization Analysis, Biomarkers blood, Proteomics methods
Abstract

Competing Interests: Funding Support and Author Disclosures This study has been funded by the Canadian Institutes of Health Research (CIHR), the Heart and Stroke Foundation of Canada (HSFC), the National Institutes of Health, and the U.S. Department of Veterans Affairs. Dr Natarajan has received research grants from Allelica, Apple, Amgen, Boston Scientific, Genentech/Roche, and Novartis; has received personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Eli Lilly & Co, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, and Novartis; has held scientific advisory board membership for Esperion Therapeutics, Preciseli, and TenSixteen Bio; has served as a scientific cofounder of TenSixteen Bio; has held equity in MyOme, Preciseli, and TenSixteen Bio; and has disclosed spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. Dr Thanassoulis has received consulting fees from Ionis Pharmaceuticals; and has participated in advisory boards for Amgen, Sanofi, Novartis, HLS Therapeutics, and Silence. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Published
2024
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50. What Guidelines Say About Risk Reduction: Major Data on the Link Between Lipid Lowering and Outcomes.

Author

Thanassoulis G, Welsh RC, and Hegele RA

Subjects
Humans, Apolipoproteins B blood, Atherosclerosis prevention & control, Risk Reduction Behavior, Cardiovascular Diseases prevention & control, Canada epidemiology, Cholesterol, LDL blood, Hypolipidemic Agents therapeutic use, Practice Guidelines as Topic, Dyslipidemias blood, Dyslipidemias diagnosis, Dyslipidemias therapy
Abstract

Atherosclerotic cardiovascular disease (ASCVD) is a significant health challenge, and apolipoprotein B (ApoB)-containing lipoproteins are increasingly recognized as central to its progression. Initially labelled as the "low-density lipoprotein hypothesis," our understanding of the etiology of ASCVD has evolved into the "ApoB principle," which highlights the causal and consistent role of all ApoB lipoproteins in ASCVD development. We review the large body of data from genetic studies, to epidemiologic studies, to clinical trials that support this foundational principle. We also provide an overview of the recommendations from guideline committees across the globe on dyslipidemia management and compare these with recent Canadian guidelines. With a few key differences, recent guidelines worldwide provide largely concordant recommendations for diagnosing and managing dyslipidemia with general consensus regarding the need for optimal control of low-density lipoprotein cholesterol and ApoB-containing lipoproteins to prevent cardiovascular events and improve patient care., (Copyright © 2024. Published by Elsevier Inc.)

Published
2024
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