Why Current Detection of Vascular Calcification Falls Short and How to Improve on It

Abstract

Vascular calcification is a common phenomenon in various vascular diseases, where its presence heralds increased occurrence of adverse disease events, which invariably lead to increased morbidity and mortality in patients. Although the impact of calcification has become apparent, adequate and early detection of the most damaging form of early microcalcification is still in its infancy, preventing reliable identification of locations that would benefit from intervention. In this review, we will provide an overview of the current state-of-the-art noninvasive calcification imaging and its persisting limitations. We discuss promising approaches that may address these limitations in the future. In this context particular attention will be paid to imaging modalities such as CT, PET, and ultrasonography and molecular and cellular mechanisms and agents involved in physiological bone formation.

Keywords

imaging - cardiovascular disease - noninvasive imaging - early detection - vascular calcification

Publikationsverlauf

Eingereicht: 04. Juli 2024

Angenommen: 02. Dezember 2024

Artikel online veröffentlicht:
27. Dezember 2024

• References

• 1 Otsuka F, Kramer MCA, Woudstra P. et al. Natural progression of atherosclerosis from pathologic intimal thickening to late fibroatheroma in human coronary arteries: a pathology study. Atherosclerosis 2015; 241 (02) 772-782
• 2 Mikael LR, Paiva AMG, Gomes MM. et al. Vascular aging and arterial stiffness. Arq Bras Cardiol 2017; 109 (03) 253-258
• 3 Lee SJ, Lee IK, Jeon JH. Vascular calcification—new insights into its mechanism. Int J Mol Sci 2020; 21 (08) 32
• 4 Wang D, Wang Z, Zhang L, Wang Y. Roles of cells from the arterial vessel wall in atherosclerosis. Mediators Inflamm 2017; 2017: 8135934
• 5 Brown AJ, Teng Z, Evans PC, Gillard JH, Samady H, Bennett MR. Role of biomechanical forces in the natural history of coronary atherosclerosis. Nat Rev Cardiol 2016; 13 (04) 210-220
• 6 Gimbrone Jr MA, García-Cardeña G. Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ Res 2016; 118 (04) 620-636
• 7 Tabas I, García-Cardeña G, Owens GK. Recent insights into the cellular biology of atherosclerosis. J Cell Biol 2015; 209 (01) 13-22
• 8 Bakogiannis C, Sachse M, Stamatelopoulos K, Stellos K. Platelet-derived chemokines in inflammation and atherosclerosis. Cytokine 2019; 122: 154157
• 9 Wang Z-T, Wang Z, Hu Y-W. Possible roles of platelet-derived microparticles in atherosclerosis. Atherosclerosis 2016; 248: 10-16
• 10 Hansson GK, Libby P, Tabas I. Inflammation and plaque vulnerability. J Intern Med 2015; 278 (05) 483-493
• 11 Shioi A, Ikari Y. Plaque calcification during atherosclerosis progression and regression. J Atheroscler Thromb 2018; 25 (04) 294-303
• 12 Harman JL, Jørgensen HF. The role of smooth muscle cells in plaque stability: therapeutic targeting potential. Br J Pharmacol 2019; 176 (19) 3741-3753
• 13 Sakakura K, Nakano M, Otsuka F, Ladich E, Kolodgie FD, Virmani R. Pathophysiology of atherosclerosis plaque progression. Heart Lung Circ 2013; 22 (06) 399-411
• 14 Rysz J, Franczyk B, Rysz-Górzyńska M, Gluba-Brzózka A. Ageing, age-related cardiovascular risk and the beneficial role of natural components intake. Int J Mol Sci 2021; 23 (01) 183
• 15 Kawai K, Finn AV, Virmani R. Subclinical Atherosclerosis Collaborative. Subclinical atherosclerosis: Part 1: What is it? Can it be defined at the histological level?. Arterioscler Thromb Vasc Biol 2024; 44 (01) 12-23
• 16 Barrett HE, Van der Heiden K, Farrell E, Gijsen FJH, Akyildiz AC. Calcifications in atherosclerotic plaques and impact on plaque biomechanics. J Biomech 2019; 87: 1-12
• 17 Bucerius J, Dijkgraaf I, Mottaghy FM, Schurgers LJ. Target identification for the diagnosis and intervention of vulnerable atherosclerotic plaques beyond ¹⁸F-fluorodeoxyglucose positron emission tomography imaging: promising tracers on the horizon. Eur J Nucl Med Mol Imaging 2019; 46 (01) 251-265
• 18 Hafiane A. Vulnerable plaque, characteristics, detection, and potential therapies. J Cardiovasc Dev Dis 2019; 6 (03) 24
• 19 Saba L, Moody AR, Saam T. et al. Vessel wall-imaging biomarkers of carotid plaque vulnerability in stroke prevention trials: a viewpoint from the Carotid Imaging Consensus Group. JACC Cardiovasc Imaging 2020; 13 (11) 2445-2456
• 20 van Dam-Nolen DHK, Truijman MTB, van der Kolk AG. et al; PARISK Study Group. Carotid plaque characteristics predict recurrent ischemic stroke and TIA: the PARISK (Plaque At RISK) study. JACC Cardiovasc Imaging 2022; 15 (10) 1715-1726
• 21 Kolte D, Libby P, Jang IK. New insights into plaque erosion as a mechanism of acute coronary syndromes. JAMA 2021; 325 (11) 1043-1044
• 22 Libby P, Pasterkamp G, Crea F, Jang IK. Reassessing the mechanisms of acute coronary syndromes. Circ Res 2019; 124 (01) 150-160
• 23 Criqui MH, Knox JB, Denenberg JO. et al. Coronary artery calcium volume and density: potential interactions and overall predictive value: the Multi-Ethnic Study of Atherosclerosis. JACC Cardiovasc Imaging 2017; 10 (08) 845-854
• 24 Heseltine TD, Murray SW, Ruzsics B, Fisher M. Latest advances in cardiac CT. Eur Cardiol 2020; 15: 1-7
• 25 Bos D, Arshi B, van den Bouwhuijsen QJA. et al. Atherosclerotic carotid plaque composition and incident stroke and coronary events. J Am Coll Cardiol 2021; 77 (11) 1426-1435
• 26 Gupta A, Baradaran H, Schweitzer AD. et al. Carotid plaque MRI and stroke risk: a systematic review and meta-analysis. Stroke 2013; 44 (11) 3071-3077
• 27 Joshi NV, Vesey AT, Williams MC. et al. 18F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: a prospective clinical trial. Lancet 2014; 383 (9918) 705-713
• 28 Vesey AT, Jenkins WSA, Irkle A. et al. ¹⁸F-fluoride and ¹⁸F-fluorodeoxyglucose positron emission tomography after transient ischemic attack or minor ischemic stroke. Circ Cardiovasc Imaging 2017; 10: e004976
• 29 Andrews JPM, Fayad ZA, Dweck MR. New methods to image unstable atherosclerotic plaques. Atherosclerosis 2018; 272: 118-128
• 30 Kitagawa T, Nakano Y. Innovative atherosclerosis imaging using ¹⁸F-NaF PET/CT: its clinical potential. J Nucl Cardiol 2022; 29 (04) 1724-1728
• 31 Zhang L, Li L, Feng G, Fan T, Jiang H, Wang Z. Advances in CT techniques in vascular calcification. Front Cardiovasc Med 2021; 8: 716822
• 32 Nakahara T, Narula J, Strauss HW. Molecular imaging of vulnerable plaque. Semin Nucl Med 2018; 48 (03) 291-298
• 33 Pack JD, Xu M, Wang G, Baskaran L, Min J, De Man B. Cardiac CT blooming artifacts: clinical significance, root causes and potential solutions. Vis Comput Ind Biomed Art 2022; 5 (01) 29
• 34 de Weert TT, de Monyé C, Meijering E. et al. Assessment of atherosclerotic carotid plaque volume with multidetector computed tomography angiography. Int J Cardiovasc Imaging 2008; 24 (07) 751-759
• 35 Holcombe SA, Horbal SR, Ross BE, Brown E, Derstine BA, Wang SC. Variation in aorta attenuation in contrast-enhanced CT and its implications for calcification thresholds. PLoS One 2022; 17 (11) e0277111
• 36 Bartlett ES, Symons SP, Fox AJ. Correlation of carotid stenosis diameter and cross-sectional areas with CT angiography. AJNR Am J Neuroradiol 2006; 27 (03) 638-642
• 37 Meloni A, Frijia F, Panetta D. et al. Photon-counting computed tomography (PCCT): technical background and cardio-vascular applications. Diagnostics (Basel) 2023; 13 (04) 645
• 38 Leyssens L, Pestiaux C, Kerckhofs G. A review of ex vivo X-ray microfocus computed tomography-based characterization of the cardiovascular system. Int J Mol Sci 2021; 22 (06) 3263
• 39 Holme MN, Schulz G, Deyhle H. et al. Complementary X-ray tomography techniques for histology-validated 3D imaging of soft and hard tissues using plaque-containing blood vessels as examples. Nat Protoc 2014; 9 (06) 1401-1415
• 40 Jinnouchi H, Sato Y, Sakamoto A. et al. Calcium deposition within coronary atherosclerotic lesion: implications for plaque stability. Atherosclerosis 2020; 306: 85-95
• 41 Moss AJ, Doris MK, Andrews JPM. et al. Molecular coronary plaque imaging using ¹⁸F-fluoride. Circ Cardiovasc Imaging 2019; 12 (08) e008574
• 42 Fiz F, Piccardo A, Morbelli S. et al. Longitudinal analysis of atherosclerotic plaques evolution: an ¹⁸F-NaF PET/CT study. J Nucl Cardiol 2022; 29 (04) 1713-1723
• 43 Grant FD, Fahey FH, Packard AB, Davis RT, Alavi A, Treves ST. Skeletal PET with 18F-fluoride: applying new technology to an old tracer. J Nucl Med 2008; 49 (01) 68-78
• 44 Dweck MR, Jenkins WSA, Vesey AT. et al. 18F-sodium fluoride uptake is a marker of active calcification and disease progression in patients with aortic stenosis. Circ Cardiovasc Imaging 2014; 7 (02) 371-378
• 45 Alavi A, Werner TJ, Høilund-Carlsen PF. What can be and what cannot be accomplished with PET to detect and characterize atherosclerotic plaques. J Nucl Cardiol 2018; 25 (06) 2012-2015
• 46 Sriranjan RS, Tarkin JM, Evans NR, Le EPV, Chowdhury MM, Rudd JHF. Atherosclerosis imaging using PET: insights and applications. Br J Pharmacol 2021; 178 (11) 2186-2203
• 47 Andrews JPM, MacNaught G, Moss AJ. et al. Cardiovascular ¹⁸F-fluoride positron emission tomography-magnetic resonance imaging: a comparison study. J Nucl Cardiol 2021; 28 (05) 1-12
• 48 Irkle A, Vesey AT, Lewis DY. et al. Identifying active vascular microcalcification by (18)F-sodium fluoride positron emission tomography. Nat Commun 2015; 6: 7495
• 49 Blau M, Ganatra R, Bender MA. 18 F-fluoride for bone imaging. Semin Nucl Med 1972; 2 (01) 31-37
• 50 Wang X, Matsumura M, Mintz GS. et al. In vivo calcium detection by comparing optical coherence tomography, intravascular ultrasound, and angiography. JACC Cardiovasc Imaging 2017; 10 (08) 869-879
• 51 Lee H, Kim H, Han H. et al. Microbubbles used for contrast enhanced ultrasound and theragnosis: a review of principles to applications. Biomed Eng Lett 2017; 7 (02) 59-69
• 52 Neleman T, Liu S, Tovar Forero MN. et al. The prognostic value of a validated and automated intravascular ultrasound-derived calcium score. J Cardiovasc Transl Res 2021; 14 (05) 992-1000
• 53 Chong WK, Papadopoulou V, Dayton PA. Imaging with ultrasound contrast agents: current status and future. Abdom Radiol (NY) 2018; 43 (04) 762-772
• 54 Rix A, Curaj A, Liehn E, Kiessling F. Ultrasound microbubbles for diagnosis and treatment of cardiovascular diseases. Semin Thromb Hemost 2020; 46 (05) 545-552
• 55 Izadifar Z, Babyn P, Chapman D. Ultrasound cavitation/microbubble detection and medical applications. J Med Biol Eng 2019; 39: 259-276
• 56 Curaj A, Wu Z, Rix A. et al. Molecular ultrasound imaging of junctional adhesion molecule A depicts acute alterations in blood flow and early endothelial dysregulation. Arterioscler Thromb Vasc Biol 2018; 38 (01) 40-48
• 57 Chen J, Zhang X, Millican R. et al. Recent advances in nanomaterials for therapy and diagnosis for atherosclerosis. Adv Drug Deliv Rev 2021; 170: 142-199
• 58 Jamburidze A, Huerre A, Baresch D, Poulichet V, De Corato M, Garbin V. Nanoparticle-coated microbubbles for combined ultrasound imaging and drug delivery. Langmuir 2019; 35 (31) 10087-10096
• 59 Deprez J, Lajoinie G, Engelen Y, De Smedt SC, Lentacker I. Opening doors with ultrasound and microbubbles: beating biological barriers to promote drug delivery. Adv Drug Deliv Rev 2021; 172: 9-36
• 60 Pellow C, O'Reilly MA, Hynynen K, Zheng G, Goertz DE. Simultaneous intravital optical and acoustic monitoring of ultrasound-triggered nanobubble generation and extravasation. Nano Lett 2020; 20 (06) 4512-4519
• 61 Florea A, Sigl JP, Morgenroth A. et al. Sodium [¹⁸F]fluoride PET can efficiently monitor in vivo atherosclerotic plaque calcification progression and treatment. Cells 2021; 10 (02) 275
• 62 Aizaz M, Moonen RPM, van der Pol JAJ, Prieto C, Botnar RM, Kooi ME. PET/MRI of atherosclerosis. Cardiovasc Diagn Ther 2020; 10 (04) 1120-1139
• 63 Kwiecinski J, Slomka PJ, Dweck MR, Newby DE, Berman DS. Vulnerable plaque imaging using ¹⁸F-sodium fluoride positron emission tomography. Br J Radiol 2020; 93 (1113) 20190797
• 64 Ahrens BJ, Li L, Ciminera AK. et al. Diagnostic PET imaging of mammary microcalcifications using ⁶⁴Cu-DOTA-alendronate in a rat model of breast cancer. J Nucl Med 2017; 58 (09) 1373-1379
• 65 Sim AM, Rashdan NA, Cui L. et al. A novel fluorescein-bisphosphonate based diagnostic tool for the detection of hydroxyapatite in both cell and tissue models. Sci Rep 2018; 8 (01) 17360
• 66 Chin DD, Wang J, Mel de Fontenay M, Plotkin A, Magee GA, Chung EJ. Hydroxyapatite-binding micelles for the detection of vascular calcification in atherosclerosis. J Mater Chem B 2019; 7 (41) 6449-6457
• 67 McKenney-Drake ML, Moghbel MC, Paydary K. et al. ¹⁸F-NaF and ¹⁸F-FDG as molecular probes in the evaluation of atherosclerosis. Eur J Nucl Med Mol Imaging 2018; 45 (12) 2190-2200
• 68 Carreira AC, Lojudice FH, Halcsik E, Navarro RD, Sogayar MC, Granjeiro JM. Bone morphogenetic proteins: facts, challenges, and future perspectives. J Dent Res 2014; 93 (04) 335-345
• 69 Yang P, Troncone L, Augur ZM, Kim SSJ, McNeil ME, Yu PB. The role of bone morphogenetic protein signaling in vascular calcification. Bone 2020; 141: 115542
• 70 Speer MY, Yang HY, Brabb T. et al. Smooth muscle cells give rise to osteochondrogenic precursors and chondrocytes in calcifying arteries. Circ Res 2009; 104 (06) 733-741
• 71 Durham AL, Speer MY, Scatena M, Giachelli CM, Shanahan CM. Role of smooth muscle cells in vascular calcification: implications in atherosclerosis and arterial stiffness. Cardiovasc Res 2018; 114 (04) 590-600
• 72 Cappariello A, Loftus A, Muraca M, Maurizi A, Rucci N, Teti A. Osteoblast-derived extracellular vesicles are biological tools for the delivery of active molecules to bone. J Bone Miner Res 2018; 33 (03) 517-533
• 73 Kapustin AN, Chatrou MLL, Drozdov I. et al. Vascular smooth muscle cell calcification is mediated by regulated exosome secretion. Circ Res 2015; 116 (08) 1312-1323
• 74 Doherty TM, Asotra K, Fitzpatrick LA. et al. Calcification in atherosclerosis: bone biology and chronic inflammation at the arterial crossroads. Proc Natl Acad Sci U S A 2003; 100 (20) 11201-11206
• 75 Haraszti RA, Didiot M-C, Sapp E. et al. High-resolution proteomic and lipidomic analysis of exosomes and microvesicles from different cell sources. J Extracell Vesicles 2016; 5: 32570
• 76 Konkoth A, Saraswat R, Dubrou C. et al. Multifaceted role of extracellular vesicles in atherosclerosis. Atherosclerosis 2021; 319: 121-131
• 77 Krohn JB, Hutcheson JD, Martínez-Martínez E, Aikawa E. Extracellular vesicles in cardiovascular calcification: expanding current paradigms. J Physiol 2016; 594 (11) 2895-2903
• 78 Genetos DC, Wong A, Weber TJ, Karin NJ, Yellowley CE. Impaired osteoblast differentiation in annexin A2- and -A5-deficient cells. PLoS One 2014; 9 (09) e107482
• 79 Wuthier RE, Lipscomb GF. Matrix vesicles: structure, composition, formation and function in calcification. Front Biosci (Landmark Ed) 2011; 16 (08) 2812-2902
• 80 Chen NX, O'Neill KD, Chen X, Moe SM. Annexin-mediated matrix vesicle calcification in vascular smooth muscle cells. J Bone Miner Res 2008; 23 (11) 1798-1805
• 81 New SEP, Goettsch C, Aikawa M. et al. Macrophage-derived matrix vesicles: an alternative novel mechanism for microcalcification in atherosclerotic plaques. Circ Res 2013; 113 (01) 72-77
• 82 Boersma HH, Kietselaer BL, Stolk LML. et al. Past, present, and future of annexin A5: from protein discovery to clinical applications. J Nucl Med 2005; 46 (12) 2035-2050
• 83 De Saint-Hubert M, Bauwens M, Deckers N. et al. In vivo molecular imaging of apoptosis and necrosis in atherosclerotic plaques using microSPECT-CT and microPET-CT imaging. Mol Imaging Biol 2014; 16 (02) 246-254
• 84 Bozycki L, Mroczek J, Bessueille L. et al. Annexins A2, A6 and fetuin-A affect the process of mineralization in vesicles derived from human osteoblastic hFOB 1.19 and osteosarcoma Saos-2 cells. Int J Mol Sci 2021; 22 (08) 3993
• 85 Xiao X, Yang C, Qu SL. et al. S100 proteins in atherosclerosis. Clin Chim Acta 2020; 502: 293-304
• 86 Gonzalez LL, Garrie K, Turner MD. Role of S100 proteins in health and disease. Biochim Biophys Acta Mol Cell Res 2020; 1867 (06) 118677
• 87 McCormick MM, Rahimi F, Bobryshev YV. et al. S100A8 and S100A9 in human arterial wall. Implications for atherogenesis. J Biol Chem 2005; 280 (50) 41521-41529
• 88 Lau W, Devery JM, Geczy CL. A chemotactic S100 peptide enhances scavenger receptor and Mac-1 expression and cholesteryl ester accumulation in murine peritoneal macrophages in vivo. J Clin Invest 1995; 95 (05) 1957-1965
• 89 Hofmann Bowman MA, Gawdzik J, Bukhari U. et al. S100A12 in vascular smooth muscle accelerates vascular calcification in apolipoprotein E-null mice by activating an osteogenic gene regulatory program. Arterioscler Thromb Vasc Biol 2011; 31 (02) 337-344
• 90 Bakhshian Nik A, Hutcheson JD, Aikawa E. Extracellular vesicles as mediators of cardiovascular calcification. Front Cardiovasc Med 2017; 4: 78
• 91 Millán JL. The role of phosphatases in the initiation of skeletal mineralization. Calcif Tissue Int 2013; 93 (04) 299-306
• 92 Thakkar S, Sharma D, Kalia K, Tekade RK. Tumor microenvironment targeted nanotherapeutics for cancer therapy and diagnosis: a review. Acta Biomater 2020; 101: 43-68
• 93 Moe SM, Reslerova M, Ketteler M. et al. Role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease (CKD). Kidney Int 2005; 67 (06) 2295-2304
• 94 Jahnen-Dechent W, Heiss A, Schäfer C, Ketteler M. Fetuin-A regulation of calcified matrix metabolism. Circ Res 2011; 108 (12) 1494-1509
• 95 Dzhanaev R, Hasberg C, Gorgels A. et al. Application of the mineral-binding protein fetuin-A for the detection of calcified lesions. Theranostics 2023; 13 (02) 659-672
• 96 Jaminon AMG, Akbulut AC, Rapp N. et al. Development of the BioHybrid assay: combining primary human vascular smooth muscle cells and blood to measure vascular calcification propensity. Cells 2021; 10 (08) 2097
• 97 Emoto M, Mori K, Lee E. et al. Fetuin-A and atherosclerotic calcified plaque in patients with type 2 diabetes mellitus. Metabolism 2010; 59 (06) 873-878
• 98 Dorai H, Vukicevic S, Sampath TK. Bone morphogenetic protein-7 (osteogenic protein-1) inhibits smooth muscle cell proliferation and stimulates the expression of markers that are characteristic of SMC phenotype in vitro. J Cell Physiol 2000; 184 (01) 37-45
• 99 Mathew S, Davies M, Lund R, Saab G, Hruska KA. Function and effect of bone morphogenetic protein-7 in kidney bone and the bone-vascular links in chronic kidney disease. Eur J Clin Invest 2006; 36 (Suppl. 02) 43-50
• 100 Shanahan CM, Proudfoot D, Farzaneh-Far A, Weissberg PL. The role of Gla proteins in vascular calcification. Crit Rev Eukaryot Gene Expr 1998; 8 (3-4): 357-375
• 101 Kapustin AN, Schoppet M, Schurgers LJ. et al. Prothrombin loading of vascular smooth muscle cell-derived exosomes regulates coagulation and calcification. Arterioscler Thromb Vasc Biol 2017; 37 (03) e22-e32
• 102 Schurgers LJ, Teunissen KJF, Knapen MHJ. et al. Novel conformation-specific antibodies against matrix γ-carboxyglutamic acid (Gla) protein: undercarboxylated matrix Gla protein as marker for vascular calcification. Arterioscler Thromb Vasc Biol 2005; 25 (08) 1629-1633
• 103 Schurgers LJ, Spronk HMH, Skepper JN. et al. Post-translational modifications regulate matrix Gla protein function: importance for inhibition of vascular smooth muscle cell calcification. J Thromb Haemost 2007; 5 (12) 2503-2511
• 104 Cranenburg ECM, Vermeer C, Koos R. et al. The circulating inactive form of matrix Gla Protein (ucMGP) as a biomarker for cardiovascular calcification. J Vasc Res 2008; 45 (05) 427-436
• 105 Jaminon AMG, Dai L, Qureshi AR. et al. Matrix Gla protein is an independent predictor of both intimal and medial vascular calcification in chronic kidney disease. Sci Rep 2020; 10 (01) 6586
• 106 Levy RJ, Gundberg C, Scheinman R. The identification of the vitamin K-dependent bone protein osteocalcin as one of the gamma-carboxyglutamic acid containing proteins present in calcified atherosclerotic plaque and mineralized heart valves. Atherosclerosis 1983; 46 (01) 49-56
• 107 Yamanouchi D, Takei Y, Komori K. Balanced mineralization in the arterial system: possible role of osteoclastogenesis/osteoblastogenesis in abdominal aortic aneurysm and stenotic disease. Circ J 2012; 76 (12) 2732-2737
• 108 Abousaway O, Rakhshandehroo T, Van den Abbeele AD, Kircher MF, Rashidian M. Noninvasive Imaging of Cancer Immunotherapy. Nanotheranostics 2021; 5 (01) 90-112
• 109 Karakose S, Bal Z, Sezer S. The comparison of paricalcitol and calcitriol effects on pulse wave velocity, osteocalcin, and fetuin-A in chronic hemodialysis patients. Semin Dial 2024; 37 (02) 131-137