BACKGROUND:Structural remodeling of the left atrium contributes to the progression of heart failure (HF), even in the absence of atrial fibrillation (AF). However, the underlying mechanisms and extent of atrial remodeling across the spectrum of left ventricular ejection fraction (LVEF) remain poorly defined. This study aimed to characterize anatomical and functional left atrial changes using multimodal imaging and biomarker profiling in patients with HF without AF. METHODS:A total of 264 ambulatory patients with HF and no prior AF, all under continuous rhythm monitoring, were prospectively studied. All underwent transthoracic echocardiography with functional analysis of the left atrium and plasma biomarker assessment. Patients were classified according to LVEF into three groups: preserved, mildly reduced, and reduced. Correlations between echocardiographic parameters and circulating biomarkers were analyzed. RESULTS:Patients with reduced LVEF showed larger atrial volumes, lower reservoir strain, impaired conduit function, and higher atrial stiffness. Biomarker profiling revealed increased levels of natriuretic peptides and extracellular matrix proteins, along with moderate elevations in inflammation-related markers. Atrial strain was significantly correlated with markers of fibrosis, inflammation, and wall stress, particularly in patients with lower LVEF. CONCLUSIONS:In patients with HF without AF, the severity of atrial remodeling increases as LVEF declines and aligns with biomarkers of hemodynamic overload and fibrosis. The integration of imaging and molecular parameters may improve risk stratification and phenotyping in HF.

OBJECTIVE:To assess the impact of Continuity of Care (COC)-care provided by the same Primary Care Physician (PCP)-on outcomes in patients with atrial fibrillation (AF). METHODS:We conducted a retrospective cohort study including all patients with AF referred by PCPs (n=17,889) between January 2010 and December 2023 in the Santiago de Compostela healthcare area (Spain). COC was categorized as "PCP stability" (care by the assigned PCP) or "interrupted COC" (care by multiple rotating PCPs). The association between COC and outcomes (hospitalization, mortality, stroke, and haemorrhage) was estimated using Cox regression and Fine-Gray competing risk models, adjusted for potential confounders. RESULTS:Patients with PCP stability had a significantly lower annual referral rate (1.5 vs. 1.8, p<0.001) and a higher rate of adequate Oral Anticoagulation (OAC) indication according to the CHA2DS2-VASc score (79.5% vs. 69.1%, p<0.001). COC was independently associated with reduced all-cause mortality (Hazard Ratio [95% CI]: 0.79 [0.69-0.91]), a benefit that remained robust after sensitivity analyses. No significant differences were observed in stroke or haemorrhagic complications; however, competing risk analysis suggests that the higher mortality rate in the interrupted COC group likely precluded the observation of non-fatal events in this high-risk subset. CONCLUSIONS:Longitudinal COC in Primary Care is associated with improved clinical management, including better OAC indication, and a significant reduction in all-cause mortality among patients with AF. The survival benefit of seeing the same physician appears to extend beyond anticoagulation optimization, highlighting the pleiotropic value of the patient-physician relationship.

AIMS:Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve outcomes in heart failure (HF) across the left ventricular ejection fraction (LVEF) spectrum, but patients with severe valvular heart disease have been excluded from pivotal trials. We investigated the efficacy and safety of dapagliflozin across the full range of baseline LVEF in elderly patients undergoing transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS:DapaTAVI was a pragmatic, multicentre, randomized, open-label trial with blinded endpoint adjudication conducted at 39 Spanish centres. Patients with severe aortic stenosis undergoing TAVI were randomized after the procedure to dapagliflozin 10 mg once daily or standard of care. The primary endpoint was a composite of all-cause death or worsening HF. Among 1223 patients with available baseline LVEF, 213 (17.4%) had LVEF ≤40% and 1010 (82.6%) had LVEF >40%. During 1-year follow-up, the primary endpoint occurred in 20.2% of patients with LVEF ≤40% and 17.0% of those with LVEF >40% (adjusted HR 1.28, 95% CI 0.91-1.80; P = .15). Dapagliflozin reduced the risk of the primary endpoint consistently across LVEF subgroups, with no significant interaction between treatment effect and baseline LVEF (P for interaction = .41). Analyses modelling LVEF as a continuous variable confirmed a homogeneous treatment effect across the entire LVEF spectrum. Dapagliflozin was well tolerated, with a safety profile comparable to control across all LVEF categories, although genitourinary infections were more frequent with dapagliflozin. CONCLUSION:In elderly patients undergoing TAVI, dapagliflozin reduced the risk of all-cause death or worsening HF irrespective of baseline LVEF and was safe across the full LVEF spectrum. These findings extend the benefits of SGLT2 inhibition to patients with severe aortic stenosis treated with TAVI, independent of systolic function.

Introduction:Severe aortic stenosis (AS) management increasingly requires multidisciplinary coordination across diagnostic, interventional, and rehabilitation stages. Integrated care pathways (ICPs) supported by structured data systems may improve safety and outcomes, but real-world evidence in AS remains limited. We aimed to characterize a contemporary cohort of patients with severe AS managed within an ICP at a tertiary hospital, comparing profiles and outcomes by treatment strategy, and to describe diagnostic procedures and the implementation of cardiac rehabilitation (CR) interventions embedded in the pathway. Methods:Prospective observational study of all consecutive patients with AS evaluated by a multidisciplinary heart team between 2018 and 2022. Baseline characteristics and frailty, diagnostic tests, CR interventions, procedural details, and outcomes were collected via an interoperable data management platform and compared across treatment groups: surgical (SAVR) or transcatheter (TAVR) valve replacement, or conservative management. Early survival was assessed using Kaplan-Meier analysis with log-rank testing. Results:Among 984 patients (median age 78 years, 42% women), 43.9% underwent SAVR, 49.8% TAVR, and 6.3% were managed conservatively. TAVR and conservative groups were older, frailer, and had higher comorbidity. Device success at 30 days was high (≈91%), with periprocedural death at 2.5% for interventions, vs. 9.7% early mortality for conservative management (p < 0.001). Early survival differed significantly (log-rank p = 0.004). TAVR had higher permanent pacemaker implantation (21.7% vs. 7.4% for SAVR, p < 0.001) and major vascular complications (4.1% vs. 0.2%, p < 0.001), while SAVR had more reoperations (8.3% vs. 0.2%, p < 0.001) and atrial fibrillation (18.9% vs. 10.1%, p = 0.001). Prehabilitation was implemented in 64.6% of candidates, while postprocedural CR remained underutilized (11.3%). Conclusions:Integrated care for a cohort of patients with AS, supported by structured data management, enabled comprehensive profiling, systematic outcome monitoring, and identification of improvement areas. Both SAVR and TAVR achieved high success with low early mortality, while conservative management had poor survival.

IntroductionRegulatory reviews in 2023-2024 reignited concern about possible suicidality with Glucagon-like peptide-1 (GLP-1) receptor agonists used for weight management. While clinical trials and real-world studies have not confirmed an increased risk, comparative post-marketing analyses across all anti-obesity agents are scarce.AimTo compare disproportional reporting of suicidality-related adverse events among GLP-1/dual incretin versus non-GLP-1 anti-obesity drugs in the FDA Adverse Event Reporting System (FAERS).MethodWe conducted a retrospective disproportionality study using FAERS (January 2012-February 2025). Reports submitted from the United States with the study drug listed as primary suspect were retrieved via openFDA. Suicidality terms were predefined (MedDRA Preferred Terms: suicidal ideation, suicide attempt, completed suicide). Reporting Odds Ratios (RORs) with 95% confidence intervals (CIs) were calculated for each drug and at class level (GLP-1/dual incretin vs non-GLP-1). Haldane-Anscombe corrections were applied where needed.ResultsAmong approximately 78,000 anti-obesity reports, 207 (approximately 0.3%) involved suicidality-related events. For semaglutide, RORs were 1.39 (95% CI 0.99-1.94) for suicidal ideation, 1.38 (0.46-4.15) for suicide attempt, and 1.72 (0.62-4.74) for completed suicide, none statistically significant. Liraglutide showed ROR 1.01 (0.66-1.55) for suicidal ideation and 18.11 (6.96-47.15) for completed suicide based on 14 cases. Tirzepatide yielded RORs below unity for all outcomes. Naltrexone/bupropion showed elevated disproportional reporting for suicidal ideation (ROR 3.84; 95% CI 2.89-5.12) and suicide attempt (ROR 4.11; 95% CI 1.62-10.45.ConclusionGLP-1 and dual-incretin agents did not show disproportionality signals for suicidal ideation or suicide attempt. A statistically significant disproportionality signal for completed suicide was observed for liraglutide; however, this estimate was based on few cases and displayed wide confidence intervals, warranting cautious interpretation. These findings support an overall neutral psychiatric safety profile for incretin-based therapies while underscoring the need for continued monitoring of rare events such as completed suicide.

AIMS:Heart failure (HF) often coexists with chronic kidney disease (CKD), impacting prognosis. This study aims to evaluate renal function trajectories and their impact on major clinical outcomes in a cohort of patients hospitalised for 'de novo' HF with reduced ejection fraction (HFrEF). METHODS:This is a prospective cohort study that included patients hospitalised for 'de novo' HFrEF at two university hospitals. Renal function was assessed using the CKD-Epidemiology Collaboration formula. Total mortality and the combined total mortality and HF readmissions were evaluated during follow-up. RESULTS:Of 370 patients, 306 were eligible. At discharge, 24.6% had estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2. Higher eGFR at discharge was associated with better outcomes. During follow-up, 79.1% showed eGFR ≥45 mL/min/1.73 m2. Patients with stable or improved eGFR had lower total mortality and HF readmission rates. Factors associated with renal function improvement or stabilisation included less prior CKD, hypertension and younger age, higher eGFR values at discharge and more use of quadruple therapy at the end of uptitration period. CONCLUSIONS:In patients with 'de novo' HFrEF, renal function deterioration at discharge correlated with poorer outcomes. However, stabilisation or improvement during follow-up was linked to better prognosis. Routine renal function assessment is crucial in HFrEF management, guiding personalised treatment strategies to mitigate renal function decline and improve patient care.

Abstract Background Heart failure (HF) is a complex clinical syndrome with heterogeneous aetiologies and impaired cardiac function, leading to high morbidity, mortality, and frequent hospitalisations. Despite advances in pharmacological and device therapy, outcomes remain variable and prognosis is often difficult to predict. Genetic testing is recommended in selected patients, particularly when an inherited cardiomyopathy or arrhythmia is suspected, but its prognostic role in HF remains uncertain. Purpose To evaluate whether the presence of rare pathogenic or likely pathogenic (P/LP) variants in genes related to inherited cardiovascular disease is associated with more adverse clinical phenotypes in patients with HF. Methods We included 196 patients with a clinical diagnosis of HF and a minimum follow-up of two years. Whole-exome sequencing was performed, and rare variants were filtered through a virtual panel of 190 genes associated with inherited cardiomyopathies and arrhythmias. Variant classification followed ACMG/AMP and ACGS standards. Clinical risk stratification considered: family history of cardiomyopathy (yes/no), left ventricular ejection fraction (LVEF <40% vs ≥40%), and major cardiovascular events (atrial fibrillation, ventricular tachycardia, or cardiac death; yes/no). Patients with ≤1 criterion were classified as lower-risk HF, while those with ≥2 criteria were classified as higher-risk HF. Results 88 patients (45%) were classified as higher-risk HF and 108 as lower-risk HF (55%). P/LP variants were identified in 12 patients: 6 in the lower-risk group and 6 in the higher-risk group [OR = 1.24; 95% CI: 0.39-4.00; p = 0.71]. Although not statistically significant, a trend towards a higher prevalence of P/LP variants was observed in the higher-risk group. Conclusions In this HF cohort, P/LP variants were not significantly enriched in patients with a more adverse clinical profile. Nevertheless, the observed trend suggests that integrating genetic testing with conventional risk stratification may enhance prognostic assessment. Larger studies are warranted to clarify the contribution of inherited variants to HF prognosis and to guide personalised therapeutic strategies.

Substance-use disorders are major accelerators of cardiometabolic disease, yet this dimension remains insufficiently recognized within addiction care. Individuals with substance-use disorders frequently exhibit hypertension, adverse lipid profiles, visceral adiposity, metabolic syndrome, chronic low-grade inflammation and autonomic imbalance, contributing to markedly elevated cardiovascular morbidity and premature mortality. The recent European Society of Cardiology Clinical Consensus Statement on mental health and cardiovascular disease highlights this gap and calls for structured cardiometabolic assessment and prevention strategies within behavioural and psychiatric population. Glucagon-like peptide-1 receptor therapies have emerged as multisystem agents relevant to both addictive behaviour and cardiometabolic health. Experimental and early clinical evidence demonstrates reductions in craving, improved reward regulation and attenuation of impulsive consumption across alcohol, nicotine, stimulant use and binge-type eating, mediated through gut-brain communication, mesolimbic dopamine circuitry, hypothalamic pathways and stress-responsive networks. In parallel, these therapies induce clinically meaningful reductions in body weight, visceral adiposity, blood pressure and inflammatory burden, while improving glucose regulation and cardiometabolic markers. Large cardiovascular outcome trials demonstrate reductions in major adverse cardiovascular events in high-risk populations, and emerging primary-prevention analyses report favourable changes in estimated cardiovascular risk even without established cardiovascular disease. This review integrates biological, clinical and real-world evidence to propose a unified neurocardiometabolic framework in which glucagon-like peptide-1 receptor therapies may simultaneously influence addictive behaviour and long-term cardiovascular risk trajectories. We outline mechanistic foundations and potential clinical applications within detoxification programmes, relapse-prevention settings, dual-diagnosis services and addiction care, while highlighting the need for further clinical validation before routine implementation.

INTRODUCTION:Cryptogenic stroke (CS) represents a heterogeneous group in terms of etiology. Atrial cardiopathy (AC) has emerged as a relevant underlying substrate for both stroke and atrial fibrillation (AF) in these patients. However, no reliable tools are currently available for the early and accurate identification of AC. MATERIAL AND METHODS:We conducted a prospective study including consecutive patients with cardioembolic stroke due to AF (CES-AF), non-cardioembolic stroke (NCES) and cryptogenic stroke (CS). Left atrial strain (LAS) assessed by speckle-tracking echocardiography, and serum markers of AC were evaluated in CES-AF versus NCES patients using ROC curve analysis. Based on these results, we developed a logistic regression model to calculate the probability of AC in CS patients, aiming to discriminate between cardioembolic and non-cardioembolic etiology. Clinical characteristics were compared between CS patients with high (>0.5) and low (<0.5) predicted probability of AC. RESULTS:A total of 136 patients were included: 44 with CES-AF, 52 with NCES, and 40 with CS. The combination of N-terminal pro-brain natriuretic peptide (NT-proBNP) levels ⩾ 469 pg/mL and biplanar LAS during the contraction phase (LASct) ⩾ -10.2% demonstrated the best-performing AC biomarker combination among those evaluated for identifying cardioembolic etiology (AUC = 0.995). Based on this combination, 30% of CS patients had a predicted probability > 0.5 for AC. These patients were older (77.3 ± 8 vs 68.8 ± 10 years; p = 0.011), had more severe strokes (NIHSS score 10.1 ± 7.5 vs 4.6 ± 5.2; p = 0.024) and showed a higher incidence of AF during follow-up (6 vs 0 cases; p = 0.029). CONCLUSIONS:The combination of NT-proBNP levels and biplanar LASct provides highly sensitive and specific biomarkers of AC. This multiparametric model allows for individualized estimation of AC probability in CS patients, supporting its potential utility in discriminating cardioembolic from non-cardioembolic etiologies and guiding personalized clinical management.

INTRODUCTION AND OBJECTIVES:Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1ra) reduce cardiovascular events through different mechanisms, but their association with cancer remains unclear. The aim of this study was to compare the effect of combined treatment (SGLT2i and GLP1ra) and monotherapy (SGLT2i or GLP1ra) on hospitalization and/or death from cancer in a general population and a subgroup of patients with cardiovascular disease (CVD). METHODS:We conducted a nonconcurrent observational prospective study of patients prescribed SGLT2i, GLP1ra, or both. Multinomial propensity scores were performed in the entire population and in a subgroup of patients with CVD. A multivariate Cox regression analysis was used to determine the hazard ratio (HR) for age, sex, risk factors, and treatment for each outcome. RESULTS:We included 14 709 patients (11366 with SGLT2i, 1016 with GLP1ra, and 2327 with both treatments) from treatment initiation. Diabetes was present in 97% of the patients. The subgroup with CVD included 4957 (33.7%) patients. After a median of 33 months of follow-up, the risk of adverse cancer events was similar between patients with and without CVD (3.4% or 3.7%, respectively). The main risk factors for cancer mortality were male sex and age. Combined treatment and its duration reduced the risk of cancer mortality compared with monotherapy with SGLT2i or GLP1ra in the overall population (HR, 0.2216; 95%CI, 0.1106-0.4659; P<.001; and HR, 0.1928; 95%CI, 0.071-0.5219; P=.001, respectively) and in the subgroup of patients with CVD (HR, 0.2879; 95%CI, 0.0878-0.994; P<.049; and HR, 0.1329; 95%CI, 0.024-0.6768; P=.014, respectively). CONCLUSIONS:Initiation of combined therapy (SGLT2i and GLP1ra) vs monotherapy with SGLT2i or GLP1ra was associated with a lower risk of cancer mortality, mostly in diabetic patients with or without CVD. Although clinical trials are needed, these results might be explained by the complementary mechanisms of these drugs, including their antiproliferative, anti-inflammatory, and metabolic effects. Future clinical trials and mechanistic studies will clarify the possible role of these drugs in carcinogenesis.

Background and aims Combined therapy, sodium-glucose cotransporter 2 inhibitors (SGLT2i), and glucagon-like peptide-1 receptor agonists (GLP1ra) reduce all-cause mortality in patients with diabetes. We aimed to analyse the differential behaviour of combined therapy between women and men regarding all-cause mortality. Methods and Results This is a retrospective observational cohort study. using “Big data” according to electronic medical records in the Santiago-Barbanza health area, which covers 450,000 patients. Out of 15,118 patients, 41% were women. The median follow-up was 33 months. Women were older (71[62-78] vs. 67[59-75], p: <0.001) and with a higher incidence of obesity (53% vs. 41%, p: <0.001), meanwhile, men presented more coronary artery disease (CAD) (19% vs. 9%, p: <0.001). The multinomial propensity score and multivariate Cox regression were used for statistical analysis. All-cause mortality was compared between combined vs. monotherapy in women or men. Men had a higher risk of all-cause mortality than women in this population (HR [95% CI] 1.50 [1.28-1.75]). Combined regarding monotherapy (GLP1ra (HR [95% CI] 0.19 [0.14-0.27]), or SGLT2i (HR [95% CI] 0.30 [0.23-0.40]), and treatment duration (HR [95% CI] 0.95 [0.94-0.96] were associated with lower risk of all-cause mortality; with higher benefit in women (GLP1ra (HR [95% CI] 0.14 [0.08-0.27]), or SGLT2i (HR [95% CI] 0.18 [0.11-0.30]) regarding men (HR [95% CI] 0.25 [0.16-0.40] for GLP1ra, and HR [95% CI] 0.41 [0.29-0.58] for SGLT2i). Conclusions Combined therapy vs. monotherapy was associated with a lower risk of all-cause mortality in patients regardless of sex. Nevertheless, a higher benefit was observed in women regarding men.

We examined current evidence regarding the effects of anti-inflammatory therapies in patients with acute heart failure (AHF) on the risk of cardiovascular outcomes, inflammatory markers, natriuretic peptides, and renal function. Despite growing evidence that inflammation plays a pivotal role in both the development and progression of heart failure, including AHF, only a few trials have been conducted to date in patients with AHF. A systematic literature search of PubMed, Medline, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov was conducted in November 2024 to identify randomized controlled trials (RCTs) evaluating anti-inflammatory therapies in adult patients with AHF. Meta-analyses were conducted to estimate effects on clinical outcomes (death, HF readmission, or worsening HF) and inflammatory and other markers. Five RCTs were identified that enrolled a total of 289 patients to an anti-inflammatory intervention and 273 to a control. Prednisone was examined in two RCTs, anakinra in two, and colchicine in one. Three of the five trials required elevated C-reactive protein (CRP) level for entry. Anti-inflammatory therapy was associated with a reduced risk of the composite outcome (hazard ratio 0.55 [95

BACKGROUND:The SCN5A gene polymorphism histidine-558-to-arginine (H558R) has been associated with atrial fibrillation (AF) and may affect the therapeutic effects of flecainide. This study aimed to assess the prevalence of the H558R polymorphism in a European cohort of patients with AF and examine its association with flecainide's effects on AF recurrence and toxicity. METHODS:This cohort study included patients diagnosed with AF and prescribed flecainide between 2017 and 2021 in a regional health area. Patients without the polymorphism (H558R-/-) were compared with heterozygous patients (H558R+/-) for a primary outcome of combined 6-month AF recurrence or toxicity. Secondary analyses evaluated the long-term outcomes and compared the prevalence of H558R in the AF cohort to a general population sample (n=3401). RESULTS:A total of 104 patients were enrolled, with 57% H558R-/-, 37% H558R+/- and 6% H558R+/+. The prevalence of the H558R polymorphism was significantly higher in the AF cohort than in the general population (43.27% vs 24.37%, prevalence ratio 1.78, 95% CI 1.41 to 2.23, p<0.01). H558R+/- patients had a significantly lower risk of 6-month AF recurrence or toxicity (p=0.023, risk ratio 0.423, 95% CI 0.189 to 0.947), corresponding to an absolute risk difference of 21.5%. These findings were similar in the multivariable analysis. In long-term follow-up, H558R+/- patients continued to demonstrate a lower risk of AF recurrence or toxicity (p=0.039, HR 0.53, 95% CI 0.276 to 0.999). CONCLUSIONS:The H558R polymorphism is more prevalent in patients with AF compared with the general population and its presence is associated with a more favourable response to flecainide treatment.

BACKGROUND:Treatment with icosapent ethyl (IPE) has been shown to reduce the incidence of major adverse cardiovascular events (MACE) in patients at high cardiovascular risk with mildly to moderately elevated triglyceride values (>135 mg/dL) and well-controlled (<100 mg/dL) low-density lipoprotein cholesterol (LDLc). The main objective of this study was to estimate the number of patients eligible for IPE after an acute coronary syndrome (ACS). METHODS:Multicenter retrospective study based on ACS registries of patients from 8 hospitals in Spain. Patients with LdLc <100 mg/dL and triglyceride values >135 mg/dL were analyzed as candidates for IPE. The study endpoints were MACE (cardiovascular mortality, ACS, or readmission for heart failure or stroke) and all-cause mortality. RESULTS:A total of 14,483 patients with ACS were included in the registry; the mean (SD) LDLc was 99.8 mg/dL (38.5), and the median value for triglycerides was 120.5 mg/dL (IQR: 90-197 mg/dL). Of this population, 3028 (20.9%) were classified as candidates for IPE. Median follow-up was 1223 days. Candidates for IPE had significantly higher rates of MACE (39.0% vs 33.6%) and mortality (18.4% vs 14.0%). Multivariate analysis identified an independently higher risk for MACE (hazard ratio [HR]: 1.14, 95% CI: 1.05-1.20) and all-cause mortality (HR: 1.10, 95% CI: 1.04-1.26) among candidates for IPE. CONCLUSIONS:Approximately 20% of patients discharged after an ACS could be candidates for IPE, and this subset of patients are at higher risk of MACE or death.