Daily Cardiology Research Analysis
Across cardiology this week: a meta-analysis of 26 randomized trials suggests semaglutide reduces new-onset atrial fibrillation, particularly with oral formulation. Large multicenter data indicate left bundle branch area pacing (LBBAP) lowers heart failure hospitalizations and procedural complications versus biventricular pacing for cardiac resynchronization. A randomized trial in HFpEF with chronotropic incompetence shows supervised aerobic plus moderate-to-high intensity strength training yiel
Summary
Across cardiology this week: a meta-analysis of 26 randomized trials suggests semaglutide reduces new-onset atrial fibrillation, particularly with oral formulation. Large multicenter data indicate left bundle branch area pacing (LBBAP) lowers heart failure hospitalizations and procedural complications versus biventricular pacing for cardiac resynchronization. A randomized trial in HFpEF with chronotropic incompetence shows supervised aerobic plus moderate-to-high intensity strength training yields the largest gains in peak VO2 and improves chronotropic response and quality of life.
Research Themes
- Metabolic therapy reducing arrhythmia risk (GLP-1RA and incident AF)
- Physiologic conduction-system pacing for CRT (LBBAP vs BVP)
- Exercise prescription optimization in HFpEF with chronotropic incompetence
Selected Articles
1. Reduction of New Onset of Atrial Fibrillation in Patients Treated with Semaglutide: An updated systematic review and meta regression analysis of randomized controlled trials.
Pooling 26 RCTs (n=48,583), semaglutide reduced incident atrial fibrillation by 17% versus controls (OR 0.83) with no heterogeneity. The effect was stronger with oral semaglutide (OR 0.48) and persisted across baseline characteristics and in trials without SGLT2 inhibitors.
Impact: This synthesis of randomized evidence suggests GLP-1 receptor agonists, particularly oral semaglutide, may confer primary arrhythmia prevention beyond glycemic and weight control. It could influence cardiometabolic therapy selection in individuals at risk of AF.
Clinical Implications: When choosing antidiabetic/anti-obesity therapy for patients at elevated AF risk, semaglutide—especially oral—may offer incremental AF risk reduction. However, dedicated AF prevention trials and standardized AF ascertainment are needed before guideline changes.
Key Findings
- Across 26 RCTs (48,583 participants), semaglutide reduced new-onset AF by 17% versus control (OR 0.83, 95% CI 0.70–0.98; I²=0%).
- Oral semaglutide showed a 52% reduction in incident AF (OR 0.48, 95% CI 0.24–0.95).
- Effect size remained significant in studies without SGLT2 inhibitors (OR 0.79) and was not modified by baseline BMI or HbA1c in meta-regression.
Methodological Strengths
- Meta-analysis restricted to randomized controlled trials with large aggregate sample and no heterogeneity (I²=0%).
- Pre-specified subgroup/meta-regression analyses examining formulation, concomitant therapies, and baseline covariates.
Limitations
- AF was not a primary endpoint in most included trials; ascertainment methods likely varied.
- Limited data to compare oral vs injectable head-to-head and potential publication/reporting biases were not fully detailed.
Future Directions: Conduct dedicated, adjudicated AF prevention trials of semaglutide (oral vs injectable), evaluate mechanisms (weight loss, inflammation, autonomic effects), and assess additive effects with SGLT2 inhibitors.
AIM: This meta-analysis aims to evaluate the effect of semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RAs), on new-onset atrial fibrillation (AF) in randomized clinical trials (RCTs). METHODS AND RESULTS: Twenty-six RCTs involving 48,583 participants (of whom 25,879 on semaglutide) with 541 new onset AF were analyzed. Semaglutide treatment resulted in a 17% reduction in AF incidence compared to controls (OR 0.83, 95% CI 0.70-0.98, p = 0.03) with no heterogeneity (I² = 0%). The effect was more pronounced with the oral formulation, which reduced AF incidence by 52% (OR 0.48, 95% CI 0.24-0.95, p = 0.04), while studies with active comparators showed a 59% reduction in AF risk (OR 0.41, 95% CI 0.20-0.83, p = 0.01). In trials without Sodium-Glucose Co-Transporter 2 inhibitors (SGLT2i) concomitant therapy, there was a significant reduction of 21% in new-onset AF (OR 0.79, 95% CI, 0.63-0.99; p=0.04). Meta-regression revealed no influence of baseline covariates, including BMI and HbA1c. An additional meta-regression analysis evaluating the percentage of patients on SGLT2 inhibitors as a potential moderator revealed no statistically significant association (p= 0.336). CONCLUSIONS: Treatment with semaglutide significantly reduces the incidence of new-onset AF. This effect appears more evident with the oral formulation and independent of baseline characteristics. This study evaluates whether semaglutide can reduce the risk of developing atrial fibrillation (AF). By analyzing data from 26 randomized controlled trials involving about 49,000 participants, the findings highlight semaglutide's potential role in offering additional cardiovascular benefits beyond its established effects on weight loss and blood sugar control. Key Findings:Treatment with semaglutide reduced the risk of new-onset atrial fibrillation by 17%, with the strongest effects observed in its oral formulation.The reduction in AF risk was independent of patient characteristics such as age, body mass index, or blood sugar levels and was particularly significant in studies without other concurrent therapies like SGLT2 inhibitors.
2. Left bundle branch area pacing compared with biventricular pacing for cardiac resynchronization therapy in patients with left ventricular ejection fraction ≤50%: Results from the International Collaborative LBBAP Study (I-CLAS).
In a multicenter propensity-matched cohort (n=1,560), LBBAP achieved shorter paced QRS, reduced the composite of death or first HF hospitalization (HR 0.81), and lowered HF hospitalizations (HR 0.63) versus biventricular CRT, with fewer procedural complications. Mortality did not differ significantly.
Impact: This large multicenter analysis supports conduction-system pacing as a pragmatic alternative to biventricular CRT, with fewer HF hospitalizations and complications—data likely to influence device strategy pending RCT confirmation.
Clinical Implications: For CRT candidates with LVEF ≤50%, LBBAP may be considered to enhance resynchronization and reduce HF hospitalizations with lower procedural risk, especially where coronary sinus anatomy limits BVP. Shared decision-making should weigh nonrandomized evidence.
Key Findings
- In propensity-matched patients (n=780 per group), LBBAP shortened paced QRS (129±19 ms vs 143±22 ms; P<.001).
- LBBAP reduced death or first HF hospitalization (HR 0.81, 95% CI 0.66–0.98) and HF hospitalization alone (HR 0.63, 95% CI 0.49–0.82).
- Procedural complications were lower with LBBAP (3.5% vs 6.5%), with no significant difference in all-cause mortality.
Methodological Strengths
- Large, multicenter cohort with propensity score matching and time-to-event analyses.
- Consistent improvements in electrical and clinical endpoints with supportive safety signals.
Limitations
- Observational design with potential residual confounding and selection bias.
- Follow-up duration and adjudication details are not fully specified; randomized trials are needed.
Future Directions: Undertake randomized head-to-head LBBAP vs BVP trials powered for mortality/HF hospitalization and remodeling, with standardized implantation and long-term device performance tracking.
BACKGROUND: Cardiac resynchronization therapy (CRT) with biventricular pacing (BVP) is an established treatment of heart failure with reduced ejection fraction and wide QRS. Left bundle branch area pacing (LBBAP) has emerged as a physiologic alternative by directly engaging the His-Purkinje system, potentially improving electrical resynchronization and clinical outcomes. OBJECTIVE: The aim of the study was to compare the clinical outcomes between BVP and LBBAP in patients with left ventricular ejection fraction (LVEF) ≤50% undergoing CRT. METHODS: This multicenter observational study included patients with LVEF ≤50% receiving CRT with either LBBAP or BVP at 18 centers from January 2018 to June 2023. The primary outcome was a composite of all-cause mortality or first heart failure hospitalization (HFH). Secondary outcomes included separate analyses of HFH and all-cause mortality. Propensity score matching was used to balance baseline characteristics. Kaplan-Meier curves, Cox proportional hazards models, and competing risk analyses were performed. RESULTS: A total of 2579 patients were included (BVP, 1118; LBBAP, 1461). In the propensity score-matched cohort (BVP, 780; LBBAP, 780), LBBAP demonstrated shorter paced QRS duration (129 ± 19 ms vs 143 ± 22 ms; P < .001). LBBAP was associated with a significantly lower risk of the composite primary outcome (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.66-0.98; P = .048) and reduced HFH (HR, 0.63; 95% CI, 0.49-0.82; P < .001). No significant difference in all-cause mortality was observed (HR, 0.82; 95% CI, 0.63-1.07; P = .156). Procedural complications were lower with LBBAP (3.5% vs 6.5%, P = .004). CONCLUSION: LBBAP was associated with superior electrical resynchronization, fewer HFHs, and lower procedural complications compared with BVP in patients with LVEF <50% requiring CRT. Randomized trials are needed to confirm long-term benefits.
3. Effect of Exercise Training in Patients with Chronotropic Incompetence and Heart Failure with Preserved Ejection Fraction: The TRAINING-HR Randomized Clinical Trial.
In 80 HFpEF patients with chronotropic incompetence, all supervised programs improved peak VO2 versus non-supervised advice, with aerobic plus moderate-to-high intensity strength training yielding the largest gain (+4.0 mL/kg/min) and superiority over aerobic alone. Supervised training also improved chronotropic index and KCCQ.
Impact: Provides randomized evidence to refine cardiac rehabilitation in HFpEF with chronotropic incompetence, supporting multidimensional (aerobic plus strength) supervised programs to optimize functional capacity and patient-reported outcomes.
Clinical Implications: For HFpEF with chronotropic incompetence, prescribe supervised aerobic training combined with moderate-to-high intensity resistance training to maximize peak VO2, improve chronotropic response, and enhance quality of life; avoid relying on unsupervised advice alone.
Key Findings
- Supervised training improved peak VO2 versus non-supervised advice: AT/HRT +4.0, AT/LRT +3.6, AT +2.9 mL/kg/min (all p<0.001).
- AT/HRT was superior to aerobic training alone for peak VO2 (between-group Δ+1.1 mL/kg/min; p=0.046).
- Chronotropic index and KCCQ improved with supervised programs across groups.
Methodological Strengths
- Randomized, registered, multi-arm trial with clinically meaningful endpoints (peak VO2, chronotropic index, KCCQ).
- Direct comparison of aerobic versus combined aerobic-strength programs enables actionable exercise prescription.
Limitations
- Modest sample size and 12-week duration limit generalizability and long-term outcome assessment.
- Single-center setting and lack of hard clinical endpoints (e.g., hospitalization) in the trial period.
Future Directions: Test longer-duration supervised multidimensional exercise programs with hard outcomes, stratify by chronotropic reserve and sex, and explore remote/sensor-supported supervision models.
AIMS: Chronotropic incompetence (ChI) in heart failure with preserved ejection fraction (HFpEF) is associated with a reduced exercise capacity. The role of exercise training in improving chronotropic response (ChR) and functional capacity in these patients remains uncertain. This study assessed the effects of four different exercise programs on peak oxygen consumption (peakVO₂), Kansas City Cardiomyopathy Questionnaire (KCCQ) score and ChR in patients with the ChI HFpEF phenotype. METHODS: In this randomized clinical trial, 80 symptomatic (NYHA class II-III/IV) patients with the ChI HFpEF phenotype were randomized (1:1:1:1) to one of four interventions: (a) a 12-week supervised aerobic training (AT) program, (b) AT with low-intensity strength training (AT/LRT), (c) AT with moderate- to high-intensity strength training (AT/HRT), or (d) non-supervised exercise recommendations (ER). The primary endpoint was the change in peakVO2 at 12 weeks. Secondary endpoints included changes in ChR and KCCQ. A linear regression model was used. RESULTS: The mean age of 80 participants was 75.1±7.2 years, and 59.6% were women. Baseline values for peakVO2, chronotropic index, and KCCQ were 11.8±2.6 mL/kg/min, 0.4±0.2, and 63.5±17.9, respectively, with no significant differences across arms. All supervised training programs led to significant improvements in peakVO2 compared to ER: AT/HRT: Δ+4.0, (95% CI: 2.9 to 5.1, p< 0.001), AT/LRT: Δ+3.6, (95% CI: 2.5-4.6, p<0.001), and AT: Δ+2.9, (95% CI: 1.9-4.0, p<0.001). AT/HRT was superior over AT alone: Δ+1.1, (95% CI, 0.1 to 2.2, p=0.046). Likewise, supervised exercise improved ChR and KCCQ without statistical differences between groups. CONCLUSIONS: Different supervised exercise training improved peakVO2, ChR and KCCQ in patients with ChI HFpEF phenotype. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT05649787). This study investigates the impact of different exercise interventions on improving functional capacity, heart rate response, and quality of life in patients with heart failure with preserved ejection fraction and chronotropic incompetence.Supervised exercise training significantly improved peak oxygen consumption, heart rate response during exercise, and quality of life compared to non-supervised recommendations.Programs combining aerobic and moderate to high-intensity strength training offered the most pronounced benefits, highlighting the importance of tailored, multidimensional exercise interventions for this patient population.