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Aims International guidelines mandate the use of fractional flow reserve (FFR) and/or non-hyperaemic pressure ratios to assess the physiological significance of moderate coronary artery lesions to guide revascularization decisions. However, they remain underused such that visual estimation of lesion severity continues to be the predominant decision-making tool. It would be pragmatic to have an improved understanding of the relationship between lesion morphology and haemodynamics. The aim of this study was to compute virtual FFR (vFFR) in idealized coronary artery geometries with a variety of stenosis and vessel characteristics. Methods and results Coronary artery geometries were modelled, based upon physiologically realistic branched arteries. Common stenosis characteristics were studied, including % narrowing, length, eccentricity, shape, number, position relative to branch, and distal (myocardial) resistance. Computational fluid dynamics modelling was used to calculate vFFRs using the VIRTUheart™ system. Percentage lesion severity had the greatest effect upon FFR. Any ≥80% diameter stenosis in two views (i.e. concentric) was physiologically significant (FFR ≤ 0.80), irrespective of length, shape, or vessel diameter. Almost all eccentric stenoses and all 50% concentric stenoses were physiologically non-significant, whilst 70% uniform concentric stenoses about 10 mm long straddled the ischaemic threshold (FFR 0.80). A low microvascular resistance (MVR) reduced FFR on average by 0.05, and a high MVR increased it by 0.03. Conclusion Using computational modelling, we have produced an analysis of vFFR that relates stenosis characteristics to haemodynamic significance. The strongest predictor of a positive vFFR was a concentric, ≥80% diameter stenosis. The importance of MVR was quantified. Other lesion characteristics have a limited impact.

Non-invasive estimation of the pressure gradient in cardiovascular stenosis has much clinical importance in assisting the diagnosis and treatment of stenotic diseases. In this research, a systematic comparison is conducted to investigate the accuracy of a group of stenosis models against the MRI- and catheter-measured patient data under the aortic coarctation condition. Eight analytical stenosis models, including six from the literature and two proposed in this study, are investigated to examine their prediction accuracy against the clinical data. The two improved models proposed in this study consider comprehensively the Poiseuille loss, the Bernoulli loss in its exact form, and the entrance effect, of the blood flow. Comparison of the results shows that one of the proposed models demonstrates a cycle-averaged mean prediction error of −0.15 ± 3.03 mmHg, a peak-to-peak prediction error of −1.8 ± 6.89 mmHg, which is the best among the models studied., This research was funded by the European Community’s Seventh Framework Programme (FP7/2007–2013) under the grant agreement number 224495 (euHeart project).

Aims To extend the benefits of physiologically guided percutaneous coronary intervention to many more patients, angiography-derived, or ‘virtual’ fractional flow reserve (vFFR) has been developed, in which FFR is computed, based upon the images, instead of being measured invasively. The effect of operator experience with these methods upon vFFR accuracy remains unknown. We investigated variability in vFFR results based upon operator experience with image-based computational modelling techniques. Methods and results Virtual fractional flow reserve was computed using a proprietary method (VIRTUheart) from the invasive angiograms of patients with coronary artery disease. Each case was processed by an expert (>100 vFFR cases) and a non-expert (, Graphical Abstract

The role of ‘stand-alone’ coronary angiography (CAG) in the management of patients with chronic coronary syndromes is the subject of debate, with arguments for its replacement with CT angiography on the one hand and its confinement to the interventional cardiac catheter laboratory on the other. Nevertheless, it remains the standard of care in most centres. Recently, computational methods have been developed in which the laws of fluid dynamics can be applied to angiographic images to yield ‘virtual’ (computed) measures of blood flow, such as fractional flow reserve. Together with the CAG itself, this technology can provide an ‘all-in-one’ anatomical and functional investigation, which is particularly useful in the case of borderline lesions. It can add to the diagnostic value of CAG by providing increased precision and reduce the need for further non-invasive and functional tests of ischaemia, at minimal cost. In this paper, we place this technology in context, with emphasis on its potential to become established in the diagnostic workup of patients with suspected coronary artery disease, particularly in the non-interventional setting. We discuss the derivation and reliability of angiographically derived fractional flow reserve (CAG-FFR) as well as its limitations and how CAG-FFR could be integrated within existing national guidance. The assessment of coronary physiology may no longer be the preserve of the interventional cardiologist.

Aims Ischaemic heart disease is the reduction of myocardial blood flow, caused by epicardial and/or microvascular disease. Both are common and prognostically important conditions, with distinct guideline-indicated management. Fractional flow reserve (FFR) is the current gold-standard assessment of epicardial coronary disease, but is only a surrogate of flow and only predicts percentage flow changes. It cannot assess absolute (volumetric) flow or microvascular disease. The aim of this study was to develop and validate a novel method that predicts absolute coronary blood flow and microvascular resistance (MVR) in the catheter laboratory. Methods and Results A computational fluid dynamics (CFD) model was used to predict absolute coronary flow (QCFD) and coronary microvascular resistance (MVR) using data from routine invasive angiography and pressure-wire assessment. QCFD was validated in an in vitro flow circuit which incorporated patient-specific, 3-D printed coronary arteries; and then in vivo, in patients with coronary disease. In vitro, QCFD agreed closely with the experimental flow over all flow rates (bias +2.08 mL/min; 95% CI (error range) -4.7 to + 8.8 mL/min; R2=0.999, p

Three dimensional (3D) coronary anatomy, reconstructed from coronary angiography (CA), is now being used as the basis to compute ‘virtual’ fractional flow reserve (vFFR), and thereby guide treatment decisions in patients with coronary artery disease (CAD). Reconstruction accuracy is therefore important. Yet the methods required remain poorly validated. Furthermore, the magnitude of vFFR error arising from reconstruction is unkown. We aimed to validate a method for 3D CA reconstruction and determine the effect this had upon the accuracy of vFFR. Clinically realistic coronary phantom models were created comprosing seven standard stenoses in aluminium and 15 patient-based 3D-printed, imaged with CA, three times, according to standard clinical protocols, yielding 66 datasets. Each was reconstructed using epipolar line projection and intersection. All reconstructions were compared against the real phantom models in terms of minimal lumen diameter, centreline and surface similarity. 3D-printed reconstructions (n = 45) and the reference files from which they were printed underwent vFFR computation, and the results were compared. The average error in reconstructing minimum lumen diameter (MLD) was 0.05 (± 0.03 mm) which was

The current management of acute coronary syndromes (ACS) is with an invasive strategy to guide treatment. However, identifying the lesions which are physiologically significant can be challenging. Non-invasive imaging is generally not appropriate or timely in the acute setting, so the decision is generally based upon visual assessment of the angiogram, supplemented in a small minority by invasive pressure wire studies using fractional flow reserve (FFR) or related indices. Whilst pressure wire usage is slowly increasing, it is not feasible in many vessels, patients and situations. Limited evidence for the use of FFR in non-ST elevation (NSTE) ACS suggests a 25% change in management, compared with traditional assessment, with a shift from more to less extensive revascularisation. Virtual (computed) FFR (vFFR), which uses a 3D model of the coronary arteries constructed from the invasive angiogram, and application of the physical laws of fluid flow, has the potential to be used more widely in this situation. It is less invasive, fast and can be integrated into catheter laboratory software. For severe lesions, or mild disease, it is probably not required, but it could improve the management of moderate disease in 'real time' for patients with non-ST elevation acute coronary syndromes (NSTE-ACS), and in bystander disease in ST elevation myocardial infarction. Its practicability and impact in the acute setting need to be tested, but the underpinning science and potential benefits for rapid and streamlined decision-making are enticing.

AIMS Fractional flow reserve (FFR) represents the percentage reduction in coronary flow relative to a hypothetically normal artery; however, percutaneous coronary intervention (PCI) seldom achieves physiological normality (FFR 1.00), particularly in the context of diffuse disease. In this study we describe a method for calculating the vessel-specific maximal achievable FFR (FFRmax) providing a personalised assessment of what PCI can achieve. METHODS AND RESULTS FFR measurements were obtained from 71 patients (100 arteries) undergoing angiography. Three-dimensional (3D) coronary anatomy was reconstructed from angiographic images. An ideal intervention, in which all stenoses are removed, was modelled, and the FFRmax calculated. The "personalised" FFR (FFRpers) was calculated as measured FFR/FFRmax. PCI was performed in 52 vessels and post-PCI FFR measured in 50. FFRmax was compared to post-PCI measured FFRs. The mean FFRmax was 0.92 (±0.04). This was on average 0.04 (±0.05) higher than the corresponding post-PCI measured FFR (p

[Background] Non-invasive estimation of the pressure gradient in aortic coarctation has much clinical importance in assisting the diagnosis and treatment of the disease. Previous researchers applied computational fluid dynamics for the prediction of the pressure gradient in aortic coarctation. The accuracy of the prediction was satisfactory but the procedure was time-consuming and resource-demanding., [Method] In this research a magnetic resonance imaging (MRI)-based non-invasive modeling procedure is implemented to predict the pressure gradient in 14 patient cases of aortic coarctation. Multi-cycle patient flow and pressure data are processed to produce the flow and pressure conditions in the patient cases. Bernoulli equation-based friction loss model combined with the inertial effect of the blood flow in the vessel segments are applied to model the pressure gradient in the aortic coarctation. The model-predicted pressure gradient data are then compared with the catheter in vivo measurement data for validation., [Results] The MRI-based model prediction technique produces results that are consistent with those from the catheter measurement, based on the criteria of both the cycle-averaged instantaneous pressure gradient and the peak-to-peak pressure gradient., [Conclusion] This study suggests that the MRI-based non-invasive modeling procedure has much potential to be applied in clinical practice for the prediction of the pressure gradient in aortic coarctation patients., This research was supported by the European Commission's Seventh Framework Programme (FP7/2007-2013) under the grant agreement number 224495 (euHeart project).

Introduction In patients with heart failure with reduced ejection fraction (HFrEF), a raised serum parathyroid hormone (PTH) level is associated with increased morbidity and mortality. Previous studies suggest that PTH levels correlate with peak VO2 and markers of endothelial dysfunction in HFrEF. We examined the role of PTH in the pathophysiological difference between response and non-response to cardiac resynchronisation therapy (CRT) in HFrEF. Methods All patients met National Institute for Health and Care Excellence criteria for CRT implantation and were prospectively recruited from a single centre. A positive response to CRT was defined as an improvement in all four of the following domains: 1) a greater than 1ml/kg/min increase in peak VO2; 2) a 10% reduction in left ventricular end-systolic volume (LVESV); 3) a 10% reduction in symptoms as measured by the Minnesota living with heart failure questionnaire (MLWHFQ); 4); over 10% increase in 6 minute walk distance (6MWD). PTH levels were measured at baseline and at 6 months following CRT. Percentage change in PTH level was calculated as (6 month PTH level – baseline PTH level)/(baseline PTH level). Data are presented as mean ± standard error of the mean. Analyses were performed using IBM SPSS version 24. Paired continuous data were compared with paired t test; unpaired continuous data with independent sample t test. Tests were 2-tailed. p Results A total of 19 patients were studied (9 responders, 10 non-responders; 95% male, age 70 ± 1.9 years). At baseline, there was no significant difference in estimated glomerular filtration rate (64.1 ± 3.2 ml/min/1.73m2 in responders, 58.3 ± 3.9 ml/min/1.73m2 in non-responders; p=0.27), corrected serum calcium level (2.31 ± 0.02 mg/dL in responders, 2.36 ± 0.02 mg/dL in non-responders; p=0.13), or serum 25-hydroxy vitamin D levels (56.5 ± 6.8 ng/mL in responders and 45.1 ± 12 ng/mL in non-responders; p=0.44) in between the two groups. At baseline, PTH levels in responders were 85.4 ± 9.9 pg/mL, compared to 63.4 ± 9.8 pg/mL in non-responders (p=0.06). At 6 months, PTH levels in responders were 72.3 ± 11.5 pg/mL, compared to 87.8 ± 10.7 pg/mL in non-responders (p=0.2). There was a significant difference in the percentage change in PTH levels between responders (an average reduction of 16 ± 3.6 %) and non-responders (an average increase of 38 ± 3.4 %) (p=0.002) (figure 1A). All responders had a decrease in serum PTH level at 6 months, whereas 8 out of 10 non-responders had an increase in serum PTH levels at 6 months (figure 1B). Conclusion This small, single-centre study suggests that a positive response to CRT is associated with a reduction in serum PTH levels at 6 months following the procedure. Conversely, non-response to CRT is generally characterised by an increase in PTH levels at 6 months. The pathophysiological role of PTH in CRT response warrants further investigation. Conflict of Interest Nil.

Background Ischaemic heart disease causes reduced coronary blood flow (CBF). CBF is not routinely measured in the catheterisation laboratory. Cardiologists therefore rely upon surrogate indices of CBF like fractional flow reserve (FFR). Whilst valuable in guiding revascularisation decisions, FFR reports CBF as a fraction of a hypothetical and unknown value. It is therefore, semi-quantitative and cannot assess microvascular physiology. FFR-guided PCI is associated with incomplete symptom resolution in around 20% of patients. These limitations may be resolved by a new method (virtuQ™) which computes absolute coronary blood flow (aCBF) and coronary microvascular resistance (CMVR) from angiography and standard pressure wire measurements. The aims of our study were to establish the relationship between FFR and aCBF, and to investigate the contribution of CMVR to aCBF. Methods virtuQ™ software was used to reconstruct the 3-D arterial anatomy of 229 vessels from 151 patients undergoing angiography and FFR assessment for coronary syndromes. aCBF and CMVR were computed by a numerical method based upon the reconstructed anatomy, pressure conditions and Navier-Stokes equations. The reduction in aCBF due to epicardial disease was also calculated. Percentage flow reduction (predicted by FFR) was compared to aCBF reduction in mL/min. A threshold for intervention for aCBF reduction was derived. Agreement between FFR and aCBF reduction was assessed by Cohen’s kappa (κ) statistic. Results virtuQ™ computed all physiological parameters in 207/229 cases (90%). Physiological results are summarised in table 1. Calculated by regression intercept using an FFR-aCBF plot, the derived threshold for physiological significance for aCBF reduction was ≥23 mL/min (figure 1). Overall agreement between FFR and aCBF reduction was moderate (κ=0.70). Agreement between FFR and aCBF reduction was high in cases where FFR was >0.80 (90.0%) and perfect when FFR ≤0.70 (100%), but poor when FFR was 0.70-0.80 (68.2%). For cases in which FFR was ≤0.80 (n=109), 19.5% were discordant, associated with increased CMVR (1.24 vs 0.58 mmHg.min/mL, P 0.80 or ≤0.70, with aCBF used if FFR 0.70-0.80) increased agreement to near perfect (κ=0.90) and required aCBF to be measured in 32% of cases. CMVR was higher in females at baseline and hyperaemia (1.59 vs 1.21 and 0.86 vs 0.68 mmHg·mL·min-1, respectively, P Conclusions In the largest study of aCBF to date, 19.5% of cases identified as physiologically significant by FFR were identified as non-significant by aCBF reduction criteria. Pressure-flow discordance was associated with variability in CMVR and may explain why around 20% of patients experience persistent angina following FFR-guided PCI. Combined FFR + aCBF assessment may be valuable, particularly in the FFR grey zone. virtuQ™ may have a complementary role in selecting patients for PCI and help diagnose microvascular disease. Conflict of Interest None

Background Using fractional flow reserve (FFR) to guide percutaneous coronary intervention for patients with coronary artery disease (CAD) improves clinical decision making but remains under-used. Virtual FFR (vFFR, computed from angiographic images) permits physiological assessment without a pressure wire and can be extended to virtual coronary intervention (VCI) facilitating treatment planning. This study investigated the effect of adding vFFR and VCI to angiography in patient assessment and management. Methods Two cardiologists independently reviewed clinical data and angiograms of 50 patients undergoing invasive management of coronary syndromes, and their management plans were recorded. The vFFRs were computed and disclosed, and the cardiologists submitted revised plans. Then, using VCI, the physiological results of various interventional strategies were shown, and further revision was invited. Results Disclosure of vFFR led to a change in strategy in 27%. VCI led to a change in stent size in 48%. Disclosure of vFFR and VCI resulted in an increase in operator confidence in their decision. Twelve cases were reviewed by six additional cardiologists. There was limited agreement in the management plans between cardiologists based upon either angiography (kappa=0.31) or vFFR (kappa=0.39). Conclusions vFFR has the potential to alter decision making, and VCI can guide stent sizing. However, variability in management strategy remains considerable between operators, even when presented with the same anatomical and physiological data.

Background Many patients with ST-segment elevation myocardial infarction (STEMI) have non-culprit lesions (NCLs) in other coronary arteries, for which optimal management is uncertain. In the COMPLETE trial, percutaneous coronary intervention (PCI) of eligible NCLs (vessel diameter ≥2.5mm) improved hard clinical outcomes, compared with conservative treatment. However, 99.3% of NCLs were assessed by visualisation of the angiogram using a threshold of ≥70% stenosis, which is an inaccurate method for assessing haemodynamic significance. A pressure wire was used to assess physiological significance (FFR ≤0.80) in only 0.7% of NCLs that visually had 50-69% stenosis. Hypothesis: In the ‘real-world’, the proportion of STEMI patients with NCL stenoses ≥50% that are of physiological significance, based upon fractional flow reserve (FFR) estimation, is low. Methods The angiograms of consecutive STEMI patients undergoing primary PCI were retrospectively reviewed by an interventional cardiologist to identify cases that either had NCL stenoses of 50-69% that would have been eligible for COMPLETE if FFR was ≤0.80 or fulfilled the COMPLETE eligibility criteria by visual assessment (stenosis ≥70%). The virtual FFRs of NCLs were computed using the VIRTUheart™ tool. The primary outcome was the proportion of all ‘real world’ STEMI patients with NCL stenoses ≥50%. Secondary outcomes were a) the proportion of patients with NCL stenoses of 50-69% who had vFFR ≤0.80 (‘FFR-guided PCI’ group; b) the proportion of NCL stenoses of >70% with a virtual FFR ≤0.80 (‘PCI without FFR’ group). Results Angiograms from 248 patients presenting with STEMI and undergoing primary PCI were reviewed. 70 cases (28%), were found with 86 NCLs that would have been potentially suitable for inclusion in COMPLETE (95% CI: 22.4% to 33.6%). Of these 70 cases, 59% of NCLs fell into the ‘FFR-guidance’ (50-69% stenosis) group and 41% into the ‘PCI without FFR’ (≥70% stenosis) group. Of the 70, 49 angiograms (70%) were technically suitable for modelling. A positive vFFR was found in 47% of NCLs (95% CI: 33.7% to 60.6%) (see Table 1). Conclusion In a ‘real-world’ STEMI population, 28% of patients could be considered for either FFR assessment (NCL stenosis 50-69%) or PCI without FFR according to the COMPLETE study criteria. However, of those, nearly 60% should undergo physiological assessment, according to COMPLETE eligibility criteria, even though very few were actually enrolled on this basis. Of the 60%, only 32% were physiologically significant; and, of all the NCLs, only 47% were physiologically significant. Further work is required to determine whether virtual FFR might provide a cost-effective means of identifying patients who will benefit from NCL revascularisation. Conflict of Interest none

Recent efforts have demonstrated the ability of computational models to predict fractional flow reserve from coronary artery imaging without the need for invasive instrumentation. However, these models include only larger coronary arteries as smaller side branches cannot be resolved and are therefore neglected. The goal of this study was to evaluate the impact of neglecting the flow to these side branches when computing angiography-derived fractional flow reserve (vFFR) and indices of volumetric coronary artery blood flow. To compensate for the flow to side branches, a leakage function based upon vessel taper (Murray’s Law) was added to a previously developed computational model of coronary blood flow. The augmented model with a leakage function (1Dleaky) and the original model (1D) were then applied to predict FFR as well as inlet and outlet flow in 146 arteries from 80 patients who underwent invasive coronary angiography and FFR measurement. The results show that the leakage function did not significantly change the vFFR but did significantly impact the estimated volumetric flow rate and predicted coronary flow reserve. As both procedures achieved similar predictive accuracy of vFFR despite large differences in coronary blood flow, these results suggest careful consideration of the application of this index for quantitatively assessing flow. This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Lal K, Gosling R, Priest J, Stephenson T, Lee T, Robinson N, O’Connor T, Gregory B, Son S, Hodgson A, Dunnill J, Lawford P, Hose R, Morris PD, Gunn J Sheffield Teaching Hospitals NHS Foundation Trust and Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Introduction Visual estimation of the physiological significance of coronary artery disease (CAD) is inaccurate. Fractional flow reserve (FFR) is better but is under-used. A less invasive alternative is ‘virtual’ FFR (vFFR) calculated from computational fluid dynamics (CFD) modelling from angiographic images. The aim of this study was to quality assess the vFFRs analysed by non-expert operators by comparing their results to those of fully trained experts. Methods Two expert operators re-processed vFFRs from patients with CAD that had previously been processed by seven non-experts. The vFFRs were computed using the VIRTUheart™ tool (University of Sheffield). Figure 1 shows an example from the workflow. The vFFR results of the expert and non-expert analysed were compared on the basis of the recommendation for percutaneous coronary intervention vs medical therapy and the reason for the differences were documented. Inter- and intra-expert differences and the impact of the expert decisions upon potential clinical management were also assessed. Results The angiograms from 1098 patients with CAD were screened, from which 316 cases for vFFR analysis were identified as being suitable for processing. From these, one expert selected 264 consecutive cases for re-processing at random, of which 214 were successfully re-processed. Reasons for unsuccessful segmentation included inadequate images, poor opacification, overlap of vessels and unworkable geometry. The expert mean vFFR was 0.76 and the non-expert was 0.75 (mean per case difference 0.11, SD 0.12), with 73% agreement and 27% disagreement about treatment strategy (see figure 2). Of those, 18% would have been incorrectly revascularised and 9% incorrectly managed conservatively. The mean inter-observer (1st vs 2nd expert) and intra-observer (1st vs 1st expert) differences were 0.06 and 0.09 respectively, and agreement in management interpretations 89% and 90% respectively (p Conclusion There is a large difference in vFFR modelling between expert and less expert modellers. The differences are due to errors in 3-D vessel construction. There is little inter- or intra-observer variation between expert modellers. However good the modelling system, training is required to produce accurate vFFR results. Expert vFFR can improve the clinical management of patients with CAD, altering revascularisation decision in 37% cases. Conflict of Interest None

Introduction Fractional flow reserve (FFR) is the gold standard method for assessing the physiological significance of coronary artery lesions. A ‘virtual’ FFR can be computed from angiographic images, using computational fluid dynamics, avoiding the need for a pressure wire. FFR is influenced by several factors including; stenosis severity, length of stenosis, vessel size and myocardial resistance. However, how each of these contribute to the overall FFR is not fully understood. We sought to create a range of 3D geometries, with varying characteristics and determine their corresponding vFFRs, to inform clinicians about the impact upon blood flow caused by commonly encountered disease patterns. Methods Geometries were created using ANSYS Design Modeler™ that included stenoses of different shape, severity, number and length, within straight and branched models using variations on a basic standard vessel size (a rigid tubular 3.5mm diameter main vessel, 50mm long, with any branches obeying Huo-Kassab’s law). vFFR values were calculated using our in-house VIRTUheart™ workflow. Results were displayed in easy-to-understand pictorial form. Results 187 geometries were created. The total reduction in cross sectional area had the greatest effect on FFR. All 80% concentric stenoses studied had an FFR of Conclusion vFFR is most affected by stenosis severity. However, changes to lesion shape, length, number and vessel diameter also impact vFFR. This data places these variables into perspective for clinicians when judging the significance of lesions in a diseased vessel. Conflict of Interest None

Introduction Using fractional flow reserve (FFR) to guide percutaneous coronary intervention (PCI) improves outcomes and reduces costs. In FAME, FFR guidance reduced the total length of stent per patient from 52mm to 38mm and the number from 2.7 to 1.9(1), yet FFR is currently used in Methods Patients who had undergone PCI without FFR guidance were identified from the Sheffield archive. A 3D reconstruction of the diseased artery was generated from the angiogram. Baseline vFFR was calculated using computational fluid dynamics (CFD) analysis(4). If vFFR was 0.90 (6). For each strategy, the total number and length of stent per patient was determined and compared to the actual procedure, which was conducted in the normal way, guided by the angiogram alone. Results Forty-three patients (56 vessels) were studied. Mean vFFR pre-PCI was 0.74±0.16. Twenty-four (43%) vessels had a baseline FFR >0.80. For the actual procedure, mean post-PCI vFFR was 0.90±0.09. The number of stents per patient was 1.4±0.6. Total stent length per patient was 29±15mm. Mean FFRmax was 0.92±0.07. FFRmax was 0.02±0.03 higher than the corresponding measured post-PCI FFR. When the virtual procedure was planned to achieve FFRmax, the number of stents per patient was 0.9±1.0 (p=0.003). Total stent length per patient was 22±27mm (p=0.04). When the virtual procedure was planned to achieve a post VCI FFR >0.90, the number of stents per patient was 0.93±1.02 (p=0.002). Total stent length per patient was 20±25mm (p=0.01). Conclusion In our cohort, 43% of vessels had a vFFR >0.80 suggesting PCI could have been avoided. Using vFFR and VCI to plan PCI led to a significant reduction in the total number and length of stents recommended per patient. Further work on a larger cohort is required to determine if these findings would translate to improved clinical outcomes. Figure 1: The 3D reconstruction of the artery is displayed and the operator marks the location where they wish to deploy a stent identified by the red and the blue markers (A). The operator can adjust the radius of the desired virtual stent in the box labelled ‘stent size’. The length can be altered by moving the position of the red and blue dots. In the example shown, a 3.0mmx20mm virtual stent has been inserted. The virtually stented artery is shown overlaying the original vessel in panel B. Reproduced from JACC: Cardiovascular Imaging(3) under creative commons license CC BY 4.0 Conflict of Interest None

Fractional flow reserve (FFR) is the gold standard method for guiding percutaneous coronary intervention. ‘Virtual’ FFR (vFFR) offers a less-invasive alternative but accuracy is critically dependent on accurate 3D arterial reconstruction. This is especially challenging with angiography-based solutions due to practical challenges relating to image acquisition, notably table movement between image acquisitions. Some existing methods rely upon restricting table movement, but this poses difficulty in clinical practice. The aim of this study was to validate a novel method for 3D coronary arterial reconstruction under clinically realistic conditions. Six branched coronary arterial models (3 left and 3 right, 15 vessels) were generated in silico using patient angiograms and 3D printed in PLA (RepRap X400 PRO). All physical models underwent standard coronary angiography imaging. Each model was imaged three times with different restrictions on table movement (18 image datasets, 45 single-vessels). For 3D reconstruction, vessel centrelines were manually traced on two images >30° apart; automatic detection of the borders and diameter optimisation followed (Figure 1). All reconstructions were subjected to vFFR computation. Reconstructions were compared to the reference 3D files in terms of surface similarity (defined using Hausdorff measurements; averaged distance between a randomised sample of points on both meshes) and physiological analysis (vFFR). The effect of surface reconstruction error on physiological accuracy (vFFR) was described using Pearson’s correlation coefficient. To assess accuracy of diameter capture, three aluminium coronary phantoms were fabricated with concentric and eccentric stenoses (diameter range 0.74–1.77mm, % narrowing: 44.7–77.2%). These phantoms also underwent angiography and 3D reconstruction as previously described. Reconstructions were compared with physical micrometer measurements of percentage stenosis and minimum diameter. Accuracy was expressed as mean delta (±SD) and absolute error. Forty-five single-vessel reconstructions were analysed (Figure 2). The average distance between reconstructed and reference meshes (reconstruction error) was 0.65mm (±0.30) indicating excellent similarity throughout variation of table movement. Mean vFFR was 0.94 (±0.049) with an average absolute error of 0.008 ±0.0098 and a maximum absolute error of ±0.03. A weak positive relationship between error in reconstruction and physiology was demonstrated (r = 0.370, p = 0.013). Mean error of stenosis estimation using the metal phantoms was 1.2% (±1.2%). Accuracy of diameter reconstruction at maximum stenosis (minimum diameter) was excellent, with an error of 0.02mm (±0.06mm). Coronary anatomy can be reconstructed under realistic conditions with an accuracy that is acceptable for clinical decision-making. This novel method has the potential to facilitate interventional decision making as part of a vFFR workflow and may also have value in other areas of anatomical reconstruction. Conflict of Interest n/a

AIMS: Fractional flow reserve (FFR), the reference-standard for guiding coronary revascularisation, is most commonly acquired during intravenous adenosine infusion. Results may be sensitive to system- and operator-dependent variability in how pressure data are analysed and interpreted. We developed a computational protocol to process the recorded pressure signals in a consistent manner to objectively quantify FFR. We studied the impact upon lesion (re)classification and compared this with the operator-selected FFR obtained during cardiac catheterisation. METHODS AND RESULTS: The algorithm used a moving average and Fourier transformation to identify the Pd/Pa ratio at its nadir (FFRmin) and during the stable hyperaemic period (FFRstable) in

Heart failure is not simply a single organ disease; rather it is a complex multi-system clinical syndrome, with impairment of endocrine, haematological, musculoskeletal, renal, respiratory and vascular systems, which influence morbidity and mortality.

Medical Physics and Biomedical Engineering provides broad coverage appropriate for senior undergraduates and graduates in medical physics and biomedical engineering. Divided into two parts, the first part presents the underlying physics, electronics, anatomy, and physiology and the second part addresses practical applications. The structured approach means that later chapters build and broaden the material introduced in the opening chapters; for example, students can read chapters covering the introductory science of an area and then study the practical application of the topic. Coverage includes biomechanics; ionizing and nonionizing radiation and measurements; image formation techniques, processing, and analysis; safety issues; biomedical devices; mathematical and statistical techniques; physiological signals and responses; and respiratory and cardiovascular function and measurement. Where necessary, the authors provide references to the mathematical background and keep detailed derivations to a minimum. They give comprehensive references to junior undergraduate texts in physics, electronics, and life sciences in the bibliographies at the end of each chapter.

The implantation of stents has been used to treat coronary artery stenosis for several decades. Although stenting is successful in restoring the vessel lumen and is a minimally invasive approach, the long-term outcomes are often compromised by in-stent restenosis (ISR). Animal models have provided insights into the pathophysiology of ISR and are widely used to evaluate candidate drug inhibitors of ISR. Such biological models allow the response of the vessel to stent implantation to be studied without the variation of lesion characteristics encountered in patient studies. This paper describes the development of complementary in silico models employed to improve the understanding of the biological response to stenting using a porcine model of restenosis. This includes experimental quantification using microCT imaging and histology and the use of this data to establish numerical models of restenosis. Comparison of in silico results with histology is used to examine the relationship between spatial localization of fluid and solid mechanics stimuli immediately post-stenting. Multi-scale simulation methods are employed to study the evolution of neointimal growth over time and the variation in the extent of neointimal hyperplasia within the stented region. Interpretation of model results through direct comparison with the biological response contributes to more detailed understanding of the pathophysiology of ISR, and suggests the focus for follow-up studies. In conclusion we outline the challenges which remain to both complete our understanding of the mechanisms responsible for restenosis and translate these models to applications in stent design and treatment planning at both population-based and patient-specific levels.

Structural and fluid stresses acting on the artery wall are proposed as mechanical mediators of in-stent restenosis (ISR). This study reports an investigation of the correlation between stresses obtained from computational simulations with the magnitude of ISR at the level of individual stent struts observed in an in vivo model of restenosis. Structural and fluid dynamic analyses were undertaken in a model based on volumetric micro-CT data from an in vivo stent deployment in a porcine right coronary artery. Structural and fluid mechanics were compared with histological data from the same stented vessel sample. Interpretation of the combined data at the level of individual stent struts was possible by identifying the location of each 2-D histological section within the 3-D micro-CT volume. Linear correlation between structural and fluid stimuli and neointimal thickness at the level of individual struts is less clear when individual stimuli are considered [compressive force (CF), R 2 = 0.19, wall shear stress (WSS), R 2 = 0.25, oscillatory shear index (OSI), R 2 = 0.28]. Closer correlation is observed if combined structural and fluid stimuli are assumed to stimulate ISR (CF/WSS, R 2 = 0.64). The use of micro-CT to characterise stent geometry after deployment enhances the clinical relevance of computational simulations, allowing direct comparison with histology. The results support the combined role of both structural and fluid mechanics to determine the magnitude of ISR at the level of individual struts. This finding is consistent with other studies which consider these stimuli averaged over a transverse section of the vessel.

Objectives The aim of this study was to develop a computer model that accurately predicts myocardial fractional flow reserve (FFR) from angiographic images alone, in patients with coronary artery disease. Background Percutaneous coronary intervention (PCI) guided by FFR is superior to standard assessment alone. FFR-guided PCI results in improved clinical outcomes, a reduction in the number of stents implanted, and reduced cost. Currently FFR is used in few patients. A less invasive FFR would be a valuable tool. Methods Nineteen patients with stable coronary artery disease awaiting elective PCI were studied. They underwent rotational coronary angiography. The FFR was measured, physiologically significant lesions were stented, and angiography and FFR were repeated. Three-dimensional arterial anatomy pre- and post-stenting was reconstructed offline. Generic boundary conditions for computational fluid dynamics analysis were applied. The virtual fractional flow reserve (vFFR) and measured fractional flow reserve (mFFR) values were compared. Results Thirty-five matched anatomical and physiological datasets were obtained: 10 right coronary arteries (RCA) (5 pre- and post-stenting), and 12 left coronary arteries (LCA) (8 pre- and post-stenting). The computational fluid dynamics model predicted which lesions were physiologically significant (FFR 0.80) with accuracy, sensitivity, specificity, positive and negative predictive values of 97%, 86%, 100%, 100%, and 97% respectively. On average, the vFFR values deviated from mFFR by ±0.06 (mean delta = 0.02, SD = 0.08). The vFFR and mFFR were closely correlated (r = 0.84). Conclusions We have developed a model of intracoronary physiology based upon a rotational coronary angiogram. Significant lesions were identified with 97% accuracy. The FFR was reliably predicted without the need for invasive measurements or inducing hyperemia.

Left ventricular assist devices (LVADs) are carefully designed, but the significance of the implantation configuration and interaction with the vasculature is complex and not fully determined. The present study employs computational fluid dynamics to investigate the importance of applying a realistic LVAD profile when evaluating assisted aortic flow fields and subsequently compares a number of potential anastomosis locations in a patient-specific aortic geometry. The outflow profile of the Berlin Heart INCOR® device was provided by Berlin Heart GmbH (Berlin, Germany) and the cannula was attached at a number of locations on the aorta. Simulations were conducted to compare a flat profile against the real LVAD profile. The results illustrate the importance of applying an LVAD profile. It not only affects the magnitude and distribution of oscillatory shear index, but also the distribution of flow to the great arteries. The ascending aorta was identified as the optimal location for the anastomosis.

This study presents a numerical simulation of cardiovascular response in the heart failure condition under the support of a Berlin Heart INCOR impeller pump-type ventricular assist device (VAD). The model is implemented using the CellML modelling language. To investigate the potential of using the Berlin Heart INCOR impeller pump to produce physiologically meaningful arterial pulse pressure within the various physiological constraints, a series of VAD-assisted cardiovascular cases are studied, in which the pulsation ratio and the phase shift of the VAD motion profile are systematically changed to observe the cardiovascular responses in each of the studied cases. An optimization process is proposed, including the introduction of a cost function to balance the importance of the characteristic cardiovascular variables. Based on this cost function it is found that a pulsation ratio of 0.35 combined with a phase shift of 200° produces the optimal cardiovascular response, giving rise to a maximal arterial pulse pressure of 12.6 mm Hg without inducing regurgitant pump flow while keeping other characteristic cardiovascular variables within appropriate physiological ranges.

In-stent restenosis, the maladaptive response of a blood vessel to injury caused by the deployment of a stent, is a multiscale system involving a large number of biological and physical processes. We describe a Complex Automata model for in-stent restenosis, coupling bulk flow, drug diffusion, and smooth muscle cell models, all operating on different time scales. Details of the single scale models and of the coupling interfaces are described, together with first simulation results, obtained with a dedicated software environment for Complex Automata simulations. Preliminary results show that the model can reproduce growth trends observed in experimental studies and facilitate testing of hypotheses concerning the interaction of key factors.

This paper reports the application of two commercial codes to the study of distinct cardiovascular problems: dynamics of a mechanical heart valve prosthesis and function of a native venous valve. The choice of code is driven by the characteristics of the problem. The ANSYS-CFX implicit finite volume code is employed for the mechanical valve where the solution is dominated by the interaction between the local fluid domain and the rigid valve leaflets. The LS-DYNA explicit dynamics code is used due to the stability of this approach when applied to systems with very flexible structural components such as the leaflets of a venous valve. The mechanical valve dynamics remain consistent for a range of mesh densities and residual criteria but begin to vary once the solution time step is increased above 2E–4 s. Venous valve function after application of a gravitational body load is shown to be dependent on parent vessel elastic modulus, E. The venous valve initially closes to a greater extent with a ‘softer’ parent vessel. Both approaches show promise for further study of these biomedical systems including the cavitation and thrombotic potential of mechanical valves and the local residence of blood constituents in the region of venous valve sinuses. Copyright © 2009 John Wiley & Sons, Ltd.

This paper presents a validated model of calf compression with an external pressure cuff as used for deep vein thrombosis. Magnetic resonance (MR) images of calf geometry were used to generate subject-specific finite-element (FE) models of the calf cross section. Ultrasound images of deep vessel collapse obtained through a water-filled cuff were used to validate model behavior. Calf/cuff pressure interface measurements were applied to the FE model and the resulting tissue deformation was compared with MR image in normal volunteers (three females, four males, age range 20-55) using two distinct cuffs. MR observations and the model results showed good qualitative agreement. A similar reduction in cross-sectional area of the posterior tibial veins was obtained under both symmetric compression (89%) and asymmetric compression (81%), but greater compression of the anterior tibial veins was achieved with symmetric compression. The need to account for the effective compressibility of the calf tissue suggests that external measurements of the calf tissue deformation will not accurately predict deep vessel collapse. These results have implications for the modification of venous haemodynamics by such systems and could help to improve cuff design.

This book is concerned with cardiovascular biomechanics; this is the study of the function and the structure of the cardiovascular system using the methods of mechanics. It has become clear that this area lies at the heart of all the major cardiovascular diseases such as atherosclerosis and aneurysms; diseases which are responsible for some one-third of world’s deaths. The underpinning principle which will be referred to several times in this book is that the cardiovascular system adapts in order to normalise its own mechanical environment. The cardiovascular system is able to do this because mechanical forces are sensed by tissues, and deviations from 'normal' result in biological changes which affect structure. The study of cardiovascular biomechanics therefore requires an interdisciplinary approach involving biology, medicine, physics, engineering and mathematics.

The interacting factors relating to thrombogenesis were defined by Virchow in 1856 to be abnormalities of blood chemistry, the vessel wall and haemodynamics. Together, these factors are known as Virchow's triad. Many attempts have been made to simulate numerically certain aspects of the complex phenomena of thrombosis, but a comprehensive model, which includes the biochemical and physical aspects of Virchow's triad, and is capable of predicting thrombus development within physiological geometries has not yet been developed. Such a model would consider the role of platelets and the coagulation cascade along with the properties of the flow in the chosen vessel.A lattice Boltzmann thrombosis framework has been developed, on top of an existing flow solver, to model the formation of thrombi resulting from platelet activation and initiation of the coagulation cascade by one or more of the strands of Virchow's triad. Both processes then act in parallel, to restore homeostasis as the deposited thrombus disturbs the flow. Results are presented in a model of deep vein thrombosis (DVT), resulting from hypoxia and associated endothelial damage.

The normal and malignant cellular morphological parameters (intra- and extracellular spaces of the human urinary bladder) were obtained from analysis of digital images of bladder histology sections. Then these cellular morphological parameters were compared with the same parameters obtained from the literature for the bladder tissue. However, the limited quantitative data about these parameters available in the literature for bladder cell sizes and other geometrical parameters such as extra-cellular space does not provide a scientific basis to construct accurate structural models of normal and malignant bladder tissue. Therefore, there is usually no quantitative discussion of cell sizes in literature but the measured data in this work can provide a reasonable estimation of expected morphological parameter changes of bladder tissue with pathology. To produce this quantitative information, and also, to build a suitable models in another study using electrical properties of the tissue, 10 digital images of histological sections of normal, and six sections from malignant areas of the human urinary bladder, were chosen randomly (ex vivo). Finally, the measured data showed that there is a significant difference between the cell dimensions (in basal and intermediate layers) of normal and malignant bladder tissues.

A finite element model of the eye and the orbit was used to examine the hypothesis that the orbital fat provides an important mechanism of eye stability during head trauma. The model includes the globe, the orbital fat, the extra-ocular muscles, and the optic nerve. MRI images of an adult human orbit were used to generate an idealized geometry of the orbital space. The globe was approximated as a sphere 12 mm in radius. The optic nerve and the sclera were represented as thin shells, whereas the vitreous and the orbital fat were represented as nearly incompressible solids of low stiffness. The orbital bone was modelled as a rigid shell. Frontal head impact resulting from a fall onto a hard floor was simulated by prescribing to the orbital bone a triangular acceleration pulse of 200 g (1962 m/s(2)) peak for a duration of 4.5 ms. The results show that the fat provides the crucial passive mechanism of eye restraint. The mechanism is a consequence of the fact that the fat is incompressible and that its motion is restricted by the rigidity of the orbital walls. Thus, the acceleration loads of short duration cannot generate significant distortion of the fat. In contrast, the passive muscles provide little support to the globe. When the connection between the orbital fat and the eye is absent the eye is held mainly by the optic nerve. We discuss the possible role that this loss of contact may have in some cases of the evulsion of the eye and the optic nerve.

The terms abusive head injury and shaken baby syndrome are used to describe a unique pattern of nonaccidental traumatic injuries occurring in children that many clinicians and researchers have good reason to believe is caused by violent shaking. Typical injuries include severe brain injury, with intracranial and retinal hemorrhages, but the pathogenesis of injuries is poorly understood. A major paradox in head trauma in infants is that the injuries induced by a shaking event are much more severe than those caused by even very violent single-impact head trauma, despite the relatively low accelerations in shaking. We have developed a finite element computer model of the eye, orbit, and orbital bone and used it to simulate the effects of single-impact and oscillatory motion inputs. The model was informed by data from semiquantitative in vitro anatomical traction experiments on in situ rabbit eyes. The new results reported here strongly suggest that suction between the eye and its surrounding fat dominates the dynamical stability of the system composed of the eye, its socket, and the components and material supporting the eye. Computer simulations incorporating this functional anatomical relationship show that deceleration of the head generates pressure gradients inside and outside the eye; these could cause damaging shear stresses in structures such as the retina and blood vessels. Simulations also show that oscillating the bone of the orbit causes the eye to move anteriorly and posteriorly with an increasing amplitude, building up the stresses within the eye over time. This is the first time that any biomechanical mechanism has been identified that might explain the disproportionally severe injuries caused by an oscillatory mechanism such as violent shaking of an abused infant. However, further study is required and this conclusion is therefore preliminary and provisional.

The burden of valvular heart disease (VHD) is rising rapidly as life expectancy increases. The prevalence in the USA alone is 13% in those aged over 75 years,1 while the global prevalence of rheumatic heart disease is estimated at 15.6–19.6 million.2 Despite this, the treatment of VHD still lacks an adequate research base. None of the 64 recommendations in the 2012 European Society of Cardiology (ESC) VHD guidelines3 had Level A evidence and only 14% had Level B evidence. This compares with 28% at Level A and 42% at Level B among the 270 recommendations in the 2010 ESC myocardial revascularisation guidelines.4 Therefore, there is an urgent need to stimulate the investigation. In this article, we identify deficits in our knowledge which may be amenable to research and make a call for national and international collaborative efforts to address this evidence gap. The prevalence of VHD in industrialised countries has been extrapolated from studies predominantly conducted in the USA,1 while the prevalence of rheumatic disease in sub-Saharan Africa is extrapolated from studies in North Africa. True figures need to be established nationally, while for rare causes of VHD (eg, carcinoid or antiphospholipid syndrome), this might be better done using international registries with standardised protocols. Serial echocardiography within these projects will improve our understanding of the contemporary natural history of VHD, which was previously determined in small cohorts of patients and generally with fewer comorbidities compared with the present. The genetics and developmental biology of VHD are poorly understood. Collation of genetic analyses from established bio-banks and twin studies may identify new determinants of disease or its progression. Such techniques may also provide clues towards the development of treatments for challenging conditions such as endomyocardial fibrosis. Lipid-lowering therapy has not been successful in modifying the progression …

Re-establishing a functional endothelium following endovascular treatment is an important factor in arresting neointimal proliferation. In this study, both histology ( in vivo ) and computational simulations ( in silico ) are used to evaluate neointimal growth patterns within coronary arteries along the axial direction of the stent. Comparison of the growth configurations in vivo and in silico was undertaken to identify candidate mechanisms for endothelial repair. Stent, lumen and neointimal areas were measured from histological sections obtained from eight right coronary stented porcine arteries. Two re-endothelialization scenarios (endothelial cell (EC) random seeding and EC growth from proximal and distal ends) were implemented in silico to evaluate their influence on the morphology of the simulated lesions. Subject to the assumptions made in the current simulations, comparison between in vivo and in silico results suggests that endothelial growth does not occur from the proximal and distal ends alone, but is more consistent with the assumption of a random seeding process. This may occur either from the patches of endothelium which survive following stent implantation or from attachment of circulating endothelial progenitor cells.

There is evidence that glutaraldehyde used routinely in the fixation process of bioprosthetic heart valves may be a major factor in their subsequent calcification. A further complication is introduced by the use of a formaldehyde treatment step, whether for sterilization or storage. The effects of this second aldehyde on calcification is also unknown. The aim of the present work is to determine the degree of glutaraldehyde and formaldehyde incorporation into commercial valve leaflets and to establish whether there is a relationship between the aldehyde treatment and tissue calcification. Both pre- and post-implantation concentrations of aldehydes were estimated by high performance liquid chromatography of acid hydrolyzates of commercial valve tissue. Control samples were taken from freshly prepared porcine aortic valves and bovine pericardium fixed in glutaraldehyde. The degree of calcification was investigated using the rat subcutaneous implant model. Samples were retrieved after 56 days and calcium estimated by atomic absorption spectroscopy. The results indicated that storage of both porcine and pericardial valves for periods of 5 years or longer reduced calcification. A greater reduction in calcification was noted when tissue was treated sequentially with glutaraldehyde and formaldehyde rather than glutaraldehyde alone. From this work it can be concluded that bioprosthetic valves calcify less in the rat model when they are stored for extended periods of time in glutaraldehyde solution. This effect is enhanced when formaldehyde storage is employed.

Introduction\ud \ud The American Heart Association (AHA)/American College of Cardiology (ACC) guidelines for the classification of heart failure (HF) are descriptive but lack precise and objective measures which would assist in categorising such patients. Our aim was two fold, firstly to demonstrate quantitatively the progression of HF through each stage using a meta-analysis of existing left ventricular (LV) pressure-volume (PV) loop data and secondly use the LV PV loop data to create stage specific HF models.\ud \ud Methods and Results\ud \ud A literature search yielded 31 papers with PV data, representing over 200 patients in different stages of HF. The raw pressure and volume data were extracted from the papers using a digitising software package and the means were calculated. The data demonstrated that, as HF progressed, stroke volume (SV), ejection fraction (EF%) decreased while LV volumes increased. A 2-element lumped parameter model was employed to model the mean loops and the error was calculated between the loops, demonstrating close fit between the loops. The only parameter that was consistently and statistically different across all the stages was the elastance (Emax).\ud \ud Conclusions\ud \ud For the first time, the authors have created a visual and quantitative representation of the AHA/ACC stages of LVSD-HF, from normal to end-stage. The study demonstrates that robust, load-independent and reproducible parameters, such as elastance, can be used to categorise and model HF, complementing the existing classification. The modelled PV loops establish previously unknown physiological parameters for each AHA/ACC stage of LVSD-HF, such as LV elastance and highlight that it this parameter alone, in lumped parameter models, that determines the severity of HF. Such information will enable cardiovascular modellers with an interest in HF, to create more accurate models of the heart as it fails.

Around 20% of the population over 60-years-old have peripheral arterial disease. Symptoms can cause major lifestyle limitation through pain on walking (intermittent claudication). Progressive disease can also lead to critical limb ischemia, which is the major cause of amputation for adults. The implant of a stent is the endovascular therapy of election for the treatment of peripheral arterial disease. This, however, can increase the risk of fatigue fracture of the implanted device, under in vivo loading conditions. RT3S (real time simulations for safer vascular stenting) is a scientific project involving both universities and private companies, for a funded budget of more than $4.5 million (www.rt3s.eu). The project aims at providing physicians with interactive clinical software for an enhanced pre-operative planning of femoral artery stenting including a prediction of in vivo stent fracture risk, computed by means of numerical simulations. Software-developing companies developed an interactive application allowing physicians to upload the patient's clinical images and plan the stenting procedure, estimating the device fatigue fracture risk, for a specific case of stent and anatomical geometry/boundary conditions. Thanks to the application of innovative response surface techniques, results obtained with the numerical model (requiring 8-day running time) can be exploited quasi real time by the software user. Outcomes of the project will be also exploited for designing activities of next-generation stent devices.

Vascular stent deployment in peripheral arteries is a medical intervention in which a wire mesh tube is inserted into the artery to provide internal support. However, stents positioned in locations such as the femoral artery are subject to cyclic bending, and are therefore at risk of fatigue fracture. A software tool chain, called AimaSimul, is being implemented to support stent modeling, surgical simulation and risk calculation for surgical planning. In particular, the AimaSimul preoperative planning tool allows clinicians, starting from patient-specific medical images, to interactively assess different stent models and deployment options for the risk of breakage. This paper describes the main functionalities of AimaSimul and, in particular, the stent deployment and deformation.

Summarization: RT3S is an EU-funded project in an area of ehealth – ICT for Patient Safety. Specifically, RT3S is developing a patient-centred, probabilistic model for peripheral stent fatigue-fracture, integrated within a real-time, computeraided surgery planning application. RT3S will provide advice on fracture risk for individual combinations of patient anatomy and stent design. Alongside the pre-operational software tool, which is addressed mainly to interventional radiologists, RT3S has also developed a training application that will be of benefit to trainee vascular interventionists and engineers in medical device companies. This paper provides an overview of the work performed during nearly three years of project activities and also addresses the motivation leading to RT3S and the expected impact. Παρουσιάστηκε στο: IEEE 13th International Conference on Bioinformatics and Bioengineering

Background Sarcopenia, a reduction in skeletal muscle performance, is common in heart failure (HF) and grip strength (GS) is a measure of such. No trial has investigated the role of cardiac resynchronisation therapy (CRT) in reversing sarcopenia. Methods GS was measured at baseline and 12 months following CRT. The patient group were 94% male, mean age 69 ± 8 years, New York Heart Association (NYHA) functional class II-IV, QRSd 173 ± 21 ms and had a left ventricular ejection fraction (LVEF) 26 ± 8%. Results 70% of patients were found to have responded at 12 months. Responders had significant improvements in VO2 (12.6 ± 1.7 to 14.7 ± 1.5 ml/kg/min, p < 0.05), quality of life score (43 ± 23 to 24 ± 22, p < 0.01), left ventricular end diastolic volume (210 ± 125 ml to 173 ± 125 ml, p < 0.01), 6 min walk distance (379 ± 117 m at baseline to 418 ± 105 m ( p < 0.05) and N-terminal pro-B-type natriuretic peptide (2422 ± 829 to 1732 ± 976 pg/ml, p < 0.01). GS significantly increased, by over 18% in responders during follow-up. Conclusion This study demonstrates responders demonstrate a significant improvement in GS following CRT. This demonstrates that CRT improves not only cardiac performance but also secondary gains in skeletal muscle function.

Background Cardiac resynchronisation therapy (CRT) improves morbidity and mortality in heart failure (HF). Impaired endothelial function, as measured by flow mediated dilation (FMD) is associated with increased morbidity and mortality in heart failure (HF) and may help to differentiate responders from non-responders. Methods FMD was measured at baseline and 12 months following CRT. The patient group were 94% male, mean age 69 ± 8 years, New York Heart Association (NYHA) functional class II-IV, QRSd 173 ± 21 ms and had a left ventricular ejection fraction (LVEF) 26 ± 8%. Results 70% of patients were found to have responded at 12 months. Responders had significant improvements in VO 2 (12.6 ± 1.7 to 14.7 ± 1.5 ml/kg/min, p p p p p p Conclusions This confirms that FMD identifies response to CRT, due to endothelium dependent mechanisms alone.

This paper comprises a study of the secondary flow patterns that can develop in the human aortic arch. Clinical evidence of these secondary flows has been obtained by Kilner et al. using magnatic resonance velocity mapping techniques. Some of their results are presented for comparison in this present paper. Four different Parametrk models of the aortic arch have been analysed using computational fluid dynamic techniques. Both steady and transient flow conditions have been considered and two different commercially available software packages were used, namely FIDAP and FLOTRAN. A satisfactory comparison of the theoretical analysis with the results, both in vivo and in vitro, obtained by Kilner et al. for their out-of-plane inlet model was found. The theoretical analysis can now be extended to anulyse the effect of different configurations and orientations of artificial aortic valves on the resulting aortic arch flow patterns.

Shedding of cytoplasm from circulating megakaryocytes (MKs) within the pulmonary vasculature suggests the lungs are an important site for normal platelet production. Fetal lungs receive only a minor fraction of the circulating blood volume. The placenta may act as a site for intrauterine platelet formation. Isolation of MKs from fetal vessels within the placenta has not been previously reported. Immediately after delivery, 3 human placentae were subjected to forward and retrograde perfusion across the placental capillary bed on the fetal side. MKs in perfusates were harvested by 'whole blood filtration' and identified by morphological and immunochemical methods. All perfusates yielded MKs. Qualitatively MKs with copious cytoplasm were more commonly found in perfusates collected from fetal arteries compared with those from fetal veins. This is consistent with filtration of MKs and fragmentation of their cytoplasm within the placental microcirculation to produce platelets. Perfusion of human placentae followed by filtration of perfusates is a useful technique for harvesting fetal MKs and permitting further elucidation of their physiological role.

Neointimal hyperplasia, a process of smooth muscle cell re-growth, is the result of a natural wound healing response of the injured artery after stent deployment. Excessive neointimal hyperplasia following coronary artery stenting results in in-stent restenosis (ISR). Regardless of recent developments in the field of coronary stent design, ISR remains a significant complication of this interventional therapy. The influence of stent design parameters such as strut thickness, shape and the depth of strut deployment within the vessel wall on the severity of restenosis has already been highlighted but the detail of this influence is unclear. These factors impact on local haemodynamics and vessel structure and affect the rate of neointima formation. This paper presents the first results of a multi-scale model of ISR. The development of the simulated restenosis as a function of stent deployment depth is compared with an in vivo porcine dataset. Moreover, the influence of strut size and shape is investigated, and the effect of a drug released at the site of injury, by means of a drug-eluting stent, is also examined. A strong correlation between strut thickness and the rate of smooth muscle cell proliferation has been observed. Simulation results also suggest that the growth of the restenotic lesion is strongly dependent on the stent strut cross-sectional profile.

The paper presents a multi-physics and multi-scale modeling approach on the closure dynamics of a bileaflet prosthetic heart valve. The modeling methodology consists of coupling a multi-scale model of the left ventricle contraction to a 3D CFD-FSI model, in order to investigate the closure of a cavity pivot bileaflet valve. The rebound motion of the valve is also modeled. The potential of the valve to generate thrombogenic and cavitation effects are assessed on the basis of the duration for which the blood flow is exposed to elevated wall shear stress, large negative pressure transients and increased flow vorticity. A special attention is given to the flow field in the hinge region of the valve.