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The contribution of amyloid deposition in the aortic valve to calcification and aortic stenosis

Nature Reviews Cardiology volume 20, pages 418–428 (2023)Cite this article

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Abstract

Calcific aortic valve disease (CAVD) and stenosis have a complex pathogenesis, and no therapies are available that can halt or slow their progression. Several studies have shown the presence of apolipoprotein-related amyloid deposits in close proximity to calcified areas in diseased aortic valves. In this Perspective, we explore a possible relationship between amyloid deposits, calcification and the development of aortic valve stenosis. These amyloid deposits might contribute to the amplification of the inflammatory cycle in the aortic valve, including extracellular matrix remodelling and myofibroblast and osteoblast-like cell proliferation. Further investigation in this area is needed to characterize the amyloid deposits associated with CAVD, which could allow the use of antisense oligonucleotides and/or isotype gene therapies for the prevention and/or treatment of CAVD.

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Fig. 1: Association between amyloid deposits and calcification.
Fig. 2: Apolipoproteins in human aortic valve leaflets.
Fig. 3: The possible involvement of lipoproteins and apolipoproteins in amyloidogenesis.
Fig. 4: Biomineralogical features of calcification in heart valves.
Fig. 5: Aortic valve amyloid deposits and aortic stenosis.

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References

  1. Lindman, B. R. et al. Calcific aortic stenosis. Nat. Rev. Dis. Prim. 2, 16006 (2016).

    Article  PubMed  Google Scholar 

  2. Aikawa, E. & Hutcheson, J. D. The developmental origin of calcific aortic stenosis. N. Engl. J. Med. 386, 1372–1374 (2022).

    Article  PubMed  Google Scholar 

  3. Rapp, A. H., Hillis, L. D., Lange, R. A. & Cigarroa, J. E. Prevalence of coronary artery disease in patients with aortic stenosis with and without angina pectoris [abstract A1217]. Am. J. Cardiol. 87, 1216–1217 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Thanassoulis, G. et al. Genetic associations with valvular calcification and aortic stenosis. N. Engl. J. Med. 368, 503–512 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yan, A. T. et al. Association between cardiovascular risk factors and aortic stenosis: the CANHEART Aortic Stenosis study. J. Am. Coll. Cardiol. 69, 1523–1532 (2017).

    Article  PubMed  Google Scholar 

  6. Chan, K. L. et al. Effect of lipid lowering with rosuvastatin on progression of aortic stenosis results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation 121, 306–314 (2010).

    Article  CAS  PubMed  Google Scholar 

  7. Cowell, S. J. et al. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N. Engl. J. Med. 352, 2389–2397 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Rossebo, A. B. et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N. Engl. J. Med. 359, 1343–1356 (2008).

    Article  PubMed  Google Scholar 

  9. Goffin, Y. Microscopic amyloid deposits in the heart valves: a common local complication of chronic damage and scarring. J. Clin. Pathol. 33, 262–268 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Buxbaum, J. N. et al. Amyloid nomenclature 2022: update, novel proteins, and recommendations by the International Society of Amyloidosis (ISA) Nomenclature Committee. Amyloid https://doi.org/10.1080/13506129.2022.2147636 (2022).

    Article  PubMed  Google Scholar 

  11. Sawaya, M. R. et al. The expanding amyloid family: structure, stability, function, and pathogenesis. Cell 184, 4857–4873 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wisniewski, T. & Drummond, E. ApoE-amyloid interaction: therapeutic targets. Neurobiol. Dis. 138, 104784 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lewkowicz, E., Jayaraman, S. & Gursky, O. Protein amyloid cofactors: charged side-chain arrays meet their match? Trends Biochem. Sci. 46, 626–629 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tao, Y. et al. Heparin induces α-synuclein to form new fibril polymorphs with attenuated neuropathology. Nat. Commun. 13, 4226 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kittleson, M. M. et al. Cardiac amyloidosis: evolving diagnosis and management: a scientific statement from the American Heart Association. Circulation 142, E7–E22 (2020).

    Article  PubMed  Google Scholar 

  16. Obici, L. et al. Structure, function and amyloidogenic propensity of apolipoprotein A-1. Amyloid 13, 191–205 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Rocken, C. et al. Prevalence and pathology of amyloid in atherosclerotic arteries. Arterioscler. Thromb. Vasc. Biol. 26, 676–677 (2006).

    Article  PubMed  Google Scholar 

  18. Wong, Y. Q., Binger, K. J., Howlett, G. J. & Griffin, M. D. Methionine oxidation induces amyloid fibril formation by full-length apolipoprotein A-I. Proc. Natl Acad. Sci. USA 107, 1977–1982 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhao, L., Buxbaum, J. N. & Reixach, N. Age-related oxidative modifications of transthyretin modulate its amyloidogenicity. Biochemistry 52, 1913–1926 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Iwata, T. et al. Amyloid deposits in heart valves. Acta Pathol. Jpn 32, 23–29 (1982).

    CAS  PubMed  Google Scholar 

  21. Cooper, J. H. Localized dystrophic amyloidosis of heart valves. Hum. Pathol. 14, 649–653 (1983).

    Article  CAS  PubMed  Google Scholar 

  22. Kristen, A. V. et al. High prevalence of amyloid in 150 surgically removed heart valves: a comparison of histological and clinical data reveals a correlation to atheroinflammatory conditions. Cardiovasc. Pathol. 19, 228–235 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Audet, A. et al. Amyloid substance within stenotic aortic valves promotes mineralization. Histopathology 61, 610–619 (2012).

    Article  PubMed  Google Scholar 

  24. Ladefoged, C. & Rohr, N. Amyloid deposits in aortic and mitral valves: a clinicopathological investigation of material from 100 consecutive heart valve operations. Virchows Arch. A Pathol. Anat. Histopathol. 404, 301–312 (1984).

    Article  CAS  PubMed  Google Scholar 

  25. Das, M. & Gursky, O. Amyloid-forming properties of human apolipoproteins: sequence analyses and structural insights. Adv. Exp. Med. Biol. 855, 175–211 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tintut, Y., Hsu, J. J. & Demer, L. L. Lipoproteins in cardiovascular calcification: potential targets and challenges. Front. Cardiovasc. Med. 5, 172 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mamarelis, I. et al. FT-IR spectroscopic study of amyloid protein formation and aortic valve calcification. Hell. J. Cardiol. 58, 148–150 (2017).

    Article  Google Scholar 

  28. Schlotter, F. et al. ApoC-III is a novel inducer of calcification in human aortic valves. J. Biol. Chem. 296, 100193 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zuckerman, S. H., Evans, G. F. & Oneal, L. Cytokine regulation of macrophage apo E secretion: opposing effects of GM-CSF and TGF-β. Atherosclerosis 96, 203–214 (1992).

    Article  CAS  PubMed  Google Scholar 

  30. Novaro, G. M. et al. Association between apolipoprotein E alleles and calcific valvular heart disease. Circulation 108, 1804–1808 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Lommi, J. I. et al. High-density lipoproteins (HDL) are present in stenotic aortic valves and may interfere with the mechanisms of valvular calcification. Atherosclerosis 219, 538–544 (2011).

    Article  CAS  PubMed  Google Scholar 

  32. Schlotter, F. et al. Spatiotemporal multi-omics mapping generates a molecular atlas of the aortic valve and reveals networks driving disease. Circulation 138, 377–393 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Capoulade, R. et al. ApoCIII-Lp(a) complexes in conjunction with L(a)-OxPL predict rapid progression of aortic stenosis. Heart 106, 738–745 (2020).

    Article  CAS  PubMed  Google Scholar 

  34. Kaiser, Y. et al. Lipoprotein(a) is associated with the onset but not the progression of aortic valve calcification. Eur. Heart J. 43, 3960–3967 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Capoulade, R. et al. Oxidized phospholipids, lipoprotein(a), and progression of calcific aortic valve stenosis. J. Am. Coll. Cardiol. 66, 1236–1246 (2015).

    Article  CAS  PubMed  Google Scholar 

  36. Zheng, K. H. et al. Lipoprotein(a) and oxidized phospholipids promote valve calcification in patients with aortic stenosis. J. Am. Coll. Cardiol. 73, 2150–2162 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bhatia, H. S. et al. Trends in testing and prevalence of elevated Lp(a) among patients with aortic valve stenosis. Atherosclerosis 349, 144–150 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kamstrup, P. R. et al. Oxidized phospholipids and risk of calcific aortic valve disease: the Copenhagen General Population Study. Arterioscler. Thromb. Vasc. Biol. 37, 1570–1578 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Torzewski, M. et al. Lipoprotein(a) associated molecules are prominent components in plasma and valve leaflets in calcific aortic valve stenosis. JACC Basic Transl Sci. 2, 229–240 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Heuschkel, M. A. et al. Integrative multi-omics analysis in calcific aortic valve disease reveals a link to the formation of amyloid-like deposits. Cells 9, 2164 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Xiong, M. et al. ApoE immunotherapy reduces cerebral amyloid angiopathy and amyloid plaques while improving cerebrovascular function. Sci. Transl Med. 13, eabd7522 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Jayaraman, S., Sanchez-Quesada, J. L. & Gursky, O. Triglyceride increase in the core of high-density lipoproteins augments apolipoprotein dissociation from the surface: potential implications for treatment of apolipoprotein deposition diseases. Biochim. Biophys. Acta Mol. Basis Dis. 1863, 200–210 (2017).

    Article  CAS  PubMed  Google Scholar 

  43. Medeiros, L. A. et al. Fibrillar amyloid protein present in atheroma activates CD36 signal transduction. J. Biol. Chem. 279, 10643–10648 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Luciunaite, A. et al. Soluble abeta oligomers and protofibrils induce NLRP3 inflammasome activation in microglia. J. Neurochem. 155, 650–661 (2020).

    Article  CAS  PubMed  Google Scholar 

  45. Martin-Rojas, T. et al. iTRAQ proteomic analysis of extracellular matrix remodeling in aortic valve disease. Sci. Rep. 5, 17290 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Meng, X. Z. et al. Expression of functional Toll-like receptors 2 and 4 in human aortic valve interstitial cells: potential roles in aortic valve inflammation and stenosis. Am. J. Physiol. Cell Physiol. 294, C29–C35 (2008).

    Article  CAS  PubMed  Google Scholar 

  47. Cottignoli, V., Cavarretta, E., Salvador, L., Valfre, C. & Maras, A. Morphological and chemical study of pathological deposits in human aortic and mitral valve stenosis: a biomineralogical contribution. Pathol. Res. Int. 2015, 342984 (2015).

    Article  Google Scholar 

  48. Ternacle, J. et al. Aortic stenosis and cardiac amyloidosis. J. Am. Coll. Cardiol. 74, 2638–2651 (2019).

    Article  PubMed  Google Scholar 

  49. Mamarelis, I. et al. The role of oxidative stress on amyloid-like protein formation and aortic valve calcification. Eur. Heart J. 37, 313 (2016).

    Google Scholar 

  50. Dittfeld, C. et al. Molecular spectroscopic imaging offers a systematic assessment of pathological aortic valve and prosthesis tissue in biomineralization. Crystals 10, 763 (2020).

    Article  CAS  Google Scholar 

  51. Stats, M. A. & Stone, J. R. Varying levels of small microcalcifications and macrophages in attr and al cardiac amyloidosis: implications for utilizing nuclear medicine studies to subtype amyloidosis. Cardiovasc. Pathol. 25, 413–417 (2016).

    Article  CAS  PubMed  Google Scholar 

  52. Simard, L. et al. Sex-related discordance between aortic valve calcification and hemodynamic severity of aortic stenosis: is valvular fibrosis the explanation? Circ. Res. 120, 681–691 (2017).

    Article  CAS  PubMed  Google Scholar 

  53. Caponetti, A. G. et al. Sex-related risk of cardiac involvement in hereditary transthyretin amyloidosis: insights from THAOS. JACC Heart Fail. 9, 736–746 (2021).

    Article  PubMed  Google Scholar 

  54. Jenkins, M. C. & Potter, M. Calcified pseudotumoural mediastinal amyloidosis. Thorax 46, 686–687 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Westermark, P., Mucchiano, G., Marthin, T., Johnson, K. H. & Sletten, K. Apolipoprotein A1-derived amyloid in human aortic atherosclerotic plaques. Am. J. Pathol. 147, 1186–1192 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Li, X. A., Hatanaka, K., Ishibashi-Ueda, H., Yutani, C. & Yamamoto, A. Characterization of serum amyloid P component from human aortic atherosclerotic lesions. Arterioscler. Thromb. Vasc. Biol. 15, 252–257 (1995).

    Article  CAS  PubMed  Google Scholar 

  57. Howlett, G. J. & Moore, K. J. Untangling the role of amyloid in atherosclerosis. Curr. Opin. Lipidol. 17, 541–547 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. Hellberg, S. et al. Amyloid-targeting PET tracer [18F]flutemetamol accumulates in atherosclerotic plaques. Molecules 24, 1072 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Abdelbaky, A. et al. Focal arterial inflammation precedes subsequent calcification in the same location: a longitudinal FDG-PET/CT study. Circ. Cardiovasc. Imaging 6, 747–754 (2013).

    Article  PubMed  Google Scholar 

  60. Akkineni, S. et al. Amyloid-like amelogenin nanoribbons template mineralization via a low-energy interface of ion binding sites. Proc. Natl Acad. Sci. USA 119, e2106965119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Bai, Y. et al. Protein nanoribbons template enamel mineralization. Proc. Natl Acad. Sci. USA 117, 19201–19208 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ajili, W. et al. Inorganic phosphate in growing calcium carbonate abalone shell suggests a shared mineral ancestral precursor. Nat. Commun. 13, 1496 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Iadanza, M. G. et al. A new era for understanding amyloid structures and disease. Nat. Rev. Mol. Cell Biol. 19, 755–773 (2018).

    Article  CAS  PubMed  Google Scholar 

  64. Yang, Y. et al. Cryo-EM structures of amyloid-β 42 filaments from human brains. Science 375, 167–172 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Poulsen, E. T., Pedersen, K. W., Marzeda, A. M. & Enghild, J. J. Serum amyloid P component (SAP) interactome in human plasma containing physiological calcium levels. Biochemistry 56, 896–902 (2017).

    Article  CAS  PubMed  Google Scholar 

  66. Richards, D. B. et al. Therapeutic clearance of amyloid by antibodies to serum amyloid P component. N. Engl. J. Med. 373, 1106–1114 (2015).

    Article  CAS  PubMed  Google Scholar 

  67. Moura, L. M. et al. Rosuvastatin affecting aortic valve endothelium to slow the progression of aortic stenosis. J. Am. Coll. Cardiol. 49, 554–561 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Tsimikas, S. et al. Lipoprotein(a) reduction in persons with cardiovascular disease. N. Engl. J. Med. 382, 244–255 (2020).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

E. Aikawa has received support from the NIH (grant numbers R01 HL136431, R01 HL141917 and R01 HL147095). S.G. has received support from the National Institute on Aging – Designated Alzheimer’s Disease Research Center (P50 AG005138 and P30 AG066514). O.G. has received support from the NIH (grants R01 GM067260 and R01 GM135158).

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  1. These authors contributed equally: Karan Sud, Navneet Narula.

Authors and Affiliations

  1. Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Karan Sud, Robert S. Rosenson, Edgar Argulian, Amir Ahmadi, Valentin Fuster, Sam Gandy & Jagat Narula

  2. New York University Grossman School of Medicine, New York, NY, USA

    Navneet Narula, Fang Zhou & Andre L. Moreira

  3. Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Elena Aikawa

  4. IRCCS Foundation Policlinico San Matteo, Pavia, Italy

    Eloisa Arbustini & Giampaolo Merlini

  5. Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Canada

    Philippe Pibarot & Nancy Côté

  6. Weill Cornell Medicine, New York, NY, USA

    Surya V. Seshan

  7. University of California San Diego, San Diego, CA, USA

    Sotirios Tsimikas

  8. Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Robert O. Bonow

  9. Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA

    Olga Gursky

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Contributions

K.S. and N.N. researched data for the article. K.S., N.N., E. Aikawa, E. Arbustini, P.P., G.M., R.S.R., E. Argulian and J.N. discussed the content of the article. K.S., N.N., S.G., O.G. and J.N. wrote the manuscript. All the authors reviewed and/or edited the article before submission.

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Correspondence to Navneet Narula.

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Competing interests

P.P. has received grant funding from Cardiac Phoenix, Edwards Lifesciences, Medtronic and Pi-Cardia for echocardiography core laboratory analyses and research studies in the field of transcatheter valve therapies, for which he received no personal compensation; he has also received lecture fees from Edwards Lifesciences and Medtronic. R.S.R. has received research grants to his institution from Amgen, Arrowhead, NIH, Novartis and Regeneron, is a member of the advisory board of Amgen, Novartis, Regeneron and 89 Bio, has received honoraria for non-promotional speaking from Kowa, has stock holdings with MediMergent, and receives royalties from Wolters Kluwer (UpToDate). S.T. is a co-inventor who receives royalties from patents owned by University of California, San Diego on oxidation-specific antibodies and biomarkers related to oxidized lipoproteins, and is a co-founder who has equity interests in Kleanthi Diagnostics and in Oxitope and affiliates. Although these relationships have been identified for conflict of interest management based on the overall scope of the project and its potential benefit to Kleanthi and Oxitope, the research findings included in this particular publication do not necessarily relate to the interests of Kleanthi and Oxitope. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with conflict of interest policies. S.G. serves as a consultant for Altpep, Cognition Therapeutics, and Ritrova Therapeutics and is a founder of Recuerdo Pharmaceuticals (inactive), has served as a consultant in the past for Diagenic, has received research support in the past from Avid, Baxter, Pfizer and Warner-Lambert, and also receives compensation for chart review in connection with medical litigation in the area of cognitive function. The other authors declare no competing interests.

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Sud, K., Narula, N., Aikawa, E. et al. The contribution of amyloid deposition in the aortic valve to calcification and aortic stenosis. Nat Rev Cardiol 20, 418–428 (2023). https://doi.org/10.1038/s41569-022-00818-2

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