Advertisement

Calcium deposition within coronary atherosclerotic lesion: Implications for plaque stability

      Highlights

      • Calcification appears as microcalcifications and calcifications become larger as plaques progress.
      • Pathologic studies show sheet calcification is highly prevalent in stable plaques.
      • Microcalcifications, punctate and fragmented calcified areas are more frequent in unstable lesions.
      • Fibrocalcific plaque has the highest proportion of histological calcification, followed by healed plaque rupture.

      Abstract

      Atherosclerotic lesion progression is associated with intimal calcification. The earliest lesion that shows calcification is pathologic intimal thickening in which calcifications appear as microcalcifications that vary in size from <0.5 to 15 μm. The calcifications become larger as plaques progress, becoming punctate (>15 μm to 1 mm in diameter), fragmented (>1 mm), and eventually sheet-like calcification (>3 mm). When stratified by plaque type, maximum calcifications are observed in fibrocalcific plaques, followed by healed plaque ruptures. Lesions of acute thrombi, i.e., plaque rupture and erosions, which are the most frequent causes of acute coronary syndromes, show much less calcification than stable fibrocalcific plaques. Conversely, a calcified nodule, the least common lesion of acute thrombosis, occurs in highly calcified lesions. Pro-inflammatory cytokines observed in unstable plaques may provoke an early phase of osteogenic differentiation of smooth muscle cells (SMCs), a release of calcifying extracellular matrix vesicles, and/or induce apoptosis of macrophages and SMCs, which also calcify. Recent pathologic and imaging based studies indicate that lesions with dense calcifications are more likely to be stable plaques (fibrocalcific plaques), while micro, punctate, or fragmented calcifications are associated with either early stage plaques or unstable lesions (plaque rupture or erosion). Clinical non-invasive computed tomography (CT) studies show that the greater the calcium score, the higher the likelihood of patients developing future acute coronary events. This appears contradictory with the findings from pathologic autopsy studies. However, CT analysis of calcium subtypes is limited by resolution and blooming artifacts. Thus, areas of heavy calcification may not be the cause of future events as pathologic studies suggest. Rather, calcium may be an overall marker for the extent of disease. These types of discrepancies can perhaps be resolved by invasive or non-invasive high resolution imaging studies carried out at intervals in patients who present with acute coronary syndromes versus stable angina patients. Coronary calcium burden is greater in stable plaques than unstable plaques and there is a negative correlation between necrotic core area and area of calcification. Recent clinical studies have demonstrated that statins can reduce plaque burden by demonstrating a reduction in percent and total atheroma volume. However, calcification volume increases. In summary, pathologic studies show that sheet calcification is highly prevalent in stable plaques, while microcalcifications, punctate, and fragmented calcifications are more frequent in unstable lesions. Both pathologic and detailed analysis of imaging studies in living patients can resolve some of the controversies in our understanding of coronary calcification.

      Keywords

      Abbreviations:

      AIT (adaptive intimal thickening), AMI (acute myocardial infarction), CKD (chronic kidney disease), CT (computed tomography), CTA (cardiac computed tomography angiography), DM (diabetes mellitus), HRP (healed plaque rupture), IVUS (intravascular ultrasound), LP (lipid pool), NC (necrotic core), PIT (pathologic intimal thickening), SMC (smooth muscle cell), TCFA (thin-cap fibroatheroma)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Demer L.L.
        • Tintut Y.
        Inflammatory, metabolic, and genetic mechanisms of vascular calcification.
        Arterioscler. Thromb. Vasc. Biol. 2014; 34: 715-723
        • Mori H.
        • Torii S.
        • Kutyna M.
        • Sakamoto A.
        • Finn A.V.
        • Virmani R.
        Coronary artery calcification and its progression: what does it really mean?.
        JACC Cardiovasc. Imag. 2018; 11: 127-142
        • Qiao J.H.
        • Mertens R.B.
        • Fishbein M.C.
        • Geller S.A.
        Cartilaginous metaplasia in calcified diabetic peripheral vascular disease: morphologic evidence of enchondral ossification.
        Hum. Pathol. 2003; 34: 402-407
        • Nakahara T.
        • Dweck M.R.
        • Narula N.
        • Pisapia D.
        • Narula J.
        • Strauss H.W.
        Coronary artery calcification: from mechanism to molecular imaging.
        JACC Cardiovasc. Imag. 2017; 10: 582-593
        • Otsuka 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: 724-736
        • Hutcheson J.D.
        • Goettsch C.
        • Bertazzo S.
        • et al.
        Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques.
        Nat. Mater. 2016; 15: 335-343
        • Lomashvili K.A.
        • Cobbs S.
        • Hennigar R.A.
        • Hardcastle K.I.
        • O'Neill W.C.
        Phosphate-induced vascular calcification: role of pyrophosphate and osteopontin.
        J. Am. Soc. Nephrol. : JASN. 2004; 15: 1392-1401
        • Pugliese G.
        • Iacobini C.
        • Blasetti Fantauzzi C.
        • Menini S.
        The dark and bright side of atherosclerotic calcification.
        Atherosclerosis. 2015; 238: 220-230
        • Ikari Y.
        • McManus B.M.
        • Kenyon J.
        • Schwartz S.M.
        Neonatal intima formation in the human coronary artery.
        Arterioscler. Thromb. Vasc. Biol. 1999; 19: 2036-2040
        • Schaefer H.E.
        The role of macrophages in atherosclerosis.
        Haematol. Blood Transfus. 1981; 27: 137-142
        • Hoff H.F.
        • Bradley W.A.
        • Heideman C.L.
        • Gaubatz J.W.
        • Karagas M.D.
        • Gotto Jr., A.M.
        Characterization of low density lipoprotein-like particle in the human aorta from grossly normal and atherosclerotic regions.
        Biochim. Biophys. Acta. 1979; 573: 361-374
        • Nakashima Y.
        • Fujii H.
        • Sumiyoshi S.
        • Wight T.N.
        • Sueishi K.
        Early human atherosclerosis: accumulation of lipid and proteoglycans in intimal thickenings followed by macrophage infiltration.
        Arterioscler. Thromb. Vasc. Biol. 2007; 27: 1159-1165
        • Nakashima Y.
        • Wight T.N.
        • Sueishi K.
        Early atherosclerosis in humans: role of diffuse intimal thickening and extracellular matrix proteoglycans.
        Cardiovasc. Res. 2008; 79: 14-23
        • Tabas I.
        Cholesterol and phospholipid metabolism in macrophages.
        Biochim. Biophys. Acta. 2000; 1529: 164-174
        • Virmani R.
        • Kolodgie F.D.
        • Burke A.P.
        • Farb A.
        • Schwartz S.M.
        Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions.
        Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1262-1275
        • Burke A.P.
        • Farb A.
        • Malcom G.T.
        • Liang Y.H.
        • Smialek J.
        • Virmani R.
        Coronary risk factors and plaque morphology in men with coronary disease who died suddenly.
        N. Engl. J. Med. 1997; 336: 1276-1282
        • Kolodgie F.D.
        • Narula J.
        • Burke A.P.
        • et al.
        Localization of apoptotic macrophages at the site of plaque rupture in sudden coronary death.
        Am. J. Pathol. 2000; 157: 1259-1268
        • Gijsen F.J.
        • Wentzel J.J.
        • Thury A.
        • et al.
        Strain distribution over plaques in human coronary arteries relates to shear stress.
        Am. J. Physiol. Heart Circ. Physiol. 2008; 295: H1608-H1614
        • Sukhova G.K.
        • Schonbeck U.
        • Rabkin E.
        • et al.
        Evidence for increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous plaques.
        Circulation. 1999; 99: 2503-2509
        • Vengrenyuk 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: 14678-14683
        • 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
        • Maldonado 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-H628
        • Cardoso 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: 870-877
        • Cheng G.C.
        • Loree H.M.
        • Kamm R.D.
        • Fishbein M.C.
        • Lee R.T.
        Distribution of circumferential stress in ruptured and stable atherosclerotic lesions. A structural analysis with histopathological correlation.
        Circulation. 1993; 87: 1179-1187
        • Cilla M.
        • Pena E.
        • Martinez M.A.
        3D computational parametric analysis of eccentric atheroma plaque: influence of axial and circumferential residual stresses.
        Biomech. Model. Mechanobiol. 2012; 11: 1001-1013
        • Ruiz J.L.
        • Hutcheson J.D.
        • Aikawa E.
        Cardiovascular calcification: current controversies and novel concepts.
        Cardiovasc. Pathol. : Off. J. Soc. Cardiovasc. Pathol. 2015; 24: 207-212
        • Farb A.
        • Burke A.P.
        • Tang A.L.
        • et al.
        Coronary plaque erosion without rupture into a lipid core. A frequent cause of coronary thrombosis in sudden coronary death.
        Circulation. 1996; 93: 1354-1363
        • Kolodgie F.D.
        • Burke A.P.
        • Farb A.
        • et al.
        Differential accumulation of proteoglycans and hyaluronan in culprit lesions: insights into plaque erosion.
        Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1642-1648
        • Yahagi K.
        • Kolodgie F.D.
        • Otsuka F.
        • et al.
        Pathophysiology of native coronary, vein graft, and in-stent atherosclerosis.
        Nat. Rev. Cardiol. 2016; 13: 79-98
        • Mann J.
        • Davies M.J.
        Mechanisms of progression in native coronary artery disease: role of healed plaque disruption.
        Heart (British Cardiac Society). 1999; 82: 265-268
        • Kragel A.H.
        • Reddy S.G.
        • Wittes J.T.
        • Roberts W.C.
        Morphometric analysis of the composition of atherosclerotic plaques in the four major epicardial coronary arteries in acute myocardial infarction and in sudden coronary death.
        Circulation. 1989; 80: 1747-1756
        • Kockx M.M.
        • De Meyer G.R.
        • Muhring J.
        • Jacob W.
        • Bult H.
        • Herman A.G.
        Apoptosis and related proteins in different stages of human atherosclerotic plaques.
        Circulation. 1998; 97: 2307-2315
        • Goettsch C.
        • Hutcheson J.D.
        • Aikawa M.
        • et al.
        Sortilin mediates vascular calcification via its recruitment into extracellular vesicles.
        J. Clin. Invest. 2016; 126: 1323-1336
        • Jansen F.
        • Xiang X.
        • Werner N.
        Role and function of extracellular vesicles in calcific aortic valve disease.
        Eur. Heart J. 2017; 38: 2714-2716
        • Torii S.
        • Mustapha J.A.
        • Narula J.
        • et al.
        Histopathologic characterization of peripheral arteries in subjects with abundant risk factors: correlating imaging with pathology.
        JACC Cardiovasc. Imag. 2019; 12: 1501-1513
        • Sugiyama T.
        • Yamamoto E.
        • Fracassi F.
        • et al.
        Calcified plaques in patients with acute coronary syndromes.
        JACC Cardiovasc. Interv. 2019; 12: 531-540
        • Lee T.
        • Mintz G.S.
        • Matsumura M.
        • et al.
        Prevalence, predictors, and clinical presentation of a calcified nodule as assessed by optical coherence tomography.
        JACC Cardiovasc. Imag. 2017; 10: 883-891
        • Jinnouchi H.
        • Torii S.
        • Kutyna M.
        • et al.
        Micro-computed tomography demonstration of multiple plaque ruptures in a single individual presenting with sudden cardiac death.
        Circ. Cardiovasc. Imag. 2018; 11e008331
        • Sakamoto A.
        • Virmani R.
        • Finn A.V.
        Coronary artery calcification: recent developments in our understanding of its pathologic and clinical significance.
        Curr. Opin. Cardiol. 2018; 33: 645-652
        • Wilson P.W.
        • D'Agostino R.B.
        • Levy D.
        • Belanger A.M.
        • Silbershatz H.
        • Kannel W.B.
        Prediction of coronary heart disease using risk factor categories.
        Circulation. 1998; 97: 1837-1847
        • Neumann F.J.
        • Sousa-Uva M.
        • Ahlsson A.
        • et al.
        ESC/EACTS Guidelines on myocardial revascularization.
        Eur. Heart J. 2018; 2019: 87-165
        • Motoyama S.
        • Ito H.
        • Sarai M.
        • et al.
        Plaque characterization by coronary computed tomography angiography and the likelihood of acute coronary events in mid-term follow-up.
        J. Am. Coll. Cardiol. 2015; 66: 337-346
        • Joshi N.V.
        • Vesey A.T.
        • Williams M.C.
        • et al.
        18F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: a prospective clinical trial.
        Lancet (London, England). 2014; 383: 705-713
        • Ehara 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: 3424-3429
        • Mizukoshi 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: 34-40
        • Kataoka 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: 460-469
        • Ong D.S.
        • Lee J.S.
        • Soeda T.
        • et al.
        Coronary calcification and plaque vulnerability: an optical coherence tomographic study.
        Circ. Cardiovasc. Imag. 2016; 9
        • Shaw L.J.
        • Narula J.
        • Chandrashekhar Y.
        The never-ending story on coronary calcium: is it predictive, punitive, or protective?.
        J. Am. Coll. Cardiol. 2015; 65: 1283-1285
        • Lee S.E.
        • Chang H.J.
        • Sung J.M.
        • et al.
        Effects of statins on coronary atherosclerotic plaques: the PARADIGM study.
        JACC Cardiovasc. Imag. 2018; 11: 1475-1484
        • Motoyama S.
        • Sarai M.
        • Harigaya H.
        • et al.
        Computed tomographic angiography characteristics of atherosclerotic plaques subsequently resulting in acute coronary syndrome.
        J. Am. Coll. Cardiol. 2009; 54: 49-57
        • Motoyama S.
        • Kondo T.
        • Sarai M.
        • et al.
        Multislice computed tomographic characteristics of coronary lesions in acute coronary syndromes.
        J. Am. Coll. Cardiol. 2007; 50: 319-326
        • Kataoka 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: 1592-1597
        • Nicholls S.J.
        • Tuzcu E.M.
        • Wolski K.
        • et al.
        Coronary artery calcification and changes in atheroma burden in response to established medical therapies.
        J. Am. Coll. Cardiol. 2007; 49: 263-270
        • Burke A.P.
        • Weber D.K.
        • Kolodgie F.D.
        • Farb A.
        • Taylor A.J.
        • Virmani R.
        Pathophysiology of calcium deposition in coronary arteries.
        Herz. 2001; 26: 239-244
        • Narula J.
        • Nakano M.
        • Virmani R.
        • et al.
        Histopathologic characteristics of atherosclerotic coronary disease and implications of the findings for the invasive and noninvasive detection of vulnerable plaques.
        J. Am. Coll. Cardiol. 2013; 61: 1041-1051
        • Vengrenyuk 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. : MCB. 2008; 5: 37-47
        • Mauriello A.
        • Servadei F.
        • Zoccai G.B.
        • et al.
        Coronary calcification identifies the vulnerable patient rather than the vulnerable Plaque.
        Atherosclerosis. 2013; 229: 124-129
        • Otsuka F.
        • Finn A.V.
        • Virmani R.
        Do vulnerable and ruptured plaques hide in heavily calcified arteries?.
        Atherosclerosis. 2013; 229: 34-37
        • Yahagi K.
        • Kolodgie F.D.
        • Lutter C.
        • et al.
        Pathology of human coronary and carotid artery atherosclerosis and vascular calcification in diabetes mellitus.
        Arterioscler. Thromb. Vasc. Biol. 2017; 37: 191-204
        • Mintz G.S.
        • Pichard A.D.
        • Popma J.J.
        • et al.
        Determinants and correlates of target lesion calcium in coronary artery disease: a clinical, angiographic and intravascular ultrasound study.
        J. Am. Coll. Cardiol. 1997; 29: 268-274
        • Schwartz G.G.
        • Olsson A.G.
        • Ezekowitz M.D.
        • et al.
        Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial.
        JAMA. 2001; 285: 1711-1718
        • Cannon C.P.
        • Braunwald E.
        • McCabe C.H.
        • et al.
        Intensive versus moderate lipid lowering with statins after acute coronary syndromes.
        N. Engl. J. Med. 2004; 350: 1495-1504
      1. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.
        N. Engl. J. Med. 1998; 339: 1349-1357
        • Nissen S.E.
        • Nicholls S.J.
        • Sipahi I.
        • et al.
        Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial.
        JAMA. 2006; 295: 1556-1565
        • Nicholls S.J.
        • Ballantyne C.M.
        • Barter P.J.
        • et al.
        Effect of two intensive statin regimens on progression of coronary disease.
        N. Engl. J. Med. 2011; 365: 2078-2087
        • Banach M.
        • Serban C.
        • Sahebkar A.
        • et al.
        Impact of statin therapy on coronary plaque composition: a systematic review and meta-analysis of virtual histology intravascular ultrasound studies.
        BMC Med. 2015; 13: 229
        • Puri R.
        • Nicholls S.J.
        • Shao M.
        • et al.
        Impact of statins on serial coronary calcification during atheroma progression and regression.
        J. Am. Coll. Cardiol. 2015; 65: 1273-1282
        • Raber L.
        • Taniwaki M.
        • Zaugg S.
        • et al.
        Effect of high-intensity statin therapy on atherosclerosis in non-infarct-related coronary arteries (IBIS-4): a serial intravascular ultrasonography study.
        Eur. Heart J. 2015; 36: 490-500
        • Singh P.
        • Emami H.
        • Subramanian S.
        • et al.
        Coronary plaque morphology and the anti-inflammatory impact of atorvastatin: a multicenter 18F-fluorodeoxyglucose positron emission tomographic/computed tomographic study.
        Circ. Cardiovasc. Imag. 2016; 9