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Fractional flow reserve (FFR) is the current gold standard invasive assessment of coronary artery disease (CAD). FFR reports coronary blood flow (CBF) as a fraction of a hypothetical and unknown normal value. Although used routinely to diagnose CAD and guide treatment, how accurately FFR predicts actual CBF changes remains unknown. In this study, we compared fractional CBF with absolute CBF (aCBF, in ml min−1), measured with a computational method during standard angiography and pressure wire assessment, on 203 diseased arteries (143 patients). We found a substantial correlation between the two measurements (r = 0.89 and Cohen’s kappa = 0.71). Concordance between fractional and absolute CBF reduction was high when FFR was >0.80 (91%) but reduced when FFR was ≤0.80 (81%), 0.70–0.80 (68%) and, particularly, 0.75–0.80 (62%). Discordance was associated with coronary microvascular resistance, vessel diameter and mass of myocardium subtended, all factors to which FFR is agnostic. Assessment of aCBF complements FFR and may be valuable to assess CBF, particularly in cases within the FFR ‘gray zone’.

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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

Background\ud \ud 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.\ud \ud \ud \ud Methods\ud \ud 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.\ud \ud \ud \ud Results\ud \ud 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).\ud \ud \ud \ud Conclusions\ud \ud 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.

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\ud \ud 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.\ud \ud \ud Methods and Results\ud \ud 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

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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.

A novel enoxaparin regimen consisting of intra-arterial bolus (0.75 mg/kg) followed by intravenous infusion (0.75 mg/kg/6 hours) has been developed as a possible solution to the delayed absorption of oral P2Y12 inhibitors in opiate-treated ST-elevation myocardial infarction (STEMI) patients undergoing primary angioplasty. We aimed to study the feasibility of this regimen as an alternative to standard-of-care treatment (SOC) with unfractionated heparin ± glycoprotein IIb/IIIa antagonist (GPI). One hundred opiate-treated patients presenting with STEMI and accepted for primary angioplasty were randomized (1:1) to either enoxaparin or SOC. Fifty patients were allocated enoxaparin (median age 61, 40% females) and 49 allocated SOC (median age 62, 22% females). One developed stroke before angiography and was withdrawn. One SOC patient had a gastrointestinal bleed resulting in 1 g drop in hemoglobin and early cessation of GPI infusion. Two enoxaparin patients had transient minor bleeding: one transient gingival bleed and one episode of coffee ground vomit with no hemoglobin drop or hemodynamic instability. Two SOC and no enoxaparin group patients had acute stent thrombosis. These preliminary data support further study of this novel 6-hour enoxaparin regimen in opiate-treated PPCI patients.

Evidence robustly demonstrates that ischemia, rather than anatomy, is the optimal target for coronary revascularization. In the cardiac catheter laboratory, fractional flow reserve (FFR) and corresponding diastolic indices are regarded as the gold standard for physiological lesion assessment and ischemia detection (Table 1). Yet, despite a wealth of supporting data and indications in international guidelines, the use of FFR remains surprisingly low in the diagnostic assessment of coronary artery disease across the world.1, 2 To address this, multiple groups have developed methods for computing FFR from invasive angiography, without the need for passing a pressure wire or inducing hyperemia, thus removing the main barriers to uptake. Angiography‐derived FFR therefore has the potential to extend the benefits of physiological coronary lesion assessment to considerably more patients. Given the size of the interventional cardiology market, clinical and commercial motivation to deliver these tools as quickly as possible could hardly be greater. Several models are now approved as medical devices. Imminently, physicians and healthcare providers will have to decide whether to use these tools. But do they truly deliver physiology, and are they accurate enough? There are 3 particular areas of that deserve close scrutiny.

Objectives: This study sought to assess the ability of a novel virtual coronary intervention (VCI) tool based on invasive angiography to predict the patient's physiological response to stenting. Background: Fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) is associated with improved clinical and economic outcomes compared with angiographic guidance alone. Virtual (v)FFR can be calculated based upon a 3-dimensional (3D) reconstruction of the coronary anatomy from the angiogram, using computational fluid dynamics (CFD) modeling. This technology can be used to perform virtual stenting, with a predicted post-PCI FFR, and the prospect of optimized treatment planning. Methods: Patients undergoing elective PCI had pressure-wire-based FFR measurements pre- and post-PCI. A 3D reconstruction of the diseased artery was generated from the angiogram and imported into the VIRTUheart workflow, without the need for any invasive physiological measurements. VCI was performed using a radius correction tool replicating the dimensions of the stent deployed during PCI. Virtual FFR (vFFR) was calculated pre- and post-VCI, using CFD analysis. vFFR pre- and post-VCI were compared with measured (m)FFR pre- and post-PCI, respectively. Results: Fifty-four patients and 59 vessels underwent PCI. The mFFR and vFFR pre-PCI were 0.66 ± 0.14 and 0.68 ± 0.13, respectively. Pre-PCI vFFR deviated from mFFR by ±0.05 (mean Δ = -0.02; SD = 0.07). The mean mFFR and vFFR post-PCI/VCI were 0.90 ± 0.05 and 0.92 ± 0.05, respectively. Post-VCI vFFR deviated from post-PCI mFFR by ±0.02 (mean Δ = -0.01; SD = 0.03). Mean CFD processing time was 95 s per case. Conclusions: The authors have developed a novel VCI tool, based upon the angiogram, that predicts the physiological response to stenting with a high degree of accuracy.

Background—Ticagrelor has superior efficacy to clopidogrel in the management of acute coronary syndromes but has not been assessed in patients undergoing percutaneous coronary intervention (PCI) for stable coronary artery disease (CAD). We compared the pharmacodynamic effects of ticagrelor and clopidogrel in this stable population.\ud \ud Methods—180 aspirin-treated stable CAD patients, who were planned to undergo elective PCI in a single center, were randomized 1:1:1 to either a standard clopidogrel regimen or one of two regimens of ticagrelor, either 90mg (T90) or 60mg twice-daily (T60), both with 180mg loading dose. Cellular adenosine uptake was assessed, at the time of the procedure and pre- and post-dose at 1 month, by adding adenosine 1 μmol/L to aliquots of anticoagulated whole blood and mixing with a stop solution at 0, 15, 30 and 60 seconds then measuring residual plasma adenosine concentration by high-performance liquid chromatography. Systemic plasma adenosine concentration and platelet reactivity were assessed at the same timepoints. High-sensitivity troponin T (hsTnT) was measured pre- and 18-24 hours post-PCI.\ud \ud Results—174 patients underwent an invasive procedure, of which 162 patients received PCI (mean age 65 years, 18% female, 21% with diabetes mellitus). No effect on in vitro adenosine uptake was seen post-dose at 1 month for either ticagrelor dose compared with clopidogrel (residual adenosine at 15s, mean ± SD: clopidogrel 0.274 ± 0.101 μmol/L; T90 0.278 ± 0.134 μmol/L; T60 0.288 ± 0.149 μmol/L; P = 0.37). Similarly no effect of ticagrelor on in vitro adenosine uptake was seen at other timepoints, nor was plasma adenosine concentration affected (all P > 0.1). Both maintenance doses of ticagrelor achieved more potent and consistent platelet inhibition than clopidogrel (VerifyNow PRU, 1 month, mean ± SD: pre-dose, T60: 62 ± 47, T90: 40 ± 38, clopidogrel 181 ± 44; post-dose, T60: 34 ± 30, T90: 24 ± 21, clopidogrel 159 ± 57; all P < 0.0001 for ticagrelor vs clopidogrel). High platelet reactivity was markedly less with both T60 and T90 compared with clopidogrel (VerifyNow PRU>208, 1-month post-dose: 0%, 0% and 21%, respectively). Median (IQR) hsTnT increase was 16.9 (6.5-46.9) ng/l for clopidogrel, 22.4 (5.5-53.8) ng/L for T60 and 17.7 (8.1-43.5) ng/L for T90 (P = 0.95). There was a trend towards less dyspnea with T60 versus T90 (7.1% vs 19.0%; P = 0.09).\ud \ud Conclusions—Maintenance therapy with T60 or T90 had no detectable effect on cellular adenosine uptake at 1 month, nor was there any effect on systemic plasma adenosine levels. Both regimens of ticagrelor achieved greater and more consistent platelet inhibition than clopidogrel but did not appear to affect troponin release after percutaneous coronary intervention

Delayed onset of action of oral P2Y 12 inhibitors in ST-elevation myocardial infarction (STEMI) patients may increase the risk of acute stent thrombosis. Available parenteral anti-thrombotic strategies, to deal with this issue, are limited by added cost and increased risk of bleeding. We investigated the pharmacodynamic effects of a novel regimen of enoxaparin in STEMI patients undergoing primary percutaneous coronary intervention (PPCI). Twenty patients were recruited to receive 0.75 mg/kg bolus of enoxaparin (pre-PPCI) followed by infusion of enoxaparin 0.75 mg/kg/6 h. At four time points (pre-anti-coagulation, end of PPCI, 2–3 hours into infusion and at the end of infusion), anti-Xa levels were determined using chromogenic assays, fibrin clots were assessed by turbidimetric analysis and platelet P2Y 12 inhibition was determined by VerifyNow P2Y12 assay. Clinical outcomes were determined 14 hours after enoxaparin initiation. Nineteen of 20 patients completed the enoxaparin regimen; one patient, who developed no-reflow phenomenon, was switched to tirofiban after the enoxaparin bolus. All received ticagrelor 180 mg before angiography. Mean (± standard error of the mean) anti-Xa levels were sustained during enoxaparin infusion (1.17 ± 0.06 IU/mL at the end of PPCI and 1.003 ± 0.06 IU/mL at 6 hours), resulting in prolonged fibrin clot lag time and increased lysis potential. Onset of platelet P2Y 12 inhibition was delayed in opiate-treated patients. No patients had thrombotic or bleeding complications. In conclusion, enoxaparin 0.75 mg/kg bolus followed by 0.75 mg/kg/6 h provides sustained anti-Xa levels in PPCI patients. This may protect from acute stent thrombosis in opiate-treated PPCI patients who frequently have delayed onset of oral P2Y 12 inhibition.

Objectives (i) Develop and validate a method which computes fractional flow reserve (FFR) in 26h. Mean error was

Three oral platelet P2Y12 inhibitors, clopidogrel, prasugrel, and ticagrelor, are available for reducing the risk of cardiovascular death and stent thrombosis in patients with acute coronary syndromes (ACS). We sought to compare the efficacy of these antiplatelet drugs in contemporary practice.\ud \ud Data were collected for 10 793 consecutive ACS patients undergoing coronary angiography at Sheffield, UK (2009–2015). Since prasugrel use was mostly restricted to the STEMI subgroup, clopidogrel and ticagrelor were compared for all ACS patients, and all three agents were compared in the STEMI subgroup. Differences in outcomes were evaluated at 12 months by KM curves and log-rank test after adjustment for independent risk factors.\ud \ud Of 10 793 patients with ACS (36% STEMI), 43% (4653) received clopidogrel, 11% (1223) prasugrel and 46% (4917) ticagrelor, with aspirin for all. In the overall group, ticagrelor was associated with lower all-cause mortality compared with clopidogrel (adjusted hazard ratio (adjHR) 0.82, 95% confidence intervals (CI) 0.71–0.96, p = 0.01). In the STEMI subgroup, both prasugrel and ticagrelor were associated with a lower mortality compared with clopidogrel (prasugrel vs. clopidogrel: adjHR 0.65, CI 0.48–0.89, p = 0.007; ticagrelor vs. clopidogrel: adjHR 0.70, CI 0.61–0.99, p = 0.05). Of the 7595 patients who underwent PCI, 78 (1.0%) had definite stent thrombosis by 12 months. Patients treated with ticagrelor had a lower incidence of definite stent thrombosis compared with clopidogrel (0.6% vs. 1.1%; adjHR 0.51, CI 0.29–0.89, p = 0.03). In the STEMI subgroup, there was no significant difference between the three groups (ticagrelor 1.0%, clopidogrel = 1.5%, prasugrel = 1.6%; p = 0.29).\ud \ud In conclusion, ticagrelor was superior to clopidogrel for reduction in both mortality and stent thrombosis in unselected invasively managed ACS patients. In STEMI patients, both ticagrelor and prasugrel were associated with lower mortality compared with clopidogrel, but there was no significant difference in the incidence of stent thrombosis.

Edge plasma studies on the COMPASS Tokamak.

This paper reviews the methods, benefits and challenges associated with the adoption and translation of computational fluid dynamics (CFD) modelling within cardiovascular medicine. CFD, a specialist area of mathematics and a branch of fluid mechanics, is used routinely in a diverse range of safety-critical engineering systems, which increasingly is being applied to the cardiovascular system. By facilitating rapid, economical, low-risk prototyping, CFD modelling has already revolutionised research and development of devices such as stents, valve prostheses, and ventricular assist devices. Combined with cardiovascular imaging, CFD simulation enables detailed characterisation of complex physiological pressure and flow fields and the computation of metrics which cannot be directly measured, for example, wall shear stress. CFD models are now being translated into clinical tools for physicians to use across the spectrum of coronary, valvular, congenital, myocardial and peripheral vascular diseases. CFD modelling is apposite for minimally-invasive patient assessment. Patient-specific (incorporating data unique to the individual) and multi-scale (combining models of different length-And time-scales) modelling enables individualised risk prediction and virtual treatment planning. This represents a significant departure from traditional dependence upon registry-based, populationaveraged data. Model integration is progressively moving towards 'digital patient' or 'virtual physiological human' representations. When combined with population-scale numerical models, these models have the potential to reduce the cost, time and risk associated with clinical trials. The adoption of CFD modelling signals a new era in cardiovascular medicine. While potentially highly beneficial, a number of academic and commercial groups are addressing the associated methodological, regulatory, education-And service-related challenges.

Fractional flow reserve (FFR) is the “gold standard” for assessing the physiological significance of coronary artery disease during invasive coronary angiography. FFR-guided percutaneous coronary intervention improves patient outcomes and reduces stent insertion and cost; yet, due to several practical and operator related factors, it is used in

Background: Acute Coronary Syndromes account for 15% of deaths in the UK, and patients remain at significant risk of re-admission for future complications and death. Pathologically the underlying process of atherosclerosis is driven by inflammatory mechanisms, which are activated in ACS patients. Previous studies have investigated the role of inflammatory markers in this process, including interleukin 1 (IL-1) and C Reactive Protein (CRP). Pre-clinical studies indicate that IL-1 may be a primary driver of ACS and that the naturally occurring interleukin-1 receptor antagonist (IL-1ra) may inhibit the atherosclerotic process. This study will investigate the effects of IL-1ra on inflammatory markers in man.\ud \ud Methods/design: Three centres in the UK are planning to recruit 186 Non-ST elevation myocardial infarction patients to receive either interleukin-1 receptor antagonist (Anakinra) or matching placebo. Patients will receive a daily subcutaneous injection of either study drug or placebo over a 14 day period. The primary outcome is area under the curve of high sensitivity C-Reactive Protein (CRP) over the first 7 days.\ud \ud Discussion: The MRC-ILA-HEART Study is a proof of concept clinical trial investigating the effects of IL-1ra upon markers of inflammation in patients with Non-ST elevation myocardial infarction. It is hoped this will provide new and exciting information in relation to an "anti-inflammatory" strategy for patients with acute coronary syndrome.

A clear and reproducible transition to a regime with an improved particle confinement is routinely observed on the CASTOR tokamak, if the biasing electrode is inserted deep enough into the plasma (r/a ~ 0.5) and biased up to +250V. The steepening of the radial profiles of the plasma density and potential demonstrate the formation of a transport barrier just inside the last closed flux surface. Fast relaxations of the edge plasma parameters, with a frequency of about 10 kHz, are observed when the average radial electric field within the barrier prevails values of about 20 kV/m. A detailed analysis of the spatial-temporal behavior of these relaxations is presented. На токамаке CASTOR устойчиво наблюдается отчетливый и воспроизводимый переход в режим с улучшенным удержанием частиц при достаточно глубоком введении в плазму (r/a - 0,5) электрода, на который подаётся смещение до +250 В. У кручение радиальных профилей плотности плазмы и потенциала свидетельствуют об образовании транспортного барьера сразу внутри последней замкнутой магнитной поверхности. Наблюдаются быстрые релаксации параметров краевой плазмы с частотой около 10 кГц, когда среднее радиальное электрическое поле внутри барьера превышает значение около 20 кВ/м. Приводится обстоятельный анализ пространственно-временного поведения этих релаксаций. На токамаці CASTOR стійко спостерігається чіткий та відтворений перехід до режиму з поліпшеним утриманням частинок при достатньо глибокому введенні у плазму (r/a ~ 0,5) електрода, на який подано зміщення до +250 В. Радіальні профілі густини плазми та потенціалу стають більш крутими, що свідчить про створення потенціального бар'єру зразу усередині останньої замкненої магнітної поверхні. Спостерігаються швидкі релаксації параметрів крайової плазми з частотою порядку 10 кГц, коли середнє радіальне електричне поле усередині бар'єра перевищує значення приблизно 20 кВ/м. Надається докладний аналіз просторово-часової поведінки цих релаксацій.