High Endothelial Shear Stress Research Articles

Heterogeneity of plaque burden natural history within individual human coronary atherosclerotic plaques is based on local endothelial shear stress: insights for culprit areas and clinical events

Abstract Background Patterns of local endothelial shear stress (ESS) are heterogeneous along the course of individual coronary artery plaques. It is unknown how this heterogeneity affects the local natural history of plaque burden (PB) over time. Objectives To determine the effect of local ESS patterns along the course of coronary plaques at baseline on the heterogeneity of subsequent PB progression, regression, and quiescence in human coronary arteries and its link to clinical events. Methods 302 patients from the PREDICTION study were included in the study. The PREDICTION study was an anatomic natural history followup study of patients treated for an acute coronary syndrome (ACS) performed in 15 Japanese clinical sites, as previously published [1]. Invasive imaging was performed at baseline and, per protocol, at 6-10 months follow-up. Arterial geometry and ESS were derived from angiography/intravascular ultrasound-based vascular profiling. Plaques were identified as regions with plaque thickness > 0.5 mm in at least 3 consecutive 3-mm segments. Plaque progression was defined as change in PB (plaque area/total vessel area*100%) PB >+5% increase, regression as <-5% decrease, and quiescence as no change. The location of each sequential 3-mm segment along the plaque was related to the minimum lumen area (MLA). Performance of PCI in followup was assessed relative to the magnitude of PB change over time. Results 661 plaques (5,658 3-mm segments) from 591 coronary arteries were identified. 56% of 3-mm segments per plaque manifested PB progression, 60% PB regression, and 96% quiescence, and the presence and number of these PB changes were significantly related to plaque length (p<0.002). PB change >20% was associated with low ESS (0.75±0.31 Pa) and marked regression (PB change <-20%) with high ESS (3.94±0.04 Pa) (p<0.001, Figure 1 right panel). 3-mm segments exhibiting substantial PB progression were located along the full length of the plaque, and seldom at the MLA (p=0.874, (Figure 1 left panel), while substantial PB regression was significantly located at the MLA (p<0.001). With increasing ∆PB progression in individual 3-mm segments, a significant increase in performance of PCI was observed (p=0.012, Figure 2). Conclusions PB natural history of 3-mm segments within an individual plaque is heterogeneous, driven by local ESS, with substantial plaque progression/luminal encroachment developing along the entire course of the plaque, and typically not near the MLA. PCI was associated with the magnitude of PB progression/luminal encroachment, regardless of where the progression occurred.Figure 1Figure 2

The role of endothelial shear stress, shear stress gradient, and plaque topography in plaque erosion

Background and aimsPlaque erosion is a common underlying cause of acute coronary syndromes. The role of endothelial shear stress (ESS) and endothelial shear stress gradient (ESSG) in plaque erosion remains unknown.We aimed to determine the role of ESS metrics and maximum plaque slope steepness in plaques with erosion versus stable plaques. MethodsThis analysis included 46 patients/plaques from TOTAL and COMPLETE trials and Brigham and Women's Hospital's database who underwent angiography and OCT. Plaques were divided into those with erosion (n = 24) and matched stable coronary plaques (n = 22). Angiographic views were used to generate a 3-D arterial reconstruction, with centerlines merged from angiography and OCT pullback. Local ESS metrics were assessed by computational fluid dynamics. Among plaque erosions, the up- and down-slope (Δ lumen area/frame) was calculated for each culprit plaque. ResultsCompared with stable plaque controls, plaques with an erosion were associated with higher max ESS (8.3 ± 4.8 vs. 5.0 ± 1.9 Pa, p = 0.02) and max ESSG any direction (9.2 ± 7.5 vs. 4.3 ± 3.11 Pa/mm, p = 0.005). Proximal erosion was associated with a steeper plaque upslope while distal erosion with a steeper plaque downslope. Max ESS and Max ESSG any direction were independent factors in the development of plaque erosion (OR 1.32, 95%CI 1.06–1.65, p = 0.014; OR 1.22, 95% CI 1.03–1.45, p = 0.009, respectively). ConclusionsIn plaques with similar luminal stenosis, plaque erosion was strongly associated with higher ESS, ESS gradients, and plaque slope as compared with stable plaques. These data support that ESS and slope metrics play a key role in the development of plaque erosion and may help prognosticate individual plaques at risk for future erosion.

Role of triggering receptor expressed on myeloid cells-1 in the mechanotransduction signaling pathways that link low shear stress with inflammation

This study sought to investigate the role of triggering receptor expressed on myeloid cells-1 (TREM-1) in the mechanotransduction signaling pathways that link low shear stress with inflammation. Human coronary artery endothelial cells, human coronary artery smooth muscle cells, and THP-1 monocytes were co-cultured and exposed to varying endothelial shear stress (ESS) conditions: low (5 ± 3 dynes/cm2), medium (10 ± 3 dynes/cm2), and high (15 ± 3 dynes/cm2). We showed that low ESS increased the expression of TREM-1 by the cultured cells leading to increased production of inflammatory mediators and matrix-degrading enzymes, whereas high ESS did not have a significant effect in the expression of TREM-1 and inflammatory mediators. Furthermore, TREM-1 transcriptional inhibition with siRNA in endothelial cells, smooth muscle cells, and monocytes exposed to low ESS, led to a significant reduction in the production of vascular inflammatory mediators and matrix-degrading enzymes. Additionally, we identified the transcription factors that appear to upregulate the TREM-1 gene expression in response to low ESS. To the best of our knowledge, this is the first study to investigate the pathophysiologic association and molecular pathways that link low ESS, TREM-1, and inflammation using a sophisticated in-vitro model of atherosclerosis. Future studies on animals and humans are warranted to investigate the potential of TREM-1 inhibitors as adjunctive anti-atherosclerotic therapies.

Abstract 14699: Effect of Shear Stress on Arterial Inflammation and Development of Healed Plaque: A Comprehensive Shear Stress-Molecular Imaging Study Based on a Novel Multispectral Fluorescence Lifetime Imaging Catheter

Introduction and Hypothesis: Endothelial shear stress (ESS) is the tangential force produced by luminal blood flow on arterial endothelium. Both high ESS and low ESS are known to have atherogenic effects, however, it remains poorly understood how these different forces influence coronary atherosclerosis. We evaluated the impact of ESS changes on biochemical and phenotypic difference of coronary atheroma, as assessed by a novel dual-modal optical coherence tomography-fluorescence lifetime imaging (OCT-FLIm) in vivo in beating human coronary arteries. Methods and Results: We constructed a fully-integrated OCT and multispectral FLIm system based on a low-profile dual-modal imaging catheter. High-speed OCT-FLIm could be performed safely in patients undergoing coronary revascularization (Pullback speed: 10-20mm/sec). 3D artery model for computational fluid dynamics was reconstructed by fusion of OCT and angiography. We analyzed spatial associations between ESS and multispectral FLIm information: ch.3(542nm) = fibroatheroma with inflammation; ch.1 (390nm) = loose fibrous tissue (healed plaque). OCT-FLIm visualized coronary microstructure clearly and offered correctly-coregistered biochemical readouts of coronary atherosclerotic plaque in vivo in a label-free manner. Fibroatheromas with increased inflammation activity, as assessed by ch.3 FLIm, were found in low ESS area. On the other hands, high ESS area colocalized with regions with increased ch.1 lifetime, a FLIm signature of loose fibrous tissue (healed plaque). Based on a coregistered ESS-FLIm data, we found a statistically significant negative correlation between ESS and ch.3 lifetime (p>0.001) and a positive correlation between ESS and ch.1 lifetime (p>0.001). Conclusions: Low ESS was associated with lipid and macrophage infiltration whereas high ESS was associated with presence of loose fibrous tissue, a histologic marker of recent plaque disruption leading to rapid plaque progression. Our novel imaging strategy enabling comprehensive evaluation of complex interaction between ESS and biochemical phenotype of plaques is expected to enhance understanding of coronary atherosclerosis biology.

Abstract 9504: Endothelial Shear Stress Metrics Correlate With Inflammatory Markers at the Culprit Site of Erosion in Patients With an Acute Coronary Syndrome: An OPTICO-ACS Substudy

Introduction: The pathobiological mechanisms of coronary plaque erosion are unclear. Low endothelial shear stress (ESS) is a proinflammatory/proatherogenic stimulus associated with coronary plaque progression/destabilization. Intravascular imaging studies suggest that high ESS gradient (low ESS areas adjacent to high ESS areas), and steepness of plaque upslope/downslope correlate with plaque erosion. We investigated the relationship of local fluid hemodynamics to the inflammatory microenvironment at the culprit site of erosion in patients with an acute coronary syndrome. Hypothesis: ESS metrics associate with proinflammatory/proatherogenic cells and cytokines, and contribute to plaque erosion. Methods: We studied 30 patients with erosion from the OPTIcal-COherence Tomography in Acute Coronary Syndrome study (OPTICO-ACS). OCT images were segmented, co-registered with the angiogram to create a 3D-reconstruction of the coronary artery. ESS metrics were calculated by Computational Fluid Dynamics. Systemic and local blood samples and thrombectomy specimens were collected at the culprit lesion and analyzed by flow cytometry-based immunophenotyping and plasma cytokine and chemokine profiling, and statistically tested for correlations of continuous variables using Spearman rank correlation (r). Results: Proinflammatory cytokines (IL6, MIP-1, IL1β, IL2) and local concentration of T-cells, including subsets of T-cells (CD4+, CD8+, and NKT-cells), were significantly higher at the culprit site of erosion and correlate with local adverse ESS metrics (Min ESS, Max ESS, Plaque Topographical Slope) (Table). Conclusion: Biomechanical features likely trigger activation of the adaptive immune system, including T-lymphocytes and their cytotoxic effector molecules. These results provide novel insights into the links between fluid hemodynamics, inflammatory activation, and mechanisms involved in the pathogenesis of coronary plaque erosion.

Abstract 10038: Combined Low Endothelial Shear Stress and High Plaque Structural Stress Heterogeneity Predicts Non-Culprit Major Adverse Cardiovascular Events; Insights From the PROSPECT Study

Introduction: Low endothelial shear stress (ESS) is a pro-atherogenic stimulus associated with coronary plaque development, while high plaque structural stress (PSS) and its heterogeneity is associated with plaque destabilization. Previous studies showed that combining ESS and PSS additively predicts plaque progression, but no studies have determined their ability to predict major adverse cardiovascular events (MACE). We examined whether combining ESS and PSS improves MACE prediction in patients with acute coronary syndrome. Methods: We examined baseline ESS, ESS gradient, PSS, and PSS heterogeneity index (HI) in 22 non-culprit lesions (NCL) leading to future MACE, and 64 randomly selected control NCLs without MACE from the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study. ESS was calculated by computational fluid dynamics and PSS by finite element analysis on co-registered lesions. Results: 86 lesions (55 thin-cap and 31 thick-cap fibroatheromas) were analyzed from 67 patients. Lesions that caused future MACE showed baseline higher PSS HI (0.32 vs. 0.24, p<0.001), lower ESS (0.56 vs. 0.91 Pa, p=0.007), higher ESS gradient (3.82 vs. 1.96 Pa/mm, p=0.007), smaller minimum lumen area (MLA, 3.83 vs. 5.05 mm 2 , p=0.002), and larger plaque burden (PB, 70% vs. 59.4%, p<0.001). Independent predictors of MACE in multivariate analysis included high PSS HI (hazard ratio [HR] 3.9, 95% confidence interval [CI] 1.5-10.4, p=0.006), high ESS gradient (HR 3.4, 95% CI 1.4-8.1, p=0.007), and high PB at the MLA (HR 2.6, 95% CI 1.1-6.3, p=0.035). Combining low ESS and high PSS HI improved test specificity to 0.83 and positive predictive value (PPV) to 59.3%, while maintaining high sensitivity at 0.73 and high negative predictive value (NPV) at 89.8%. Combining low ESS, high ESS gradient, and high PSS HI further improved prognostication, predicting 80% of MACE over 3-year follow-up (p<0.001). Conclusions: Combining baseline low ESS, high ESS gradient and high PSS heterogeneity significantly improves risk stratification of NCLs over each parameter alone. Combining parameters exceeds PPV and NPV achieved by imaging alone, and may identify lesions suitable for preemptive intervention strategies to avert future MACE.

Development and validation of non-invasive endothelial shear stress (ESS) estimations of coronary artery haemodynamics using computational modelling

Abstract Background Vascular remodelling is influenced by various biomechanical forces such as endothelial shear stress (ESS) and is associated with development and progression of coronary artery disease (CAD). ESS is the parallel frictional force exerted by blood flow on the endothelial luminal surface of the arterial wall. While ESS may not be the only cause of atherosclerosis, it is postulated that low ESS creates a pro-atherogenic environment and high ESS is athero-protective. Computational fluid dynamics (CFD) is an engineering method used to analyse fluid flow and has been increasingly applied to simulate ESS in cardiovascular research. However, current CFD-derived ESS estimates have never been validated and can display significant variability between research groups. Purpose This study aims to provide a comparative analysis of coronary flow using in-silico modelling of coronary flow and particle image velocimetry (PIV). Methods A proximal left anterior descending (pLAD) coronary phantom model was constructed from a patient who had received same day cardiac computed tomography angiography (CTCA) and invasive coronary haemodynamic (Combowire XT) assessment. Patient-specific coronary flow data was applied to CFD boundary conditions and a mock circulatory loop. CFD was validated using PIV under steady flow in a 4-times-scaled model. Same plane velocity field and flow patterns (at mid-luminal of pLAD) from both in-silico and in-vivo data were compared and analysed. Results Mean velocity contours and magnitude were analysed from CFD and PIV. Patient specific average peak velocity obtained from invasive assessment was 0.21m/s. Patient-specific velocity average from CFD was 0.22m/s. The approximated magnitude difference is 4.7%. Both same-axial average cross-sectional velocity estimated by CFD-pLAD and PIV-pLAD are 0.087m/s. Velocity contours and flow patterns simulated in the CFD were also comparable with the PIV results. Conclusion Simulation data from CFD correlate well with experimental PIV results. This early data allows for a non-invasive approach to determine patient-specific coronary haemodynamics (such as velocity profiling and ESS) and form the basis of personalising cardiovascular risk. Insights from this work may aid future development of a novel tool that incorporates CFD-derived ESS estimates with patient-specific risk factors to better predict rapid CAD progression. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Cardiac Society of Australia and New Zealand Monash Institute of Medical Engineering

Exercise‐Induced Shear Stress Upregulates eNOS Protein in vitro

BackgroundEndothelial cell dysfunction has been shown to be the first step in the pathogenesis of cardiovascular disease. A risk factor in the development of cardiovascular disease is physical inactivity. Endothelial shear stress (ESS) involves mechanoreceptors on the surface of endothelial cells that are capable of sensing different forces, triggering a biochemical response leading to cellular adaptations. Exercise‐induced ESS might act as a protective mechanism in preventing endothelial cell dysfunction. Endothelial nitric oxide synthase (eNOS), a key enzyme involved maintaining vascular homeostasis has been shown to be upregulated in response to higher shear stress levels. Although exercise has been shown to improve endothelial cell function, the role of varying exercise intensities on endothelial cell homeostasis has not been explored. The purpose of this study was to determine the effects of in vitro exercise‐induced ESS during 3 different exercise intensities on eNOS expression.MethodsCommercially available human umbilical vein endothelial cells (HUVEC; Sigma‐Aldrich, St Louis, MO) were cultured until 90‐100% confluence. Exercise‐induced ESS in vivo was obtained from our previous reports. Cultured cells were exposed to pulsatile resting ESS (18 dynes/cm2) for 2 hours, followed by 1 hour at resting ESS, low‐intensity exercise‐induced ESS (35 dynes/cm2), moderate‐intensity exercise‐induced ESS (50 dynes/cm2), or high‐intensity exercise‐induced ESS (75 dynes/cm2) on a closed circuit pump and channeled slide (Ibidi pump system (PumpControl Software 1.5.4) and slides, Ibidi Inc., Fitchburg, WI). A set of cells were exposed to physiologically low shear stress levels (10 dynes/cm2) for 3 hours as a control. Following ESS conditions, total protein was extracted, and western immunoblotting was performed to measure eNOS protein expression with GAPDH used as the normalizing protein. Statistical analysis was performed using graphpad prism 8 software (Graphpad Software.). Significance was considered at p<0.05.ResultsLow and moderate intensity ESS increased eNOS protein expression compared to physiologically low conditions (P<0.05). There was a trend showing high intensity ESS increasing eNOS expression compared to physiologically low conditions (p<0.10). Additionally, moderate intensity ESS showed a significant increase in eNOS compared to resting conditions (P<0.05).ConclusionsOur data shows that exercise‐induced ESS upregulates eNOS expression. Moderate intensity exercise was shown to produce the highest levels of eNOS expression. Our results from previous studies also show that moderate intensity exercise is capable of activating eNOS, which may act as a protective mechanism to prevent atherosclerosis development.

High endothelial shear stress and stress gradient at plaque erosion persist up to 12 months

BackgroundLocal hemodynamics are known to play an important role in the development of plaque erosion. Recent studies showed that erosion patients might be treated conservatively without stent implantation. We investigated evolution of hemodynamic parameters on the plaque erosion site in conservatively treated patients. MethodsComputational fluid dynamics (CFD) simulations were performed using the coronary angiogram and optical coherence tomography (OCT) images of non-stent treated erosion patients who had serial OCT studies. Calculated CFD parameters included endothelial shear stress (ESS), ESS gradient (ESSG), and oscillatory shear index (OSI). ResultsThe CFD parameters at the erosion and non-erosion sites were compared among baseline (n = 23), and 1-month (n = 20) and 12-month (n = 16) follow-ups. The erosion site had higher ESS and ESSG values than the non-erosion sites at baseline (mean ESS: 3.00 vs 1.36 Pa, p < 0.01; mean ESSG: 1.71 vs. 0.65 Pa/mm, p = 0.01), 1-month (mean ESS: 2.89 vs 1.19 Pa, p < 0.01; mean ESSG: 1.71 vs. 0.60 Pa/mm, p < 0.01), and 12-month (mean ESS: 3.26 vs 1.59 Pa, p < 0.01; mean ESSG: 1.87 vs. 0.78 Pa/mm, p < 0.01). OSI was not different between erosion and and non-erosion sites. ConclusionsESS and ESSG values were higher at the plaque erosion sites compared to non-erosion sites. Elevated ESS and ESSG at the erosion site persisted up to 12 months. These data indicate that a local thrombogenic milieu related to hemodynamic perturbation persists up to 12 months at the plaque erosion sites following conservative treatment.Clinical Trial Registration: https://clinicaltrials.gov: NCT02041650

One-year performance of biorestorative polymeric coronary bypass grafts in an ovine model: correlation between early biomechanics and late serial Quantitative Flow Ratio.

This study aimed to investigate the impact of mechanical factors at baseline on the patency of a restorative conduit for coronary bypass grafts in an ovine model at serial follow-up up to 1 year. The analyses of 4 mechanical factors [i.e. bending angle, superficial wall strain and minimum and maximum endothelial shear stress (ESS)] were performed in 3D graft models reconstructed on baseline (1-month) angiograms frame by frame by a core laboratory blinded for the late follow-up. The late patency was documented by Quantitative Flow Ratio (QFR®) that reflects the physiological status of the graft. The correlation between 4 mechanical factors and segmental QFR (△QFR) were analysed on 10 equal-length segments of each graft. A total of 69 graft geometries of 7 animals were performed in the study. The highest △QFR at 12 months was colocalized in segments of the grafts with the largest bending angles at baseline. Higher △QFR at 3 months were both at the anastomotic ends and were colocalized with the highest superficial wall strain at baseline. High baseline ESS was topographically associated with higher △QFR at the latest follow-up. Correlations of minimum and maximum ESS with △QFR at 3 months were the strongest among these parameters (ρ = 0.30, 95% CI [-0.05 to 0.56] and ρ = 0.27, 95% CI [-0.05 to 0.54], respectively). Despite the limited number of grafts, this study suggests an association between early abnormal mechanical factors and late flow metrics of the grafts. The understanding of the mechanical characteristics could help to improve this novel conduit.

Abstract 11768: Role of Endothelial Shear Stress and Endothelial Shear Stress Gradient in Plaques Associated With Acute Erosion vs. Stable Control Plaques and Relationship Between Plaque Slope and Localization of Plaque Erosion

Introduction: The role of endothelial shear stress (ESS) in the development of coronary plaque erosion is unknown. High ESS gradient (ESSG) has been hypothesized to promote plaque erosion, but no studies have included matched control stable plaques with the same minimal and reference lumen area (MLA, RLA, respectively). No studies examined the location of plaque erosion (proximal vs distal to MLA of the culprit plaque) related to the max magnitude of upslope vs downslope of the lumen obstruction. Aims: (1) to compare ESSG between plaques with erosion and similar control plaques that remained stable; (2) among erosion plaques, to study the effect of max slope steepness (Δ lumen area/frame) up- and down-stream from the culprit plaque MLA on thrombus location. Methods: We studied 46 patients from TOTAL and COMPLETE trials who underwent angiography and OCT imaging: 46 arteries: 27 LAD, 6 LCX, 13 RCA. Plaques were divided into Plaque Erosion (n=24) with OCT features of erosion before PCI (17 definite, 7 probable erosion) and matched coronary plaques from separate control patients (n=22) without plaque disruption. Orthogonal angiographic views were used to generate a 3-D arterial reconstruction, and angio centerline was combined with OCT centerline. Local ESS distribution was assessed by computational fluid dynamics and reported in consecutive 3-mm segments. Among the plaque erosions, we calculated the up- and down-slope (Δ lumen area/frame) of lumen obstruction for each culprit plaque. Results: See Table Conclusion: In plaques with similarly severe obstruction, plaque erosion is associated with higher max ESS and max ESSG vs plaques that remain stable. Proximal plaque erosion/thrombus is associated with steeper plaque upslope vs downslope, and distal plaque erosion/thrombus is associated with steeper plaque downslope vs upslope. Absolute ESSG is higher in downslope vs upslope erosions. These features may help prognosticate individual plaques at risk for future erosion.

Abstract 15794: Role of Endothelial Shear Stress and Endothelial Shear Stress Gradient in Plaques Associated With Acute Erosion vs. Stable Control Plaques

Introduction: The role of endothelial shear stress (ESS) in the natural history of plaque growth and TCFA formation/destabilization has been studied, but the role in plaque erosion is unknown. High ESS gradient (ESSG) has been hypothesized to promote plaque erosion, but no studies have included matched “control” stable plaques with the same minimal luminal area (MLA) and reference luminal area (RLA) but no adverse coronary event. Hypothesis: To compare ESS and ESSG between coronary plaques that developed erosion and similar morphology plaques that remain stable. Methods: We studied a subset of patients from both TOTAL and COMPLETE trials who underwent angiography and OCT evaluation: 27 patients (27 arteries: 18 LAD, 3 LCX, 6 RCA). Plaques were divided into Plaque Erosion (n=16) from TOTAL study with OCT features of plaque erosion and Control (n=11) plaques (non-culprit lesions from COMPLETE) with matched MLA and RLA and no OCT evidence of plaque disruption. Orthogonal angiographic views were used to generate a 3-D arterial reconstruction, and angio centerline was merged with OCT centerline. Local ESS distribution was assessed by computational flow dynamics and reported in consecutive 3-mm segments. Results: Table 1 shows differences in ESS between Plaque Erosion and Control Plaques Conclusions: In coronary plaques with similar severe obstruction (MLA) and reference area (RLA), plaque erosion is associated with higher coronary flow, max ESS, and ESSG in any direction, in the proximal-to-distal direction, and in the circumferential direction compared to plaques that remain stable. Future studies will determine which "feature (s)" of high ESS or ESSG are independently associated with erosion.

High spatial endothelial shear stress gradient independently predicts site of acute coronary plaque rupture and erosion.

To investigate local haemodynamics in the setting of acute coronary plaque rupture and erosion. Intracoronary optical coherence tomography performed in 37 patients with acute coronary syndromes caused by plaque rupture (n = 19) or plaque erosion (n = 18) was used for three-dimensional reconstruction and computational fluid dynamics simulation. Endothelial shear stress (ESS), spatial ESS gradient (ESSG), and oscillatory shear index (OSI) were compared between plaque rupture and erosion through mixed-effects logistic regression. Lipid, calcium, macrophages, layered plaque, and cholesterol crystals were also analysed. By multivariable analysis, only high ESSG [odds ratio (OR) 5.29, 95% confidence interval (CI) 2.57-10.89, P < 0.001], lipid (OR 12.98, 95% CI 6.57-25.67, P < 0.001), and layered plaque (OR 3.17, 95% CI 1.82-5.50, P < 0.001) were independently associated with plaque rupture. High ESSG (OR 13.28, 95% CI 6.88-25.64, P < 0.001), ESS (OR 2.70, 95% CI 1.34-5.42, P = 0.005), and OSI (OR 2.18, 95% CI 1.33-3.54, P = 0.002) independently associated with plaque erosion. ESSG was higher at rupture sites than erosion sites [median (interquartile range): 5.78 (2.47-21.15) vs. 2.62 (1.44-6.18) Pa/mm, P = 0.009], OSI was higher at erosion sites than rupture sites [1.04 × 10-2 (2.3 × 10-3-4.74 × 10-2) vs. 1.29 × 10-3 (9.39 × 10-5-3.0 × 10-2), P < 0.001], but ESS was similar (P = 0.29). High ESSG is independently associated with plaque rupture while high ESSG, ESS, and OSI associate with plaque erosion. While ESSG is higher at rupture sites than erosion sites, OSI is higher at erosion sites and ESS was similar. These results suggest that ESSG and OSI may play critical roles in acute plaque rupture and erosion, respectively.

Carotid artery plaque composition and distribution: near-infrared spectroscopy and intravascular ultrasound analysis.

Most atherosclerotic plaques (APs) form in typical predilection areas of low endothelial shear stress (ESS). On the contrary, previous data hinted that plaques rupture in their proximal parts where accelerated blood flow causes high ESS. It was postulated that high ESS plays an important role in the latter stages of AP formation and in its destabilization. Here, we used near-infrared spectroscopy (NIRS) to analyse the distribution of lipid core based on the presumed exposure to ESS. A total of 117 carotid arteries were evaluated using NIRS and intravascular ultrasound (IVUS) prior to carotid artery stenting. The point of minimal luminal area (MLA) was determined using IVUS. A stepwise analysis of the presence of lipid core was then performed using NIRS. The lipid core presence was quantified as the lipid core burden index (LCBI) within 2 mm wide segments both proximally and distally to the MLA. The analysed vessel was then divided into three 20 mm long thirds (proximal, middle, and distal) for further analysis. The maximal value of LCBI (231.9 ± 245.7) was noted in the segment localized just 2 mm proximally to MLA. The mean LCBI in the middle third was significantly higher than both the proximal (121.4 ± 185.6 vs. 47.0 ± 96.5, P < 0.01) and distal regions (121.4 ± 185.6 vs. 32.4 ± 89.6, P < 0.01). Lipid core was more common in the proximal region when compared with the distal region (mean LCBI 47.0 ± 96.5 vs. 32.4 ± 89.6, P < 0.01).

Shear Stress Estimated by Quantitative Coronary Angiography Predicts Plaques Prone to Progress and Cause Events

ObjectivesThis study examined the value of endothelial shear stress (ESS) estimated in 3-dimensional quantitative coronary angiography (3D-QCA) models in detecting plaques that are likely to progress and cause events. BackgroundCumulative evidence has shown that plaque characteristics and ESS derived from intravascular ultrasound (IVUS)−based reconstructions enable prediction of lesions that will cause cardiovascular events. However, the prognostic value of ESS estimated by 3D-QCA in nonflow limiting lesions is yet unclear. MethodsThis study analyzed baseline virtual histology (VH)-IVUS and angiographic data from 28 lipid-rich lesions (i.e., fibroatheromas) that caused major adverse cardiovascular events or required revascularization (MACE-R) at 5-year follow-up and 119 lipid-rich plaques from a control group that remained quiescent. The segments studied by VH-IVUS at baseline were reconstructed using 3D-QCA software. In the obtained geometries, blood flow simulation was performed, and the pressure gradient across the lipid-rich plaque and the mean ESS values in 3-mm segments were estimated. The additive value of these hemodynamic indexes in predicting MACE-R beyond plaque characteristics was examined. ResultsMACE-R lesions were longer, had smaller minimum lumen area, increased plaque burden (PB), were exposed to higher ESS, and exhibited a higher pressure gradient. In multivariable analysis, PB (hazard ratio: 1.08; p = 0.004) and the maximum 3-mm ESS value (hazard ratio: 1.11; p = 0.001) were independent predictors of MACE-R. Lesions exposed to high ESS (>4.95 Pa) with a high-risk anatomy (minimal lumen area <4 mm2 and PB >70%) had a higher MACE-R rate (53.8%) than those with a low-risk anatomy exposed to high ESS (31.6%) or those exposed to low ESS who had high- (20.0%) or low-risk anatomy (7.1%; p < 0.001). ConclusionsIn the present study, 3D-QCA-derived local hemodynamic variables provided useful prognostic information, and, in combination with lesion anatomy, enabled more accurate identification of MACE-R lesions.

P858High endothelial shear stress and local Reynolds number are associated with lipid growth of coronary plaques

Abstract Background Local haemodynamic disturbances in coronary blood flow are associated with abnormal endothelial shear stress (ESS) and progressive atherosclerosis. However, standard techniques to estimate ESS lack the diagnostic specificity necessary for future clinical utility. Possible improvements include use of a more realistic non-Newtonian model of blood, which may provide more accurate ESS measurements and is further able to detect local variations in blood viscosity. Purpose To compare accuracy of ESS generated by Newtonian versus non-Newtonian rheological models to detect coronary plaque progression. To investigate local Reynolds number (ReL), a viscosity-based haemodynamic metric calculated by the non-Newtonian model, as an independent marker of plaque progression. Methods Sixteen patients with non-culprit plaques completely visualised in serial optical coherence tomography (OCT) imaging were identified. Plaques were analysed in 0.2mm intervals at each timepoint for lipid and calcium arc. Computational fluid dynamic simulations were performed using Newtonian and non-Newtonian models to calculate ESS, whereas ReL was calculated by the non-Newtonian simulations. Each haemodynamic index was compared to interval changes in lipid and calcium using multivariate regression. Results In total, 894 matched arterial segments from baseline and follow up imaging were analysed. In the Newtonian results, baseline segments exposed to ESS&gt;1.7Pa had a 12.5° increase in lipid arc (95% CI 2.2° to 22.8°, p=0.018) while segments exposed to ESS&lt;1.1Pa had an 8.1° decrease in calcium (95% CI −14.0° to −2.2°, p=0.007). In the non-Newtonian results, baseline regions exposed to ESS&gt;2.2Pa had a 14.4° increase in lipid (95% CI 4.2° to 24.7°, p=0.006) while areas with ESS&lt;1.4Pa had an 8.7° decrease in calcium (95% CI −14.6° to −2.8°, p=0.004). Baseline regions exposed to ReL&lt;34 showed an average 11.9° increase in lipid arc (95% CI 0.6° to 23.2°, p=0.039). Regions exposed to ReL&gt;55 had an average increase in lipid arc of 26.6° (95% CI 14.5° to 38.6°, p&lt;0.001). Conclusions Both Newtonian and non-Newtonian rheological models show that high ESS is associated with increased lipid while low ESS is associated with decreased calcium. ReL is independently associated with interval increases in lipid arc, suggesting a mechanistic role of local blood viscosity in lipid accumulation. ReL may serve as a novel haemodynamic marker of plaque progression.

P869Predictive value of the endothelial shear stress distribution in three-dimensional quantitative coronary angiography models in detecting vulnerable plaques

Abstract Background Low Endothelial shear stress (ESS) is a well-known instigator of coronary atherosclerosis. Prospective intravascular ultrasound (IVUS)-based imaging studies with computational fluid dynamic analysis revealed its predictive merit in-vivo. However, whether coronary modelling derived from quantitative coronary angiography (QCA) is equally effective in detecting high-risk plaques remains to be established. Purpose To examine the value of endothelial shear stress (ESS) estimated in three-dimensional (3D) QCA models in detecting plaques that are likely to progress and cause events. Method We analysed the baseline intravascular ultrasound virtual histology (IVUS-VH) and angiographic data from 28 non-culprit lesions with a vulnerable phenotype (i.e., fibroatheroma or thin cap fibroatheroma) that caused major adverse cardiac events or required revascularization (nc-MACE-R) at 5-year follow-up and from a control group of 119 vulnerable plaques that remained quiescent. The segments studied by IVUS-VH at baseline were reconstructed using 3D-QCA software and in the obtained geometries blood flow simulation was performed and we estimated the resting Pd/Pa across the vulnerable plaque and the mean ESS values in 3mm sub-segments. A propensity score was built by the baseline plaque characteristics and the hemodynamic indices and its efficacy in detecting nc-MACE-R lesions was examined. Results Nc-MACE-R lesions were longer (32.5mm [18.0, 41.6], vs. 19.6mm [12.7, 31.3], p=0.03), had smaller minimum lumen area (MLA) (3.65mm2 [3.26, 4.36] vs. 5.03mm2 [3.98, 6.66], p&lt;0.01), increased plaque burden (PB) (69.4% [63.5, 72.0] vs. 60.8% [53.7, 66.5], p&lt;0.01), were exposed to higher ESS (9.40Pa [6.3, 12.5] vs. 4.1Pa [3.0, 6.9], p&lt;0.01), and exhibited a lower resting Pd/Pa (0.97 [0.95, 0.98] vs. 0.98 [0.97, 0.99], p&lt;0.01]. In multivariable analysis the only independent predictor of nc-MACE-R was the maximum 3mm ESS value (hazard ratio: 1.08 [1.02, 1.16], P=0.016). Lesions exposed to high ESS (&gt;4.95Pa) with a high-risk anatomy (MLA&lt;4mm2and PB&gt;70%) had a higher nc-MACE-R rate (53.8%) than those with a low-risk anatomy exposed to high ESS (31.6%) or those exposed to low ESS that had high (20.0%) or low-risk anatomy (7.1%, P&lt;0.001). Conclusion In the present study, 3D-QCA-derived local hemodynamic variables provided useful prognostic information and in combination with lesion anatomy enabled more accurate identification of nc-MACE-R lesions. Further research in a larger number of patients is need to confirm these findings before the conduction of large scale prospective studies that will combine intravascular imaging and 3D-QCA modelling to more accurately detect vulnerable plaques.

Association of Coronary Wall Shear Stress With Atheromatous Plaque Vulnerability: A Systematic Review

Abstract Acute coronary syndromes are usually triggered by the erosion or rupture of a vulnerable coronary plaque. A vulnerable plaque (VP) is an atheromatous plaque which, after suffering different transformations, is prone to rupture causing an acute coronary event. Such a VP carries inside several biomarkers considered as “signatures of vulnerability”, which, if identified, can prompt timely initiation of therapeutic measures in order to prevent the development of an acute myocardial infarction. The most freqeuntly used techniques for identification of vulnerability markers are computed tomographic angiography (CTA), intravascular ultrasound and optical coherence tomography. Endothelial shear stress (ESS) represents a new promising biomarker associated with plaque vulnerability. Determination of ESS is nowadays possible using noninvasive imaging techniques, based on complex computational post-processing of multiple datasets extracted from CTA images and advanced computational fluid dynamics technologies. The aim of this systematic review was to evaluate the role of the coronary ESS, determined using advanced computational techniques for image post-processing, as a feature associated with CTA-derived biomarkers of atheromatous plaque vulnerability, underlining the conceptual differences between high ESS and low ESS as promotors of vulnerability.

Complement activation associated with ADAMTS13 deficiency may contribute to the characteristic glomerular manifestations in Upshaw-Schulman syndrome

IntroductionUpshaw-Schulman syndrome (USS) is a congenital form of thrombotic thrombocytopenic purpura (TTP) associated with loss-of-function mutations in the ADAMTS13 gene, possibly leading to aberrant complement activation and vascular injury. However, USS is extremely rare, and there have been no systematic studies correlating histopathological severity with local ADAMTS13 expression and complement activation. Materials and methodsHere, we compared histopathological features, ADAMTS13 immunoreactivity, and immunoreactivity of complement proteins C4d and C5b-9 among renal biopsy tissues from five USS cases, ten acquired TTP cases, and eleven controls. ResultsPathological analysis revealed chronic glomerular sclerotic changes in the majority of USS cases (4 of 5), with minor glomerular pathology in the remaining case. In two of these four severe cases, more than half of the glomerular segmental sclerosis area was localized in the perihilar region. The average number of ADAMTS13-positive cells per glomerulus was significantly lower in USS cases than controls (p < 0.05). Conversely, C4d staining was significantly more prevalent in the glomerular capillary walls of USS cases than controls (p < 0.05), while C5b-9 staining did not differ significantly among groups. ConclusionsThese findings suggest that the severity of glomerular injury in USS is associated with deficient ADAMTS13 expression and local complement activation, particularly in vascular regions with higher endothelial shear stress. We suggest that C4d immunostaining provides evidence for complement-mediated glomerular damage in USS.

Implications of the local hemodynamic forces on the formation and destabilization of neoatherosclerotic lesions

ObjectiveTo examine the implications of endothelial shear stress (ESS) distribution in the formation of neoatherosclerotic lesions. MethodsThirty six patients with neoatherosclerotic lesions on optical coherence tomography (OCT) were included in this study. The OCT data were used to reconstruct coronary anatomy. Blood flow simulation was performed in the models reconstructed from the stent borders which it was assumed that represented the lumen surface at baseline, immediate after stent implantation, and the estimated ESS was associated with the neointima burden, neoatherosclerotic burden and neointima characteristics. In segments with neointima rupture blood flow simulation was also performed in the model representing the lumen surface before rupture and the ESS was estimated at the ruptured site. ResultsAn inverse association was noted between baseline ESS and the incidence and the burden of neoatherosclerotic (β = −0.60, P < 0.001, and β = −4.05, P < 0.001, respectively) and lipid-rich neoatherosclerotic tissue (β = −0.54, P < 0.001, and β = −3.60, P < 0.001, respectively). Segments exposed to low ESS (<1 Pa) were more likely to exhibit macrophages accumulation (28.2% vs 10.9%, P < 0.001), thrombus (11.0% vs 2.6%, P < 0.001) and evidence of neointima discontinuities (8.1% vs 0.9%, P < 0.001) compared to those exposed to normal or high ESS. In segments with neointima rupture the ESS was high at the rupture site compared to the average ESS over the culprit lesion (4.00 ± 3.65 Pa vs 3.14 ± 2.90 Pa, P < 0.001). ConclusionsLocal EES is associated with neoatherosclerotic lesion characteristics, which suggests involvement of ESS in the formation of vulnerable plaques in stented segments.