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Bridging the divide between academia and industry is the sacred goal of many researchers, but few are equipped to take their ideas from the bench to the boardroom.
Comparison of troponin and natriuretic peptides in Takotsubo syndrome and acute coronary syndrome: a meta-analysis.
OBJECTIVE: Takotsubo syndrome (TTS) is an acute heart failure syndrome which resembles acute coronary syndrome (ACS) at presentation. Differentiation requires coronary angiography, but where this does not occur immediately, cardiac biomarkers may provide additional utility. We performed a meta-analysis to compare troponin and natriuretic peptides (NPs) in TTS and ACS to determine if differences in biomarker profile can aid diagnosis. METHODS: We searched five literature databases for studies reporting NPs (Brain NP (BNP)/NT-pro-BNP) or troponin I/T in TTS and ACS, identifying 28 studies for troponin/NPs (5618 and 1145 patients, respectively). RESULTS: Troponin was significantly lower in TTS than ACS (standardised mean difference (SMD) -0.86; 95% CI, -1.08 to -0.64; p<0.00001), with an absolute difference of 75 times the upper limit of normal (×ULN) higher in ACS than TTS. Conversely, NPs were significantly higher in TTS (SMD 0.62; 95% CI, 0.44 to 0.80; p<0.00001) and 5.8×ULN greater absolutely. Area under the curve (AUC) for troponin in ACS versus TTS was 0.82 (95% CI, 0.70 to 0.93), and 0.92 (95% CI, 0.80 to 1.00) for ST-segment elevation myocardial infarction versus TTS. For NPs, AUC was 0.69 (95% CI, 0.48 to 0.89). Combination of troponin and NPs with logistic regression did not improve AUC. Recursive Partitioning and Regression Tree analysis calculated a troponin threshold ≥26×ULN that identified 95% cases as ACS where and specificity for ACS were 85.71% and 53.57%, respectively, with 94.32% positive predictive value and 29.40% negative predictive value. CONCLUSIONS: Troponin is lower and NPs higher in TTS versus ACS. Troponin had greater power than NPs at discriminating TTS and ACS, and with troponin ≥26×ULN patients are far more likely to have ACS.
Myocardial Metabolism in Heart Failure with Preserved Ejection Fraction
Heart failure with preserved ejection fraction (HFpEF) is increasingly prevalent and now accounts for half of all heart failure cases. This rise is largely attributed to growing rates of obesity, hypertension, and diabetes. Despite its prevalence, the pathophysiological mechanisms of HFpEF are not fully understood. The heart, being the most energy-demanding organ, appears to have a compromised bioenergetic capacity in heart failure, affecting all phenotypes and aetiologies. While metabolic disturbances in heart failure with reduced ejection fraction (HFrEF) have been extensively studied, similar insights into HFpEF are limited. This review collates evidence from both animal and human studies, highlighting metabolic dysregulations associated with HFpEF and its risk factors, such as obesity, hypertension, and diabetes. We discuss how changes in substrate utilisation, oxidative phosphorylation, and energy transport contribute to HFpEF. By delving into these pathological shifts in myocardial energy production, we aim to reveal novel therapeutic opportunities. Potential strategies include modulating energy substrates, improving metabolic efficiency, and enhancing critical metabolic pathways. Understanding these aspects could be key to developing more effective treatments for HFpEF.
Hyaluronic acid drives mesenchymal stromal cell-derived extracellular matrix assembly by promoting fibronectin fibrillogenesis
Hyaluronic acid (HA) is present at sites of ongoing fibronectin fibrillogenesis (fibrillar adhesions) and necessary for efficient fibronectin fibrillogenesis. As a result, fibronectin deposition can be enhanced by exogenous HA.
Atrial proteomic profiling reveals a switch towards profibrotic gene expression program in CREM-IbΔC-X mice with persistent atrial fibrillation.
BACKGROUND: Overexpression of the CREM (cAMP response element-binding modulator) isoform CREM-IbΔC-X in transgenic mice (CREM-Tg) causes the age-dependent development of spontaneous AF. PURPOSE: To identify key proteome signatures and biological processes accompanying the development of persistent AF through integrated proteomics and bioinformatics analysis. METHODS: Atrial tissue samples from three CREM-Tg mice and three wild-type littermates were subjected to unbiased mass spectrometry-based quantitative proteomics, differential expression and pathway enrichment analysis, and protein-protein interaction (PPI) network analysis. RESULTS: A total of 98 differentially expressed proteins were identified. Gene ontology analysis revealed enrichment for biological processes regulating actin cytoskeleton organization and extracellular matrix (ECM) dynamics. Changes in ITGAV, FBLN5, and LCP1 were identified as being relevant to atrial fibrosis and structural based on expression changes, co-expression patterns, and PPI network analysis. Comparative analysis with previously published datasets revealed a shift in protein expression patterns from ion-channel and metabolic regulators in young CREM-Tg mice to profibrotic remodeling factors in older CREM-Tg mice. Furthermore, older CREM-Tg mice exhibited protein expression patterns reminiscent of those seen in humans with persistent AF. CONCLUSIONS: This study uncovered distinct temporal changes in atrial protein expression patterns with age in CREM-Tg mice consistent with the progressive evolution of AF. Future studies into the role of the key differentially abundant proteins identified in this study in AF progression may open new therapeutic avenues to control atrial fibrosis and substrate development in AF.
Cell-Derived Extracellular Matrix for Tissue Engineering and Regenerative Medicine
Cell-derived extracellular matrices (CD-ECMs) captured increasing attention since the first studies in the 1980s. The biological resemblance of CD-ECMs to their in vivo counterparts and natural complexity provide them with a prevailing bioactivity. CD-ECMs offer the opportunity to produce microenvironments with costumizable biological and biophysical properties in a controlled setting. As a result, CD-ECMs can improve cellular functions such as stemness or be employed as a platform to study cellular niches in health and disease. Either on their own or integrated with other materials, CD-ECMs can also be utilized as biomaterials to engineer tissues de novo or facilitate endogenous healing and regeneration. This review provides a brief overview over the methodologies used to facilitate CD-ECM deposition and manufacturing. It explores the versatile uses of CD-ECM in fundamental research and therapeutic approaches, while highlighting innovative strategies. Furthermore, current challenges are identified and it is accentuated that advancements in methodologies, as well as innovative interdisciplinary approaches are needed to take CD-ECM-based research to the next level.
Isolation and Characterization of Human Adipocyte-derived Extracellular Vesicles Using Filtration and Ultracentrifugation
ABSTRACT Extracellular vesicles (EVs) are lipid enclosed envelopes that carry biologically active material such as proteins, RNA, metabolites and lipids. EVs can modulate the cellular status of other cells locally in tissue microenvironments or through liberation into peripheral blood. Adipocyte- derived EVs are elevated in the peripheral blood and show alterations in their cargo (RNA and protein) during metabolic disturbances including, obesity and diabetes. Adipocyte-derived EVs can regulate the cellular status of neighboring vascular cells, such as endothelial cells and adipose tissue resident macrophages to promote adipose tissue inflammation. Investigating alterations in adipocyte-derived EVs in vivo is complex because EVs derived from peripheral blood are highly heterogenous and contain EVs from other sources, namely platelets, endothelial cells, erythrocytes and muscle. Therefore, the culture of human adipocytes provides a model system for the study of adipocyte derived EVs. Here, we provide a detailed protocol for the extraction of total small EVs from cell culture media of human gluteal and abdominal adipocytes using filtration and ultracentrifugation. We further demonstrate the use of Nanoparticle Tracking Analysis (NTA) for quantification of EV size and concentration and show the presence of EV-protein tumor susceptibility gene 101 (TSG101) in the gluteal and abdominal adipocyte derived-EVs. Isolated EVs from this protocol can be used for downstream analysis including, transmission electron microscopy, proteomics, metabolomics, small RNA-sequencing, microarray and utilized in functional in vitro/in vivo studies. SUMMARY We describe the isolation of human adipocyte-derived extracellular vesicles (EVs) from gluteal and abdominal adipose tissue using filtration and ultracentrifugation. We characterize the isolated adipocyte-derived EVs by determining their size and concentration by Nanoparticle Tracking Analysis and by western blotting for the presence of EV-protein tumor susceptibility gene 101 (TSG101).
Development of diagnostic algorithm for Cushing's syndrome: a tertiary centre experience.
PURPOSE: No consensus exists as the gold standard for Cushing's Syndrome (CS) screening. This study aimed to evaluate the diagnostic accuracy and utility of late-night salivary cortisol (LNSC) and cortisone (LNSE), overnight dexamethasone suppression test (ODST), and urinary free cortisol (UFC) in developing a screening algorithm for CS. METHODS: A retrospective, single-centre analysis on 93 adult patients referred to the Oxford Centre for Diabetes, Endocrinology, and Metabolism for CS evaluation (2017-2022). Data were analysed using binomial logistic regression and area under the receiver-operating curve (AUROC). RESULTS: Fifty-three patients were diagnosed with CS. LNSC (sensitivity 87.5%, specificity 64.9%, AUC 0.76), LNSE (sensitivity 72.4%, specificity 85.7%, AUC 0.79), and ODST (sensitivity 94.7%, specificity 52.1%; AUC 0.74) demonstrated comparable effectiveness for CS diagnosis. Their combined application increased diagnostic accuracy (AUC 0.91). UFC was not statistically significant. Pre-test clinical symptom inclusion improved screening test performance (AUC LNSC: 0.83; LNSE: 0.84; ODST: 0.82). For CD diagnosis, LNSE + LNSC (AUC 0.95) outperformed ODST. Combining these with ACTH levels
Metabolic profiling of aortic stenosis and hypertrophic cardiomyopathy identifies mechanistic contrasts in substrate utilization
Aortic stenosis (AS) and hypertrophic cardiomyopathy (HCM) are distinct disorders leading to left ventricular hypertrophy (LVH), but whether cardiac metabolism substantially differs between these in humans remains to be elucidated. We undertook an invasive (aortic root, coronary sinus) metabolic profiling in patients with severe AS and HCM in comparison with non-LVH controls to investigate cardiac fuel selection and metabolic remodeling. These patients were assessed under different physiological states (at rest, during stress induced by pacing). The identified changes in the metabolome were further validated by metabolomic and orthogonal transcriptomic analysis, in separately recruited patient cohorts. We identified a highly discriminant metabolomic signature in severe AS in all samples, regardless of sampling site, characterized by striking accumulation of long-chain acylcarnitines, intermediates of fatty acid transport across the inner mitochondrial membrane, and validated this in a separate cohort. Mechanistically, we identify a downregulation in the PPAR-α transcriptional network, including expression of genes regulating fatty acid oxidation (FAO). In silico modeling of β-oxidation demonstrated that flux could be inhibited by both the accumulation of fatty acids as a substrate for mitochondria and the accumulation of medium-chain carnitines which induce competitive inhibition of the acyl-CoA dehydrogenases. We present a comprehensive analysis of changes in the metabolic pathways (transcriptome to metabolome) in severe AS, and its comparison to HCM. Our results demonstrate a progressive impairment of β-oxidation from HCM to AS, particularly for FAO of long-chain fatty acids, and that the PPAR-α signaling network may be a specific metabolic therapeutic target in AS.
Progress is impossible without change: understanding the evolving nomenclature of steatotic liver disease and its effect on hepatology practice.
The American, European, and Latin American liver societies have proposed a change in the nomenclature we use to describe alcohol-related liver disease and non-alcoholic fatty liver disease. Additionally, a term encompassing both is now advocated: steatotic liver disease, which includes metabolic dysfunction associated steatotic liver disease (MASLD) and MASLD with greater alcohol consumption (MetALD). These classifications offer increased relevance for clinicians, researchers, and patients alike. In this Viewpoint, we discuss the basis for this nomenclature shift and how it was developed. We also explore the challenges that will be faced in the adoption of such change. The proposed change seeks to banish stigma associated with phrasing such as alcoholic and fatty. However stigma, particularly related to the term fatty, is culturally nuanced, and reflects different entities depending on location. If such a change is internationally accepted, there will be wide-reaching effects on practitioners in primary care and metabolic medicine, and on patients. We discuss those effects and the opportunities the nomenclature change could offer, particularly for patients with alcohol and metabolic risk factors who represent a group previously ignored by clinical trials.
Retinal imaging for the assessment of stroke risk: a systematic review.
BACKGROUND: Stroke is a leading cause of morbidity and mortality. Retinal imaging allows non-invasive assessment of the microvasculature. Consequently, retinal imaging is a technology which is garnering increasing attention as a means of assessing cardiovascular health and stroke risk. METHODS: A biomedical literature search was performed to identify prospective studies that assess the role of retinal imaging derived biomarkers as indicators of stroke risk. RESULTS: Twenty-four studies were included in this systematic review. The available evidence suggests that wider retinal venules, lower fractal dimension, increased arteriolar tortuosity, presence of retinopathy, and presence of retinal emboli are associated with increased likelihood of stroke. There is weaker evidence to suggest that narrower arterioles and the presence of individual retinopathy traits such as microaneurysms and arteriovenous nicking indicate increased stroke risk. Our review identified three models utilizing artificial intelligence algorithms for the analysis of retinal images to predict stroke. Two of these focused on fundus photographs, whilst one also utilized optical coherence tomography (OCT) technology images. The constructed models performed similarly to conventional risk scores but did not significantly exceed their performance. Only two studies identified in this review used OCT imaging, despite the higher dimensionality of this data. CONCLUSION: Whilst there is strong evidence that retinal imaging features can be used to indicate stroke risk, there is currently no predictive model which significantly outperforms conventional risk scores. To develop clinically useful tools, future research should focus on utilization of deep learning algorithms, validation in external cohorts, and analysis of OCT images.
What is the environmental impact of a blood transfusion? A life cycle assessment of transfusion services across England.
BACKGROUND: Healthcare activities significantly contribute to greenhouse gas (GHG) emissions. Blood transfusions require complex, interlinked processes to collect, manufacture, and supply. Their contribution to healthcare emissions and avenues for mitigation is unknown. STUDY DESIGN AND METHODS: We performed a life cycle assessment (LCA) for red blood cell (RBC) transfusions across England where 1.36 million units are transfused annually. We defined the process flow with seven categories: donation, transportation, manufacturing, testing, stockholding, hospital transfusion, and disposal. We used direct measurements, manufacturer data, bioengineering databases, and surveys to assess electrical power usage, embodied carbon in disposable materials and reagents, and direct emissions through transportation, refrigerant leakage, and disposal. RESULTS: The central estimate of carbon footprint per unit of RBC transfused was 7.56 kg CO2 equivalent (CO2 eq). The largest contribution was from transportation (2.8 kg CO2 eq, 36% of total). The second largest was from hospital transfusion processes (1.9 kg CO2 eq, 26%), driven mostly by refrigeration. The third largest was donation (1.3 kg CO2 eq, 17%) due to the plastic blood packs. Total emissions from RBC transfusion are ~10.3 million kg CO2 eq/year. DISCUSSION: This is the first study to estimate GHG emissions attributable to RBC transfusion, quantifying the contributions of each stage of the process. Primary areas for mitigation may include electric vehicles for the blood service fleet, improving the energy efficiency of refrigeration, using renewable sources of electricity, changing the plastic of blood packs, and using methods of disposal other than incineration.