SpringerLink
Log in

Calcium Crystals in Arterial Disease

  • Chapter
  • First Online:
Cholesterol Crystals in Atherosclerosis and Other Related Diseases

Part of the book series: Contemporary Cardiology ((CONCARD))

  • 176 Accesses

Abstract

Calcification in the vascular bed relates to the formation of calcium crystals that organize into aggregates and sheet-like lattices that mostly consist of calcium phosphate (hydroxyapatite), but in some rare conditions consist of calcium oxalate.

The appearance of detectable amounts of calcium in atheromatous plaque in the coronary circulation by computerized tomography (CT) scanning marks an inflection point in the natural history of coronary artery disease.

This chapter focuses on how calcification develops in atheromatous plaque and highlights how it differs in nature from calcification in the media of the vessel wall. The distinction is important as the treament varies with the location of calcium. Whereas atherosclerosis is generally widespread in the systemic circulation, calcification in the media is unrelated to the atherosclerosis and is rarely seen in the coronary arteries. Thus, while the detection of coronary calcification by CT scanning is specific for atherosclerosis, vascular calcification beyond the coronary tree may over-estimate the atherosclerotic load that often co-exists with it.

Currently there is no compelling evidence that reducing vascular calcification impacts the natural history of patients with coronary atherosclerosis or peripheral vascular disease. However, it is possible that the measurement of total coronary calcium scores are too blunt as an instrument to measure the potential benefits of therapies that can truly modify the formation and morphology of calcium crystals as they begin to develop in the atherosclerotic matrix.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 119.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 159.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Otsuka F, Sakakura K, Yahagi K, Joner M, Virmani R. Has our understanding of calcification in human coronary atherosclerosis progressed? Arterioscler Thromb Vasc Biol. 2014;34:724–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wang L, Jerosch-Herold M, Jacobs DR Jr, Shahar E, Detrano R, Folsom AR, MESA Study Investigators. Coronary artery calcification and myocardial perfusion in asymptomatic adults: the MESA (multi-ethnic study of atherosclerosis). J Am Coll Cardiol. 2006;48:1018–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kalra SS, Shanahan CM. Vascular calcification and hypertension: cause and effect. Ann Med. 2012;44(Suppl 1):S85–92.

    Article  CAS  PubMed  Google Scholar 

  4. Greenland P, LaBree L, Azen SP, Doherty TM, Detrano RC. Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals. JAMA. 2004;291:210–5.

    Article  CAS  PubMed  Google Scholar 

  5. Criqui MH, Denenberg JO, Ix JH, et al. Calcium density of coronary artery plaque and risk of incident cardiovascular events. JAMA. 2014;311:271–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kockx MM, De Meyer GR, Muhring J, Jacob W, Bult H, Herman AG. Apoptosis and related proteins in different stages of human atherosclerotic plaques. Circulation. 1998;97:2307–15.

    Article  CAS  PubMed  Google Scholar 

  7. Vengrenyuk Y, Carlier S, Xanthos S, et al. A hypothesis for vulnerable plaque rupture due to stress-induced debonding around cellular microcalcifications in thin fibrous caps. Proc Natl Acad Sci U S A. 2006;103:14678–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kelly-Arnold A, Maldonado N, Laudier D, Aikawa E, Cardoso L, Weinbaum S. Revised microcalcification hypothesis for fibrous cap rupture in human coronary arteries. Proc Natl Acad Sci U S A. 2013;110:10741–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. New SE, Goettsch C, Aikawa M, et al. Macrophage-derived matrix vesicles: an alternative novel mechanism for microcalcification in atherosclerotic plaques. Circ Res. 2013;113:72–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mori H, Torii S, KutynaM SA, Finn AV, Virmani R. Coronary artery calcification and its progression: what does it really mean. JACC Cardiovasc Imaging. 2018;11:127–42.

    Article  PubMed  Google Scholar 

  11. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2000;20:1262–75.

    Article  CAS  PubMed  Google Scholar 

  12. Dorozhkina E, Dorozhkin S. In vitro crystallization of carbonateapatite on cholesterol from a modified simulated body fluid. Colloids Surf. 2003;223:231–7. https://doi.org/10.1016/S0927-7757(03)00221-8.

    Article  CAS  Google Scholar 

  13. Laird DF, Mucalo MR, Yokogawa Y. Growth of calcium hydroxyapatite (ca-HAp) on cholesterol and cholestanol crystals from a simulated body fluid: a possible insight into the pathological calcifications associated with atherosclerosis. J Colloid Interface Sci. 2006;295:348–63. https://doi.org/10.1016/j.jcis.2005.09.013.

    Article  CAS  PubMed  Google Scholar 

  14. Abedin M, Tintut Y, Demer LL. Vascular calcification: mechanisms and clinical ramifications. Arterioscler Thromb Vasc Biol. 2004;24:1161–70. https://doi.org/10.1161/01.ATV.0000133194.94939.42.

    Article  CAS  PubMed  Google Scholar 

  15. Johnson RC, Leopold JA, Loscalzo J. Vascular calcification: pathobiological mechanisms and clinical implications. Circ Res. 2006;99:1044–59. https://doi.org/10.1161/01.RES.0000249379.55535.21.

    Article  CAS  PubMed  Google Scholar 

  16. Fishbein GA, Micheletti RG, Currier JS, Singer E, Fishbein MC. Atherosclerotic oxalosis in coronary arteries. Cardiovasc Pathol. 2008;17:117–23. https://doi.org/10.1016/j.carpath.2007.07.002.

    Article  CAS  PubMed  Google Scholar 

  17. Khan SR, Pearle MS, Robertson WG, Gambaro G, Canles BK, Doizi S, Traxer O, Tiselius H-G. Kidney stones. Nat Rev Dis Primers. 2016;2:16008. https://doi.org/10.1038/nrdp.2016.8.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Abela GS, Kalavakunta JK, Janoudi A, Leffler D, Dhar G, Salehi N, Cohn J, Shah I, Karve M, Kotaru VPK, Gupta V, David S, Narisetty KK, Rich M, Vanderberg A, Pathak DR, Shamoun FE. Frequency of cholesterol crystals in culprit coronary artery aspirate during acute myocardial infarction and their relation to inflammation and myocardial injury. Am J Cardiol. 2017;120:1699–707. https://doi.org/10.1016/j.amjcard.2017.07.075.

    Article  CAS  PubMed  Google Scholar 

  19. Nadra I, Mason JC, Philippidis P, Florey O, Smythe CDW, McCarthy GM, Landis RC, Haskard DO. Proinflammatory activation of macrophages by basic calcium phosphate crystals via protein kinase C and MAP kinase pathways: a vicious cycle of inflammation and arterial calcification? Circ Res. 2005;96:1248–56. https://doi.org/10.1161/01.RES.0000171451.88616.c2.

    Article  CAS  PubMed  Google Scholar 

  20. DĂ¼ewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nuñez G, Schnurr M, Espevik T, Lien E, Fitzgerald KA, Rock KL, Moore KJ, Wright SD, Hornung V, Latz E. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464:1357–61. https://doi.org/10.1038/nature08938.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rajamaki K, Lappalainen J, Oorni K, Valimaki E, Matikainen S, Kovanen PT, Eklund KK. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS One. 2010;5(7):e11765.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Patel R, Janoudi A, Vedre A, Aziz K, Tamhane U, Rubinstein J, Abela OG, Berger K, Abela GS. Plaque rupture and thrombosis is reduced by lowering cholesterol levels and crystallization with ezetimibe and is correlated with FDG-PET. Arterioscler Thromb Vasc Biol. 2011;31:2007–14. https://doi.org/10.1161/ATVBAHA.111.226167.

    Article  CAS  PubMed  Google Scholar 

  23. Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440(7081):237–41. https://doi.org/10.1038/nature04516.

    Article  CAS  PubMed  Google Scholar 

  24. McCullough PA, Chinnaiyan KM, Agrawal V, Danielewicz E, Abela GS. Amplification of atherosclerotic calcification and Mönckeberg’s sclerosis: a spectrum of the same disease process. Adv Chronic Kidney Dis. 2008;4:396–412.

    Article  Google Scholar 

  25. Doherty TM, Asotra K, Fitzpatrick LA, Qiao J-H, Wilkin DJ, Detrano RC, Dunstan CR, Shah PK, Rajavashisth TB. Calcification in atherosclerosis: bone biology and chronic inflammation at the arterial crossroads. PNAS. 2003;100:11201–6. https://doi.org/10.1073/pnas.1932554100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Speer MY, Yang HY, Brabb T, Leaf E, Look A, Lin WL, Frutkin A, Dichek D, Giachelli CM. Smooth muscle cells give rise to osteochondrogenic precursors and chondrocytes in calcifying arteries. Circ Res. 2009;104:733–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hsu JJ, Tintut Y, Demer LL. Vitamin D and osteogenic differentiation in the artery wall. Clin J Am Soc Nephrol. 2008;3:1542–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ter Btaake AD, Shahahan CM, de Baaij JHF. Magnesium counteracts vascular calcification; passive interference or active modulation? Atheroscler Thromb Vasc Biol. 2017;37:1431–45. https://doi.org/10.1161/ATVBAHA.117.309182.

    Article  CAS  Google Scholar 

  29. Boistelle R, Lopez-Valero I, Abbona F. Crystallization of calcium phosphate in the presence of magnesium. Nephrologie. 1993;14:265–9.

    CAS  PubMed  Google Scholar 

  30. Eanes ED, Posner AS. Kinetics and mechanism of conversion of noncrystalline calcium phosphate to hydroxyapatite. Trans N Y Acad Sci. 1965;28:233–41.

    Article  CAS  Google Scholar 

  31. Termine JD, Peckauskas RA, Posner AS. Calcium phosphate formation in vitro. II. Effects of environment on amorphous-crystalline transformation. Arch Biochem Biophys. 1970;140:318–25.

    Article  CAS  PubMed  Google Scholar 

  32. Boskey AL, Posner AS. Magnesium stabilization of amorphous calcium phosphate: a kinetic study. Mater Res Bull. 1974;9:907–16.

    Article  CAS  Google Scholar 

  33. Aghagolzadeh P, Bachtler M, Bijarnia R, Jackson C, Smith ER, Odermatt A, Radpour R, Pasch A. Calcification of vascular smooth muscle cells is induced by secondary calciprotein particles and enhanced by tumor necrosis factor-α. Atherosclerosis. 2016;251:404–14. https://doi.org/10.1016/j.atherosclerosis.2016.05.044.

    Article  CAS  PubMed  Google Scholar 

  34. Inoue T, Kawashima H. 1,25-Dihydroxyvitamin D3 stimulates 45Ca2+−uptake by cultured vascular smooth muscle cells derived from rat aorta. Biochem Biophys Res Commun. 1988;152:1388–94.

    Article  CAS  PubMed  Google Scholar 

  35. Jono S, Nishizawa Y, Shioi A, Morii H. 1,25-Dihydroxyvitamin D3 increases in vitro vascular calcification by modulating secretion of endogenous parathyroid hormone-related peptide. Circulation. 1998;98:1302–6.

    Article  CAS  PubMed  Google Scholar 

  36. Ix JH, Barrett-Connor E, Wassel CL, Cummins K, Bergstrom J, Daniels LB, Laughlin GA. The associations of fetuin-A with subclinical cardiovascular disease in community-dwelling persons: the rancho Bernardo study. J Am Coll Cardiol. 2011;58:2372–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Shalhoub V, Shatzen EM, Ward SC, Young JI, Boedigheimer M, Twehues L, McNinch J, Scully S, Twomey B, Baker D, Kiaei P, Damore MA, Pan Z, Haas K, Martin D. Chondro/osteoblastic and cardiovascular gene modulation in human artery smooth muscle cells that calcify in the presence of phosphate and calcitriol or paricalcitol. J Cell Biochem. 2010;111:911–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zittermann A, Schleithoff SS, Koerfer R. Putting cardiovascular disease and vitamin D insufficiency into perspective. Br J Nutr. 2005;94:483–92.

    Article  CAS  PubMed  Google Scholar 

  39. Aoshima Y, Mizobuchi M, Ogata H, Kumata C, Nakazawa A, Kondo F, Ono N, Koiwa F, Kinugasa E, Akizawa T. Vitamin D receptor activators inhibit vascular smooth muscle cell mineralization induced by phosphate and TNF-α. Nephrol Dial Transplant. 2012;27:1800–6.

    Article  CAS  PubMed  Google Scholar 

  40. Watson KE, Abrolat ML, Malone LL, Hoeg JM, Doherty T, Detrano R, Demer LL. Active serum vitamin D levels are inversely correlated with coronary calcification. Circulation. 1997;96:1755–60.

    Article  CAS  PubMed  Google Scholar 

  41. Braam LA, Hoeks AP, Brouns F, HamulyĂ¡k K, Gerichhausen MJ, Vermeer C. Beneficial effects of vitamins D and K on the elastic properties of the vessel wall in postmenopausal women: a follow-up study. Thromb Haemost. 2004;91:373–80.

    Article  CAS  PubMed  Google Scholar 

  42. Doherty TM, Tang W, Dascalos S, Watson KE, Demer LL, Shavelle RM, Detrano RC. Ethnic origin and serum levels of 1alpha,25- Dihydroxyvitamin D3 are independent predictors of coronary calcium mass measured by electron-beam computed tomography. Circulation. 1997;96:1477–81.

    Article  CAS  PubMed  Google Scholar 

  43. McCullough PA, Sandberg KR, Dumler F, Yanez JE. Determinants of coronary vascular calcification in patients with chronic kidney disease and end-stage renal disease: a systematic review. J Nephrol. 2004;17:205–15.

    PubMed  Google Scholar 

  44. Memon F, El-Abbadi M, Nakatani T, Taguchi T, Lanske B, Razzaque MS. Does Fgf23-klotho activity influence vascular and soft tissue calcification through regulating mineral ion metabolism? Kidney Int. 2008;74:566–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Razzaque MS, Lanske B. Hypervitaminosis D and premature aging: lessons learned from Fgf23 and klotho mutant mice. Trends Mol Med. 2006;12:298–305.

    Article  CAS  PubMed  Google Scholar 

  46. Schoppet M, Shroff RC, Hofbauer LC, Shanahan CM. Exploring the biology of vascular calcification in chronic kidney disease: what’s circulating? Kidney Int. 2008;73:384–90.

    Article  CAS  PubMed  Google Scholar 

  47. Zittermann A, Schleithoff SS, Koerfer R. Vitamin D and vascular calcification. Curr Opin Lipidol. 2007;18:41–6.

    Article  CAS  PubMed  Google Scholar 

  48. Hewison M. Vitamin D and the immune system: new perspectives on an old theme. Rheum Dis Clin N Am. 2012;38:125–39.

    Article  Google Scholar 

  49. Kassi E, Adamopoulous C, Basdra EK, Papavassiliou AG. Role of vitamin D in atherosclerosis. Circulation. 2013;128:2517–31.

    Article  PubMed  Google Scholar 

  50. Jildeh TR, Janoudi A, Abela GS. Vitamin D3 alters the crystallization and volume expansion of cholesterol. J Clin Lipidol. 2012;6 Suppl A:154.

    Google Scholar 

  51. Sultan S, Murarka S, Jahanfir A, Mookadam F, Tajik AJ, Jahangir A. Chelation therapy in cardiovascular disease: an update. Expert Rev Clin Pharmacol. 2017;10:843–54.

    Article  CAS  PubMed  Google Scholar 

  52. Singh D, Das K, Sheth R, Abela GS. Perspectives on the role of chelation therapy in the treatment of atherosclerosis: principles of application, clinical results, and practical implications. In: Topaz O, editor. Debulking in cardiovascular interventions and revascularization strategies-between the rock and the heart. London: Elsevier; 2022. p. 795–804.

    Chapter  Google Scholar 

  53. Lamas GA, Goertz C, Boineau R, et al. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. JAMA. 2013;309:1241–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Mark DB, Anstrom KJ, Clapp-Channing NE, et al. Quality-of-life outcomes with a disodium EDTA chelation regimen for coronary disease: results from the trial to assess chelation therapy rando- mized trial. Circ Cardiovasc Qual Outcomes. 2014;7:508–16.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Centers for Disease Control and Prevention (CDC). Deaths associated with hypocalcemia from chelation therapy—Texas, Pennsylvania, and Oregon, 2003-2005. MMWR Morb Mortal Wkly Rep. 2006;55:204–7.

    Google Scholar 

  56. Whayne TF Jr. What should medical practitioners know about the role of alternative medicines in cardiovascular disease management? Cardiovasc Ther. 2010;28:106–23.

    Article  CAS  PubMed  Google Scholar 

  57. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/ PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2012;126(25):3097–137; Erratum in: Circulation. 2014;129(16):e462.

    Article  PubMed  Google Scholar 

  58. Lamas GA, Anstrom KJ, Navas-Acien A, et al. The trial to assess chelation therapy 2 [RACT 2]: rationale and design. Am Heart J. 2022;252:1–11. https://doi.org/10.1016/j.ahj.2022.05.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Qunibi W, Moustafa M, Muenz LR, et al. A 1-year randomized trial of calcium acetate versus sevelamer on progression of coronary artery calcification in hemodialysis patients with comparable lipid control: the calcium acetate renagel evaluation-2 (CARE-2) study. Am J Kidney Dis. 2008;51:952–65.

    Article  CAS  PubMed  Google Scholar 

  60. Madhavan MV, Tarigopula M, Mintz GS, Maehara A, Stone GW, Généreux P. Coronary artery calcification pathogenesis and prognostic implications. J Am Coll Cardiol. 2014;63:1703–14. https://doi.org/10.1016/j.jacc.2014.01.017.

    Article  CAS  PubMed  Google Scholar 

  61. Sakaguchi Y, Fujii N, Shoji T, Hayashi T, Rakugi H, Isaka Y. Hypomagnesemia is a significant predictor of cardiovascular and non-cardiovascular mortality in patients undergoing hemodialysis. Kidney Int. 2014;85(1):174–81. https://doi.org/10.1038/ki.2013.327; Epub 2013 Aug 28.

    Article  CAS  PubMed  Google Scholar 

  62. DiNicolantonio JJ, Liu J, O’Keefe JH. Magnesium for the prevention and treatment of cardiovascular disease. Open Heart. 2018;5:e000775. https://doi.org/10.1136/openhrt-2018-000775.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, Davignon J, Erbel R, Fruchart JC, Tardif J-C, Schoenhagen P, Crowe T, Cain V, Wolski K, Goormastic M, Tuzcu EM, ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295:1556–65. https://doi.org/10.1001/jama.295.13.jpc60002.

    Article  CAS  PubMed  Google Scholar 

  64. Katzmann JL, Gouni-Berthhold I, Laufs U. PCSK9 inhibition:insight from clinical trials and future prospects. Front Physiol. 2020;11:595819. https://doi.org/10.3389/fphys.2020.595819.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Henein M, GranĂ¥sen G, Wiklund U, Schmermund A, Guerci A, Erbel R, Raggi P. High dose and long-term statin therapy accelerate coronary artery calcification. Int J Cardiol. 2015;184:581–6.

    Article  PubMed  Google Scholar 

  66. Dykun I, Lehmann N, Kälsch H, Möhlenkamp S, Moebus S, Budde T, Seibel R, Grönemeyer D, Jöckel KH, Erbel R, et al. Statin medication enhances progression of coronary artery calcification: the Heinz Nixdorf recall study. J Am Coll Cardiol. 2016;68:2123–5.

    Article  PubMed  Google Scholar 

  67. Saremi A, Bahn G, Reaven PD, VADT Investigators. Progression of vascular calcification is increased with statin use in the veterans affairs diabetes trial (VADT). Diabetes Care. 2012;35:2390–2.

    Article  PubMed  PubMed Central  Google Scholar 

  68. **an JZ, Lu M, Fong F, Qiao R, Patel NR, Abeydeera D, Iriana S, Demer LL, Tintut Y. Statin effects on vascular calcification: microarchitectural changes in aortic calcium deposits in aged hyperlipidemic mice. Arterioscler Thromb Vasc Biol. 2021;41(4):e185–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Wang Y, Osborne MT, Tung B, Li M, Li Y. Imaging cardiovascular calcification. J Am Heart Assoc. 2018;7(13):e008564. https://doi.org/10.1161/JAHA.118.008564.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrao R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol. 1990;15:827–32.

    Article  CAS  PubMed  Google Scholar 

  71. Detrano R, Guerci AD, Carr JJ, et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med. 2008;358:1336–45.

    Article  CAS  PubMed  Google Scholar 

  72. Kavousi M, Elias-Smale S, Rutten JHW, et al. Evaluation of newer risk markers for coronary heart disease risk classification: a cohort study. Ann Intern Med. 2012;156:438–44.

    Article  PubMed  Google Scholar 

  73. Erbel R, Möhlenkamp S, Moebus S, et al. Coronary risk stratification, discrimination, and reclassification improvement based on quantification of subclinical coronary atherosclerosis: the Heinz Nixdorf recall study. J Am Coll Cardiol. 2010;56:1397–406.

    Article  PubMed  Google Scholar 

  74. Carr JJ, Jacobs DR Jr, Terry JG, et al. Association of coronary artery calcium in adults aged 32 to 46 years with incident coronary heart disease and death. JAMA Cardiol. 2017;2:391–9.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Budoff MJ, Young R, Burke G, et al. Ten-year association of coronary artery calcium with atherosclerotic cardiovascular disease (ASCVD) events: the multi-ethnic study of atherosclerosis (MESA). Eur Heart J. 2018;39:2401–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Agatston AS, Janowitz WR, Hildner FJ, et al. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol. 1990;15:827–32. https://doi.org/10.1016/0735-1097(90)90282-t.

    Article  CAS  PubMed  Google Scholar 

  77. Gupta A, Lau E, Varshney R, et al. The identification of calcified coronary plaque is associated with initiation and continuation of pharmacological and lifestyle preventive therapies: a systematic review and meta-analysis. JACC Cardiovasc Imaging. 2017;10:833–42. https://doi.org/10.1016/j.jcmg.2017.01.030.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Cainzos-Achirica M, Miedema MD, McEvoy JW, et al. Coronary artery calcium for personalized allocation of aspirin in primary prevention of cardiovascular disease in 2019: the MESA study (multi-ethnic study of atherosclerosis). Circulation. 2020;141:1541–53. https://doi.org/10.1161/CIRCULATIONAHA.119.045010.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Kim J, McEvoy JW, Nasir K, et al. Critical review of high-sensitivity C-reactive protein and coronary artery calcium for the guidance of statin allocation: head-to-head comparison of the JUPITER and St. Francis heart trials. Circ Cardiovasc Qual Outcomes. 2014;7:315–22. https://doi.org/10.1161/CIRCOUTCOMES.113.000519.

    Article  PubMed  Google Scholar 

  80. Kofler T, Kurmann R, Lehnick D, Cioffi GM, Chandran S, Attinger-Toller A, Toggweiler S, Kobza R, Moccetti F, Cuculi F, Jolly SS, Bossard M. Colchicine in patients with coronary artery disease: a systematic review and meta-analysis of randomized trials. J Am Heart Assoc. 2021;10(16):e021198. https://doi.org/10.1161/JAHA.121.021198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Greenland P, Blaha MJ, Budoff MJ, Erbel R, Watson KE. Coronary calcium score and cardiovascular risk. J Am Coll Cardiol. 2018;72:434–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: executive summary. J Am Coll Cardiol. 2019;73:3168–209.

    Article  PubMed  Google Scholar 

  83. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol. 2019;74:e177–232.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Osei AD, Mirbolouk M, Berman D, Budoff MJ, Miedema MD, Rozanski A, Rumberger JA, Shaw L, Al Rifai M, Dzaye O, Graham GN, Banach M, Blumenthal RS, Dardari ZA, Nasir K, Blaha MJ. Prognostic value of coronary artery calcium score, area, and density among individuals on statin therapy vs. non-users: the coronary artery calcium consortium. Atherosclerosis. 2021;316:79–83. https://doi.org/10.1016/j.atherosclerosis.2020.10.009.

    Article  CAS  PubMed  Google Scholar 

  85. Lee S-E, Chang H-J, Sung JM, et al. Effects of statins on coronary atherosclerotic plaques: the PARADIGM study. JACC Cardiovasc Imaging. 2018;11:1475–84.

    Article  PubMed  Google Scholar 

  86. Achenbach S, Ropers D, Pohle K, et al. Influence of lipid-lowering therapy on the progression of coronary artery calcification: a prospective evaluation. Circulation. 2002;106:1077–82.

    Article  CAS  PubMed  Google Scholar 

  87. Nakazato R, Gransar H, Berman DS, et al. Statins use and coronary artery plaque composition: results from the international multicenter CONFIRM registry. Atherosclerosis. 2012;225:148–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Shemesh J, Apter S, Itzchak Y, Motro M. Coronary calcification compared in patients with acute versus in those with chronic coronary events by using dual-sector spiral CT. Radiology. 2003;226:483–8.

    Article  PubMed  Google Scholar 

  89. Henein M, GranĂ¥sen G, Wiklund U, et al. High dose and long-term statin therapy accelerate coronary artery calcification. Int J Cardiol. 2015;184:581–6.

    Article  PubMed  Google Scholar 

  90. Puri R, Nicholls SJ, Shao M, et al. Impact of statins on serial coronary calcification during atheroma progression and regression. J Am Coll Cardiol. 2015;65:1273–82.

    Article  CAS  PubMed  Google Scholar 

  91. Gonzalo N, et al. Coronary plaque composition as assessed by greyscale intravascular ultrasound and radiofrequency spectral data analysis. Int J Cardiovasc Imaging. 2008;24:811–8. https://doi.org/10.1007/s10554-008-9324-2.

    Article  PubMed  Google Scholar 

  92. Li S, et al. Proprotein convertase subtilisin-kexin type 9 as a biomarker for the severity of coronary artery disease. Ann Med. 2015;47:386–93. https://doi.org/10.3109/07853890.2015.1042908.

    Article  CAS  PubMed  Google Scholar 

  93. Li JJ, et al. Proprotein convertase subtilisin/kexin type 9, C-reactive protein, coronary severity, and outcomes in patients with stable coronary artery disease: a prospective observational cohort study. Medicine. 2015;94:52–60.

    Article  Google Scholar 

  94. Abela OG, Singh D, Abela GS. The resistant atherosclerotic plaques: pathologic features and their impact on revascularization. In: Topaz O, editor. Debulking in cardiovascular interventions and revascularization strategies-between the rock and the heart. London: Elsevier; 2022. p. 29–59.

    Chapter  Google Scholar 

  95. Fitzgerald PJ, Ports TA, Yock PG. Contribution of localized calcium deposits to dissection after angioplasty. An observational study using intravascular ultrasound. Circulation. 1992;86:64–70.

    Article  CAS  PubMed  Google Scholar 

  96. DĂ­az JF, GĂ³mez-Menchero A, Cardenal R, et al. Extremely high-pressure dilation with a new noncompliant balloon. Tex Heart Inst J. 2012;39:635–8.

    PubMed  PubMed Central  Google Scholar 

  97. Ertelt K, Généreux P, Mintz GS, Reiss GR, Kirtane AJ, Madhavan MV, Fahy M, Williams MR, Brener SJ, Mehran R, Stone GW. Impact of the severity of coronary artery calcification on clinical events in patients undergoing coronary artery bypass grafting (from the acute catheterization and urgent intervention triage strategy trial). Am J Cardiol. 2013;2013(112):1730–7. https://doi.org/10.1016/j.amjcard.2013.07.038.

    Article  Google Scholar 

  98. Gonzalez JN, Macias AE, Salerno TA, Magarakis M. Coronary calcifications: effect on coronary artery bypass surgery. In: Topaz O, editor. Debulking in cardiovascular interventions and revascularization strategies-between the rock and the heart. London: Elsevier; 2022. p. 361–76.

    Chapter  Google Scholar 

  99. Kircelli F, Peter ME, Sevinc Ok E, Celenk FG, Yilmaz M, Steppan S, Asci G, Ok E, Passlick-Deetjen J. Magnesium reduces calcification in bovine vascular smooth muscle cells in a dose-dependent manner. Nephrol Dial Transplant. 2012;27:514–21. https://doi.org/10.1093/ndt/gfr321.

    Article  CAS  PubMed  Google Scholar 

  100. Montezano AC, Zimmerman D, Yusuf H, Burger D, Chignalia AZ, Wadhera V, van Leeuwen FN, Touyz RM. Vascular smooth muscle cell differentiation to an osteogenic phenotype involves TRPM7 modulation by magnesium. Hypertension. 2010;56:453–62.

    Article  CAS  PubMed  Google Scholar 

  101. Louvet L, BĂ¼chel J, Steppan S, Passlick-Deetjen J, Massy ZA. Magnesium prevents phosphate-induced calcification in human aortic vascular smooth muscle cells. Nephrol Dial Transplant. 2013;28:869–78. https://doi.org/10.1093/ndt/gfs520.

    Article  CAS  PubMed  Google Scholar 

  102. Shao JS, Cheng SL, **sterhaus JM, Charlton-Kachigian N, Loewy AP, Towler DA. Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals. J Clin Invest. 2005;115:1210–20. https://doi.org/10.1172/JCI24140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Montes de Oca A, Guerrero F, Martinez-Moreno JM, Madueño JA, Herencia C, Peralta A, Almaden Y, Lopez I, Aguilera-Tejero E, Gundlach K, BĂ¼chel J, Peter ME, Passlick-Deetjen J, Rodriguez M, MuñozCastañeda JR. Magnesium inhibits Wnt/β-catenin activity and reverses the osteogenic transformation of vascular smooth muscle cells. PLoS One. 2014;9:e89525. https://doi.org/10.1371/journal.pone.0089525.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Brigant B, Metzinger-Le Meuth V, Massy ZA, et al. Serum microRNAs are altered in various stages of chronic kidney disease: a preliminary study. Clin Kidney J. 2017;10:30–7.

    Article  CAS  PubMed  Google Scholar 

  105. Cui RR, Li SJ, Liu LJ, Yi L, Liang QH, Zhu X, Liu GY, Liu Y, Wu SS, Liao XB, Yuan LQ, Mao DA, Liao EY. MicroRNA-204 regulates vascular smooth muscle cell calcification in vitro and in vivo. Cardiovasc Res. 2012;96:320–9. https://doi.org/10.1093/cvr/cvs258.

    Article  CAS  PubMed  Google Scholar 

  106. Louvet L, Metzinger L, BĂ¼chel J, Steppan S, Massy ZA. Magnesium attenuates phosphate-induced deregulation of a microRNA signature and prevents modulation of Smad1 and osterix during the course of vascular calcification. Biomed Res Int. 2016;2016:7419524. https://doi.org/10.1155/2016/7419524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Altura BM, Altura BT, Carella A, Gebrewold A, Murakawa T, Nishio A. Mg2+-Ca2+ interaction in contractility of vascular smooth muscle: Mg2+ versus organic calcium channel blockers on myogenic tone and agonist-induced responsiveness of blood vessels. Can J Physiol Pharmacol. 1987;65:729–45.

    Article  CAS  PubMed  Google Scholar 

  108. Iseri LT, French JH. Magnesium: nature’s physiologic calcium blocker. Am Heart J. 1984;108:188–93.

    Article  CAS  PubMed  Google Scholar 

  109. Shanahan CM, Crouthamel MH, Kapustin A, Giachelli CM. Arterial calcification in chronic kidney disease: key roles for calcium and phosphate. Circ Res. 2011;109:697–711. https://doi.org/10.1161/CIRCRESAHA.110.234914.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Proudfoot D, Skepper JN, Hegyi L, Bennett MR, Shanahan CM, Weissberg PL. Apoptosis regulates human vascular calcification in vitro: evidence for initiation of vascular calcification by apoptotic bodies. Circ Res. 2000;87:1055–62.

    Article  CAS  PubMed  Google Scholar 

  111. Rodenbeck SD, Zarse CA, McKenney-Drake ML, et al. Intracellular calcium increases in vascular smooth muscle cells with progression of chronic kidney disease in a rat model. Nephrol Dial Transplant. 2017;32:450–8.

    CAS  PubMed  Google Scholar 

  112. Blumenthal NC, Betts F, Posner AS. Stabilization of amorphous calcium phosphate by mg and ATP. Calcif Tissue Res. 1977;23:245–50.

    Article  CAS  PubMed  Google Scholar 

  113. LeGeros RZ, Contiguglia SR, Alfrey AC. Pathological calcifications associated with uremia: two types of calcium phosphate deposits. Calcif Tissue Res. 1973;13:173–85.

    Article  CAS  PubMed  Google Scholar 

  114. Massy ZA, DrĂ¼eke TB. Magnesium and outcomes in patients with chronic kidney disease: focus on vascular calcification, atherosclerosis and survival. Clin Kidney J. 2012;5(suppl 1):i52–61. https://doi.org/10.1093/ndtplus/sfr167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, Sun A, Hediger MA, Lytton J, Hebert SC. Cloning and characterization of an extracellular ca(2+)-sensing receptor from bovine parathyroid. Nature. 1993;366:575–80. https://doi.org/10.1038/366575a0.

    Article  CAS  PubMed  Google Scholar 

  116. Riccardi D. Cell surface, Ca2+(cation)-sensing receptor(s): one or many? Cell Calcium. 1999;26:77–83. https://doi.org/10.1054/ceca.1999.0066.

    Article  CAS  PubMed  Google Scholar 

  117. Ruat M, Snowman AM, Hester LD, Snyder SH. Cloned and expressed rat Ca2+−sensing receptor. J Biol Chem. 1996;271:5972–5.

    Article  CAS  PubMed  Google Scholar 

  118. RodrĂ­guez-Ortiz ME, Canalejo A, Herencia C, MartĂ­nez-Moreno JM, Peralta-RamĂ­rez A, Perez-Martinez P, Navarro-GonzĂ¡lez JF, RodrĂ­guez M, Peter M, Gundlach K, Steppan S, Passlick-Deetjen J, MuñozCastañeda JR, Almaden Y. Magnesium modulates parathyroid hormone secretion and upregulates parathyroid receptor expression at moderately low calcium concentration. Nephrol Dial Transplant. 2014;29:282–9. https://doi.org/10.1093/ndt/gft400.

    Article  CAS  PubMed  Google Scholar 

  119. Alesutan I, Tuffaha R, Auer T, et al. Inhibition of osteo/chondrogenic transformation of vascular smooth muscle cells by MgCl2 via calcium sensing receptor. J Hypertens. 2016;35:523–32.

    Article  Google Scholar 

  120. Louvet L, Bazin D, BĂ¼chel J, Steppan S, Passlick-Deetjen J, Massy ZA. Characterization of calcium phosphate crystals on calcified human aortic vascular smooth muscle cells and potential role of magnesium. PLoS One. 2015;10:e0115342. https://doi.org/10.1371/journal.pone.0115342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Doran AC, Meller N, McNamara CA. Role of smooth muscle cells in the initiation and early progression of atherosclerosis. Arterioscler Thromb Vasc Biol. 2008;28:812–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Kawashima H. Receptor for 1,25-dihydroxyvitamin D in a vascular smooth muscle cell line derived from rat aorta. Biochem Biophys Res Commun. 1987;146:1–6.

    Article  CAS  PubMed  Google Scholar 

  123. Somjen D, Weisman Y, Kohen F, Gayer B, Limor R, Sharon O, Jaccard N, Knoll E, Stern N. 25-hydroxyvitamin D3-1alpha-hydroxylase is expressed in human vascular smooth muscle cells and is upregulated by parathyroid hormone and estrogenic compounds. Circulation. 2005;111:1666–71.

    Article  CAS  PubMed  Google Scholar 

  124. Carthy EP, Yamashita W, Hsu A, Ooi BS. 1,25-Dihydroxyvitamin D3 and rat vascular smooth muscle cell growth. Hypertension. 1989;13(2):954–9.

    Article  CAS  PubMed  Google Scholar 

  125. Wu-Wong JR, Nakane M, Ma J. Effects of vitamin D analogs on the expression of plasminogen activator inhibitor-1 in human vascular cells. Thromb Res. 2006;118:709–14.

    Article  CAS  PubMed  Google Scholar 

  126. Mitsuhashi T, Morris RC, Ives HE. 1,25-Dihydroxyvitamin D3 modulates growth of vascular smooth muscle cells. J Clin Invest. 1991;87:1889–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Chen S, Law CS, Gardner DG. Vitamin D-dependent suppression of endothelin-induced vascular smooth muscle cell proliferation through inhibition of CDK2 activity. J Steroid Biochem Mol Biol. 2010;118:135–41.

    Article  CAS  PubMed  Google Scholar 

  128. Davies MR, Hruska KA. Pathophysiological mechanisms of vascular calcification in end-stage renal disease. Kidney Int. 2001;60:472–9.

    Article  CAS  PubMed  Google Scholar 

  129. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM, Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:1911–30.

    Article  CAS  Google Scholar 

  130. Arad Y, Spadaro LA, Roth M, Scordo J, Goodman K, Sherman S, Lerner G, Newstein D, Guerci AD. Serum concentration of calcium, 1,25 vitamin D and parathyroid hormone are not correlated with coronary calcifications: an electron beam computed tomography study. Coron Artery Dis. 1998;9:513–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cardiology, Michigan State University/Sparrow Hospital, Lansing, MI, USA

    Sandeep Banga

  2. Department of Cardiology, Ascension Borgess Center, Michigan State University/Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI, USA

    Jagadeesh K. Kalavakunta

  3. Department of Medicine, Cardiology Section, Advent Health, Tampa, FL, USA

    Oliver Abela

  4. Duke University School of Medicine, Durham, NC, USA

    On Topaz

Authors
  1. Sandeep Banga
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jagadeesh K. Kalavakunta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Oliver Abela
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. On Topaz
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Medicine, Division of Cardiovascular Medicine, Michigan State University, East Lansing, MI, USA

    George S. Abela

  2. The Heart and Vascular Research Institute, Sir Charles Gairdner Hospital, Perth, WA, Australia

    Stefan Mark Nidorf

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Banga, S., Kalavakunta, J.K., Abela, O., Topaz, O. (2023). Calcium Crystals in Arterial Disease. In: Abela, G.S., Nidorf, S.M. (eds) Cholesterol Crystals in Atherosclerosis and Other Related Diseases. Contemporary Cardiology. Humana, Cham. https://doi.org/10.1007/978-3-031-41192-2_19

Download citation

  • DOI: https://doi.org/10.1007/978-3-031-41192-2_19

  • Published:

  • Publisher Name: Humana, Cham

  • Print ISBN: 978-3-031-41191-5

  • Online ISBN: 978-3-031-41192-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation