European Journal of Preventive Cardiology

BackgroundSex hormone alterations, such as estrogen deficiency or testosterone excess, substantially increase cardiovascular disease (CVD) risk in females. Dietary fibre and its microbial by-products, short-chain fatty acids (SCFAs), have cardioprotective effects, but it remains unclear whether these benefits extend to females with an altered sex hormone profile. In this study, we aim to investigate whether dietary fibre intake, measured via plasma acetate--the most abundant SCFA--is associated with improved cardiovascular outcomes in females with altered sex hormone profiles. MethodsThis cohort study included 116,235 female participants from the UK Biobank and Biobank Japan with up to 10 years of follow-up. We analysed early menopause (as a surrogate for estrogen insufficiency) and plasma free testosterone (in a subset). The primary outcome was major adverse cardiovascular events (MACE). Secondary outcomes were blood pressure. Proteomics analyses explored potential mechanisms. ResultsAcetate levels were associated with lower 10-year MACE incidence (-0.618/1000 woman-year, HR=0.900, p=0.002) and systolic blood pressure (-0.231 mmHg per 1 SD, p<0.001) in the UK Biobank. High acetate levels attenuated the increased MACE risk associated with early menopause (HR=1.158, p=0.057) compared with low acetate (HR=1.425, p<0.001), with similar patterns replicated in Biobank Japan (high: HR=1.322, p=0.090; low: HR=1.385, p=0.042). Proteomics analyses suggested a mechanism involving pro-inflammatory proteins. Moreover, high acetate levels attenuated the increased MACE associated with elevated free testosterone in the UK Biobank (high: HR=1.238, p=0.024; low: HR=1.056, p=0.666). A significant interaction between acetate and free testosterone on systolic blood pressure indicated that the effect of rising testosterone on blunting acetates effect ({beta}=0.167, 95% CI: [5.212x10-2-2.818x10-1], p=0.004) was partially mediated by central obesity (waist-to-hip ratio). ConclusionsHigher plasma acetate levels were associated with lower cardiovascular risk, particularly in females with early menopause or elevated free testosterone, potentially via inflammatory pathways. These findings underscore the importance of hormonal context in shaping cardiometabolic resilience and support personalised CVD prevention strategies for females with altered sex hormone profiles, including increasing dietary fibre intake.

Background and AimSedentary lifestyle and obesity are considered to be significant risk factors that create a pathway for the appearance of the sedentary cardiac phenotype consisting of cardiac atrophy, myocardial stiffening, and altered haemodynamics. Although exercise training has the potential to reverse this detrimental process, the literature data on the magnitude of improvements and the certainty of evidence are inconsistent. This systematic review and meta-analysis aimed to evaluate the effects of exercise interventions on cardiac morphology, systolic/diastolic function, and haemodynamics in sedentary and obesity-prone individuals. MethodIn accordance with the PRISMA guidelines, the study was conducted by searching the PubMed, Web of Science, and Scopus databases from 1990 to 2025 without applying any filters, using Covidence software. As a result of this comprehensive search, 15 randomised controlled trials (RCTs; N=559) comparing exercise training with a control group in sedentary individuals were included in the analysis. Data were pooled using the Standardised Mean Difference (SMD) and a random-effects model. Publication bias and methodological robustness of the results were tested using the Egger regression test, the Trim-and-Fill method, and Leave-One-Out sensitivity analysis. The certainty of the evidence was graded using the GRADE system. ResultsExercise training was associated with a significant reduction in resting HRs and SBPs, which was a strong improvement in the haemodynamic profile. The improvements in SV and LVEF, although on the statistical threshold in the primary analysis, were statistically significant and methodologically stable in the Leave-One-Out sensitivity analysis, which excluded confounding studies. The exercise training was associated with a marked improvement in the E/A ratio and S wave, and the triggering of a physiological athletes heart-like eccentric hypertrophy, defined by improvements in LVMass and LVEDV. The exercise training was associated with diastolic adaptation and mass increase, with HIIT being the most superior method for diastolic adaptation and mass increase, and aerobic exercise being the most effective method for blood pressure reduction. Importantly, the meta-regression analyses revealed two important findings: first, the improvement in blood pressure and diastolic function was independent of weight loss; second, the improvement in structure and function was linearly related to improvements in body composition. ConclusionExercise acts as a cardiac polypill reversing the sedentary phenotype by improving hemodynamics and diastolic function independently of weight loss, while linking structural remodeling to BMI optimization; our data prioritize HIIT for structural/diastolic gains and Aerobic training for blood pressure control.

BackgroundInflammation plays a key role in atrial fibrillation (AF) pathogenesis. The empirical dietary inflammatory potential (EDIP) score predicts circulating inflammatory biomarkers and adverse cardiac outcomes, but its association with incident AF is unclear. This study aimed to examine the relationship between EDIP score and AF risk. MethodsParticipants from the Atherosclerosis Risk in Communities (ARIC) free of baseline AF who completed a validated food frequency questionnaire were included. Correlation of EDIP with inflammatory biomarkers (factor VIII, fibrinogen, von Willebrand factor, and C-reactive protein) was examined at baseline. Incident AF was ascertained using electrocardiograms, hospital records, and death certificates. Cox proportional hazards models estimated hazard ratios of AF across EDIP quantiles and per SD increase, adjusting for sociodemographic and cardiovascular risk factors. ResultsAmong 8,277 participants (54.1 years old, 51.3% women, 80% white), higher EDIP score correlated with circulating inflammatory biomarkers at baseline. Over a median 24.2 years of follow-up, 1,453 had incident AF (incident rate 8.6 per 1,000 person-years). Compared with the most anti-inflammatory diet (EDIP Q1), the most pro-inflammatory diet (EDIP Q5) was associated with increased AF risk (HR 1.21; 95% CI 1.03-1.43). Sex-stratified analyses showed a stronger association in men (HR 1.43; 95% CI 1.14-1.79), while no significant association was observed in women. ConclusionsPro-inflammatory dietary patterns are independently associated with higher AF risk in a middle-aged cohort. These findings would support incorporating dietary inflammatory load into AF risk stratification. Clinical Perspective What Is New?O_LIHigher Empirical Dietary Inflammatory Potential (EDIP) scores, indicating a more pro inflammatory diet, were associated with an increased long-term risk of atrial fibrillation (AF) in a large, biracial, community-based cohort followed for over two decades. C_LIO_LISex stratified analyses revealed a significant sex difference: higher EDIP scores were consistently associated with increased AF risk in men, whereas no significant association was observed in women, suggesting sex-specific susceptibility to EDIP. C_LIO_LIObesity modified the association between EDIP and AF, with the strongest risk observed among individuals with BMI [&ge;]30, while an inverse or attenuated association was seen among normal weight participants. C_LI What Are the Clinical Implications?O_LIDietary inflammatory load may serve as a meaningful and modifiable upstream AF risk factor, complementing conventional cardiovascular risk assessment, particularly in men and individuals with obesity. C_LIO_LIIncorporating dietary pattern assessment into routine AF risk stratification may help identify individuals who could benefit most from targeted lifestyle interventions. C_LIO_LIPublic health and clinical prevention strategies promoting anti-inflammatory dietary patterns (e.g., increased intake of fruits, vegetables, and whole grains; reduced intake of processed meats and refined carbohydrates) could meaningfully reduce AF incidence. C_LIO_LIRecognition of sex specific differences in AF pathways reinforces the need for personalized preventive strategies, as diet inflammation mechanisms appear to influence AF development more prominently in men. C_LI

BackgroundVitamin D supplementation has been investigated for potential associations with cardiometabolic risk factors related to cardiovascular disease (CVD); however, findings from randomized controlled trials (RCTs) remain inconsistent. This meta-analysis aimed to assess the effects of vitamin D supplementation on cardiometabolic risk factors--including lipid profile, blood pressure, and glycaemic parameters--and to explore whether age and baseline serum vitamin D concentrations modify these associations. Research Design and MethodsWe conducted a systematic review and meta-analysis of RCTs comparing oral vitamin D supplementation with placebo in adults. PubMed, the Cochrane Library, and ClinicalTrials.gov. Risk of bias was evaluated using the Cochrane tool, and pooled effect sizes with 95% confidence intervals (CIs) were calculated using random-effects models. Results14,051 abstracts were retrieved, of which 45 were used for data analysis. Vitamin D supplementation reduced low-density lipoprotein cholesterol (LDL-C) by 0.136 mmol/L (95%CI: -0.215, -0.56), systolic blood pressure by 2.79 mm Hg (95% CI: -4.648, -0.938), fasting blood glucose by -0.11 (95%CI:-0.185, -0.036), and hemoglobin A1c by 0.164% (95%CI: -0.322, -0.006) compared with placebo. Subgroup analyses revealed reductions in SBP and LDL cholesterol among participants aged [&ge;]55 years and reductions in fasting blood glucose in participants with age < 55 years. While favourable effects on fasting blood glucose and hemoglobin A1c were observed with a baseline blood level of vitamin D of concentrations (<50 nmol/L). ConclusionsVitamin D supplementation may be associated with modest modifications in selected cardiometabolic risk factors; including systolic blood pressure, LDL-cholesterol, fasting blood glucose, and hemoglobin A1c. Age and baseline vitamin D status appear to modulate these effects. The clinical relevance of these modest effects remains uncertain. Well-designed RCTs with standardized protocols are required to clarify potential effect modification by age and baseline vitamin D status. Trial RegistrationPROSPERO (CRD42020165293) FundingThis research received funding from the Hashemite University, P.O. Box 330127, Zarqa 13133, Jordan

We performed a systematic review and meta-analysis of randomized controlled trials evaluating glucagon-like peptide-1 receptor agonists (GLP-1 RAs) versus placebo in adults with heart failure (HF), searching PubMed, Cochrane CENTRAL, and ClinicalTrials.gov through February 2026. The primary outcome was the composite of cardiovascular death and first HF hospitalization. Random-effects meta-analysis used restricted maximum likelihood estimation with Hartung-Knapp-Sidik-Jonkman adjustment. We included 14 studies (6 dedicated HF trials and 8 cardiovascular outcomes trial HF subgroup analyses) encompassing 18,558 patients, of whom 2,499 were randomized in dedicated HF trials. The primary composite did not reach statistical significance (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.73-1.01; P=0.067; I2=47%). GLP-1 RAs significantly reduced all-cause mortality (HR 0.87, 95% CI 0.81-0.93; P<0.001; I2=0%), major adverse cardiovascular events (HR 0.83, 95% CI 0.73-0.95; P=0.019), and improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (+7.4 points, 95% CI 6.3-8.5) and 6-minute walk distance (+17.6 m, 95% CI 13.4-21.7). Excluding the FIGHT trial (acute HFrEF) yielded a significant primary composite (HR 0.83, P=0.011). The mortality signal was driven primarily by CVOT subgroups; the largest dedicated HFpEF trial (SUMMIT) showed numerically higher mortality (HR 1.25). The strongest evidence supports GLP-1 RAs in HFpEF with obesity. HighlightsO_LIPrimary composite of CV death + HHF was not significant (HR 0.86, P=0.067) C_LIO_LIGLP-1 RAs reduced all-cause mortality (HR 0.87) with no heterogeneity C_LIO_LIKCCQ-CSS improved by 7.4 points and 6MWD by 17.6 m in HFpEF trials C_LIO_LIMortality benefit driven by CVOT subgroups, not dedicated HF trials C_LIO_LIStrongest evidence supports GLP-1 RAs in HFpEF with obesity C_LI

BackgroundLong-term electrocardiogram (ECG) monitoring with wearable devices enables large-scale characterisation of cardiac rhythms, but population-based evidence remains limited. The UK Biobank Cardiac Monitoring Study integrates 14-day patch-based ECG monitoring with accelerometry and detailed phenotypic and lifestyle data. Here, we report the acquisition protocol, data processing, and initial findings from 27,658 participants. MethodsParticipants in the UK Biobank imaging study were invited to undergo 14-day cardiac monitoring using a Zio XT (pilot phase; 2015-18) or BodyGuardian MINI (main phase; 2019- ongoing) monitor. ECGs were analysed by certified technicians and automated algorithms to identify atrial, ventricular, and conduction arrhythmias. In parallel, beat-to-beat RR intervals were derived using in-house algorithms, and physical activity from calibrated triaxial accelerometer data. Analyses assessed wear time, arrhythmia prevalence, circadian patterns, and repeatability. FindingsIn total, 27,658 participants (mean age 71 years; 49.9% women) were analysed, including 7,795 from the pilot phase and 21,141 from the main phase; 1,353 (4.9%) had repeat recordings. In the main phase, median wear time was 13.2 days (IQR 11.9-13.9), and undiagnosed atrial fibrillation (AF) was detected more frequently in men than women (3.2% vs 1.7%; p<0.001); 68% was paroxysmal, with 27.4% detected during week two. Ventricular tachycardia occurred in 12.1% (8.4% in women), with sustained episodes rare (0.4%) but observed. Arrhythmia timing varied markedly with activity, with AF peaking during nocturnal inactivity and ventricular ectopy increasing during activity, peaking at midday. Repeat assessments showed strong reproducibility of diurnal heart rate and activity profiles, with more modest arrhythmia consistency. InterpretationExtended ECG monitoring enables detection of subclinical arrhythmias and long-term physiological rhythms in older adults. Linkage to imaging, multi-omics, and clinical outcomes in UK Biobank will enable unprecedented evaluation of the natural history of asymptomatic rhythm disturbances and their impact on brain health. FundingBritish Heart Foundation and Wellcome Trust.

BackgroundKetone bodies have shown potential to improve cardiac metabolism and function in patients with heart failure (HF). ObjectiveTo evaluate the effects of exogenous ketone-based interventions on cardiac function in patients with HF or related cardiometabolic risk factors. MethodsWe conducted a systematic review based on a search of MEDLINE, EMBASE, CINAHL, Cochrane Library, and Scopus from inception to January 2025. Eligible studies included randomized controlled trials evaluating exogenous ketones (oral ketones or ketone infusions) compared to placebo in adults with HF or patients with risk factors for HF including type 2 diabetes mellitus, hypertension, or coronary artery disease. Paired reviewers independently screened and identified hits at title-and-abstract and full-text levels to determine eligibility and extracted data from eligible studies. Random-effects meta-analysis was performed. Effects of interventions were summarized as mean differences (MD). Risk of bias was assessed using Cochrane RoB 2.0 tool. Certainty of evidence was evaluated using the GRADE (grading of recommendations assessment, development and evaluation) approach. ResultsOut of 565 unique records, 22 full-text articles were reviewed, and 8 studies met inclusion criteria. Exogenous ketone administration increased left ventricular ejection fraction (LVEF) (MD = 3.94, 95% CI 2.18-5.70, p = 0.001), cardiac output (CO) (MD = 1.11 L/min, 95% CI 0.55-1.67, p = 0.002), heart rate (4.85 bpm, 95% CI 2.24-7.46, p = 0.003), and stroke volume (SV) (MD = 10.21 mL, 95% CI 4.06-16.35, p = 0.005). Pulmonary capillary wedge pressure (PCWP) decreased (MD = -0.93 mmHg, 95% CI -1.44 to -0.43, p = 0.003), while mean arterial pressure showed no change (MD = -1.37 mmHg, 95% CI -3.53 to 0.79, p = 0.18). ConclusionsExogenous ketone-based therapies are associated with improvements in hemodynamic markers of cardiac function, including increases in LVEF, CO, and SV, along with a reduction in PCWP. These findings suggest that ketone supplementation may offer clinical benefits for patients with HF or vascular disease.

BackgroundMetabolic vulnerability index (MVX), a novel biomarker of systemic inflammation and metabolic malnutrition, is associated with mortality in patients with cardiovascular diseases. Nevertheless, little is known about its association with cardiometabolic diseases (CMDs) and multimorbidity (CMM). We aimed to examine the associations of MVX with the risk of individual CMDs, their progression to CMM, and all-cause mortality in the general population. MethodsIn a prospective cohort of 218,635 UK Biobank participants free of CMDs, MVX was calculated based on plasma metabolomics data. CMM was defined as coexistence of two or more CMDs, including coronary heart disease (CHD), stroke, and type 2 diabetes mellitus (T2DM). Cox proportional hazard and multi-state models were employed to evaluate the associations of MVX with the risks of individual CMDs, CMM, and all-cause mortality. ResultsDuring a median follow-up of 14.4 years, 27,805 (12.7%) participants developed at least one CMD, 3,006 (1.4%) progressed to CMM, and 14,211 (6.5%) died. Each standard deviation increase of MVX score was associated with 9% (95% confidence interval: 8%-10%), 11% (7%-15%), and 12% (10%-14%) higher risks of developing CMDs, CMM, and mortality, respectively. The MVX-CMM associations were more prominent in females and in the sequential onset pattern of T2DM followed by CHD or stroke. Multi-state model analysis further uncovered consistent associations between higher scores of MVX and higher risks of transitions from CMDs free to CMD, subsequently to CMM, and to death. ConclusionsHigher MVX scores were significantly associated with higher risks of incident CMDs, their progressions to CMM, and all-cause mortality. These results underscored the potential of MVX in the primary prevention and management of CMDs and CMM.

BackgroundInhaled combusted cannabis and co-use of combusted cannabis and nicotine electronic cigarettes (nECIGs) are on the rise, yet their long-term cardiovascular risk is unclear due to the high prevalence of confounders in observational human studies. Using primary plasma and monocytes and a novel ex vivo mechanistic model of two early steps in atherogenesis, this study examined whether chronic combusted cannabis use is associated with atherogenic changes, as estimated by 1) monocyte transendothelial migration (MTEM), and 2) monocyte-derived foam cell formation (MDFCF), and whether nECIG co-use further amplifies this risk. MethodsA cross-sectional parallel group comparison study was conducted in healthy adults (21-30 years) who chronically 1) used combusted cannabis, 2) co-used both combusted cannabis and nECIGs, and 3) were non-using controls. Using our ex vivo atherogenesis assay, primary outcomes of MTEM, MDFCF, and median fluorescence intensity (MFI) of the lipid-staining fluorochrome BODIPY were determined using primary plasma and autologous primary monocytes from participants. Using flow cytometry and the fluorochrome CELLROX, cellular oxidative stress (COS) in monocytes was determined. ResultsOf the 134 participants, 59 used cannabis, 26 co-used cannabis/nECIG, and 49 were non-using controls. The groups had similar age, sex, and race. Median MTEM was 1.13 fold greater in people who used cannabis compared to non-users 27.8% (IQR 26.1:29.2%) vs 24.5%, (IQR 22.9:27.4%), p<0.0001, and tended to be greater in people who co-used cannabis/nECIG by 1.22-fold 34.1%, (IQR 29.9:38.3%, p=0.17). Median MDFCF and MFI were also increased in people who used cannabis compared to non-users (MDFCF 36.3%, IQR 31.8:35.8%, vs 26.6%, IQR 23.8:25.8%, 1.36-fold and MFI 1163.8, IQR 1042.8:1155.0, vs 940.2 IQR 849.9:1101.4, 1.24-fold) and were further increased in people who co-used cannabis/nECIG (MDFCF 48.7%, IQR 37.3:52.4%, 1.34-fold, MFI 1433.7, IQR 1263.8:1686.4, 1.23-fold; all comparisons p<0.008). Foam cell formation, but not transendothelial migration, was strongly positively correlated with COS. All primary outcomes increased with greater frequency of cannabis and/or nECIG use. ConclusionsIn healthy young adults, exclusive cannabis use is associated with increased atherogenic properties of monocytes and plasma, and this atherogenic effect is further amplified by co-use of nECIGs.

Abstract Introduction Cardiovascular disease (CVD) is an important complication of type 2 diabetes (T2D). Current incident CVD-prediction models use single baseline measurements and achieve moderate performance in people with T2D, with C-indices around 0.7. Modern healthcare registries contain repeated measurements of HbA1c, LDL-cholesterol and eGFR, which could carry incremental predictive value. However, the added value of trajectory measures for CVD-risk prediction remains unclear. We aimed to investigate the utility of HbA1c, LDL-cholesterol and eGFR trajectory measures for incident CVD-risk prediction in people with T2D. Methods We studied 83,326 people with T2D from Danish nation-wide registers, who were without a CVD-history at baseline (January 1st 2015), and had [&ge;]2 recorded HbA1c, LDL-cholesterol and eGFR measurements between 2012-2014. Their last measurement was considered as baseline. Across 2012-2014, three types of paired trajectory measures were calculated for each participant (mean & standard deviation (SD), median & interquartile range (IQR), and intercept & slope from a fitted growth model), for HbA1c, LDL-cholesterol, and eGFR, respectively. Reference Cox-regression models for CVD-events (ICD-10 codes assessed prospectively from 2015- 2020) included only baseline measurements (age, sex , age at T2D onset, HbA1c, LDL-cholesterol, HDL-cholesterol, eGFR, and medication use). Next, the paired trajectory measures were sequentially added to the reference model, computing Hazard Ratios, C-indices and Net reclassification index (NRI) with 95% confidence intervals. Lastly, a combined model was fitted. Results At baseline, mean age was 65 (SD{+/-}12), median HbA1c was 48 (mmol/mol, IQR43-56), and 48% were female. During a median 6 years of follow-up 11,280 (14%) people had a CVD-event (ischemic heart disease: 40%; stroke: 32%; heart failure: 24%; CVD-mortality: 5%). Accounting for the reference model, trajectory measures of dispersion and change were associated with CVD-events, with hazard ratios {approx} 1.1 for HbA1c and eGFR, and >1.4 for LDL-cholesterol. Measures centrality did not show an association with CVD events. Addition of trajectory measures produced minimal gains in discrimination (C index {Delta} +0.001-+0.003) but modest improvements in net reclassification (continuous NRI {approx} +3-+9%). Conclusions Trajectory dispersion or change measures for HbA1c, eGFR and especially LDL-cholesterol, easily obtained from routine data, might moderately enhance incident CVD-risk prediction in people with T2D.

Societies are aging rapidly in parallel with the increasingly earlier onset of serious diseases in younger populations. These and other factors are creating a substantial disparity between healthspan, the period of life where an individual is free from serious chronic disease or disability, and lifespan -- expanding the morbidity span. Extending healthspan has thus become a major priority. To pursue an integrated strategy toward healthspan support, we launched DELTA, a prospective, open-label, interventional, and participatory N=1 study (NCT06630637) conducted on a healthy individual (DELTA001, author D.H.). The study was conducted with methodological rigor to support repeatability, transparency, and balanced reporting. The core focus of the DELTA protocol was to assess and enhance human biological resilience. This was demonstrated through the subjects adaptive capacity, revealed through changes and trajectories in cardiometabolic and pleiotropic biomarker levels based upon systematically administered challenges (e.g., fasting). Specifically, the interventional DELTA protocol integrates time-restricted eating (TRE, fasting), strength and cardiovascular fitness regimens, a Mediterranean-inspired dietary protocol, and supplementation alongside an analytics and reporting framework comprised of artificial intelligence (AI), digital health, and wearables-based sleep performance monitoring, microbiome assessment, and longitudinal tracking of biomarker dynamics and performance outcomes. This study introduces new methods and metrics for assessing these biomarker dynamics, including the development of digital biomarkers that reflect dynamic human functional resilience. Findings from DELTA may actionably guide the design of larger participatory human trials to monitor biomarker resilience, design appropriate interventions for dynamic administration, and subsequently fortify healthspan at a population level.

O_FIG O_LINKSMALLFIG WIDTH=189 HEIGHT=200 SRC="FIGDIR/small/26346796v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1303a7aorg.highwire.dtl.DTLVardef@14f223forg.highwire.dtl.DTLVardef@51672eorg.highwire.dtl.DTLVardef@4d273a_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOCentral IllustrationC_FLOATNO C_FIG HIGHLIGHTSO_LIAtrial fibrillation and depression are linked via central autonomic network disruption, cardiovascular risk, and inflammation. C_LIO_LIHeightened inflammatory response and cardiovascular risk mediates the bidirectional relationship between atrial fibrillation and depression. C_LIO_LIAtrial fibrillation, depression, and their comorbidity exhibit distinct, non-additive neural and autonomic signatures. C_LI BACKGROUNDAtrial fibrillation (AF) and major depressive disorder (MDD) frequently co-occur and are each associated with adverse cardiovascular outcomes, yet the biological pathways linking these conditions remain poorly defined. Using the UK Biobank, we evaluated shared neurocardiac, inflammatory, and cardiovascular correlates underlying the AF-MDD association. OBJECTIVESTo assess bidirectional associations between AF and MDD and determine whether shared inflammatory, cardiovascular, autonomic, and neuroimaging correlates characterize their comorbidity. METHODSWe analyzed individuals with AF (N>1,716), MDD (N>4,550), comorbid AF-MDD (N>243), and healthy comparators (HCs; N>33,041). Bidirectional associations were examined using cross-sectional and Cox proportional hazard models. Mediation analyses evaluated contributions of inflammatory markers and cardiovascular risk. Central autonomic network structure and function was assessed using MRI-derived morphometry and resting-state connectivity. RESULTSAF and MDD demonstrated bidirectional associations: AF was associated with a 44% higher risk of incident MDD, and MDD with a 26% higher risk of incident AF. Inflammatory biomarkers and cardiovascular risk partially mediated these associations (6.85% and 32.01%, respectively). AF was associated with greater gray matter volume in ventromedial prefrontal and insular cortices and increased central autonomic network connectivity, whereas MDD showed opposite structural and functional patterns. The comorbid AF-MDD group exhibited distinct, non-additive neural profiles. CONCLUSIONSAF and MDD demonstrate bidirectional associations characterized by shared inflammatory, cardiovascular, and neural correlates, alongside distinct and non-additive alterations within central autonomic network circuits. These findings support a systems-level neurocardiac framework linking cardiac and psychiatric disease and highlight the importance of integrated approaches to risk assessment and multidisciplinary management in patients with AF-MDD comorbidity.

Background and AimsDespite advances in reperfusion and medical therapy, survivors of acute myocardial infarction (AMI) remain at risk for adverse left ventricular remodeling (LVR), a precursor to heart failure. Building on prior work outlining 12-month biomarker trajectories linked to early ventricular dysfunction, we aimed to assess whether these circulating biomarkers predict long-term adverse LVR. MethodsWe prospectively enrolled 155 patients experiencing their first AMI. Clinical, biochemical, and echocardiographic data were obtained at pre-percutaneous coronary intervention (pre-PCI), 24 h post-PCI, discharge (day 3), 6 months, and 12 months. Adverse LVR was defined as an increase of [&ge;]15 % in left ventricular end-systolic volume at 12 months. ResultsAdverse LVR occurred in 34 % of patients and was associated with cardiometabolic dysregulation (higher glucose, triglycerides, BMI, HOMA-IR; lower HDL-C). Among the six baseline biomarkers, only insulin-like growth factor-binding protein 2 (IGFBP-2) differed significantly between groups (p = 0.021) and remained independently associated in multivariable analysis (p = 0.036). Inclusion of IGFBP-2 increased the predictive models area under the receiver-operating characteristic curve from 0.735 to 0.801. ConclusionsIGFBP-2 is an independent predictor of adverse LVR following AMI, highlighting the interplay between metabolic dysfunction and maladaptive remodeling. Incorporating IGFBP-2 into clinical risk models could improve stratification and guide precision therapies for high-risk patients.

ObjectiveThe objective of this study was to explore the predictors of statin intolerance in the primary and secondary prevention of CVD among patients in the first two years after the date of first prescription using real-world data. MethodsThis study used the Electronic Practice Based Research Network Linked Dataset. An algorithm, which considered the muscle symptoms and creatinine kinase of patients, was used to identify statin intolerant patients. The R software was used for all analyses. Descriptive and multivariate logistic regression analyses were performed along with sensitivity analysis which was done using the Akaike Information Criterion model selection method. ResultsOverall, 4,016 patients accounting for 60,873 visits met the selection criteria. About 3.5% of the patients were statin intolerant. After adjusting for all other variables, statin intolerance was positively associated with gender (AOR 1.5, 95% CI 1.0 - 2.2), SEIFA index (AOR 3.8, 95% CI 2.3 - 6.7), employment status (AOR 2.4, 95% CI 1.1 - 5.7), and comorbidities (AOR 7.0, 95% CI 2.2 - 19.0). A similar direction of associations was seen for the exposures of the model from the sensitivity analysis and the regression model. However, since the unrecorded employment status showed a positive association, the sensitivity analysis suggests that the relationship may be influenced by residual confounding or information bias, indicating that this finding should be interpreted with caution. ConclusionStatin intolerance within the diverse community represented in the dataset is driven by gender, employment status, area-based social advantage and disadvantage index, and comorbidities.

BackgroundElevated resting heart rate (HR) and atrial cardiopathy are each linked to higher mortality risk, yet their interrelationship and joint prognostic value remain unclear. MethodsWe analyzed 7,326 adults (mean age 59 {+/-} 13 years) without cardiovascular disease from the Third National Health and Nutrition Examination Survey with available electrocardiograms. Atrial cardiopathy was defined by electrocardiogram as abnormal P-wave axis or deep terminal P-wave negativity in V1. Multivariable logistic regression assessed cross-sectional associations between HR categories and atrial cardiopathy. Cox proportional hazards models evaluated independent and joint associations of HR categories and atrial cardiopathy with all-cause mortality. ResultsAtrial cardiopathy was present in 1,833 participants (13.5%). After adjustment, sinus tachycardia ([&ge;]100 bpm) was associated with higher odds of atrial cardiopathy (OR 1.76, 95% CI 1.06-2.92), whereas sinus bradycardia ([&le;]50 bpm) was associated with lower odds (OR 0.61, 95% CI 0.43-0.84). Each 10-bpm HR increase corresponded to 25% higher odds of atrial cardiopathy. Over a median 13.8-year follow-up, 2,415 deaths (33.0%) occurred. Sinus tachycardia (HR 3.58, 95% CI 2.61-4.91) and atrial cardiopathy (HR 1.27, 95% CI 1.16-1.39) were independently associated with mortality. Individuals with both conditions had the highest risk (HR 4.11, 95% CI 2.63-6.41). Associations varied by age and race. ConclusionsElevated resting HR is associated with higher odds of atrial cardiopathy, and their coexistence confers markedly increased mortality risk. Integrating resting HR into atrial cardiopathy metrics may enable granular population-level risk profiling.

BackgroundScreening for atherosclerosis focuses on identifying Standard Modifiable Risk Factors (SMuRFs), including diabetes, hypertension, hyperlipidaemia, and smoking. PurposeTo compare the extracardiac thoracoabdominal atherosclerotic plaque burden, as measured by computed tomography angiography (CTA), among heart transplant candidates with ischemic or non-ischemic cardiomyopathy (ICM, NICM), and evaluate potential associations between plaque burden and SMuRFs. MethodsThis retrospective study identified heart transplant candidates with ICM or NICM matched for age and sex, undergoing thoracoabdominal CTA. Patients were classified as with SMuRFs or SMuRF-less. Extracardiac thoracoabdominal non-calcified and calcified atherosclerotic plaque was classified as present or absent across 78 arterial segments per patient. ResultsAmong included patients (n=167, median [interquartile range] age 58 [53-63] years, 16% female, 51% NICM), 40 patients (24%) were SMuRF-less (ICM: 16/82 (20%), NICM: 24/85 (28%), age 56 [50-67] years). Overall, out of 13,026 arterial segments analysed, 1,746 (13%) were affected by atherosclerotic plaque (9 [4-15] segments per patient). ICM had a higher total plaque burden than NICM (11 [7-18] vs 6 [3-11] segments per patient, p<0.001). SMuRF-less patients showed no difference in non-calcified, calcified, or total plaque burden compared to patients with SMuRFs, among all patients (ICM+NICM, p>0.17) and within the ICM and NICM groups, respectively (p>0.30). ConclusionsThe burden of extracardiac thoracoabdominal atherosclerotic plaque is higher among heart transplant candidates with ICM. However, it does not differ between SMuRF-less or those with SMuRFs, regardless of underlying ICM or NICM. The prevalence of SMuRFs is not an effective marker to determine the need to screen for extracardiac atherosclerotic plaque among heart transplant candidates. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/26347056v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@1aff6b1org.highwire.dtl.DTLVardef@16cfb07org.highwire.dtl.DTLVardef@1d4894corg.highwire.dtl.DTLVardef@81e9d3_HPS_FORMAT_FIGEXP M_FIG C_FIG

The objective of this systematic review and meta-analysis was to identify the interventions used to manage intolerance in patients receiving statins for primary prevention of CVD and to determine the effectiveness of these interventions. This study was conducted according to the PRISMA checklist. The electronic databases MEDLINE (PubMed), SCOPUS, EMBASE, and CINAHL were searched for studies published until June 2025. Based on the NLA definition of statin intolerance, the outcomes were split into adverse effects caused by statins and statin discontinuation. In total, 1,238 studies were identified and screened. Nine studies were eligible for systematic review, and six studies were eligible for meta-analysis. The identified intervention strategies were adjuvant therapy, statin titration, replacing statins with other lipid-lowering agents and switching to different statin. The meta-analysis showed that the pooled risk ratio (RR) relative to control was 0.97 (95% CI, 0.86-1.08) in randomized controlled trials and 0.94 (95% CI, 0.63-1.42) in overall, with point estimates in favour of intervention arms. Moderate to substantial heterogeneity was observed, with I2 between 27% to 57%. Due to the smaller number of studies, no clear conclusions can be drawn regarding how the implemented interventions may affect statin discontinuation. This study showed no strong evidence that the implemented interventions reduced statin intolerance. PROSPERO registration numberCRD42024587573 HighlightsThis study found that the intervention strategies used to manage intolerance in patients receiving statins for the primary prevention of cardiovascular diseases were adjuvant therapy, statin titration, replacing statins with other lipid-lowering agents and switching to different statin. O_LIThis study showed no strong evidence that the implemented interventions reduced statin intolerance C_LIO_LIDue to the smaller number of studies, no clear conclusions can be drawn regarding how the implemented interventions may affect statin discontinuation C_LI

BACKGROUNDPeak oxygen uptake (pVO2) is a strong, independent predictor of adverse cardiovascular outcomes, supporting cardiopulmonary exercise testing as a primary end point assessing efficacy of novel drug therapies in obstructive hypertrophic cardiomyopathy (oHCM) clinical trials. However, characterizing changes in pVO2 that patients perceive as beneficial or meaningful (ie, minimal important difference [MID]) has not been determined. METHODSData from patients with symptomatic oHCM enrolled in SEQUOIA-HCM and MAPLE-HCM were pooled. A total of 282 patients were randomized 1:1 to aficamten (5-20 mg daily) or matching placebo in SEQUOIA-HCM, and 175 patients were randomized 1:1 to aficamten (5-20mg daily) or to metoprolol (50-200 mg) in MAPLE-HCM; follow-up in both trials was 24 weeks. Primary outcome was change from baseline to week 24 ({Delta}) in pVO2 using Patient Global Impression of Change with anchor-based analysis to define MID. RESULTSAt week 24, {Delta}pVO2 (mL/kg/min) that corresponded to no change, one-category improvement, and one-category worsening were -0.05 (95% CI, -0.58 to 0.48), +0.35 (95% CI, -0.22 to 0.91), and -0.61 (95% CI, -1.36 to 0.13), respectively. Similarly, minute ventilation to carbon dioxide production ratio (VE/VCO2) slope that corresponded to no change, one-category improvement, and one-category worsening were 0.16 (95% CI, -0.59 to 0.90), -1.15 (95% CI, - 1.89 to -0.42), and 0.88 (95% CI, -0.42 to 2.19), respectively. In a responder analysis using this new threshold for pVO2, 60% of patients receiving aficamten achieved a {Delta}pVO2 [&ge;]0.35 versus 31% of patients on placebo or metoprolol (odds ratio, 3.4 [95% CI, 2.3-4.9], P<0.001). Consistent findings were seen with VE/VCO2 responder analysis. CONCLUSIONSChanges in pVO2 of +0.35 and -0.61 mL/kg/min were associated with a small but perceptible clinical improvement and worsening, respectively, in patients with oHCM. Applying this newly defined threshold resulted in excellent differentiation of treatment effect in a clinical trial. These novel data provide a measure of clarity to patients and clinicians regarding the interpretation of changes in pVO2 following therapeutic interventions, with potential impact on HCM management strategies and future clinical trials. Clinical Trial RegistrationSEQUOIA-HCM (NCT05186818; https://clinicaltrials.gov/study/NCT05186818?term=sequoia-hcm&rank=1); MAPLE-HCM (NCT05767346; https://clinicaltrials.gov/study/NCT05767346?term=maple-hcm&rank=1) Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIUsing pooled data from over 440 patients with symptomatic obstructive hypertrophic cardiomyopathy enrolled in two phase 3 clinical trials, we define, for the first time, the minimally important difference for peak oxygen uptake (pVO2) and ventilatory efficiency (VE/VCO2) using patient-anchored and distribution-based methodologies. C_LIO_LIA change in pVO2 of +0.35 mL/kg/min and a change in VE/VCO2 of -1.15 represent the minimal thresholds associated with patient-perceived clinical improvement. C_LIO_LIResponder analyses using these thresholds demonstrated robust differentiation between aficamten and placebo/metoprolol, with an odds ratio exceeding 3 for achieving a meaningful improvement in pVO2. C_LI What Are the Clinical Implications?O_LIThese newly defined thresholds bridge the gap between statistically significant changes in cardiopulmonary exercise testing measures and clinically meaningful benefit as perceived by patients with obstructive hypertrophic cardiomyopathy. C_LIO_LIClinicians can use these benchmarks to contextualize individual patient responses to medical therapy, informing shared decision-making regarding treatment continuation or modification. C_LIO_LIThese data provide a standardized, patient-centered framework for designing and interpreting primary end points in future hypertrophic cardiomyopathy clinical trials. C_LI

BackgroundHDL particles can carry microRNAs (miRNAs), capable of regulating gene expression connected to HDL functions. Despite links to some cardiovascular risk factors, miRNA association with incident acute myocardial infarction (AMI) remains unclear. ObjectivesOur aim was to elucidate the association between HDL-bound miRNAs (HDL-miRNAs) and incident AMI using a non-targeted approach in a population-based study. MethodsWe conducted a case-cohort study including 247 participants from the REGICOR cohort in northeastern Spain (51 AMI cases and a random sample of 196 participants, including seven overlapping AMI cases). HDL-miRNAs were isolated from apolipoprotein B-depleted serum and quantified by whole-genome miRNA sequencing. Associations between HDL-miRNAs and incident AMI were assessed using multivariable Cox proportional hazards model. For AMI-associated HDL-miRNAs (p-value <0.10), we retrieved their experimentally validated targets and assessed pathway enrichment of these targets via over-representation analysis. ResultsTwo HDL-miRNAs were associated with incident AMI after FDR correction: miR-628-3p (HR 1.69, 95% CI 1.30 to 2.19) and miR-28-3p (HR 1.58, 95% CI 1.21 to 2.06). Nine additional HDL-miRNAs were nominally associated with AMI incidence (p-value <0.05), eight with a direct association (miR-93-5p, miR-26b-5p, miR-106a-5p, miR-126-3p, miR-15b-5p, let-7a-5p, let-7e-5p, and let-7f-5p) and one with an inverse association (miR-361-5p). These miRNAs regulate the expression of genes in pathways involved in cholesterol regulation, particularly cholesterol efflux and homeostasis. The AMI group exhibited higher variance and a greater number of significant and strong correlations. ConclusionsTwo HDL-miRNAs (miR-628-3p and miR-28-3p) were significantly associated with AMI incidence. A tighter coregulatory network in cases was observed, underscoring their potential clinical utility in risk prediction and cardiovascular prevention. Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIIn a population-based case-cohort study we profiled the HDL-bound miRNome and found two miRNAs (miR-628-3p and miR-28-3p) associated with incident AMI. C_LIO_LIThe use of HDL-enriched serum fractions provided a focused analysis on HDL functionality. These miRNAs regulate the expression of genes in pathways involved in cholesterol efflux and homeostasis (ABCA1, ARL4C, SIRT1, NFKBIA, ANXA2, LRP6) and show a tighter coregulatory network among significant miRNAs among cases, supporting biological coherence. C_LI What Are the Clinical Implications?O_LIHDL-miRNA signatures may complement traditional risk factors to refine AMI risk stratification and provide a rationale for HDL-guided, miRNA-targeted preventive interventions using HDL-like delivery platforms. C_LI

BackgroundHypertension is a major modifiable risk factor for cardiovascular disease, yet blood pressure (BP) control remain suboptimal, particularly in socially disadvantaged communities. Guidelines recommend initiating single-pill combination (SPC) therapy to improve adherence and BP control, but uptake in primary care is limited. ObjectivesTo evaluate the SOLO care improvement project, promoting SPC initiation among general practitioners (GPs) in Amsterdam Zuidoost, a disadvantaged, multi-ethnic community in The Netherlands with a high hypertension burden. MethodsIn a cluster quasi-randomized cluster design, adult hypertensive patients from nine general practices within one health facility were allocated to intervention (IC; n=5) or usual care (UC; n=4). Intervention practices received case-specific guidance on SPC therapy. Outcomes were SPC uptake, changes in systolic and diastolic BP (SBP and DBP), target BP achievement and cardiovascular events. Analyses used intention-to-treat adjusted regression and Cox models, with additional as-treated analysis among SPC users. ResultsAmong 438 patients (mean age 64.5{+/-}12.2 years; median follow-up of 367 days [213-467]), SPC initiation was higher in the IC than US (25.1% vs. 9.6%, p<0.001). SBP/DBP decreased by -15.7/-6.9 mmHg in the IC and -10.4/-4.6 mmHg in the UC. Target BP was more often achieved in the IC (57.3% vs. 48.1%; OR: 1.4, 95%CI:1.0-2.1). Among SPC users, SBP/DBP decreased by -22.4/-10.5 mmHg. ConclusionPromoting SPC therapy improved blood pressure control, supporting local, targeted implementation as a pragmatic strategy to enhance hypertension management. Summary box, bullet points- In the SOLO care improvement project, SPC initiation was increased and improved blood pressure control in routine primary care. - The real-world implementation and cluster-based comparison enhanced practical relevance and reduced contamination between practices. - Although conducted in a large community health center, generalizability cannot be assumed; the non-blinded, non-randomized design allows residual confounding.