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Abstract Aims In patients with heart failure (HF), we aimed to assess (i) the time trends in N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) testing; (ii) patient characteristics associated with NT‐proBNP testing; (iii) distribution of NT‐proBNP levels, focusing on the subgroups with (WHFE) vs. without (NWHFE) a worsening HF event, defined as an HF hospitalization; and (iv) changes of NT‐proBNP levels over time. Methods and results NT‐proBNP testing and levels were investigated in HF patients enrolled in the Swedish Heart Failure Registry (SwedeHF) linked with the Stockholm CREAtinine Measurements project from January 2011 to December 2018. Index date was the first registration in SwedeHF. Patterns of change in NT‐proBNP levels before (in the previous 6 ± 3 months) and after (in the following 6 ± 3 months) the index date were categorized as follows: (i)

ABSTRACTChina has recorded impressive economic achievements driving the structural transformation of its society. However, this transformation is marked by rising inequality, environmental pollution and stark provincial disparities. In 2015, the launching of the Agenda 2030 provided a common ground at the international level conceptualizing the United Nations’ Sustainable Development Goals (SDGs). This paper analyses the provincial performances towards the Agenda 2030 in the period 2015–19 by introducing the integrated sustainable development index cluster; convergence and econometric analyses are then used to explore synergies and trade-offs among SDGs. The empirical results capture the dynamics of sustainable development of China’s provinces and provide a clearer understanding of how policies may influence different the SDGs’ achievements, exploring the relationship between environmental versus different aspects of development. These results are used to draw policy recommendations that highlight the importance of identifying the appropriate mix of strategies to promote integrated sustainable development.

AimsTo assess the barriers to guideline-directed medical therapy (GDMT) use in heart failure (HF), diagnostic workup and general knowledge about HF among physicians in Sweden.MethodsA survey about the management of HF was sent to 828 Swedish physicians including general practitioners (GPs) and specialists during 2021–2022. Answers were reported as percentages and comparisons were made by specialty (GPs vs. specialists).ResultsOne hundred sixty-eight physicians participated in the survey (40% females, median age 43 years; 41% GPs and 59% specialists). Electrocardiography and New York Heart Association class evaluations are mostly performed once a year by GPs (46%) and at every outpatient visit by specialists (40%). Echocardiography is mostly requested if there is clinical deterioration (60%). One-third of participants screen for iron deficiency only if there is anemia. Major obstacles to implementation of different drug classes in HF with reduced ejection fraction are related to side effects, with no significant differences between specialties. Device implantation is deemed appropriate regardless of aetiology (69%) and patient age (86%). Specialists answered correctly to knowledge questions more often than GPs. Eighty-six percent of participants think that GDMT should be implemented as much as possible. Most participants (57%) believe that regular patient assessment in nurse-led HF clinics improve adherence to GDMT.ConclusionObstacles to GDMT implementation according to physicians in Sweden mainly relate to potential side effects, lack of specialist knowledge and organizational aspects. Further efforts should be placed in educational activities and structuring of nurse-led clinics.

Introduction Chronic autoimmune (type 1 diabetes and coeliac disease) and metabolic/cardiovascular (type 2 diabetes, dyslipidaemia, hypertension) diseases are highly prevalent across all age ranges representing a major public health burden. Universal screening for prediction/early identification of these conditions is a potential tool for reducing their impact on the general population. The aim of this study is to assess whether universal screening using capillary blood sampling is feasible at a population-based level.Methods and analysis This is a low-risk interventional, single-centre, pilot study for a population-based screening programme denominated UNISCREEN. Participants are volunteers aged 1–100 who reside in the town of Cantalupo (Milan, Italy) undergoing: (1) interview collecting demographics, anthropometrics and medical history; (2) capillary blood collection for measurement of type 1 diabetes and coeliac disease-specific autoantibodies and immediate measurement of glucose, glycated haemoglobin and lipid panel by point-of-care devices; (3) venous blood sampling to confirm autoantibody-positivity; (4) blood pressure measurement; (5) fulfilment of a feasibility and acceptability questionnaire. The outcomes are the assessment of feasibility and acceptability of capillary blood screening, the prevalence of presymptomatic type 1 diabetes and undiagnosed coeliac disease, distribution of glucose categories, lipid panel and estimate of cardiovascular risk in the study population. With approximately 3000 inhabitants, the screened population is expected to encompass at least half of its size, approaching nearly 1500 individuals.Ethics and dissemination This protocol and the informed consent forms have been reviewed and approved by the San Raffaele Hospital Ethics Committee (approval number: 131/INT/2022). Written informed consent is obtained from all study participants or their parents if aged

BackgroundType 1 diabetes results from autoimmune-mediated destruction of β cells. The tyrosine kinase inhibitor imatinib might affect relevant immunological and metabolic pathways, and preclinical studies show that it reverses and prevents diabetes. Our aim was to evaluate the safety and efficacy of imatinib in preserving β-cell function in patients with recent-onset type 1 diabetes.MethodsWe did a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Patients with recent-onset type 1 diabetes (

Abstract Background Plasma mannose, an emerging novel biomarker of insulin resistance, is associated with both diabetes mellitus and coronary atherosclerosis, but the relationship between mannose concentrations and myocardial infarction (MI) across different glycaemic states remains to be elucidated. The aim of this study was to investigate the independent association between mannose and a first MI in a group of subjects characterized according to their glycaemic state. Methods Fasting plasma mannose concentrations were analysed in 777 patients 6–10 weeks after a first myocardial infarction and in 770 matched controls by means of high-performance liquid chromatography coupled to tandem mass spectrometry. Participants without known diabetes mellitus were categorized by an oral glucose tolerance test (OGTT) as having normal glucose tolerance (NGT, n = 1045), impaired glucose tolerance (IGT, n = 246) or newly detected type 2 diabetes (T2DM, n = 112). The association between mannose and MI was investigated across these glycaemic states by logistic regression. Results Mannose levels increased across the glycaemic states (p

Abstract Background Raised liver function tests (LFTs) have been correlated with multiple metabolic abnormalities and variably associated with cardiorenal outcomes. We sought to systematically test the relationship between LFT levels within the accepted range and major cardiorenal outcomes in a large clinical trial in type 2 diabetes, and the possible impact of placebo-controlled canagliflozin treatment. Methods We measured serum alanine aminotransferase (ALT), aspartic aminotransferase (AST), gamma-glutamyl transferase (γGT), alkaline phosphatase (ALP), and bilirubin concentrations in 10,142 patients, at baseline and repeatedly over follow-up. The relation of LFTs to first hospitalized heart failure (HHF), cardiovascular (CV) and all-cause mortality, and progression of renal impairment was investigated using multivariate proportional-hazards models. Results In univariate association, ALT was reciprocally predictive, and ALP was positively predictive, of all adjudicated outcomes; γGT also was directly associated with CV—but not renal—outcomes. In multivariate models including all 5 LFTs and 19 potential clinical confounders, ALT was independently associated with lower, and γGT with higher, CV outcomes risk. Canagliflozin treatment significantly reduced ALT, AST, and γGT over time. In a fully adjusted model including updated LFT levels and treatment, γGT was independently associated with CV and all-cause mortality, ALP with renal dysfunction progression, and canagliflozin treatment with significant reduction in HHF and renal risk. Conclusions Higher γGT levels are top LFT markers of risk of HHF and death in patients with diabetes and high CV risk, while ALT are protective. Canagliflozin lowers the risk of HHF and renal damage independently of LFTs and potential confounders.

Background Genome-wide association studies for glycemic traits have identified hundreds of loci associated with these biomarkers of glucose homeostasis. Despite this success, the challenge remains to link variant associations to genes, and underlying biological pathways. Methods To identify coding variant associations which may pinpoint effector genes at both novel and previously established genome-wide association loci, we performed meta-analyses of exome-array studies for four glycemic traits: glycated hemoglobin (HbA1c, up to 144,060 participants), fasting glucose (FG, up to 129,665 participants), fasting insulin (FI, up to 104,140) and 2hr glucose post-oral glucose challenge (2hGlu, up to 57,878). In addition, we performed network and pathway analyses. Results Single-variant and gene-based association analyses identified coding variant associations at more than 60 genes, which when combined with other datasets may be useful to nominate effector genes. Network and pathway analyses identified pathways related to insulin secretion, zinc transport and fatty acid metabolism. HbA1c associations were strongly enriched in pathways related to blood cell biology. Conclusions Our results provided novel glycemic trait associations and highlighted pathways implicated in glycemic regulation. Exome-array summary statistic results are being made available to the scientific community to enable further discoveries.

Sodium-glucose cotransporter (SGLT) inhibitors are new oral antidiabetes medications shown to effectively reduce glycated hemoglobin (A1C) and glycemic variability, blood pressure, and body weight without intrinsic properties to cause hypoglycemia in people with type 1 diabetes. However, recent studies, particularly in individuals with type 1 diabetes, have demonstrated increases in the absolute risk of diabetic ketoacidosis (DKA). Some cases presented with near-normal blood glucose levels or mild hyperglycemia, complicating the recognition/diagnosis of DKA and potentially delaying treatment. Several SGLT inhibitors are currently under review by the U.S. Food and Drug Administration and European regulatory agencies as adjuncts to insulin therapy in people with type 1 diabetes. Strategies must be developed and disseminated to the medical community to mitigate the associated DKA risk. This Consensus Report reviews current data regarding SGLT inhibitor use and provides recommendations to enhance the safety of SGLT inhibitors in people with type 1 diabetes.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF

Abstract N-acetylaspartate (NAA) is the second most abundant metabolite in the human brain; although it is assumed to be a proxy for a neuronal marker, its function is not fully elucidated. NAA is also detectable in plasma, but its relation to cerebral NAA levels, cognitive performance, or features of cerebral disease has not been investigated. To study whether circulating NAA tracks cerebral NAA levels, and whether circulating NAA correlates with cognitive function and features of cerebral small vessel disease (SVD). Two datasets were analyzed. In dataset 1, structural MRI was acquired in 533 subjects to assess four features of cerebral SVD. Cognitive function was evaluated with standardized test scores (N = 824). In dataset 2, brain 1H-MRS from the occipital region was acquired (N = 49). In all subjects, fasting circulating NAA was measured with mass spectrometry. Dataset 1: in univariate and adjusted for confounders models, we found no correlation between circulating NAA and the examined features of cerebral SVD. In univariate analysis, circulating NAA levels were associated inversely with the speed in information processing and the executive function score, however these associations were lost after accounting for confounders. In line with the negative findings of dataset 1, in dataset 2 there was no correlation between circulating and central NAA or total NAA levels. This study indicates that circulating NAA levels do not reflect central (occipital) NAA levels, cognitive function, or cerebral small vessel disease in man.

Abstract Background Mannose binding lectin (MBL) has been suggested to be associated with an impaired cardiovascular prognosis in dysglycaemic conditions, but results are still contrasting. Our aims are (i) to examine whether MBL levels differ between patients with an acute myocardial infarction (MI) and healthy controls and between subgroups with different glucose tolerance status, and (ii) to investigate the relation between MBL and future cardiovascular events. Methods MBL levels were assessed at discharge and after 3 months in 161 AMI patients without any previously known glucose perturbations and in 183 age- and gender-matched controls from the Glucose metabolism in patients with Acute Myocardial Infarction (GAMI) study. Participants were classified as having dysglycaemia, i.e. type 2 diabetes or impaired glucose tolerance, or not by an oral glucose tolerance test. The primary outcome was a composite of cardiovascular events comprising cardiovascular death, AMI, stroke or severe heart failure during 11 years of follow-up. Total and cardiovascular mortality served as secondary outcomes. Results At hospital discharge patients had higher MBL levels (median 1246 μg/L) than three months later (median 575 μg/L; p

Background and Aim: The study 'Periodontitis and Its Relation to Coronary Artery Disease' (PAROKRANK) reported an association between periodontitis (PD) and the first myocardial infarction (MI). This follow‐up study aims to test the hypothesis that those with PD—compared to periodontally healthy individuals—are at increased risk for cardiovascular (CV) events and death. Methods: A total of 1587 participants (age <75 years; females 19%) had a dental examination including panoramic radiographs between 2010 and 2014. PD was categorized as healthy (≥80% alveolar bone height), mild/moderate (79%–66%) or severe (<66%). A composite CV event (first of all‐cause death, non‐fatal MI or stroke and hospitalization following to heart failure) was investigated during a mean follow‐up period of 9.9 years (range 0.2–12.5 years). Participants were divided into two groups: those with and without PD. The primary event rate, stratified by periodontal status at baseline, was calculated using the Kaplan–Meier method and Cox regression. Results: The number of events was 187 in the 985 periodontally healthy participants (19%) and 174 in the 602 participants with PD (29%; p < 0.0001). Those with PD had a higher likelihood for a future event (hazard ratio [HR] = 1.26; 95% CI: 1.01–1.57; p = 0.038), following adjustment for age, smoking and diabetes. Conclusion: The PAROKRANK follow‐up revealed that CV events were more common among participants with PD, which supports the assumption that there might be a direct relation between PD and CV disease. [ABSTRACT FROM AUTHOR]

Abstract The impressive results of recent clinical trials with glucagon-like peptide-1 receptor agonists (GLP-1Ra) and sodium glucose transporter 2 inhibitors (SGLT-2i) in terms of cardiovascular protection prompted a huge interest in these agents for heart failure (HF) prevention and treatment. While both classes show positive effects on composite cardiovascular endpoints (i.e. 3P MACE), their actions on the cardiac function and structure, as well as on volume regulation, and their impact on HF-related events have not been systematically evaluated and compared. In this narrative review, we summarize and critically interpret the available evidence emerging from clinical studies. While chronic exposure to GLP-1Ra appears to be essentially neutral on both systolic and diastolic function, irrespective of left ventricular ejection fraction (LVEF), a beneficial impact of SGLT-2i is consistently detectable for both systolic and diastolic function parameters in subjects with diabetes with and without HF, with a gradient proportional to the severity of baseline dysfunction. SGLT-2i have a clinically significant impact in terms of HF hospitalization prevention in subjects at high and very high cardiovascular risk both with and without type 2 diabetes (T2D) or HF, while GLP-1Ra have been proven to be safe (and marginally beneficial) in subjects with T2D without HF. We suggest that the role of the kidney is crucial for the effect of SGLT-2i on the clinical outcomes not only because these drugs slow-down the time-dependent decline of kidney function and enhance the response to diuretics, but also because they attenuate the meal-related anti-natriuretic pressure (lowering postprandial hyperglycemia and hyperinsulinemia and preventing proximal sodium reabsorption), which would reduce the individual sensitivity to day-to-day variations in dietary sodium intake.

BackgroundProteomics of atypical phenotypes may help unravel cardiovascular disease mechanisms.AimWe aimed to prospectively screen the proteome of four types of individuals: with or without coronary artery disease (CAD), each with or without multiple risk factors. Associations with individual risk factors and circulating biomarkers were also tested to provide a functional context to the protein hits.Materials and MethodsThe CAPIRE study (ClinicalTrials.gov Identifier: NCT02157662) is a cross-sectional study aimed at identifying possible new mechanisms promoting or protecting against atherothrombosis. Quantification (by aptamer technology), ranking (using partial least squares), and correlations (by multivariate regression) of ~5000 plasma proteins were performed in consecutive individuals aged 45–75 years, without previous cardiovascular disease, undergoing computed tomography angiography for suspected CAD, showing either >5/16 atherosclerotic segments (CAD+) or completely clean arteries (CAD−) and either ≤ 1 risk factor (RF+) or ≥3 risk factors (RF−) (based on history, blood pressure, glycemia, lipids, and smoking).ResultsOf 544 individuals, 39% were atypical (93 CAD+/RF−; 120 CAD−/RF+) and 61% typical (102 CAD+/RF+; 229 CAD−/RF−). In the comparison with CAD+/RF− adjusted for sex and age, CAD−/RF+ was associated with increased atrial myosin regulatory light chain 2 (MYO) and C-C motif chemokine-22 (C-C-22), and reduced protein shisa-3 homolog (PS-3) and platelet-activating factor acetylhydrolase (PAF-AH). Extending the analysis to the entire cohort, an additional 8 proteins were independently associated with CAD or RF; by logistic regression, the 12-protein panel alone discriminated the four groups with AUCROC's of 0.72–0.81 (overall p = 1.0e−38). Among them, insulin-like growth factor binding protein-3 is positively associated with RF, lower BMI, and HDL-cholesterol, renin with CAD higher glycated hemoglobin HbA1c, and smoking.ConclusionsIn a CCTA-based cohort, four proteins, involved in opposing vascular processes (healing vs. adverse remodeling), are specifically associated with low CAD burden in high CV-risk individuals (high MYO and C-C-22) and high CAD burden in low-risk subjects (high PS-3 and PAF-AH), in interaction with BMI, smoking, diabetes, HDL-cholesterol, and HbA1c. These findings could contribute to a deeper understanding of the atherosclerotic process beyond traditional risk profile assessment and potentially constitute new treatment targets.

Treatment with glucagon-like peptide 1 receptor agonists reduces liver steatosis and cardiometabolic risk (CMR). Few data are available on lipid metabolism, and no information is available on the postprandial lipidomic profile. Thus, we investigated how exenatide treatment changes lipid metabolism and composition during fasting and after a mixed-meal tolerance test (MMTT) in adults with severe obesity without diabetes. Thirty individuals (26 females and 4 males, 30–60 years old, BMI >40 kg/m2, HbA1c 5.76%) were assigned (1:1) to diet with exenatide 10 μg twice daily treatment (n = 15) or without treatment as control (n = 15) for 3 months. Fasting and postprandial lipidomic profile (by liquid chromatography quadrupole time-of-flight mass spectrometry) and fatty acid metabolism (following a 6-h MMTT/tracer study) and composition (by gas chromatography-mass spectrometry) were evaluated before and after treatment. Both groups had slight weight loss (−5.5% vs. −1.9%, exenatide vs. control; P = 0.052). During fasting, exenatide, compared with control, reduced some ceramides (CERs) and lysophosphatidylcholines (LPCs) previously associated with CMR, while relatively increasing unsaturated phospholipid species (phosphatidylcholine [PC], LPC) with protective effects on CMR, although concentrations of total lipid species were unchanged. During MMTT, both groups showed suppressed lipolysis equal to baseline, but exenatide significantly lowered free fatty acid clearance and postprandial triacyclglycerol (TAG) concentrations, particularly saturated TAGs with 44–54 carbons. Exenatide also reduced some postprandial CERs, PCs, and LPCs previously linked to CMR. These changes in lipidomic profile remained statistically significant after adjusting for weight loss. Exenatide improved fasting and postprandial lipidomic profiles associated with CMR mainly by reducing saturated postprandial TAGs and CERs independently of weight loss and diabetes. Article Highlights: Few data are available on the effect of glucagon-like peptide 1 receptor agonists on lipid metabolism, and no information is available on the postprandial lipidomic profile. In adults without diabetes but with severe obesity, 3-month treatment with exenatide improved fasting and postprandial lipidomic profiles associated with cardiometabolic risk by decreasing saturated species (triacylglycerols [TAGs], ceramides, lysophosphatidylcholines) while increasing seven unsaturated phospholipid species (phosphatidylcholine, lysophosphatidylcholine) with protective effects on cardiometabolic risk compared with control. Exenatide blunted the rise in postprandial triglycerides, especially saturated TAGs. Postprandial triglyceride reduction was associated to decreased postprandial free fatty acid clearance, with lower saturated free fatty acid incorporation into newly synthesized lipids (TAGs and ceramides). [ABSTRACT FROM AUTHOR]

OBJECTIVE: The aim of this study was to investigate the impact of the sodium–glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin on tissue fatty acid (FA) uptake in the skeletal muscle, brain, small intestine, and subcutaneous and visceral adipose tissue of individuals with type 2 diabetes by using positron emission tomography (PET). RESEARCH DESIGN AND METHODS: In a 6-week randomized double-blind placebo-controlled trial, 53 patients with type 2 diabetes treated with metformin received either 10 mg dapagliflozin or placebo daily. Tissue FA uptake was quantified at baseline and end of treatment with PET and the long-chain FA analog radiotracer 14(R , S)-[18F]fluoro-6-thia-heptadecanoic acid. Treatment effects were assessed using ANCOVA, and the results are reported as least square means and 95% CIs for the difference between groups. RESULTS: A total of 38 patients (dapagliflozin n = 21; placebo n = 17) completed the study. After 6 weeks, skeletal muscle FA uptake was increased by dapagliflozin compared with placebo (1.0 [0.07, 2.0] μmol ⋅ 100 g−1 ⋅ min−1; P = 0.032), whereas uptake was not significantly changed in the small intestine or visceral or subcutaneous adipose tissue. Dapagliflozin treatment significantly increased whole-brain FA uptake (0.10 [0.02, 0.17] μmol ⋅ 100 g−1 ⋅ min−1; P = 0.01), an effect observed in both gray and white matter regions. CONCLUSIONS: Six weeks of treatment with dapagliflozin increases skeletal muscle and brain FA uptake, partly driven by a rise in free FA availability. This finding is in accordance with previous indirect measurements showing enhanced FA metabolism in response to SGLT2 inhibition and extends the notion of a shift toward increased FA use to muscle and brain. [ABSTRACT FROM AUTHOR]