Osteologie 2022; 31(04): 289-297
DOI: 10.1055/a-1962-6699
Review

Pathologische Gefäßkalzifizierung – klinische Relevanz und molekulare Mechanismen

Pathophysiological Calcification – Clinical Relevance and Molecular Mechanisms
Nicolas Hense
1   Medizinische Klinik 1 – Kardiologie, Rheinisch-Westfälische Technische Hochschule Aachen Medizinische Fakultät, Aachen, Germany
,
Claudia Goettsch
1   Medizinische Klinik 1 – Kardiologie, Rheinisch-Westfälische Technische Hochschule Aachen Medizinische Fakultät, Aachen, Germany
› Author Affiliations

Zusammenfassung

Die kardiovaskuläre Kalzifizierung stellt als pathologische Mineralablagerung in Herzklappen und Arterien einen Prädiktor und Risikofaktor für die kardiovaskuläre Morbidität und Mortalität dar – ein globales Gesundheitsproblem. Die kardiovaskuläre Kalzifizierung ist ein ‚Unmet need‘ in der kardiovaskulären Medizin, da es bisher keine therapeutischen Ansatzpunkte gibt, die diesen Prozess aufhalten oder modifizieren können. Diese Übersichtsarbeit fasst die Manifestationsformen der kardiovaskulären Kalzifizierung mit ihren klinischen Relevanzen zusammen. Dabei wird der Fokus insbesondere auf die arterielle Mikrokalzifizierung der Tunica intima, sowie Makrokalzifizierung der Tunica media und der Aortenklappe gelegt. Die zellulären und molekularen Mechanismen, die die kardiovaskuläre Kalzifizierung regulieren, sind vielfältig und zeigen Parallelen zum Knochenstoffwechsel. Neben den klassischen Signalwegen, wird die Rolle epigenetischer Veränderungen diskutiert. Letztlich werden offene Fragen aufgezeigt, deren Beantwortung wichtig ist, um Therapieansätze zur Prävention und Behandlung kardiovaskulärer Kalzifizierung entwickeln zu können, die die Knochengesundheit nicht beeinflussen.

Abstract

Cardiovascular calcification, the pathological mineral deposition in heart valves and arteries, is a predictor and risk factor for cardiovascular morbidity and mortality – a global health problem. Cardiovascular calcification represents an ‘unmet need’ in cardiovascular medicine, as there are currently no therapeutic approaches that can stop or modify this process. This review article summarizes the manifestations of cardiovascular calcification with their clinical relevance, focusing mainly on arterial microcalcification of the tunica intima and macrocalcification of the tunica media and the aortic heart valve. The cellular and molecular mechanisms that regulate cardiovascular calcification are diverse and show parallels to bone metabolism. In addition to the classic signaling pathways, the role of epigenetic changes are discussed. Finally, open questions are identified, whose answers are essential to develop therapeutic approaches for preventing and treating cardiovascular calcification that do not affect bone health.



Publication History

Received: 05 September 2022

Accepted: 15 October 2022

Article published online:
14 December 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag
Rüdigerstraße 14,70469 Stuttgart, Germany

 
  • Literatur

  • 1 Ahmad FB, Anderson RN. The Leading Causes of Death in the US for 2020. JAMA 2021; 325: 1829-1830
  • 2 Bundesamt S. Todesursachen in Deutschland – Statistisches Bundesamt (destatis.de)
  • 3 Silverman MG, Blaha MJ, Krumholz HM, Budoff MJ, Blankstein R, Sibley CT. et al. Impact of coronary artery calcium on coronary heart disease events in individuals at the extremes of traditional risk factor burden: the Multi-Ethnic Study of Atherosclerosis. Eur Heart J 2014; 35: 2232-2241
  • 4 Taylor AJ, Bindeman J, Feuerstein I, Cao F, Brazaitis M, O’Malley PG. Coronary calcium independently predicts incident premature coronary heart disease over measured cardiovascular risk factors: mean three-year outcomes in the Prospective Army Coronary Calcium (PACC) project. J Am Coll Cardiol 2005; 46: 807-814
  • 5 Peng ALW, Dardari ZA, Blumenthal RS, Dzaye O, Obisesan OH, Uddin SMI. et al. Very High Coronary Artery Calcium (>=1000) and Association With Cardiovascular Disease Events, Non-Cardiovascular Disease Outcomes, and Mortality Results From MESA. Circulation 2021; 143: 1571-1583
  • 6 Raggi P, Gongora MC, Gopal A, Callister TQ, Budoff M, Shaw LJ. Coronary artery calcium to predict all-cause mortality in elderly men and women. J Am Coll Cardiol 2008; 52: 17-23
  • 7 Hutcheson JD, Goettsch C, Rogers MA, Aikawa E. Revisiting cardiovascular calcification: A multifaceted disease requiring a multidisciplinary approach. Semin Cell Dev Biol 2015; 46: 68-77
  • 8 Hunt JL, Fairman R, Mitchell ME, Carpenter JP, Golden M, Khalapyan T. et al. Bone formation in carotid plaques: a clinicopathological study. Stroke. 2002; 33: 1214-1219
  • 9 Perrotta I, Perri E. Ultrastructural, Elemental and Mineralogical Analysis of Vascular Calcification in Atherosclerosis. Microsc Microanal 2017; 23: 1030-1039
  • 10 Fishbein GA, Micheletti RG, Currier JS, Singer E, Fishbein MC. Atherosclerotic oxalosis in coronary arteries. Cardiovasc Pathol 2008; 17: 117-123
  • 11 Duer MJ, Friscic T, Proudfoot D, Reid DG, Schoppet M, Shanahan CM. et al. Mineral surface in calcified plaque is like that of bone: further evidence for regulated mineralization. Arterioscler Thromb Vasc Biol 2008; 28: 2030-2034
  • 12 Allison MA, Criqui MH, Wright CM. Patterns and risk factors for systemic calcified atherosclerosis. Arterioscler Thromb Vasc Biol 2004; 24: 331-336
  • 13 Yahagi K, Kolodgie FD, Lutter C, Mori H, Romero ME, Finn AV. et al. Pathology of Human Coronary and Carotid Artery Atherosclerosis and Vascular Calcification in Diabetes Mellitus. Arterioscler Thromb Vasc Biol 2017; 37: 191-204
  • 14 Marwick TH, Amann K, Bangalore S, Cavalcante JL, Charytan DM, Craig JC. et al. Chronic kidney disease and valvular heart disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 2019; 96: 836-849
  • 15 Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D. et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000; 342: 1478-1483
  • 16 Raggi P, Boulay A, Chasan-Taber S, Amin N, Dillon M, Burke SK. et al. Cardiac calcification in adult Hemodialysis patients – A link between end-stage renal disease and cardiovascular disease?. Journal of the American College of Cardiology 2002; 39: 695-701
  • 17 Wang XR, Zhang JJ, Xu XX, Wu YG. Prevalence of coronary artery calcification and its association with mortality, cardiovascular events in patients with chronic kidney disease: a systematic review and meta-analysis. Ren Fail 2019; 41: 244-256
  • 18 Buttner P, Feistner L, Lurz P, Thiele H, Hutcheson JD, Schlotter F. Dissecting Calcific Aortic Valve Disease-The Role, Etiology, and Drivers of Valvular Fibrosis. Front Cardiovasc Med 2021; 8: 660797
  • 19 Hoang K, Bravo-Jaimes K, Ocazionez D. Myocardial Calcifications: Thinking Beyond the Heart. Am J Med 2020; 133: e591-e592
  • 20 Chen TY, Lehman JS, Gibson LE, Lohse CM, El-Azhary RA. Histopathology of Calciphylaxis: Cohort Study With Clinical Correlations. Am J Dermatopathol 2017; 39: 795-802
  • 21 Thompson RC, Allam AH, Lombardi GP, Wann LS, Sutherland ML, Sutherland JD. et al. Atherosclerosis across 4000 years of human history: the Horus study of four ancient populations. Lancet 2013; 381: 1211-1222
  • 22 O’Donnell CJ, Chazaro I, Wilson PW, Fox C, Hannan MT, Kiel DP. et al. Evidence for heritability of abdominal aortic calcific deposits in the Framingham Heart Study. Circulation 2002; 106: 337-341
  • 23 McClelland RL, Chung H, Detrano R, Post W, Kronmal RA. Distribution of coronary artery calcium by race, gender, and age: results from the Multi-Ethnic Study of Atherosclerosis (MESA). Circulation 2006; 113: 30-37
  • 24 Rutsch F, Nitschke Y, Terkeltaub R. Genetics in arterial calcification: pieces of a puzzle and cogs in a wheel. Circ Res 2011; 109: 578-592
  • 25 O’Donnell CJ, Kavousi M, Smith AV, Kardia SL, Feitosa MF, Hwang SJ. et al. Genome-wide association study for coronary artery calcification with follow-up in myocardial infarction. Circulation 2011; 124: 2855-2864
  • 26 Rutsch F, Buers I, Nitschke Y. Hereditary Disorders of Cardiovascular Calcification. Arterioscler Thromb Vasc Biol 2021; 41: 35-47
  • 27 Blaha M, Budoff MJ, Shaw LJ, Khosa F, Rumberger JA, Berman D. et al. Absence of Coronary Artery Calcification and All-Cause Mortality. Jacc-Cardiovasc Imag 2009; 2: 692-700
  • 28 Peng AW, Dardari ZA, Blumenthal RS, Dzaye O, Obisesan OH, Iftekhar Uddin SM. et al. Very High Coronary Artery Calcium (>/=1000) and Association With Cardiovascular Disease Events, Non-Cardiovascular Disease Outcomes, and Mortality: Results From MESA. Circulation 2021; 143: 1571-1583
  • 29 Raggi P, Cooil B, Callister TQ. Use of electron beam tomography data to develop models for prediction of hard coronary events. Am Heart J 2001; 141: 375-382
  • 30 Rennenberg RJ, Kessels AG, Schurgers LJ, van Engelshoven JM, de Leeuw PW, Kroon AA. Vascular calcifications as a marker of increased cardiovascular risk: a meta-analysis. Vasc Health Risk Manag 2009; 5: 185-197
  • 31 Criqui MH, Denenberg JO, Ix JH, McClelland RL, Wassel CL, Rifkin DE. et al. Calcium density of coronary artery plaque and risk of incident cardiovascular events. JAMA. 2014; 311: 271-278
  • 32 Ehara S, Kobayashi Y, Yoshiyama M, Shimada K, Shimada Y, Fukuda D. et al. Spotty calcification typifies the culprit plaque in patients with acute myocardial infarction: an intravascular ultrasound study. Circulation. 2004; 110: 3424-3429
  • 33 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: 10741-10746
  • 34 Maldonado N, Kelly-Arnold A, Vengrenyuk Y, Laudier D, Fallon JT, Virmani R. et al. A mechanistic analysis of the role of microcalcifications in atherosclerotic plaque stability: potential implications for plaque rupture. Am J Physiol Heart Circ Physiol 2012; 303: H619-H628
  • 35 Maldonado N, Kelly-Arnold A, Cardoso L, Weinbaum S. The explosive growth of small voids in vulnerable cap rupture; cavitation and interfacial debonding. J Biomech 2013; 46: 396-401
  • 36 Rambhia SH, Liang X, Xenos M, Alemu Y, Maldonado N, Kelly A. et al. Microcalcifications increase coronary vulnerable plaque rupture potential: a patient-based micro-CT fluid-structure interaction study. Ann Biomed Eng 2012; 40: 1443-1454
  • 37 Wang Y, Osborne MT, Tung B, Li M, Li Y. Imaging Cardiovascular Calcification. J Am Heart Assoc 2018; 7: 13
  • 38 Tzolos E, Dweck MR. (18)F-Sodium Fluoride ((18)F-NaF) for Imaging Microcalcification Activity in the Cardiovascular System. Arterioscler Thromb Vasc Biol 2020; 40: 1620-1626
  • 39 Irkle A, Vesey AT, Lewis DY, Skepper JN, Bird JL, Dweck MR. et al. Identifying active vascular microcalcification by (18)F-sodium fluoride positron emission tomography. Nat Commun 2015; 6: 7495
  • 40 Creager MD, Hohl T, Hutcheson JD, Moss AJ, Schlotter F, Blaser MC. et al. (18)F-Fluoride Signal Amplification Identifies Microcalcifications Associated With Atherosclerotic Plaque Instability in Positron Emission Tomography/Computed Tomography Images. Circ Cardiovasc Imaging 2019; 12: e007835
  • 41 Klose-Jensen R, Tse JJ, Keller KK, Barnabe C, Burghardt AJ, Finzel S. et al. High-Resolution Peripheral Quantitative Computed Tomography for Bone Evaluation in Inflammatory Rheumatic Disease. Front Med (Lausanne) 2020; 7: 337
  • 42 Szulc P, Planckaert C, Foesser D, Patsch J, Chapurlat R. High Cardiovascular Risk in Older Men With Severe Peripheral Artery Calcification on High-Resolution Peripheral QCT Scans: The STRAMBO Study. Arterioscler Thromb Vasc Biol 2021; 41: 1818-1829
  • 43 Paccou J, Edwards MH, Patsch JM, Jameson KA, Ward KA, Moss C. et al. Lower leg arterial calcification assessed by high-resolution peripheral quantitative computed tomography is associated with bone microstructure abnormalities in women. Osteoporosis Int 2016; 27: 3279-3287
  • 44 St Hilaire C. Medial Arterial Calcification: A Significant and Independent Contributor of Peripheral Artery Disease. Arterioscler Thromb Vasc Biol 2022; 42: 253-260
  • 45 Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol 2010; 55: 1318-1327
  • 46 O’Neill WC, Han KH, Schneider TM, Hennigar RA. Prevalence of nonatheromatous lesions in peripheral arterial disease. Arterioscler Thromb Vasc Biol 2015; 35: 439-447
  • 47 Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M. Burden of valvular heart diseases: a population-based study. Lancet. 2006; 368: 1005-1011
  • 48 Eveborn GW, Schirmer H, Heggelund G, Lunde P, Rasmussen K. The evolving epidemiology of valvular aortic stenosis. the Tromso study. Heart. 2013; 99: 396-400
  • 49 Schoen FJ. Morphology, Clinicopathologic Correlations, and Mechanisms in Heart Valve Health and Disease. Cardiovasc Eng Technol 2018; 9: 126-140
  • 50 Yutzey KE, Demer LL, Body SC, Huggins GS, Towler DA, Giachelli CM. et al. Calcific aortic valve disease: a consensus summary from the Alliance of Investigators on Calcific Aortic Valve Disease. Arterioscler Thromb Vasc Biol 2014; 34: 2387-2393
  • 51 Sacks MS, Yoganathan AP. Heart valve function: a biomechanical perspective. Philos Trans R Soc Lond B Biol Sci 2007; 362: 1369-1391
  • 52 Guerraty MA, Chai B, Hsu JY, Ojo AO, Gao Y, Yang W. et al. Relation of aortic valve calcium to chronic kidney disease (from the Chronic Renal Insufficiency Cohort Study). Am J Cardiol 2015; 115: 1281-1286
  • 53 Schulz E, Arfai K, Liu X, Sayre J, Gilsanz V. Aortic calcification and the risk of osteoporosis and fractures. J Clin Endocrinol Metab 2004; 89: 4246-4253
  • 54 Kim H, Lee J, Lee KB, Kim YH, Hong N, Park JT. et al. Low bone mineral density is associated with coronary arterial calcification progression and incident cardiovascular events in patients with chronic kidney disease. Clin Kidney J 2022; 15: 119-127
  • 55 Szulc P. Vascular calcification and fracture risk. Clin Cases Miner Bone Metab 2015; 12: 139-141
  • 56 Handy CE, Desai CS, Dardari ZA, Al-Mallah MH, Miedema MD, Ouyang P. et al. The Association of Coronary Artery Calcium With Noncardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis. JACC Cardiovasc Imaging 2016; 9: 568-576
  • 57 Alissa EM, Alnahdi WA, Alama N, Ferns GA. Bone mineral density and cardiovascular risk factors in postmenopausal women with coronary artery disease. Bonekey Rep 2015; 4: 758
  • 58 Goettsch C, Rauner M, Hamann C, Sinningen K, Hempel U, Bornstein SR. et al. Nuclear factor of activated T cells mediates oxidised LDL-induced calcification of vascular smooth muscle cells. Diabetologia 2011; 54: 2690-2701
  • 59 Helas S, Goettsch C, Schoppet M, Zeitz U, Hempel U, Morawietz H. et al. Inhibition of receptor activator of NF-kappaB ligand by denosumab attenuates vascular calcium deposition in mice. Am J Pathol 2009; 175: 473-478
  • 60 Iseri K, Watanabe M, Yoshikawa H, Mitsui H, Endo T, Yamamoto Y. et al. Effects of Denosumab and Alendronate on Bone Health and Vascular Function in Hemodialysis Patients: A Randomized, Controlled Trial. J Bone Miner Res 2019; 34: 1014-1024
  • 61 Samelson EJ, Miller PD, Christiansen C, Daizadeh NS, Grazette L, Anthony MS. et al. RANKL inhibition with denosumab does not influence 3-year progression of aortic calcification or incidence of adverse cardiovascular events in postmenopausal women with osteoporosis and high cardiovascular risk. J Bone Miner Res 2014; 29: 450-457
  • 62 Suzuki S, Suzuki M, Hanafusa N, Tsuchiya K, Nitta K. Denosumab Recovers Aortic Arch Calcification During Long-Term Hemodialysis. Kidney Int Rep 2021; 6: 605-612
  • 63 Hortells L, Sur S, St Hilaire C. Cell Phenotype Transitions in Cardiovascular Calcification. Front Cardiovasc Med 2018; 5: 27
  • 64 Owens GK, Kumar MS, Wamhoff BR. Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev 2004; 84: 767-801
  • 65 Almalki SG, Agrawal DK. Key transcription factors in the differentiation of mesenchymal stem cells. Differentiation 2016; 92: 41-51
  • 66 Yap C, Mieremet A, de Vries CJM, Micha D, de Waard V. Six Shades of Vascular Smooth Muscle Cells Illuminated by KLF4 (Kruppel-Like Factor 4). Arterioscler Thromb Vasc Biol 2021; 41: 2693-2707
  • 67 Petsophonsakul P, Furmanik M, Forsythe R, Dweck M, Schurink GW, Natour E. et al. Role of Vascular Smooth Muscle Cell Phenotypic Switching and Calcification in Aortic Aneurysm Formation. Arterioscler Thromb Vasc Biol 2019; 39: 1351-1368
  • 68 Tyson J, Bundy K, Roach C, Douglas H, Ventura V, Segars MF. et al. Mechanisms of the Osteogenic Switch of Smooth Muscle Cells in Vascular Calcification: WNT Signaling, BMPs, Mechanotransduction, and EndMT. Bioengineering (Basel) 2020; 7
  • 69 Hutcheson JD, Goettsch C, Bertazzo S, Maldonado N, Ruiz JL, Goh W. et al. Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques. Nat Mater 2016; 15: 335-343
  • 70 Ouyang L, Su X, Li W, Tang L, Zhang M, Zhu Y. et al. ALKBH1-demethylated DNA N6-methyladenine modification triggers vascular calcification via osteogenic reprogramming in chronic kidney disease. J Clin Invest 2021; 131
  • 71 Chen J, Zhang X, Zhang H, Liu T, Zhang H, Teng J. et al. Indoxyl Sulfate Enhance the Hypermethylation of Klotho and Promote the Process of Vascular Calcification in Chronic Kidney Disease. Int J Biol Sci 2016; 12: 1236-1246
  • 72 Alexander MR, Owens GK. Epigenetic control of smooth muscle cell differentiation and phenotypic switching in vascular development and disease. Annu Rev Physiol 2012; 74: 13-40
  • 73 Shvedunova M, Akhtar A. Modulation of cellular processes by histone and non-histone protein acetylation. Nat Rev Mol Cell Biol 2022; 23: 329-349
  • 74 Kurozumi A, Nakano K, Yamagata K, Okada Y, Nakayamada S, Tanaka Y. IL-6 and sIL-6R induces STAT3-dependent differentiation of human VSMCs into osteoblast-like cells through JMJD2B-mediated histone demethylation of RUNX2. Bone. 2019; 124: 53-61
  • 75 Malhotra R, Mauer AC, Lino Cardenas CL, Guo X, Yao J, Zhang X. et al. HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype. Nat Genet 2019; 51: 1580-1587
  • 76 Hemming S, Cakouros D, Vandyke K, Davis MJ, Zannettino AC, Gronthos S. Identification of Novel EZH2 Targets Regulating Osteogenic Differentiation in Mesenchymal Stem Cells. Stem Cells Dev 2016; 25: 909-921
  • 77 Wang FS, Chen YS, Ko JY, Kuo CW, Ke HJ, Hsieh CK. et al. Bromodomain Protein BRD4 Accelerates Glucocorticoid Dysregulation of Bone Mass and Marrow Adiposis by Modulating H3K9 and Foxp1. Cells 2020; 9
  • 78 Grootaert MOJ, Bennett MR. Vascular smooth muscle cells in atherosclerosis: time for a re-assessment. Cardiovasc Res 2021; 117: 2326-2339
  • 79 Chen J, Budoff MJ, Reilly MP, Yang W, Rosas SE, Rahman M. et al. Coronary Artery Calcification and Risk of Cardiovascular Disease and Death Among Patients With Chronic Kidney Disease. JAMA Cardiol 2017; 2: 635-643
  • 80 Patel J, Pallazola VA, Dudum R, Greenland P, McEvoy JW, Blumenthal RS. et al. Assessment of Coronary Artery Calcium Scoring to Guide Statin Therapy Allocation According to Risk-Enhancing Factors: The Multi-Ethnic Study of Atherosclerosis. JAMA Cardiol 2021; 6: 1161-1170
  • 81 Greenland P, Blaha MJ, Budoff MJ, Erbel R, Watson KE. Coronary Calcium Score and Cardiovascular Risk. J Am Coll Cardiol 2018; 72: 434-447