OBJECTIVE: Obesity and diabetes frequently coexist, yet their individual contributions to cardiovascular risk remain debated. We explored cardiovascular disease biomarkers, events, and mortality in the UK Biobank stratified by BMI and diabetes. RESEARCH DESIGN AND METHODS: A total of 451,355 participants were stratified by ethnicity-specific BMI categories (normal, overweight, obese) and diabetes status. We examined cardiovascular biomarkers including carotid intima-media thickness (CIMT), arterial stiffness, left ventricular ejection fraction (LVEF), and cardiac contractility index (CCI). Poisson regression models estimated adjusted incidence rate ratios (IRRs) for myocardial infarction, ischemic stroke, and cardiovascular death, with normal-weight nondiabetes as comparator. RESULTS: Five percent of participants had diabetes (10% normal weight, 34% overweight, and 55% obese vs. 34%, 43%, and 23%, respectively, without diabetes). In the nondiabetes group, overweight/obesity was associated with higher CIMT, arterial stiffness, and CCI and lower LVEF (P < 0.005); these relationships were diminished in the diabetes group. Within BMI classes, diabetes was associated with adverse cardiovascular biomarker phenotype (P < 0.005), particularly in the normal-weight group. After 5,323,190 person-years follow-up, incident myocardial infarction, ischemic stroke, and cardiovascular mortality rose across increasing BMI categories without diabetes (P < 0.005); this was comparable in the diabetes groups (P-interaction > 0.05). Normal-weight diabetes had comparable adjusted cardiovascular mortality to obese nondiabetes (IRR 1.22 [95% CI 0.96–1.56]; P = 0.1). CONCLUSIONS: Obesity and diabetes are additively associated with adverse cardiovascular biomarkers and mortality risk. While adiposity metrics are more strongly correlated with cardiovascular biomarkers than diabetes-oriented metrics, both correlate weakly, suggesting that other factors underpin the high cardiovascular risk of normal-weight diabetes.

Oxidative stress within the vascular endothelium, due to excess generation of reactive oxygen species (ROS), is thought to be fundamental to the initiation and progression of the cardiovascular complications of type 2 diabetes mellitus. The term ROS encompasses a variety of chemical species including superoxide anion (O₂^•−), hydroxyl radical (OH⁻) and hydrogen peroxide (H₂O₂). While constitutive generation of low concentrations of ROS are indispensable for normal cellular function, excess O₂^•− can result in irreversible tissue damage. Excess ROS generation is catalysed by xanthine oxidase, uncoupled nitric oxide synthases, the mitochondrial electron transport chain and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. Amongst enzymatic sources of O₂^•− the Nox2 isoform of NADPH oxidase is thought to be critical to the oxidative stress found in type 2 diabetes mellitus. In contrast, the transcriptionally regulated Nox4 isoform, which generates H₂O₂, may fulfil a protective role and contribute to normal glucose homeostasis. This review describes the key roles of Nox2 and Nox4, as well as Nox1 and Nox5, in glucose homeostasis, endothelial function and oxidative stress, with a key focus on how they are regulated in health, and dysregulated in type 2 diabetes mellitus.

RNA-sequencing (RNA-seq) is an important tool to explore molecular mechanisms of disease. Technological advances mean this can be performed at the single-cell level, but the large sample sizes needed in clinical studies are currently prohibitively expensive and complex. Deconvolution of bulk RNA-seq offers an opportunity to bridge this gap by defining the cell lineage composition of samples. This approach is widely used in immunology studies, but currently there are no validated pipelines for researchers analysing human myocardium or skeletal muscle. Here, we describe the application and in silico validation of two pipelines to deconvolute human right atrium, left ventricle and skeletal muscle bulk RNA-seq data. Specifically, we have defined the major cell lineages of these tissues using single cell/nucleus RNA-seq data from the Heart Cell Atlas, which are then applied during deconvolution using the CIBERSORTx or BayesPrism deconvolution packages. Both pipelines gave robust estimates of the proportion of all major cell lineages in these tissues. We demonstrate their value in defining age- and sex-differences in tissue composition using bulk RNA-seq data from the GTEx consortium. Our validated pipelines can be rapidly applied by researchers working with existing or novel bulk RNA-seq of myocardium or skeletal muscle to gain novel insights.

Background: Continuous positive airway pressure (CPAP) and high-flow nasal oxygen (HFNO) have been used to manage hypoxaemic respiratory failure secondary to coronavirus disease 2019 (COVID-19) pneumonia. Limited data are available for patients treated with noninvasive respiratory support outside of the intensive care setting.Methods: In this single-centre observational study we observed the characteristics, physiological observations, laboratory tests and outcomes of all consecutive patients with COVID-19 pneumonia between April 2020 and March 2021 treated with noninvasive respiratory support outside of the intensive care setting.Results: We report the outcomes of 140 patients (mean±sdage: 71.2±11.1, 65% male (n=91)) treated with CPAP/HFNO outside of the intensive care setting. Overall mortality was 59% and was higher in those deemed unsuitable for mechanical ventilation (72%). The mean age of survivors was significantly lower than those who died (66.1versus74.4 years, p<0.001). Those who survived their admission also had a significantly lower median Clinical Frailty Score than the non-survivor group (2versus4, p<0.001). We report no significant difference in mortality between those treated with CPAP (n=92, mortality: 60%) or HFNO (n=48, mortality: 56%). Treatment was well tolerated in 86% of patients receiving either CPAP or HFNO.Conclusions: CPAP and HFNO delivered outside of the intensive care setting are viable treatment options for patients with hypoxaemic respiratory failure secondary to COVID-19 pneumonia, including those considered unsuitable for invasive mechanical ventilation. This provides an opportunity to safeguard intensive care capacity for COVID-19 patients requiring invasive mechanical ventilation.

Cardiology training in the UK is facing significant challenges due to a range of factors. Recent curriculum changes have further compounded this issue and significantly risk the ability to produce adequately trained consultants capable of managing patients with increasingly complex cardiovascular disease. The introduction of mandatory dual accreditation in general internal medicine (GIM) alongside cardiology, by design, results in significantly reduced training opportunities, including procedural and subspecialty exposure. Despite prolongation in training duration to mitigate these effects, most trainees now report needing post-certificate of completion of training fellowships to gain the standard competencies required for consultant roles, undermining the curriculum’s aim of fostering independent practice. Furthermore, the current training model is misaligned with patient needs, lacking provisions for training in key and expanding services, such as complex structural interventions and inherited cardiac conditions. The increasing complexity of expectations placed on trainees also has the potential to significantly hinder academic training, discouraging research and innovation, thereby risking the future of UK clinical academia. Urgent curriculum reform is not only desirable but also essential and should include limiting GIM training time, improving subspecialty accreditation pathways and revising academic training provisions. If current bodies overseeing cardiology training fail to implement these essential changes, additional options, including an independent regulatory framework for cardiology training, should be considered. Without immediate action, UK cardiology training risks facing a generational crisis of inadequately skilled consultants, which could compromise future patient care.

Infections are a major cause of morbidity and mortality in people with heart failure, accounting for approximately 25% of hospitalisations and deaths. Infection hospitalisations in people with heart failure last twice as long as other hospitalisations, with mortality rates after discharge being comparable to those seen after acute decompensated heart failure. Addressing this major challenge is essential to further improving the survival and quality of life of this population. However, very few studies have sought to understand why people with heart failure are predisposed to adverse infection outcomes and there are currently very few interventions that target this problem. In this review, we explore the underlying factors that may predispose individuals with heart failure to infection, highlight the impact of infections on outcomes, explore the potential strategies that may reduce adverse infection outcomes, and highlight future research priorities.