Predictors for target lesion microcalcifications in patients with stable coronary artery disease: an optical coherence tomography study
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.
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.
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.
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.
KeywordsMicrocalcification Optical coherence tomography Plaque morphology Plaque vulnerability
- 18F-NaF 18
Acute coronary syndrome
Coronary artery disease
Fibrous cap thickness
Fractional flow reserve
Optical coherence tomography
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 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
- 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
- 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.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.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
- 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
- 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.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.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.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.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
- 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
- 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
- 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.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.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.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
- 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
- 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.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
- 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
- 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
- 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.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