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Clinical Research in Cardiology

, Volume 107, Issue 9, pp 763–771 | Cite as

Predictors for target lesion microcalcifications in patients with stable coronary artery disease: an optical coherence tomography study

  • Sebastian Reith
  • Andrea Milzi
  • Rosalia Dettori
  • Nikolaus Marx
  • Mathias Burgmaier
Original Paper

Abstract

Background

The minimal fibrous cap thickness overlying the necrotic lipid core as well as the presence of macrophages are established characteristics of coronary plaque vulnerability. Recently, the presence of microcalcifications has emerged as a novel feature of vulnerable lesions. However, clinical and plaque morphological predictors of microcalcifications are unknown.

Methods

In patients with stable coronary artery disease, analysis of plaque morphology (n = 112) was performed using optical coherence tomography prior to coronary intervention to assess predictors of microcalcifications.

Results

Microcalcifications were present in 21/112 (18.7%) lesions. Segments with microcalcifications showed a higher total number of calcifications per lesion (6.7 ± 3.0 vs. 3.2 ± 2.5, p < 0.001), a lower percent area stenosis (70.9 ± 11.1 vs. 76.2 ± 9.7%, p = 0.028), and a higher frequency of macrophage infiltration (66.7 vs. 37.4%, p = 0.014). In lesions with vs. without microcalcifications, macrophage infiltration was characterized by a wider macrophage angle (31.1° ± 34.4° vs. 13.7° ± 20.6°, p = 0.003), a higher macrophage index (105.6 ± 269.0 vs. 31.6 ± 66.5° mm, p = 0.020), and an increased frequency of calcium–macrophage co-localization (47.6 vs. 15.6%, p = 0.001). In multivariable logistic regression analysis, the total number of calcifications per lesion (OR 1.53, 95% CI 1.23–1.91, p < 0.001), average macrophage angle (OR 1.28 for 10°-variation, 95% CI 1.03–1.60, p = 0.024), and percent area stenosis (OR 0.59 for 10% increase, 95% CI 0.34–1.04, p = 0.070) were independent predictors for the presence of microcalcifications, whereas the latter did not reach statistical significance.

Conclusion

Microcalcifications are related to a less advanced stenosis severity and to extensive plaque inflammation, but not to clinical parameters. Our data may add to the understanding and role of microcalcifications in coronary artery lesions.

Keywords

Microcalcification Optical coherence tomography Plaque morphology Plaque vulnerability 

Abbreviations

18F-NaF 18

Sodium fluoride

ACS

Acute coronary syndrome

CAD

Coronary artery disease

CT

Computed tomography

FCT

Fibrous cap thickness

FFR

Fractional flow reserve

IVUS

Intravascular ultrasound

OCT

Optical coherence tomography

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Yamamoto H, Imazu M, Hattori Y, Tadehara F, Yamakido M, Nakanishi T et al (1998) Predicting angiographic narrowing> or = 50% in diameter in each of the three major arteries by amounts of calcium detected by electron beam computed tomographic scanning in patients with chest pain. Am J Cardiol 81(6):778–780CrossRefPubMedGoogle Scholar
  2. 2.
    Frink RJ, Achor RW, Brown AL, Kincaid OW, Brandenburg RO (1970) Significance of calcification of the coronary arteries. Am J Cardiol 26(3):241–247CrossRefPubMedGoogle Scholar
  3. 3.
    Tanenbaum SR, Kondos GT, Veselik KE, Prendergast MR, Brundage BH, Chomka EV (1989) Detection of calcific deposits in coronary arteries by ultrafast computed tomography and correlation with angiography. Am J Cardiol 63(12):870–872CrossRefPubMedGoogle Scholar
  4. 4.
    Arad Y, Spadaro LA, Goodman K, Newstein D, Guerci AD (2000) Prediction of coronary events with electron beam computed tomography. J Am Coll Cardiol 36(4):1253–1260CrossRefPubMedGoogle Scholar
  5. 5.
    Vengrenyuk Y, Carlier S, Xanthos S, Cardoso L, Ganatos P, Virmani R et al (2006) A hypothesis for vulnerable plaque rupture due to stress-induced debonding around cellular microcalcifications in thin fibrous caps. Proc Natl Acad Sci USA 103(40):14678–14683.  https://doi.org/10.1073/pnas.0606310103 CrossRefPubMedGoogle Scholar
  6. 6.
    Sinclair H, Bourantas C, Bagnall A, Mintz GS, Kunadian V (2015) OCT for the identification of vulnerable plaque in acute coronary syndrome. JACC Cardiovasc Imaging 8(2):198–209.  https://doi.org/10.1016/j.jcmg.2014.12.005 CrossRefPubMedGoogle Scholar
  7. 7.
    Burgmaier M, Hellmich M, Marx N, Reith S (2014) A score to quantify coronary plaque vulnerability in high-risk patients with type 2 diabetes: an optical coherence tomography study. Cardiovasc Diabetol 13:117.  https://doi.org/10.1186/s12933-014-0117-8 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Ehara S, Kobayashi Y, Yoshiyama M, Shimada K, Shimada Y, Fukuda D et al (2004) Spotty calcification typifies the culprit plaque in patients with acute myocardial infarction: an intravascular ultrasound study. Circulation 110(22):3424–3429.  https://doi.org/10.1161/01.CIR.0000148131.41425.E9 CrossRefPubMedGoogle Scholar
  9. 9.
    Mizukoshi M, Kubo T, Takarada S, Kitabata H, Ino Y, Tanimoto T et al (2013) Coronary superficial and spotty calcium deposits in culprit coronary lesions of acute coronary syndrome as determined by optical coherence tomography. Am J Cardiol 112(1):34–40.  https://doi.org/10.1016/j.amjcard.2013.02.048 CrossRefPubMedGoogle Scholar
  10. 10.
    Sakaguchi M, Hasegawa T, Ehara S, Matsumoto K, Mizutani K, Iguchi T et al (2016) New insights into spotty calcification and plaque rupture in acute coronary syndrome: an optical coherence tomography study. Heart Vessels 31(12):1915–1922.  https://doi.org/10.1007/s00380-016-0820-3 CrossRefPubMedGoogle Scholar
  11. 11.
    Ong DS, Lee JS, Soeda T, Higuma T, Minami Y, Wang Z et al. (2016). Coronary calcification and plaque vulnerability: an optical coherence tomographic study. Circ Cardiovasc Imaging.  https://doi.org/10.1161/CIRCIMAGING.115.003929 CrossRefPubMedGoogle Scholar
  12. 12.
    Kataoka Y, Puri R, Hammadah M, Duggal B, Uno K, Kapadia SR et al (2014) Spotty calcification and plaque vulnerability in vivo: frequency-domain optical coherence tomography analysis. Cardiovasc Diagn Ther 4(6):460–469.  https://doi.org/10.3978/j.issn.2223-3652.2014.11.06 PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Kelly-Arnold A, Maldonado N, Laudier D, Aikawa E, Cardoso L, Weinbaum S (2013) Revised microcalcification hypothesis for fibrous cap rupture in human coronary arteries. Proc Natl Acad Sci USA 110(26):10741–10746.  https://doi.org/10.1073/pnas.1308814110 CrossRefPubMedGoogle Scholar
  14. 14.
    Cardoso L, Kelly-Arnold A, Maldonado N, Laudier D, Weinbaum S (2014) Effect of tissue properties, shape and orientation of microcalcifications on vulnerable cap stability using different hyperelastic constitutive models. J Biomech 47(4):870–877.  https://doi.org/10.1016/j.jbiomech.2014.01.010 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Maldonado N, Kelly-Arnold A, Vengrenyuk Y, Laudier D, Fallon JT, Virmani R et al (2012) A mechanistic analysis of the role of microcalcifications in atherosclerotic plaque stability: potential implications for plaque rupture. Am J Physiol Heart Circ Physiol 303(5):H619–H628.  https://doi.org/10.1152/ajpheart.00036.2012 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Blachutzik F, Boeder N, Wiebe J, Mattesini A, Dörr O, Most A et al (2017) Post-dilatation after implantation of bioresorbable everolimus- and novolimus-eluting scaffolds: an observational optical coherence tomography study of acute mechanical effects. Clin Res Cardiol 106(4):271–279.  https://doi.org/10.1007/s00392-016-1048-z CrossRefPubMedGoogle Scholar
  17. 17.
    Nijhoff F, Stella PR, Troost MS, Belkacemi A, Nathoe HM, Voskuil M et al (2016) Comparative assessment of the antirestenotic efficacy of two paclitaxel drug-eluting balloons with different coatings in the treatment of in-stent restenosis. Clin Res Cardiol 105(5):401–411.  https://doi.org/10.1007/s00392-015-0934-0 CrossRefPubMedGoogle Scholar
  18. 18.
    Poerner TC, Duderstadt C, Goebel B, Kretzschmar D, Figulla HR, Otto S (2017) Fractional flow reserve-guided coronary angioplasty using paclitaxel-coated balloons without stent implantation: feasibility, safety and 6-month results by angiography and optical coherence tomography. Clin Res Cardiol 106(1):18–27.  https://doi.org/10.1007/s00392-016-1019-4 CrossRefPubMedGoogle Scholar
  19. 19.
    Florian A, Fischer D, Yilmaz A (2016) The “spastic” coronary plaque: dynamic deformation of an atheromatous plaque demonstrated by optical coherence tomography. Clin Res Cardiol 105(7):636–638.  https://doi.org/10.1007/s00392-016-0976-y CrossRefPubMedGoogle Scholar
  20. 20.
    Reith S, Battermann S, Hellmich M, Marx N, Burgmaier M (2015) Correlation between optical coherence tomography-derived intraluminal parameters and fractional flow reserve measurements in intermediate grade coronary lesions: a comparison between diabetic and non-diabetic patients. Clin Res Cardiol 104(1):59–70.  https://doi.org/10.1007/s00392-014-0759-2 CrossRefPubMedGoogle Scholar
  21. 21.
    Kume T, Okura H, Kawamoto T, Yamada R, Miyamoto Y, Hayashida A et al (2011) Assessment of the coronary calcification by optical coherence tomography. Eurointervention 6(6):768–772.  https://doi.org/10.4244/EIJV6I6A130 CrossRefPubMedGoogle Scholar
  22. 22.
    Krishnamoorthy P, Vengrenyuk Y, Ueda H, Yoshimura T, Pena J, Motoyama S et al (2017) Three-dimensional volumetric assessment of coronary artery calcification in patients with stable coronary artery disease by OCT. Eurointervention 13(3):312–319.  https://doi.org/10.4244/EIJ-D-16-00139 CrossRefPubMedGoogle Scholar
  23. 23.
    Wang X, Matsumura M, Mintz GS, Lee T, Zhang W, Cao Y et al (2017) In vivo calcium detection by comparing optical coherence tomography, intravascular ultrasound, and angiography. JACC Cardiovasc Imaging 10(8):869–879.  https://doi.org/10.1016/j.jcmg.2017.05.014 CrossRefPubMedGoogle Scholar
  24. 24.
    van der Giessen AG, Gijsen FJ, Wentzel JJ, Jairam PM, van Walsum T, Neefjes LA et al (2011) Small coronary calcifications are not detectable by 64-slice contrast enhanced computed tomography. Int J Cardiovasc Imaging 27(1):143–152.  https://doi.org/10.1007/s10554-010-9662-8 CrossRefPubMedGoogle Scholar
  25. 25.
    Milzi A, Burgmaier M, Burgmaier K, Hellmich M, Marx N, Reith S (2017) Type 2 diabetes mellitus is associated with a lower fibrous cap thickness but has no impact on calcification morphology—an intracoronary optical coherence tomography study. Cardiovasc Diabetol 16:152.  https://doi.org/10.1186/s12933-017-0635-2 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Reith S, Battermann S, Hellmich M, Marx N, Burgmaier M (2014) Impact of type 2 diabetes mellitus and glucose control on fractional flow reserve measurements in intermediate grade coronary lesions. Clin Res Cardiol 103(3):191–201.  https://doi.org/10.1007/s00392-013-0633-7 CrossRefPubMedGoogle Scholar
  27. 27.
    Tearney GJ, Regar E, Akasaka T, Adriaenssens T, Barlis P, Bezerra HG et al (2012) Consensus standards for acquisition, measurement, and reporting of intravascular optical coherence tomography studies: a report from the international working group for intravascular optical coherence tomography standardization and validation. J Am Coll Cardiol 59(12):1058–1072.  https://doi.org/10.1016/j.jacc.2011.09.079 CrossRefPubMedGoogle Scholar
  28. 28.
    Criqui MH, Denenberg JO, Ix JH, McClelland RL, Wassel CL, Rifkin DE et al (2014) Calcium density of coronary artery plaque and risk of incident cardiovascular events. JAMA 311(3):271–278.  https://doi.org/10.1001/jama.2013.282535 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Criqui MH, Knox JB, Denenberg JO, Forbang NI, McClelland RL, Novotny TE et al (2017) Coronary artery calcium volume and density: potential interactions and overall predictive value: the multi-ethnic study of atherosclerosis. JACC Cardiovasc Imaging 10(8):845–854.  https://doi.org/10.1016/j.jcmg.2017.04.018 CrossRefPubMedGoogle Scholar
  30. 30.
    Maldonado N, Kelly-Arnold A, Cardoso L, Weinbaum S (2013) The explosive growth of small voids in vulnerable cap rupture; cavitation and interfacial debonding. J Biomech 46(2):396–401.  https://doi.org/10.1016/j.jbiomech.2012.10.040 CrossRefPubMedGoogle Scholar
  31. 31.
    Hsu JJ, Lim J, Tintut Y, Demer LL (2016) Cell-matrix mechanics and pattern formation in inflammatory cardiovascular calcification. Heart 102(21):1710–1715.  https://doi.org/10.1136/heartjnl-2016-309667 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    New SE, Aikawa E (2011) Cardiovascular calcification: an inflammatory disease. Circ J 75(6):1305–1313CrossRefPubMedGoogle Scholar
  33. 33.
    Nadra I, Mason JC, Philippidis P, Florey O, Smythe CDW, McCarthy GM et al (2005) Proinflammatory activation of macrophages by basic calcium phosphate crystals via protein kinase C and map kinase pathways. Circ Res 96:1248–1256.  https://doi.org/10.1161/01.RES.0000171451.88616.c2 CrossRefPubMedGoogle Scholar
  34. 34.
    New SE, Goettsch C, Aikawa M, Marchini JF, Shibasaki M, Yabusaki K et al (2013) Macrophage-derived matrix vesicles: an alternative novel mechanism for microcalcification in atherosclerotic plaques. Circ Res 113(1):72–77.  https://doi.org/10.1161/CIRCRESAHA.113.301036 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    New SE, Aikawa E (2013) Role of extracellular vesicles in de novo mineralization: an additional novel mechanism of cardiovascular calcification. Arterioscler Thromb Vasc Biol 33(8):1753–1758.  https://doi.org/10.1161/ATVBAHA.112.300128 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Ikeda K, Souma Y, Akakabe Y, Kitamura Y, Matsuo K, Shimoda Y et al (2012) Macrophages play a unique role in the plaque calcification by enhancing the osteogenic signals exerted by vascular smooth muscle cells. Biochem Biophys Res Commun 425(1):39–44.  https://doi.org/10.1016/j.bbrc.2012.07.045 CrossRefPubMedGoogle Scholar
  37. 37.
    Liu H, Yuan L, Xu S, Wang K (2007) Endothelial cell and macrophage regulation of vascular smooth muscle cell calcification modulated by cholestane-3beta, 5alpha, 6beta-triol. Cell Biol Int 31(9):900–907.  https://doi.org/10.1016/j.cellbi.2007.02.009 CrossRefPubMedGoogle Scholar
  38. 38.
    Shioi A, Katagi M, Okuno Y, Mori K, Jono S, Koyama H et al (2002) Induction of bone-type alkaline phosphatase in human vascular smooth muscle cells: roles of tumor necrosis factor-alpha and oncostatin M derived from macrophages. Circ Res 91(1):9–16CrossRefPubMedGoogle Scholar
  39. 39.
    Derlin T, Richter U, Bannas P, Begemann P, Buchert R, Mester J et al (2010) Feasibility of 18F-sodium fluoride PET/CT for imaging of atherosclerotic plaque. J Nucl Med 51(6):862–865.  https://doi.org/10.2967/jnumed.110.076471 CrossRefPubMedGoogle Scholar
  40. 40.
    Derlin T, Tóth Z, Papp L, Wisotzki C, Apostolova I, Habermann CR et al (2011) Correlation of inflammation assessed by 18F-FDG PET, active mineral deposition assessed by 18F-fluoride PET, and vascular calcification in atherosclerotic plaque: a dual-tracer PET/CT study. J Nucl Med 52(7):1020–1027.  https://doi.org/10.2967/jnumed.111.087452 CrossRefPubMedGoogle Scholar
  41. 41.
    Dweck MR, Chow MW, Joshi NV, Williams MC, Jones C, Fletcher AM et al (2012) Coronary arterial 18F-sodium fluoride uptake: a novel marker of plaque biology. J Am Coll Cardiol 59(17):1539–1548.  https://doi.org/10.1016/j.jacc.2011.12.037 CrossRefPubMedGoogle Scholar
  42. 42.
    Joshi NV, Vesey AT, Williams MC, Shah AS, Calvert PA, Craighead FH et al (2014) 18F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: a prospective clinical trial. Lancet 383(9918):705–713.  https://doi.org/10.1016/S0140-6736(13)61754-7 CrossRefPubMedGoogle Scholar
  43. 43.
    Chatrou ML, Cleutjens JP, van der Vusse GJ, Roijers RB, Mutsaers PH, Schurgers LJ (2015) Intra-section analysis of human coronary arteries reveals a potential role for micro-calcifications in macrophage recruitment in the early stage of atherosclerosis. PLoS One 10(11):e0142335.  https://doi.org/10.1371/journal.pone.0142335 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Abedin M, Tintut Y, Demer LL (2004) Vascular calcification: mechanisms and clinical ramifications. Arterioscler Thromb Vasc Biol 24(7):1161–1170CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Sebastian Reith
    • 1
  • Andrea Milzi
    • 1
  • Rosalia Dettori
    • 1
  • Nikolaus Marx
    • 1
  • Mathias Burgmaier
    • 1
  1. 1.Department of Cardiology, Medical Clinic IUniversity Hospital of the RWTH AachenAachenGermany

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