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• W2617605845 abstract "Intravascular imaging studies, initially using intravascular ultrasonography (IVUS) and more recently using optical coherence tomography (OCT) as well an noninvasive imaging using multidetector computed tomography (CT), have reported spotty calcification—small calcium deposits within an atherosclerotic plaque—to be a distinct morphologic finding of both plaque instability in patients with acute coronary syndrome (ACS) and future atheroma progression, even in patients with stable coronary artery disease. Ehara et al.1Ehara S. Kobayashi Y. Yoshiyama M. et al.Spotty calcification typifies the culprit plaque in patients with acute myocardial infarction: an intravascular ultrasound study.Circulation. 2004; 110: 3424-3429Crossref PubMed Scopus (539) Google Scholar first reported the relationship between spotty calcium (arc < 90° as assessed by IVUS) and clinical presentation in 61 patients with acute myocardial infarction, 70 patients with unstable angina, and 47 patients with stable angina. The frequency of spotty calcium was 51%, 40%, and 30%, respectively (P < 0.0001). These findings were supported by an IVUS study by van der Hoeven et al.2van der Hoeven B.L. Liem S.S. Oemrawsingh P.V. et al.Role of calcified spots detected by intravascular ultrasound in patients with ST-segment elevation acute myocardial infarction.Am J Cardiol. 2006; 98: 309-313Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar and a multidetector computed CT study by Motoyama et al.,3Motoyama S. Kondo T. Sarai M. et al.Multislice computed tomographic characteristics of coronary lesions in acute coronary syndromes.J Am Coll Cardiol. 2007; 50: 319-326Abstract Full Text Full Text PDF PubMed Scopus (796) Google Scholar and by 1, but not another, OCT study4Mizukoshi M. Kubo T. Takarada S. et al.Coronary superficial and spotty calcium deposits in culprit coronary lesions of acute coronary syndrome as determined by optical coherence tomography.Am J Cardiol. 2013; 112: 34-40Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 5Ong D.S. Lee J.S. Soeda T. et al.Coronary calcification and plaque vulnerability: an optical coherence tomographic study.Circ Cardiovasc Imaging. 2016; 9: 1Crossref Scopus (0) Google Scholar; by histopathologic findings (although the authors were careful to indicate that methodologies differed6Otsuka 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: 724-736Crossref PubMed Scopus (295) Google Scholar, 7Yahagi K. Joner M. Virmani R. The mystery of spotty calcification: can we solve it by optical coherence tomography?.Circ Cardiovasc Imaging. 2016; 9: 1Crossref Scopus (9) Google Scholar); and especially by Kataoka et al.8Kataoka Y. Wolski K. Uno K. et al.Spotty calcification as a marker of accelerated progression of coronary atherosclerosis: insights from serial intravascular ultrasound.J Am Coll Cardiol. 2012; 59: 1592-1597Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar who showed that in patients with stable coronary artery disease enrolled in 7 IVUS progression/regression studies, 922 lesions with spotty calcification had a greater percentage of atheroma volume at the time of enrollment (36.0% ± 7.6% vs 29.0% ± 8.5% in 425 lesions without calcium; P < 0.001) and a greater progression in percentage of atheroma volume at a mean follow-up of 650 days (+ 0.43% ± 0.07% vs + 0.02% ± 0.11%; P = 0.002). The studies were Reversal of Atherosclerosis With Aggressive Lipid Lowering (REVERSAL), Comparison of Amlodipine Versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT), Acyl: Cholesterol Acyltransferase Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE), A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID), Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by Cholesteryl Ester Transfer Protein Inhibition and High-Density Lipoprotein Elevation (ILLUSTRATE), Efficacy Study of Pioglitazone Compared to Glimepiride on Coronary Atherosclerotic Disease Progression in Subjects With Type 2 Diabetes Mellitus (PERISCOPE), and Effect of Rimonabant on Progression of Atherosclerosis in Patients With Abdominal Obesity and Coronary Artery Disease (STRADIVARIUS). The difference in progression was even greater after adjusting for low-density lipoprotein (LDL), high-density lipoprotein, statin drug use, and baseline percentage of atheroma volume (+ 0.68% ± 0.12% vs + 0.05% ± 0.17%; P = 0.002), and although intensive LDL and blood pressure–lowering therapy slowed disease progression, efficacy was attenuated in lesions with spotty calcification. There are 2 possible explanations for the importance of spotty calcium as a unique finding indicating plaque instability—explanations that are not mutually exclusive. First, spotty calcium can merely indicate the presence of unstable plaque without invoking any pathophysiological mechanism. In fact, spotty calcium may be a marker of previous plaque rupture and healing9Burke A.P. Weber D.K. Kolodgie F.D. et al.Pathophysiology of calcium deposition in coronary arteries.Herz. 2001; 26: 239-244Crossref PubMed Scopus (185) Google Scholar; multiple spotty calcifications are often seen in culprit lesions in patients with ACS,2van der Hoeven B.L. Liem S.S. Oemrawsingh P.V. et al.Role of calcified spots detected by intravascular ultrasound in patients with ST-segment elevation acute myocardial infarction.Am J Cardiol. 2006; 98: 309-313Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 10Fujii K. Carlier S.G. Mintz G.S. et al.Intravascular ultrasound study of patterns of calcium in ruptured coronary plaques.Am J Cardiol. 2005; 96: 352-357Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 11Kataoka Y. Puri R. Hammadah M. et al.Spotty calcification and plaque vulnerability in vivo: frequency-domain optical coherence tomography analysis.Cardiovasc Diagn Ther. 2014; 4: 460-469PubMed Google Scholar and the recurrent plaque rupture and healing cycle may be the major pathway to atherosclerotic disease progression.12Burke A.P. Kolodgie F.D. Farb A. et al.Healed plaque ruptures and sudden coronary death: evidence that subclinical rupture has a role in plaque progression.Circulation. 2001; 103: 934-940Crossref PubMed Scopus (733) Google Scholar Alternatively, spotty calcium can be instrumental and play an important role in the mechanism of plaque destabilization (more about this further on). Using IVUS in an in vitro study in which histologic examination was the gold standard, Pu et al.13Pu J. Mintz G.S. Biro S. et al.Insights into echo-attenuated plaques, echolucent plaques, and plaques with spotty calcification: novel findings from comparisons among intravascular ultrasound, near-infrared spectroscopy, and pathological histology in 2,294 human coronary artery segments.J Am Coll Cardiol. 2014; 63: 2220-2233Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar showed that 62.4% of spotty calcium–containing lesions were fibroatheromas with calcium deposits, with a specificity of 71.7% and a sensitivity of 69.4%.13Pu J. Mintz G.S. Biro S. et al.Insights into echo-attenuated plaques, echolucent plaques, and plaques with spotty calcification: novel findings from comparisons among intravascular ultrasound, near-infrared spectroscopy, and pathological histology in 2,294 human coronary artery segments.J Am Coll Cardiol. 2014; 63: 2220-2233Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar When classified by location, 72.6% of IVUS-detected superficial spotty calcifications (defined as closer to the lumen than to the adventitia) were seen in fibroatheromas with calcium deposits (45.3% late necrotic cores and 27.3% early necrotic cores), and superficial spotty calcifications tended to be more frequent in patients who died of cardiovascular causes. Conversely, 67.4% of IVUS-detected deep spotty calcifications were seen in fibrocalcific plaques without necrotic cores, and when present, deep fibroatheromas uncommonly contained large necrotic cores. IVUS spotty calcifications were also associated with more near-infrared, spectroscopy-derived, lipid-rich plaque—a finding that was supported in a clinical study by Madder et al.14Madder R. Wohns D. McNamara R. et al.TCT-266 frequency of spotty calcification among lipid-core plaques using combined intracoronary near-infrared spectroscopy and intravascular ultrasound [abstract].J Am Coll Cardiol. 2012; 60: B76Abstract Full Text Full Text PDF PubMed Google Scholar at Transcatheter Cardiovascular Therapeutics 2012. Rupture of an atheroma is due to increased mechanical stresses that exceed the tissue's peak circumferential stress at failure. As suggested by a series of micro-CT studies by the group of Cardoso and Weinbaum from the City University of New York,15Vengrenyuk 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: 14678-14683Crossref PubMed Scopus (412) Google Scholar, 16Vengrenyuk Y. Cardoso L. Weinbaum S. Micro-CT based analysis of a new paradigm for vulnerable plaque rupture: cellular microcalcifications in fibrous caps.Mol Cell Biomech. 2008; 5: 37-47PubMed Google Scholar, 17Rambhia S.H. Liang X. Xenos M. et al.Microcalcifications increase coronary vulnerable plaque rupture potential: a patient-based micro-CT fluid-structure interaction study.Ann Biomed Eng. 2012; 40: 1443-1454Crossref PubMed Scopus (47) Google Scholar, 18Maldonado N. Kelly-Arnold A. Vengrenyuk Y. 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-H628Crossref PubMed Scopus (166) Google Scholar, 19Kelly-Arnold A. Maldonado N. Laudier D. et al.Revised microcalcification hypothesis for fibrous cap rupture in human coronary arteries.Proc Natl Acad Sci U S A. 2013; 110: 10741-10746Crossref PubMed Scopus (218) Google Scholar, 20Cardoso L. Kelly-Arnold A. Maldonado N. Laudier D. Weinbaum S. Effect of tissue properties, shape and orientation of microcalcifications on vulnerable cap stability using different hyperelastic constitutive models.J Biomech. 2014; 47: 870-877Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar and also by Li et al,21Li Z.Y. Howarth S. U-King-Im J. Gillard J. Atheroma: is calcium important or not? A modelling study of stress within the atheromatous fibrous cap in relation to position and size of calcium deposits.Conf Proc IEEE Eng Med Biol Soc. 2005; 3: 2236-2239PubMed Google Scholar several factors, including the cap thickness, morphologic features, residual stresses, and tissue composition of the atheroma, affect the peak circumferential stress—but especially microcalcifications that are a common feature in human atheroma fibrous caps and that behave as local stress concentrators to surpass the ultimate stress threshold for fibrous cap tissue rupture depending on location, number, spacing, and alignment. Conversely, if the cap has no calcium, it needs to thin to approximately 30 μm to reach the rupture threshold, and calcification in the lipid pool does not increase fibrous cap stress when it is distant to the fibrous cap. In the current issue of the Canadian Journal of Cardiology, Zhan et al.22Zhan Y. Zhang Y. Hou J. Lin G. Yu B. Relation between superficial calcifications and plaque rupture: an optical coherence tomography study.Can J Cardiol. 2017; 33: 991-997Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar contribute to the concept that spotty calcium is part of the pathophysiology of plaque destabilization. They report on a select population of patients with ACS whose culprit lesions contain both lipid and spotty calcium. In this in vivo OCT study of 78 patients with ACS, lipid-rich culprit lesions having small superficial calcifications were more common in patients presenting with ST-elevation or non–ST-elevation myocardial infarction compared with unstable angina, and small superficial calcifications within 63 μm of the intimal surface were more likely to be associated with plaque rupture (n = 45). These findings support the previous “mechanistic” studies noted earlier. However, it is worth exploring the relationship between the exquisitely detailed in vitro micro-CT observations and those by OCT in vivo, including the report by Zhan et al.22Zhan Y. Zhang Y. Hou J. Lin G. Yu B. Relation between superficial calcifications and plaque rupture: an optical coherence tomography study.Can J Cardiol. 2017; 33: 991-997Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Although OCT has the highest resolution of any in vivo intravascular imaging device, it does not have the resolution of micro-CT that is needed to detect and differentiate among clusters of microcalcifications as small as 5 μm. This is especially true of stress-concentrating microcalcifications in a fibrous cap whose impact depends on number and proximity and spacing, aspect ratio, and alignment—especially when closely spaced and aligned along the tensile axis of the cap. The reported resolution of OCT is 15-20 μm axially (along the light beam) and 20-40 μm laterally (perpendicular to the light beam). First, this is a calculated resolution and not measured conventionally as the minimum distance that can be resolved between 2 adjacent objects. Therefore, OCT may not be able to detect microcalcifications and, especially, provide the necessary detail associated with clusters of microcalcifications. Second, and even more critically, if microcalcifications are distributed along the tensile axis of the fibrous cap, resolution is much more dependent on the mechanical properties of the system, including the rotation of the fiber (and its uniformity), the spacing of the individual cross-sections (during pullback), and the movement of the fiber within the coronary artery during the cardiac cycle.23van Ditzhuijzen N.S. Karanasos A. Bruining N. et al.The impact of Fourier-Domain optical coherence tomography catheter induced motion artefacts on quantitative measurements of a PLLA-based bioresorbable scaffold.Int J Cardiovasc Imaging. 2014; 30: 1013-1026Crossref PubMed Scopus (15) Google Scholar As a result, it may be necessary to wait for developments such as micro-OCT with 1-μm axial resolution24Featured Lecture: Innovations in OCT Technology: Current Developments and Future Trends. Available at: https://www.tctmd.com/slide/featured-lecture-innovations-oct-technology-current-developments-and-future-trends. Accessed June 21, 2017.Google Scholar before it will be possible to extend the in vitro modeling observations to what can be assessed in vivo and to determine whether spotty calcium is merely a marker of vulnerable plaque or whether small calcium deposits in the fibrous cap and close to the luminal surface may predict plaque rupture as suggested by Zhan et al.22Zhan Y. Zhang Y. Hou J. Lin G. Yu B. Relation between superficial calcifications and plaque rupture: an optical coherence tomography study.Can J Cardiol. 2017; 33: 991-997Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar in the current issue of the Canadian Journal of Cardiology. Dr Mintz is a consultant or receives honoraria from BostonScientific, Volcano, ACIST, and Infraredx. The Cardiovascular Research Foundation received research, grant, or fellowship support from BostonScientific, Volcano, and St Jude Medical." @default.
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• W2617605845 date "2017-08-01" @default.
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• W2617605845 title "The Curious Incident of Spotty Calcium in Unstable Atherosclerotic Plaque" @default.
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