Risk Of Plaque Rupture Research Articles

Molecular mechanism of vascular calcification.

Intimal and medial calcification are increased with type 1 and type 2 diabetes, metabolic syndrome, chronic kidney disease, and ageing. There are several biological mechanisms through which vascular calcification increases all-cause mortality and atherosclerotic plaque rupture. Arterial medial calcification increases arterial stiffness that causes systolic hypertension and diastolic dysfunction and heart failure. In contrast, arterial intimal calcification is strongly associated with atherosclerotic plaque burden, predicting adverse arterial events. In particular, micro-calcifications within the fibrous caps are through to increase local stress and risk of plaque rupture. While vascular calcification has originally through to be a passive process, it has become increasingly clear that calcification of both intimal and medial layers is an active and tightly regulated process in which dynamic phenotypic changes of vascular smooth muscle cells plays a major role. Interestingly, the driving factors for medial and intimal calcification differ. Whilst uremia and senescence, high serum calcium and phosphate levels drives medial calcification, inflammation and oxidative stress are critical for intimal calcification. Despite the different drivers and environmental cues, the medial and intimal arterial calcification shares common intracellular signaling cascades to promoter cellular reprogramming and phenotypic switching. Recent studies employing new technologies demonstrate that calcifying extracellular vesicles(EVs)that have specific mineralization-promoting cargos such as tissue nonspecific alkaline phosphatase(TNAP), annexins Ⅱ and Ⅵ, are released from vascular smooth muscle, macrophages, and valvular interstitial cells, and serve as calcifying foci. Recent study identified a specific trafficking protein, sortilin, as a key player in the formation of calcifying EVs secreted by vascular smooth muscle cells. Research on aortic valve calcification using spatiotemporal multi-omics identified many secreted and structural matrix proteins not previously implicated in valvular calcification, and revealed that inflammation is likely to be a significant contributor regardless of the layers and stages of the aortic stenosis progression. Increased understanding of the precise molecular mechanisms of phenotypic switching of vascular smooth muscle offers the best chance to identify the potential drug targets for vascular calcification.

Personalized Assessment of the Coronary Atherosclerotic Arteries by Intravascular Ultrasound Imaging: Hunting the Vulnerable Plaque.

The term “vulnerable plaque” is commonly used to refer to an atherosclerotic plaque that is prone to rupture and the formation of thrombosis, which can lead to several cardiovascular and cerebrovascular events. Coronary artery atherosclerosis has a wide variety of different phenotypes among patients who may have a substantially variable risk for plaque rupture and cardiovascular events. Mounting evidence has proposed three distinctive histopathological mechanisms: plaque rupture, plaque erosion and calcified nodules. Studies have demonstrated the characteristics of plaques with high vulnerability such as the presence of a thin fibrous cap, a necrotic lipid-rich core, abundant infiltrating macrophages and neovascularization. However, traditional coronary angiographic imaging fails to determine plaque vulnerability features, and its ability to individualize treatment strategies is limited. In recent decades, catheter-based intravascular ultrasound imaging (IVUS) modalities have been developed to identify vulnerable plaques and ultimately vulnerable patients. The aim is to individualize prediction, prevention and treatment of acute coronary events based on the identification of specific features of high-risk atherosclerotic plaques, and to identify the most appropriate interventional procedures for their treatment. In this context, the aim of this review is to discuss how personalized assessment of coronary atherosclerotic arteries can be achieved by intravascular ultrasound imaging focusing on vulnerable plaque detection.

The Influence of Enhanced External Counterpulsation Intervention on the Biomechanical Stress Distribution of Advanced Plaque: A 3D FSI Study Based on in vivo Animal Experiment

Enhanced external counterpulsation (EECP) is an effective therapy to provide beneficial assistance for the failing heart by reducing cardiac afterload and increasing blood flow perfusion noninvasively. The technique of EECP involves the use of the EECP device to inflate and deflate a series of compression cuffs wrapped around the patient’s calves, lower thighs, and upper thighs. As the result, the enhanced flow perfusion is derived from the device’s propelling blood from veins of lower body to arteries of upper body and increases the blood supply for the important organs and brain. In the ACCF/AHA Guideline and ESC Guideline on the management of stable ischemic heart disease and coronary artery disease, EECP has been given a Class IIb and Class IIa recommendation respectively. In the ASA Guideline on the early management of Acute Ischemic stroke, EECP has been given a Class IIa recommendation. However, considering that EECP performance significantly elevates the acute blood pressure level as well as the perfusion level in systemic arterial tree and in diastolic, whether it will increase the risk of hypertension-related events such as atherosclerotic plaque rupture causes great concern in its clinical applications. But, the influence of EECP intervention on plaque progression remains elusive to this day and need to be assessed. It is generally agreed that biomechanical stresses play important roles in advanced atherosclerotic plaque progression and rupture. We hypothesized that EECP may intervene the advanced plaque progression via induced the variation of mechanical stresses in plaques. In this present paper, a pilot study containing animal experiment and numerical simulation was conducted to quantify the variations of biomechanical stresses of the plaque during EECP intervention. An experimentally induced hypercholesterolemic porcine model was developed and the basic hemodynamic measurements were performed in vivo before and during EECP intervention. Meanwhile, 3D multi-component idealized models with fluid-structure interactions (FSI) for carotid atherosclerotic plaques were introduced to solve the wall shear stress (WSS) and plaque structural stress (PWS) before and during intervention. Three cases of fibrous cap thickness (FC=600, 200 and 65μm) and three cases of material properties of the plaque components (normal, hard and soft) were involved in the current study. Numerical results showed that the max WSS level at the throat of the plaque, the 3D critical plaque wall stress (3D CPWS) level at the fibrous cap and the global max plaque wall stress (GMPWS) level at the shoulder of the plaque were all significantly augmented during EECP. When FC=65μm, EECP intervention augmented 118.1%±1.1% of the Max WSS level, 15.56%±1.68% of the 3D CPWS level and 14.78%±0.24% of the GMPWS level comparing to situations without EECP intervention. Considering that blood flow shear stress and structural stress are indexes that are presently thought might contribute to advanced plaque progression and its final rupture, our pilot study thus suggests that EECP treatment may intervene the plaque progression by elevating the levels of these indexes. But whether EECP treatment will increase the risk of plaque rupture and should be taken into account in its patient selection need a further detailed study and follow-up observation.

Pulse Wave Imaging in Carotid Artery Stenosis Human Patients in Vivo

Carotid stenosis involves narrowing of the lumen in the carotid artery potentially leading to a stroke, which is the third leading cause of death in the United States. Several recent investigations have found that plaque structure and composition may represent a more direct biomarker of plaque rupture risk compared with the degree of stenosis. In this study, pulse wave imaging was applied in 111 (n = 11, N = 13 plaques) patients diagnosed with moderate (>50%) to severe (>80%) carotid artery stenosis to investigate the feasibility of characterizing plaque properties based on the pulse wave-induced arterial wall dynamics captured by pulse wave imaging. Five (n = 5 patients, N = 20 measurements) healthy volunteers were also imaged as a control group. Both conventional and high-frame-rate plane wave radiofrequency imaging sequences were used to generate piecewise maps of the pulse wave velocity (PWV) at a single depth along stenotic carotid segments, as well as intra-plaque PWV mapping at multiple depths. Intra-plaque cumulative displacement and strain maps were also calculated for each plaque region. The Bramwell-Hill equation was used to estimate the compliance of the plaque regions based on the PWV and diameter. Qualitatively, wave convergence, elevated PWV and decreased cumulative displacement around and/or within regions of atherosclerotic plaque were observed and may serve as biomarkers for plaque characterization. Intra-plaque mapping revealed the potential to capture wave reflections between calcified inclusions and differentiate stable (i.e., calcified) from vulnerable (i.e., lipid) plaque components based on the intra-plaque PWV and cumulative strain. Quantitatively, one-way analysis of variance indicated that the pulse wave-induced cumulative strain was significantly lower (p < 0.01) in the moderately and severely calcified plaques compared with the normal controls. As expected, compliance was also significantly lower in the severely calcified plaques regions compared with the normal controls (p < 0.01). The results from this pilot study indicated the potential of pulse wave imaging coupled with strain imaging to differentiate plaques of varying stiffness, location and composition. Such findings may serve as valuable information to compensate for the limitations of currently used methods for the assessment of stroke risk.

Defective autophagy in vascular smooth muscle cells enhances atherosclerotic plaque instability

Autophagy is considered as an evolutionarily conserved cellular catabolic process. Defective autophagy has been implicated in various human diseases, including cardiovascular diseases. Recently, we and others demonstrated that defective autophagy in vascular smooth muscle cells (SMCs) promotes the progression of atherosclerosis. In this study, we investigated the role of autophagy in SMCs on plaque instability in vivo. We generated mice with a defect atg7in which is an essential gene for autophagy, in SMCs by crossing Atg7f/f mice with transgelin (Tagln) Cre+/0 mice (Atg7cKO). Then, Atg7cKO and apolipoprotein E (apoe)-deficient (apoeKO) mice were crossed to generate Atg7cKO:apoeKO mice. To generate a mouse model of plaque instability, we conducted to form a tandem stenosis in the carotid artery of Atg7cKO:apoeKO mice and their controls (apoeKO mice) at the age of 10 weeks. At 5 weeks after surgery, the percentage of cross-sectional stenosis area in the operated common carotid artery of Atg7cKO:apoeKO mice was significantly higher than that in apoeKO mice. In addition, thrombus, which was not observed in apoeKO mice, was frequently found in Atg7cKO:apoeKO mice. Furthermore, the number of Berlin blue staining-positive areas, which indicated intraplaque hemorrhage, was significantly higher in Atg7cKO:apoeKO mice than in control apoeKO mice. Taken together, our data suggest that defective autophagy in SMCs enhances plaque instability and the risk of plaque rupture.

The effect of plaque eccentricity on blood hemodynamics and drug release in a stented artery

Atherosclerosis in the coronary arteries is one of the leading causes of death in the world. Percutaneous coronary interventions (PCI) associated with the implantation of drug eluting stents (DES) is one of the most common forms of revascularization in patients with atherosclerotic coronary artery disease. The use of DES is considered as an effective tool to reduce restenosis after PCI. However despite all the progress made in DES procedures, the rate of restenosis remains relatively high. Mathematical modeling and numerical simulation are believed to play an essential role in identifying zones with a higher risk of in-stent restenosis. In this work the local delivery of a therapeutic agent, from a stent implanted in a coronary artery, is mathematically modeled and numerically simulated. The mathematical model includes the diffusion of the dissolved drug in the biodegradable polymeric coating of the stent, the diffusion and convection of the drug with reversible binding in the viscoelastic arterial wall with plaques of different morphology and the local hemodynamics. The study is an attempt to detect zones with a higher risk of in-stent restenosis and their relation to plaque eccentricity. The location of zones with highest risk of thrombosis and plaque rupture is also addressed. The results are in agreement with claims presented in clinical papers.

Oxidized lipids in atherosclerotic plaque instability

A large body of evidence suggests a mechanistic link between oxidized lipids and atherosclerosis. Oxysterols and 4-hydroxynonenal (HNE), the major products deriving from LDL oxidation, are consistently present in inflamed and atherosclerotic arteries and they play a key role in the development of atherosclerosis (1,2). Due to the fact that atherosclerosis is a leading cause of mortality in Western countries, it is of increasing importance to understand the various molecular mechanisms induced by oxysterols and HNE, as well as to identify new markers to distinguish between stable and unstable atherosclerotic plaques. Since chronic inflammation and matrix degradation might play a key role in plaque instability, we investigated the effect of oxysterols and HNE on various inflammatory molecules and MMP-9 expression in promonocytic U937 cells. In U937 cells, both oxysterols and HNE induced the expression of several cytokines and MMP-9 through TLR4 activation. These oxidized lipids also sustained inflammation by upregulating COX-2 and mPGES-1 levels, enzymes that cooperate to catalyze the conversion of arachidonic acid to PGE2. Inhibition of inflammatory molecule formation decrease MMP-9 release by macrophages, underlying the crucial role of inflammatory response in MMP-9 overexpression, a major marker of atherosclerotic plaque instability. Recently, it has been reported that proprotein convertase PCSK6, a new marker of plaque instability, is overexpressed in symptomatic carotid plaques. In connection with this, we are now investigating whether an oxysterol mixture and HNE can modulate the expression of PCSK6. Preliminary results indicate that both oxysterols and HNE upregulate PCSK6 in U937 cells. The downregulation of PCSK6 by siRNA significantly reduced MMP-9 activity induced by oxidized lipids, underlying a possible link between PCSK6 activity and MMP activation. Our results suggest that oxysterols and HNE contribute to atherosclerotic plaque instability by enhancing the inflammatory response and favouring matrix degradation through MMP-9 upregulation. Moreover, preliminary results indicate that PCSK6, upregulated by oxysterols or HNE, might play a key role in plaque instability by increasing MMP activity. These results might provide strong incentive for the development of new therapeutic strategies to counteract the risk of atherosclerotic plaque rupture and thrombosis, which cause acute coronary syndromes.

Imaging Cardiovascular Calcification

Cardiovascular disease is the leading cause of morbidity and mortality worldwide. Atherosclerosis is a complex and multifactorial process, characterized by early asymptomatic formation of plaque in the arterial walls, silent plaque progression that poses flow limitation, and risk of sudden rupture and subsequent thrombotic occlusion.1 The early assessment and predictive value of atherosclerotic plaque development and rupture are critically important to prevent clinical consequences. Inflammation and calcification play important roles in the pathophysiological progression of atherosclerosis. In the early stage, inflammation is the predominant process involved that promotes plaque progression and calcification.2 The repeated cycles of inflammatory damage and repair ultimately lead to calcification of the vessel walls,3 whose extent provides an important estimate of atherosclerotic progression and clinical prognosis. Macrocalcification is considered the stable stage of vascular disease, whereas the dynamic process of microcalcification may increase the risk of plaque rupture and adverse clinical events.4 Therefore, imaging early calcification is important to identify individuals with enhanced risk of cardiovascular events. Furthermore, many studies have demonstrated coronary artery calcification as a marker for the extent of atherosclerosis and overall plaque burden, and as an important independent predictor of cardiovascular events, mortality, and morbidity.5, 6, 7, 8 Over the past few decades, advanced imaging methods have improved our assessment of atherosclerotic calcification and have provided insights into cardiovascular risk and have contributed to the understanding of the underlying pathophysiologic mechanisms of atherosclerosis. This review aims to summarize current imaging techniques for vascular calcification (Table) and their applications in clinical research. Table 1 Current Imaging Techniques for Vascular Calcification

Three-dimensional biomechanics of coronary arteries

The focus of this paper is to model and simulate the nonlinear dynamics of atherosclerotic coronary arteries as a tool to predict the initiation of heart attack. A dynamic three-dimensional visco/hyperelastic fluid–structure interaction model of an atherosclerotic coronary artery is developed by means of the finite element method (FEM) using ANSYS. Simulations are undertaken using the model to examine the risk of plaque rupture with the following parameters taken into account with varying levels of stenosis: physiological pulsatile blood flow; tapered shape of the artery; viscoelasticity and hyperelasticity of the artery wall; effect of the motion of the heart; active artery muscle contraction; the lipid core inside the plaque; three layers of the artery wall; non-Newtonian characteristics of the blood flow; and micro-calcification; this paper is the first to incorporate all these effects. The generated model can potentially be used as a predictive tool for plaque rupture to identify the conditions that are high risk for atherosclerosis plaque rupture.

A fluid-structure interaction study on vulnerability of different coronary plaques to blood flow increase during physical exercise

Pathological studies have shown that coronary atherosclerotic plaques are more prone to rupture under physical exercise. In this paper, using a fully coupled fluid-structure interaction (FSI) analysis based on arbitrary Lagrangian-Eulerian (ALE) finite element method, the effect of the coronary blood flow rate increase during physical exercise on the plaque rupture risk is investigated for different plaque types. It is proved that the increase in coronary blood flow rate during physical exercise considerably increases the maximum stress in the plaque fibrous cap which can potentially lead to the plaque rupture. The issue is investigated for different plaque shapes and their vulnerability to exercise condition is compared. It is observed that the diffused plaque type which experiences the maximum stress of 187.9 kPa at rest and 544 kPa at exercise is the most critical plaque type. Because it is subjected to the highest stress in both of these conditions. However, the descending plaque type exhibits the highest susceptibility to physical activity, since its maximum stress increases from 68.9 kPa at rest to 280.5 kPa at exercise which means an increase of about 308%.

Effect of distal thickening and stiffening of plaque cap on arterial wall mechanics.

To investigate the effect of longitudinal variations of cap thickness and tissue properties on wall stresses and strains along the atherosclerotic stenosis, stenotic plaque models (uniformly thick, distally thickened, homogenous, and distally stiffened) were constructed and subjected to computational stress analyses with due consideration of fluid-structure interactions (FSI). The analysis considered three different cap thicknesses-45, 65, and 200μm-and tissue properties-soft, fibrous, and hard. The maximum peak cap stress (PCS) and strain were observed in the upstream throat section and demonstrated increases of the order of 345 and 190%, respectively, as the cap thickness was reduced from 200 to 45μm in uniformly thick models. Distal stiffening increased PCS in the downstream region; however, the overall effect of this increase was rather small. Distal thickening did not affect maximum PCS and strain values for cap thicknesses exceeding 65μm; however, a noticeable increase in maximum PCS and corresponding longitudinal variation (or spatial gradient) in stress was observed in the very thin (45-μm-thick) cap. It was, therefore, inferred that existence of a rather thin upstream cap demonstrating distal cap thickening indicates an increased risk of plaque progression and rupture. Graphical Abstract ᅟ.

Effects of Nanoprobe Morphology on Cellular Binding and Inflammatory Responses: Hyaluronan-Conjugated Magnetic Nanoworms for Magnetic Resonance Imaging of Atherosclerotic Plaques.

Atherosclerosis is an inflammatory disease of arterial walls and the rupturing of atherosclerotic plaques is a major cause of heart attack and stroke. Imaging techniques that can enable the detection of atherosclerotic plaques before clinical manifestation are urgently needed. Magnetic resonance imaging (MRI) is a powerful technique to image the morphology of atherosclerotic plaques. In order to better analyze molecular processes in plaques, contrast agents that can selectively bind to plaque receptors will prove invaluable. CD44 is a cell surface protein overexpressed in plaque tissues, the level of which can be correlated with the risks of plaque rupture. Thus, targeting CD44 is an attractive strategy for detection of atherosclerotic plaques. Herein, we report the synthesis of hyaluronan-conjugated iron oxide nanoworms (HA-NWs). A new purification and gel electrophoresis protocol was developed to ensure the complete removal of free HA from HA-NWs. Compared to the more traditional spherical HA-bearing nanoparticles, HA-NWs had an elongated shape, which interacted much stronger with CD44-expressing cells in CD44- and HA-dependent manners. Furthermore, the HA-NWs did not induce much inflammatory response compared to the spherical HA nanoparticles. When assessed in vivo, HA-NWs enabled successful imaging of atherosclerotic plaques in a clinically relevant model of ApoE knockout transgenic mice for noninvasive plaque detection by MRI. Thus, nanoprobe shape engineering can be a useful strategy to significantly enhance their desired biological properties.

Assessment of atherosclerotic plaque activity in patients with sleep apnea using hybrid positron emission tomography/magnetic resonance imaging (PET/MRI): a feasibility study

Evidence suggests that the inflammatory state of an atherosclerotic plaque is important in predicting future risk of plaque rupture. This study aims to investigate the feasibility of measuring plaque inflammation in patients with obstructive sleep apnea (OSA) utilizing advanced vascular imaging-hybrid positron-emission tomography/magnetic resonance imaging (PET/MRI) with fluorodeoxyglucose (FDG) tracer-before and after continuous positive airway pressure (CPAP). Patients with newly diagnosed moderate to severe OSA underwent baseline PET/MRI for assessment of vascular inflammation of the carotid arteries and thoracic aorta prior to initiation of CPAP. Those adherent to CPAP returned for repeat imaging after 3-6months of CPAP use. Atherosclerotic plaque activity, as measured by arterial wall FDG uptake, was calculated using target-to-background ratios (TBR) before and after CPAP. Five patients were recruited as part of a focused project. Mean age was 52years (80% male), and mean apnea-hypopnea index (AHI) was 33. Three patients were objectively adherent with CPAP. In the pre-CPAP phase, all patients had focal FDG uptake in the carotid arteries and aorta. After CPAP, there was an average reduction in TBR of 5.5% (TBRmean) and 6.2% (TBRmax) in carotid and aortic plaque inflammation, similar in magnitude to the reduction observed with statin therapy alone in non-OSA patients (previously reported by others). We demonstrate the feasibility of using hybrid PET/MRI to assess atherosclerotic plaque inflammation in patients with OSA before and after CPAP. Use of the vascular PET/MRI platform in patients with OSA may provide better insight into the role of OSA and its treatment in reducing atherosclerotic inflammation.

Potential role of insulin receptor isoforms and IGF receptors in plaque instability of human and experimental atherosclerosis

BackgroundClinical complications associated with atherosclerotic plaques arise from luminal obstruction due to plaque growth or destabilization leading to rupture. We previously demonstrated that overexpression of insulin receptor isoform A (IRA) and insulin-like growth factor-I receptor (IGF-IR) confers a proliferative and migratory advantage to vascular smooth muscle cells (VSMCs) promoting plaque growth in early stages of atherosclerosis. However, the role of insulin receptor (IR) isoforms, IGF-IR or insulin-like growth factor-II receptor (IGF-IIR) in VSMCs apoptosis during advanced atherosclerosis remains unclear.MethodsWe evaluated IR isoforms expression in human carotid atherosclerotic plaques by consecutive immunoprecipitations of insulin receptor isoform B (IRB) and IRA. Western blot analysis was performed to measure IGF-IR, IGF-IIR, and α-smooth muscle actin (α-SMA) expression in human plaques. The expression of those proteins, as well as the presence of apoptotic cells, was analyzed by immunohistochemistry in experimental atherosclerosis using BATIRKO; ApoE−/− mice, a model showing more aggravated vascular damage than ApoE−/− mice. Finally, apoptosis of VSMCs bearing IR (IRLoxP+/+ VSMCs), or not (IR−/− VSMCs), expressing IRA (IRA VSMCs) or expressing IRB (IRB VSMCs), was assessed by Western blot against cleaved caspase 3.ResultsWe observed a significant decrease of IRA/IRB ratio in human complicated plaques as compared to non-complicated regions. Moreover, complicated plaques showed a reduced IGF-IR expression, an increased IGF-IIR expression, and lower levels of α-SMA indicating a loss of VSMCs. In experimental atherosclerosis, we found a significant decrease of IRA with an increased IRB expression in aorta from 24-week-old BATIRKO; ApoE−/− mice. Furthermore, atherosclerotic plaques from BATIRKO; ApoE−/− mice had less VSMCs content and higher number of apoptotic cells. In vitro experiments showed that IGF-IR inhibition by picropodophyllin induced apoptosis in VSMCs. Apoptosis induced by thapsigargin was lower in IR−/− VSMCs expressing higher IGF-IR levels as compared to IRLoxP+/+ VSMCs. Finally, IRB VSMCs are more prone to thapsigargin-induced apoptosis than IRA or IRLoxP+/+ VSMCs.ConclusionsIn advanced human atherosclerosis, a reduction of IRA/IRB ratio, decreased IGF-IR expression, or increased IGF-IIR may contribute to VSMCs apoptosis, promoting plaque instability and increasing the risk of plaque rupture and its clinical consequences.

Assessment of superficial coronary vessel wall deformation and stress: validation of in silico models and human coronary arteries in vivo.

Cyclic biomechanical stress at the lumen-intima interface plays a crucial role in the rupture of coronary plaque. We performed a comprehensive assessment of a novel angiography-based method for four-dimensional (4D) dynamic assessment of superficial wall stress (SWS) and deformation with a total of 32 analyses in virtual stenosis models with equal lumen dimensions and 16 analyses in human coronary arteries in vivo. The in silico model analyses demonstrated that the SWS, derived by the proposed global displacement method without knowledge of plaque components or blood pressure, was comparable with the result calculated by traditional finite element method. Cardiac contraction-induced vessel deformation increased SWS. Softer plaque and positive arterial remodeling, associated with a greater plaque burden, showed more variation in mean lumen diameter within the cardiac cycle and resulted in higher SWS. In vivo patient analyses confirmed the accuracy of computed superficial wall deformation. The centerlines predicted by our method at random selected time instant matched well with the actual one in angiograms by Procrustes analysis (scaling: 0.995 ± 0.018; dissimilarity: 0.007 ± 0.014). Over 50% of the maximum SWS occurred at proximal plaque shoulders. This novel 4D approach could be successfully to predict superficial wall deformation of coronary artery in vivo. The dynamic SWS might be more realistic to evaluate the risk of plaque rupture.

The Impact of Plaque Attenuation and Echogenicity on Clinical Outcome: Insight from Intravascular Ultrasound

Background: Intravascular ultrasound-derived attenuated plaque (AP) and echolucent plaque (ELP) have been recognised as high risk for plaque rupture. However, the impact on cardiovascular events has not been fully elucidated.

Microcalcifications, Their Genesis, Growth, and Biomechanical Stability in Fibrous Cap Rupture.

For many decades, cardiovascular calcification has been considered as a passive process, accompanying atheroma progression, correlated with plaque burden, and apparently without a major role on plaque vulnerability. Clinical and pathological analyses have previously focused on the total amount of calcification (calcified area in a whole atheroma cross section) and whether more calcification means higher risk of plaque rupture or not. However, this paradigm has been changing in the last decade or so. Recent research has focused on the presence of microcalcifications (μCalcs) in the atheroma and more importantly on whether clusters of μCalcs are located in the cap of the atheroma. While the vast majority of μCalcs are found in the lipid pool or necrotic core, they are inconsequential to vulnerable plaque. Nevertheless, it has been shown that μCalcs located within the fibrous cap could be numerous and that they behave as an intensifier of the background circumferential stress in the cap. It is now known that such intensifying effect depends on the size and shape of the μCalc as well as the proximity between two or more μCalcs. If μCalcs are located in caps with very low background stress, the increase in stress concentration may not be sufficient to reach the rupture threshold. However, the presence of μCalc(s) in the cap with a background stress of about one fifth to one half the rupture threshold (a stable plaque) will produce a significant increase in local stress, which may exceed the cap rupture threshold and thus transform a non-vulnerable plaque into a vulnerable one. Also, the classic view that treats cardiovascular calcification as a passive process has been challenged, and emerging data suggest that cardiovascular calcification may encompass both passive and active processes. The passive calcification process comprises biochemical factors, specifically circulating nucleating complexes, which would lead to calcification of the atheroma. The active mechanism of atherosclerotic calcification is a cell-mediated process via cell death of macrophages and smooth muscle cells (SMCs) and/or the release of matrix vesicles by SMCs.

Development of a 3 French Dual-Frequency Intravascular Ultrasound Catheter

Coronary plaque morphology, including plaque size and fibrous cap thickness, is thought to contribute to the risk of plaque rupture and future cardiac events. Dual-frequency intravascular ultrasound has been proposed as a possible technique to visualize both large-scale features and superficial detail of coronary plaque; however, it has not been found to be feasible within the constraints of a clinically functional intravascular ultrasound catheter. In this study, we describe the design and fabrication of a dual-frequency catheter using a bidirectional transducer stack with center frequencies of approximately 30 and 80 MHz. We describe how the high-frequency transducer achieves significantly improved axial and lateral resolution (16 and 120 µm, respectively, vs. 50 and 220 µm) at the expense of penetration depth. Finally, imaging of ex vivo human coronary artery segments reveals that the catheter can provide complementary images of the deeper arterial wall and superficial plaque features.

Circulating inflammation-resolving lipid mediators RvD1 and DHA are decreased in patients with acutely symptomatic carotid disease

BackgroundEfficient biomarkers for early prediction and diagnosis of an acutely symptomatic carotid plaque rupture event are currently lacking, impairing the ability to diagnose and treat patients with an acute plaque rupture events in a timely fashion. Resolvins are endogenous inflammation-resolving lipid mediators that are induced by inflammatory insults. We hypothesized that resolvin and other lipid profiles in sera likely mark the process towards plaque rupture. MethodsCirculating lipids associated with plaque rupture events were quantitatively profiled via targeted mediator-lipidomics using ultraperformance liquid chromatography tandem mass spectrometry in patients with acutely symptomatic and asymptomatic carotid disease. ResultsResolvin D1 (RvD1, 82 ± 11pM vs. 152 ± 17pM, p = 0.001) and docosahexaenoic acid (DHA) (0.052 ± 0.007µM versus 0.076 ± 0.008µM, p = 0.025) levels are decreased in the sera of patients presenting with an acutely symptomatic carotid plaque rupture event (n = 21) compared to patients with asymptomatic (n = 24) high-grade carotid stenosis. Circulating arachidonic acid (AA) levels, however, were higher (0.429 ± 0.046µM versus 0.257 ± 0.035µM, p < 0.01) in acutely symptomatic compared to asymptomatic carotid patients. ROC curve analysis demonstrates that the serum ratio AA:RvD1 (AUC 0.84, sensitivity 0.71, specificity 0.92) and AA:DHA (AUC 0.86, sensitivity 0.90, specificity 0.71) are biomarkers for the risk of atherosclerotic plaque rupture. ConclusionsA circulating pro-inflammatory lipid profile, characterized by high AA:RvD1 and AA:DHA, is associated with acutely symptomatic carotid disease and stroke.

A pilot study on the noninvasive fluid hemodynamic investigation of coronary plaque

Objective: To characterize the hemodynamic force towards coronary plaque based on noninvasive coronary computed tomographic angiography and to investigate its relationship with plaque features and stenosis severity by computational fluid dynamics. Methods: Twenty-six patients underwent invasive fractional flow reserve measurement following coronary computed tomography angiography examination from March to September 2016 were retrospectively included. Computational fluid dynamics was applied and wall shear stress (WSS) and axial plaque stress (APS), which extracted the axial component of hemodynamic stress acting on stenotic lesions, were calculated based on the results of noninvasive coronary computed tomographic angiography. Plaque analysis was performed to elucidate plaque features and relative plaque burden. The fluid dynamics distributions in lesions with different stenosis severity were investigated. Results: Thirty-one coronary plaques with satisfactory imaging quality were analyzed, there were 11 (35.5%) dominant low WSS (<1 Pa) lesion and 20 high WSS lesion (64.5%), 8(25.8%) net retrograde APS lesion and 23(74.2%) anterograde lesion. Plaque volume was (78.5±48.6) mm(3) and plaque burden was (69.1±12.1)% in the low WSS group, which was(60.5±57.3) mm(3), and(57.5±14.0)%, respectively in the high WSS group, the plaque burden was significantly higher in the low WSS group than in the high WSS group (P=0.028), while the percentage of calcified plaque, fibrotic plaque and lipid core volume were similar between the two groups (P>0.05). Plaque volume was (79.7±69.1) mm(3) and plaque burden was(68.7±13.7)% in the group with anterograde-dominant APS plaque, which was(61.7±24.9)mm(3), and(68.9±10.4)%, respectively in the net retrograde APS lesion group (P>0.05). Percentage of lipid core area was significantly higher in the anterograde lesion group than in the retrograde lesion group ((25.1±18.1)% vs.(10.8±12.7)%, P=0.049). Both WSS and APS were significant higher in the severe obstructive coronary stenosis group than in non-severe obstructive coronary stenosis group (P<0.05). Although there was no difference in WSS between functional coronary ischemia group and non-functional coronary ischemia group ( (13.3±8.7) Pa vs. (12.5±14.2) Pa, P>0.05), the distribution of APS was different between the functional coronary ischemia group and non-functional coronary ischemia group ((1 698.8±652.6) Pa vs. (981.4±787.5) Pa, P<0.05). Conclusion: WSS and APS can uniquely characterize the stenotic segment and has a strong relationship with lesion geometry. APS may be related to the necrotic core plaque and functional coronary ischemia. Clinical application of these hemodynamic and geometric indices may be helpful to assess the future risk of plaque progress and plaque rupture, which will be helpful on determining respective treatment strategy for patients with coronary artery disease.