Plaque Rupture and Thrombosis Are Reduced by Lowering Cholesterol Levels and Crystallization With Ezetimibe and Are Correlated With Fluorodeoxyglucose Positron Emission Tomography

Patel, Roshan; Janoudi, Abed; Vedre, Ameeth; Aziz, Kusai; Tamhane, Umesh; Rubinstein, Jack; Abela, Oliver G.; Berger, Kevin L.; Abela, George S.

doi:10.1161/atvbaha.111.226167

Cited by 54 publications

(31 citation statements)

References 30 publications

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“…Hence, the current study provides the first such relationship between index inflammatory imaging and subsequent local plaque progression. Prior animal studies have shown that areas with high FDG uptake were associated with plaque thrombosis, 29,30 whereas human studies have shown that high aortic and carotid FDG uptake is related to subsequent risk of plaque rupture and clinical events. [31][32][33] However, in those studies, the relationship between location of inflammation and the location (or vessel bed) of the subsequent atherothrombotic event was not reported.…”

Section: Discussionmentioning

confidence: 99%

Focal Arterial Inflammation Precedes Subsequent Calcification in the Same Location

Abdelbaky

Corsini

Figueroa

et al. 2013

Circ: Cardiovascular Imaging

153

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Background— Arterial calcium (Ca) deposition has been identified as an active inflammatory process. We sought to test the hypothesis that local vascular inflammation predisposes to subsequent arterial calcium deposition in humans. Methods and Results— From a hospital database, we identified 137 patients (age, 61±13 years; 48.1% men) who underwent serial positron-emission tomography/computed tomography (1–5 years apart). Focal arterial inflammation was prospectively determined by measuring 18F-flourodeoxyglucose uptake (using baseline positron-emission tomography) within predetermined locations of the thoracic aortic wall and was reported as a standardized uptake value. A separate, blinded investigator evaluated calcium deposition (on the baseline and follow-up computed tomographic scans) along the same standardized sections of the aorta. New calcification was prospectively defined using square root–transformed difference of calcium volume score, with a cutoff value of 2.5. Accordingly, vascular segment was classified as either with or without subsequent calcification. Overall, 67 (9%) of aortic segments demonstrated subsequent calcification. Baseline median (interquartile range) standardized uptake value was higher in segments with versus without subsequent calcification (2.09 [1.84–2.44] versus 1.92 [1.72–2.20], P =0.002). This was also true in the subset of segments with Ca present at baseline (2.08 [1.81–2.40] versus 1.86 [1.66–2.09], P =0.02), as well as those without (2.17 [1.87–2.51] versus 1.93 [1.73–2.20], P =0.04). Furthermore, across all patients, subsequent Ca deposition was associated with the underlying 18F-flourodeoxyglucose uptake (inflammatory signal), measured as standardized uptake value (odds ratio [95% confidence interval]=2.94 [1.27–6.89], P =0.01) or target-to-background ratio (2.59 [1.18–5.70], P =0.02), after adjusting for traditional cardiovascular risk factors. Conclusions— Here, we provide first-in-man evidence that arterial inflammation precedes subsequent Ca deposition, a marker of plaque progression, within the underlying location in the artery wall.

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Section: Discussionmentioning

confidence: 99%

Focal Arterial Inflammation Precedes Subsequent Calcification in the Same Location

Abdelbaky

Corsini

Figueroa

et al. 2013

Circ: Cardiovascular Imaging

153

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“…Local extracellular factors include a mild drop in local temperature, increased saturation of cholesterol, hydration of the cholesterol molecule and an alkaline milieu [ 20 ] . The formation of CCs is associated with an inflammatory response both locally and systemically [ 21- 22 ] . Crystals form early in the atherosclerotic process and activate the inflammasome NLRP3 leading to the secretion of IL-1β [ 22 ] .…”

Section: Pathogenesismentioning

confidence: 99%

“…Autopsy findings demonstrate that only patients who died of acute myocardial infarction had CCs perforating the intima while those who died of other causes and had significant arterial plaques did not have CCs perforating the intima [ 27 ] . In an atherosclerotic rabbit model, those with a greater plaque burden had more CCs, serum inflammation, macrophage infiltration and thrombosis [ 21 ] . Also, in the rabbit model, light and scanning electron microscopy demonstrated CCs in the inflamed fibrous cap and perforating the intima at the sites of plaque rupture [ 21, 28 ] .…”

Section: Pathogenesismentioning

confidence: 99%

“…In an atherosclerotic rabbit model, those with a greater plaque burden had more CCs, serum inflammation, macrophage infiltration and thrombosis [ 21 ] . Also, in the rabbit model, light and scanning electron microscopy demonstrated CCs in the inflamed fibrous cap and perforating the intima at the sites of plaque rupture [ 21, 28 ] . Moreover, CCs can readily puncture the vasa vasorum within the plaque causing intra-plaque hemorrhage that can contribute to plaque rupture [ 25, 27 ] .…”

Section: Pathogenesismentioning

confidence: 99%

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

et al. 2017

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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.

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“…Cholesterol crystals are highly pathogenic as they can cause rupture of cell membranes 27 and of the intimal surface of the plaque at the tissue level. 28,29 Intracellular cholesterol crystals can promote NLRP3 inflammasome activation in macrophages. 30,31 Downstream, the NLRP3 complex activates caspase-1 that cleaves and releases active interleukin-1b, a major chemokine for leukocyte attraction.…”

Section: Unesterified Cholesterol and Crystal Formationmentioning

confidence: 99%

From intraplaque haemorrhages to plaque vulnerability

Michel

Delbosc

Ho‐Tin‐Noé

et al. 2012

Journal of Cardiovascular Medicine

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Intraplaque hemorrhages are mainly related to inward neoangiogenesis, initiated from the adventitia by lipid-dependent outwardly convected signals, and by the immaturity of these neovessels, allowing leaks and hemorrhages. Repeated intraplaque hemorrhages play a major role in the evolution of thrombotic occlusive disease, similar to the role of intraluminal thrombus in the progression of abdominal aortic aneurysm toward rupture. Red blood cells (RBCs) are an important source of unesterified cholesterol, because their membranes are particularly cholesterol rich. This unesterified cholesterol is rapidly organized in cholesterol crystals, highly toxic for cell and membranes. Oxidized cholesterol and LDL provoke the irreversible covalent aggregation of proteins, including hemoglobin, forming ceroids, which are also highly toxic. Hemoglobin play a major role of prooxydant molecules in this context, by its ability to release heme and iron, the main catalyser of oxidative reaction. In the context of type 2 diabetes, the oxidative potential of intraplaque-free hemoglobin play a predominant role in the progression of atherothrombotic disease toward clinical expression. Associated to RBC, intraplaque hemorrhages convey leukocyte, mainly neutrophils in human, and plasma zymogen that are the main source of proteases, including coagulation proteases, activation of the fibrinolytique system, release of leukocyte serine proteases and cathepsins and activation of MMPs. These proteases concentrate in the hemorrhagic/necrotic core rendered plaque highly vulnerable. An adaptive immune response takes place in the adventitia, in regard of hemorrhagic plaques, in relation to outwardly convected oxidized or proteolyzed neoantigens, and chemokinic signals. Finally, intraplaque hemorrhages and thrombi are the site of weak pathogen entrapment, which promote all these oxydative and proteolytic phenomenons.

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Plaque Rupture and Thrombosis Are Reduced by Lowering Cholesterol Levels and Crystallization With Ezetimibe and Are Correlated With Fluorodeoxyglucose Positron Emission Tomography

Abstract: Lowering cholesterol levels with ezetimibe reduced plaque burden, crystallization, and inflammation, preventing plaque disruption and thrombosis.

Cited by 54 publications

References 30 publications

Focal Arterial Inflammation Precedes Subsequent Calcification in the Same Location

Focal Arterial Inflammation Precedes Subsequent Calcification in the Same Location

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

From intraplaque haemorrhages to plaque vulnerability

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