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The Autumn Meeting of the British Society for Cardiovascular Research in 2023 was organized by Carolyn Carr, Lisa Heather and Claudia Montes Aparicio at Wadham College at the University of Oxford and was the 50th Anniversary Meeting of the Society. The theme of the meeting was “The impact of dysregulated metabolism on cardiovascular function” and included an early career symposium on “Life in academia and beyond”. The Annual Bernard and Joan Marshall Distinguished Investigator Lecture was given by Professor Doug Lewandowski on “Metabolic flux in the driver’s seat during cardiac health and disease”. This paper presents the abstracts selected for oral and poster presentation.

Background and aims: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver condition. It is tightly associated with an adverse metabolic phenotype (including obesity and type 2 diabetes) as well as with obstructive sleep apnoea (OSA) of which intermittent hypoxia is a critical component. Hepatic de novo lipogenesis (DNL) is a significant contributor to hepatic lipid content and the pathogenesis of NAFLD and has been proposed as a key pathway to target in the development of pharmacotherapies to treat NAFLD. Our aim is to use experimental models to investigate the impact of hypoxia on hepatic lipid metabolism independent of obesity and metabolic disease. Methods: Human and rodent studies incorporating stable isotopes and hyperinsulinaemic euglycaemic clamp studies were performed to assess the regulation of DNL and broader metabolic phenotype by intermittent hypoxia. Cell-based studies, including pharmacological and genetic manipulation of hypoxia-inducible factors (HIF), were used to examine the underlying mechanisms. Results: Hepatic DNL increased in response to acute intermittent hypoxia in humans, without alteration in glucose production or disposal. These observations were endorsed in a prolonged model of intermittent hypoxia in rodents using stable isotopic assessment of lipid metabolism. Changes in DNL were paralleled by increases in hepatic gene expression of acetyl CoA carboxylase 1 and fatty acid synthase. In human hepatoma cell lines, hypoxia increased both DNL and fatty acid uptake through HIF-1α and -2α dependent mechanisms. Conclusions: These studies provide robust evidence linking intermittent hypoxia and the regulation of DNL in both acute and sustained in vivo models of intermittent hypoxia, providing an important mechanistic link between hypoxia and NAFLD.

Xin Su Ning (XSN), a China patented and certified multi-herbal medicine, has been available in China since 2005 for treating cardiac ventricular arrhythmia including arrhythmia induced by ischemic heart diseases and viral myocarditis, without adverse reactions being reported. It is vitally important to discover pharmacologically how XSN as a multicomponent medicine exerts its clinical efficacy, and whether the therapeutic effect of XSN can be verified by standard clinical trial studies. In this paper we report our discoveries in a cellular electrophysiological study and in a three-armed, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. Conventional electrophysiological techniques were used to study the cellular antiarrhythmic mechanism of XSN. Data was then modeled with computational simulation of human action potential (AP) of the cardiac ventricular myocytes. The clinical trial was conducted with a total of 861 eligible participants randomly assigned in a ratio of 2:2:1 to receive XSN, mexiletine, or the placebo for 4 weeks. The primary and secondary endpoint was the change of premature ventricular contraction (PVC) counts and PVC-related symptoms, respectively. This trial was registered in the Chinese Clinical Trial Register Center (ChiCTR-TRC-14004180). We found that XSN prolonged AP duration of the ventricular myocytes in a dose-dependent, reversible manner and blocked potassium channels. Patients in XSN group exhibited significant total effective responses in the reduction of PVCs compared to those in the placebo group (65.85% vs. 27.27%, P < 0.0001). No severe adverse effects attributable to XSN were observed. In conclusion, XSN is an effective multicomponent antiarrhythmic medicine to treat PVC without adverse effect in patients, which is convincingly supported by its class I & III pharmacological antiarrhythmic mechanism of blocking hERG potassium channels and hNaV1.5 sodium channel reported in our earlier publication and prolongs AP duration both in ventricular myocytes and with computational simulation of human AP presented in this report.

cAMP/PKA signalling plays important roles in physiology, but there are a lack of tools to spatially distinguish cAMP. Here the authors present a FRET-based cAMP biosensor they call CUTie that can directly compare cAMP signals at multiple subcellular sites and detect nanoscale heterogeneity in cAMP in cardiac myocytes.

Xin Su Ning (XSN) is a China patented and certified traditional Chinese herbal medicine used to treat premature ventricular contractions (PVCs) since 2005. XSN is formulated with 11 herbs, designed to treat arrhythmia with phlegm-heat heart-disturbed syndrome (PHHD) according to Chinese medicine theory. The rational compatibility of the 11 herbs decides the therapeutic outcome of XSN. Due to the multicomponent nature of traditional Chinese medicine, it is difficult to use conventional pharmacology to interpret the therapeutic mechanism of XSN in terms of clear-cut drug molecule and target interactions. Network pharmacology/systematic pharmacology usually consider all the components in a formula with the same weight; therefore, the proportion of the weight of the components has been ignored. In the present study, we introduced a novel coefficient to mimic the relative amount of all the components in relation with the weight of the corresponding herb in the formula. The coefficient is also used to weigh the pharmacological effect of XSN on all relative biological pathways. We also used the cellular electrophysiological data generated in our lab, such as the effect of liensinine and isoliquiritigenin on NaV1.5 channels; we therefore set sodium channel as one of the targets of these two components, which would support the clinical efficacy of XSN in treating tachyarrhythmia. Combining the collected data and our discovery, a panoramagram of the pharmacological mechanism of XSN was established. Pathway enrichment and analysis showed that XSN treated PHHD arrhythmia through multiple ion channels regulation, protecting the heart from I/R injury, inhibiting the apoptosis of cardiomyocyte, and improving glucose and lipid metabolism.

Background: Following myocardial infarction (MI), the myocardium is prone to calcium-driven alternans, which typically precedes ventricular tachycardia and fibrillation. MI is also associated with remodeling of the sympathetic innervation in the infarct border zone, although how this influences arrhythmogenesis is controversial. We hypothesize that the border zone is most vulnerable to alternans, that β-adrenergic receptor stimulation can suppresses this, and investigate the consequences in terms of arrhythmogenic mechanisms.Methods and Results: Anterior MI was induced in Sprague-Dawley rats (n = 8) and allowed to heal over 2 months. This resulted in scar formation, significant (p < 0.05) dilation of the left ventricle, and reduction in ejection fraction compared to sham operated rats (n = 4) on 7 T cardiac magnetic resonance imaging. Dual voltage/calcium optical mapping of post-MI Langendorff perfused hearts (using RH-237 and Rhod2) demonstrated that the border zone was significantly more prone to alternans than the surrounding myocardium at longer cycle lengths, predisposing to spatially heterogeneous alternans. β-Adrenergic receptor stimulation with norepinephrine (1 μmol/L) attenuated alternans by 60 [52–65]% [interquartile range] and this was reversed with metoprolol (10 μmol/L, p = 0.008). These results could be reproduced by computer modeling of the border zone based on our knowledge of β-adrenergic receptor signaling pathways and their influence on intracellular calcium handling and ion channels. Simulations also demonstrated that β-adrenergic receptor stimulation in this specific region reduced the formation of conduction block and the probability of premature ventricular activation propagation.Conclusion: While high levels of overall cardiac sympathetic drive are a negative prognostic indicator of mortality following MI and during heart failure, β-adrenergic receptor stimulation in the infarct border zone reduced spatially heterogeneous alternans, and prevented conduction block and propagation of extrasystoles. This may help explain recent clinical imaging studies using meta-iodobenzylguanidine (MIBG) and 11C-meta-hydroxyephedrine positron emission tomography (PET) which demonstrate that border zone denervation is strongly associated with a high risk of future arrhythmia.

In addition to biocompatibility, an ideal scaffold for the regeneration of valvular tissue should also replicate the natural heart valve extracellular matrix (ECM) in terms of biomechanical properties and structural stability. In our previous paper, we demonstrated the development of collagen type I and hyaluronic acid (HA)-based scaffolds with interlaced microstructure. Such hybrid scaffolds were found to be compatible with cardiosphere-derived cells (CDCs) to potentially regenerate the diseased aortic heart valve. This paper focused on the quantification of the effect of crosslinking density on the mechanical properties under dry and wet conditions as well as degradation resistance. Elastic moduli increased with increasing crosslinking densities, in the dry and wet state, for parent networks, whereas those of interlaced scaffolds were higher than either network alone. Compressive and storage moduli ranged from 35 ± 5 to 95 ± 5 kPa and 16 ± 2 kPa to 113 ± 6 kPa, respectively, in the dry state. Storage moduli, in the dry state, matched and exceeded those of human aortic valve leaflets (HAVL). Similarly, degradation resistance increased with increasing the crosslinking densities for collagen-only and HA-only scaffolds. Interlaced scaffolds showed partial degradation in the presence of either collagenase or hyaluronidase as compared to when exposed to both enzymes together. These results agree with our previous findings that interlaced scaffolds were composed of independent collagen and HA networks without crosslinking between them. Thus, collagen/HA interlaced scaffolds have the potential to fill in the niche for designing an ideal tissue engineered heart valve (TEHV).

Despite great advances in therapy over the past decades, ischemic heart disease (IHD) remains the leading cause of death worldwide because the decrease in mortality after acute myocardial infarction (AMI) leads to a longer life span in patients with chronic postinfarct heart failure (HF). There are no existing medical treatments that can cure chronic HF and the only currently available therapeutic option for end-stage HF is heart transplantation. However, transplantation is limited by the shortage of donor organs and patients require lifelong immunosuppression. In the past 10 years, stem cell-based cardiac therapy has been proposed as a promising approach for the treatment of IHD. There is a variety of potential stem cell types for cardiac repair and regeneration, including bone marrow cells (BMCs), resident cardiac stem cells (CSCs) and induced pluripotent stem cells (iPSCs). Stem cell-based therapy may comprise cell transplantation or cardiac tissue engineering (CTE), which might be an attractive alternative to solve the problems of low retention and poor survival of transplanted cells. This review focuses on the characteristics of stem cells from various sources and discusses the strategies of stem cell-based therapy for the treatment of IHD.

The purpose of this study was to assess the impact of measures designed to mitigate the spread of coronavirus disease 2019 (COVID-19) on worldwide cancer screening. We systematically searched PubMed, Ovid MEDLINE, the Cochrane COVID-19 Study Register, ClinicalTrials.gov, and EMBASE without language restrictions for studies published between January 1, 2021, and February 10, 2021. Studies selected for full-text review contained data on patients screened for any type of cancer during the COVID-19 pandemic and comparison data from a time interval just prior to the pandemic. Data were obtained through dual extraction. All the included studies were assessed for quality and risk of bias. A meta-analysis was performed on 13 studies: 7 on screening mammography, 5 on colon cancer screening, and 3 on cervical cancer screening. Two of our studies reported on more than one type of cancer screening. The screening outcomes were reported as pooled incidence rate ratios using the inverse variance method and random effects models. All studies included in our meta-analysis reported the number of patients screened for cancer in defined time intervals before and during the COVID-19 pandemic. We found that the pooled incidence rate ratios were significantly lower for screening during the COVID-19 pandemic for breast cancer (0.63; 95% CI, 0.53 to 0.77; P

New durable elastomeric materials are commercially available for 3D printing, enabling a new class of consumer wearable applications. The mechanical response of soft 3D printed lattices can now be tailored for improved safety and comfort by (a) leveraging functional grading and (b) customizing the outer envelope to conform specifically to the anatomy of the subject (e.g. patient, athlete, or consumer). Furthermore, electronics can be unobtrusively integrated into these 3D printed structures to provide feedback relating to athletic performance or physical activity. A proposed sensor system was developed that weaves unjacketed wires at two distinct layers in a lattice to form a complex capacitor; the capacitance increases as the lattice is compressed and can detect lattice deformation. A structure was fabricated and demonstrated with both static compression as well as low-velocity impact to highlight the utility for wearable applications. This work is focused on improving the performance of American football helmets as highlighted by the National Football League (NFL) Helmet Challenge Symposium; however, the lattice sensing concept can be extended to metal and ceramic lattices as well - relevant to the automotive and aerospace industries.

Polyetheretherketone (PEEK) has been the focus of substantial additive manufacturing research for two principal reasons: (a) the mechanical performance approaches that of aluminum at relatively high temperatures for thermoplastics and (b) the potential for qualification in both the aerospace and biomedical industries. Although PEEK provides outstanding strength and thermal stability, printing can be difficult due to the high melting point. Recently, high-temperature soluble support has enabled the printing of lattices and stochastic foams with overhanging features in these high-performance carbon fiber thermoplastics, in which density can be optimized to strike a balance between weight and strength to enhance performance in applications such as custom implants or aerospace structures. Although polymer powder bed fusion has long been capable of the combination of these geometries and materials, material extrusion with high-temperature sacrificial support is dramatically less expensive. This research provides a comprehensive mechanical analysis and CT-scan-based dimensional study of carbon fiber PEEK lattice structures enabled with high-temperature support and including model validation.

In the above article [1], Figure 3 should read “Isometric view of two wires forming a capacitor in the measured configuration. The yellow wire is the top plate and the red is the bottom plate of a capacitor. The gray is a dielectric elastomer lattice, the deformation of which can be indirectly determined by measuring the capacitance.” Figure 4 should read “Isometric (A) and bottom view (B) of a lattice with an alternative configuration in four quadrants for selective sensing. The selectivity can be extended to any combination of cells in both vertical and horizontal configurations.” In Figure 9, the ${x}$ -axis should read “Min Deformation Slow; Min Deformation Fast; Max Deformation Slow; Max Deformation Fast.” A sentence in the introduction should read “Within the context of additive manufacturing, lattices are the focus of significant research since they...” The authors requested this correction for clarity purposes.