Lipid-rich Necrotic Core Research Articles

Association between plaque vulnerability and neutrophil extracellular traps (NETs) levels: The Plaque At RISK study

Carotid atherosclerotic plaque rupture and its sequelae are among the leading causes of acute ischemic stroke. The risk of rupture and subsequent thrombosis is, among others, determined by vulnerable plaque characteristics and linked to activation of the immune system, in which neutrophil extracellular traps (NETs) potentially play a role. The aim of this study was to investigate how plaque vulnerability is associated with NETs levels. We included 182 patients from the Plaque At RISK (PARISK) study in whom carotid imaging was performed to measure plaque ulceration, fibrous cap integrity, intraplaque hemorrhage, lipid-rich necrotic core, calcifications and plaque volume. Principal component analysis generated a 'vulnerability index' comprising all plaque characteristics. Levels of the NETs marker myeloperoxidase-DNA complex were measured in patient plasma. The association between the vulnerability index and low or high NETs levels (dependent variable) was assessed by logistic regression. No significant association between the vulnerability index and NETs levels was detected in the total population (odds ratio 1.28, 95% confidence interval 0.90-1.83, p = 0.18). However, in the subgroup of patients naive to statins or antithrombotic medication prior to the index event, this association was statistically significant (odds ratio 2.08, 95% confidence interval 1.04-4.17, p = 0.04). Further analyses revealed that this positive association was mainly driven by intraplaque hemorrhage, lipid-rich necrotic core and ulceration. In conclusion, plaque vulnerability is positively associated with plasma levels of NETs, but only in patients naive to statins or antithrombotic medication prior to the index event.

Role of diffusion-weighted imaging in carotid plaque vulnerability assessment

BackgroundMR plaque imaging is a valuable tool in characterizing carotid atherosclerotic plaque and identifying high-risk features. There are limited data on the role of the widely available single-shot diffusion-weighted imaging (DWI) in plaque characterization along with histological correlation. This study aimed to correlate the plaque characteristics identified by MR imaging in vivo at the level of maximum stenosis with histological plaque characteristics in the postoperative specimen.MethodsPatients who underwent carotid endarterectomy in a tertiary care center during one and half years were prospectively recruited for non-contrast MR carotid plaque imaging (including single-shot EPI-DWI sequence) in a 3 Tesla MRI using a dedicated carotid coil. An experienced radiologist correlated DWI sequence findings with histopathology of postsurgical sections to confirm the high-risk features.ResultsTwenty-three patients (mean age 66.1 years ± SD 6.25) were evaluated, of which 65% were males and 96% were symptomatic. Apparent diffusion coefficient (ADC) values in location of plaques could differentiate histopathological unstable from stable plaques (0.83 × 10–3 mm2/s vs 1.7 × 10–3 mm2/s; p 0.001), with a sensitivity and specificity of 75% and 79%, respectively, at an ADC cutoff of 1.24 × 10–3 mm2/s. Plaques with and without lipid-rich necrotic core (0.86 × 10–3 mm2/s vs 1.44 × 10–3 mm2/s; p = 0.042) as well as intraplaque hemorrhage could be differentiated (0.751 × 10–3 mm2/s vs 1.352 × 10–3 mm2/s; p 0.037) using the apparent diffusion coefficients.ConclusionThe widely available single-shot EPI-DWI in assessing plaque characteristics in carotid stenosis is promising and correlated with histopathological features. Diffusion-weighted imaging will be a helpful adjunct in patients when contrast administration is intolerable.

Associations between pericarotid fat density and image-based risk characteristics of carotid plaque

ObjectivesIn this study, we aimed to evaluate the associations between pericarotid fat density (PFD) and various risk characteristics of carotid plaque. MethodsWe retrospectively evaluated consecutive patients who were subjected to both high-resolution MRI and carotid artery CT angiography CTA at our institution between January 2016 and April 2021. The section of the carotid artery with the most severe lumen stenosis was selected from each patient for analysis. Two separated regions of interest (ROI) (each with an area of 2.5 mm2 and located at least 1 mm from the outer margin of the carotid artery wall) were defined in the perivascular fat tissue. The mean value of PFD (mean HU) was measured on the plaque side and the same axial non-plaque side. Then, the bilateral difference (D-value HU) was calculated (plaque side mean HU minus non-plaque side mean HU). According to carotid plaque risk characteristics (American Heart Association VI type [AHA VI], intraplaque hemorrhage [IPH], thinning and/or rupture of the fibrous cap [TRFC], lipid-rich necrotic core [LRNC], and calcification [CA]), the associations between PFD and five different risk characteristic subgroups were analyzed. The Student’s t-test, Mann-Whitney U test, and Chi-square test were used to compare differences between different risk subgroups. Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive efficacy of PFD for carotid plaque risk characteristics. P < 0.05 was considered statistically significant. ResultsA total of 71 eligible patients (mean age 61.25 ± 10.35 years, 57 male) were examined in this study. For the plaque side and the non-plaque side, the mean PFD values were −36.25 ± 20.65 HU and −66.87 ± 15.00 HU, respectively. In the non-AHA VI and AHA VI subgroups, the values for the mean HU of the plaque side were −49.50 ± 20.53 and –33.55 ± 19.78, respectively (P = 0.014). The D-value HU was higher for the AHA VI group compared to the non-AHA VI group (33.61 ± 16.72 vs. 15.91 ± 14.52, respectively; P = 0.001). Compared to the non-IPH subgroup, the IPH subgroup had a higher mean HU value for the plaque side (-47.68 ± 18.26 vs. −29.63 ± 19.16, respectively; P < 0.001) and a higher D-value HU (17.80 ± 13.27 vs. 38.03 ± 15.46, respectively; P < 0.001). Compared to the low risk non-TRFC subgroup, the TRFC subgroup had a higher D-value HU (24.51 ± 16.16 vs. 33.55 ± 17.65, respectively; P = 0.042). The D-value of PFD was found to be a significant predictor of both AHA VI classification (AUC: 0.79; SE: 64.41%; SP: 83.33%; P = 0.0001) and IPH (AUC: 0.83; SE: 88.89%; SP: 65.38%; P < 0.0001). ConclusionOur study found that PFD was significantly associated with high risk AHA VI plaque characterization, IPH, and TRFC. Therefore, PFD has the potential to be used as an indirect clinical marker of plaque instability.

Carotid Plaque Composition and the Importance of Non-Invasive in Imaging Stroke Prevention.

Luminal stenosis has been the standard feature for the current management strategies in patients with atherosclerotic carotid disease. Histological and imaging studies show considerable differences between plaques with identical degrees of stenosis. They indicate that specific plaque characteristics like Intraplaque hemorrhage, Lipid Rich Necrotic Core, Plaque Inflammation, Thickness and Ulceration are responsible for the increased risk of ischemic events. Intraplaque hemorrhage is defined by the accumulation of blood components within the plaque, Lipid Rich Necrotic Core is composed of macrophages loaded with lipid, Plaque Inflammation is defined as the process of atherosclerosis itself and Plaque thickness and Ulceration are defined as morphological features. Advances in imaging methods like Magnetic Resonance Imaging, Ultrasound, Computed Tomography and Positron Emission Tomography have enabled a more detailed characterization of the plaque, and its vulnerability is linked to these characteristics, changing the management of these patients based only on the degree of plaque stenosis. Studies like Rotterdam, ARIC, PARISK, CAPIAS and BIOVASC were essential to evaluate and prove the relevance of these characteristics with cerebrovascular symptoms. A better approach for the prevention of stroke is needed. This review summarizes the more frequent carotid plaque features and the available validation from recent studies with the latest evidence.

Sub-micrometer morphology of human atherosclerotic plaque revealed by synchrotron radiation-based μCT—A comparison with histology

Histology is a long standing and well-established gold standard for pathological characterizations. In recent years however, synchrotron radiation-based micro-computed tomography (SRμCT) has become a tool for extending the imaging of two-dimensional thin sections into three-dimensional imaging of tissue blocks, enabling so-called virtual histology with arbitrary clipping planes, volumetric rendering and automatic segmentation. In this study, we present a thorough characterization of human carotid plaques after endarterectomy of patients with stroke or transient ischemic attack (TIA), investigating several different pathologic structures using both SRμCT and histology. Phase-contrast SRμCT was performed with two different magnifications (voxel sizes 6.5 μm and 0.65 μm, respectively), and histology was performed with multiple different stainings (Alpha-actin, Glycophorin A, von Kossa, Movat, CD68). The 0.65 μm high-resolution SRμCT was performed on selected areas with plaque typical relevant morphology, identified on the 6.5 μm low-resolution SRμCT. The tomography datasets were reconstructed with additional 3D volume rendering and compared to histology. In total, nine different regions with typical pathologic structures were identified and imaged with high-resolution SRμCT. The results show many characteristics typical for advanced atherosclerotic plaques, clinically relevant, namely ruptures with thrombosis, neo-vascularization, inflammatory infiltrates in shoulder regions, lipid rich necrotic cores (LRNC), thin fibrous cap, calcifications, lumen irregularities, and changes in vessel wall structures such as the internal elastic membrane. This method’s non-destructive nature renders details of micro-structures with an excellent visual likeness to histology, with the additional strength of multiplanar and 3D visualization and the possibility of multiple re-scans.

Comparison of carotid atherosclerotic plaque characteristics between symptomatic patients with transient ischemic attack and stroke using high-resolution magnetic resonance imaging

BackgroundThis study aimed to compare the characteristics of carotid plaques between patients with transient ischemic attack (TIA) and ischemic stroke using magnetic resonance (MR) imaging.MethodsPatients with a recent ischemic stroke or TIA who exhibited atherosclerotic plaques of carotid arteries in the symptomatic sides determined by MR vessel wall imaging were recruited. The plaque morphology and compositions including intraplaque hemorrhage (IPH), lipid-rich necrotic-core (LRNC) and calcification were compared between TIA and stroke patients. Logistic regression was performed to relate the plaque characteristics to the types of ischemic events.ResultsA total of 270 patients with TIA or ischemic stroke were recruited. Stroke patients had a significantly higher prevalence of diabetes (42.2% vs. 28.2%, p = 0.021), greater mean wall area (35.1 ± 10.1 mm2 vs. 32.0 ± 7.7 mm2, p = 0.004), mean wall thickness (1.3 ± 0.2 mm vs. 1.2 ± 0.2 mm, p = 0.001), maximum normalized wall index (NWI)(63.9% ± 6.0% vs. 62.2% ± 5.9%, p = 0.023) and %volume of LRNC (9.7% ± 8.2% vs. 7.4% ± 7.9%, p = 0.025) in the carotid arteries compared to those with TIA. After adjustment for clinical factors, above characteristics of carotid arteries were significantly associated with the type of ischemic events. After further adjustment for maximum NWI, this association remained statistically significant (OR, 1.41; CI, 1.01–1.96; p = 0.041).ConclusionsIschemic stroke patients had larger plaque burden and greater proportion of LRNC in carotid plaques compared to those with TIA. This study suggests that ischemic stroke patients had more vulnerable plaques compared to those with TIA.

Co-existing Hypertension and Hyperhomocysteinemia Increases the Risk of Carotid Vulnerable Plaque and Subsequent Vascular Event: An MR Vessel Wall Imaging Study

PurposeThis study sought to determine the associations of co-existing hypertension and hyperhomocysteinemia (H-Hcy) with carotid vulnerable plaque features and subsequent vascular events.MethodsSymptomatic patients with carotid atherosclerosis were enrolled and underwent carotid magnetic resonance (MR) vessel wall imaging. The patients were divided into the following groups: co-existing hypertension and H-Hcy group; isolated hypertension group; isolated H-Hcy group; and control group. The morphological and compositional characteristics of carotid plaques were assessed on MR images and compared among different groups. Univariate and multivariate cox regressions were used to calculate the hazard ratio (HR) and corresponding 95% confidence interval (CI) of co-existing hypertension and H-Hcy in predicting subsequent vascular events after at least 1-year followed-up.ResultsIn total, 217 patients (mean age, 59.4 ± 11.9 years; 154 males) were recruited. Patients in co-existing hypertension and H-Hcy group had a significantly higher prevalence of carotid lipid-rich necrotic core (LRNC) than isolated H-Hcy and control group (73.2 vs. 43.3 vs. 50%, p = 0.015). During the median follow-up time of 12.2 ± 4.3 months, 61 (39.8%) patients experienced vascular events. After adjusting for baseline confounding factors, co-existing hypertension and H-Hcy (HR, 1.82; 95% CI, 1.01–3.27; p = 0.044), presence of carotid LRNC (HR, 2.25; 95% CI, 1.09–4.65; p = 0.029), and combination of co-existing hypertension and H-Hcy and carotid LRNC (HR, 2.39; 95% CI, 1.26–4.43; p = 0.007) were significantly associated with subsequent vascular events.ConclusionsCo-existing hypertension and H-Hcy are associated with carotid vulnerable plaque features, such as LRNC. Combining co-existing hypertension and H-Hcy with carotid vulnerable plaque features has a stronger predictive value for subsequent vascular events than each measurement alone.

Detection of Vulnerable Coronary Plaques Using Invasive and Non-Invasive Imaging Modalities.

Acute coronary syndrome (ACS) mostly arises from so-called vulnerable coronary plaques, particularly prone for rupture. Vulnerable plaques comprise a specific type of plaque, called the thin-cap fibroatheroma (TFCA). A TCFA is characterized by a large lipid-rich necrotic core, a thin fibrous cap, inflammation, neovascularization, intraplaque hemorrhage, microcalcifications or spotty calcifications, and positive remodeling. Vulnerable plaques are often not visible during coronary angiography. However, different plaque features can be visualized with the use of intracoronary imaging techniques, such as intravascular ultrasound (IVUS), potentially with the addition of near-infrared spectroscopy (NIRS), or optical coherence tomography (OCT). Non-invasive imaging techniques, such as computed tomography coronary angiography (CTCA), cardiovascular magnetic resonance (CMR) imaging, and nuclear imaging, can be used as an alternative for these invasive imaging techniques. These invasive and non-invasive imaging modalities can be implemented for screening to guide primary or secondary prevention therapies, leading to a more patient-tailored diagnostic and treatment strategy. Systemic pharmaceutical treatment with lipid-lowering or anti-inflammatory medication leads to plaque stabilization and reduction of cardiovascular events. Additionally, ongoing studies are investigating whether modification of vulnerable plaque features with local invasive treatment options leads to plaque stabilization and subsequent cardiovascular risk reduction.

Carotid Plaque Composition and Prediction of Incident Atherosclerotic Cardiovascular Disease.

Whether information on carotid plaque composition contributes to prediction of incident atherosclerotic cardiovascular disease (ASCVD) remains to be investigated. We determined the sex-specific added value of carotid plaque components for predicting incident ASCVD events, beyond traditional cardiovascular risk factors. Between 2007 and 2012, participants from the population-based Rotterdam Study with asymptomatic carotid wall thickening >2.5 mm on ultrasonography were invited for carotid magnetic resonance imaging. Among 1349 participants (mean age: 72 years [SD±9.3], 49.5% women) without cardiovascular disease, we assessed plaque thickness, luminal stenosis (>30%), presence of intraplaque hemorrhage, lipid-rich necrotic core, and calcification. Follow-up for ASCVD was complete until January 1, 2015. Using Cox proportional hazards models, we fitted sex-specific prediction models including traditional cardiovascular risk factors (base model). We extended the base model by single and simultaneous additions of plaque characteristics and calculated improvement of model performance by the C statistics. During a median follow-up of 4.8 years, 60 men and 48 women developed ASCVD. In women, presence of intraplaque hemorrhage was associated with incident ASCVD (adjusted hazard ratio, 3.37 [95% CI, 1.81-6.25]). The C statistic (95% CI) improved from 0.73 (0.66-0.79) to 0.76 (0.70-0.83) after single addition of intraplaque hemorrhage to the base model. Simultaneous addition of plaque components, plaque thickness, and stenosis did not change the results. In men, only carotid stenosis was statistically significantly associated with incident ASCVD (adjusted hazard ratio, 1.75 [95% CI, 1.00-3.08]); yet, the association diminished after the addition of other plaque characteristics, and no improvements were observed in C statistics. Presence of intraplaque hemorrhage contributes to the prediction of incident ASCVD in women, beyond traditional cardiovascular risk factors, other plaque components, plaque size, and stenosis.

Imaging Approaches to the Diagnosis of Vascular Diseases.

Vascular imaging is a complex field including numerous modalities and imaging markers. This review is focused on important and recent findings in atherosclerotic carotid artery plaque imaging with an emphasis on developments in magnetic resonance imaging (MRI) and computed tomography (CT). Recent evidence shows that carotid plaque characteristics and not onlyestablished measures of carotid plaque burden and stenosis are associatedindependently with cardiovascular outcomes. On carotid MRI, the presence of a lipid-rich necrotic core (LRNC) has been associated with incident cardiovascular disease (CVD) events independent of wall thickness, a traditional measure of plaque burden. On carotid MRI, intraplaque hemorrhage (IPH) presence has been identified as an independent predictor of stroke. The presence of a fissured carotid fibrous cap has been associated with contrast enhancement on CT angiography imaging. Carotid artery plaque characteristics have been associated with incident CVD events, and advanced plaque imaging techniques may gain additional prominence in the clinical treatment decision process.

Sex Differences in Plaque Composition and Morphology Among Symptomatic Patients With Mild-to-Moderate Carotid Artery Stenosis.

Incidence of ischemic stroke differs between men and women, with substantially higher rates in men. The underlying mechanism of this difference remains poorly understood but may be because of differences in carotid atherosclerosis. Using an in-depth imaging-based approach, we investigated differences between carotid plaque composition and morphology in male and female patients with stroke, taking into account differences in total plaque burden. Additionally, we investigated all possible within-artery combinations of plaque characteristics to explore differences between various plaque phenotypes. We included 156 men and 68 women from the PARISK (Plaque At Risk) study, a prospective cohort study of patients with recent ischemic cerebrovascular symptoms and <70% ipsilateral carotid stenosis. Plaque characteristics (intraplaque hemorrhage [IPH], lipid-rich necrotic core [LRNC], calcifications, thin-or-ruptured fibrous cap, ulcerations, total plaque volume) were assessed with magnetic resonance imaging and multidetector-row computed tomography angiography. We used multivariable logistic and linear regression analyses to assess sex differences in plaque characteristics. We found significant difference in total plaque volume between men and women (β=22.9 mm3 [95% CI, 15.4-30.5]; mean volume in men 1399±425 mm3, in women 1011±242 mm3). Additionally, men were more likely to have IPH (odds ratio [OR]=2.8 [95% CI, 1.3-6.3]; IPH proportion in men 49%, in women 16%) and LRNC (OR=2.4 [95% CI, 1.2-4.7]; LRNC proportion in men 73%, in women 41%) even after adjustment for total plaque volume. We found no sex-specific differences in plaque volume-corrected volumes of IPH, LRNC, and calcifications. In terms of coexistence of plaque characteristics, we found that men had more often a plaque with coexistence of calcifications, LRNC, and IPH (OR=2.7 [95% CI, 1.2-7.0]), with coexistence of thin-or-ruptured fibrous cap/ulcerations, LRNC, and IPH (OR=2.4 [95% CI, 1.1-5.9]), and with coexistence of all plaque characteristics (OR=3.0 [95% CI, 1.2-8.6]). In symptomatic patients with mild-to-moderate carotid stenosis, men are more likely to have a high-risk carotid plaque with IPH and LRNC than women, regardless of total plaque burden. Men also have more often a plaque with multiple vulnerable plaque components, which could comprise an even higher stroke risk. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01208025.

Atherosclerosis: Pathogenesis and Key Cellular Processes, Current and Emerging Therapies, Key Challenges, and Future Research Directions.

Atherosclerosis is the principal cause of cardiovascular disease that continues to be a substantial drain on healthcare systems, being responsible for about 31% of all global deaths. Atherogenesis is influenced by a range of factors, including oxidative stress, inflammation, hypertension, and hyperlipidemia, and is ultimately driven by the accumulation of low-density lipoprotein cholesterol within the arterial wall of medium and large arteries. Lipoprotein accumulation stimulates the infiltration of immune cells (such as monocytes/macrophages and T-lymphocytes), some of which take up the lipoprotein, leading to the formation of lipid-laden foam cells. Foam cell death results in increased accumulation of dead cells, cellular debris and extracellular cholesterol, forming a lipid-rich necrotic core. Vascular smooth muscle cells from the arterial media also migrate into the intima layer and proliferate, taking up the available lipids to become foam cells and producing extracellular matrix proteins such as collagen and elastin. Plaque progression is characterized by the formation of a fibrous cap composed of extracellular matrix proteins and smooth muscle cells, which acts to stabilize the atherosclerotic plaque. Degradation, thinning, and subsequent rupture of the fibrous cap leads to lumen-occlusive atherothrombosis, most commonly resulting in heart attack or stroke. This chapter describes the pathogenesis of atherosclerosis, current and emerging therapies, key challenges, and future directions of research.

Association Between 18-FDG Positron Emission Tomography and MRI Biomarkers of Plaque Vulnerability in Patients With Symptomatic Carotid Stenosis.

Purpose: Pathologic studies suggest that unstable plaque morphology and inflammation are associated with cerebrovascular events. 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) is a validated technique for non-invasive imaging of inflammation-related plaque metabolism, and MRI can identify morphologic features of plaque instability. The aim of this study was to investigate the association of selected imaging characteristics of plaque vulnerability measured with MRI and PET in patients with symptomatic carotid stenosis.Methods: Patients from the BIOVASC study were selected based on the following inclusion criteria: (1) age ≥ 50 years; (2) recent (<30 days) ischaemic stroke (modified Rankin scale ≤3) or motor/speech/vision TIA; (3) ipsilateral internal carotid artery stenosis (≥5 0% lumen-narrowing); (4) carotid PET/CTA and MRI completed. Semi-automated plaque analysis of MRI images was performed to quantify morphologic features of plaque instability. PET images were co-registered with CTA and inflammation-related metabolism expressed as maximum standardised uptake value (SUVmax).Results: Twenty-five patients met inclusion criteria (72% men, mean age 65 years). MRI-measured plaque volume was greater in men (1,708–1,286 mm3, p = 0.03), patients who qualified with stroke (1,856–1,440 mm3, p = 0.05), and non-statin users (1,325–1,797 mm3, p = 0.03). SUVmax was associated with MRI-measured plaque lipid-rich necrotic core (LRNC) in the corresponding axial slice (rs = 0.64, p < 0.001) and was inversely associated with whole-plaque fibrous cap thickness (rs = −0.4, p = 0.02) and calcium volume (rs = −0.4, p = 0.03).Conclusion: This study demonstrated novel correlations of non-invasive imaging biomarkers of inflammation-related plaque metabolism with morphological MRI markers of plaque instability. If replicated, our findings may support the application of combined MRI and PET to detect vulnerable plaque in future clinical practise and randomised trials.

Optimal management of asymptomatic carotid stenosis in 2021: the jury is still out. An international, multispecialty, expert review and position statement.

The recommendations of international guidelines for the management of asymptomatic carotid stenosis (ACS) often vary considerably and extend from a conservative approach with risk factor modification and best medical treatment (BMT) alone, to a more aggressive approach with a carotid intervention plus BMT. The aim of the current multispecialty position statement was to reconcile the conflicting views on the topic. A literature review was performed with a focus on data from recent studies. Several clinical and imaging high-risk features have been identified that are associated with an increased long-term ipsilateral ischemic stroke risk in patients with ACS. Such high-risk clinical/imaging features include intraplaque hemorrhage, impaired cerebrovascular reserve, carotid plaque echolucency/ulceration/ neovascularization, a lipid-rich necrotic core, a thin or ruptured fibrous cap, silent brain infarction, a contralateral transient ischemic attack/stroke episode, male patients <75 years and microembolic signals on transcranial Doppler. There is growing evidence that 80-99% ACS indicate a higher stroke risk than 50-79% stenoses. Although aggressive risk factor control and BMT should be implemented in all ACS patients, several high-risk features that may increase the risk of a future cerebrovascular event are now documented. Consequently, some guidelines recommend a prophylactic carotid intervention in high-risk patients to prevent future cerebrovascular events. Until the results of the much-anticipated randomized controlled trials emerge, the jury is still out regarding the optimal management of ACS patients.

Abdominal Visceral Adiposity Is Associated with Coronary Artery Plaque Lipid-Rich Necrotic Core Partly Mediated by Bone Marrow Uptake of 18F-FDG Positron Emission Tomography/Computed Tomography in Psoriasis

Psoriasis is a chronic inflammatory disease with heightened cardiometabolic risk and adverse cardiovascular (CV) events (Greb et al., 2016). Patients with psoriasis tend to be overweight and have increased visceral adipose tissue (VAT) volume. VAT, a metabolically active fat depot (Wong et al., 2019) accompanied by immune cell dysfunction, is associated with early signs of coronary plaque progression such as noncalcified burden (NCB) and vascular inflammation (Hjuler et al., 2017; Sajja et al., 2020) beyond traditional CV risk factors.

Heightened splenic and bone marrow uptake of 18F-FDG PET/CT is associated with systemic inflammation and subclinical atherosclerosis by CCTA in psoriasis: An observational study

Background and aimsPsoriasis is an immune-mediated inflammatory disease with increased risk of myocardial infarction. Preclinical studies in psoriasis models show an association between chronic inflammation and immune cell proliferation in the spleen and bone marrow (BM). We sought to test the hypothesis that splenic and BM 18F-fluorodeoxyglucose (18F-FDG) uptake is heightened in psoriasis and that higher uptake associates with systemic inflammation and subclinical atherosclerotic disease measures in this cohort. MethodsMultimodality imaging and biomarker assays were performed in 240 participants (210 with psoriasis and 30 healthy). Splenic and BM uptake was obtained using 18F-FDG positron emission tomography/computed tomography (PET/CT). Coronary artery plaque characteristics including non-calcified burden (NCB) and lipid rich necrotic core (LRNC) were quantified using a dedicated software for CT angiography. All analyses were performed with StataIC 16 (Stata Corp., College Station, TX, USA). ResultsSplenic and BM 18F-FDG uptake was increased in psoriasis (vs. healthy volunteers) and significantly associated with proatherogenic lipids, immune cells and systemic inflammation. Higher splenic 18F-FDG uptake associated with higher total coronary burden (β = 0.37; p<0.001), NCB (β = 0.39; p<0.001), and LRNC (β = 0.32; p<0.001) in fully adjusted models. Similar associations were seen for BM 18F-FDG uptake in adjusted models (β = 0.38; β = 0.41; β = 0.24; respectively, all p<0.001). ConclusionsHeightened splenic and BM uptake of 18F-FDG is associated with proatherogenic lipids, immune cells, inflammatory markers and coronary artery disease. These findings provide insights into atherogenic mechanisms in psoriasis and suggest that immune cell proliferation in the spleen and BM is associated with subclinical atherosclerosis.

Chronic inflammation in psoriasis promotes visceral adipose tissue association with lipid-rich necrotic core through atherogenic myeloid score

Abstract Background/Introduction Psoriasis is a chronic inflammatory condition associated with adipose dysfunction and high-risk coronary artery disease features, including non-calcified coronary burden (NCB) and lipid-rich necrotic core (LRNC). Visceral adipose tissue (VAT) is a metabolically-active depot that secretes inflammatory and proatherogenic factors, and is associated with increased NCB. Additionally, an atherogenic myeloid score (AMS) comprised of classical monocytes, low-density granulocytes, and platelets was shown to associate with psoriasis severity and NCB. Purpose To investigate the relationship between VAT and high-risk plaque features and test whether this relationship was potentially mediated by myeloid cells. Methods A cohort of 131 psoriasis patients were included in this study. Atherogenic myeloid score components were calculated using complete blood count data (platelets) and by flow cytometry (monocytes, LDGs). Coronary NCB and LRNC were quantified using QAngio and vascuCAP respectively. VAT was defined as intra-abdominal fat and was quantified using an automated contouring software with abdominal CT scans. Statistical analyses were performed using STATA 12. Results The cohort was middle-aged 50 (42–61) (median (IQR)), and predominantly male (61%). High VAT vs low VAT groups differed significantly in their NCB ((0.910±0.279) vs (1.431±0.517)); p&amp;lt;0.001), (mean ± SD). After adjustment for cardiovascular risk factors, VAT associated with the atherogenic myeloid score (β=0.221, p=0.044), with LRNC (β=0.128, p=0.047), and atherogenic myeloid score associated with LRNC (β=0.161, p=0.003). The relationship of VAT to LRNC was partially mediated by atherogenic myeloid score (25.14%, p=0.029) (Figure 1). Conclusions VAT associated with LRNC, and this relationship was partially mediated by the atherogenic myeloid score. These findings suggest that bioactive VAT may impart risk on coronary artery disease in part through myeloid cells. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Heart, Lung, and Blood Institute Intramural Research Program in Bethesda, Maryland Figure 1. Log-transformed atherogenic myeloid score partially mediates the relationship between VAT and log-transformed LRNC. Adjusted by Framingham Risk Score, PASI score, biologic therapy, statin therapy, type 2 diabetes, hyperlipidemia, and subcutaneous adipose tissue volume. Red arrow: represents indirect effect; Beta: standard regression coefficient.

Bone marrow and splenic metabolic activity by 18F-FDG PET/CT are associated with noncalcified coronary burden and lipid-rich necrotic core in psoriasis

Abstract Background/Introduction Psoriasis is an immune-mediated inflammatory skin condition with an increased risk of myocardial infarction (MI). Elevated bone marrow (BM) and splenic hematopoiesis occurs after MI. In stable patients without chronic inflammation, higher splenic hematopoiesis predicts major adverse cardiovascular events (MACE). Nevertheless, studies in humans investigating these relationships in states of chronic inflammation on coronary artery disease features associated with MACE are limited. Purpose To investigate the relationships between bone marrow and splenic metabolic activity by [18]-fluorodeoxyglucose (FDG) PET/CT and subclinical cardiovascular disease in psoriasis. Methods Healthy participants (N=30) and psoriasis participants (N=210) were age and sex matched. All participants underwent 18FDG PET/CT and CT angiography (Toshiba 320 slice). Coronary artery plaque characteristics were assessed using QAngio CT (Medis, The Netherlands) and lipid rich necrotic core (LRNC) was assessed using vascuCAP (Elucid Bioimaging, Boston, MA). For tissue metabolic activities target-to-background ratio (TBR) was calculated as the ratio of arterial and venous standardized uptake values (SUV). Results The psoriasis cohort was middle aged 49.2 (±SD 11.9) years and predominantly male (64%). Those with psoriasis vs. healthy participants had higher BM (1.58 (IQR 1.35–1.89) vs. 1.23 (IQR 1.14–1.35); p&amp;lt;0.001) and splenic (1.40 (IQR 1.21–1.66) vs.1.17 (IQR 1.11–1.26); p&amp;lt;0.001) metabolic activity. After adjustment for cardiovascular risk factors bone marrow metabolic activity was associated with total burden, non-calcified burden (NCB) and LRNC (β=0.36, β=0.39, β=0.26; all p&amp;lt;0.001) respectively. Similar findings were observed for splenic activity (β=0.33, β=0.36, β=0.36; all p&amp;lt;0.001). In ROC analysis, when comparing area under the curve, BM activity better incrementally predicted non-calcified burden and lipid rich necrotic core compared to splenic activity (Figure). Conclusions BM and splenic metabolic activity are increased in psoriasis. Both are associated with coronary artery disease but there was a slightly stronger association with BM activity compared to splenic activity, These findings warrant further study to understand immune mechanisms underlying these observations. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Heart, Lung and Blood Institute Intramural Research Program in Bethesda, Maryland Figure 1. Median values of NCB and LRNC were used to convert these continuous variables into dichotomous variables such that values ≤ median were designated as 0 and values &amp;gt;median were designated 1. Bone marrow model compared to base model and splenic model added incremental value in predicting NCB (p&amp;lt;0.0001) and LRNC (p=0.0003). Base model: Framingham risk score, lipid treatment, biologic therapy, homeostasis model assessment as an index of insulin resistance (HOMA-IR), low density lipoprotein (LDL).

Directly quantified abdominal subcutaneous adipose tissue volume is negatively associated with subclinical coronary artery disease in men with psoriasis

Abstract Background Psoriasis is a common chronic inflammatory condition associated with an increased risk of obesity and higher coronary atherosclerosis burden by coronary computed tomography angiography (CCTA). Prior studies have shown that the ability to expand subcutaneous adipose tissue (SAT) may serve to identify individuals at a lower risk of atherosclerotic cardiovascular disease. However, the relationship between abdominal SAT and high-risk subclinical coronary artery disease requires exploration. Purpose To characterize the relationship between abdominal SAT volume measured on low-dose computed tomography, and coronary artery disease assessed as noncalcified and lipid-rich necrotic core burden by CCTA in psoriasis. Methods We performed a cross-sectional study of 232 participants with psoriasis and without known cardiovascular disease. All participants underwent CCTA to characterize coronary artery disease burden and low dose abdominal computed tomography to quantify subcutaneous adipose tissue volumes. Fat depot volumes were first adjusted in a sex specific manner for each participant's body mass index in a linear regression model. The residual values from the sex stratified linear regression models were used for analyses. Coronary artery disease burden was quantified in the three main coronary arteries (QAngio, Medis, The Netherlands) and averaged. Analyses were performed with StataIC 16 (Stata Corp., College Station, TX, USA). Results Of the 232 participants, 92 (40%) were women and the average age was 50 years. In women, there was a positive correlation between abdominal SAT and systemic inflammation as assessed by hs-CRP (r=0.30; p=0.004) and GlycA (r=0.29; p=0.007) as well as total cholesterol (r=0.24; p=0.02) and LDL cholesterol (r=0.22; p=0.04). In men, abdominal SAT correlated with hs-CRP (r=0.18; p=0.04) and insulin resistance as assessed by the homeostatic model for insulin resistance (r=0.17; p=0.04). In models fully adjusted for traditional cardiovascular risk factors, abdominal SAT volume negatively associated with noncalcified and lipid-rich necrotic core burden in men (β=−0.17; p=0.03, β=−0.21; p=0.02, respectively), but not women (β=−0.04; p=0.72, β=0.05; p=0.68, respectively) with psoriasis (Table). Conclusions In psoriasis, for a given body mass index, abdominal SAT negatively associated with coronary atherosclerosis burden in men. The observed sex-specific effects on subclinical coronary artery disease warrant further study of abdominal SAT in states of chronic inflammation. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Heart, Lung and Blood Institute Intramural Research Program in Bethesda, Maryland

Intraplaque CTA characteristics as predictors of symptomatology: a semiautomated volumetric analysis.

Prior studies comparing CT characteristics of carotid plaques to symptomatology have relied on gross morphologic imaging features. This study sought to determine if volumetric measurements of carotid plaque components are associated with ipsilateral neurologic symptoms. CTA images of consecutive patients that underwent a carotid endarterectomy were reviewed with a semiautomated software package. Intraplaque volumes of intraplaque hemorrhage (IPH), lipid-rich necrotic core (LRNC), and matrix were computed, as was the degree of arterial stenosis. Statistics were analyzed on a per cerebral hemisphere basis, and dichotomized into symptomatic and asymptomatic. Clinical and radiological endpoints included transient ischemic attack (TIA), ischemic stroke diagnosed on imaging studies, ophthalmologically diagnosed central or branch retinal artery occlusion (RAO), or amaurosis fugax. One hundred sixty-eight carotid plaques were reviewed. The average age is 70.8years (SD = 8.8); 32/87 (36.8%) were female. Sixty-seven of eighty-seven (77.0%) patients were symptomatic. Sixty-six of one hundred sixty-eight (39.3%) plaques were ipsilateral to the patient's symptoms, while 102/168 (60.7%) were ipsilateral to an asymptomatic hemisphere. Greater intraplaque volumes of IPH (p = 0.03), LRNC (p = 0.008), and matrix (p = 0.0008) were associated with symptoms, as was greater proportion of LRNC in regard to plaque volume (p = 0.04). All but proportion of LRNC remained statistically significant after adjustment for plaque size. More severe luminal stenosis was also associated with ipsilateral neurologic symptoms, both when calculated by smallest diameter or by area (p < 0.0001 for both). Higher volumes of intraplaque IPH, LRNC, matrix, and degree of arterial stenosis are associated with ipsilateral neurologic symptoms. Greater intraplaque proportions of LRNC are also associated with ipsilateral ischemic manifestations, suggesting that larger relative composition of lipids may be particularly predictive of symptomatology.