INTRODUCTION: In patients with ischemic cardiomyopathy (ICM), recurrent VF may be treated with catheter ablation by targeting triggering premature ventricular complexes (PVCs) and/or ventricular scar homogenization. Data on optimal ablation strategies in patients with non-ischemic cardiomyopathy (NICM) remain limited. This study aimed to compare ablation strategies and outcomes in patients with recurrent VF due to ICM versus NICM. METHODS AND RESULTS: We retrospectively analyzed consecutive patients with structural heart disease and recurrent VF undergoing catheter ablation. Catheter ablation was performed, including targeting the triggering and/or clinically frequent PVC, targeting any inducible ventricular tachycardia, and/or scar homogenization. Procedural characteristics, arrhythmogenic substrate features, and post-ablation clinical outcomes were compared between ICM and NICM groups. Forty-five patients were included (17 ICM, 28 NICM; mean age 60 ± 15 years; 87% male). PVC ablation was performed in 42% of ICM and 39% of NICM patients, while scar homogenization was undertaken in 76% and 57%, respectively. Left ventricular scar burden, assessed by bipolar and unipolar voltage mapping, was significantly greater in the ICM, whereas the prevalence of abnormal Purkinje potentials was similar between groups. VF-free survival after multiple procedures did not differ between groups, with estimated 1-year rates of 87 ± 9% in ICM and 85 ± 8% in NICM (log-rank p = 0.93). CONCLUSIONS: In patients with NICM and recurrent VF, catheter ablation targeting arrhythmogenic substrate-including unipolar low-voltage regions-combined with PVC ablation yields outcomes comparable to those in ICM, supporting this approach as a reasonable treatment strategy.

INTRODUCTION: Diagnosis and treatment of children and adolescents with suspected Brugada syndrome (BrS) is challenging. Aim of the study was to evaluate the applicability of current diagnostic criteria for pediatric patients with suspected BrS in the German multicenter study COGIA and to assess clinical outcome. METHODS: Data analysis of 76 pediatric patients from 12 German tertiary care centers. Primary outcome was defined by the occurrence of a major arrhythmic event (MAE), secondary outcome by symptoms, pharmacotherapy and implantation of devices. MAE was defined as sudden cardiac death (SCD), aborted cardiac arrest (ACA) and appropriate implantable cardioverter-defibrillator (ICD) therapy. RESULTS: Criteria for BrS diagnosis were fulfilled in 39/76 pediatric patients (51.3%) according to ESC Guidelines, including 34 patients (44.7%) according to Shanghai Score. Genetic testing identified a (likely) pathogenic SCN5A variant in 31/66 tested children (47.0%) (14/30 with clinical diagnosis (46.7%) and 17/36 without clinical diagnosis (47.2%)). Twenty-four patients (31.6%) showed a spontaneous type 1 ECG pattern, in 6 patients (7.9%) it was induced by fever. Ajmaline challenge was positive in 19/25 patients (76.0%). Syncope occurred in 15 patients (19.7%) and an ICD was implanted in 7 pediatric patients (9.2%). Four patients (5.3%) experienced a MAE (ACA), all of them fulfilling diagnostic criteria. "Symptoms at first consultation" was identified as an independent risk factor for MAE in the whole cohort (HR = 11.3, p = 0.04). CONCLUSION: Establishing the diagnosis of BrS remains challenging in the pediatric cohort. MAE occurred in 5.3% of patients with suspected BrS. Symptoms at first consultation increased risk for MAE. CLINICAL TRIAL REGISTRATION: The study is registered at the German Clinical Trial Register (DRKS) of the Federal Institute for Drugs and Medical Devices (BfArM), DRKS-ID DRKS00028138.

BACKGROUND: Cardiac fibrosis is a central driver of adverse remodeling and heart failure (HF), yet effective antifibrotic therapies remain limited. SerpinA3, a member of the serine protease inhibitor family, has been implicated in cardiovascular disease, but its functional role and underlying mechanisms in cardiac remodeling are poorly defined. METHODS AND RESULTS: Using a transverse aortic constriction (TAC) model, we observed that SerpinA3K expression was markedly reduced in failing mouse hearts and in circulation. Pharmacological supplementation or genetic augmentation of SerpinA3 markedly attenuated cardiac dysfunction and fibrotic remodeling in response to pressure overload. Single-cell transcriptomic analyses further demonstrated that SerpinA3 suppresses profibrotic fibroblast programs by promoting a transition from activated and extracellular matrix-producing fibroblasts toward a quiescent, pro-angiogenesis state. Mechanistically, SerpinA3 binds to the extracellular domain of TGF-beta receptor type-1, and disrupts TGF-β receptor type-1-TGF-β receptor type-2 complex formation, thereby preventing downstream Smad2/3 phosphorylation in cardiac fibroblasts. CONCLUSIONS: SerpinA3 functions as an endogenous inhibitor of TGF-β signaling that restrains cardiac fibroblast activation and fibrotic remodeling. By targeting receptor complex assembly, SerpinA3 provides a selective mechanism to modulate profibrotic signaling. These findings identify SerpinA3 as a promising therapeutic target for HF associated with pathological fibrosis.

Nicotinamide adenine dinucleotide (NAD) plays a central role in energy metabolism, and its decline is linked to various degenerative diseases. While NAD restoration holds therapeutic promise, its long term, tissue-specific consequences remain poorly understood. We investigated effects of nicotinamide riboside (NR) supplementation for "mutator" mice manifesting mitochondrial progeria. Our results reveal strikingly divergent outcomes: in proliferative bone marrow, NR-treated mutators show reductive stress with accumulation of NADH/NADPH, altered amino acid, nucleotide, folate levels, and impaired heme biosynthesis. In blood, erythrocyte maturation defects are aggravated, exacerbating anemia. Conversely, in postmitotic cardiac tissue, NR enhanced contractility, reduces stress response markers and normalized metabolic profile. These findings indicate that while beneficial for heart, chronic NAD boosting can compromise erythrocyte maturation in the context of mitochondrial disease. The data emphasize importance of evaluating systemic effects of NAD boosting therapies beyond the primary affected tissues and development of tissue-specific metabolic interventions for degenerative diseases.

This cross-sectional study investigated the moderated mediating roles of coping style and hospitalization frequency in the benefit finding-fear of progression relationship among 332 heart failure patients. Findings suggested that resignation coping mediated the impact of benefit finding on fear of progression, implying that alleviating such resignation coping may improve patients' fear of progression. Furthermore, hospitalization frequency emerged as a significant negative moderator of resignation coping's mediating effect. Consequently, this suggests that interventions aimed at improving resignation coping may mitigate the detrimental effect of benefit finding on fear of progression, especially for those experiencing more frequent hospitalizations.

AIMS: Blood pressure (BP) control is a Class I recommendation for the management of heart failure with preserved ejection fraction (HFpEF); however, evidence supporting systolic BP (SBP) targets remains limited. We investigated associations between BP control and subsequent outcomes in patients with HF with mildly reduced EF (HFmrEF)/HFpEF. METHODS: We pooled TOPCAT (Americas), PARAGON-HF, DELIVER, and FINEARTS-HF, which tested spironolactone, sacubitril/valsartan, dapagliflozin, and finerenone, respectively, versus placebo or active control in patients with HF and an LVEF >40% (DELIVER), ≥40% (FINEARTS-HF), or ≥45% (TOPCAT-Americas, PARAGON-HF). Daily BPs were estimated by interpolation from standardized office measurements obtained at randomization and prespecified visits. Time in target range (TIR) was the percentage of the first year after randomization during which SBP was 110-<130 mmHg. Continuous associations between TIR and subsequent risk of HF hospitalization or cardiovascular death, its individual components, and all-cause death was assessed using landmark Cox proportional hazards models with linear splines, adjusted for baseline cardiovascular risk factors. RESULTS: Among 17,788 patients (mean age 72±9 years; 47% women; mean baseline SBP 129±15 mmHg), the median TIR was 38% (≈139 days). Randomization to active therapies increased TIR by 2% (95% CI: -2 to 6) with spironolactone, 7% (5 to 9) with sacubitril/valsartan, 2% (0 to 4) with dapagliflozin, and 3% (1 to 5) with finerenone. Higher TIR was associated with lower subsequent risk of the composite outcome (P=0.021), primarily driven by lower HF hospitalization risk (P=0.007); associations with cardiovascular death and all-cause death were not significant. Sensitivity analyses using stricter (120-<130 mmHg) or more liberal ranges (100-<130 and 120-<140 mmHg) yielded qualitatively similar findings. CONCLUSIONS: In patients with HFmrEF/HFpEF, BP control during the first year was associated with a lower subsequent risk of HF hospitalization. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov ID NCT00094302 (TOPCAT), NCT01920711 (PARAGON-HF), NCT03619213 (DELIVER), NCT04435626 (FINEARTS-HF).

BACKGROUND AND AIMS: Healthcare professionals (HCPs) play a central role in preventive care, yet their own cardiovascular health management remains poorly characterised. We evaluated cardiovascular risk profiles, awareness, treatment use, target achievement and subclinical atherosclerosis among HCPs attending the European Society of Cardiology (ESC) Congress. METHODS: HCPs participating in the ESC Congress Cardiovascular Health Check 2025 (n=1366) underwent standardised assessment of cardiovascular risk factors, medication use, treatment targets, and carotid ultrasonography in a subgroup. HCPs without established atherosclerotic cardiovascular disease (ASCVD) were compared with age- and sex-matched individuals from the general population (REACT initiative; n=2732). RESULTS: Among HCPs, excess body weight was the most prevalent modifiable risk factor (46.8%), followed by hypertension (23.2%), and hyperlipidaemia (22.7%). Established ASCVD was present in 11.1% and subclinical atherosclerosis was detected in 21.8% of HCPs without established ASCVD. Compared with matched controls, unrecognised hyperlipidaemia (7.5% vs. 8.4%; P=0.293), hypertension (11.9% vs. 13.9%; P=0.079), and diabetes (0.4% vs. 0.4%; P=0.864) were similarly frequent; awareness was higher only for hyperlipidaemia (62.2% vs. 54.9%; P=0.049). In primary prevention, HCPs were less likely to use recommended antihypertensive (27.6% vs. 46.5%; P<0.001) and glucose-lowering therapy (60.0% vs. 85.0%; P=0.001), but more often achieved LDL-C (57.5% vs. 32.0%; P<0.001) and systolic blood pressure targets (47.5% vs. 24.6%; P=0.003). In secondary prevention, 41.4% of HCPs used lipid-lowering therapy, only 9.2% used antiplatelet therapy, and only 22.2% of those using lipid-lowering therapy achieved the LDL-C target. CONCLUSIONS: HCPs showed important gaps in cardiovascular prevention, particularly regarding the use of guideline-recommended therapy, highlighting the need for systematic implementation strategies among HCPs.Clinical Trial Registration: NCT07613229.

Observational studies and intervention trials provide the evidence base for developing strategies for primary and secondary prevention of cardiovascular disease (CVD). The Joint European Society of Cardiology recommendations on prevention of coronary heart disease published in 1994 was the first European guideline to summarize this evidence and propose prevention strategies for clinical practice with regular updates since. The implementation of these recommendations, and subsequent guidelines, was evaluated from 1996 onwards through the EUROASPIRE programme of surveys, which have evolved over a 30-year period, involving thousands of coronary and high-risk patients from hundreds of medical centres across 30 countries. This cycle of surveys over six iterations is described in this historical review, informing the need for quality improvements in real-life practice, both to prevent the development of atherosclerotic disease in high-risk individuals (primary prevention) and in those with established CVD (secondary prevention).

BACKGROUND: Although the effectiveness of Lp(a) (lipoprotein[a])-lowering therapies remains under study, lipid guidelines now recommend Lp(a) testing in all adults to identify individuals who need more aggressive risk factor modification. Therefore, we evaluate contemporary patterns of Lp(a) testing and the impact of testing on LDL-C (low-density lipoprotein cholesterol) management. METHODS: Electronic health record patient data from 13 US health systems from January 1, 2021 to January 1, 2025, were utilized to assess the annual proportion of patients with atherosclerotic cardiovascular disease who underwent Lp(a) testing. Multivariable logistic regression was used to identify factors associated with (1) Lp(a) testing and (2) high Lp(a) (≥125 nmol/L or ≥50 mg/dL). Changes in lipid-lowering therapy after Lp(a) testing were evaluated, stratified by Lp(a) level. RESULTS: Among 1 948 540 patients with atherosclerotic cardiovascular disease (44% female sex; mean age, 70.9±12.8 years), 36 410 (1.9%) had an Lp(a) test. Testing increased slightly over time but remained low: from 0.2% in 2021 to 0.8% in 2024. Among tested patients, 31.1% had elevated Lp(a). Although female sex (odds ratio, 0.95 [95% CI, 0.93-0.98]) and non-Hispanic Black patients (0.79 [95% CI, 0.76-0.82]) were less likely to undergo testing, these groups had higher odds of elevated Lp(a) (1.19 [95% CI, 1.14-1.25] and 2.83 [95% CI, 2.63-3.05], respectively). Intensification of lipid-lowering therapy in those with LDL-C≥55 mg/dL increased with higher Lp(a) levels: 32.7% with Lp(a) 125 to <200 nmol or 50 to <80 mg/dL, and 38.2% with Lp(a)≥200 nmol or ≥80 mg/dL had lipid-lowering therapy intensification (<0.001). CONCLUSIONS: Lp(a) testing remains low despite guideline recommendations. Although those with elevated Lp(a) were more likely to undergo lipid-lowering therapy intensification, over half of those with Lp(a)≥200 nmol/L or ≥ 80 mg/dL had no change in therapy. These results highlight a significant gap in clinical care and an opportunity to improve the use of Lp(a) testing to guide LDL-C management.

The ramus intermedius (RI) is a variant artery arising from the trifurcation of the left main (LM) coronary artery. While prior work from our group has demonstrated that RI is associated with greater atherosclerotic plaque burden in the LM, whether this anatomical variant is associated with increased overall coronary plaque burden across the entire coronary tree remains unknown. This study aimed to evaluate the relationship between RI presence and total coronary plaque, stenosis, and segment involvement. A large retrospective single-center study was conducted among 11,497 adults who underwent coronary computed tomography angiography (CCTA) between October 2006 and December 2022 in Los Angeles, California. The total plaque score (TPS), total stenosis score (TSS), and segment involvement score (SIS) were quantified for each participant. Differences between individuals with and without an RI were assessed using the Wilcoxon rank-sum test. Negative binomial regression models were constructed with TPS, TSS, and SIS as dependent variables and RI presence as the independent variable, adjusting for traditional cardiovascular risk factors. Among 11,497 subjects (mean age 62.0 ± 12.4 years, 64% male), 1,269 (11%) had an RI. Individuals with RI demonstrated significantly higher TPS (median 6.0 [IQR 2.0-11.0] vs. 3.0 [IQR 0.0-8.0]), TSS (6.0 [IQR 2.0-12.0] vs. 3.0 [IQR 0.0-9.0]), and SIS (5.0 [IQR 2.0-8.0] vs. 3.0 [IQR 0.0-6.0]) compared to those without RI (all p < 0.0001). On multivariable negative binomial regression, RI presence was independently associated with higher TPS (adjusted rate ratio 1.25 [95% CI 1.18-1.33]), TSS (1.27 [1.19-1.35]), and SIS (1.27 [1.21-1.33]) after adjustment for traditional cardiovascular risk factors. The presence of RI is independently associated with greater overall coronary plaque burden, higher stenosis severity, and more widespread coronary segment involvement. These findings suggest that RI may promote diffuse atherosclerosis throughout the coronary vasculature, potentially through hemodynamic perturbations introduced by the additional branching point.

RATIONALE: The time-dependent contributions of coronary atherosclerotic plaque burden and myocardial ischemia to clinical outcomes in suspected coronary artery disease (CAD) remain uncertain. This study aimed to evaluate the temporal associations of quantitatively assessed plaque burden and ischemia with cardiovascular events. METHODS: We studied 1,385 patients with suspected CAD who underwent coronary computed tomography angiography (CCTA) and [O]H₂O positron emission tomography (PET) perfusion imaging. Plaque burden was measured as percent atheroma volume (PAV) using AI-based CCTA analysis. Myocardial perfusion was evaluated by regional hyperemic myocardial blood flow (hMBF) using PET. Adjusted Cox regression models, including both PAV and hMBF, were used to assess associations with a composite outcome (death, non-fatal myocardial infarction, unstable angina) at 3, 6, and 9 years. RESULTS: The median follow-up time was 7.1 years, during which 185 patients (13.4%) experienced the outcome. Higher per-patient PAV (per 1%) was consistently and independently associated with increased event rate across all three timepoints (aHR 1.035-1.047, all p < 0.001). Lower regional hMBF (per 0.1 mL/min/g) was independently associated with events at 3 years (aHR 1.050, p = 0.004) and 6 years (aHR 1.028, p = 0.024), but not at 9 years (aHR 1.020, p = 0.063). After excluding early revascularization patients, regional hMBF remained associated with outcomes at all timepoints. CONCLUSIONS: Plaque burden and regional hMBF are independent markers of cardiovascular risk. Plaque burden remained consistently associated with adverse clinical outcomes throughout follow-up, whereas regional hMBF was primarily related to short- and intermediate-term events, likely influenced by the effects of myocardial revascularization.

AIMS: Adherence with a holistic or integrated care management of atrial fibrillation (AF) based on the AF better care (ABC) pathway has been associated with improved clinical outcomes. Two prospective randomized trials (mAFA and MIRACLE-AF) have evaluated this approach. The multicentre mAFA-II trial delivered the ABC pathway via mobile health using an mAFA App, while the MIRACLE-AF trial relied on village doctors supported by telehealth in rural communities. We conducted a pooled analysis of individual participant data to assess the overall efficacy of ABC pathway-based management in patients with AF. METHODS AND RESULTS: We combined patient-level data from the mAFA-II and MIRACLE-AF trials. The primary endpoint was defined as a composite of all-cause mortality, ischaemic stroke, haemorrhagic stroke, heart failure (HF), acute coronary syndrome (ACS), and major bleeding events. The secondary endpoints included individual components and two grouped outcomes: all stroke and HF/ACS. A one-stage marginal Cox proportional hazards model stratified by trial and with robust standard errors clustered at the site level was used, with adjustment for CHA2DS2-VASc and other clinically relevant baseline variables. Cumulative event rates were estimated using Kaplan-Meier methods. Subgroup and sensitivity analyses were conducted to assess the robustness of the findings. Between-trial heterogeneity was further explored using a two-stage approach, incorporating trial-level effect estimates and inverse-variance weighting. We studied 4363 patients with AF [mean age 70.3 (SD 12.8) years; 60.5% male]. During 0.8 [SD 0.4] years of follow-up, the primary endpoint occurred in 329 (7.5%). Kaplan-Meier curves demonstrated lower cumulative incidence of events in the intervention group. On multivariable mixed-effects Cox models, the intervention group demonstrated a significantly lower risk of the primary endpoint compared to the control group (adjusted hazard ratio: 0.72; 95% confidence interval: 0.56-0.93). Subgroup analyses suggested potential effect modification, whereas sensitivity analyses consistently supported the primary findings. A two-stage analysis showed directionally consistent effects across trials for the primary endpoint. CONCLUSION: In this pooled individual participant data from two prospective randomized trials, ABC pathway-based integrated care was associated with improved clinical outcomes in patients with AF vs. usual care, with the observed benefit primarily driven by reductions in HF/ACS-related events rather than classical AF-specific outcomes, supporting further implementation studies and context-specific adoption in clinical practice.

AIMS: : Sport-type classification frameworks recommended by European (ESC) and American (AHA/ACC) guidelines are used to contextualize cardiac remodelling in athletes but remain unvalidated against cardiac magnetic resonance (CMR) phenotypes. We aimed to evaluate whether sport classifications predict CMR-determined cardiac remodelling phenotypes in elite athletes. METHODS AND RESULTS: : We included 1,024 individuals: 775 elite athletes (310 women, 48 disciplines) and 249 controls. Athletes were classified by the ESC (four-category) and AHA/ACC (static-dynamic, four-quadrant) frameworks. CMR metrics were transformed to sex-specific z-scores (remodelling: z≥1.645). Because no CMR convention defines geometric phenotypes in athletes, the most strongly associated CMR metric was used to define each framework's assumed phenotype. Performance was evaluated at population (R2) and individual (balanced accuracy) levels. ESC categories were most strongly associated with RVEDV (R2=0.170); RV remodelling prevalence increased from skill to endurance (8.3%-62.2%; OR 3.82 per category; P<0.001). The AHA/ACC static component was most strongly associated with LV mass (R2=0.077) and the dynamic component with RVEDV (R2=0.072). Individual-level discrimination was poor: balanced accuracy was 34.2% (ESC) and 37.7% (AHA/ACC) (vs 25% chance). LV mass and RVEDV showed coupled increases (R2=0.23), with 67% of athletes demonstrating concordant patterns rather than discrete static or dynamic phenotypes. Misclassification was most pronounced for predominantly high-static athletes, of whom 73.8% showed normal geometry rather than expected LV hypertrophy (17.5%). CONCLUSIONS: : ESC and AHA/ACC sport classifications capture population-level remodelling but cannot reliably be used to predict individual cardiac phenotypes. In individual athletes interpretation should prioritise observed mass-volume relationships and the overall clinical context rather than sport type alone.

Premature ventricular complexes (PVCs) are common cardiac arrhythmias that can lead to cardiomyopathy when frequent. Post-extrasystolic potentiation (PESP), which is the transient increase in contractility following a PVC, may serve as a predictive marker for heart failure risk; yet, the underlying calcium-mediated mechanisms and their relative contribution compared to loading conditions remain poorly understood. We integrated a mechanochemical model coupling intracellular calcium dynamics to sarcomere mechanics within the CircAdapt closed-loop cardiovascular framework. A novel calcium source model incorporating the force-interval relationship was calibrated using experimental canine data. We simulated single PVCs across varying coupling intervals and systematically investigated the contributions of calcium dynamics versus loading conditions to PESP, quantified as changes in systolic blood pressure (∆SBP), maximum rate of left ventricular pressure rise (∆max(dP/dt)), and left ventricular ejection fraction (∆LVEF). The calcium-based force-interval relationship reproduced experimental mechanical restitution curves with high accuracy (RMSE 9.59 ± 0.08%). Shorter coupling intervals reduced premature beat contractility while enhancing PESP in subsequent beats. Systematic variation of preload, afterload, and intrinsic contractility revealed that calcium dynamics reproduce the observed PESP patterns, with loading conditions as modulators. Notably, ∆max(dP/dt) and ∆SBP responded differently, with ∆SBP exhibiting complex non-monotonic behavior. The model qualitatively reproduced pressure-volume patterns from a single clinical quadrigeminy case. This study demonstrates that a calcium-based force-interval formulation reproduces the qualitative features of PESP within this framework, with preload and afterload modulating the pattern of beat-to-beat pressure response. The divergent behavior among contractility metrics emphasizes the need for multimetric assessment. This framework enables distinguishing intrinsic myocardial dysfunction from extrinsic loading effects, facilitating patient-specific risk stratification in PVC-induced cardiomyopathy.

BACKGROUND: RADICAL PC-2 (RAndomizeD Intervention for CArdiovascular and Lifestyle Risk Factors in Prostate Cancer Patients) was a pragmatic randomized controlled trial that tested whether routine referral to a cardiologist or an internist for cardiovascular (CV) risk-factor and lifestyle modification improves outcomes in patients with prostate cancer or receiving androgen-deprivation therapy. The intervention group had more favorable outcomes overall, driven by improved cholesterol control, with no differences in rates of CV death, myocardial infarction (MI), stroke, or heart failure (HF). OBJECTIVES: The authors aim to identify patient subgroups more likely to benefit from routine CV care referral. METHODS: Prespecified subgroup analyses were used to assess whether patients at higher CV risk derived greater benefit from specialist referral, with treatment-effect heterogeneity assessed using interaction tests. The first primary outcome was a hierarchical composite of CV death, MI, stroke, HF, suboptimal cholesterol, and systolic blood pressure (SBP) control, evaluated using the win ratio. The second primary outcome was time to CV death, MI, stroke, or HF. RESULTS: Among 2487 participants, treatment effect differed by baseline total cholesterol ≤4 mmol/L vs >4 mmol/L (interaction P = 0.016), with respective win ratios of 1.21 (95% CI: 0.89-1.64) and 1.75 (95% CI: 1.51-2.03), and by baseline BP status (SBP ≥130 mm Hg or diastolic BP ≥80 mm Hg vs BP <130/80 mm Hg; interaction P = 0.003), with respective subdistribution HRs (sHRs) for CV death, MI, stroke, or HF of 0.86 (95% CI: 0.61-1.21) and 4.85 (95% CI: 1.65-14.26). The interaction for diabetes did not reach statistical significance (interaction P = 0.054) although the intervention effect estimates suggested a potential difference by diabetes status, with sHRs of 0.53 (95% CI: 0.24-1.15) among participants with diabetes and 1.25 (95% CI: 0.88-1.78) among participants without diabetes. The win ratio was higher among participants with total cholesterol >4 mmol/L, and sHRs were numerically lower among those with SBP ≥130 mm Hg or diastolic BP ≥80 mm Hg and diabetes. CONCLUSIONS: Uncontrolled modifiable CV risk factors may identify patients with prostate cancer who are more likely to benefit from routine CV care referral.

BACKGROUND: Safe and effective decongestion remains an important therapeutic goal in patients hospitalized for heart failure. OBJECTIVES: The authors evaluated the effect of dapagliflozin on multiple clinically relevant measures of congestion among patients hospitalized for heart failure. METHODS: This was a prespecified analysis of DAPA ACT HF-TIMI 68 (Dapagliflozin Effect on Cardiovascular Events in Acute Heart Failure-Thrombolysis in Myocardial Infarction 68), a randomized, placebo-controlled trial evaluating in-hospital initiation of dapagliflozin on clinical outcomes through 2 months. The authors assessed placebo-adjusted changes from baseline in modified EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure) Composite Congestion Score (CCS), body weight, mean daily loop diuretic dose (furosemide 40 mg intravenous [IV] equivalents), and body weight adjusted for mean daily loop diuretic dose (diuretic efficiency) at 1 week, 1 month, and 2 months using linear mixed-effects models for repeated measures. RESULTS: At randomization, 12%, 63%, and 24% had no congestion (CCS 0), mild-to-moderate congestion (CCS 1-3), and severe congestion (CCS 4-9), respectively. Compared with placebo, dapagliflozin improved all decongestion-related endpoints by 1 week, including CCS (least squares mean difference [LSMD]: -0.18; 95% CI: -0.33 to -0.04; P = 0.011), body weight (LSMD: -0.60 kg; 95% CI: -0.95 to -0.26; P < 0.001), mean daily loop diuretic dose (LSMD: -0.12 furosemide 40-mg IV equivalents; 95% CI: -0.22 to -0.02; P = 0.014), and diuretic efficiency (LSMD: -0.93 kg/furosemide 40 mg IV equivalents; 95% CI: -1.61 to -0.25; P = 0.008). These improvements were sustained through 2 months, with progressive increases in diuretic efficiency through 2 months (LSMD: -1.99 kg/furosemide 40 mg IV equivalents; 95% CI: -3.19 to -0.78; P < 0.001). CONCLUSIONS: In-hospital initiation of dapagliflozin led to modest but significant improvements across multiple measures of congestion within 1 week that were sustained through 2 months. Diuretic efficiency progressively improved through 2 months. (Dapagliflozin Effect on Cardiovascular Events in Acute Heart Failure-Thrombolysis in Myocardial Infarction 68 [DAPA ACT HF-TIMI 68]; NCT04363697).

BACKGROUND: Vutrisiran, an RNA interference therapeutic that suppresses hepatic transthyretin production, improved survival and cardiovascular outcomes in transthyretin amyloidosis with cardiomyopathy (ATTR-CM) in HELIOS-B (A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy). Tafamidis, a transthyretin stabilizer, also improves clinical outcomes. Although combining these therapies is mechanistically appealing, clinical evidence supporting this approach is limited. OBJECTIVES: We sought to evaluate whether the treatment effects of vutrisiran differed according to baseline tafamidis use in HELIOS-B. METHODS: In HELIOS-B, patients with ATTR-CM were randomized to vutrisiran 25 mg or placebo every 3 months for up to 36 months, with tafamidis use permitted and stratified. We assessed treatment effects according to baseline tafamidis use for the primary outcome of all-cause mortality and recurrent cardiovascular events and secondary endpoints, including individual components of the primary outcome, composite of all-cause mortality, cardiovascular events and outpatient worsening heart failure events, functional capacity (6-minute walk distance), and health status (Kansas City Cardiomyopathy Questionnaire-overall summary score [KCCQ-OSS]). RESULTS: Among 654 participants, 259 (40%) were receiving tafamidis at baseline. Patients on tafamidis were slightly younger and had higher baseline 6-minute walk distance and higher KCCQ-OSS, while baseline characteristics were generally balanced between randomized groups. The treatment effect estimates of vutrisiran compared with placebo for the primary outcome were directionally consistent across baseline tafamidis strata (rate ratio: 0.79 [95% CI: 0.51-1.21] with tafamidis vs 0.67 [95% CI: 0.49-0.93] without), with no statistically significant interaction (P = 0.55). Similar patterns were observed for all-cause mortality, cardiovascular events, and outpatient worsening heart failure (all P > 0.20), although the magnitudes of the estimated effects were numerically smaller among patients receiving tafamidis at baseline. Vutrisiran preserved 6-minute walk distance in both baseline tafamidis strata (P = 0.24), whereas improvement in KCCQ-OSS appeared attenuated among patients receiving tafamidis at baseline. CONCLUSIONS: Treatment effect estimates for vutrisiran on clinical outcomes were consistent across baseline tafamidis strata, with no statistically significant interaction according to baseline tafamidis use, with reduced effect size noted in those receiving baseline stabilizers in comparison to monotherapy. These data underscore the need for future prospective studies examining combination therapy in this population. (HELIOS-B: A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy; NCT04153149).

BACKGROUND: C-reactive protein (CRP) is a biomarker of vascular inflammation with prognostic value for future cardiovascular events. This meta-analysis investigates the effect of colchicine, a cheap and widely available anti-inflammatory medication, on CRP levels in the months following myocardial infarction (MI). METHODS: PubMed, EMBASE, and Cochrane were queried from inception to April 2026 to identify randomized controlled trials comparing colchicine to placebo for at least 1 month following MI. The primary outcome was mean CRP level at follow-up. Effect estimates were pooled with random-effects models and reported as mean differences for continuous variables using 95% confidence intervals. RESULTS: Four studies met inclusion criteria comprising 3384 patients (mean age 60.7 years; 78.3% male), including 1669 patients randomized to the colchicine arm, and 1715 to placebo. Median follow-up period was 3 months (range: 1-6 months). Colchicine following MI resulted in a statistically significant decrease in mean CRP level (mg/L) at follow-up versus placebo (MD: -0.69; [-1.21, -0.17], p = 0.009). Heterogeneity of effect size estimates was high (I = 97%). CONCLUSION: Daily colchicine following MI decreases CRP at a median follow-up period of 3 months compared to placebo. The correlation between CRP reduction with colchicine and adverse cardiovascular event reduction warrants additional study.

IMPORTANCE: Gene-silencing therapies reduce hepatic transthyretin (TTR) production and have been evaluated in phase 3 trials in TTR amyloid cardiomyopathy (ATTR-CM). However, differences in trial design and background therapies have limited assessment of the overall treatment effect and its consistency according to baseline TTR stabilizer use. OBJECTIVE: To assess the effect of TTR gene-silencing therapies in patients with ATTR-CM. DATA SOURCES AND STUDY SELECTION: PubMed was searched through June 15, 2026, for randomized, placebo-controlled, phase 3 outcome trials of gene-silencing therapies in ATTR-CM. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted data, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Fixed-effects meta-analysis estimated rate ratios (RRs) or hazard ratios (HRs) with 95% CIs. MAIN OUTCOMES AND MEASURES: The prespecified primary outcome was the composite of all-cause mortality and recurrent cardiovascular events. Secondary outcomes included all-cause mortality, cardiovascular death, time to first primary outcome, functional capacity (6-minute walk distance), and health status (Kansas City Cardiomyopathy Questionnaire-Overall Summary Score). RESULTS: A total of 2 studies (HELIOS-B and CARDIO-TTRansform) met the inclusion criteria and included 2086 patients with ATTR-CM. The studies included 1902 men with a median age of 77 years (range for HELIOS-B, 45-85 years; for CARDIO-TTRansform, 41-91 years). Gene-silencing therapy reduced the primary end point by 20% (RR, 0.80; 95% CI, 0.69-0.94; P = .006), with no heterogeneity between trials (P for heterogeneity = .28). Gene-silencing therapy also reduced the risk of all-cause death (HR, 0.74; 95% CI, 0.61-0.91) and time to first all-cause death or cardiovascular events (HR, 0.77; 95% CI, 0.67-0.89) compared with placebo. Gene silencers preserved 6-minute walk distance (placebo-corrected difference, +22.2 m; 95% CI, 14.3-30.0) and Kansas City Cardiomyopathy Questionnaire-Overall Summary Score (+4.5; 95% CI, 2.7-6.2), with no evidence of between-trial heterogeneity. Treatment effects on primary end points differed according to baseline stabilizer use, with significant benefits observed among patients not receiving background stabilizer therapy (RR, 0.69; 95% CI, 0.57-0.85) and no significant incremental benefit observed for those receiving concomitant stabilizer at baseline (RR, 0.97; 95% CI, 0.77-1.23; P for heterogeneity = .03). Similar heterogeneity was observed for functional capacity and health status. CONCLUSIONS AND RELEVANCE: The findings from this meta-analysis support TTR gene silencing for ATTR-CM. The attenuated benefit observed for patients receiving concomitant TTR stabilizer therapy may reflect residual differences in case mix, disease duration, or magnitude of TTR suppression or a true ceiling on additional benefit of gene silencing in the setting of background TTR stabilization. TRIAL REGISTRATION: PROSPERO registration: CRD420261421656. ClinicalTrials.gov Identifier: HELIOS-B, NCT04153149; and CARDIO-TTRansform, NCT04136171.

BACKGROUND: Whether COVID-19 vaccination is associated with lower long-term cardiovascular risk after SARS-CoV-2 infection and how much infection prevention mediates this association remain unclear. OBJECTIVE: To evaluate associations of vaccination, including its timing relative to SARS-CoV-2 infection, with post-COVID-19 cardiovascular disease (CVD), and quantify the contribution of infection prevention. METHODS: This statewide population-based cohort study used linked administrative health data for 2,391,456 adults in Victoria, Australia (2019-2025). Associations of pre- or post-infection vaccination with major adverse cardiovascular events (MACE; primary outcome), stroke, heart failure, acute myocardial infarction (AMI), acute coronary syndrome (ACS), atrial fibrillation (AF), and venous thromboembolism (VTE) were evaluated using time-varying Cox proportional hazards regression, causal mediation analysis, and target trial emulation. RESULTS: Vaccination was associated with lower hazards of MACE and all secondary outcomes. Estimated absolute risk reductions for MACE were 0.21% with pre-infection vaccination and 0.24% with post-infection vaccination. Three or more vaccine doses were associated with progressively lower hazards across cardiovascular outcomes. Mediation analysis suggested that approximately 68% of the estimated association between vaccination and lower post-COVID cardiovascular risk was not explained by prevention of SARS-CoV-2 infection. CONCLUSION: Vaccination before or after SARS-CoV-2 infection was associated with lower hazards of post-COVID-19 cardiovascular outcomes, with stronger observed associations at higher dose numbers. Most of the estimated association was not explained by infection prevention alone. These findings support COVID-19 vaccination as an important component of strategies to reduce the burden of post-COVID-19 CVD while highlighting the need for further studies to clarify the mechanisms underlying these associations.