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Cholesterol crystal embolization following plaque rupture: a systemic disease with unusual features.

ABSTRACT: Cholesterol crystal embolic (CCE) syndrome is often a clinically challenging condition that has a poor prognostic implication. It is a result of plaque rupture with release of cholesterol crystals into the circulation that embolize into various tissue organs. Plaque rupture seems to be triggered by an expanding necrotic core during cholesterol crystallization forming sharp tipped crystals that perforate and tear the fibrous cap. Embolizing cholesterol crystals then initiate both local and systemic inflammation that eventually lead to vascular fibrosis and obstruction causing symptoms that can mimic other vasculitic conditions. In fact, animal studies have demonstrated that cholesterol crystals can trigger an inflammatory response via NLRP3 inflammasome similar to that seen with gout. The diagnosis of CCE syndrome often requires a high suspicion of the condition. Serum inflammation biomarkers including elevated sedimentation rate, abnormal renal function tests and eosinophilia are useful but non-specific. Common target organ involvement includes the skin, kidney, and brain. Various testing including fundoscopic eye examination and other non-invasive procedures such as trans-esophageal echocardiography and magnetic resonance imaging may be helpful in identifying the embolic source. Treatment includes aspirin and clopidogrel, high dose statin and possibly steroids. In rare cases, mechanical intervention using covered stents may help isolate the ruptured plaque. Anticoagulation with warfarin is not recommended and might even be harmful. Overall, CCE syndrome is usually a harbinger of extensive and unstable atherosclerotic disease that is often associated with acute cardiovascular events.

SUBMITTER: Ghanem F

PROVIDER: S-EPMC5445211 | biostudies-other | 2017 Jan

REPOSITORIES: biostudies-other

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Project description:RATIONALE:Plaque rupture is the proximate cause of most myocardial infarctions and many strokes. However, the molecular mechanisms that precipitate plaque rupture are unknown. OBJECTIVE:By applying proteomic and bioinformatic approaches in mouse models of protease-induced plaque rupture and in ruptured human plaques, we aimed to illuminate biochemical pathways through which proteolysis causes plaque rupture and identify substrates that are cleaved in ruptured plaques. METHODS AND RESULTS:We performed shotgun proteomics analyses of aortas of transgenic mice with macrophage-specific overexpression of urokinase (SR-uPA+/0 mice) and of SR-uPA+/0 bone marrow transplant recipients, and we used bioinformatic tools to evaluate protein abundance and functional category enrichment in these aortas. In parallel, we performed shotgun proteomics and bioinformatics studies on extracts of ruptured and stable areas of freshly harvested human carotid plaques. We also applied a separate protein-analysis method (protein topography and migration analysis platform) to attempt to identify substrates and proteolytic fragments in mouse and human plaque extracts. Approximately 10% of extracted aortic proteins were reproducibly altered in SR-uPA+/0 aortas. Proteases, inflammatory signaling molecules, as well as proteins involved with cell adhesion, the cytoskeleton, and apoptosis, were increased. ECM (Extracellular matrix) proteins, including basement-membrane proteins, were decreased. Approximately 40% of proteins were altered in ruptured versus stable areas of human carotid plaques, including many of the same functional categories that were altered in SR-uPA+/0 aortas. Collagens were minimally altered in SR-uPA+/0 aortas and ruptured human plaques; however, several basement-membrane proteins were reduced in both SR-uPA+/0 aortas and ruptured human plaques. Protein topography and migration analysis platform did not detect robust increases in proteolytic fragments of ECM proteins in either setting. CONCLUSIONS:Parallel studies of SR-uPA+/0 mouse aortas and human plaques identify mechanisms that connect proteolysis with plaque rupture, including inflammation, basement-membrane protein loss, and apoptosis. Basement-membrane protein loss is a prominent feature of ruptured human plaques, suggesting a major role for basement-membrane proteins in maintaining plaque stability.

Project description:ObjectivesThe aim of this study was to identify the determinants of plaque structural stress (PSS) and the relationship between PSS and plaques with rupture.BackgroundPlaque rupture is the most common cause of myocardial infarction, occurring particularly in higher risk lesions such as fibroatheromas. However, prospective intravascular ultrasound-virtual histology studies indicate that <10% higher risk plaques cause clinical events over 3 years, indicating that other factors also determine plaque rupture. Plaque rupture occurs when PSS exceeds its mechanical strength; however, the determinants of PSS and its association with plaques with proven rupture are not known.MethodsWe analyzed plaque structure and composition in 4,053 virtual histology intravascular ultrasound frames from 32 fibroatheromas with rupture from the intravascular ultrasound-virtual histology in Vulnerable Atherosclerosis study and 32 fibroatheromas without rupture on optical coherence tomography from a stable angina cohort. Mechanical loading in the periluminal region was estimated by calculating maximum principal PSS by finite element analysis.ResultsPSS increased with increasing lumen area (r = 0.46; p = 0.001), lumen eccentricity (r = 0.32; p = 0.001), and necrotic core ≥10% (r = 0.12; p = 0.001), but reduced when dense calcium was ≥10% (r = -0.12; p = 0.001). Ruptured fibroatheromas showed higher PSS (133 kPa [quartiles 1 to 3: 90 to 191 kPa] vs. 104 kPa [quartiles 1 to 3: 75 to 142 kPa]; p = 0.002) and variation in PSS (55 kPa [quartiles 1 to 3: 37 to 75 kPa] vs. 43 kPa [quartiles 1 to 3: 34 to 59 kPa]; p = 0.002) than nonruptured fibroatheromas, with rupture primarily occurring either proximal or immediately adjacent to the minimal luminal area (87.5% vs. 12.5%; p = 0.001). PSS was higher in segments proximal to the rupture site (143 kPa [quartiles 1 to 3: 101 to 200 kPa] vs. 120 kPa [quartiles 1 to 3: 78 to 180 kPa]; p = 0.001) versus distal segments, associated with increased necrotic core (19.1% [quartiles 1 to 3: 11% to 29%] vs. 14.3% [quartiles 1 to 3: 8% to 23%]; p = 0.001) but reduced fibrous/fibrofatty tissue (63.6% [quartiles 1 to 3: 46% to 78%] vs. 72.7% [quartiles 1 to 3: 54% to 86%]; p = 0.001). PSS >135 kPa was a good predictor of rupture in higher risk regions.ConclusionsPSS is determined by plaque composition, plaque architecture, and lumen geometry. PSS and PSS variability are increased in plaques with rupture, particularly at proximal segments. Incorporating PSS into plaque assessment may improve identification of rupture-prone plaques.

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Cholesterol crystal embolization following plaque rupture: a systemic disease with unusual features.

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