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Lina Shibib,1 Mo Al-Qaisi,1 Nicola Guess,2 Alexander D Miras,3 Steve E Greenwald,4 Marc Pelling,1 Ahmed Ahmed1 1Department of Surgery and Cancer, Imperial College London, London, UK; 2Nuffield Department of Primary Care Health Sciences, Oxford University, Oxford, UK; 3School of Medicine, Ulster University, Coleraine, UK; 4Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UKCorrespondence: Mo Al-Qaisi, Email mrcgp74@yahoo.co.ukAbstract: This review paper explores post-prandial glycemia in type 2 diabetes. Post-prandial glycemia is defined as the period of blood glucose excursion from immediately after the ingestion of food or drink to 4 to 6 hours after the end of the meal. Post-prandial hyperglycemia is an independent risk factor for cardiovascular disease with glucose “excursions” being more strongly associated with markers of oxidative stress than the fasting or pre-prandial glucose level. High blood glucose is a major promoter of enhanced free radical production and is associated with the onset and progression of type 2 diabetes. Oxidative stress impairs insulin action creating a vicious cycle where repeated post-prandial glucose spikes are key drivers in the pathogenesis of the vascular complications of type 2 diabetes, both microvascular and macrovascular. Some authors suggest post-prandial hyperglycemia is the major cause of death in type 2 diabetes. Proper management of post-prandial hyperglycemia could yield up to a 35% cut in overall cardiovascular events, and a 64% cut in myocardial infarction. The benefits of managing post-prandial hyperglycemia are similar in magnitude to those seen in type 2 diabetes patients receiving secondary prevention with statins – prevention which today is regarded as fundamental by all practitioners. Given all the evidence surrounding the impact of post-prandial glycemia on overall outcome, it is imperative that any considered strategy for the management of type 2 diabetes should include optimum dietary, pharma, and lifestyle interventions that address glucose excursion. Achieving a low post-prandial glucose response is key to prevention and progression of type 2 diabetes and cardiometabolic diseases. Further, such therapeutic interventions should be sustainable and must benefit patients in the short and long term with the minimum of intrusion and side effects. This paper reviews the current literature around dietary manipulation of post-prandial hyperglycemia, including novel approaches. A great deal of further work is required to optimize and standardize the dietary management of post-prandial glycemia in type 2 diabetes, including consideration of novel approaches that show great promise.Keywords: glycemic response, post-prandial, hyperglycemia, diabetes, acarbose, GLP-1, metformin, plant fibre, whey protein, gastric emptying, intestinal absorption, glycemic index, glucose excursion

Lina Shibib,1 Mo Al-Qaisi,1 Ahmed Ahmed,1 Alexander D Miras,2 David Nott,1 Marc Pelling,1 Stephen E Greenwald,3 Nicola Guess4 1Department of Surgery and Cancer, Imperial College London, London, UK; 2Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK; 3Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, UK; 4School of Life Sciences, Westminster University, London, UKCorrespondence: Mo Al-Qaisi, Imperial Weight Centre, Imperial College Healthcare NHS Trust, Praed Street, London, W2 1NY, UK, Tel +44 7968 016315, Email mrcgp74@yahoo.co.ukAbstract: Over the past 50 years, many countries around the world have faced an unchecked pandemic of obesity and type 2 diabetes (T2DM). As best practice treatment of T2DM has done very little to check its growth, the pandemic of diabesity now threatens to make health-care systems economically more difficult for governments and individuals to manage within their budgets. The conventional view has been that T2DM is irreversible and progressive. However, in 2016, the World Health Organization (WHO) global report on diabetes added for the first time a section on diabetes reversal and acknowledged that it could be achieved through a number of therapeutic approaches. Many studies indicate that diabetes reversal, and possibly even long-term remission, is achievable, belying the conventional view. However, T2DM reversal is not yet a standardized area of practice and some questions remain about long-term outcomes. Diabetes reversal through diet is not articulated or discussed as a first-line target (or even goal) of treatment by any internationally recognized guidelines, which are mostly silent on the topic beyond encouraging lifestyle interventions in general. This review paper examines all the sustainable, practical, and scalable approaches to T2DM reversal, highlighting the evidence base, and serves as an interim update for practitioners looking to fill the practical knowledge gap on this topic in conventional diabetes guidelines.Keywords: weight loss, very low energy, very low calorie, bariatric surgery, orlistat, electrical muscle stimulation, low carbohydrate, behaviour change, diabetes reversal, diabetes remission

Falls among the elderly are a common and serious health risk that can lead to physical injuries and other complications. To promptly detect and respond to fall events, radar-based fall detection systems have gained widespread attention. In this paper, a deep learning model is proposed based on the frequency spectrum of radar signals, called the convolutional bidirectional long short-term memory (CB-LSTM) model. The introduction of the CB-LSTM model enables the fall detection system to capture both temporal sequential and spatial features simultaneously, thereby enhancing the accuracy and reliability of the detection. Extensive comparison experiments demonstrate that our model achieves an accuracy of 98.83% in detecting falls, surpassing other relevant methods currently available. In summary, this study provides effective technical support using the frequency spectrum and deep learning methods to monitor falls among the elderly through the design and experimental validation of a radar-based fall detection system, which has great potential for improving quality of life for the elderly and providing timely rescue measures.

Coronary artery segmentation is an essential procedure in the computer-aided diagnosis of coronary artery disease. It aims to identify and segment the regions of interest in the coronary circulation for further processing and diagnosis. Currently, automatic segmentation of coronary arteries is often unreliable because of their small size and poor distribution of contrast medium, as well as the problems that lead to over-segmentation or omission. To improve the performance of convolutional-neural-network (CNN) based coronary artery segmentation, we propose a novel automatic method, DR-LCT-UNet, with two innovative components: the Dense Residual (DR) module and the Local Contextual Transformer (LCT) module. The DR module aims to preserve unobtrusive features through dense residual connections, while the LCT module is an improved Transformer that focuses on local contextual information, so that coronary artery-related information can be better exploited. The LCT and DR modules are effectively integrated into the skip connections and encoder-decoder of the 3D segmentation network, respectively. Experiments on our CorArtTS2020 dataset show that the dice similarity coefficient (DSC), Recall, and Precision of the proposed method reached 85.8%, 86.3% and 85.8%, respectively, outperforming 3D-UNet (taken as the reference among the 6 other chosen comparison methods), by 2.1%, 1.9%, and 2.1%., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Xu, Wang, Yang, Sun, Yang and Greenwald.)

Arterial stiffness, as measured by pulse wave velocity, for the early non-invasive screening of cardiovascular disease is becoming ever more widely used and is an independent prognostic indicator for a variety of pathologies including arteriosclerosis. Carotid-femoral pulse wave velocity (cfPWV) is regarded as the gold standard for aortic stiffness. Existing algorithms for cfPWV estimation have been shown to have good repeatability and accuracy, however, further assessment is needed, especially when signal quality is compromised. We propose a method for calculating cfPWV based on a simplified tube-load model, which allows for the propagation and reflection of the pulse wave. In-vivo cfPWV measurements from 57 subjects and numerical cfPWV data based on a one-dimensional model were used to assess the method and its performance was compared to three other existing approaches (waveform matching, intersecting tangent, and cross-correlation). The cfPWV calculated using the simplified tube-load model had better repeatability than the other methods (Intra-group Correlation Coefficient, ICC = 0.985). The model was also more accurate than other methods (deviation, 0.13 ms -1 ) and was more robust when dealing with noisy signals. We conclude that the determination of cfPWV based on the proposed model can accurately and robustly evaluate arterial stiffness., (© 2022. The Author(s).)

Ballistocardiography (BCG) is considered a good alternative to HRV analysis with its non-contact and unobtrusive acquisition characteristics. However, consensus about its validity has not yet been established. In this study, 50 healthy subjects (26.2 ± 5.5 years old, 22 females, 28 males) were invited. Comprehensive statistical analysis, including Coefficients of Variation (CV), Lin’s Concordance Correlation Coefficient (LCCC), and Bland-Altman analysis (BA ratio), were utilized to analyze the consistency of BCG and ECG signals in HRV analysis. If the methods gave different answers, the worst case was taken as the result. Measures of consistency such as Mean, SDNN, LF gave good agreement (the absolute value of CV difference < 2%, LCCC > 0.99, BA ratio < 0.1) between J-J (BCG) and R-R intervals (ECG). pNN50 showed moderate agreement (the absolute value of CV difference < 5%, LCCC > 0.95, BA ratio < 0.2), while RMSSD, HF, LF/HF indicated poor agreement (the absolute value of CV difference ≥ 5% or LCCC ≤ 0.95 or BA ratio ≥ 0.2). Additionally, the R-R intervals were compared with P-P intervals extracted from the pulse wave (PW). Except for pNN50, which exhibited poor agreement in this comparison, the performances of the HRV indices estimated from the PW and the BCG signals were similar.

Background: The ideal treatment strategy for stable three-vessel coronary artery disease (CAD) patients are difficult to determine and for patients undergoing conservative treatment, imaging evidence of coronary atherosclerotic severity progression remains limited. Epicardial fat volume (EFV) on coronary CT angiography (CCTA) has been considered to be associated with coronary atherosclerosis. Therefore, this study aims to evaluate the relationship between EFV level and coronary atherosclerosis severity in three-vessel CAD., Methods: This retrospective study enrolled 252 consecutive patients with three-vessel CAD and 252 normal control group participants who underwent CCTA between January 2018 and December 2019. A semi-automatic method was developed for EFV quantification on CCTA images, standardized by body surface area. Coronary atherosclerosis severity was evaluated and scored by the number of coronary arteries with ≥ 50% stenosis on coronary angiography. Patients were subdivided into groups on the basis of lesion severity: mild (score = 3 vessels, n = 85), moderate (3.5 vessels ≤ score < 4 vessels, n = 82), and severe (4 vessels ≤ score ≤ 7 vessels, n = 85). The independent sample t-test, analysis of variance, and logistic regression analysis were used to evaluate the associations between EFV level and severity of coronary atherosclerosis., Results: Compared with normal controls, three-vessel CAD patients had significantly higher EFV level (65 ± 22 mL/m 2 vs. 48 ± 19 mL/m 2 ; P < 0.001). In patients with three-vessel CAD, there was a progressive decline in EFV level as the score of coronary atherosclerosis severity increased, especially in those patients with a body mass index (BMI) ≥ 25 kg/m 2 (75 ± 21 mL/m 2 vs. 72 ± 22 mL/m 2 vs. 62 ± 17 mL/m 2 ; P < 0.05). Multivariable regression analysis showed that both BMI (OR 3.40, 95% CI 2.00-5.78, P < 0.001) and the score of coronary atherosclerosis severity (OR 0.49, 95% CI 0.26-0.93, P < 0.05) were independently related to the change of EFV level., Conclusion: Three-vessel CAD patients do have higher EFV level than the normal controls. While, there may be an inverse relationship between EFV level and the severity of coronary atherosclerosis in patients with three-vessel CAD., (© 2022. The Author(s).)

Purpose: Myocardial infarction (MI) is one of the most common cardiovascular diseases, frequently resulting in death. Early and accurate diagnosis is therefore important, and the electrocardiogram (ECG) is a simple and effective method for achieving this. However, it requires assessment by a specialist; so many recent works have focused on the automatic assessment of ECG signals., Methods: For the detection and localization of MI, deep learning models have been proposed, but the diagnostic accuracy of this approaches still need to be improved. Moreover, with deep learning methods the way in which a given result was achieved lacks interpretability. In this study, ECG data was obtained from the PhysioBank open access database, and was analyzed as follows. Firstly, the 12-lead ECG signal was preprocessed to identify each beat and obtain each heart interval. Secondly, a multi-scale deep learning model combined with a residual network and attention mechanism was proposed, where the input was the 12-lead ECG recording. Through the SENet model and the Grad-CAM algorithm, the weighting of each lead was calculated and visualized. Using existing knowledge of the way in which different types of MI gave characteristic patterns in specific ECG leads, the model was used to provisionally diagnose the type of MI according to the characteristics of each of the 12 ECG leads., Results: Ten types of MI anterior, anterior lateral, anterior septal, inferior, inferior lateral, inferior posterior, inferior posterior lateral, lateral, posterior, and posterior lateral were diagnosed. The average accuracy, sensitivity, and specificity for MI detection of all lesion types was 99.98, 99.94, and 99.98%, respectively; and the average accuracy, sensitivity, and specificity for MI localization was 99.79, 99.88, and 99.98%, respectively., Conclusion: When compared to existing models based on traditional machine learning methods, convolutional neural networks and recurrent neural networks, the results showed that the proposed model had better diagnostic performance, being superior in accuracy, sensitivity, and specificity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cao, Liu, Zhang, Xu, Zhu, Cui, Geng, Han and Greenwald.)

The tendon interfascicular matrix (IFM) binds tendon fascicles together. As a result of its low stiffness behaviour under small loads, it enables non-uniform loading and increased overall extensibility of tendon by facilitating fascicle sliding. This function is particularly important in energy storing tendons, with previous studies demonstrating enhanced extensibility, recovery and fatigue resistance in the IFM of energy storing compared to positional tendons. However, the compositional specialisations within the IFM that confer this behaviour remain to be elucidated. It is well established that the IFM is rich in elastin, therefore we sought to test the hypothesis that elastin depletion (following elastase treatment) will significantly impact IFM, but not fascicle, mechanical properties, reducing IFM resilience in all samples, but to a greater extent in younger tendons, which have a higher elastin content. Using a combination of quasi-static and fatigue testing, and optical imaging, we confirmed our hypothesis, demonstrating that elastin depletion resulted in significant decreases in IFM viscoelasticity, fatigue resistance and recoverability compared to untreated samples, with no significant changes to fascicle mechanics. Ageing had little effect on fascicle or IFM response to elastase treatment. This study offers a first insight into the functional importance of elastin in regional specific tendon mechanics. It highlights the important contribution of elastin to IFM mechanical properties, demonstrating that maintenance of a functional elastin network within the IFM is essential to maintain IFM and thus tendon integrity. STATEMENT OF SIGNIFICANCE: Developing effective treatments or preventative measures for musculoskeletal tissue injuries necessitates the understanding of healthy tissue function and mechanics. By establishing the contribution of specific proteins to tissue mechanical behaviour, key targets for therapeutics can be identified. Tendon injury is increasingly prevalent and chronically debilitating, with no effective treatments available. Here, we investigate how elastin modulates tendon mechanical behaviour, using enzymatic digestion combined with local mechanical characterisation, and demonstrate for the first time that removing elastin from tendon affects the mechanical properties of the interfascicular matrix specifically, resulting in decreased recoverability and fatigue resistance. These findings provide a new level of insight into tendon hierarchical mechanics, important for directing development of novel therapeutics for tendon injury., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

The accurate measurement of the arterial pulse wave is beneficial to clinical health assessment and is important for the effective diagnosis of many types of cardiovascular disease. A variety of sensors have been developed for the non-invasive detection of these waves, but the type of sensor has an impact on the measurement results. Therefore, it is necessary to compare and analyze the signals obtained under a range of conditions using various pulse sensors to aid in making an informed choice of the appropriate type. From the available types we have selected four: a piezoresistive strain gauge sensor (PESG) and a piezoelectric Millar tonometer (the former with the ability to measure contact force), a circular film acceleration sensor, and an optical reflection sensor. Pulse wave signals were recorded from the left radial, carotid, femoral, and digital arteries of 60 subjects using these four sensors. Their performance was evaluated by analyzing their susceptibilities to external factors (contact force, measuring site, and ambient light intensity) and by comparing their stability and reproducibility. Under medium contact force, the peak-to-peak amplitude of the signals was higher than that at high and low force levels and the variability of signal waveform was small. The optical sensor was susceptible to ambient light. Analysis of the intra-class correlation coefficients (ICCs) of the pulse wave parameters showed that the tonometer and accelerometer had good stability (ICC > 0.80), and the PESG and optical sensor had moderate stability (0.46 < ICC < 0.86). Intra-observer analysis showed that the tonometer and accelerometer had good reproducibility (ICC > 0.75) and the PESG and optical sensor had moderate reproducibility (0.42 < ICC < 0.91). Inter-observer analysis demonstrated that the accelerometer had good reproducibility (ICC > 0.85) and the three other sensors had moderate reproducibility (0.52 < ICC < 0.96). We conclude that the type of sensor and measurement site affect pulse wave characteristics and the careful selection of appropriate sensor and measurement site are required according to the research and clinical need. Moreover, the influence of external factors such as contact pressure and ambient light should be fully taken into account., (Copyright © 2020 Wang, Wang, Sun, Yao, Hao, Xu and Greenwald.)

Background: It is widely accepted by the scientific community that bioelectrical signals, which can be used for the identification of neurophysiological biomarkers indicative of a diseased or pathological state, could direct patient treatment towards more effective therapeutic strategies. However, the design and realisation of an instrument that can precisely record weak bioelectrical signals in the presence of strong interference stemming from a noisy clinical environment is one of the most difficult challenges associated with the strategy of monitoring bioelectrical signals for diagnostic purposes. Moreover, since patients often have to cope with the problem of limited mobility being connected to bulky and mains-powered instruments, there is a growing demand for small-sized, high-performance and ambulatory biopotential acquisition systems in the Intensive Care Unit (ICU) and in High-dependency wards. Finally, to the best of our knowledge, there are no commercial, small, battery-powered, wearable and wireless recording-only instruments that claim the capability of recording electrocorticographic (ECoG) signals., Methods: To address this problem, we designed and developed a low-noise (8 nV/√Hz), eight-channel, battery-powered, wearable and wireless instrument (55 × 80 mm 2 ). The performance of the realised instrument was assessed by conducting both ex vivo and in vivo experiments., Results: To provide ex vivo proof-of-function, a wide variety of high-quality bioelectrical signal recordings are reported, including electroencephalographic (EEG), electromyographic (EMG), electrocardiographic (ECG), acceleration signals, and muscle fasciculations. Low-noise in vivo recordings of weak local field potentials (LFPs), which were wirelessly acquired in real time using segmented deep brain stimulation (DBS) electrodes implanted in the thalamus of a non-human primate, are also presented., Conclusions: The combination of desirable features and capabilities of this instrument, namely its small size (~one business card), its enhanced recording capabilities, its increased processing capabilities, its manufacturability (since it was designed using discrete off-the-shelf components), the wide bandwidth it offers (0.5-500 Hz) and the plurality of bioelectrical signals it can precisely record, render it a versatile and reliable tool to be utilized in a wide range of applications and environments.

Key Points: Intrauterine growth restriction (IUGR), induced by maternal undernutrition, leads to impaired aortic development. This is followed by hypertrophic remodelling associated with accelerated growth during lactation. Fetal nutrient restriction is associated with increased aortic compliance at birth and at weaning, but not in adult animals. This mechanical alteration may be related to a decreased perinatal collagen deposition. Aortic elastin scaffolds purified from young male and female IUGR animals also exhibit increased compliance, only maintained in adult IUGR females. These mechanical alterations may be related to differences in elastin deposition and remodelling. Fetal undernutrition induces similar aortic structural and mechanical alterations in young male and female rats. Our data argue against an early mechanical cause for the sex differences in hypertension development induced by maternal undernutrition. However, the larger compliance of elastin in adult IUGR females may contribute to the maintenance of a normal blood pressure level., Abstract: Fetal undernutrition programmes hypertension development, males being more susceptible. Deficient fetal elastogenesis and vascular growth is a possible mechanism. We investigated the role of aortic mechanical alterations in a rat model of hypertension programming, evaluating changes at birth, weaning and adulthood. Dams were fed ad libitum (Control) or 50% of control intake during the second half of gestation (maternal undernutrition, MUN). Offspring aged 3 days, 21 days and 6 months were studied. Blood pressure was evaluated in vivo. In the thoracic aorta we assessed gross structure, mechanical properties (intact and purified elastin), collagen and elastin content and internal elastic lamina (IEL) organization. Only adult MUN males developed hypertension (systolic blood pressure: MUN males  = 176.6 ± 5.6 mmHg; Control males  = 136.1 ± 4.9 mmHg). At birth MUN rats were lighter, with smaller aortic cross-sectional area (MUN males  = (1.51 ± 0.08) × 10 5  μm 2 , Control males  = (2.8 ± 0.04) × 10 5  μm 2 ); during lactation MUN males and females exhibited catch-up growth and aortic hypertrophy (MUN males  = (14.5 ± 0.5) × 10 5  μm 2 , Control males  = (10.4 ± 0.9) × 10 5  μm 2 ), maintained until adulthood. MUN aortas were more compliant until weaning (functional stiffness: MUN males  = 1.0 ± 0.04; Control males  = 1.3 ± 0.03), containing less collagen with larger IEL fenestrae, returning to normal in adulthood. Purified elastin from young MUN offspring was more compliant in both sexes; only MUN adult females maintained larger elastin compliance (slope: MUN females  = 24.1 ± 1.9; Control females  = 33.3 ± 2.8). Fetal undernutrition induces deficient aortic development followed by hypertrophic remodelling and larger aortic compliance in the perinatal period, with similar alterations in collagen and elastin in both sexes. The observed alterations argue against an initial mechanical cause for sex differences in hypertension development. However, the maintenance of high elastin compliance in adult females might protect them against blood pressure rise., (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)

Objective: This study aimed to compare differences in cardiorespiratory function between untreated hypertensive subjects (UHS) and healthy subjects (HS) during cardiopulmonary exercise testing (CPET). Additionally, it also aimed to explore the potential mechanisms of different exercise responses in cardiorespiratory function before, during and after CPET. Methods: Thirty subjects (15 UHS and 15 HS) were enrolled. Photoplethysmography (PPG), respiratory signal, and ECG were simultaneously collected while subjects were performing CPET. Fiducial points (a, b, c, d, e) were extracted from the second derivative of the PPG (SDPPG), and the ratios b/a, c/a, d/a, e/a, and (b-c-d-e)/a (named Aging Index, AGI) were calculated as markers of systolic and diastolic function. Additionally, respiratory rate was calculated and analyzed. Results: Before CPET, there were no significant differences in b/a, d/a, and AGI between two groups. However, after CPET, b/a (-0.9 ± 0.19 vs. -1.06 ± 0.19, p -value = 0.03) and AGI (-0.49 ± 0.75 vs. -1.15 ± 0.59, p -value = 0.011) of the UHS group were significantly higher than those of the HS. The d/a (-0.32 ± 0.24 vs. -0.14 ± 0.17, p -value = 0.024), and c/a (-0.33 ± 0.26 vs. -0.07 ± 0.19, p -value = 0.004) were significantly lower in UHS than those in HS. In contrast, before CPET, e/a (0.22 ± 0.11 vs. 0.32 ± 0.09, p -value = 0.007) in UHS was significantly lower than that in HS, while after CPET there was no significant difference between the two groups in this variable. In addition, during CPET, AGI ( p -value = 0.003), and respiratory rate ( p -value = 0.000) in UHS were significantly higher in comparison with before CPET. Conclusions: Different exercise responses showed the differences of cardiorespiratory function between UHS and HS. These differences not only can highlight the CV risk of UHS, but also can predict the appearance of arterial stiffness in UHS. Additionally, during CPET, significant differences in AGI, autonomic nervous function and respiratory activity assessed by respiratory rate were found between the two groups in comparison with before CPET.

Background: Exercise is accepted as an important contribution to the rehabilitation of patients with cardiovascular disease (CVD). This study aims to better understand the possible causes for lack of consensus and reviews the effects of three exercise modalities (aerobic, resistance and combined exercise) on central hemodynamics, arterial stiffness and cardiac function for better rehabilitation strategies in CVD., Methods: The electronic data sources, Cochrane Library, MEDLINE, Web of Science, EBSCO (CINAHL), and ScienceDirect from inception to July 2017 were searched for randomized controlled trials (RCTs) investigating the effect of exercise modalities in adult patients with CVD. The effect size was estimated as mean differences (MD) with 95% confidence intervals (CI). Subgroup analysis and meta-regression were used to study potential moderating factors., Results: Thirty-eight articles describing RCTs with a total of 2089 patients with CVD were included. The pooling revealed that aerobic exercise [MD(95%CI) = -5.87 (-8.85, -2.88), P = 0.0001] and resistance exercise [MD(95%CI) = -7.62 (-10.69, -4.54), P<0.00001] significantly decreased aortic systolic pressure (ASP). Resistance exercise significantly decreased aortic diastolic pressure [MD(95%CI) = -4(-5.63, -2.37), P<0.00001]. Aerobic exercise significantly decreased augmentation index (AIx) based on 24-week exercise duration and patients aged 50-60 years. Meanwhile, aerobic exercise significantly improved carotid-femoral pulse wave velocity (cf-PWV) [MD(95%CI) = -0.42 (-0.83, -0.01), P = 0.04], cardiac output (CO) [MD(95% CI) = 0.36(0.08, 0.64), P = 0.01] and left ventricular ejection fraction (LVEF) [MD(95%CI) = 3.02 (2.11, 3.93), P<0.00001]. Combined exercise significantly improved cf-PWV [MD(95%CI) = -1.15 (-1.95, -0.36), P = 0.004] and CO [MD(95% CI) = 0.9 (0.39, 1.41), P = 0.0006]., Conclusions: Aerobic and resistance exercise significantly decreased ASP, and long-term aerobic exercise reduced AIx. Meanwhile, aerobic and combined exercise significantly improved central arterial stiffness and cardiac function in patients with CVD. These findings suggest that a well-planned regime could optimize the beneficial effects of exercise and can provide some evidence-based guidance for those involved in cardiovascular rehabilitation of patients with CVD., Competing Interests: The authors have declared that no competing interests exist.

Tendon is composed of fascicles bound together by the interfascicular matrix (IFM). Energy storing tendons are more elastic and extensible than positional tendons; behaviour provided by specialisation of the IFM to enable repeated interfascicular sliding and recoil. With ageing, the IFM becomes stiffer and less fatigue resistant, potentially explaining why older tendons become more injury-prone. Recent data indicates enrichment of elastin within the IFM, but this has yet to be quantified. We hypothesised that elastin is more prevalent in energy storing than positional tendons, and is mainly localised to the IFM. Further, we hypothesised that elastin becomes disorganised and fragmented, and decreases in amount with ageing, especially in energy storing tendons. Biochemical analyses and immunohistochemical techniques were used to determine elastin content and organisation, in young and old equine energy storing and positional tendons. Supporting the hypothesis, elastin localises to the IFM of energy storing tendons, reducing in quantity and becoming more disorganised with ageing. These changes may contribute to the increased injury risk in aged energy storing tendons. Full understanding of the processes leading to loss of elastin and its disorganisation with ageing may aid in the development of treatments to prevent age related tendinopathy.

Metabolic syndrome is a cluster of metabolic abnormalities characterized by obesity, insulin resistance, hypertension and dyslipidemia. Ferulic acid (FA) is the major phenolic compound found in rice oil and various fruits and vegetables. In this study, we examined the beneficial effects of FA in minimizing insulin resistance, vascular dysfunction and remodeling in a rat model of high-carbohydrate, high-fat diet-induced metabolic changes, which is regarded as an analogue of metabolic syndrome (MS) in man. Male Sprague-Dawley rats were fed a high carbohydrate, high fat (HCHF) diet and 15% fructose in drinking water for 16 weeks, where control rats were fed with standard chow diet and tap water. FA (30 or 60 mg/kg) was orally administered to the HCHF and control rats during the last six weeks of the study. We observed that FA significantly improved insulin sensitivity and lipid profiles, and reduced elevated blood pressure, compared to untreated controls (p < 0.05). Moreover, FA also improved vascular function and prevented vascular remodeling of mesenteric arteries. The effects of FA in HCHF-induced MS may be realized through suppression of oxidative stress by down-regulation of p47phox, increased nitric oxide (NO) bioavailability with up-regulation of endothelial nitric oxide synthase (eNOS) and suppression of tumor necrosis factor-α (TNF-α). Our results suggest that supplementation of FA may have health benefits by minimizing the cardiovascular complications of MS and alleviating its symptoms.

Background: Cadmium (Cd) is a nonessential heavy metal, causing oxidative damage to various tissues and associated with hypertension. Tetrahydrocurcumin (THU), a major metabolite of curcumin, has been demonstrated to be an antioxidant, anti-diabetic, anti-hypertensive and anti-inflammatory agent. In this study, we investigated the protective effect of THU against Cd-induced hypertension, raised arterial stiffness and vascular remodeling in mice., Methods: Male ICR mice received CdCl2 (100 mg/l) via drinking water for 8 weeks. THU was administered intragastrically at dose of 50 or 100 mg/kg/day concurrently with Cd treatment., Results: Administration of CdCl2 significantly increased arterial blood pressure, blunted vascular responses to vasoactive agents, increased aortic stiffness, and induced hypertrophic aortic wall remodeling by increasing number of smooth muscle cells and collagen deposition, decreasing elastin, and increasing matrix metalloproteinase (MMP)-2 and MMP-9 levels in the aortic medial wall. Supplementation with THU significantly decreased blood pressure, improved vascular responsiveness, and reversed the structural and mechanical alterations of the aortas, including collagen and elastin deposition. The reduction on the adverse response of Cd treatment was associated with upregulated eNOS and downregulated iNOS protein expressions, increased nitrate/nitrite level, alleviated oxidative stress and enhanced antioxidant glutathione. Moreover, THU also reduced the accumulation of Cd in the blood and tissues., Conclusions: Our results suggest that THU ameliorates cadmium-induced hypertension, vascular dysfunction, and arterial stiffness in mice through enhancing NO bioavailability, attenuating oxidative stress, improving vascular remodeling and decreasing Cd accumulation in other tissues. THU has a beneficial effect in moderating the vascular alterations associated with Cd exposure.

Objectives: To compare cardiac function at 10 years of age in four groups of monochorionic diamniotic (MCDA) twin pairs: uncomplicated MCDA twins (n = 6) (Group 1); twins that had had twin-twin transfusion syndrome (TTTS) managed by amnioreduction (TTTS-amnio, n = 9) (Group 2) or laser photocoagulation (TTTS-laser, n = 10) (Group 3); and dichorionic diamniotic controls (DCDA, n = 6) (Group 4)., Methods: Echocardiograms optimizing apical four-chamber and short-axis left ventricular views were stored for offline speckle-tracking analysis, blinded to twin type. Myocardial long-axis shortening and lengthening velocities were measured using pulsed Doppler ultrasound at the cardiac base. M-mode measurements of fractional shortening (short axis) and maximal excursion of the atrioventricular annulus (four-chamber) were recorded. Syngo Vector Velocity Imaging software tracked left ventricular myocardial motion offline to produce free wall strain, strain rate and rotation. Intertwin pair and group differences were investigated using ANOVA., Results: Cardiac measurements were within the normal ranges for 10-year-olds. No significant within-twin-pair and intergroup differences were found in current size, heart rates, strain or strain rate. Compared to DCDA controls, TTTS twins showed less cardiac rotation (TTTS-laser, P < 0.001 and TTTS-amnio, P = 0.054) with significant intertwin reduction in the ex-recipient (TTTS-amnio, P = 0.006) and larger MCDA twins (P = 0.027) compared with their cotwins. A similar pattern was seen in left ventricular early diastolic mitral valve tissue velocity (MVE') in all monochorionic groups, but only achieving significance in TTTS-amnio twins (P = 0.037). Intrapair differences in rotation and MVE' were significantly different following treatment at Quintero stages III or IV., Conclusions: Within-twin-pair patterns of left ventricular rotation and diastolic function differ at 10 years of age in ex-recipients of TTTS twins treated with amnioreduction compared with those treated by laser photocoagulation and controls. ., (Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.)

Background: Increased arterial stiffness is a cardiovascular outcome of metabolic syndrome (MetS). The chromosome 9p21 locus has been identified as a major locus for risk of coronary artery disease (CAD). The single nucleotide polymorphism (SNP), rs1333049 on chromosome 9p21.3 has been strongly associated with CAD and myocardial infarction. Increased arterial stiffness could be the link between the 9p21 polymorphism and increased cardiovascular risk. Since the impact of a genetic polymorphism on arterial stiffness especially in Asian populations has not been well defined, we aimed to investigate the association of arterial stiffness with rs 1333049 variant on chromosome 9p21.3 in Thai subjects with and without MetS risk factors., Methods: A total of 208 Thai subjects, aged 35-75 years, 135 with and 73 without MetS, according to IDF and NCEP-ATPIII criteria, were included in this study. Aortic-femoral pulse wave velocity (afPWV), brachial-ankle pulse wave velocity (baPWV) and aortic ankle pulse wave velocity (aaPWV) were measured and used as markers of arterial stiffness. The chromosome 9p21.3 locus, represented by the rs 1333049 variant and blood biochemistry were evaluated., Results: Arterial stiffness was elevated in subjects with MetS when compared with nonMetS subjects. PWV, especially afPWV increased progressively with increasing number of MetS risk factors (r = 0.322, P <0.001). We also found that the frequency distribution of the rs1333049 genotypes is significantly associated with the afPWV (P <0.05). In multivariate analyses, there was an association between homozygous C allele and afPWV (Odds ratio (OR), 8.16; 95% confidence interval (CI), 1.91 to 34.90; P = 0.005), while the GC genotype was not related to afPWV (OR, 1.79; 95% CI, 0.84 to 3.77; P = 0.129) when compared with the GG genotype., Conclusions: Our findings demonstrate for the first time that arterial stiffness is associated with genetic polymorphism in 9p21 and metabolic risk factors in a Thai population.

The spherical anatomy of human and rat liver lobules implies that more central cells have less time to carry out their function than more peripherally located cells because blood flows past them more rapidly. This problem could be overcome if more centrilobular cells could operate at higher temperatures than periportal cells. This study presents evidence for such a temperature gradient. Firstly, we use mathematical modelling to demonstrate that temperature increases towards the centre of the lobule. Secondly, we examine the distribution of a heat-generating protein and of a heat-sensitive protein across the rat and human liver lobules. Double-antibody staining of healthy liver from rat and human was used for visual scoring and for automated histomorphometric quantitation of the localisation of uncoupling protein-2 (known to generate heat) and of the transient receptor potential-v4 protein (known as a highly temperature-sensitive membrane protein). Both these proteins were found to be located predominantly in the centrilobular region of liver lobules. These findings support the suggestion that temperature gradients across the liver lobule may have evolved as a solution to the problem of reduced contact time between blood and cells at the centre as compared to the periphery of mammalian liver lobules.

The microstructural orientation of vascular wall constituents is of interest to scientists and clinicians because alterations in their native states are associated with various cardiovascular diseases. In the arterial media, the orientation of these constituents is often described as circumferential. However, it has been noted that, just below the endothelial surface, the vascular wall constituents are oriented axially. To further study this reported change in orientation, and to resolve previous observations (which were made under conditions of no load), we used nonlinear optical microscopy to examine the orientation of collagen and elastin fibers in the inner medial region of bovine common carotid arteries. Images were obtained from this part of the arterial wall under varying degrees of mechanical strain: 0%, 10% axial, 10% circumferential, and 10% biaxial. We observed that close to the endothelium these components are aligned in the axial direction but abruptly change to a circumferential alignment at a depth of approximately 20 mum from the endothelial surface. The application of mechanical strain resulted in a significantly greater degree of fiber alignment, both collagen and elastin, in the strain direction, regardless of their initial unloaded orientation. Furthermore, variations in strain conditions resulted in an increase or a decrease in the overall degree of fiber alignment in the subendothelial layer depending on the direction of the applied strain. This high-resolution investigation adds more detail to existing descriptions of complex structure-function relationships in vascular tissue, which is essential for a better understanding of the pathophysiological processes resulting from injury, disease progression, and interventional therapies.

Tendon is multi-level fibre composite material, responsible for the transmission of forces from muscles to the skeleton. It is composed of a hierarchical arrangement of collagenous units surrounded by a proteoglycan-rich matrix, arranged to support strain transfer, and thus contribute to the mechanical behaviour of tendon. This study examines the effect of swelling and enzymatic degradation on structural integrity at different levels of the tendon hierarchy. Biochemical and microstructural analysis are used to examine the effects of incubation on the composition and swelling of the matrix, prior to a mechanical characterisation of sample integrity. Results indicated significant swelling of tendon fibrils and interfibrillar matrix after incubation in phosphate buffered saline, leading to a reduction in ultimate tensile load, with failure initiated between fibrils and sub-fibrils. In contrast, incubation with the enzyme chondroitinase ABC resulted in a total removal of glycosaminoglycan from the samples, and a subsequent reduction in the extent of swelling. These fascicles also demonstrated an increase in failure loads, with failure predominating between fibres. The findings from this work confirm the importance of the non-collagenous matrix components in controlling strain transfer within tendon structures. It also highlights the necessity to maintain samples within a suitable and controlled environment prior to testing.

Background: In twin-twin transfusion syndrome (TTTS), the donor and recipient fetus are exposed to differing volume loads and show discordant intertwin vascular compliance in childhood despite identical genotype. We hypothesized that discordance is prevented by intrauterine endoscopic laser ablation of placental anastomoses, which abolishes intertwin transfusion. We tested this by examining pulse wave velocity (PWV) in brachial arteries of twin survivors of TTTS treated with and without laser therapy., Methods and Results: One hundred children (50 twin pairs, 27 with TTTS) were studied. Group 1 comprised 14 monochorionic (MC) twin pairs with TTTS treated symptomatically; group 2 comprised 13 MC twin pairs with TTTS treated by laser. The control groups comprised 12 MC twin pairs without TTTS (group 3) and 11 dichorionic twin pairs (group 4). Fetal cardiovascular data, predictive factors for, and duration of TTTS and cord blood were collected prospectively. We measured blood pressure and PWV photoplethysmographically at a median corrected postnatal age of 11 months (range, 1 week to 66 months). Both TTTS groups showed marked intertwin PWV discordance, unlike MCDA control subjects. The PWV discordance seen in laser treated twin pairs resembled that of dichorionic control subjects (heavier individual with higher PWV), whereas group 1 showed the opposite (negative) intertwin discordance (ANOVA F (1,45)=4.5, P=0.04). No significant differences in blood pressure or intrauterine growth were observed between TTTS groups., Conclusions: Vascular programming is evident in monozygotic twins with intertwin transfusion and is altered but not abolished by intrauterine therapy to resemble that seen in dichorionic twins.

Background: Cardiovascular disease is the most common cause of premature death in patients with end-stage renal disease, possibly due to a specific 'uraemic cardiomyopathy'. This study was designed to investigate the cardiac changes induced by a moderate impairment of renal function in a model of uraemia., Methods: Male Wistar rats (n=11) were rendered uraemic by 5/6 nephrectomy or sham operated (n=11). After 4 weeks, cardiac dimensions were measured from fixed tissue sections using a digital image analysis technique. In parallel groups of animals, cardiac myocytes were isolated and studied for evidence of functional changes attributable to uraemia. After steady-state field stimulation at 0.5 Hz, intracellular Ca(2+) handling (using Fura-2) was investigated. Up to 20 consecutive transients were averaged as the extracellular Ca(2+) was increased., Results: The 5/6 nephrectomy group had a 75% reduction in glomerular filtration rate, and a 2- to 3-fold increase in serum urea and creatinine compared with sham-operated control animals (P<0.0001). However, the blood pressure was found to be similar in each group. Histology of the intact hearts (five pairs) showed a significant increase in tissue cross-sectional area (14%; P<0.04), cross-sectional area of the left ventricle (22%; P<0.04), and a significant increase in left ventricular wall thickness (15%; P<0.03). In the single cardiac cell study, under basal conditions (1-2 mM extra-cellular Ca(2+)) no significant differences in intracellular Ca(2+) were observed, but in high extracellular Ca(2+) the uraemic cells were slower to return to diastolic intracellular Ca(2+) levels (P<0.05)., Conclusions: The data provide evidence of altered myocardial structure and function in early experimental uraemia. The changes described are consistent with concentric hypertrophy of the left ventricle, which occurs in the absence of hypertension.

Aim: To determine which, if any, of five commercially available desmin clones is most reliable at labelling desmin filaments and whether the enhanced polymer one step (EPOS) method of labelling is of any advantage in the routine diagnostic laboratory., Methods: Thirty four rhabdomyosarcomas from the files at The Hospital for Sick Children, Great Ormond Street, London, were studied. Four different desmin clones, DE-R-11, D33, DE-U-10, and PDE, were applied to each using the conventional extravidin biotin peroxidase method. The D33 clone was also applied using the EPOS method., Results: The EPOS method incorporating D33 persistently scored more cells as desmin positive and was positive in four cases which were negative on staining with the other clones., Conclusions: The D33 desmin clone used with the EPOS method is more reliable for identifying desmin filaments in tumours than other desmin antibodies tested. Different desmin clones using a routine technique label different rhabdomyosarcoma cells and therefore it is justifiable to use more than one clone.

The design and use of a perfusion system, using a modified flow chamber for studies on cultured animal cells, is described. Rat thoracic aorta smooth muscle cells were isolated by an explant method and grown on Thermanox coverslips. These were introduced into the flow chamber. A flow rate of 25ml/min and a shear stress of 14.6 dynes/cm2 (12 dyne = 10 microN) (both within physiological limits) were maintained. Cells remained attached to the coverslips after 8h of perfusion with culture medium. The effect of exposing rat smooth muscle cells to the cardiovascular toxin, allylamine, is also described. The components of the system are routinely available, simple to clean, easy to assemble and sterilize. The incorporation of an in-line sensor that monitors pH, PO2, PCO2 and temperature ensures that the perfusion conditions remain within physiological limits. Automation means that minimal supervision is required. This system provides a potential mechanism in which cultured vascular cells may be perfused under controlled haemodynamic conditions, and their response to a cytotoxin may be evaluated.

The hearts of six neonates with Ebstein's anomaly of the tricuspid valve who died in the 1st month of life were compared with hearts of six age- and size-matched control neonates. All six hearts had morphologically severe disease with gross right atrial dilation and marked apical displacement of the tricuspid valve. All had a secundum atrial septal defect and four had additional cardiac lesions (pulmonary atresia in two, ventricular septal defect in two). There was significant thinning of the right ventricular free wall distal to the tricuspid valve (3 +/- 0.2 mm vs. control 4.2 +/- 0.2, p less than 0.01) and right ventricular fiber diameter was reduced (7.2 +/- 0.3 microns vs. control 11.4 +/- 0.6, p less than 0.001). The fibrous tissue content of both right and left ventricular free walls was increased (right, 29.3 +/- 2.6% vs. control 8.7 +/- 1.1, p less than 0.001; left, 23.2 +/- 1.5% vs. control 8.5 +/- 0.7%, p less than 0.001). Although the right ventricular abnormalities might be explained by hemodynamic stress in utero, abnormalities of the left ventricular free wall suggest that either genetic or nonhemodynamic environmental factors are involved in the morphogenesis of this condition. Increased right and left ventricular fibrosis may contribute to the poor early outcome in this group and may predispose to late complications, such as subnormal exercise performance, hemodynamic deterioration or late sudden death that may occur in patients with Ebstein's anomaly who survive the neonatal period.

The local reflection coefficient (r) at the aortoiliac junction was estimated in vessels removed at autopsy from 15 females and 31 males aged 2 months to 88 years by calculating the characteristic impedance (Zc) of the abdominal aorta and the two common iliac arteries. Zc was evaluated for each vessel by measuring cross-sectional area from radiographs and propagation velocity of an isolated pressure impulse generated by a solenoid-driven piston connected to the distal end of the abdominal aorta, and detected at several sites a known distance from the junction. Attenuation coefficients in the aorta were estimated from the peak amplitude of the impulse at these several sites. We observed significant decreases with age in abdominal aortic attenuation coefficient (gamma = 0.053-5 x 10(-4) age [yr], r = -0.42, p less than 0.005), and the area ratio (AR) of the junction (sum of the iliac cross-sectional areas/aortic cross-sectional area) (AR = 0.93-0.002 x age [yr], r = -0.31, p less than 0.05). Bifurcation angle (Angle) and aortic propagation velocity (caorta) increased significantly (angle = 40.2 + 0.26 x age [yr], r = 0.41, p less than 0.01; caorta (ms-1) = 7.59 + 0.175 x age [yr], r = 0.69, p less than 0.0001). No significant association between age and iliac propagation velocity was found. On the basis of area measurements alone, it has been argued that the observed decrease in area ratio with age causes r to become more positive. The lack of age-related changes in iliac propagation velocity (and hence stiffness), an observation confirmed by most of the few reports in the literature, and the large increase in abdominal aortic stiffness, however, greatly outweighed the area ratio changes and caused a significant decline in reflection coefficient from +0.3 in early life to -0.3 in old age. (Reflection coefficient = 0.30-0.0065 x age [yr], r = -0.68, p less than 0.0001). Between the ages of 30 and 60 years, its absolute value was less than 0.1, confirming in vivo work on subjects within this age range. In children, a significant positive reflection at the distal end of the aorta will amplify the pulse wave in this region. As this vessel becomes stiffer with increasing age, amplification will increase, whereas the increasingly negative value of r will partially offset this rise, reducing pulse pressure on either side of the junction.(ABSTRACT TRUNCATED AT 400 WORDS)

The static elasticity and scleroprotein content of the aorta have been measured in 24 Okamoto spontaneously hypertensive rats aged 22-25 weeks, and 24 Wistars of the same age in which hypertension had been induced by nephrectomy and treated with a steroid. From the age of 4 weeks half the animals in each group were treated with a diuretic drug. By the age of 15 weeks caudal artery systolic blood pressure was significantly lower than control values in both drug-treated groups and remained so until death. Both types of hypertension were associated with larger diameter, thicker-walled and heavier aortas than those in the drug-treated animals. Vessels from Okamoto animals contained more collagen than those from the Wistars, although the collagen content was unchanged by drug treatment. Neither drug nor strain had any clear-cut affect on elastin content. In spite of these differences in wall thickness and chemical composition, values of the functional stiffness of the aorta measured over a wide range of pressure were similar in all four groups of animals. Using a simple model of the aorta in which elastin and collagen bear stress in parallel we find that the relationship between vessel composition and static incremental elastic modulus (structural stiffness) is similar in both models of hypertension and is not changed by drug treatment in spite of the consequent reduction in blood pressure.