Background:Adult-onset diabetes comprises subgroups differing in pathophysiology, clinical presentation, and risk of comorbidities. We investigated early phenotypic differences between individuals who later developed diabetes, stratified by subgroup at diabetes diagnosis. Methods:We conducted a pooled analysis of nine prospective European cohorts with 3309 individuals developing incident diabetes and 13,963 age- and sex-matched controls without diabetes. Cases were assigned to previously defined cluster-based subgroups: severe autoimmune (SAID), insulin-deficient (SIDD), or insulin-resistant diabetes (SIRD), and moderate obesity- (MOD) or age-related diabetes (MARD). Clinical and metabolic characteristics were retroactively assessed for three time periods (>12, 6-12, 1-6 years) before diagnosis. Findings:Despite similarly high body mass index (BMI) in MOD and SIRD at diagnosis, MOD differed from controls already >12 years before diagnosis (31% higher than controls), while BMI increased progressively in SIRD (from 14% to 25% higher than controls). Compared to controls in period 1-6 years, age-, sex-, and BMI-adjusted insulin-glucose ratio was higher in SIRD, MOD and MARD at fasting (88%, 45% and 14%, respectively) and 120 min (110%, 70%, 26%) during an oral glucose tolerance test (p < 0.0001 for all), and the first-phase insulin-glucose ratio was higher in SIRD (23% [6; 43] p = 0.0072) but lower in SIDD (-30% [-37; -22], p < 0.0001) and MARD (-29% [-34; -24], p < 0.0001). The autoimmune subgroup SAID also exhibited features of metabolic syndrome. Despite differences in HOMA2-B and HbA1c at diagnosis, insulin and glucose levels did not differ significantly between the SIDD and MARD subgroups 1-6 years earlier suggesting a rapid deterioration in glycemic control in SIDD around diagnosis. Interpretation:Subgroups of diabetes display different trajectories of insulin resistance, insulin deficiency, and features of the metabolic syndrome before diagnosis. Funding:ERC, local governments, private foundations, University of Helsinki, and Research councils of Finland and Sweden.

Abstract Background Individuals with diabetes have an increased risk of cardiovascular disease, infection, hospitalization, and premature mortality. However, less is known about how diabetes shapes the broader pattern of emergency department (ED) presentations, acute care use, clinical complexity, and short-term mortality in an unselected ED population. We aimed to describe ED presentation patterns and outcomes among individuals with and without diabetes in a large regional cohort. Methods We conducted a population-based cohort study including all adult ED visits to nine hospitals in Region Skåne, Sweden, between 2017 and 2018. ED visits for patients with a registered diabetes diagnosis ( n = 60,654) were compared with those without diabetes ( n = 502,800). We analysed ED visit frequency, recurrent ED use, arrival by ambulance, triage priority, length of stay, comorbidity burden, presenting complaints, and mortality after ED presentation. Results The most common presenting complaints were broadly similar in both groups, with dyspnoea, chest pain, and abdominal pain among the leading causes of ED presentation. However, diabetes visits were characterized by greater acute care complexity. Compared with visits by individuals without diabetes, visits by individuals with diabetes more often involved a previous ED visit within 90 days, higher triage priority, ambulance arrival, longer ED stay, and substantially higher comorbidity burden. Early mortality after ED presentation was also higher among individuals with diabetes and occurred at younger ages, particularly among men. Mortality diagnoses differed between groups, with cardiovascular causes more prominent among individuals with diabetes. Conclusions In this large population-based ED cohort, individuals with diabetes presented with broadly similar symptom categories as those without diabetes, but with markedly greater clinical complexity, higher acuity, recurrent acute care use, and earlier mortality. Diabetes in emergency care may therefore identify a patient group with substantial multimorbidity, reduced physiological reserve, and increased vulnerability during acute illness.

Obesity is a key contributor to heart failure, driving increased morbidity, mortality, and healthcare costs. This association is supported by multiple pathophysiological mechanisms and consistent epidemiological evidence, particularly not only in heart failure with preserved ejection fraction (HFpEF), but also in heart failure with reduced ejection fraction (HFrEF). Given the rising prevalence of both diseases, integrated management strategies are essential. This review outlines current management options in patients with heart failure and obesity, from lifestyle modification to pharmacological and surgical treatment, and explores emerging treatments aimed at mitigating this growing burden.

BACKGROUND:Cardiovascular disease is a leading cause of global mortality. Carotid-femoral pulse wave velocity (cfPWV) is the gold-standard noninvasive measure of arterial stiffness and is commonly used to assess early vascular aging, as it predicts future cardiovascular events. Although the influence of cardiovascular risk factors on cfPWV is well studied in adults, evidence in youth is limited. This study aimed to identify common cardiovascular risk factors that best explain variation in cfPWV among young people. METHODS:This study included 6763 participants aged 5 to 40 years with cfPWV measured using the SphygmoCor device, drawn from the Youth Vascular Consortium. Analyses were conducted across 5 subsets based on data completeness. Multiple linear regression models, stratified by sex and age (≤19 and >19 years), were developed to identify cardiovascular risk factors explaining cfPWV variation. Model selection was guided by Akaike information criterion and adjusted R2. RESULTS:Age and systolic blood pressure were consistent predictors, explaining <40% of cfPWV variance in cfPWV. Heart rate and waist circumference also emerged as key predictors of cfPWV, although lipids contributed modestly only in young adults. Waist circumference was the strongest anthropometric predictor in most groups. CONCLUSIONS:Age, systolic blood pressure, and heart rate were the strong contributors among traditional risk factors, yet explained <40% of variance in cfPWV in most groups. These findings highlight the role of hemodynamic load in shaping arterial stiffness even in childhood and adolescence, when structural changes are evolving. A large proportion of variance remains unexplained, suggesting that genetic, prenatal, environmental, and behavioral factors warrant investigation.

[This corrects the article DOI: 10.1016/j.lanepe.2026.101715.].

Context Statin use is associated with increased risk of type 2 diabetes (T2D) and mild hyperglycemia. The underlying mechanisms are not well studied, and the effect of statin treatment on glucagon-like peptide 1 (GLP-1) secretion or production is unknown. Objective This work aimed to assess the effects of rosuvastatin on GLP-1 secretion and production. Methods We performed association studies in the Malmö Diet and Cancer study cardiovascular cohort (MDCS-CC) reexamination cohort, in vitro investigations using GLUTag cells and acute and chronic studies in female, normoglycemic C57Bl/6j mice. Results Studies in the MDCS-CC reexamination cohort (n = 3734) revealed that in individuals without T2D, statin usage was associated with higher fasting glucose-dependent insulinotropic peptide (GIP), insulin, glucose, glucagon, and homeostatic model assessment of insulin resistance, but not GLP-1. However, in patients with T2D, statin usage was associated with higher fasting GLP-1 levels. Rosuvastatin treatment or 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (Hmgcr) knockdown (KD) reduced GLP-1 secretion and increased Gcg messenger RNA in GLUTag cells. Rosuvastatin acutely reduced postprandial GLP-1 secretion, whereas chronic rosuvastatin treatment in mice caused hyperglycemia and increased postprandial GLP-1 levels. The acute effect of Hmgcr KD on GLP-1 secretion could be mimicked by targeting intracellular cholesterol using a PCSK9 inhibitor. Finally, transcriptomic alterations induced by rosuvastatin were limited to genes involved in cholesterol biosynthesis. Conclusion We have established HMGCR as a regulator of GLP-1 secretion and provide a plausible explanation for the clinically observed mild hyperglycemia associated with statin use. Given the negative acute effect on GLP-1 secretion, monitoring of blood glucose levels is recommended after prescribing rosuvastatin.

AIMS:We aimed to (i) investigate associations between leisure time physical activity level cumulated over 20 years and multiple plasma proteins and (ii) explore if proteins significantly associated with physical activity are also associated with risk of imminent myocardial infarction (MI), long-term MI, and mortality. METHODS AND RESULTS:In the cohort Uppsala Longitudinal Study of Adult Men, leisure time physical activity was self-reported at Ages 50, 60, and 70. At Age 70, 720 plasma proteins were analysed in 782 participants with up to 19.3 years of follow-up for MI and 26.3 years follow-up for mortality. In the nested case-cohort study Markers of Imminent Myocardial Infarction, plasma proteins were measured in disease-free individuals from six European cohorts. Cases (n = 420) were those with acute MI within 6 months of a blood draw, with up to four cohort representatives per case (n = 1598). A higher level of leisure time physical activity level was inversely associated with 12 plasma proteins after adjusting for age, education, smoking, and established cardiovascular risk factors (Bonferroni-corrected P < 0.000069). Of these 12 proteins, interleukin-6 was associated with increased incidence of imminent MI [hazard ratio, HR 1.22; 95% confidence interval, CI (1.09-1.37)], tumour necrosis factor receptor superfamily member 11A was associated with increased long-term MI incidence [HR 1.22 (1.01-1.48)] and 11 proteins were associated with increased mortality [HR 1.14-1.30 (1.01-1.42)]. CONCLUSION:These findings confirm and extend our understanding of how physical activity could assert its beneficial effect on cardiovascular health through proteins involved with modulating inflammatory, immune, and metabolic pathways. Further research is needed to explore the causal mechanisms behind these associations. LAY SUMMARY:In this study, we aimed to investigate (i) whether leisure time physical activity level cumulated over 20 years is associated with 720 plasma proteins and (ii) if proteins that are significantly associated with leisure time physical activity level across 20 years in Part 1 are also associated with imminent and long-term risk of myocardial infarction (MI) and mortality.Higher physical activity level over 20 years was inversely associated with 12 plasma proteins involved in inflammatory, immune, and metabolic processes. Several plasma proteins were in turn associated with MI and mortality.Findings confirm and extend our understanding how physical activity could assert its beneficial effect on cardiovascular health via the circulating plasma proteins.

AIMS:Diagnosing heart failure with preserved ejection fraction (HFpEF) remains challenging, particularly in older individuals. We hypothesized that machine learning (ML) approaches could improve diagnostic accuracy compared with HFpEF scores. METHODS:We evaluated the diagnostic performance of four supervised ML algorithms (random forest [RF], extreme gradient boosting [XGBoost], support vector machines, and decision trees) to identify HFpEF in individuals aged 60 to 80 years. The models were trained on three derivation cohorts (N = 1474; HFpEF: KaRen, MEDIA cohorts; community-based without HF: Malmö Preventive Project) and validated in two independent cohorts (N = 542; HFpEF: HF-Nancy cohort; community-based without HF: STANISLAS cohort). Performance metrics included accuracy, F-measure, area under the receiver operating characteristic curve (AUC), and C-index. ML models were also compared with HFA-PEFF, H2FPEF, and HFpEF-ABA scores. RESULTS:Among 2017 participants, RF and XGBoost demonstrated the highest diagnostic value, outperforming traditional HFpEF scores (AUC: RF, 0.98; XGBoost, 0.96; HFA-PEFF, 0.86; H2FPEF, 0.79). RF and XGBoost also showed the greatest gain in discriminative capacity among ML algorithms when compared with H2FPEF (ΔC-index: RF +0.20, XGBoost +0.18), HFA-PEFF (ΔC-index: RF +0.12, XGBoost +0.10), and HFpEF-ABA score (ΔC-index: RF +0.17, XGBoost +0.15). Elevated natriuretic peptides were by far the most influential feature in both RF and XGBoost models (36% of model explainability). CONCLUSIONS:Machine learning algorithms, particularly RF and XGBoost, demonstrated superior diagnostic accuracy compared to established HFpEF scoring systems. These findings support the potential integration of ML-based tools into clinical workflows to facilitate earlier identification of HFpEF and prompt initiation of guideline-recommended therapies.

BackgroundVentricular–arterial coupling (VAC) integrates cardiac and vascular function and has emerged as a relevant marker of cardiovascular efficiency and adaptability. Exercise and physical activity are believed to influence VAC through multiple physiological pathways, yet the scope, methods, and consistency of available evidence remain unclear.ObjectiveTo map and characterize the existing evidence on the relationship between exercise, physical activity, and VAC across male adult populations, assessment methods, and study designs.MethodsA scoping review was conducted in accordance with JBI methodology and reported following PRISMA-ScR guidelines. Studies published between 1990 and 2025 were identified through PubMed, Scopus, Web of Science, and the Cochrane Library. Eligible studies examined VAC in male adults in relation to exercise or physical activity using invasive or non-invasive methods. Consistent with scoping review methodology, diverse study designs were included, and no formal risk-of-bias assessment was performed.ResultsEleven studies involving 2,229 participants were included. Evidence encompassed interventional, observational, and methodological studies conducted in male healthy adults, athletes, older individuals, and populations with cardiovascular risk. VAC was assessed using multiple approaches, most commonly the arterial elastance/end-systolic elastance (Ea/Ees) ratio and pulse wave velocity/global longitudinal strain (PWV/GLS). Exercise exposure ranged from acute stress testing to structured training and lifelong physical activity. Substantial heterogeneity was observed in study designs, exercise contexts, and VAC measurement techniques. Across studies, physically active and endurance-trained individuals demonstrated preserved or optimised VAC, with aerobic exercise associated with improved ventricular efficiency and reduced arterial load, while VAC remained relatively stable during acute haemodynamic stress.ConclusionsThe literature relating exercise and VAC is conceptually and methodologically heterogeneous. Available evidence suggests that aerobic exercise and sustained physical activity are associated with preserved or favourable VAC profiles across male adult populations; however, causal inferences remain limited. This scoping review highlights important methodological gaps and provides a framework to guide future mechanistic and longitudinal research.

Smoking increases the risk of type 2 diabetes, but its role in autoimmune diabetes remains unclear. We investigated whether smoking is associated with being GAD65 autoantibody (GAD65Ab) positive or the risk of progressing to diabetes. We also assessed its interaction with genetic susceptibility to type 1 diabetes. We used data from the EPIC-InterAct case–cohort study including 11,161 incident cases of adult-onset diabetes and 14,922 subcohort participants. Logistic regression was used to estimate odds ratios (ORs) for being GAD65Ab positive at baseline by smoking status. Hazard ratios (HRs) of diabetes by baseline smoking and GAD65Ab status were estimated using Prentice-weighted Cox regression. Two- and three-way interactions between smoking, GAD65Ab status and a type 1 diabetes genetic risk score (T1D-GRS) were assessed by attributable proportion due to interaction (AP). There was no evidence that smoking was associated with being GAD65Ab positive (OR 1.00, 95

Atherosclerosis develops over many years and its underlying mechanisms are still not fully understood. Plasma metabolomics across the different stages of development may help identify biomarkers that clarify disease pathways and improve early risk assessment. We performed untargeted plasma metabolomics using ultra-performance liquid chromatography-mass spectrometry in 8,146 participants without cardiovascular disease from the population-based SCAPIS cohort. Associations of 1,171 circulating metabolites with subclinical coronary atherosclerosis burden, assessed using coronary computed tomography angiography and quantified by segment involvement score, were assessed using multivariable models. Metabolites associated with coronary atherosclerosis were then evaluated in independent cohorts representing later stages of the atherosclerotic disease continuum: imminent myocardial infarction (MIMI, n=2,018), and coronary plaque burden and vulnerability in myocardial infarction survivors (PROSPECT II, n=898). Twelve metabolites, including phosphate, malate, sphingomyelins, amino acids, and one uncharacterized feature, were robustly associated with subclinical coronary atherosclerosis independent of traditional risk factors. Notably, sphingomyelins showed inverse associations with subclinical atherosclerosis, imminent myocardial infarction, and the presence of vulnerable plaques. Malate, N-acetyl-isoputreanine and an uncharacterized molecule (X-25790) were positively associated with subclinical coronary atherosclerosis and with imminent myocardial infarctions. These findings reveal a metabolomic signature across the atherosclerosis continuum, highlighting candidate biomarkers that may enhance understanding of disease mechanisms and aid risk stratification.

Abstract Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in Type 1 Diabetes (T1D), but a subset of individuals remains free from macrovascular or renal complications despite decades of hyperglycaemia and a significant risk factor burden. We used a targeted proteomic approach (Olink Cardiovascular panel III, targeting 92 proteins) to characterize the proteomic profile of cardiovascular resilience in T1D by comparing 92 patients with long-standing T1D (age 59.8 [53.2, 69.1], duration 40.0 [35.0, 45.2] years) free from macrovascular complications or nephropathy against a reference group of 57 T1D patients with accelerated vascular pathology (age 42.0 [32.0, 56.0], duration 22.0 [18.0, 27.0] years), proliferative retinopathy and/or nephropathy in relation to diabetes duration, termed Rapid Progressors (RP). Twenty proteins differed significantly between RP and Escapers (False Discovery Rate [FDR] < 0.05) after adjustment for age, sex, HbA1c, and eGFR: Caspase-3 was significantly higher in RP (Adjusted difference: + 2.12 Normalized Protein eXpression [NPX], p < 0.001). Proteins associated with platelet activation and leukocyte adhesion with increased levels in RP included Junctional Adhesion Molecule A (+ 1.40 NPX), Glycoprotein VI (GP6: + 1.29 NPX), and P-Selectin (+ 0.82 NPX) (all p < 0.001). PECAM-1 (+ 0.55 NPX) and TNFRSF14 (+ 0.43 NPX), were also elevated. RP also showed higher levels of metabolic and tissue-remodelling proteins; Transferrin Receptor (+ 0.53 NPX) and Fatty Acid Binding Protein 4 (+ 0.52 NPX), as well as higher Bleomycin Hydrolase, Trefoil Factor 3, GDF-15, U-PAR, and Cystatin B. Conversely, von Willebrand Factor (vWF) levels (− 1.35 NPX, p < 0.001) and Paraoxonase 3 (PON3) was lower in RP (− 0.34 NPX, p = 0.003). In conclusion, escaping complications in long-term T1D appears to be associated with active molecular mechanisms. Progression is marked by apoptosis (Caspase-3), fibrosis (CHI3L1) and platelet activation (GP6), whereas resilience is associated with a distinct signature involving higher vWF and PON3. These findings highlight a profound biological divergence between extreme T1D phenotypes and provide a foundation for further research into vascular resilience.

Heart failure (HF) and arterial hypertension (AH) are strongly associated with obesity, with a linear relationship to increasing body mass index (BMI). However, some individuals with obesity do not exhibit signs of HF or AH. This study aimed to compare, for the first time in a large population-based cohort, individuals with obesity who have normal left ventricular function and remodeling (LVFR) and no AH (ObNI) with those who have impaired LVFR or AH (ObI), and corresponding individuals without obesity (NObNI and NObI). A cross-sectional analysis was performed on 4 435 participants from the Swedish CArdioPulmonary bioImage Study (SCAPIS). Participants were grouped into four categories: (1) ObNI (n = 586), (2) ObI (n = 224), (3) NObNI (n = 3 041), and (4) NObI (n = 584). Descriptive analyses compared individuals with obesity with normal LVFR and no AH (ObNI) to the other three groups. Although no significant differences between the two subgroups with obesity could be seen regarding BMI (33.1 vs. 33.5 kg/m2, p = 0.095), there was significant differences in coronary artery calcification score (CACS) levels, where ObNI participants were more prone to show no or very low CACS in comparison with ObI participants (p < 0.001). Also compared to ObI participants, ObNI individuals had lower levels of HbA1c, fasting plasma glucose, triglycerides, and troponin I (all p < 0.001). Furthermore, significant differences were observed between the two groups regarding sedentary behavior (p = 0.041), where ObNI subjects showed a more active lifestyle. Compared with ObNI, individuals with ObI exhibited a higher left ventricular mass index (LVMI; p < 0.001) and lower diastolic function parameters (p < 0.001), while left ventricular ejection fraction (EF) did not differ significantly (p = 0.27). Relative to NObNI, ObNI participants demonstrated increased LVMI (p = 0.007), lower EF (p < 0.001), and impaired diastolic function (p < 0.001). Coronary artery calcification scores (CACS) were higher in ObI than in ObNI (p < 0.001), and ObNI also showed higher CACS than NObNI (p = 0.008). ObNI participants had lower CACS levels, more favorable metabolic profiles, better cardiac function, and greater physical activity than ObI individuals. However, compared to NObNI, they showed higher CACS, increased left ventricular mass, and reduced cardiac function, highlighting distinct cardiovascular risks across obesity phenotypes.

Rare coding genetic variants may exert large effects on risk of common disease, yet their contribution to disease architecture and their utility in gene prioritization remain limited by inadequate sample sizes. Here, we performed a massive-scale rare variant association study (RVAS), analyzing over 1.1 million sequenced participants among which 130,000 had atrial fibrillation (AF). Through a multi-mask burden testing approach, we identified 15 genes significantly associated with AF through rare large-effect variation. Integrative analyses revealed strong convergence between genes implicated by rare and common variation, and highlighted instances where RVAS data may aid in GWAS prioritization. Nevertheless, several RVAS genes were not among GWAS loci ( FAM189A2 , ACTC1 , FNIP1 , FBN1 ), or were not nominated through contemporary GWAS prioritization ( KDM5B , ZFP36L2 ). Finally, we observed that ultra-rare protein-disrupting variants - concentrated in a small number of large-effect size genes - explained at least 2% of AF susceptibility across European and African ancestry groups. These findings refine the genetic architecture of AF, while highlighting the value and cost of RVAS for genomic discovery in common disease.

Context Melatonin regulates circadian rhythms and influences glucose metabolism. Altered melatonin secretion may contribute to the pathogenesis of type 2 diabetes (T2D), but prospective population-based evidence is scarce. Objective To examine whether low nocturnal melatonin secretion is associated with an increased risk of incident T2D in adults. Methods This prospective cohort study, with follow-up from 2013 to 2023 (median 6.5 years), included a total of 4491 adults (52% women, aged 18-75 years) without T2D and melatonin supplementation at baseline, from the Malmö Offspring Study, a population-based cohort in southern Sweden. Incident T2D was identified via national and regional health registers. Nocturnal melatonin secretion was assessed as the urinary 6-sulfatoxymelatonin-to-creatinine ratio (aMT6s/Cr) from first-morning urine samples, categorized into sex-specific quintiles. Results During follow-up, 171 participants developed T2D. Participants in the lowest quintile of aMT6s/Cr had a higher T2D risk than those in quintiles 2 to 5 (multivariable adjusted hazard ratio [HR] 1.51, 95% CI 1.09-2.09). The association remained significant after additional adjustment for sleep duration and disruption (HR 1.54, 95% CI 1.11-2.13). When analyzing T2D development per 1-SD higher sex-standardized log aMT6s/Cr, the HR was 0.84 (95% CI 0.73-0.97). Associations were consistent across sex, age, and BMI subgroups. Conclusion Low nocturnal melatonin secretion was independently associated with a higher incidence of T2D in adults. A key limitation is the reliance on a single morning urine sample to estimate melatonin secretion. The findings support circadian regulation as a determinant of metabolic health and warrant further investigation of melatonin pathways in diabetes prevention.

Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls. In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B. We further identified associations between AF and rare structural variants owing to deletions in CTNNA3 and duplications of GATA4. We broadly replicated our findings in independent samples from MyCode, deCODE and UK Biobank. Finally, we found that CRISPR knockout of KDM5B in stem-cell-derived atrial cardiomyocytes led to a shortening of the action potential duration and widespread transcriptomic dysregulation of genes relevant to atrial homeostasis and conduction. Our results highlight the contribution of rare coding and structural variants to AF, including genetic links between AF and cardiomyopathies, and expand our understanding of the rare variant architecture for this common arrhythmia.