Skip to main content
NCBI home page
American Heart Journal Plus: Cardiology Research and Practice logoLink to American Heart Journal Plus: Cardiology Research and Practice
. 2025 Feb 18;51:100509. doi: 10.1016/j.ahjo.2025.100509

The formation of cholesterol crystals and embolization during myocardial infarction☆

Jamal Mughal a, Venkat R Katkoori b, Stefan Mark Nidorf c, Megan Manu d, George S Abela d,e,f,⁎
PMCID: PMC11881462  PMID: 40046649

Abstract

Cholesterol crystals (CCs) released into the coronary circulation during plaque rupture have multiple adverse impacts on both the arterial conduit as well as the myocardium. CCs form within the atheromatous plaque by the saturation of free cholesterol deposition via facilitated LDL-c entry because of a dysfunctional endothelium. Once formed, CCs are viewed as a foreign body and activate inflammation via the innate immune system. Eventually, an inflamed atheromatous plaque ruptures by virtue of the growth and expansion of CCs that begin to occupy a greater volume than the liquid phase cholesterol. In some instances, the sharp edges of CCs can puncture and tear the plaque's fibrous cap causing rupture leading to thrombosis and myocardial infarction. In these circumstances, CCs are released from the ruptured plaque and travel down the coronary artery where they can scrape the endothelial lining which enhances vasospastic activity, further worsening ischemia. Moreover, when CCs lodge in the distal arteriolar and capillary beds, they not only obstruct blood flow to further aggravate ischemia but also activate an inflammatory response in the myocardium that leads to further tissue injury. Treatment of CCs has thus far been limited but studies using statins, aspirin and colchicine have demonstrated them to be effective in dissolving CCs that may provide additional benefits for both prevention and potentially for acute cardiovascular events.

1. Introduction

Viewing atherosclerosis as a crystalloid disease provides novel insights into the role of cholesterol crystals (CCs) in the development and subsequent rupture of atherosclerotic plaques, and their role in secondary ischemic and inflammatory tissue injury [1]. The realization that free cholesterol expands as it undergoes a phase change from a liquid to a solid crystalline state helps explain how the process of crystallization may lead to plaque rupture [[2], [3], [4], [5]] related to the rapid increase in pressure and volume within the plaque that occurs during crystallization. These changes stretch and thin the plaque cap and leave it more vulnerable to disruption from direct trauma by sharp tips of CCs that can directly puncture the fibrous cap of the plaque [2,4] (Fig. 1). Furthermore, CCs that form within the plaque core can tear the vasa vasorum causing intraplaque hemorrhage that can further expand the plaque's core and provide additional free cholesterol from red blood cell membranes that are deposited in the plaque matrix [6,7].

Fig. 1.

Fig. 1

Open in a new tab

Mechanism of Plaque Hemorrhage, Rupture, and/or Erosion Induced by Cholesterol Crystallization with Volume Expansion of the Plaque Necrotic Core. In the case of a large necrotic core (top), the plaque cap is torn, leading to rupture, whereas in the case of a small necrotic core (bottom), it leads to erosion (disruption of the fibrous cap with loss of endothelium and without rupture). Human plaques with rupture and erosion are shown with corresponding scanning images. Also, trauma to the vasa vasorum caused by expanding cholesterol crystals within the plaque causes intra-plaque hemorrhage. Modified with permission from [2,3,6].

As the CCs are ejected from the ruptured plaque into the coronary artery circulation, they can induce vascular injury as they travel downstream. Specifically, crystals contacting the arterial walls have been shown to scrape the intimal surface, damaging the endothelial lining and causing a loss of the normal dilatory response to acetylcholine, thus leading to vasoconstriction [8] (Fig. 2). As CCs aggregate in the microcirculation they further impair perfusion of the tissues causing regional ischemia. Moreover, CCs embedded in the tissues can trigger an inflammatory response associated with macrophage infiltration, which causes inflammatory tissue damage [9]. When these events occur during coronary intervention it is referred to as the “no reflow phenomenon” related to microvascular obstruction by platelet thrombi and CCs emboli [8,10]. Notably, plaques with greater CCs burden on intravascular ultrasound imaging during intervention have been associated with an increased risk of “the no-reflow” phenomenon during coronary intervention [11] (Fig. 3). Furthermore, following the acute plaque rupture there continues to be oozing of CCs from the ruptured plaque embolizing into the distal circulation that can obstruct the microcirculation and cause myocardial inflammation and injury as has been shown by angioscopic studies in human aortas [12].

Fig. 2.

Fig. 2

Open in a new tab

Scanning electron micrographs of arterial surface with and without crystal injury. (a,c,e) scanning electron micrographs of normal arterial surface with circulating saline. (b,d,f) Micrographs of arterial intima with circulating cholesterol crystals demonstrating crystals embedded and disrupting the intimal surface. (g) Diagram of dual perfusion chambers demonstrating the flow of normal saline and saline with cholesterol crystals and camera to evaluate arterial diameter and vasomotor activity. (h) Graphic demonstrating markedly reduced vasomotor dilatation after nor-epinephrine preconstruction followed by acetylcholine (Ne-Ach) vasodilatation with cholesterol crystal exposed arteries compared to normal saline exposed arteries. Modified and reproduced with permission [8].

Fig. 3.

Fig. 3

Open in a new tab

Schematic of multiple steps of crystal related arterial injury. 1) Plaque rupture with tethered edges of torn fibrous cap. This releases a variety of crystals that travel downstream; 2) triggers arterial spasm by disruption of the endothelium; 3) lodge in the muscle inducing myositis and necrosis. This event leads to both local and systemic inflammatory responses. Histology reproduced with permission [1,3,8,9].

2. Plaque growth at the cellular level

Plaque growth is enhanced by CCs that first appear as fatty streaks in the arterial walls in early childhood [13]. CCs are believed to enhance early plaque growth by causing endothelial dysfunction that leads to the expression of cellular adhesion molecules (i.e. ICAM-1; VACAM-1; E-selectin) that enhance the entry of LDL-c and circulating leukocytes into the subintimal space [14]. CCs also form within the lipid bilayer of the endothelial cells which occurs when the density of free cholesterol in the cell membrane is enriched [15,16]. These CCs are then ejected into the sub-intimal space where they are mostly cleared by macrophages and degraded within liposomes. However, as the free cholesterol content within liposomes increases, new CCs may begin to develop, and as they outgrow their intracellular environment they are released into the subintimal space. Further crystal growth leads to damage of liposomes with the release of lytic enzymes from the liposomes into the subintimal space leading to further tissue injury that eventually evolves into a free lipid pool [17] (Fig. 4). Notably, contact of CCs with macrophages leads to signaling that attracts more macrophages by inducing monocyte chemotactic protein or chemokine ligand 2 (CCL2) formerly MCP-1 [18]. This response is independent of CCs internalization into the macrophages. Moreover, incubation of CCs with macrophages triggers TNF-α which is known to reduce the expression of ABCA1 and reduce HDL-mediated cholesterol efflux, thus lending to accumulation of free cholesterol which is the substrate for CCs formation in the arterial wall [19].

Fig. 4.

Fig. 4

Open in a new tab

Necrotic core formation within atherosclerotic plaque. The initial step is LDL entry through dysfunctional endothelium and entrapment within the subendothelial space. Monocytes enter and differentiate into macrophages which then become lipid-laden foam cells from uptake of surrounding lipoproteins. A cycle of inflammation and cholesterol crystal formation ensues resulting in macrophage apoptosis and accumulation of lipid and cellular debris. The cycle continues and a vulnerable plaque with a lipid-rich necrotic core is formed with cholesterol crystals aggregating towards the fibrous cap. Modified and reproduced with permission [6].

3. The vulnerable atheromatous plaque

The morphologic features of plaque rupture were first described by Paris Constantinides in the 1960's who noted fissuring of the fibrous cap at the site of thrombus formation in patients who died of acute myocardial infarction [20]. Subsequent work by Davies et al. demonstrated that plaque ruptures occurred mainly at plaque edges where the fibrous cap ‘inserts' into the arterial wall [21]. Richardson et al. also demonstrated that the sites of rupture had extensive macrophage infiltration [22]. Further work by Henny et al. demonstrated that those sites were rich in collagenases that could break down the collagenous tissue support and then Gallis and Libby demonstrated that the inflammatory cells' release of metalloproteinases could weaken the plaque structure [23,24]. Although inflammation is critical to plaque instability these findings did not explain the initial trigger for the inflammatory flare and did not consider that plaque rupture could also occur independent of inflammation as a result of CC formation and expansion.

In 1909, Aschoff first described the presence of CCs in atherosclerotic plaque but those were imprints of crystals on paraffin-embedded slides processed by ethanol [25]. Since ethanol is a strong solvent of CCs their causal role in the development and rupture of atherosclerotic plaques was simply not considered. Ruptured plaque histology as seen by light microscopy in specimens obtained after fatal myocardial infarction also failed to provide clarity as to the events that led to plaque rupture, because the tissue processing for light microscopy used high concentrations of ethanol (up to 100 %) to dehydrate the tissues so they can be cut into thin sections and mounted on slides. This process readily dissolves CCs leaving behind ‘clefts’ that are empty spaces with the shape of crystals where CCs were previously present and now dissolved by the ethanol [26]. As a result, there was no appreciation of the way CCs could directly damage tissues. Thus, although the definition of the vulnerable plaque as one that progresses to rupture based on features described on light microscopy including a large lipid pool, a thin fibrous cap, loss of smooth muscle cell support and infiltration with inflammatory cells, it failed to describe the presence and potential role of CCs in plaque rupture [27].

Because multiple plaque ruptures have been found to occur concurrently in non-culprit arteries following an acute atherosclerotic event [28,29] it is now understood that clinical emphasis should look beyond the ‘vulnerable plaque’ and focus more on the ‘vulnerable patient’ [30]. This approach is clinically helpful as it brings into focus the possibility that cardiovascular atherosclerotic events may in part be triggered by a systemic process that enhances inflammation within the atherosclerotic bed and emphasizing the interplay between systemic and local inflammation.

4. Vulnerable plaque features by scanning electron, confocal and light microscopy

4.1. Scanning electron microscopy

Other microscopic procedures that can be performed on tissue samples without ethanol processing have provided unique insights into the role of CCs as they preserve CCs during tissue preparation. Specifically for SEM, ethanol tissue dehydration is avoided by dehydrating arterial and plaque specimens by either placing them in a vacuum chamber for 6–12 h or simply air drying them for 24–48 h. Since atherosclerotic arterial tissue is typically stiff, the degree of tissue shrinkage when dried by either technique is similar to that observed when samples are prepared with standard formalin or ethanol treatments. Moreover, evaluation of shrinkage by vacuum or air drying demonstrated that this is also not significantly different from shrinkage with standard formalin and ethanol treatments that ranges around 10–15 % [31] (Fig. 5). CCs are not affected by 10 % buffered formalin fixation and readily visible by SEM as sharp crystals as either needle or rhomboidal shapes. The needle shapes are composed of pure cholesterol while rhomboidal shapes are cholesterol monohydrate which is the most common form of crystal noted in human plaques [32]. By SEM, CCs can be seen piercing and arising from the intimal surface of the arterial wall typically at sites of plaque rupture not only at the site of the tear but also on the surface of the plaque adjacent to the fibrous cap rupture.

Fig. 5.

Fig. 5

Open in a new tab

Scanning Electron Micrographs of Human Coronary Artery, Fluorescence Microscopy of Carotid Plaque, and Light Microscopy of Coronary Artery. (a-d) Scanning electron micrographs of the left anterior descending artery from a patient who died of an acute cardiovascular infarction. Cholesterol crystals are noted perforating the intimal surface just below the plaque rupture site. (e) Low-power image of human carotid plaque with green fluorescence. (f,g) Higher magnification reveals selectively stained cholesterol crystals with emerging from the plaque surface without tissue processing (fluorescent dye, Bodipy-C12). (h) Postmortem angiogram of right coronary artery with arrow at the site of plaque rupture. (i,j) Cholesterol crystals noted at the site of plaque rupture with an “explosive-like” ejection of cholesterol crystals. Modified and reproduced with permission [2,26,33]. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

4.2. Confocal microscopy

When using confocal fluorescence microscopy, fresh unprocessed tissue samples are used and examined at 37 °C. Those are also maintained at 37 °C in transport immediately following acquiring them at endarterectomy from the operating room and to the laboratory for examination. Confocal microscopy with a fluorescent dye (cholesteryl Bodipy-C12) that stains CCs yielded findings similar to SEM with extensive presence of CCs perforating the plaque at rupture sites [2,26] (Fig. 5).

4.3. Light microscopy

Despite the limitations of light microscopy due to dissolving of CCs by ethanol and other solvents during tissue processing, on rare occasions CCs can also be seen transversing the fibrous cap during plaque rupture [33] (Fig. 5).

5. Plaque inflammation

Given the appearance of CCs perforating the fibrous caps of atheromatous plaques observed by SEM and confocal microcopy, Abela proposed that CCs could also cause an inflammatory response akin to that triggered by other crystalloid conditions namely uric acid crystals in gout [34,35]. In collaboration with Latz from Bonn, Germany they proceeded to demonstrate the same inflammatory process as had been described for uric acid crystals by Martinon et al. [36]. Essentially, the inflammation occurs by activating NLRP3 inflammasomes that then activate interleukin-1β (IL-1β) and subsequently IL-6 and C-reactive protein (CRP) [[37], [38], [39]]. This provided strong evidence that CCs are recognized as foreign bodies by the innate immune system and thus able to trigger an inflammatory response. Other inflammation cytokines were found to be activated by CCs including complesomes and complement. These inflammatory activities lead to plaque destabilization by releasing metalloproteinases from the macrophages that cause local tissue breakdown leading to growth of the plaque core and arterial wall positive remodeling thus enhancing the risk for plaque rupture and/or erosion.

6. Plaque rupture and distal cholesterol crystal embolization

Appreciation that atherosclerotic plaques become structurally unstable due to CC induced inflammation and CC induced trauma leads to the understanding that CC formation is critical in the development of a vulnerable plaque [31]. Although cholesterol in the plaque core is typically present in a liquid and semi-liquid state [32], local physicochemical conditions can trigger crystallization [5]. Thus, the greater the amount of liquid and free cholesterol, the greater the risk of CC formation, and the greater the risk of plaque rupture [2].

6.1. Local physicochemical effects

Local conditions within the plaque that can trigger cholesterol crystallization include increased amounts of free cholesterol, a basic pH, hydration of the cholesterol molecule to the monohydrated form and a drop in ambient temperature [5]. These physicochemical conditions may explain the increased risk of cardiovascular events during fall and winter [40] as well as the circadian early morning clustering of cardiovascular events that occur when the body core temperature may be lowered by several degrees centigrade [5].

6.2. Gender-related effects of cholesterol crystals

Another clinical aspect that may be explained by the role of CCs in plaque rupture relates to the atypical symptoms in women who present with acute myocardial infarction [41,42]. Men have been shown to have larger lipid pools in their plaques compared to women, even for the same degree of arterial stenosis by angiography [43]. This may be related to the longer time men have to accumulate cholesterol within plaques while women are protected by estrogens but then catch up later in life with men [44]. Also, estrogens have been shown to dissolve CCs being of a very similar molecular structure to cholesterol [45]. The reduced amount of cholesterol in the plaque core may still crystallize but the amount of free cholesterol is not large enough to cause plaque rupture but enough to perforate the fibrous cap to cause plaque erosion that can lead to thrombosis but in a slower and more protracted manner compared to men and explain the more ‘subtle stuttering’ symptoms in women with myocardial infarction [6]. Furthermore, CC cluster sizes are significantly smaller for women than men [46]. Hence the myocardial infarction may be less recognized clinically which could explain the higher mortality in women due to being missed [41] (Fig. 6).

Fig. 6.

Fig. 6

Open in a new tab

Left carotid artery confirming intra-plaque hemorrhage by black-blood T1-weighted cross sectional images using 3D magnetization-prepared rapid acquisition gradient echo sequence, where the intra-plaque hemorrhage is bright. (a, b) Along the inferior aspect of the intra-plaque hemorrhage there is a 1 mm thick fibrous cap between the dark lumen and the bright deep intra-plaque hemorrhage. Superiorly there is a well-defined fibrous cap (<500 μm) between the lumen and lipid core. (c) Following endarterectomy, light and scanning electron microscopy demonstrate extensive cholesterol crystals with intra-plaque hemorrhage and thin fibrous cap. (d) Graphic demonstrates that for the same degree of stenosis on magnetic resonance angiography (MRA) males had more complex plaques (thin fibrous caps and larger lipid cores) than females. (e) A representative case of large hemorrhagic lipid rich necrotic core with a ruptured fibrous cap obtained from a male patient (left). A representative case of calcified plaque from a female patient (right). Area with hypointensity on contrast-enhanced T1-weighted and hyperintensity on inversion recovery fast spoiled gradient recalled indicates a hemorrhagic lipid-rich/necrotic core (arrows). *Lumen. Modified and reproduced with permission [7,43].

6.3. Frequency of cholesterol crystals in culprit human coronary arteries

Aspirates of the obstructive material from an occluded culprit coronary artery during acute myocardial infarction reveal extensive amounts of CCs in the aspirates intermixed with thrombus. In a study of 286 patients CC size, composition, and morphology were correlated with inflammatory biomarkers, cardiac enzymes, percent coronary stenosis as well as TIMI blush and flow grades [46]. Although women had significantly smaller CC clusters than men, they had higher CRP levels. The CCs were also confirmed to be cholesterol by crystallography during SEM and by infra-red spectroscopy. Crystals were detected in ~90 % of cases and many had cholesterol crystal clusters that were large enough to occlude medium to small sized coronary arteries. Also, macrophages were found in about half the specimens and seen attached to CCs and dissolving them (Fig. 7).

Fig. 7.

Fig. 7

Open in a new tab

Aspirates from coronary artery during myocardial infarction. (a) Right coronary artery with filling defect during acute myocardial infarction (black arrow). (b) Yellow atherosclerotic materials aspirated from coronary artery in syringe. (c) Heap of aspirated materials with extensive cholesterol crystals embedded in the debris. (d) Scanning electron micrograph of a large cluster of cholesterol crystals. (e,f,g) Macrophages attached to cholesterol crystals and etching to form a groove in the crystal. (h) Macrophage stained with Boron-dipyrromethene-stained (BODIPY) with crystalline material embedded in the cytoplasm. Modified and reproduced with permission.(Reproduced with permission [46]). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

6.4. In vivo detection of ccs by angioscopy and optical coherence tomography

Recently Komatsu et al. using non-obstructive angioscopy (NOGA) demonstrated presence of CCs emerging from plaques in human aortas [12]. Shimmering crystals were seen to be floating out of atheromatous plaques by the gentle nudging of plaque with the angioscope during examination. Many CCs emanating from spontaneously ruptured plaques were captured by this process further confirming their presence in live patients. Other in vivo work with optical coherence tomography (OCT) by Tian et al. demonstrated the presence of CCs aggregates in both stable non-culprit and ruptured plaques. They proposed that the presence of CCs may provide an important independent prognostic signal of future risk of plaque instability by demonstrating that non-culprit plaques with CCs were more likely to have higher risk features including a larger lipid burden, more macrophages, and spotty calcification [47,48].

7. Cholesterol crystal emboli from ruptured plaque

Cholesterol crystal emboli released from ruptured plaque are carried down the coronary artery and then lodge into the arteriolar and capillary circulation. Here they can obstruct the micro circulation and contribute to myocardial injury [49] (Fig. 8). Even though the obstruction may not be sufficient to cause ischemic injury due to the extensive capillary bed, the presence of the CCs can lead to inflammation that can further damage the myocardium. Evidence for this process of injury was provided in an experimental model where release of CCs into the femoral artery of a rabbit model resulted in local inflammation detected by positron emission tomography (PET) scanning. These areas were biopsied and found to have marked macrophage infiltration with CCs that were embedded in the macrophage cytoplasm [9] (Fig. 9).

Fig. 8.

Fig. 8

Open in a new tab

Cholesterol Crystal Emboli during Myocardial Infarction. (a) H&E stained frozen sections of myocardial capillaries and arterioles of patient with cholesterol crystal emboli in the myocardial capillaries and arterioles shown in the frozen sections by using direct polarized light (arrows). (b) Complete occlusive free cholesterol crystal emboli are occasionally seen in the capillaries with polarized light adjacent to microinfarcts (arrow). Reproduced with permission [49].

Fig. 9.

Fig. 9

Open in a new tab

Cholesterol crystal emboli cause myositis. (A) Computer tomographic images of rabbit following CCs embolism in left femoral artery that remain patent. (B) PET scan at 48 h demonstrates localized inflammation (arrow). (C,D) Muscle biopsy from inflamed PET site demonstrates infiltration with macrophages (brown by RAM 11 stain). Arrows point to contraction band necrosis of muscle cells. (E) Fluorescence microscopy demonstrates uptake of crystalline materials by the macrophages. Modified with permission [9].

CCs = cholesterol crystals; PET = positron emission tomography. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

8. Therapy that affects CC growth and morphology

Several medications that are used to prevent and treat cardiovascular events were investigated for their potential for dissolving CCs. Agents that lower cholesterol and reduce inflammation seemed to be primary candidates and include statins, aspirin and colchicine. When statins were added to cholesterol during crystallization in test tube experiments, they inhibited the volume expansion caused by the crystals' growth and caused the CCs to become pasty and lose their sharp tips and edges. Thus, it is conceivable that one of the mechanisms whereby statins reduce the risk of cardiovascular events relates to their ability to reduce crystal growth and expansion. Moreover, the effect of statins was found to be dose-related with higher doses having a significantly a greater reduction of the volume expansion [50] (Fig. 10). Three different statins were tested and were found to have similar effects with atorvastatin being the most effective followed by simvastatin and pravastatin. A similar effect was noted in a study of human carotid plaques removed at endarterectomy where patients taking statins had evidence of dissolving CCs while those not taking stains prior to surgery had intact CCs [50]. Statins have a molecular structure that shares domains with the cholesterol molecule thus make the two molecules miscible such that statins can dissolve CCs [51]. Aspirin and colchicine have also been evaluated in an ex-vivo model using human carotid plaques and found to have similar effects of dissolving CCs [52,53]. The effect of these drugs does not appear to be non-specific, as they contrast with the effect of norepinephrine and steroids which both enhance rather than reduce CC growth [54].

Fig. 10.

Fig. 10

Open in a new tab

Effect of statin on cholesterol crystal growth and morphology. (a) Test tube with cholesterol (1.5 g) expands above the meniscus. (b) Adding 50 mg of pravastatin inhibits volume expansion completely. (c) Bar graph demonstrating a dose related effect of atorvastatin, simvastatin, and pravastatin on volume expansion with crystallization. (d) Scanning electron micrograph of normal crystal morphology with pointed tips. (e) Adding statin dissolves the crystals. (f) Scanning of plaque from patient not taking statins demonstrates intact crystal forms. (g) Scanning of plaque from patient taking atorvastatin demonstrates dissolving cholesterol crystals. Reproduced with permission [50].

9. Summary

Understanding how cholesterol in atherosclerotic plaques contributes to an acute cardiovascular event is critical to elucidating how to best treat patients with atherosclerotic disease. Although inflammation is a critical aspect of atherosclerosis, it is never-the-less a common response to an injury, which in the case of atherosclerotic plaque relates to the physical conversion of cholesterol into its crystalline phase. This process like many other crystalloid disease conditions such as gall stones, renal stones, uric acid crystals is known to trigger an inflammatory response. The presented data provides evidence that cardiovascular events fall into the same category of a crystalloid-induced condition with the atherosclerotic plaque of an artery. CCs that embolize from ruptured plaques not only obstruct arterioles and capillaries leading to ischemia but also trigger inflammation that further adds to myocaradial injury. Hence, dissolving the CCs is potentially a major therapeutic step that may prove beneficial in the prevention and regulation of the cause of injury that leads to inflammation and direct tissue injury.

CRediT authorship contribution statement

Jamal Mughal: Writing – review & editing. Venkat R. Katkoori: Writing – original draft, Data curation. Stefan Mark Nidorf: Writing – review & editing, Visualization. Megan Manu: Validation. George S. Abela: Writing – review & editing, Writing – original draft, Conceptualization.

Funding

Funding was provided by Michigan State University Department of Medicine seed fund; The Jean P. Schultz Biomedical Research Endowment, Michigan State University and Edward W. Sparrow Hospital, Lansing, MI; National Institutes of Health grant 2 R01 EY025383-05A1.

Declaration of competing interest

No author has a conflict related to this work.

Footnotes

☆

This article is part of a special issue entitled: Cholesterol Crystal Embolization published in American Heart Journal Plus: Cardiology Research and Practice.

References

  • 1.Nidorf S.M., Fiolet A., Abela G.S. Viewing atherosclerosis through a crystal lens: how the evolving sturture of cholesterol crystals in atheroscleritc plaque alters its stability. J. Clin. Lipidol. 2020;14:619–630. doi: 10.1016/j.jacl.2020.07.003. [DOI] [PubMed] [Google Scholar]
  • 2.Abela 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;28:1–10. doi: 10.1002/sca.4950280101. [DOI] [PubMed] [Google Scholar]
  • 3.Abela G.S., Aziz K., Vedre A., Pathak D., Talbott J.D., DeJong J. Effect of cholesterol crystals on plaques and intima in arteries of patients with acute coronary and cerebrovascular syndromes. Am. J. Cardiol. 2009;103:959–968. doi: 10.1016/j.amjcard.2008.12.019. [DOI] [PubMed] [Google Scholar]
  • 4.Al-Handawi M.B., Commins P., Karothu D.P., et al. Mechanical and crystallographic analysis of cholesterol crystals puncturing biological membranes. Chemistry. 2018;24:11493–11497. doi: 10.1002/chem.201802251. [DOI] [PubMed] [Google Scholar]
  • 5.Vedre A., Pathak D.R., Crimp M., Lum C., Koochesfahani M., Abela G.S. Physical factors that trigger cholesterol crystallization leading to plaque rupture. Atherosclerosis. 2009;203:89–96. doi: 10.1016/j.atherosclerosis.2008.06.027. [DOI] [PubMed] [Google Scholar]
  • 6.Abela G.S. Cholesterol crystals piercing the arterial plaque and intima triggers local and systemic inflammation. J. Clin. Lipidol. 2010;4:156–164. doi: 10.1016/j.jacl.2010.03.003. [DOI] [PubMed] [Google Scholar]
  • 7.Mughal M.M., Khan M.K., DeMarco J.K., Majid A., Shamoun F., Abela G.S. Symptomatic and asymptomatic carotid artery plaque. Expert. Rev. Cardiovasc. Ther. 2011;9:1315–1330. doi: 10.1586/erc.11.120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Gadeela N., Rubinstein J., Tamhane U., Huang R., Pathak D.R., Hosein H.A., Rich M., Dhar G., Abela G.S. The impact of circulating cholesterol crystals on vasomotor function: implications for no-reflow phenomenon. JACC Cardiovasc. Interv. 2011;4:521–529. doi: 10.1016/j.jcin.2011.02.010. [DOI] [PubMed] [Google Scholar]
  • 9.Pervaiz M.H., Durga S., Janoudi A., Berger K., Abela G.S. PET/CT detection of muscle inflammation related to cholesterol crystal emboli without arterial obstruction. J. Nucl. Cardiol. 2018;25:433–440. doi: 10.1007/s12350-017-0826-y. [DOI] [PubMed] [Google Scholar]
  • 10.Swartz R.S., Burke A., Farb A., Kaye D., Lesser J.R., Henry T.D., Virmani R. Microemboli and microvascular obstruction in acute coronary thrombosis and sudden coronary death: relation to epicardial plaque histology. J. Am. Coll. Cardiol. 2009;54:2167–2173. doi: 10.1016/j.jacc.2009.07.042. [DOI] [PubMed] [Google Scholar]
  • 11.Katayama Y., Taruya A., Kashiwagi M., Ozaki Y., Shiono Y., Tanimoto T., Yoshikawa T., Kondo T., Tanaka A. No-reflow phenomenon and in vivo cholesterol crystals combined with lipid core in acute myocardial infarction. Int J Cardiol Heart Vasculature. 2022;38 doi: 10.1016/j.ijcha.2022.100953. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Komatsu S., Yutani C., Ohara T., et al. Angioscopic evaluation of spontaneously ruptured aortic plaques. J. Am. Coll. Cardiol. 2018;71:2893–2902. doi: 10.1016/j.jacc.2018.03.539. [DOI] [PubMed] [Google Scholar]
  • 13.Guyton J.R., Klemp K.F. Transitional features in human atherosclerosis: intimal thickening, cholesterol clefts, and cell loss in human aortic fatty streaks. Am. J. Pathol. 1993;143:1444–1457. [PMC free article] [PubMed] [Google Scholar]
  • 14.Baumer Y., McCurdy S., Weatherby T.M., Mehta N.N., Halvherr S., Halbherr P., Yamazaki N., Boisvert W.A. Hyperlipidemia-induced cholesterol crystal production by endothelial cells promotes atherogenesis. Nat. Commun. 2017;8:1129. doi: 10.1038/s41467-017-01186-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Mason R.P., Jacob R.F. Membrane microdomains and vascular biology emerging role in atherogenesis. Circulation. 2003;107:2270–2273. doi: 10.1161/01.CIR.0000062607.02451.B6. [DOI] [PubMed] [Google Scholar]
  • 16.Varsano N., Fargion I., Wolf S.G., Leiserowitz L., Addadi L. Formation of 3D cholesterol crystals from 2D nucleation sites in lipid bilayer membranes: implications for atherosclerosis. J. Am. Chem. Soc. 2015;137:1601–1607. doi: 10.1021/ja511642t. [DOI] [PubMed] [Google Scholar]
  • 17.Kellner-Weibel G., Jerome W.G., et al. Effect of intracellular free cholesterol accumulation on macrophage viability: a model for foam cell death. Arterioscler. Thromb. Vasc. Biol. 1998;18:423–431. doi: 10.1161/01.atv.18.3.423. [DOI] [PubMed] [Google Scholar]
  • 18.Janoudi A., Opreanu M., Parameswaran N., Nasiri M., Abela G.S. Extracellular cholesterol crystals induce an inflammatory response in macrophages. J. Am. Coll. Cardiol. 2013;61(Suppl A17) [Google Scholar]
  • 19.Field F.J., Watt K., Mathur S.N. TNF-alpha decreases ABCA1 expression and attenuates HDL cholesterol efflux in the human intestinal cell line Caco-2. J. Lipid Res. 2010;51(6):1407–1415. doi: 10.1194/jlr.M002410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Constantinides P. Plaque fissures in human coronary thrombosis. J. Atheroscler. Res. 1996;6:1–17. [Google Scholar]
  • 21.Davies M.J., Thomas A.C. Plaque fissuring: the cause of acute myocardial infarction causing sudden ischaemic death, and crecendo angina. Br. Heart J. 1985;53:363–373. doi: 10.1136/hrt.53.4.363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Richardson P.D., Davies M.J., Born G.V.R. Influence of plaque configuration and stress-distribution on fissuring of coronary atherosclerotic plaques. Lancet. 1989;2(8669):941–944. doi: 10.1016/s0140-6736(89)90953-7. [DOI] [PubMed] [Google Scholar]
  • 23.Henney A.M., Wakeley P.R., Davies M.J., Foster K., Hembry R., Murphy G. Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization. Proc. Natl. Acad. Sci. USA. 1991;88:8154–8158. doi: 10.1073/pnas.88.18.8154. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Galis Z.S., Khatri J.J. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad and the ugly. Circ. Res. 2002;90:251–262. [PubMed] [Google Scholar]
  • 25.Aschoff A. Zur Morphologie der lipoiden Substanzen. Über Entwicklungs-Wachstums-und Altersvorgänge an den Gefäßen. Path Anat. 1909;47:1. [Google Scholar]
  • 26.Nasiri M., Janoudi A., Vanderberg A.F.M., Flegler C., Flegler S., Abela G.S. Role of cholesterol crystals in atherosclerosis is unmasked by altering tissue preparation methods. Microsc. Res. Tech. 2015;78:969–974. doi: 10.1002/jemt.22560. [DOI] [PubMed] [Google Scholar]
  • 27.Schaar J.A., Muller J.E., Falk E., et al. Terminology for high-risk and vulnerable coronary artery plaques. Eur. Heart J. 2004;25:1077–1082. doi: 10.1016/j.ehj.2004.01.002. [DOI] [PubMed] [Google Scholar]
  • 28.Goldstein J.A., Demetriou D., Grines C.L., Pica M., Shoukfeh M., O’Neill W.W. Multiple complex coronary plaques in patients with acute myocardial infarction. N. Engl. J. Med. 2000;343:915–922. doi: 10.1056/NEJM200009283431303. [DOI] [PubMed] [Google Scholar]
  • 29.Rossi A., Franceschini L., Fusaro M., et al. Carotid atherosclerotic plaque instability in patients with acute myocardial infarction. Int. J. Cardiol. 2006;111:263–266. doi: 10.1016/j.ijcard.2005.08.030. [DOI] [PubMed] [Google Scholar]
  • 30.Naghavi M., Libby P., Falk E., et al. From the vulnerable plaque to the vulnerable patient. Circulation. 2003;108:1664–1672. doi: 10.1161/01.CIR.0000087480.94275.97. [DOI] [PubMed] [Google Scholar]
  • 31.Patel R., Janoudi A., Vedre A., Aziz K., Tamhane U., Rubinstein J., Abela O., Berger K., Abela G.S. Plaque rupture and thrombosis are reduced by lowering cholesterol levels and crystallization with ezetimibe and is correlated with flurodeoxyglucose positron emission tomography. Arterioscler. Thromb. Vasc. Biol. 2011;31:2007–2014. doi: 10.1161/ATVBAHA.111.226167. [DOI] [PubMed] [Google Scholar]
  • 32.Lundber B. Chemical composition and physical state of lipid deposits in atherosclerosis. Atherosclerosis. 1985;56:93–110. doi: 10.1016/0021-9150(85)90087-5. [DOI] [PubMed] [Google Scholar]
  • 33.Frink R.J. Parallel cholesterol crystals: a sign of impending plaque rupture? J. Invasive Cardiol. 2010;22(9):406–411. (PMID: 20814046) [PubMed] [Google Scholar]
  • 34.Cardiosource American College of Cardiology: Annual Scientific Session 2006 March 11–14. Atlanta GA. Plaque Rupture by Cholesterol Crystallization—A Novel Concept for Acute Coronary Syndrome: Interviewee: George S. Abela, MD, FACC; Interviewer: C Richard Conti, MD, MACC.
  • 35.Abela G.S., Aziz K. Plaques are ruptured by cholesterol crystals during myocardial infarction. Scanning. 2006;28:59. doi: 10.1002/sca.4950280101. [DOI] [PubMed] [Google Scholar]
  • 36.Martinon F., Pe’trilli V., Mayor A., Tardivel A., Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440:237–241. doi: 10.1038/nature04516. [DOI] [PubMed] [Google Scholar]
  • 37.Düewell P., Kono H., Rayner K.J., Sirois C.M., Vladimer G., Bauernfeind F., Abela G.S., Franchi L., Nunez G., Schnurr M., Espevik T., Lien G., Fitzgerald K.A., Rock K.L., Moore K.J., Wright S.D., Hornung V., Latz E. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464:1357–1361. doi: 10.1038/nature08938. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Rajamaki K., Lappalainen J., Oorni K., Valimaki E., Matikainen S., Kovanen P.T., Eklund K.K. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS One. 2010;5(7) doi: 10.1371/journal.pone.0011765. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Samstad E.O., Niyonzima N., Nymo S., Aune M.H., Ryan L., Bakke S.S., Lappegård K.T., Brekke O.L., Lambris J.D., Damås J.K., Latz E., Mollnes T.E., Espevik T. Cholesterol crystals induce complement-dependent inflammasome activation and cytokine release. J. Immunol. 2014;192:2837–2845. doi: 10.4049/jimmunol.1302484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Spencer F.A., Goldberg R.J., Becker R.C., Gore J.M. Seasonal distribution of acute myocardial infarction in the second National Registry of myocardial infarction. J. Am. Coll. Cardiol. 1998;31:1226–1233. doi: 10.1016/s0735-1097(98)00098-9. [DOI] [PubMed] [Google Scholar]
  • 41.Bots S.H., Peteres S.A.E., Woodward M. Sex differences in coronary heart disease and stroke mortality: a global assessment of the effect of ageing between 1980 and 2010. BMJ Glob. Health. 2017;2 doi: 10.1136/bmjgh-2017-000298. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Majidi M., Eslami v, Ghorbani P, Foroughi M. Are women more susceptible to ischemic heart disease compared to men? A literature overview. J. Geriatr. Cardiol. 2021;18:289–296. doi: 10.11909/j.issn.1671-5411.2021.04.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Ota H., Reeves M.J., Zhu D.C., et al. Sex differences in patients with asymptomatic carotid atherosclerotic plaque: in vivo 3.0-T magnetic resonance study. Stroke. 2010;41:1630–1635. doi: 10.1161/STROKEAHA.110.581306. [DOI] [PubMed] [Google Scholar]
  • 44.Anand S.S., Islam S., Rosengren A., Franzosi M.A., Steyn K., Yusufali A.F., et al. Risk factors for myocardial infarction in women and men: insights from the INTERHEART study. EHJ. 2008;29:932–940. doi: 10.1093/eurheartj/ehn018. [DOI] [PubMed] [Google Scholar]
  • 45.Wang E., Al Abcha A., Osman H., Oladeji A., Boumegouas M., Abela G.S. The effect of estrogen and testosterone on cholesterol crystallization. J. Clin. Lipidol. 2022;16(3):e75–e76. doi: 10.1016/j.jacl.2022.05.063. [DOI] [Google Scholar]
  • 46.Abela G.S., Kalavakunta J.K., Janoudi A., Leffler D., Dhar G., Salehi N., 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;120:1699–1707. doi: 10.1016/j.amjcard.2017.07.075. [DOI] [PubMed] [Google Scholar]
  • 47.Qin Z., Cao M., Xi X., et al. Cholesterol crystals in non-culprit plaques of STEMI patients: a 3-vessel study. Int. J. Cardiol. 2022;364:162–168. doi: 10.1016/j.ijcard.2022.06.016. [DOI] [PubMed] [Google Scholar]
  • 48.Nishimura S., Ehara S., Hasegawa T., et al. Cholesterol crystal as a new feature of coronary vulnerable plaques: an optical coherence tomography study. J. Cardiol. 2017;69:253–259. doi: 10.1016/j.jjcc.2016.04.003. [DOI] [PubMed] [Google Scholar]
  • 49.Yutani C., Nagano T., Komatsu S., et al. Visible-free cholesterol crystal emboli adjacent to microinfarcts in myocardial capillaries and arterioles on H&E-stained frozen sections of an autopsied patient. BMJ Case Rep. 2018;2018 doi: 10.1136/bcr-2018-225558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Abela G.S., Vedre A., Janoudi A., Huang R., Durga S., Tamhane U. Effect of statins on cholesterol crystallization and atherosclerotic plaque stabilization. Am. J. Cardiol. 2011;107:1710–1717. doi: 10.1016/j.amjcard.2011.02.336. [DOI] [PubMed] [Google Scholar]
  • 51.Murphy C., Deplazes E., Carnfield C.G., Garcia A. The role of structure and biophysical properties in pleiotropic effects of statins. Int. J. Mol. Sci. 2020;21(22):8745. doi: 10.3390/ijms21228745. Nov 19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Fry L., Lee A., Khan S., Aziz K., Vedre A., Abela G.S. Effect of aspirin on cholesterol crystallization: a potential mechanism for plaque stabilization. Am Heart J Plus. 2022;13 doi: 10.1016/j.ahjo.2021.100083. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Ul Abideen Z., Pathak D.R., Sabanci R., Manu M., Abela G.S. The effect of colchicine on cholesterol crystal formation, expansion and morphology: A potential mechanism in atherosclerosis. Frontiers in Cardiology. Front. Cardiovasc. Med. 2024;11 doi: 10.3389/fcvm.2024.1345521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Durga S., Vodnala D., Xie Y., Abela G.S. Effect of stress related catecholamine levels on cholesterol crystallization and plaque rupture. J. Am. Coll. Cardiol. 2011;57; Suppl A113 [Google Scholar]

Articles from American Heart Journal Plus: Cardiology Research and Practice are provided here courtesy of Elsevier

RESOURCES