IVUS Validation of Patient Coronary Artery Lumen Area Obtained from CT Images

Aims

Accurate computed tomography (CT)-based reconstruction of coronary morphometry (diameters, length, bifurcation angles) is important for construction of patient-specific models to aid diagnosis and therapy. The objective of this study is to validate the accuracy of patient coronary artery lumen area obtained from CT images based on intravascular ultrasound (IVUS).

Methods and Results

Morphometric data of 5 patient CT scans with 11 arteries from IVUS were reconstructed including the lumen cross sectional area (CSA), diameter and length. The volumetric data from CT images were analyzed at sub-pixel accuracy to obtain accurate vessel center lines and CSA. A new center line extraction approach was used where an initial estimated skeleton in discrete value was obtained using a traditional thinning algorithm. The CSA was determined directly without any circular shape assumptions to provide accurate reconstruction of stenosis. The root-mean-square error (RMSE) for CSA and diameter were 16.2% and 9.5% respectively.

Conclusions

The image segmentation and CSA extraction algorithm for reconstruction of coronary arteries proved to be accurate for determination of vessel lumen area. This approach provides fundamental morphometric data for patient-specific models to diagnose and treat coronary artery disease.     

A new imaging technique to study 3-D plaque and shear stress distribution in human coronary artery bifurcations in vivo

OBJECTIVE: Bifurcations of coronary arteries are predilection sites for atherosclerosis and expansive remodeling, the latter being associated with plaque vulnerability. Both are related to blood flow-induced shear stress (SS). We present a new approach to generate 3-D reconstructions of coronary artery bifurcations in vivo and investigate the relationship between SS, wall thickness (WT) and remodeling. METHODS: The patient specific 3-D reconstruction of the main branch of the bifurcation was obtained by combining intravascular ultrasound and biplane angiography, and the 3-D lumen of the side branch was based on biplane angiography only. The two data sets were fused and computational methods were applied to determine the SS distribution, using patient derived flow and viscosity data. The intravascular ultrasound data allowed us to measure local WT and remodeling in the main branch. RESULTS: The lumen reconstruction procedure was successful and it was shown that the impact of the side branch on SS distribution in the main branch diminished within 3mm. Distal to the bifurcation, two continuous regions in the main branch were identified. In the proximal region, we observed lumen preservation, and expansive remodeling. Although a plaque was observed in the low SS region at the non-divider wall, no relationship between SS and WT was found. In the distal region, we observed lumen narrowing and a significant positive relationship between SS and WT. CONCLUSIONS: A new imaging technique was applied to generate a 3-D reconstruction of a human coronary artery bifurcation in vivo. The observed relationship between SS, WT and remodeling in this specific patient illustrates the spatial heterogeneity of the atherosclerosis in the vicinity of arterial bifurcations.     

Influence of the Accuracy of Angiography-Based Reconstructions on Velocity and Wall Shear Stress Computations in Coronary Bifurcations: A Phantom Study

Introduction

Wall shear stress (WSS) plays a key role in the onset and progression of atherosclerosis in human coronary arteries. Especially sites with low and oscillating WSS near bifurcations have a higher propensity to develop atherosclerosis. WSS computations in coronary bifurcations can be performed in angiography-based 3D reconstructions. It is essential to evaluate how reconstruction errors influence WSS computations in mildly-diseased coronary bifurcations. In mildly-diseased lesions WSS could potentially provide more insight in plaque progression.

Materials Methods

Four Plexiglas phantom models of coronary bifurcations were imaged with bi-plane angiography. The lumens were segmented by two clinically experienced readers. Based on the segmentations 3D models were generated. This resulted in three models per phantom: one gold-standard from the phantom model itself, and one from each reader. Steady-state and transient simulations were performed with computational fluid dynamics to compute the WSS. A similarity index and a noninferiority test were used to compare the WSS in the phantoms and their reconstructions. The margin for this test was based on the resolution constraints of angiography.

Results

The reconstruction errors were similar to previously reported data; in seven out of eight reconstructions less than 0.10 mm. WSS in the regions proximal and far distal of the stenosis showed a good agreement. However, the low WSS areas directly distal of the stenosis showed some disagreement between the phantoms and the readers. This was due to small deviations in the reconstruction of the stenosis that caused differences in the resulting jet, and consequently the size and location of the low WSS area.

Discussion

This study showed that WSS can accurately be computed within angiography-based 3D reconstructions of coronary arteries with early stage atherosclerosis. Qualitatively, there was a good agreement between the phantoms and the readers. Quantitatively, the low WSS regions directly distal to the stenosis were sensitive to small reconstruction errors.     

Coronary Computed Tomography Angiography Based Assessment of Endothelial Shear Stress and Its Association with Atherosclerotic Plaque Distribution In-Vivo

Purpose

The relationship between low endothelial shear stress (ESS) and coronary atherosclerosis is well established. ESS assessment so far depended on invasive procedures. The aim of this study was to demonstrate the relationship between ESS and coronary atherosclerosis by using non-invasive coronary computed tomography angiography (CTA) for computational fluid dynamics (CFD) simulations.

Methods

A total number of 7 consecutive patients with suspected coronary artery disease who received CTA and invasive angiography with IVUS analysis were included in this study. CTA examinations were performed using a dual-source scanner. These datasets were used to build a 3D mesh model. CFD calculations were performed using a validated CFD solver. The presence of plaque was assumed if the thickness of the intima-media complex exceeded 0.3 mm in IVUS. Plaque composition was derived by IVUS radiofrequency data analysis.

Results

Plaque was present in 32.1% of all analyzed cross-sections. Plaque prevalence was highest in areas of low ESS (49.6%) and high ESS (34.8%). In parts exposed to intermediate-low and intermediate-high ESS few plaques were found (20.0% and 24.0%) (p<0.001). Wall thickness was closely associated with local ESS. Intima-media thickness was 0.43±0.34mm in low and 0.38±0.32mm in high ESS segments. It was significantly lower when the arterial wall was exposed to intermediate ESS (0.25±0.18mm and 0.28 ± 0.20mm) (p<0.001). Fibrofatty tissue was predominately found in areas exposed to low ESS (p≤0.023).

Conclusions

In this study a close association of atherosclerotic plaque distribution and ESS pattern could be demonstrated in-vivo. Adding CFD analysis to coronary CTA offers the possibility to gather morphologic and physiologic data within one non-invasive examination.     

The influence of computational strategy on prediction of mechanical stress in carotid atherosclerotic plaques: Comparison of 2D structure-only, 3D structure-only,one-way and fully coupled fluid-structure interaction analyses

Background

Compositional and morphological features of carotid atherosclerotic plaques provide complementary information to luminal stenosis in predicting clinical presentations. However, they alone cannot predict cerebrovascular risk. Mechanical stress within the plaque induced by cyclical changes in blood pressure has potential to assess plaque vulnerability. Various modeling strategies have been employed to predict stress, including 2D and 3D structure-only, 3D one-way and fully coupled fluid-structure interaction (FSI) simulations. However, differences in stress predictions using different strategies have not been assessed.

Methods

Maximum principal stress (Stress-P1) within 8 human carotid atherosclerotic plaques was calculated based on geometry reconstructed from in vivo computerized tomography and high resolution, multi-sequence magnetic resonance images. Stress-P1 within the diseased region predicted by 2D and 3D structure-only, and 3D one-way FSI simulations were compared to 3D fully coupled FSI analysis.

Results

Compared to 3D fully coupled FSI, 2D structure-only simulation significantly overestimated stress level (94.1 kPa [65.2, 117.3] vs. 85.5 kPa [64.4, 113.6]; median [inter-quartile range], p=0.0004). However, when slices around the bifurcation region were excluded, stresses predicted by 2D structure-only simulations showed a good correlation (R²=0.69) with values obtained from 3D fully coupled FSI analysis. 3D structure-only model produced a small yet statistically significant stress overestimation compared to 3D fully coupled FSI (86.8 kPa [66.3, 115.8] vs. 85.5 kPa [64.4, 113.6]; p<0.0001). In contrast, one-way FSI underestimated stress compared to 3D fully coupled FSI (78.8 kPa [61.1, 100.4] vs. 85.5 kPa [64.4, 113.7]; p<0.0001).

Conclusions

A 3D structure-only model seems to be a computationally inexpensive yet reasonably accurate approximation for stress within carotid atherosclerotic plaques with mild to moderate luminal stenosis as compared to fully coupled FSI analysis.     

Influence of model boundary conditions on blood flow patterns in a patient specific stenotic right coronary artery

Background

In literature, the effect of the inflow boundary condition was investigated by examining the impact of the waveform and the shape of the spatial profile of the inlet velocity on the cardiac hemodynamics. However, not much work has been reported on comparing the effect of the different combinations of the inlet/outlet boundary conditions on the quantification of the pressure field and flow distribution patterns in stenotic right coronary arteries.

Method

Non-Newtonian models were used to simulate blood flow in a patient-specific stenotic right coronary artery and investigate the influence of different boundary conditions on the phasic variation and the spatial distribution patterns of blood flow. The 3D geometry of a diseased artery segment was reconstructed from a series of IVUS slices. Five different combinations of the inlet and the outlet boundary conditions were tested and compared.

Results

The temporal distribution patterns and the magnitudes of the velocity, the wall shear stress (WSS), the pressure, the pressure drop (PD), and the spatial gradient of wall pressure (WPG) were different when boundary conditions were imposed using different pressure/velocity combinations at inlet/outlet. The maximum velocity magnitude in a cardiac cycle at the center of the inlet from models with imposed inlet pressure conditions was about 29% lower than that from models using fully developed inlet velocity data. Due to the fact that models with imposed pressure conditions led to blunt velocity profile, the maximum wall shear stress at inlet in a cardiac cycle from models with imposed inlet pressure conditions was about 29% higher than that from models with imposed inlet velocity boundary conditions. When the inlet boundary was imposed by a velocity waveform, the models with different outlet boundary conditions resulted in different temporal distribution patterns and magnitudes of the phasic variation of pressure. On the other hand, the type of different boundary conditions imposed at the inlet and the outlet did not have significant effect on the spatial distribution patterns of the PD, the WPG and the WSS on the lumen surface, regarding the locations of the maximum and the minimum of each quantity.

Conclusions

The observations from this study indicated that the ways how pressure and velocity boundary conditions are imposed in computational models have considerable impact on flow velocity and shear stress predictions. Accuracy of in vivo measurements of blood pressure and velocity is of great importance for reliable model predictions.

     

A Feasibility Study of an Intravascular Imaging Antenna to Image Atherosclerotic Plaques in Swine Using 3.0 T MRI

Purpose

To investigate the feasibility of an intravascular imaging antenna to image abdominal aorta atherosclerotic plaque in swine using 3.0T magnetic resonance imaging (MRI).

Methods

Atherosclerotic model was established in 6 swine. After 8 months, swine underwent an MR examination, which was performed using an intravascular imaging guide-wire, and images of the common iliac artery and the abdominal aorta were acquired. Intravascular ultrasound (IVUS) was performed in the right femoral artery; images at the same position as for the MR examination were obtained. The luminal border and external elastic membrane of the targeted arteries were individually drawn in the MR and IVUS images. After co-registering these images, the vessel, lumen, and vessel wall areas and the plaque burden in the same lesions imaged using different modalities were calculated and compared. The diagnostic accuracy of intravascular MR examination in delineating the vessel wall and detecting plaques were analyzed and compared using IVUS.

Results

Compared with IVUS, good agreement was found between MRI and IVUS for delineating vessel, lumen, and vessel wall areas and plaque burden (r value: 0.98, 0.95, 0.96 and 0.91, respectively; P<0.001).

Conclusion

Compared with IVUS, using an intravascular imaging guide-wire to image deep seated arteries allowed determination of the vessel, lumen and vessel wall areas and plaque size and burden. This may provide an alternative method for detecting atherosclerotic plaques in the future.     

Shear stress influences spatial variations in vascular Mn-SOD expression: implication for LDL nitration

Fluid shear stress modulates vascular production of endothelial superoxide anion (O2*-) and nitric oxide (*NO). Whether the characteristics of shear stress influence the spatial variations in mitochondrial manganese superoxide dismutase (Mn-SOD) expression in vasculatures is not well defined. We constructed a three-dimensional computational fluid dynamics model simulating spatial variations in shear stress at the arterial bifurcation. In parallel, explants of arterial bifurcations were sectioned from the human left main coronary bifurcation and right coronary arteries for immunohistolocalization of Mn-SOD expression. We demonstrated that Mn-SOD staining was prominent in the pulsatile shear stress (PSS)-exposed and atheroprotective regions, but it was nearly absent in the oscillatory shear stress (OSS)-exposed regions and lateral wall of arterial bifurcation. In cultured bovine aortic endothelial cells, PSS at mean shear stress (tau ave) of 23 dyn/cm2 upregulated Mn-SOD mRNA expression at a higher level than did OSS at tau ave = 0.02 dyn/cm2 +/- 3.0 dyn.cm(-2).s(-1) and at 1 Hz (PSS by 11.3 +/- 0.4-fold vs. OSS by 5.0 +/- 0.5-fold vs. static condition; P < 0.05, n = 4). By liquid chromatography and tandem mass spectrometry, it was found that PSS decreased the extent of low-density lipoprotein (LDL) nitration, whereas OSS increased nitration (P < 0.05, n = 4). In the presence of LDL, treatment with Mn-SOD small interfering RNA increased intracellular nitrotyrosine level (P < 0.5, n = 4), a fingerprint for nitrotyrosine formation. Our findings indicate that shear stress in the atheroprone versus atheroprotective regions regulates spatial variations in mitochondrial Mn-SOD expression with an implication for modulating LDL nitration.     

Healthy and diseased coronary bifurcation geometries influence near-wall and intravascular flow: A computational exploration of the hemodynamic risk

Local hemodynamics has been identified as one main determinant in the onset and progression of atherosclerotic lesions at coronary bifurcations. Starting from the observation that atherosensitive hemodynamic conditions in arterial bifurcation are majorly determined by the underlying anatomy, the aim of the present study is to investigate how peculiar coronary bifurcation anatomical features influence near-wall and intravascular flow patterns. Different bifurcation angles and cardiac curvatures were varied in population-based, idealized models of both stenosed and unstenosed bifurcations, representing the left anterior descending (LAD) coronary artery with its diagonal branch. Local hemodynamics was analyzed in terms of helical flow and exposure to low/oscillatory shear stress by performing computational fluid dynamics simulations.Results show that bifurcation angle impacts lowly hemodynamics in both stenosed and unstenosed cases. Instead, curvature radius influences the generation and transport of helical flow structures, with smaller cardiac curvature radius associated to higher helicity intensity. Stenosed bifurcation models exhibit helicity intensity values one order of magnitude higher than the corresponding unstenosed cases. Cardiac curvature radius moderately affects near-wall hemodynamics of the stenosed cases, with smaller curvature radius leading to higher exposure to low shear stress and lower exposure to oscillatory shear stress. In conclusion, the proposed controlled benchmark allows investigating the effect of various geometrical features on local hemodynamics at the LAD/diagonal bifurcation, highlighting that cardiac curvature influences near wall and intravascular hemodynamics, while bifurcation angle has a minor effect.     

Oxidative stress-induced cyclin D1 depletion and its role in cell cycle processing

Background

Cyclin D1 is immediately down-regulated in response to reactive oxygen species (ROS) and implicated in the induction of cell cycle arrest in G2 phase by an unknown mechanism. Either treatment with a protease inhibitor alone or expression of protease-resistant cyclin D1 T286A resulted in only a partial relief from the ROS-induced cell cycle arrest, indicating the presence of an additional control mechanism.

Methods

Cells were exposed to hydrogen peroxide (H₂O₂), and analyzed to assess the changes in cyclin D1 level and its effects on cell cycle processing by kinase assay, de novo synthesis, gene silencing, and polysomal analysis, etc.

Results

Exposure of cells to excessive H₂O₂ induced ubiquitin-dependent proteasomal degradation of cyclin D1, which was subsequently followed by translational repression. This dual control mechanism was found to contribute to the induction of cell cycle arrest in G2 phase under oxidative stress. Silencing of an eIF2α kinase PERK significantly retarded cyclin D1 depletion, and contributed largely to rescuing cells from G2 arrest. Also the cyclin D1 level was found to be correlated with Chk1 activity.

Conlclusions

In addition to an immediate removal of the pre-existing cyclin D1 under oxidative stress, the following translational repression appear to be required for ensuring full depletion of cyclin D1 and cell cycle arrest. Oxidative stress-induced cyclin D1 depletion is linked to the regulation of G2/M transit via the Chk1–Cdc2 DNA damage checkpoint pathway.

General significance

The control of cyclin D1 is a gate keeping program to protect cells from severe oxidative damages.     

Curcusone D,a novel ubiquitin–proteasome pathway inhibitor via ROS-induced DUB inhibition,is synergistic with bortezomib against multiple myeloma cell growth

Background

Ubiquitin–proteasome pathway (UPP) plays a very important role in the degradation of proteins. Finding novel UPP inhibitors is a promising strategy for treating multiple myeloma (MM).

Methods

Ub-YFP reporter assays were used as cellular UPP models. MM cell growth, apoptosis and overall death were evaluated with the MTS assay, Annexin V/PI dual-staining flow cytometry, poly (ADP-ribose) polymerase (PARP) cleavage, and PI uptake, respectively. The mechanism of UPP inhibition was analyzed by western blotting for ubiquitin, in vitro and cellular proteasomal and deubiquitinases (DUBs) activity assays. Cellular reactive oxygen species (ROS) were measured with H₂DCFDA.

Results

Curcusone D, identified as a novel UPP inhibitor, causes cell growth inhibition and apoptosis in MM cells. Curcusone D induced the accumulation of poly-ubiquitin-conjugated proteins but could not inhibit proteasomal activity in vitro or in cells. Interestingly, the mono-ubiquitin level and the total cellular DUB activity were significantly downregulated following curcusone D treatment. Furthermore, curcusone D could induce ROS, which were closely correlated with DUB inhibition that could be nearly completely reversed by NAC. Finally, curcusone D and the proteasomal inhibitor bortezomib showed a strong synergistic effect against MM cells.

Conclusions

Curcusone D is novel UPP inhibitor that acts via the ROS-induced inhibition of DUBs to produce strong growth inhibition and apoptosis of MM cells and synergize with bortezomib.

General significance

The anti-MM molecular mechanism study of curcusone D will promote combination therapies with different UPP inhibitors against MM and further support the concept of oxidative stress regulating the activity of DUBs.     

Fluid flow and plaque formation in an aortic bifurcation

Considering steady laminar flow in a two-dimensional symmetric branching channel with local occlusions, a finite element model has been developed to study velocity fields including reverse flow regions, pressure profiles and wall shear stress distributions for different Reynolds numbers, bifurcation angles and lumen reductions. The flow analysis has been extended to include a new submodel for the pseudo-transient formation of plaque at sites and deposition rates defined by the physical characteristics of the flow. Specifically, simulating the onset of atherosclerotic lesions, sinusoidal plaque layers have been placed in areas of critically low wall shear stresses, and simulating the growth of particle depositions, plaque layers have been added in a stepwise fashion in regions of critically high and low shear. Thus two somewhat conflicting hypothetical correlations between critical wall shear stress levels and atheroma have been tested and a solution has been postulated. The validated computer simulation model is a predictive tool for analyzing the effects of local changes in wall curvature due to surgical reconstruction and/or atherosclerotic lesions, and for investigating the design of aortic bifurcations which mitigate plaque formation.     

Age-dependent guanine oxidation in DNA of different brain regions of Wistar rats and prematurely aging OXYS rats

Background

Oxidative damage to the cell, including the formation of 8-oxoG, has been regarded as a significant factor in carcinogenesis and aging. An inbred prematurely aging rat strain (OXYS) is characterized by high sensitivity to oxidative stress, lipid peroxidation, protein oxidation, DNA rearrangements, and pathological conditions paralleling several human degenerative diseases including learning and memory deterioration.

Methods

We have used monoclonal antibodies against a common pre-mutagenic base lesion 8-oxoguanine (8-oxoG) and 8-oxoguanine DNA glycosylase (OGG1) in combination with indirect immunofluorescence microscopy and image analysis to follow the relative amounts and distribution of 8-oxoG and OGG1 in various cells of different brain regions from OXYS and control Wistar rats.

Results

It was shown that 8-oxoG increased with age in mature neurons, nestin- and glial fibrillary acidic protein (GFAP)-positive cells of hippocampus and frontal cortex in both strains of rats, with OXYS rats always displaying statistically significantly higher levels of oxidative DNA damage than Wistar rats. The relative content of 8-oxoG and OGG1 in nestin- and GFAP-positive cells was higher than in mature neurons in both Wistar and OXYS rats. However, there was no significant interstrain difference in the content of OGG1 for all types of cells and brain regions analyzed, and no difference in the relative content of 8-oxoG between different brain regions.

Conclusions

Oxidation of guanine may play an important role in the development of age-associated decrease in memory and learning capability of OXYS rats.

General significance

The findings are important for validation of the OXYS rat strain as a model of mammalian aging.     

Bioreactors to influence stem cell fate: Augmentation of mesenchymal stem cell signaling pathways via dynamic culture systems

Background

Mesenchymal stem cells (MSCs) are a promising cell source for bone and cartilage tissue engineering as they can be easily isolated from the body and differentiated into osteoblasts and chondrocytes. A cell based tissue engineering strategy using MSCs often involves the culture of these cells on three-dimensional scaffolds; however the size of these scaffolds and the cell population they can support can be restricted in traditional static culture. Thus dynamic culture in bioreactor systems provides a promising means to culture and differentiate MSCs in vitro.

Scope of review

This review seeks to characterize key MSC differentiation signaling pathways and provides evidence as to how dynamic culture is augmenting these pathways. Following an overview of dynamic culture systems, discussion will be provided on how these systems can effectively modify and maintain important culture parameters including oxygen content and shear stress. Literature is reviewed for both a highlight of key signaling pathways and evidence for regulation of these signaling pathways via dynamic culture systems.

Major conclusions

The ability to understand how these culture systems are affecting MSC signaling pathways could lead to a shear or oxygen regime to direct stem cell differentiation. In this way the efficacy of in vitro culture and differentiation of MSCs on three-dimensional scaffolds could be greatly increased.

General significance

Bioreactor systems have the ability to control many key differentiation stimuli including mechanical stress and oxygen content. The further integration of cell signaling investigations within dynamic culture systems will lead to a quicker realization of the promise of tissue engineering and regenerative medicine. This article is part of a Special Issue entitled Biochemistry of Stem Cells.     

Definition of the margin of major coronary artery bifurcations during radiotherapy with electrocardiograph-gated 4D-CT

PurposeThe aim was to measure the cardiac motion-induced displacements of major coronary artery bifurcations utilizing electrocardiography (ECG)-gated four-dimensional computed tomography (4D-CT) and to determine the margin of coronary artery bifurcations.MethodsThirty-seven female patients who underwent retrospective ECG-gated 4D-CT in inspiratory breath hold (IBH) were enrolled. The left main coronary artery bifurcation (LM), the obtuse marginal branch bifurcation (OM), the first diagonal branch bifurcation (D₁), the second diagonal branch bifurcation (D₂), the caudal portion of the left anterior descending branch (APX), the first right ventricular artery bifurcation (V) and the acute marginal branch bifurcation (AM) were contoured. The center of the contour of the coronary arterial bifurcations at end systole was defined as the standard, and the margin were then calculated.ResultsThe margin in the left–right (LR), cranio-caudal (CC), and anterior-posterior (AP) coordinates were as follows: LM 3, 3, and 3 mm; D₁ 6, 3, and 3 mm; D₂ 3, 3, and 3 mm; APX 4, 4, and 4 mm; OM 4, 6, and 5 mm; V 6, 8, and 7 mm; and AM 6, 8, and 7 mm, respectively.ConclusionCoronary artery bifurcations should be considered a separate organ at risk (OAR), and different margin should be provided due to the differences resulting from motion displacement. The maximum margin in the LR, CC, and AP coordinates of left coronary artery bifurcations were 6, 6, and 5 mm, and those of the right coronary artery bifurcations were 6, 8, and 7 mm, respectively.     

The Role of Shear Stress in Arteriovenous Fistula Maturation and Failure: A Systematic Review

Introduction

Non-maturation and post-maturation venous stenosis are the primary causes of failure within arteriovenous fistulae (AVFs). Although the exact mechanisms triggering failure remain unclear, abnormal hemodynamic profiles are thought to mediate vascular remodelling and can adversely impact on fistula patency.

Aim

The review aims to clarify the role of shear stress on outward remodelling during maturation and evaluate the evidence supporting theories related to the localisation and development of intimal hyperplasia within AVFs.

Methods

A systematic review of studies comparing remodelling data with hemodynamic data obtained from computational fluid dynamics of AVFs during and after maturation was conducted.

Results

Outward remodelling occurred to reduce or normalise the level of shear stress over time in fistulae with a large radius of curvature (curved) whereas shear stress was found to augment over time in fistulae with a small radius of curvature (straight) coinciding with minimal to no increases in lumen area. Although this review highlighted that there is a growing body of evidence suggesting low and oscillating shear stress may stimulate the initiation and development of intimal medial thickening within AVFs. Further lines of evidence are needed to support the disturbed flow theory and outward remodelling findings before surgical configurations and treatment strategies are optimised to conform to them. This review highlighted that variation between the time of analysis, classification of IH, resolution of simulations, data processing techniques and omission of various shear stress metrics prevented forming pooling of data amongst studies.

Conclusion

Standardised measurements and data processing techniques are needed to comprehensively evaluate the relationship between shear stress and intimal medial thickening. Advances in image acquisition and flow quantifications coupled with the increasing prevalence of longitudinal studies commencing from fistula creation offer viable techniques and strategies to robustly evaluate the relationship between shear stress and remodelling during maturation and thereafter.     

Genome wide DNA methylation profiling for epigenetic alteration in coronary artery disease patients

Background

The alteration in the epigenome forms an interface between the genotype and the environment. Epigenetic alteration is expected to make a significant contribution to the development of cardiovascular disease where environmental interactions play a key role in disease progression. We had previously shown that global DNA hypermethylation per se is associated with coronary artery disease (CAD) and is further accentuated by high levels of homocysteine, a thiol amino acid which is an independent risk factor for cardiovascular disease and is also a key modulator of macromolecular methylation.

Results

We have identified 72 differentially methylated regions (DMRs) that were hypermethylated in CAD patients in the background of varying homocysteine levels. Following deep bisulfite sequencing of a few of the selected DMRs, we found significantly higher methylation in CAD cases. We get six CpG sites in three DMRs that included the intronic region of C1QL4 gene and upstream region of CCDC47 and TGFBR3 genes.

Conclusion

To the best of our knowledge, this is the first study to identify hypermethylated regions across the genome in patients with coronary artery disease. Further validation in different populations is necessary for this information to be used for disease risk assessment and management.     

Prevalence and predictors of bridging of coronary arteries in a large Indonesian population, as detected by 64-slice computed tomography scan

Background

Multislice computed tomography (MSCT) can be used to detect myocardial bridging (MB) of coronary arteries. However, most published studies included small cohorts and did not collect data about predictors. We investigated prevalence and predictors of MB in an Indonesian population.

Methods

All patients who had MSCT at Cinere Hospital, Jakarta, Indonesia between 2006 and 2009 were included in a prospective registry. MB was defined when at least half of the coronary artery was imbedded within the myocardium with a normal epicardial course of the proximal and distal portion.

Results

Of the 934 patients (mean age 53 years, 37.8 % female), MB could be observed in 152 patients (16.3 %). Patients with MB were younger compared with those without MB. Coronary risk factors were not different between the two groups. Coronary calcifications and moderate to severe coronary stenoses were less prevalent in patients with MB, also after adjusting for differences in age. At the time of diagnosis, only a few patients with MB were treated with beta-blockers (35 %) or calcium channel blockers (13 %).

Conclusions

Prevalence of myocardial bridging as detected by MSCT is relatively high. Patients with MB were younger and had a lower prevalence of coronary sclerosis. MB could be the cause of their unexplained symptoms. Follow-up studies are necessary to assess the symptoms of these patients, their response to treatment and the incidence of (coronary) events. MSCT can be used to identify patients for potential new treatment strategies.     

Estudio de la vulnerabilidad neuronal selectiva en el sistema nervioso central humano

Introduction

The concept of ‘selective neuronal vulnerability’ refers to the differential sensitivity of neuronal populations in the nervous system to stresses that cause cell damage and lead to neurodegeneration. Because oxidative stress play a causal role in the physiological aging process, and it is often invoked as an aetiopathogenic and/or pathophysiological mechanism for neurodegeneration, in the present work we propose that the molecular bases of selective neuronal vulnerability is linked with cell adaptations related to oxidative stress.

Material and methods

The grey substance of 5 different regions from healthy human subjects (n = 7) were selected: i) to evaluate their membrane fatty acid profile by chromatographic methods, ii) to determine their membrane susceptibility to peroxidation, and iii) to recognise potential mechanisms involved in its regulation.

Results

The results showed significant inter-regional differences in the fatty acid profile, basically due to the content of mono- and highly polyunsaturated fatty acids; changes that, in turn, induce significant differences in theirs susceptibilities to peroxidation, as well as differences that can be ascribed to the desaturase activity.

Conclusion

Thus, the cross-regional comparative approach seems to confirm the idea that the level of cell membrane unsaturation may be a key trait associated with selective neuronal vulnerability.     

Mitochondrial proteolysis: Its emerging roles in stress responses

Background

Mitochondria are multifunctional organelles that not only serve as cellular energy stores but are also actively involved in several cellular stress responses, including apoptosis. In addition, mitochondria themselves are also continuously challenged by stresses such as reactive oxygen species (ROS), an inevitable by-product of oxidative phosphorylation. To exert various functions against these stresses, mitochondria must be equipped with appropriate stress responses that monitor and maintain their quality.

Scope of review

Interestingly, increasing evidence indicates that mitochondrial proteolysis has important roles in mitochondrial and cellular stress responses. In this review, we summarize current advances in mitochondrial proteolysis-mediated stress responses.

Major conclusions

Mitochondrial proteases do not only function as surveillance systems of protein quality control by degrading unfolded proteins but also regulate mitochondrial stress responses by processing specific mitochondrial proteins.

General significance

Studies on the regulation of mitochondrial proteolysis-mediated stress responses will provide the novel mechanistic insights into the stress response research fields.