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• W4281652197 abstract "Atherosclerosis is a systemic disease of the arterial wall that invariably affects the aorta [[1]Roberts J.C. Moses C. Wilkins R.H. Autopsy studies in atherosclerosis I. Distribution and severity of atherosclerosis in patients dying without morphologic evidence of atherosclerotic catastrophe.Circulation. 1959; (Oct): 511-519Crossref PubMed Google Scholar]. While often extensive and exuberant, aortic atherosclerosis typically remains asymptomatic throughout life. In large part this reflects the reality that due to the size of its lumen, spontaneous ruptures of atherosclerotic plaques (SRAPs) in the aorta do not lead to atherothrombotic occlusion. As a result, viewing the luminal wall of the aorta in-vivo provides unique insights into how atherosclerosis evolves in its fully fledged unabbreviated form. In the last 5 years, Komatsu et al. have used non-obstructive general angioscopy to ‘survey the atherosclerotic landscape’ of the aorta in patients with coronary disease and have confirmed that this technique provides the most sensitive means of detecting and characterizing aortic atherosclerotic plaque in-vivo [[2]Komatsu S. Yutani C. Ohara T. et al.Angioscopic evaluation of spontaneously ruptured aortic plaques.J. Am. Coll. Cardiol. 2018; 25: 2893-2902Crossref Scopus (25) Google Scholar]. Initially, they identified and described a range of appearances of atherosclerotic plaque typically seen at autopsy, including the invariable finding of atherosclerotic lesions with features consistent with spontaneous plaque rupture. Some SRAPs were clearly seen to affect the plaque cap, as evidenced by erosion, fissuring, rupture and ulceration, while others that involved non-cap regions of the plaque were evident by discoloration of the atherosclerotic surface consistent with intra-mural hemorrhage [[3]Kojima K. Kimura S. Hayasaka K. et al.Aortic plaque distribution, and association between aortic plaque and atherosclerotic risk factors: an aortic angioscopy study.J. Atherosclerosis Thromb. 2019; 26: 997-1006Crossref PubMed Scopus (21) Google Scholar]. Subsequently, they safely harvested debris from SRAPs that extruded plaque contents and confirmed that it contained large cholesterol crystals (CCs), necrotic gruel with calcium deposits, and cellular infiltrate that mirrored the contents of atherosclerotic plaque [[4]Komatsu S. Yutani C. Ohara T. et al.Angioscopic evaluation of spontaneously ruptured aortic plaques.J. Am. Coll. Cardiol. 2018; 25 (Komatsua K, Yutanib C, Takahashia S, et.al. Debris collected in-situ from spontaneously ruptured atherosclerotic plaque invariably contains large cholesterol crystals and evidence of activation of innate inflammation: Insights from non-obstructive general angioscopy. Atherosclerosis): 2893-2902Crossref Scopus (33) Google Scholar], as observed by others who used confocal microscopy to examine fresh unprocessed debris obtained from carotid plaques [[5]Nasiri M. Janoudi A. Vanderberg A.F.M. et al.Role of cholesterol crystals in atherosclerosis is unmasked by altering tissue preparation methods.Microsc. Res. Tech. 2015; 78: 969-974Crossref PubMed Scopus (22) Google Scholar]. In this issue of Atherosclerosis, Komatsu et al. went one step further and characterized the nature of the cellular infiltrate of the debris associated with the so called puff-chandelier lesions [[6]Komatsu S, Yutani C, Takahashi S, et al. Debris Collected In-Situ from Spontaneously Ruptured Atherosclerotic Plaque Invariably Contains Large Cholesterol Crystals and Evidence of Activation of Innate Inflammation: Insights from Non-obstructive General Angioscopy. Atherosclerosis. doi:10.1016/j.atherosclerosis.2022.03.010.Google Scholar]. This confirmed that aside the presence of large CCs, which give the debris its glistening chandelier appearance, its cellular infiltrate stained positive for CD68, NLRP3, IL-1β, and IL-6 typically expressed by activated macrophages. In addition, neutrophils were identified in a significant proportion of specimens. Thus, these data provide strong circumstantial evidence that an innate inflammatory process had been triggered by CCs in these plaques [[7]Galozzi P. Bindoli S. Luisetto R. et al.Regulation of crystal induced inflammation: current understandings and clinical implications.Expet Rev. Clin. Immunol. 2021; 17 (Jul) (PMID: 34053376): 773-787https://doi.org/10.1080/1744666X.2021.1937129.Epub2021Jun18Crossref PubMed Google Scholar]. Together, their observations of the atherosclerotic landscape in-vivo provide several important insights. First, by confirming that SRAPs are common in-vivo, they remind us of the dynamic nature of the atherosclerotic process and highlight that as atherosclerosis progresses SRAPs commonly affect both the cap and non-cap regions of the plaque. This latter observation is intuitive but relevant as the bulk of most plaques sit well within the vessel wall, and only a small portion of their surface is exposed to the vessel lumen. Thus, while occasional rupture of the plaque cap in small and medium size arteries is consequential, as it leads to atherothrombosis causing ischemic stroke and myocardial infarction, frequent but clinically silent injury to the non-cap regions of atherosclerotic plaque is also consequential as it leads to disease progression. Second, the finding of large CCs within the debris extruding from some SRAPs speaks to their central role in plaque rupture. While it is well known that CCs can form within the lipid rich core of a plaque in-vivo, it is not well understood that CCs cannot continue to grow outside of a lipid rich environment. As free cholesterol molecules dissociate from lipoproteins and phospholipid structures in-situ they begin spontaneously to associate to form a series of flexible meta-stable structures. Initially, these appear as filaments that then broaden into ribbons, which twist into helices to form tubular structures [[8]Konikoff F.M. Chung D.S. Donovan J.M. Small D.M. et al.Filamentous, helical, and tubular microstructures during cholesterol crystallization from bile. Evidence that cholesterol does not nucleate classic monohydrate plates.J. Clin. Invest. 1992; 90 (Sep) (PMID: 1522223; PMCID: PMC329979): 1155-1160https://doi.org/10.1172/JCI115935Crossref PubMed Scopus (134) Google Scholar,[9]Varsano N. Beghi F. Elad N. et al.Two polymorphic cholesterol monohydrate crystal structures form in macrophage culture models of atherosclerosis.Proc. Natl. Acad. Sci. Unit. States Am. 2018; 115: 7662-7669https://doi.org/10.1073/pnas.1803119115Crossref PubMed Scopus (38) Google Scholar]. In the presence of abundant free cholesterol monohydrate, the meta-stable tubular structure begins to expand, and a myriad of microscopic ridged flat plate CCs begin to ‘snap off’ its end. This process is associated with the release of latent elastic energy, which disperses the CCs into their environment [[10]Abela G.S. Cholesterol crystals piercing the arterial plaque and intima trigger local and systemic inflammation.J. Clin. Lipidol. 2010; 4: 156-164https://doi.org/10.1016/j.jacl.2010.03.003Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar]. These microscopic flat plate CCs then become the platforms onto which any additional free cholesterol molecules in the environment may preferentially attach, causing the CC to grow into macroscopic structures. The rate of CC growth may be accelerated in the presence of calcium debris [[11]Park S. Sut T.N. Ma G.J. et al.Crystallization of cholesterol in phospholipid membranes follows ostwald's rule of stages.J. Am. Chem. Soc. 2020; 142 (Dec 30) (Epub 2020 Dec 21. PMID: 33345541): 21872-21882https://doi.org/10.1021/jacs.0c10674Crossref PubMed Scopus (10) Google Scholar]. When this process occurs within the core of a lipid rich plaque, it may lead to trauma of any of its walls as the sharp mercurate edges of flat plate CCs may puncture or perforate the plaque wall, and aggregation of CC fragments can increase the pressure and volume within the plaque causing its walls to stretch, thin and even rupture. Plaque rupture exposes plaque content to either the systemic circulation or the interstitial space [12Frincu M.C. Fleming S.D. Rohl A.L. Swift J.A. The epitaxial growth of cholesterol crystals from bile solutions on calcite substrates.J. Am. Chem. Soc. 2004; 126 (Jun 30): 7915-7924https://doi.org/10.1021/ja0488030.PMID:15212540Crossref PubMed Google Scholar, 13Abela G.S. Aziz K. Cholesterol crystals rupture biological membranes and human plaques during acute cardiovascular events - a novel insight into plaque rupture by scanning electron microscopy.Scanning. 2006; 28: 1-10Crossref PubMed Scopus (76) Google Scholar, 14Abela G.S. Kalavakunta J.K. Janoudi A. et al.Frequency of cholesterol crystals in culprit coronary artery aspirate during acute myocardial infarction and their relation to inflammation and myocardial injury.Am. J. Cardiol. 2017; 120: 1699-1707Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 15Abela G.S. Aziz K. Vedre A. et al.Effect of cholesterol crystals on plaques and intima in arteries of patients with acute coronary and cerebrovascular syndromes.Am. J. Cardiol. 2009; 103: 959-968Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar]. Since neither environment is rich in free cholesterol, CCs no longer enlarge once released from the plaque core. Thus, it is possible to speculate that the large flat plate CCs present in the debris extruded from ruptured atherosclerotic plaque must have formed and enlarged within the plaque core, making it vulnerable or actually causing it to rupture. Third, the observation that the debris extruding from SRAPs is rich in activated macrophages, and in many instances neutrophils, also speaks to the events that must have occurred in the atherosclerotic bed prior to plaque rupture. SRAPs involving non-cap regions of a plaque results in release of CCs from its acellular core directly into the interstitial space. There they may damage the vasa-vasorum causing intra-plaque hemorrhage and be recognized as foreign by complement and macrophages that then trigger an innate immune response. Fragments of CCs too large to ingest lead to frustrated phagocytosis and promote chronic inflammatory injury [[7]Galozzi P. Bindoli S. Luisetto R. et al.Regulation of crystal induced inflammation: current understandings and clinical implications.Expet Rev. Clin. Immunol. 2021; 17 (Jul) (PMID: 34053376): 773-787https://doi.org/10.1080/1744666X.2021.1937129.Epub2021Jun18Crossref PubMed Google Scholar]. The presence of CCs and inflammatory infiltrate within the debris associated with puff-chandelier ruptures therefore suggests that they involved the cap and the shoulder regions of the plaque exposed to crystal-induced inflammation. Thus, these observations nicely demonstrate that lipid rich plaques are under the constant threat of injury; from within due to enlargement and aggregation of CCs, and from without due to acute inflammatory flares triggered by the intermittent release of CCs from its core. While most inflammatory flares resolve, leading to sequestration of CCs and progressive sclerosis of the artery, on occasions a flare may precipitate SRAP by further weakening portions of the plaque wall that had stretched and thinned and thus become more vulnerable to rupture due to concomitant enlargement and aggregation of CCs in its core (Fig. 1). Finally, the observation that SRAPs associated with extrusion of atherosclerotic debris is common throughout the atherosclerotic landscape of the aorta, provides a plausible mechanism whereby the chronic release of atherosclerotic debris into the peripheries can contribute to insidious brain and renal injury that may eventually become clinically consequential [[16]Andrade-Oliveira V. Foresto-Neto O. Watanabe I.K.M. et al.New and old players.Front. Pharmacol. 2019; 10 (Oct 8) (PMID: 31649546; PMCID: PMC6792167): 1192https://doi.org/10.3389/fphar.2019.01192Crossref PubMed Scopus (148) Google Scholar,[17]Brown W.R. Thore C.R. Review: cerebral microvascular pathology in ageing and neurodegeneration.Neuropathol. Appl. Neurobiol. 2011; 37 (Feb) (PMID: 20946471; PMCID: PMC3020267): 56-74https://doi.org/10.1111/j.1365-2990.2010.01139.xCrossref PubMed Scopus (514) Google Scholar]. While each of these observations of the atherosclerotic landscape supports the importance of the development, growth, and aggregation of CCs in the plaque core as primary drivers of disease progression and SRAPs, this is only part of the story, as there is now compelling evidence that CCs also contribute to atherogenesis. Under cholesterol loading, CCs have been seen to form in the membranes of macrophages, smooth muscle cells, and endothelium, and within the lysosomes of foam cells. Akin to what occurs in the plaque core, growth of nascent CCs in cell membranes may cause membrane dysfunction, and growth of CCs in lysosomes can disrupt their membrane causing the release of CCs together with cathepsins into the cytosol, which can activate the NLRP3 inflammasome and trigger apoptosis [18Janoudi A. Shamoun F.E. Kalavakunta J.K. Abela G.S. Cholesterol crystal induced arterial inflammation and destabilization of atherosclerotic plaque.Eur. Heart J. 2016; 37: 1959-1967https://doi.org/10.1093/eurheartj/ehv653Crossref PubMed Scopus (139) Google Scholar, 19Düewell P. Kono H. Rayner K.J. et al.NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals.Nature. 2010; 464: 1357-1361https://doi.org/10.1038/nature08938Crossref PubMed Scopus (2630) Google Scholar, 20Kellner-Weibel G. Yancey P.G. Jerome W.G. et al.Crystallization of free cholesterol in model macrophage foam cells.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 1891-1898Crossref PubMed Scopus (135) Google Scholar, 21Tangirala R.K. Jerome W.G. Jones N.L. et al.Formation of cholesterol monohydrate crystals in macrophage-derived foam cells.J. Lipid Res. 1994; 35 (Jan) (PMID: 8138726): 93-104Abstract Full Text PDF PubMed Google Scholar, 22Sergin I. Evans T.D. Razani B. Degradation and beyond: the macrophage lysosome as a nexus for nutrient sensing and processing in atherosclerosis.Curr. Opin. Lipidol. 2015; 26 (Oct) (PMID: 26241101; PMCID: PMC5027838): 394-404https://doi.org/10.1097/MOL.0000000000000213Crossref PubMed Scopus (21) Google Scholar, 23Sheedy F.J. Grebe A. Rayner K.J. et al.CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation.Nat. Immunol. 2013; 14 (Aug) (Epub 2013 Jun 30. PMID: 23812099; PMCID: PMC3720827): 812-820https://doi.org/10.1038/ni.2639Crossref PubMed Scopus (632) Google Scholar, 24Baumer Y. McCurdy S. Weatherby T.M. et al.Hyperlipidemia-induced cholesterol crystal production by endothelial cells promotes atherogenesis.Nat. Commun. 2017; 8 (Oct 24) (PMID: 29066718; PMCID: PMC5654750): 1129https://doi.org/10.1038/s41467-017-01186-zCrossref PubMed Scopus (69) Google Scholar, 25Nidorf S.M. Fiolet A.T. Abela G.S. Viewing atherosclerosis through a crystal lens: how the evolving structure of cholesterol crystals in atherosclerotic plaque alters its stability.J. Clin. Lipidol. 2020; 14: 619-630Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar]. In summary, Komatsu et al. are to be commended for their in-vivo work which supports the suspicion gleaned from decades of autopsy, bench, and animal models, that it is the change in nature of cholesterol into its crystalline form within lipid rich plaques that leads to an iterative cycle of traumatic and inflammatory injury which transforms the landscape of the arterial wall from a simple flat plain into a vast volcanic range that is always at risk from what lies beneath. The author declares that he has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper." @default.
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• W4281652197 date "2022-05-01" @default.
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• W4281652197 title "Insights into the evolving nature of atherosclerosis from surveillance of the aortic landscape in-vivo" @default.
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