Karakasis, Paschalis

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

Abstract Aims Conduction system pacing (CSP) has emerged as a physiologic alternative to cardiac resynchronization therapy (CRT) with biventricular pacing (BiVP) in heart failure with reduced ejection fraction (HFrEF), yet its comparative effects remain uncertain. This meta-analysis sought to compare outcomes of CSP vs. BiVP in patients with HFrEF undergoing CRT. Methods and results MEDLINE, Embase, Scopus, and the Cochrane Database were searched through 4 May 2026. Randomized controlled trials (RCTs) were synthesized using random-effects meta-analysis. Thirteen RCTs including 1320 participants were analysed (657 CSP, 663 BiVP). Conduction system pacing was associated with a lower risk of the composite of hospitalization for heart failure (HHF) or all-cause mortality compared with BiVP (46 vs. 83 events; odds ratio [OR] 0.51, 95% confidence interval [CI] 0.28–0.93). No significant differences were observed for HHF alone (OR 0.68, 95% CI 0.36–1.27) or all-cause mortality (OR 0.75, 95% CI 0.36–1.58). Conduction system pacing was associated with greater improvement in the 6-min walk distance (mean difference [MD] 21.53 m, 95% CI 4.33–38.73) and New York Heart Association functional class (standardized mean difference [SMD] −0.27, 95% CI −0.47 to −0.07), but not quality of life. Conduction system pacing also reduced QRS duration compared with BiVP (MD −10.94 ms, 95% CI −17.55 to −4.34), with no significant differences in left ventricular ejection fraction, left ventricular end-systolic volume, overall pacing threshold, total procedure time, fluoroscopy time, any complication, or reintervention. Conclusion In patients with HFrEF undergoing CRT, CSP is associated with lower composite risk of HHF or all-cause mortality compared with BiVP. Conduction system pacing is also associated with improved functional capacity, without significant differences in safety or procedural outcomes.

ABSTRACT Introduction Cardiac myosin inhibitors (CMIs) improve hemodynamics and symptoms in hypertrophic cardiomyopathy (HCM), but recent real‐world data have raised concerns regarding an increased risk of atrial fibrillation (AF). We sought to reassess AF risk using randomized controlled trial (RCT) evidence and to contextualize discrepancies with observational reports. Methods and Results We performed a systematic review and random‐effects meta‐analysis of RCTs evaluating the effect of CMIs on incident AF in HCM. MEDLINE, Scopus, and CENTRAL were searched through November 25, 2025. Eight RCTs ( n = 1581) comparing mavacamten or aficamten with placebo or active control were included. Event counts were pooled as risk ratios (RRs) with 95% confidence intervals (CIs). CMIs were not associated with increased AF risk (RR 1.11, 95% CI 0.62–1.98; heterogeneity I 2 = 0%). No differences were observed between mavacamten and aficamten, with consistent findings across HCM subtypes (obstructive and non‐obstructive). Importantly, most trials (7/8) excluded patients with uncontrolled, persistent, or permanent AF, five excluded paroxysmal AF at screening, and one excluded any AF history. Baseline left atrial enlargement was generally in the mild to moderate range across trials, suggesting limited representation of high‐risk AF phenotypes. Conclusion Randomized evidence to date does not demonstrate an increased AF risk with CMIs. Differences between RCT populations and real‐world cohorts, including restrictive AF eligibility criteria, lower baseline atrial remodeling, and limited rhythm surveillance may explain discordant observational findings and highlight the need for longitudinal monitoring in clinical practice.

Abstract Aims Intracardiac echocardiography (ICE) is increasingly incorporated into atrial fibrillation (AF) ablation workflows, enabling real-time anatomic guidance and procedural precision. Nevertheless, ICE utilization shows substantial geographic variability, and its clinical benefit remains incompletely understood. This meta-analysis evaluated the efficacy, safety, and procedural performance of ICE-guided vs. non-ICE-guided AF ablation. Methods and results MEDLINE, the Cochrane Library, and Scopus were systematically searched through 3 August 2025. Three reviewers independently performed study selection, data extraction, and risk-of-bias assessment. Random-effects models were used to pool data from 44 AF ablation studies comprising 482 043 patients. ICE guidance was associated with lower odds of any complication (OR 0.69; 95% CI 0.53–0.89), including significant reductions in cardiac tamponade (OR 0.58; 95% CI 0.53–0.62) and mortality (OR 0.21; 95% CI 0.16–0.27). ICE-guided ablation was also associated with shorter total procedure and fluoroscopy times, reduced radiation exposure, and lower contrast agent utilization. Atrial tachyarrhythmia (AT) recurrence did not differ between groups (OR 0.92; 95% CI 0.79–1.06). However, ICE use was associated with higher odds of first-pass pulmonary vein isolation (OR 1.62; 95% CI 1.09–2.41) and successful isolation of all pulmonary veins at the end of the procedure (OR 2.12; 95% CI 1.37–3.27), and lower odds of repeat ablation (OR 0.65; 95% CI 0.59–0.72). Conclusion ICE-guided AF ablation is associated with superior procedural safety and efficiency and a similar risk of AT recurrence compared to non-ICE-guided approaches.

Abstract Background Although a rhythm control strategy is associated with an overall better prognosis in atrial fibrillation (AF), current guidelines suggest that only highly selected asymptomatic patients may be considered candidates for AF catheter ablation. Therefore, this study aimed to evaluate the association between symptom status and clinical outcomes in patients with AF. Methods A comprehensive search of Medline, the Cochrane Library, and Scopus was conducted up until September 30, 2024. Study selection, data extraction, and quality assessment were performed independently by three reviewers. Random-effects meta-analyses were used to pool the evidence. Results A total of 36 studies, comprising 217,850 participants, were included. Frequentist analysis revealed no significant difference between symptomatic and asymptomatic AF patients in terms of all-cause mortality [hazard ratio (HR) = 0.97, 95% confidence interval (CI)= (0.80, 1.17)], cardiovascular mortality (HR= 1.04, 95% CI= [0.72, 1.49]), thromboembolism (HR= 1.06, 95% CI= [0.87, 1.28]), stroke (HR= 1.06, 95% CI= [0.84, 1.34]), hospitalization (HR= 1.34, 95% CI= [0.89, 2.02]), and myocardial infarction (HR= 0.98, 95% CI= [0.70, 1.36]). However, symptomatic patients exhibited a 33% increased risk of new-onset heart failure (HR= 1.33, 95% CI= [1.19, 1.49]) and a 30% reduced risk of progression to permanent AF (HR= 0.70, 95% CI= [0.54, 0.89]). Bayesian analysis produced similar results, although the association between symptom status and new-onset heart failure was not statistically significant [HR = 1.27, 95% credible interval (CrI)= (0.76, 1.93); Bayes factor (BF10)= 1.2]. Symptomatic patients had higher odds of receiving antiarrhythmic drugs (odds ratio [OR]= 1.64, 95% CI= [1.33, 2.03]) and ablation therapy (OR= 1.47, 95% CI= [1.06, 2.05]) compared to their asymptomatic counterparts. Conclusions The risk of major clinical outcomes does not significantly differ between AF patients with and without symptoms. However, asymptomatic patients have a higher risk of progressing to permanent AF.

Abstract Background and Aims Current guidelines suggest that asymptomatic atrial fibrillation (AF) is independently associated with increased risks of stroke and mortality compared with symptomatic AF. Considering that recent investigations have provided conflicting results, the present study aimed to evaluate the association between symptom status and clinical outcomes in patients with AF. Methods Medline, Cochrane Library, and Scopus were searched until 25 March 2024. Triple-independent study selection, data extraction and quality assessment were performed. Evidence was pooled using random-effects meta-analyses. Results Thirty-six studies (217 850 participants) were included. Based on the frequentist analysis, symptomatic individuals had no significant difference in the risk of all-cause mortality [hazard ratio (HR) .97, 95% confidence interval (CI) .80–1.17], cardiovascular mortality (HR 1.04, 95% CI .72–1.49), thromboembolism (HR 1.06, 95% CI .87–1.28), stroke (HR 1.06, 95% CI .84–1.34), hospitalization (HR 1.34, 95% CI .89–2.02), and myocardial infarction (HR .98, 95% CI .70–1.36), compared to the asymptomatic group. Symptomatic patients had a 33% increased risk of new-onset heart failure (HR 1.33, 95% CI 1.19–1.49) and a 30% lower risk of progression to permanent AF (HR .70, 95% CI .54–.89). The Bayesian analysis yielded comparable results, yet the association between symptom status and new-onset heart failure was not significant (HR 1.27, 95% credible interval .76–1.93; Bayes factor = 1.2). Symptomatic patients had higher odds of receiving antiarrhythmic drugs (odds ratio [OR] 1.64, 95% CI 1.33–2.03) and ablation therapy (OR 1.47, 95% CI 1.06–2.05) compared to asymptomatic cases. Conclusions The risk of major clinical outcomes did not differ between individuals with and without AF-related symptoms. Asymptomatic patients had a greater hazard of progression to permanent AF.