Diabetes mellitus does not alter mortality or hospitalisation risk in patients with newly diagnosed heart failure with preserved ejection fraction: Time to rethink pathophysiological models of disease progression.

INTRODUCTION: Type 2 diabetes is a common and adverse prognostic co-morbidity for patients with heart failure with reduced ejection fraction (HFrEF). The effect of diabetes on long-term outcomes for heart failure with preserved ejection fraction (HFpEF) is less established. METHODS: Prospective cohort study of patients referred to a regional HF clinic with newly diagnosed with HFrEF and HFpEF according to the 2016 European Society of Cardiology guidelines. The association between diabetes, all-cause mortality and hospitalisation was quantified using Kaplan-Meier or Cox regression analysis. RESULTS: Between 1st May 2012 and 1st May 2013, of 960 unselected consecutive patients referred with suspected HF, 464 and 314 patients met the criteria for HFpEF and HFrEF respectively. Within HFpEF and HFrEF groups, patients with diabetes were more frequently male and in both groups patients with diabetes were more likely to be treated with ß-adrenoceptor antagonists and angiotensin converting enzyme inhibitors. After adjustment for age, sex, medical therapy and co-morbidities, diabetes was associated with increased mortality in individuals with HFrEF (HR 1.46 95% CI: 1.05-2.02; p = .023), but not in those with HFpEF (HR 1.26 95% CI 0.92-1.72; p = .146). CONCLUSION: In unselected patients with newly diagnosed HF, diabetes is not an adverse prognostic marker in patients with HFpEF, but is in HFrEF.

Sodium-glucose cotransporter 2 inhibitors influence skeletal muscle pathology in patients with heart failure and reduced ejection fraction.

AIMS: Patients with heart failure and reduced ejection fraction (HFrEF) exhibit skeletal muscle pathology, which contributes to symptoms and decreased quality of life. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve clinical outcomes in HFrEF but their mechanism of action remains poorly understood. We aimed, therefore, to determine whether SGLT2i influence skeletal muscle pathology in patients with HFrEF. METHODS AND RESULTS: Muscle biopsies from 28 male patients with HFrEF (New York Heart association class I-III) treated with SGLT2i (>12 months) or without SGLT2i were compared. Comprehensive analyses of muscle structure (immunohistochemistry), transcriptome (RNA sequencing), and metabolome (liquid chromatography-mass spectrometry) were performed, and serum inflammatory profiling (ELISA). Experiments in mice (n = 16) treated with SGLT2i were also performed. Myofiber atrophy was ~20% less in patients taking SGLT2i (p = 0.07). Transcriptomics and follow-up measures identified a unique signature in patients taking SGLT2i related to beneficial effects on atrophy, metabolism, and inflammation. Metabolomics identified influenced tryptophan metabolism in patients taking SGLT2i: kynurenic acid was 24% higher and kynurenine was 32% lower (p < 0.001). Serum profiling identified that SGLT2i treatment was associated with lower (p < 0.05) pro-inflammatory cytokines by 26-64% alongside downstream muscle interleukin (IL)-6-JAK/STAT3 signalling (p = 008 and 0.09). Serum IL-6 and muscle kynurenine were correlated (R = 0.65; p < 0.05). Muscle pathology was lower in mice treated with SGLT2i indicative of a conserved mammalian response to treatment. CONCLUSIONS: Treatment with SGLT2i influenced skeletal muscle pathology in patients with HFrEF and was associated with anti-atrophic, anti-inflammatory, and pro-metabolic effects. These changes may be regulated via IL-6-kynurenine signalling. Together, clinical improvements following SGLT2i treatment in patients with HFrEF may be partly explained by their positive effects on skeletal muscle pathology.

Coronary Guidewires in Temporary Cardiac Pacing and Assessment of Myocardial Viability: Current Perspectives and Future Directions.

Intracoronary guidewires used in percutaneous coronary intervention can also be configured to provide temporary ventricular pacing. Trans coronary electrophysiological parameters recorded by employing coronary guidewires may have a potential role in assessing myocardial viability and could provide a means to make an immediate on-table decision about revascularisation. To date, some small studies have demonstrated the safety of this technique in temporary cardiac pacing, but further research is required to refine this approach and establish its clinical utility in myocardial viability assessment. In this review we discuss the potential role of trans coronary electrophysiology in the assessment of myocardial viability.

Relationship Among Diabetes, Obesity, and Cardiovascular Disease Phenotypes: A UK Biobank Cohort Study.

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.

Transcoronary electrophysiological parameters in patients undergoing elective and acute coronary intervention.

INTRODUCTION: Percutaneous coronary intervention is performed routinely in the management of myocardial infarction with obstructive coronary disease, but intervention to arteries supplying nonviable myocardium may be harmful. It is important therefore to establish myocardial viability, and there is an unmet need in current clinical practice for real time viability assessment to aid in decision making. Transcoronary pacing to assess myocardial electrophysiological parameters may be a novel viability assessment technique which could be used in this regard. METHODS: Coronary intervention was carried out according to standard departmental procedure with standard equipment. An exchange length coronary guidewire was passed into both target and reference coronary vessels and an over-the-wire balloon or microcatheter was used to insulate the guidewire and allow electrophysiological parameters to be assessed. Readings were obtained from all major epicardial vessels and substantial branches. At each position, an intracoronary electrocardiogram was recorded, and R wave amplitude was measured. Transcoronary pacing was then performed to establish threshold and impedance for each myocardial segment. A viability cardiac MRI scan was performed for each patient. A standard segmental model was used to determine viability in each segment using an 'infarct score' based on degree of late gadolinium enhancement. Studies were reported blinded to the electrical parameters obtained from the coronary guidewire. The primary outcome was the relationship between pacing threshold and myocardial segment infarct score. Secondary outcomes included the relationship between segmental infarct score and R wave height, and between segmental infarct score and pacing impedance. Data were collected on the feasibility of studying the coronary segments as well as safety. RESULTS: Sixty-five patients presenting with stable coronary artery disease or acute coronary syndromes to Leeds General Infirmary between September 2019 and August 2021 were included in the study. Electrophysiological parameters from segments with an infarct score of zero were obtained, with wide variances seen, with no significant difference in impedance or threshold in any territory. There was a significant difference in sensitivity for segments in the right coronary artery territory for both elective and acute patients. This likely relates to reduced myocardial mass in these territories. No significant association between infarct score and sensitivity, impedance or threshold were seen. CONCLUSION: This study has established intracoronary electrophysiological parameters in both normal myocardium and areas of myocardial scar. No reliable association was seen between impedance, threshold or R wave amplitude and degree of myocardial viability, contrasting with prior findings from our group and others. More work is therefore required to fully understand the role of transcoronary pacing in this setting.

Loss of IGFBP2 mediates alveolar type 2 cell senescence and promotes lung fibrosis.

Accumulation of senescent cells contributes to age-related diseases including idiopathic pulmonary fibrosis (IPF). Insulin-like growth factor binding proteins (IGFBPs) regulate many biological processes; however, the functional contributions of IGFBP2 in lung fibrosis remain largely unclear. Here, we report that intranasal delivery of recombinant IGFBP2 protects aged mice from weight loss and demonstrated antifibrotic effects after bleomycin lung injury. Notably, aged human-Igfbp2 transgenic mice reveal reduced senescence and senescent-associated secretory phenotype factors in alveolar epithelial type 2 (AEC2) cells and they ameliorated bleomycin-induced lung fibrosis. Finally, we demonstrate that IGFBP2 expression is significantly suppressed in AEC2 cells isolated from fibrotic lung regions of patients with IPF and/or pulmonary hypertension compared with patients with hypersensitivity pneumonitis and/or chronic obstructive pulmonary disease. Altogether, our study provides insights into how IGFBP2 regulates AEC2-cell-specific senescence and that restoring IGFBP2 levels in fibrotic lungs can prove effective for patients with IPF.

Imaging Real-Time Coronary Anatomy Using a Three-Dimensional Electrophysiology Mapping System.

The aim of this study is to evaluate the feasibility of creating fast three-dimensional maps of coronary arteries and to develop a bipolar coronary guidewire in vitro and determine whether it can be localised accurately within the model.A total of five patients were recruited, and EnSite Precision was utilised to create 3D coronary anatomy. A water bath to accommodate a 3D-printed coronary model was developed to test the performance of the bipolar angioplasty wire.Successful guidewire localisation and 3D reconstruction of coronary anatomy were achieved in all the cases. No complications. The bipolar wire was able to collect point clouds, and localisation of the distal tip was excellent when tested in the water bath.Our study demonstrates the feasibility and safety of utilising EAMS to collect coronary anatomy. Real-time tracking with a bipolar catheter is accurate when tested in vitro.

Fractional Flow Reserve versus Angiography-Guided Management of Coronary Artery Disease: A Meta-Analysis of Contemporary Randomised Controlled Trials.

Background and Aims: Randomised controlled trials (RCTs) comparing outcomes after fractional flow reserve (FFR)-guided versus angiography-guided management for obstructive coronary artery disease (CAD) have produced conflicting results. We investigated the efficacy and safety of an FFR-guided versus angiography-guided management strategy among patients with obstructive CAD. Methods: A systematic electronic search of the major databases was performed from inception to September 2022. We included studies of patients presenting with angina or myocardial infarction (MI), managed with medications, percutaneous coronary intervention, or bypass graft surgery. A meta-analysis was performed by pooling the risk ratio (RR) using a random-effects model. The endpoints of interest were all-cause mortality, MI and unplanned revascularisation. Results: Eight RCTs, with outcome data from 5077 patients, were included. The weighted mean follow up was 22 months. When FFR-guided management was compared to angiography-guided management, there was no difference in all-cause mortality [3.5% vs. 3.7%, RR: 0.99 (95% confidence interval (CI) 0.62−1.60), p = 0.98, heterogeneity (I2) 43%], MI [5.3% vs. 5.9%, RR: 0.93 (95%CI 0.66−1.32), p = 0.69, I2 42%], or unplanned revascularisation [7.4% vs. 7.9%, RR: 0.92 (95%CI 0.76−1.11), p = 0.37, I2 0%]. However, the number patients undergoing planned revascularisation by either stent or surgery was significantly lower with an FFR-guided strategy [weighted mean difference: 14 (95% CI 3 to 25)%, p =< 0.001]. Conclusion: In patients with obstructive CAD, an FFR-guided management strategy did not impact on all-cause mortality, MI and unplanned revascularisation, when compared to an angiography-guided management strategy, but led to up to a quarter less patients needing revascularisation.

Association between operator volume and mortality in primary percutaneous coronary intervention.

BACKGROUND: There is a paucity of real-world data assessing the association of operator volumes and mortality specific to primary percutaneous coronary intervention (PPCI). METHODS: Demographic, clinical and outcome data for all patients undergoing PPCI in Leeds General Infirmary, UK, between 1 January 2009 and 31 December 2011, and 1 January 2013 and 31 December 2013, were obtained prospectively. Operator volumes were analysed according to annual operator PPCI volume (low volume: 1-54 PPCI per year; intermediate volume: 55-109 PPCI per year; high volume: ≥110 PPCI per year). Cox proportional hazards regression analyses were undertaken to investigate 30-day and 12-month all-cause mortality, adjusting for confounding factors. RESULTS: During this period, 4056 patients underwent PPCI, 3703 (91.3%) of whom were followed up for a minimum of 12 months. PPCI by low-volume operators was associated with significantly higher adjusted 30-day mortality (HR 1.48 (95% CI 1.05 to 2.08); p=0.02) compared with PPCI performed by high-volume operators, with no significant difference in adjusted 12-month mortality (HR 1.26 (95% CI 0.96 to 1.65); p=0.09). Comparisons between low-volume and intermediate-volume operators, and between intermediate and high-volume operators, showed no significant differences in 30-day and 12-month mortality. CONCLUSIONS: Low operator volume is independently associated with higher probability of 30-day mortality compared with high operator volume, suggesting a volume-outcome relationship in PPCI at a threshold higher than current recommendations.

Safety and efficacy of interrupting dual antiplatelet therapy one month following percutaneous coronary intervention: a meta-analysis of randomized controlled trials.

Very short duration of dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI) has recently attracted a lot of attention with the introduction of newer generations stents. This is appealing, especially in patients at high bleeding risk. However, none of the trials were powered for the individual ischemic and bleeding endpoints. All randomised controlled trials (RCTs) investigating one-month versus routine duration of DAPT in patients undergoing PCI and reporting outcomes from the time of cessation of DAPT (1 month) to 1 year were eligible for inclusion in the meta-analysis. The pooled risk ratios (RR) with their 95% confidence interval (CI) were calculated with the random-effects model using the Mantel-Haenszel method. Four RCTs involving 26,576 patients were included in this meta-analysis. Cessation of DAPT after 1 month was associated with significantly less major bleeding [RR 0.70, 95%CI (0.51-0.95), P = 0.02, heterogeneity (I2) = 42%]. There was no statistically significant difference in all-cause mortality [RR 0.84 (95%CI 0.69-1.03), P = 0.10, I2 = 0%] and stroke [RR 0.71 (95%CI 0.45-1.13), P = 0.15, I2 = 42%] when compared to routine duration of DAPT. There was also no difference in myocardial infarction (MI) [RR 1.12 (95%CI 0.91-1.39), P = 0.28, I2 = 0%], and definite or probable stent thrombosis [RR 1.49 (95%CI 0.92-2.41), P = 0.11, I2 = 0%] with cessation of DAPT after 1 month. Cessation of DAPT 1 month after PCI was associated with significantly less major bleeding, but there was no difference in the rate of all-cause mortality, stroke, MI and stent thrombosis.

Randomized, Placebo-Controlled Phase 2b Study to Evaluate the Safety and Efficacy of Recombinant Human Lecithin Cholesterol Acyltransferase in Acute ST-Segment-Elevation Myocardial Infarction: Results of REAL-TIMI 63B.

BACKGROUND: High-density lipoprotein plays a key role in reverse cholesterol transport. In addition, high-density lipoprotein particles may be cardioprotective and reduce infarct size in the setting of myocardial injury. Lecithin-cholesterol acyltransferase is a rate-limiting enzyme in reverse cholesterol transport. MEDI6012 is a recombinant human lecithin-cholesterol acyltransferase that increases high-density lipoprotein cholesterol. Administration of lecithin-cholesterol acyltransferase has the potential to reduce infarct size and regress coronary plaque in acute ST-segment-elevation myocardial infarction. METHODS: REAL-TIMI 63B (A Randomized, Placebo­controlled Phase 2b Study to Evaluate the Safety and Efficacy of MEDI6012 in Acute ST Elevation Myocardial Infarction) was a phase 2B multinational, placebo-controlled, randomized trial. Patients with ST-segment-elevation myocardial infarction within 6 hours of symptom onset and planned for percutaneous intervention were randomly assigned 2:1 to MEDI6012 (2- or 6-dose regimen) or placebo and followed for 12 weeks. The primary outcome was infarct size as a percentage of left ventricular mass by cardiac MRI at 10 to 12 weeks, with the primary analysis in patients with TIMI Flow Grade 0 to 1 before percutaneous intervention who received at least 2 doses of MEDI6012. The secondary outcome was change in noncalcified plaque volume on coronary computed tomographic angiography from baseline to 10 to 12 weeks with the primary analysis in patients who received all 6 doses of MEDI6012. RESULTS: A total of 593 patients were randomly assigned. Patients were a median of 62 years old, 77.9% male, and 95.8% statin naive. Median time from symptom onset to randomization was 146 (interquartile range [IQR], 103-221) minutes and from hospitalization to randomization was 12.7 (IQR, 6.6-24.0) minutes, and the first dose of drug was administered a median of 8 (IQR, 3-13) minutes before percutaneous intervention. The index myocardial infarction was anterior in 69.6% and TIMI Flow Grade 0 to 1 in 65.1% of patients. At 12 weeks, infarct size did not differ between treatment groups (MEDI6012: 9.71%, IQR 4.79-16.38; placebo: 10.48%, [IQR, 4.92-16.61], 1-sided P=0.79. There was also no difference in noncalcified plaque volume (geometric mean ratio, 0.96 [95% CI, NA-1.10], 1-sided P=0.30). There was no significant difference in treatment emergent serious adverse events. CONCLUSIONS: Administration of MEDI6012 in patients with acute ST-segment-elevation myocardial infarction did not result in a significant reduction in infarct size or noncalcified plaque volume at 12 weeks. MEDI6012 was well tolerated with no excess in overall serious adverse events. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03578809.

Routine Pressure Wire Assessment Versus Conventional Angiography in the Management of Patients With Coronary Artery Disease: The RIPCORD 2 Trial.

BACKGROUND: Measurement of fractional flow reserve (FFR) has an established role in guiding percutaneous coronary intervention. We tested the hypothesis that, at the stage of diagnostic invasive coronary angiography, systematic FFR-guided assessment of coronary artery disease would be superior, in terms of resource use and quality of life, to assessment by angiography alone. METHODS: We performed an open-label, randomized, controlled trial in 17 UK centers, recruiting 1100 patients undergoing invasive coronary angiography for the investigation of stable angina or non-ST-segment-elevation myocardial infarction. Patients were randomized to either angiography alone (angiography) or angiography with systematic pressure wire assessment of all epicardial vessels >2.25 mm in diameter (angiography+FFR). The coprimary outcomes assessed at 1 year were National Health Service hospital costs and quality of life. Prespecified secondary outcomes included clinical events. RESULTS: In the angiography+FFR arm, the median number of vessels examined was 4 (interquartile range, 3-5). The median hospital costs were similar: angiography, £4136 (interquartile range, £2613-£7015); and angiography+FFR, £4510 (£2721-£7415; P=0.137). There was no difference in median quality of life using the visual analog scale of the EuroQol EQ-5D-5L: angiography, 75 (interquartile range, 60-87); and angiography+FFR, 75 (interquartile range, 60-90; P=0.88). The number of clinical events was as follows: deaths, 5 versus 8; strokes, 3 versus 4; myocardial infarctions, 23 versus 22; and unplanned revascularizations, 26 versus 33, with a composite hierarchical event rate of 8.7% (48 of 552) for angiography versus 9.5% (52 of 548) for angiography+FFR (P=0.64). CONCLUSIONS: A strategy of systematic FFR assessment compared with angiography alone did not result in a significant reduction in cost or improvement in quality of life. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01070771.

Cixutumumab reveals a critical role for IGF-1 in adipose and hepatic tissue remodelling during the development of diet-induced obesity.

High fat diet (HFD)-induced obesity leads to perturbation in the storage function of white adipose tissue (WAT) resulting in deposition of lipids in tissues ill-equipped to deal with this challenge. The role of insulin like growth factor-1 (IGF-1) in the systemic and organ-specific responses to HFD is unclear. Using cixutumumab, a monoclonal antibody that internalizes and degrades cell surface IGF-1 receptors (IGF-1 R), leaving insulin receptor expression unchanged we aimed to establish the role of IGF-1 R in the response to a HFD. Mice treated with cixutumumab fed standard chow developed mild hyperinsulinemia with no change in WAT. When challenged by HFD mice treated with cixutumumab had reduced weight gain, reduced WAT expansion, and reduced hepatic lipid vacuole formation. In HFD-fed mice, cixutumumab led to reduced levels of genes encoding proteins important in fatty acid metabolism in WAT and liver. Cixutumumab protected against blunting of insulin-stimulated phosphorylation of Akt in liver of HFD fed mice. These data reveal an important role for IGF-1 R in the WAT and hepatic response to short-term nutrient excess. IGF-1 R inhibition during HFD leads to a lipodystrophic phenotype with a failure of WAT lipid storage and protection from HFD-induced hepatic insulin resistance.

Pericyte Insulin Receptors Modulate Retinal Vascular Remodeling and Endothelial Angiopoietin Signaling.

Pericytes regulate vascular development, stability, and quiescence; their dysfunction contributes to diabetic retinopathy. To explore the role of insulin receptors in pericyte biology, we created pericyte insulin receptor knockout mice (PIRKO) by crossing PDGFRß-Cre mice with insulin receptor (Insr) floxed mice. Their neonatal retinal vasculature exhibited perivenous hypervascularity with venular dilatation, plus increased angiogenic sprouting in superficial and deep layers. Pericyte coverage of capillaries was unaltered in perivenous and periarterial plexi, and no differences in vascular regression or endothelial proliferation were apparent. Isolated brain pericytes from PIRKO had decreased angiopoietin-1 mRNA, whereas retinal and lung angiopoietin-2 mRNA was increased. Endothelial phospho-Tie2 staining was diminished and FoxO1 was more frequently nuclear localized in the perivenous plexus of PIRKO, in keeping with reduced angiopoietin-Tie2 signaling. Silencing of Insr in human brain pericytes led to reduced insulin-stimulated angiopoietin-1 secretion, and conditioned media from these cells was less able to induce Tie2 phosphorylation in human endothelial cells. Hence, insulin signaling in pericytes promotes angiopoietin-1 secretion and endothelial Tie2 signaling and perturbation of this leads to excessive vascular sprouting and venous plexus abnormalities. This phenotype mimics elements of diabetic retinopathy, and future work should evaluate pericyte insulin signaling in this disease.

Novel Paracrine Action of Endothelium Enhances Glucose Uptake in Muscle and Fat.

[Figure: see text].

Endothelial Insulin Receptors Promote VEGF-A Signaling via ERK1/2 and Sprouting Angiogenesis.

Endothelial insulin receptors (Insr) promote sprouting angiogenesis, although the underpinning cellular and molecular mechanisms are unknown. Comparing mice with whole-body insulin receptor haploinsufficiency (Insr+/-) against littermate controls, we found impaired limb perfusion and muscle capillary density after inducing hind-limb ischemia; this was in spite of increased expression of the proangiogenic growth factor Vegfa. Insr+/- neonatal retinas exhibited reduced tip cell number and branching complexity during developmental angiogenesis, which was also found in separate studies of mice with endothelium-restricted Insr haploinsufficiency. Functional responses to vascular endothelial growth factor A (VEGF-A), including in vitro angiogenesis, were also impaired in aortic rings and pulmonary endothelial cells from Insr+/- mice. Human umbilical vein endothelial cells with shRNA-mediated knockdown of Insr also demonstrated impaired functional angiogenic responses to VEGF-A. VEGF-A signaling to Akt and endothelial nitric oxide synthase was intact, but downstream signaling to extracellular signal-reduced kinase 1/2 (ERK1/2) was impaired, as was VEGF receptor-2 (VEGFR-2) internalization, which is required specifically for signaling to ERK1/2. Hence, endothelial insulin receptors facilitate the functional response to VEGF-A during angiogenic sprouting and are required for appropriate signal transduction from VEGFR-2 to ERK1/2.

Endothelial IGF-1 receptor mediates crosstalk with the gut wall to regulate microbiota in obesity.

Changes in composition of the intestinal microbiota are linked to the development of obesity and can lead to endothelial cell (EC) dysfunction. It is unknown whether EC can directly influence the microbiota. Insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R) are critical for coupling nutritional status and cellular growth; IGF-1R is expressed in multiple cell types including EC. The role of ECIGF-1R in the response to nutritional obesity is unexplored. To examine this, we use gene-modified mice with EC-specific overexpression of human IGF-1R (hIGFREO) and their wild-type littermates. After high-fat feeding, hIGFREO weigh less, have reduced adiposity and have improved glucose tolerance. hIGFREO show an altered gene expression and altered microbial diversity in the gut, including a relative increase in the beneficial genus Akkermansia. The depletion of gut microbiota with broad-spectrum antibiotics induces a loss of the favourable metabolic differences seen in hIGFREO mice. We show that IGF-1R facilitates crosstalk between the EC and the gut wall; this crosstalk protects against diet-induced obesity, as a result of an altered gut microbiota.

Clinical validation and evaluation of a novel six-lead handheld electrocardiogram recorder compared to the 12-lead electrocardiogram in unselected cardiology patients (EVALECG Cardio).

Aims: Handheld electrocardiogram (ECG) monitors are increasingly used by both healthcare workers and patients to diagnose cardiac arrhythmias. There is a lack of studies validating the use of handheld devices against the standard 12-lead ECG. The Kardia 6L is a novel handheld ECG monitor which can produce a 6-lead ECG. In this study, we compare the 6L ECG against the 12-lead ECG. Methods and results: A prospective study consisting of unselected cardiac inpatients and outpatients at Leeds Teaching Hospital NHS Trust. All participants had a 12- and 6-lead ECGs. All ECG parameters were analysed by using a standard method template for consistency between independent observers. Electrocardiograms from the recorders were compared by the following statistical methods: linear regression, Bland-Altman, receiver operator curve, and kappa analysis. There were 1015 patients recruited. The mean differences between recorders were small for PR, QRS, cardiac axis, with receiver operator analysis area under the curve (AUC) of >80%. Mean differences for QT and QTc (between recorders) were also small, with AUCs for QT leads of >75% and AUCs for QTc leads of >60%. Key findings from Bland-Altman analysis demonstrate overall an acceptable agreement with few outliers instances (<6%, Bland-Altman analysis). Conclusion: Several parameters recorded by the Kardia 6L (QT interval in all six leads, rhythm detection, PR interval, QRS duration, and cardiac axis) perform closely to the gold standard 12-lead ECG. However, that consistency weakens for left ventricular hypertrophy, QRS amplitudes (Lead I and AVL), and ischaemic changes.

Advantages of CEMiTool for gene co-expression analysis of RNA-seq data.

Gene co-expression analysis is widely applied to transcriptomics data to associate clusters of genes with biological functions or identify therapeutic targets in diseases. Recently, the emergence of high-throughput technologies for gene expression analyses allows researchers to establish connections through gene co-expression analysis to identify clinical disease markers. However, gene co-expression analysis is complex and may be a daunting task. Here, we evaluate three co-expression analysis packages (WGCNA, CEMiTool, and coseq) using published RNA-seq datasets derived from ischemic cardiomyopathy and chronic obstructive pulmonary disease. Results show that the packages produced consensus co-expression clusters using default parameters. CEMiTool package outperformed the other two packages and required less computational resource and bioinformatics experience. This evaluation provides a basis on which data analysts can select bioinformatics tools for gene co-expression analysis.