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Plasmatic PCSK9 Levels Are Associated with Very Fast Progression of Asymptomatic Degenerative Aortic Stenosis

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Abstract

The aim of this work was to study the association of potential biomarkers with fast aortic stenosis (AS) progression. Patients with moderate-to-severe AS were classified as very fast progressors (VFP) if exhibited an annualized change in peak velocity (aΔVmax) ≥0.45m/s/year and/or in aortic valve area (aΔAVA) ≥−0.2cm2/year. Respective cut-off values of ≥0.3m/s/year and ≥−0.1cm2/year defined fast progressors (FP), whereas the remaining patients were non-fast progressors (non-FP). Baseline markers of lipid metabolism, inflammation, and cardiac overload were determined. Two hundred and nine patients (97 non-FP, 38 FP, and 74 VFP) were included. PCSK9 levels were significantly associated with VFP (OR 1.014 [95%CI 1.005-1.024], for every 10 ng/mL), as were active smoking (OR 3.48) and body mass index (BMI, OR 1.09), with an AUC of 0.704 for the model. PCSK9 levels, active smoking, and BMI were associated with very fast AS progression in our series, suggesting that inflammation and calcification participate in disease progression.

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References

  1. Otto, C. M., & Prendergast, B. (2014). Aortic-valve stenosis — From patients at risk to severe valve obstruction. The New England Journal of Medicine, 371, 744–756.

    Article  CAS  Google Scholar 

  2. Iung, B., & Vahanian, A. (2011). Epidemiology of valvular heart disease in the adult. Nature Reviews. Cardiology, 8, 162–172.

    Article  Google Scholar 

  3. Généreux, P., Stone, G. W., O’Gara, P. T., Marquis-Gravel, G., Redfors, B., Giustino, G., Pibarot, P., Bax, J. J., Bonow, R. O., & Leon, M. B. (2016). Natural history, diagnostic approaches, and therapeutic strategies for patients with asymptomatic severe aortic stenosis. Journal of the American College of Cardiology, 67, 2263–2288.

    Article  Google Scholar 

  4. Baumgartner, H., Falk, V., Bax, J. J., De Bonis, M., Hamm, C., Holm, P. J., Iung, B., Lancellotti, P., Lansac, E., Rodriguez Muñoz, D., Rosenhek, R., Sjögren, J., Tornos Mas, P., Vahanian, A., Walther, T., Wendler, O., Windecker, S., & Zamorano, J. L. (2017). Document. 2017 ESC/EACTS Guidelines on the management of valvular heart disease. European Heart Journal, 38, 2739–2791.

    Article  Google Scholar 

  5. Taniguchi, T., Morimoto, T., Shiomi, H., Ando, K., Kanamori, N., Murata, K., Kitai, T., Kawase, Y., Izumi, C., Miyake, M., Mitsuoka, H., Kato, M., Hirano, Y., Matsuda, S., Nagao, K., Inada, T., Murakami, T., Takeuchi, Y., Yamane, K., Toyofuku, M., Ishii, M., Minamino-Muta, E., Kato, T., Inoko, M., Ikeda, T., Komasa, A., Ishii, K., Hotta, K., Higashitani, N., Kato, Y., Inuzuka, Y., Maeda, C., Jinnai, T., Morikami, Y., Sakata, R., & Kimura, T. (2015). Initial Surgical Versus Conservative Strategies in Patients with Asymptomatic Severe Aortic Stenosis. Journal of the American College of Cardiology, 66, 2827–2838.

    Article  Google Scholar 

  6. Varadarajan, P., Kapoor, N., Bansal, R. C., & Pai, R. G. (2006). Clinical profile and natural history of 453 nonsurgically managed patients with severe aortic stenosis. The Annals of Thoracic Surgery, 82, 2111–2115.

    Article  Google Scholar 

  7. Milin, A. C., Vorobiof, G., Aksoy, O., & Ardehali, R. (2014). Insights Into Aortic Sclerosis and Its Relationship With Coronary Artery Disease. Journal of the American Heart Association, 3, 1–12.

    Article  Google Scholar 

  8. Rajamannan, N. M., Evans, F. J., Aikawa, E., Grande-Allen, K. J., Demer, L. L., Heistad, D. D., Simmons, C. A., Masters, K. S., Mathieu, P., O’Brien, K. D., Schoen, F. J., Towler, D. A., Yoganathan, A. P., & Otto, C. M. (2011). Calcific Aortic Valve Disease: Not Simply a Degenerative Process. Circulation., 124, 1783–1791.

    Article  Google Scholar 

  9. Cho, K. I., Sakuma, I., Sohn, I. S., Jo, S. H., & Koh, K. K. (2018). Inflammatory and metabolic mechanisms underlying the calcific aortic valve disease. Atherosclerosis., 277, 60–65.

    Article  CAS  Google Scholar 

  10. Rajamannan, N. M., Subramaniam, M., Rickard, D., Stock, S. R., Donovan, J., Springett, M., Orszulak, T., Fullerton, D. A., Tajik, A. J., Bonow, R. O., & Spelsberg, T. (2003). Human aortic valve calcification is associated with an osteoblast phenotype. Circulation., 107, 2181–2184.

    Article  Google Scholar 

  11. Baumgartner, H., Hung, J., Bermejo, J., Chambers, J. B., Edvardsen, T., Goldstein, S., Lancellotti, P., Lefevre, M., Miller, F., & Otto, C. M. (2017). Recommendations on the echocardiographic assessment of aortic valve stenosis: A focused update from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. European Heart Journal Cardiovascular Imaging, 18, 254–275.

    Article  Google Scholar 

  12. Gómez, M., Ble, M., Cladellas, M., Molina, L., Comín-Colet, J., Enjuanes, C., Roqueta, C., Soler, C., & Bruguera, J. (2015). Effect of correction of anemia on echocardiographic and clinical parameters in patients with aortic stenosis involving a three-cuspid aortic valve and normal left ventricular ejection fraction. The American Journal of Cardiology, 116, 270–274.

    Article  Google Scholar 

  13. Owens, D. S., Katz, R., Takasu, J., Kronmal, R., Budoff, M. J., & O’Brien, K. D. (2010). Incidence and progression of aortic valve calcium in the multi-ethnic study of atherosclerosis (MESA). The American Journal of Cardiology, 105, 701–708.

    Article  CAS  Google Scholar 

  14. Navarese, E. P., Kołodziejczak, M., Dimitroulis, D., Wolff, G., Busch, H. L., Devito, F., Sionis, A., & Ciccone, M. M. (2016). From proprotein convertase subtilisin/kexin type 9 to its inhibition: State-of-The-Art and clinical implications. Eur Hear J - Cardiovasc Pharmacother., 2, 44–53.

    Article  CAS  Google Scholar 

  15. Navarese, E. P., Kołodziejczak, M., Kereiakes, D. J., Tantry, U. S., O’connor, C., & Gurbel, P. A. (2016). Proprotein convertase subtilisin/kexin type 9 monoclonal antibodies for acute coronary syndrome a narrative review. Annals of Internal Medicine, 164, 600–607.

    Article  Google Scholar 

  16. Maxwell, K. N., Fisher, E. A., & Breslow, J. L. (2005). Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proceedings of the National Academy of Sciences, 102, 2069–2074.

    Article  CAS  Google Scholar 

  17. Denis, M., Marcinkiewicz, J., Zaid, A., Gauthier, D., Poirier, S., Lazure, C., Seidah, N. G., & Prat, A. (2012). Gene Inactivation of PCSK9 Reduces Atherosclerosis in Mice. Circulation., 125, 894–901.

    Article  CAS  Google Scholar 

  18. Liu, X., Suo, R., Chan, C. Z. Y., Liu, T., Tse, G., & Li, G. (2019). The immune functions of PCSK9: Local and systemic perspectives. Journal of Cellular Physiology, jcp.28612.

  19. Wang, W. G., He, Y. F., Chen, Y. L., Zhao, F. M., Song, Y. Q., Zhang, H., Ma, Y. H., Guan, X., Zhang, W. Y., Chen, X. L., Liu, C., & Cong, H. L. (2016). Proprotein convertase subtilisin/kexin type 9 levels and aortic valve calcification: A prospective, cross sectional study. The Journal of International Medical Research, 44, 865–874.

    Article  Google Scholar 

  20. Salaun, E., Mahjoub, H., Dahou, A., Mathieu, P., Larose, É., Després, J. P., Rodés-Cabau, J., Arsenault, B. J., Puri, R., Clavel, M. A., & Pibarot, P. (2018). Hemodynamic Deterioration of Surgically Implanted Bioprosthetic Aortic Valves. Journal of the American College of Cardiology, 72, 241–251.

    Article  Google Scholar 

  21. Poggio, P., Songia, P., Cavallotti, L., Barbieri, S. S., Zanotti, I., Arsenault, B. J., Valerio, V., Ferri, N., Capoulade, R., & Camera, M. (2018). PCSK9 Involvement in Aortic Valve Calcification. Journal of the American College of Cardiology, 72, 3225–3227.

    Article  Google Scholar 

  22. Aceña, Á., Franco Peláez, J. A., Pello Lázaro, A. M., Gonzalez Parra, E., Gonzalez Lorenzo, Ó., Martínez-Milla, J., Hernandez, I., Martín-Mariscal, M. L., Lopez Castillo, M., Kallmeyer, A., Lorenzo, O., González-Casaus, M. L., Egido, J., & Tuñón, J. (2020). PCSK9 and HS-CRP Predict Progression of Aortic Stenosis in Patients with Stable Coronary Artery Disease. Journal of Cardiovascular Translational Research.

  23. Langsted, A., Nordestgaard, B. G., Benn, M., Tybjærg-Hansen, A., & Kamstrup, P. R. (2016). PCSK9 R46L loss-of-function mutation reduces lipoprotein(a), LDL cholesterol, and risk of aortic valve stenosis. The Journal of Clinical Endocrinology and Metabolism, 101, 3281–3287.

    Article  CAS  Google Scholar 

  24. Mayne, J., Dewpura, T., Raymond, A., Cousins, M., Chaplin, A., Lahey, K. A., LaHaye, S. A., Mbikay, M., Ooi, T. C., & Chrétien, M. (2008). Plasma PCSK9 levels are significantly modified by statins and fibrates in humans. Lipids in Health and Disease, 7, 1–9.

    Article  Google Scholar 

  25. Mohler, E. R., Nichols, R., Harvey, W. P., Sheridan, M. J., Waller, B. F., & Waller, B. F. (1991). Development and progression of aortic valve stenosis: Atherosclerosis risk factors—a causal relationship? a clinical morphologic study. Clinical Cardiology, 14, 995–999.

    Article  CAS  Google Scholar 

  26. Stewart, B. F., Siscovick, D., Lind, B. K., Gardin, J. M., Gottdiener, J. S., Smith, V. E., Kitzman, D. W., & Otto, C. M. (2002). Clinical Factors Associated With Calcific Aortic Valve Disease. Cardiovascular Health Study. Journal of the American College of Cardiology, 29, 630–634.

    Article  Google Scholar 

  27. Palta, S., Pai, A. M., Gill, K. S., & Pai, R. G. (2012). New Insights Into the Progression of Aortic Stenosis. Circulation., 101, 2497–2502.

    Article  Google Scholar 

  28. Messner, B., & Bernhard, D. (2014). Smoking and cardiovascular disease: Mechanisms of endothelial dysfunction and early atherogenesis. Arteriosclerosis, Thrombosis, and Vascular Biology, 34, 509–515.

    Article  CAS  Google Scholar 

  29. Eveborn, G. W., Schirmer, H., Lunde, P., Heggelund, G., Hansen, J. B., & Rasmussen, K. (2014). Assessment of risk factors for developing incident aortic stenosis: The Tromsø Study. European Journal of Epidemiology, 29, 567–575.

    Article  Google Scholar 

  30. Rosa, M., Paris, C., Sottejeau, Y., Corseaux, D., Robin, E., Tagzirt, M., Juthier, F., Jashari, R., Rauch, A., Vincentelli, A., Staels, B., Van Belle, E., Susen, S., & Dupont, A. (2017). Leptin induces osteoblast differentiation of human valvular interstitial cells via the Akt and ERK pathways. Acta Diabetologica, 54, 551–560.

    Article  CAS  Google Scholar 

  31. Kamath, A. R., & Pai, R. G. (2008). Risk factors for progression of calcific aortic stenosis and potential therapeutic targets. International Journal of Angiology, 17, 63–70.

    Article  Google Scholar 

  32. Mathieu, P., Lemieux, I., & Després, J. P. (2010). Obesity, inflammation, and cardiovascular risk. Clinical Pharmacology and Therapeutics, 87, 407–416.

    Article  CAS  Google Scholar 

  33. Rogge, B. P., Cramariuc, D., Lønnebakken, M. T., Gohlke-Bärwolf, C., Chambers, J. B., Boman, K., & Gerdts, E. (2013). Effect of overweight and obesity on cardiovascular events in asymptomatic aortic stenosis: A SEAS substudy (Simvastatin Ezetimibe in Aortic Stenosis). Journal of the American College of Cardiology, 62, 1683–1690.

    Article  Google Scholar 

  34. Rosenhek, R., Binder, T., Porenta, G., Lang, I., Christ, G., Schemper, M., Maurer, G., & Baumgartner, H. (2002). Predictors of Outcome in Severe, Asymptomatic Aortic Stenosis. The New England Journal of Medicine, 343, 611–617.

    Article  Google Scholar 

  35. Eisenga, M. F., Zelle, D. M., Sloan, J. H., Gaillard, C. A. J. M., Bakker, S. J. L., & Dullaart, R. P. F. (2017). High Serum PCSK9 Is Associated With Increased Risk of New-Onset Diabetes After Transplantation in Renal Transplant Recipients. Diabetes Care, 40, 894–901.

    Article  CAS  Google Scholar 

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Funding

This study was funded by the Fundació La Marató de TV3 (REF 2015-1910).

Author information

Authors and Affiliations

  1. Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain

    Natalia Mateos, Miquel Gómez, Arianna Homar & Begoña Benito

  2. Hospital del Mar Medical Research Institute (IMIM), Parc de Salut Mar, Barcelona, Spain

    Miquel Gómez, Anna Garcia-Elias & Begoña Benito

  3. Cardiology Department, Hospital de Barcelona, Barcelona, Spain

    Miquel Gómez

  4. Research Center, Montreal Heart Institute, Montreal, Canada

    Anna Garcia-Elias

  5. Vascular Biology and Metabolism, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain

    Laia Yáñez & Begoña Benito

  6. Bio-Heart Cardiovascular Diseases Research Group, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain

    Marta Tajes

  7. Cardiology Department, Hospital del Mar, Barcelona, Spain

    Lluís Molina, Mireia Ble & Mercè Cladellas

  8. Geriatrics Department, Hospital del Mar, Barcelona, Spain

    Cristina Roqueta

  9. Cardiology Department, Vall d’Hebron Research Institute (VHIR), Hospital Vall d’Hebron, Edifici Mediterrània, Pg de la Vall d’Hebron 119-129, 08035, Barcelona, Spain

    Begoña Benito

  10. Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBER-CV), Instituto de Salud Carlos III, Madrid, Spain

    Begoña Benito

Authors
  1. Natalia Mateos
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  2. Miquel Gómez
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  4. Anna Garcia-Elias
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  5. Laia Yáñez
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  7. Lluís Molina
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  8. Mireia Ble
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  9. Mercè Cladellas
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  11. Begoña Benito
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Corresponding author

Correspondence to Begoña Benito.

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Ethical Approval

All procedures performed in the present study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

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The authors declare no competing interests.

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Associate Editor Craig M. Stolen oversaw the review of this article

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Clinical Relevance

• In this prospective study including 209 patients with asymptomatic moderate-to-severe degenerative AS, we found that active smoking, BMI, and levels of PCSK9 are predictors of a particularly fast progression of the disease. Our data suggest, therefore, that inflammation and subsequent calcification could be important mechanisms of AS progression.

• Our results are novel in that they suggest that PCSK9 levels could help in predicting a very rapid AS progression.

• Moreover, our results set the basis to assess the potential benefit of intensive preventive strategies to reduce modifiable risk factors such as smoking and BMI associated with fast AS progression.

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Mateos, N., Gómez, M., Homar, A. et al. Plasmatic PCSK9 Levels Are Associated with Very Fast Progression of Asymptomatic Degenerative Aortic Stenosis. J. of Cardiovasc. Trans. Res. 15, 5–14 (2022). https://doi.org/10.1007/s12265-021-10138-4

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