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Oxidized Phospholipids, Lipoprotein(a), and Progression of Calcific Aortic Valve Stenosis
Open accessAbstract
Background Elevated lipoprotein(a) (Lp[a]) is associated with aortic stenosis (AS). Oxidized phospholipids (OxPL) are key mediators of calcification in valvular cells and are carried by Lp(a).Objectives This study sought to determine whether Lp(a) and OxPL are associated with hemodynamic progression of AS and AS-related events.Methods OxPL on apolipoprotein B-100 (OxPL-apoB), which reflects the biological activity of Lp(a), and Lp(a) levels were measured in 220 patients with mild-to-moderate AS. The primary endpoint was the progression rate of AS, measured by the annualized increase in peak aortic jet velocity in m/s/year by Doppler echocardiography; the secondary endpoint was need for aortic valve replacement and cardiac death during 3.5 ± 1.2 years of follow-up.Results AS progression was faster in patients in the top tertiles of Lp(a) (peak aortic jet velocity: +0.26 ± 0.26 vs. +0.17 ± 0.21 m/s/year; p = 0.005) and OxPL-apoB (+0.26 ± 0.26 m/s/year vs. +0.17 ± 0.21 m/s/year; p = 0.01). After multivariable adjustment, elevated Lp(a) or OxPL-apoB levels remained independent predictors of faster AS progression. After adjustment for age, sex, and baseline AS severity, patients in the top tertile of Lp(a) or OxPL-apoB had increased risk of aortic valve replacement and cardiac death.Conclusions Elevated Lp(a) and OxPL-apoB levels are associated with faster AS progression and need for aortic valve replacement. These findings support the hypothesis that Lp(a) mediates AS progression through its associated OxPL and provide a rationale for randomized trials of Lp(a)-lowering and OxPL-apoB-lowering therapies in AS. (Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin [ASTRONOMER]; NCT00800800).
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“The clinical factors associated with faster stenosis progression include older age, female sex, severity of the stenosis and degree of aortic valve calcification at diagnosis, smoking, hypertension, obesity, metabolic syndrome, secondary hyperparathyroidism, renal failure elevated circulating levels of Lp(a), and increased activity of Lp-PLA2 (also called lipoprotein–associated phospholipase A2)51”
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“In particular, the presence of elevated plasma Lp(a) (>50 mg per dL; the upper normal limit is <30 mg per dL)) is associated with a twofold faster stenosis progression51.”
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“In addition, Capoulade and colleagues showed that circulating Lp(a) and Ox-PL levels were independently associated with faster progression of calcific AS51.”
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“prior studies have linked ApoB to the onset and accelerated progression of CAVD [38,39].”
From Identifying novel drug targets for calcific aortic valve disease through Mendelian randomization (2025) · cites this paper as [38]
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Role of lipoprotein(a) concentrations in bioprosthetic aortic valve degeneration
Farina, J., Chao, C., Pereyra, M., Roarke, M. C., Said, E. F., Barry, T., Alsidawi, S., Sell‐Dottin, K. A., Sweeney, J. P., Fortuin, D. F., et al. (2023) · Heart · doi:10.1136/heartjnl-2023-322987 · Cited by 20
Lp(a): Addressing a Target for Cardiovascular Disease Prevention
Vasquez, N., & Joshi, P. H. (2019) · Current Cardiology Reports · doi:10.1007/s11886-019-1182-0 · Cited by 19
Serum biomarkers in valvular heart disease
Gardezi, S. K. M., Coffey, S., Prendergast, B., & Myerson, S. G. (2017) · Heart · doi:10.1136/heartjnl-2016-310482 · Cited by 20
Lipoprotein (a): Underrecognized Risk with a Promising Future
Manzato, M., Wright, R. S., Jaffe, A. S., & Vasile, V. C. (2024) · Reviews in Cardiovascular Medicine · doi:10.31083/j.rcm2511393 · Cited by 19
Hénaut, L., Candellier, A., Huish, S., Issa, N., Sinha, S., & Massy, Z. A. (2024) · Clinical Kidney Journal · doi:10.1093/ckj/sfae421 · Cited by 22
Lee, S. H., & Choi, J. (2018) · Animal Cells and Systems · doi:10.1080/19768354.2018.1528175 · Cited by 20
Durability of transcatheter aortic valve implantation: A translational review
Fauvel, C., Capoulade, R., Durand, É., Béziau, D. M., Schott, J., Tourneau, T. L., & Eltchaninoff, H. (2020) · Archives of cardiovascular diseases · doi:10.1016/j.acvd.2019.11.007 · Cited by 20
Self-citationBlood, tissue and imaging biomarkers in calcific aortic valve stenosis
Shen, M., Tastet, L. L., Bergler-Klein, J. K., Pîbarot, P., & Clavel, M.-A. A. (2017) · Current Opinion in Cardiology · doi:10.1097/hco.0000000000000487 · Cited by 18
New Horizons: Revival of Lipoprotein (a) as a Risk Factor for Cardiovascular Disease
Nestel, P. J., Loh, W. J., Ward, N. C., & Watts, G. F. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac541 · Cited by 19
Association of Lipoprotein(a) With Severe Degenerative Aortic Valve Stenosis
Kim, A., Ahn, J., Kang, D., Jun, T. J., Sun, B. J., Kim, H. J., Kim, J. B., Kim, D., Park, D., Kim, Y., et al. (2024) · JACC Asia · doi:10.1016/j.jacasi.2024.07.007 · Cited by 18
Elevated Lipoprotein(a) Levels Lower ABCA1 Cholesterol Efflux Capacity
Tavori, H., Fenton, A. M., Plubell, D. L., Rosário, S., Yerkes, E., Gasik, R. E., Miles, J., Bergstrom, P., Minnier, J., Fazio, S., et al. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-02708 · Cited by 18
Yan, J., Pan, Y., Xiao, J., Ma, W., Li, L., Zhong, M., Long, H., Kong, F., & Shao, W. (2019) · Arquivos Brasileiros de Cardiologia · doi:10.5935/abc.20190120 · Cited by 17
Leibundgut, G., Lee, J., Strauss, B. H., Segev, A., & Tsimikas, S. (2016) · Journal of Thrombosis and Thrombolysis · doi:10.1007/s11239-016-1351-6 · Cited by 17
Self-citationLipoprotein(a) in patients with aortic stenosis: Insights from cardiovascular magnetic resonance
Vassiliou, V. S., Flynn, P. D., Raphael, C. E., Newsome, S., Khan, T. Z., Ali, A., Halliday, B. P., Bruengger, A. A. S., Malley, T. S., Sharma, P., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0181077 · Cited by 17
Therapeutic management of hyperlipoproteinemia (a)
Kosmas, C. E., Sourlas, A., Mallarkey, G., Silverio, D., Garcia, D. Y., Montan, P. D., Guzman, E., & Garcia, M. J. (2019) · Drugs in Context · doi:10.7573/dic.212609 · Cited by 17
How Does Elevated Lipoprotein(a) Cause Aortic Valve Stenosis? ∗
Nordestgaard, B. G., & Langsted, A. (2015) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2015.07.045 · Cited by 17
Lipoprotein(a) in clinical practice: A guide for the clinician
Krittanawong, C., Maitra, N. S., Sherbini, A. E., Shah, N. R., Lavie, C. J., Shapiro, M. D., & Virani, S. S. (2023) · Progress in Cardiovascular Diseases · doi:10.1016/j.pcad.2023.07.006 · Cited by 17
Familial Hypercholesterolemia and Lipoprotein(a): Two Partners in Crime?
Rodrigo Alonso, K., Argüeso, R., Álvarez-Baños, P., Muñiz-Grijalvo, O., Díaz-Díaz, J. L., & Mata, P. (2022) · Current Atherosclerosis Reports · doi:10.1007/s11883-022-01019-5 · Cited by 15
Parthymos, I., Kostapanos, M. S., Mikhailidis, D. P., & Florentin, M. (2021) · European Journal of Preventive Cardiology · doi:10.1093/eurjpc/zwab052 · Cited by 15
Liu, S.-L., Rozi, R., Shi, H.-W., Gao, Y., Guo, Y., Tang, Y., Li, J., & Wu, N. (2020) · PubMed Central · doi:10.11909/j.issn.1671-5411.2020.03.009 · Cited by 14
Mormone, A., Tortorella, G., Esposito, F., Caturano, A., Marrone, A., Cozzolino, D., Galiero, R., Marfella, R., Sasso, F. C., & Rinaldi, L. (2024) · Biomedicines · doi:10.3390/biomedicines12020432 · Cited by 17
AI-Enhanced Prediction of Aortic Stenosis Progression
Sanabria, M., Tastet, L. L., Pelletier, S., Leclercq, M., Ohl, L., Herrmann, L., Mattei, P., Precioso, F., Côté, N., Pîbarot, P., et al. (2024) · JACC Advances · doi:10.1016/j.jacadv.2024.101234 · Cited by 15
LP(a): The new marker of high cardiovascular risk
Averna, M. R., & Cefalu, A. B. (2024) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2024.103845 · Cited by 14
JCL roundtable—Lipoprotein(a): The emerging risk factor
Marcovina, S. M., Moriarty, P. M., Koschinsky, M. L., & Guyton, J. R. (2018) · Journal of clinical lipidology · doi:10.1016/j.jacl.2018.11.003 · Cited by 14
Genetics of Lipoprotein(a): Cardiovascular Disease and Future Therapy
Langsted, A., & Nordestgaard, B. G. (2021) · Current Atherosclerosis Reports · doi:10.1007/s11883-021-00937-0 · Cited by 14
Stamenković, A., Ganguly, R., Aliani, M., Ravandi, A., & Pierce, G. N. (2019) · Nutrients · doi:10.3390/nu11051179 · Cited by 14
Molecular Features of Calcific Aortic Stenosis in Female and Male Patients
Nezet, E. L., Marqueze-Pouey, C., Guisle, I., & Clavel, M.-A. A. (2024) · CJC Open · doi:10.1016/j.cjco.2024.06.002 · Cited by 13
The year in cardiology 2015: prevention
Chapman, M. J., Blankenberg, S., & Landmesser, U. (2016) · European Heart Journal · doi:10.1093/eurheartj/ehv721 · Cited by 13
The journey towards understanding lipoprotein(a) and cardiovascular disease risk: are we there yet?
Boffa, M. B., & Koschinsky, M. L. (2018) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000499 · Cited by 13
Metadata
- Authors
- Capoulade, R., Chan, K. L., Yeang, C., Mathieu, P., Bossé, Y., Dumesnil, J. G., Tam, J. W., Teo, K. K., Mahmut, A., Yang, X., Witztum, J. L., Arsenault, B. J., Després, J.-P., Pibarot, P., & Tsimikas, S.
- Affiliations
- Institut universitaire de cardiologie et de pneumologie de Québec (CA)
- Ottawa Heart Institute (CA)
- University of California San Diego (US)
- St. Boniface Hospital (CA)
- McMaster University (CA)
- Corresponding author
- Tsimikas, Sotirios
- ORCID
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2015-09
- Volume
- 66
- Issue
- 11
- Pages
- 1236-1246
- ISSN
- 0735-1097 (ISSN-L)
- OpenAlex
- W1609565130
- Cited by
- 417
- References
- 45
- Citations by year
- 2026: 26 · 2025: 49 · 2024: 37 · 2023: 37 · 2022: 52 · 2021: 30 · 2020: 40 · 2019: 47 · 2018: 26 · 2017: 38 · 2016: 32 · 2015: 3
- FWCI
- 24.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Corpus Université Laval (Université Laval) (submittedVersion)
- Funders
- Abbott Laboratories
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- Sanofi
- National Institutes of Health (HL055798, HL088093)
- University of California, San Diego
- Pfizer Canada
- Eli Lilly Canada
- Canadian Institutes of Health Research (MOP# 114997, MOP-245048, 114997, 245048)
- National Heart, Lung, and Blood Institute (HL-055798, HL093767, R01HL093767, HL119828, P01HL055798, R01HL119828, HL-088093, P01HL088093)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Valve Diseases and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Keywords
- aortic stenosis, calcific aortic stenosis, lipoprotein(a), oxidized phospholipids, apolipoprotein B-100, disease progression, aortic jet velocity, aortic valve replacement, cardiovascular mortality, valve calcification, Lp(a)-lowering therapy
- MeSH terms
- Adult, Aged, Aortic Valve, Aortic Valve Stenosis, Calcinosis, Death, Female, Humans, Male, Middle Aged, Oxidation-Reduction, Phospholipids, Ultrasonography, Biomarkers, Lipoprotein(a), Disease Progression
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