Transcatheter aortic valve replacement (TAVR) has emerged as a ground-breaking, minimally invasive alternative to traditional open-heart surgery, primarily designed for elderly patients initially considered unsuitable for surgical intervention due to severe aortic stenosis. As a result of successful large-scale trials, TAVR is now being routinely applied to a broader spectrum of patients. In deciding between TAVR and surgical aortic valve replacement, clinicians evaluate various factors, including patient suitability and anatomy through preprocedural imaging, which guides prosthetic valve sizing and access site selection. Patient surgical risk is a pivotal consideration, with a multidisciplinary team making the ultimate decision in the patient's best interest. Periprocedural imaging aids real-time visualization but is influenced by anaesthesia choices. A comprehensive postprocedural assessment is critical due to potential TAVR-related complications. Numerous trials have demonstrated that TAVR matches or surpasses surgery for patients with diverse surgical risk profiles, ranging from extreme to low risk. However, long-term follow-up data, particularly in low-risk cases, remains limited, and the applicability of published results to younger patients is uncertain. This review delves into key TAVR studies, pinpointing areas for potential improvement while delving into the future of this innovative procedure. Furthermore, it explores the expanding role of TAVR technology in addressing other heart valve replacement procedures.

Path planning in obstacle-dense environments is a key challenge in robotics, and depends on inferring scene attributes and associated uncertainties. We present a multiple-hypothesis path planner designed to navigate complex environments using obstacle detections. Path hypotheses are generated by reasoning about uncertainty and range, as initial detections are typically at far ranges with high uncertainty, before subsequent detections reduce this uncertainty. Given estimated obstacles, we build a graph of pairwise connections between objects based on the probability that the robot can safely pass between the pair. The graph is updated in real time and pruned of unsafe paths, providing probabilistic safety guarantees. The planner generates path hypotheses over this graph, then trades between safety and path length to intelligently optimize the best route. We evaluate our planner on randomly generated simulated forests, and find that in the most challenging environments, it increases the navigation success rate over an A* baseline from 20% to 75%. Results indicate that the use of evolving, range-based uncertainty and multiple hypotheses are critical for navigating dense environments.

Introduction: de Garengeot’s hernias occur when an inflamed appendix is encased within a femoral sac. This is a relatively rare type of femoral hernia. As a result, there are currently no guidelines for the management of these hernias. Case: We present a 90-year-old woman with a de Garengeot’s hernia complicated with strangulation and perforation. The diagnosis was made intraoperatively, and it was managed with hernia repair and an appendicectomy. There were no postoperative complications. Discussion: The presentation of de Garengeot’s hernias is non-specific. Enclosure of the bowel content within the hernia sac may mask systemic systems of disease. Rarely, septic signs or symptoms are identified on presentation. It is typically diagnosed intraoperatively, thus prompt emergency surgery should not be delayed by clinicians awaiting precise knowledge of the sac content via imaging. Prompt surgery with a single McEvedy incision enables treatment for both the appendicitis and abdominal wall defect, an appendectomy and hernia repair, respectively. In patients that present with an irreducible femoral hernia and biochemistry suggestive of an acute inflammatory process, there should be a high clinical suspicion for de Garengeot’s hernia due to the risk of perforation being masked by an anatomical encasement around the perforated bowel content.

Endovascular coiling (EC) has been identified in systematic reviews and meta-analyses to produce more favourable clinical outcomes in comparison to neurosurgical clipping (NC) when surgically treating a subarachnoid haemorrhage from a ruptured aneurysm. Cost-effectiveness analyses between both interventions have been done, but no cost-utility analysis has yet been published. This systematic review aims to perform an economic analysis of the relative utility outcomes and costs from both treatments in the UK. A cost-utility analysis was performed from the perspective of the National Health Service (NHS), over a 1-year analytic horizon. Outcomes were obtained from the randomised International Subarachnoid Aneurysm Trial (ISAT) and measured in terms of the patient’s modified Rankin scale (mRS) grade, a 6-point disability scale that aims to quantify a patient’s functional outcome following a stroke. The mRS score was weighted against the Euro-QoL 5-dimension (EQ-5D), with each state assigned a weighted utility value which was then converted into quality-adjusted life years (QALYs). A sensitivity analysis using different utility dimensions was performed to identify any variation in incremental cost-effectiveness ratio (ICER) if different input variables were used. Costs were measured in pounds sterling (£) and discounted by 3.5% to 2020/2021 prices. The cost-utility analysis showed an ICER of − £144,004 incurred for every QALY gained when EC was utilised over NC. At NICE’s upper willingness-to-pay (WTP) threshold of £30,000, EC offered a monetary net benefit (MNB) of £7934.63 and health net benefit (HNB) of 0.264 higher than NC. At NICE’s lower WTP threshold of £20,000, EC offered an MNB of £7478.63 and HNB of 0.374 higher than NC. EC was found to be more ‘cost-effective’ than NC, with an ICER in the bottom right quadrant of the cost-effectiveness plane—indicating that it offers greater benefits at lower costs. This is supported by the ICER being below the NICE’s threshold of £20,000–£30,000 per QALY, and both MNB and HNB having positive values (> 0).

Introduction: Syncope affects up to 50% of people during a lifetime and is a common presentation to Emergency Departments (EDs). The Ambulatory Emergency Care Unit (AECU) Syncope pathway was established at our institution as a route by which low-risk patients presenting with syncope can undergo investigations without requiring hospital admissions as well as reducing length of stay for patients awaiting cardiology input. Hypothesis: The AECU Syncope pathway at Northwick Park Hospital, London, UK is safe and effective in reducing hospital admissions. Methods: We conducted a retrospective study of patients seen via the AECU Syncope pathway in 2020. These were referrals from the Emergency Department, General Practice and Inpatient departments for 24-hour tapes and echocardiograms. Results: A total of 221 patients were referred to the AECU syncope pathway in 2020. Of these, 36 patients (16%) had abnormalities on 24-hour tape. The majority were ectopics (n=12) but patients were also found to have arrhythmias (n=10), bradycardia (n=8) and heart block (n=6). 10 patients had aortic valve dysfunction identified on echocardiogram: 4 had severe aortic stenosis and the rest had milder classifications of aortic valve dysfunction. In total, 42 of the 221 patients had an abnormality on echocardiogram and/or 24-hour tape. Of these 42 patients, 14 were discharged as their abnormalities were insignificant for further cardiology input. 28 were referred to cardiology clinic for review as an outpatient. In terms of readmissions, 6 patients had readmissions within 30 days but only 1 patient had a readmission attributed to syncope, and this was a presyncope episode for which the patient was safety netted for during the previous admission. There were no deaths reported within 30 days of presentation. Within 1 year, there were 2 deaths, but neither were attributed to a major adverse cardiovascular event. Conclusions: The AECU syncope pathway presents a viable, efficient and safe route by which low-risk patients who are under investigation for a presumed syncopal episode can receive cardiology input without requiring a prolonged hospital admission. In doing so, there is a significant benefit to hospitals by reducing strain on bed space and staffing, thereby improving patient flow.

Heart failure affects 1-2% of the adult population and one of the main contributors to its development is cardiomyopathy. Assessing a patient's risk for adverse events in heart failure is challenging and made more difficult by the heterogenous phenotypic expression of the disease. Cardiac MRI has long been a gold standard measure of myocardial function and anatomy due to its high spatial and temporal resolution. More recently, it has been posited to play a more critical role in the diagnosis and prognosis of cardiomyopathy-related heart failure. Given the limitations of more commonly used imaging modalities, increasing the clinical use of cardiac magnetic resonance imaging could potentially improve the prognosis of specific subgroups of patients at risk of adverse cardiac events. Lay abstract: Heart failure is a condition where the heart is unable to pump out enough blood to meet the body's daily needs. It can affect up to 2% of the adult population. One of the causes of heart failure is an intrinsic disease of the heart muscle, called cardiomyopathy. Assessing a patient's risk for events such as hospitalization and death in heart failure is challenging, and made more difficult by the wide variety of ways a patient can present with heart failure clinically. Cardiac MRI has long been a highly regarded imaging technique for heart function and shape due to the high level of detail it can show. More recently, it has been thought to play a more important role in investigating and predicting the course of cardiomyopathy-related heart failure. Given the limitations of more commonly used measurement techniques, increasing the clinical use of cardiac magnetic resonance imaging would potentially improve the outcomes and quality of life for patients suffering with cardiomyopathy.

Aims Takotsubo syndrome (TTS) is an acute heart failure, typically triggered by high adrenaline during physical or emotional stress. It is distinguished from myocardial infarction (MI) by a characteristic pattern of ventricular basal hypercontractility with hypokinesis of apical segments, and in the absence of culprit coronary occlusion. We aimed to understand whether recently discovered circulating biomarkers miR-16 and miR-26a, which differentiate TTS from MI at presentation, were mechanistically involved in the pathophysiology of TTS. Methods and results miR-16 and miR-26a were co-overexpressed in rats with AAV and TTS induced with an adrenaline bolus. Untreated isolated rat cardiomyocytes were transfected with pre-/anti-miRs and functionally assessed. Ventricular basal hypercontraction and apical depression were accentuated in miR-transfected animals after induction of TTS. In vitro miR-16 and/or miR-26a overexpression in isolated apical (but not basal), cardiomyocytes produced strong depression of contraction, with loss of adrenaline sensitivity. They also enhanced the initial positive inotropic effect of adrenaline in basal cells. Decreased contractility after TTS-miRs was reproduced in non-failing human apical cardiomyocytes. Bioinformatic profiling of miR targets, followed by expression assays and functional experiments, identified reductions of CACNB1 (L-type calcium channel Cavβ subunit), RGS4 (regulator of G-protein signalling 4), and G-protein subunit Gβ (GNB1) as underlying these effects. Conclusion miR-16 and miR-26a sensitize the heart to TTS-like changes produced by adrenaline. Since these miRs have been associated with anxiety and depression, they could provide a mechanism whereby priming of the heart by previous stress causes an increased likelihood of TTS in the future.

Introduction: Antiplatelet monotherapy is recommended for prevention of ischaemic events and death following acute coronary syndrome, particularly if contraindications preclude the use of dual antiplatelet therapy. We aimed to scrutinise the effects of clopidogrel vs aspirin when given as secondary prevention monotherapy on mortality independent of baseline cardiometabolic risk factors in a large real-world UK cohort. Methods: Between 2012 and 2017, consecutive patients (n = 12967) discharged on clopidogrel or aspirin monotherapy were enrolled at our institution in London, UK (median follow-up 244 days, IQR 659). The primary endpoint was all-cause mortality. Kaplan-Meier curves with a log rank test were used to compare all-cause mortality between patients discharged on clopidogrel monotherapy vs aspirin monotherapy. Cox proportional hazards models were constructed to investigate the relationship between antiplatelet monotherapy and all-cause mortality in multivariable analyses. Results: Overall, the primary endpoint of all-cause mortality occurred in 2585 (19.9%) patients: 1642 (18.3%) in the aspirin monotherapy group, compared with 943 (23.5%) on clopidogrel monotherapy (log rank p < 0.001), depicted in Figure 1. Clopidogrel monotherapy conferred an 16% increased risk of mortality compared with aspirin in the unadjusted Cox model (HR 1.16, 95% CI 1.07 - 1.25, p < 0.001). Following adjustment for age, ischaemic heart disease, stroke hypertension, heart failure, atrial fibrillation, diabetes mellitus, chronic kidney disease and chronic obstructive pulmonary disease, clopidogrel remained significantly associated with increased mortality (HR 1.09, 95% CI 1.00 - 1.18, p = 0.045). Conclusions: In this large UK cohort, clopidogrel monotherapy associated with increased all-cause mortality compared with aspirin independently of common cardiometabolic comorbidities.

Sacubitril/valsartan is a first-in-class Angiotensin Receptor-Neprilysin inhibitor (ARNi) to be approved for the treatment of heart failure with reduced ejection fraction (HFrEF). The combination tablet has become a mainstay of treatment in the management of heart failure (HF) due to its composite inhibition of the neurohumoral system. There is growing support to show that sacubitril/valsartan may enhance glycaemic control through the augmentation of neprilysin substrates - in particular, glucagon-like peptide 1 (GLP-1). Given that HF and Diabetes Mellitus (DM) frequently coexist, with 44% of patients hospitalised with heart failure also having diabetes as a co-morbidity, it is plausible that sacubitril/valsartan may represent a novel way to address glucose intolerance in HF. However, the role of neprilysin in the degradation of GLP-1 raises important clinical considerations such as the risk of hypoglycaemia and potential drug-drug interactions in patients with and without concurrent DM. We review the current body of research addressing the effect of neprilysin inhibition on GLP-1 receptor signalling and discuss the implications for treatment of HF and DM.

Introduction: Chest pain is a common presentation to the Emergency Department (ED). Current international guidelines emphasise the importance of triage pathways involving patient-centric algorithms. In 2019, a front-door ED pathway (Figure 1) was created to direct low-risk chest pain towards ambulatory care. We aimed to characterise clinical outcomes with this pathway in a real-world UK ED cohort presenting with cardiac chest pain. Methods: The chest pain pathway stratified patients as low-, intermediate- and high-risk at presentation. Patients presenting to the ED at our institution in London, UK, were consecutively included in two groups: a pre-pathway group prior to implementation of the chest pain pathway and a post-pathway group following implementation. Baseline demographics were compared using Pearson’s χ 2 test for categorical variables and unpaired t-tests for continuous variables. Primary endpoints were 30-day readmissions, and all-cause mortality. Multiple logistic regression models were constructed to assess the impact of the pathway on the primary outcomes, adjusting for age, sex, risk category and HEART score. Results: Baseline demographics were similar between pre-pathway and post-pathway groups, except for presence of a smoking history ( p = 0.04). Smoking was therefore adjusted for in multivariable analyses. Approximately 10% (13/136) of post-pathway patients avoided hospital admission and were triaged towards ambulatory care. There was no significant difference in 30-day readmissions: 18/139 post-pathway vs 12/167 pre-pathway (OR 1.79, 95% CI 0.79 - 4.22, p = 0.17); or all-cause mortality: 2/167 pre-pathway vs 5/139 post-pathway (OR 2.96, 95% CI 0.49 - 25.68, p = 0.26). Conclusions: This novel chest pain pathway demonstrated a 10% reduction in hospital admissions without concurrent increases in 30-day readmissions or all-cause mortality. This is likely to reduce burdens on hospital resources and patient flow whilst maintaining safety.

Engagement of the sarcoplasmic reticulum (SR) Ca2+ stores for excitation–contraction (EC)-coupling is a fundamental feature of cardiac muscle cells. Extracellular matrix (ECM) proteins that form the extracellular scaffolding supporting cardiac contractile activity are thought to play an integral role in the modulation of EC-coupling. At baseline, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) show poor utilisation of SR Ca2+ stores, leading to inefficient EC-coupling, like developing or human CMs in cardiac diseases such as heart failure. We hypothesised that integrin ligand–receptor interactions between ECM proteins and CMs recruit the SR to Ca2+ cycling during EC-coupling. hiPSC-CM monolayers were cultured on fibronectin-coated glass before 24 h treatment with fibril-forming peptides containing the integrin-binding tripeptide sequence arginine–glycine–aspartic acid (2 mM). Micropipette application of 40 mM caffeine in standard or Na+/Ca2+-free Tyrode’s solutions was used to assess the Ca2+ removal mechanisms. Microelectrode recordings were conducted to analyse action potentials in current-clamp. Confocal images of labelled hiPSC-CMs were analysed to investigate hiPSC-CM morphology and ultrastructural arrangements in Ca2+ release units. This study demonstrates that peptides containing the integrin-binding sequence arginine–glycine–aspartic acid (1) abbreviate hiPSC-CM Ca2+ transient and action potential duration, (2) increase co-localisation between L-type Ca2+ channels and ryanodine receptors involved in EC-coupling, and (3) increase the rate of SR-mediated Ca2+ cycling. We conclude that integrin-binding peptides induce recruitment of the SR for Ca2+ cycling in EC-coupling through functional and structural improvements and demonstrate the importance of the ECM in modulating cardiomyocyte function in physiology.

The coronavirus disease 2019 (COVID-19) pandemic has resulted in over 6 million deaths and significant morbidity across the globe. Alongside common respiratory symptoms, COVID-19 is associated with a variety of cardiovascular complications in the acute and post-acute phases of infection. The suggested pathophysiological mechanisms that underlie these complications include direct viral infection of the myocardium via the angiotensin-converting enzyme 2 (ACE2) protein and a cytokine release syndrome that results in indirect inflammatory damage to the heart. Patients with pre-existing cardiovascular disease and co-morbidities are generally more susceptible to the cardiac manifestations of COVID-19. However, studies have identified a variety of complications in low-risk individuals, including young adults and children. Myocarditis and paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS) are among the adverse events reported in the acute phase of infection. Furthermore, patients have reported cardiac symptoms persisting beyond the acute phase in post-COVID syndrome. This review summarises the acute and chronic cardiac consequences of COVID-19 in low-risk patients, explores the pathophysiology behind them, and discusses new predictive factors for poor outcomes.

Cardiac fibroblasts regulate the development of the adult cardiomyocyte phenotype and cardiac remodeling in disease. We investigate the role that cardiac fibroblasts-secreted extracellular vesicles (EVs) have in the modulation of cardiomyocyte Ca2+ cycling–a fundamental mechanism in cardiomyocyte function universally altered during disease. EVs collected from cultured human cardiac ventricular fibroblasts were purified by centrifugation, ultrafiltration and size-exclusion chromatography. The presence of EVs and EV markers were identified by dot blot analysis and electron microscopy. Fibroblast-conditioned media contains liposomal particles with a characteristic EV phenotype. EV markers CD9, CD63 and CD81 were highly expressed in chromatography fractions that elute earlier (Fractions 1–15), with most soluble contaminating proteins in the later fractions collected (Fractions 16–30). Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were treated with fibroblast-secreted EVs and intracellular Ca2+ transients were analyzed. Fibroblast-secreted EVs abbreviate the Ca2+ transient time to peak and time to 50% decay versus serum-free controls. Thus, EVs from human cardiac fibroblasts represent a novel mediator of human fibroblast-cardiomyocyte interaction, increasing the efficiency of hiPSC-CM Ca2+ handling.

Background Catheter-based renal denervation has been studied as a potential therapeutic option to reduce high blood pressure (BP). Preclinical studies in some experimental models have demonstrated an antihypertensive effect of renal denervation but reports from clinical trials have been mixed Methods We performed a literature search using combinations of the key terms 'Cardiovascular diseases, Clinical trial, Pre-clinical trials, Resistant hypertension, Renal denervation, Ablation technique, Radiofrequency ablation, Ultrasound ablation, RADIANCE SOLO, SYMPLICITY HTN, SYPRAL HTN'. The databases searched were PubMed and OVID Medline. Results The initial SYMPLICITY HTN-1 AND HTN-2 clinical trials reported significant decreases in office BP but results from the more robustly designed SYMPLICITY HTN-3 trial, which included sham controls and ambulatory BP monitoring, showed no significant antihypertensive effect. Interest in the use of renal denervation in hypertension was once again sparked by favourable results from the SPYRAL HTN-OFF Med trial Conclusion We provide a thorough, critical analysis of key preclinical and clinical studies investigating the efficacy of catheter-based renal denervation as a treatment for hypertension and highlight future areas for research to allow better translation into clinical practice

In this study, we report static and perfused models of human myocardial-microvascular interaction. In static culture, we observe distinct regulation of electrophysiology of human induced pluripotent stem cell derivedcardiomyocytes (hiPSC-CMs) in co-culture with human cardiac microvascular endothelial cells (hCMVECs) and human left ventricular fibroblasts (hLVFBs), including modification of beating rate, action potential, calcium handling, and pro-arrhythmic substrate. Within a heart-on-a-chip model, we subject this three-dimensional (3D) co-culture to microfluidic perfusion and vasculogenic growth factors to induce spontaneous assembly of perfusable myocardial microvasculature. Live imaging of red blood cells within myocardial microvasculature reveals pulsatile flow generated by beating hiPSC-CMs. This study therefore demonstrates a functionally vascularized in vitro model of human myocardium with widespread potential applications in basic and translational research.

Atherosclerosis is a chronic inflammatory condition resulting in the formation of fibrofatty plaques within the intimal layer of arterial walls. The identification of resident stem cells in the vascular wall has led to significant investigation into their contributions to health and disease, as well as their therapeutic potential. Of these, mesenchymal stem cells (MSCs) are the most widely studied in human clinical trials, which have demonstrated a modulatory role in vascular physiology and disease. This review highlights the most recent knowledge surrounding the cell biology of MSCs, including their origin, identification markers and differentiation potential. The limitations concerning the implementation of MSC therapy are considered and novel solutions to overcome these are proposed.

Long QT syndrome type 2 is a life-threatening disorder of cardiac electrophysiology. It can lead to sudden cardiac death as a result of QT prolongation and can remain undetected until it presents clinically in the form of life-threatening cardiac arrythmias. Current treatment relies on symptom management largely through the use of β-adrenergic blockade and presently no mechanism-based therapies exist to treat the dysfunction in the hERG channels responsible for the rapid delayed rectifier K+ current which is the pathological source of long QT syndrome type 2. We review the pathophysiology, diagnosis and current management of this life-threatening condition and also analyze some promising potential mechanism-based therapies.

Due to recent technological innovations, digital health is quickly transforming the means of healthcare delivery. Technologies such as artificial intelligence, wearables and virtual consultations are increasingly being integrated into routine clinical care and with careful consideration; these promise to bring improvements to both professional workloads and patient outcomes. We highlight the need for dedicated digital health education in order to ensure appropriate use of patient data, patient safeguarding and the means by which we might incorporate this in a post-covid COVID curriculum. We comment on what can be learnt by Barts X Medicine, the first digital health programme in England to be integrated into the medical curriculum, to improve medical teaching.