Background Conventional antiarrhythmic drugs that target cardiac ion channels carry proarrhythmic risks, highlighting the need for alternative therapeutic approaches. Cardiac nicotinic acetylcholine receptors (nAChRs) represent a novel electrophysiological target. Objectives The aim of this exploratory, proof-of-concept phase 2 trial was to evaluate the effect of varenicline, a partial nAChR agonist, on frequent premature ventricular complexes (PVCs) after myocardial infarction (MI) and to assess its short-term safety and biological target engagement. Methods In this multicenter, randomized, double-blind, placebo-controlled trial, adults with frequent PVCs (≥1,000/24 h) assessed using 72-hour ambulatory electrocardiographic monitoring at ≥4 weeks post-MI were randomly assigned (1:1) to varenicline 0.5 mg twice daily or matching placebo for 45 days, in addition to guideline-directed medical therapy. The primary endpoint was the percentage change in 24-hour PVC count from baseline to week 6. Key secondary endpoints included responder rate (≥50% reduction in PVC count) and the incidence of nonsustained ventricular tachycardia (VT). Results Among 118 randomized patients, varenicline produced a 60.1 percentage point greater reduction in PVC burden compared with placebo (95% CI: 21.3-98.8 percentage points; P = 0.001). The responder rate was higher with varenicline (67.8% vs 30.5%; RR: 2.22; 95% CI: 1.46-3.39; P < 0.0001), and nonsustained VT incidence was lower (20.3% vs 37.3%; RR: 0.49; 95% CI: 0.29-0.85; P = 0.007). No deaths or malignant ventricular arrhythmias occurred in the varenicline group, with comparable adverse event rates between groups. Conclusions In this phase 2 trial, varenicline significantly reduced PVC burden and nonsustained VT incidence in post-MI patients without evidence of a proarrhythmic effects. These findings support cardiac nAChRs as a potential antiarrhythmic target and justify further evaluation in larger outcome-driven trials. (Efficacy of Varenicline Tartrate in Treating Frequent Premature Ventricular Contractions: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial [Var-PVC]; NCT06780215)

The safety of multi-dose mesenchymal stem cell (MSC) regimens has seldom been systematically investigated. The PRIME-HFrEF (Prospective Randomized Controlled Study of Multiple Intravenous Infusions of Umbilical Cord-derived MSCs in Patients with Heart Failure and Reduced Ejection Fraction) trial was a single-center, randomized, placebo-controlled, investigator-initiated study (ClinicalTrials.gov identifier: NCT04992832) that enrolled 40 patients. The trial aimed to evaluate the safety of three intravenous infusions of Umbilical Cord-derived MSCs (UC-MSCs) administered at six-week intervals in patients with heart failure and reduced ejection fraction (HFrEF), while also collecting exploratory efficacy data. The primary safety endpoint was the incidence of serious adverse events (SAEs), and the primary efficacy endpoint was the change (Δ) in left ventricular ejection fraction (LVEF). Secondary efficacy endpoints included changes in right ventricular (RV) end-systolic and end-diastolic volumes (ESV and EDV). Thirty-nine patients completed 12 study visits over a 360-day follow-up period or until death. The incidence of SAEs did not differ significantly between treatment groups. However, UC-MSC-treated patients exhibited elevated D-dimer levels, suggesting a treatment-associated increase in coagulability. D-dimer levels were negatively correlated with LVEF, and no significant difference in ΔLVEF was observed between groups. In contrast, the improvement in ΔRVESV was significantly greater in the UC-MSC group than in placebo-treated patients (P = 0.033). In summary, multi-dose UC-MSC infusions were safely administered to patients with HFrEF and were associated with improvements in RV volumes. However, these benefits were accompanied by transient increases in coagulability, which may have attenuated potential improvements in left ventricular contractile function.

BackgroundVentricular arrhythmia (VA) is a common complication in patients with coronary heart disease (CHD), and heart rate variability (HRV) is considered a potential marker for VA risk.AimsThis study aimed to analyse the correlation between HRV and VA in patients with CHD.MethodsFrom January 2020 to July 2024, patients with CHD who were treated at our hospital were divided into two groups, based on the presence of VA: theVA group (VA present) and the control group (no VA). Heart rate variability indices were measured using 24-hour dynamic electrocardiogram monitoring. The HRV parameters included the standard deviation of sinus R-R (N-N) interval (SDNN), the standard deviation of sinus R-R (N-N) mean value every 5 min (SDANN), the root mean square of adjacent RR interval difference (rMSSD), and the percentage of the number of adjacent R-R interval differences >50 ms in the total number of sinus beats (PNN50). Clinical data were compared between groups, and linear regression was used to explore the relationship between HRV and VA.ResultsThe HRV indices SDNN, SDANN, rMSSD, and PNN50 were significantly lower in the VA group than in the non-VA group (P < 0.05). Linear regression analysis showed that SDANN, rMSSD and PNN50 were significantly associated with VA occurrence (P < 0.05). The linear equation derived was Y = 1.976 − 0.006 × X2 − 0.009 × X3 − 0.007 × X4.ConclusionThe HRV indices, particularly SDANN, rMSSD, and PNN50, were significantly associated with the occurrence of VA in patients with CHD and may serve as potential indicators for VA risk stratification.

BACKGROUND:Left atrial low-voltage areas (LVAs), indicative of atrial fibrosis and structural remodeling, are present in a subset of patients with paroxysmal atrial fibrillation (AF). OBJECTIVE:This study aimed to develop and validate a novel predictive model for identifying LVAs in patients with paroxysmal AF. METHODS:Patients with paroxysmal AF receiving their initial radiofrequency ablation in the Department of Cardiology at Shanghai East Hospital were enrolled. LVAs were defined as regions with a bipolar voltage of <0.5 mV during left atrial voltage mapping. Logistic regression analysis was used to identify independent predictors and construct the prediction model. An independent prospective cohort and a multicenter cohort of patients with paroxysmal AF were used for validation. RESULTS:A total of 383 patients with paroxysmal AF were enrolled, of whom 104 patients (27.2%) had left atrial LVAs. Multivariate logistic regression analysis identified that female sex, prior stroke, left atrial diameter, PR interval, hemoglobin level, and serum creatinine level were independent predictors of LVAs. The HeSLeF-PC (Hemoglobin, Stroke, Left atrial diameter, Female, PR interval, Creatinine) score was developed on the basis of these factors, which could predict the presence of left atrial LVAs in patients with paroxysmal AF (area under the receiver operating characteristic curve [AUROC] 0.810; 95% confidence interval [CI] 0.762-0.859) and was further validated in the prospective cohort (AUROC 0.826; 95% CI 0.757-0.896) and the multicenter cohort (AUROC 0.767; 95% CI 0.678-0.857). Decision curve analysis confirmed its clinical utility. CONCLUSION:The HeSLeF-PC score could effectively predict the presence of left atrial LVAs in patients with paroxysmal AF and may assist in preprocedural risk stratification and ablation planning.

BACKGROUND:Desmoglein 2 (DSG2)-associated cardiomyopathy represents a distinct subset of arrhythmogenic cardiomyopathy. A founder variant, NM_001943.5 (DSG2): c.T1592G (p.Phe531Cys), was identified with high frequency in China. OBJECTIVE:The study aimed to describe clinical features and outcomes of this founder variant. METHODS:Individuals with DSG2 c.T1592G (p.Phe531Cys) variants were recruited from 9 centers across China and categorized as single heterozygous, compound heterozygous (single variant plus rare variants of uncertain significance; abbreviated as compound), and homozygous. Clinical features and risk factors for malignant ventricular arrhythmias (MVAs), end-stage heart failure, and composite events of heart transplantation or cardiac death were analyzed. RESULTS:91 subjects were included: 21 (23.1%) single heterozygous, 21 (23.1%) compound, and 49 (53.8%) homozygous. Most subjects (74.7%) showed right ventricular dilatation, and nearly half (49.5%) had biventricular involvement. In patients with contrast-enhanced magnetic resonance imaging, 75.9% exhibited biventricular involvement. Compared with single heterozygous variant carriers, compound and homozygous variant carriers had a younger age at onset, more T-wave inversion, epsilon waves, and biventricular involvement (all pairwise P < .05). Homozygous variant carriers experienced significantly earlier MVA than compound (P = .013) and single heterozygous variant carriers (P < .001), with a trend toward earlier MVA in compound than single heterozygous variant carriers (P = .089). Compound and homozygous variant carriers exhibited significantly higher incidences of end-stage heart failure and composite events, whereas single heterozygous variant carriers remained event-free (all P < .05). CONCLUSION:DSG2 c.T1592G (p.Phe531Cys) founder variant defines a distinct arrhythmogenic cardiomyopathy subset with a high prevalence of biventricular involvement. Single heterozygous variant carriers held a less severe phenotype and relatively favorable prognosis, whereas compound and homozygous variant carriers held an advanced phenotype and poorer prognosis.

Background:Esophageal fistula (EF) is a rare but devastating complication following atrial fibrillation (AF) ablation. Data regarding the impact of age on EF are scarce. Objective:To study the impact of age on the management and prognosis of EF following catheter ablation for AF. Methods:The POTTER-AF study is a worldwide registry on EF following catheter ablation for AF. A total of 553,729 patients underwent AF ablation in 214 centers between 1996 and 2022. Of them, 138 patients experienced EF, and data regarding age, management, and prognosis were available in 113 patients. The population was divided based on the median age. Results:The median age was 63 years; 54 patients were <63 years old (Group 1), and 59 patients were ≥63 years old (Group 2). The groups were similar regarding procedural characteristics. The older population had a shorter time to symptom onset [15.0 (6.0, 21.0) vs. 21.0 (10.0, 25.3) days; p = 0.031]. Group 2 was less likely to receive a brain CT or MRI for diagnosis (25.9% vs. 45.3%; p = 0.046). The older population was more likely to undergo endoscopic treatment without surgery (27.6% vs. 11.3%; p = 0.035). Conservative and surgical treatments were used in similar proportions. A trend toward higher fatality was noted in the older patients (72.9% vs. 56.6%; p = 0.078). Conclusion:The older population had a shorter time to symptom onset, was less likely to receive a brain CT or MRI, and more likely to be treated by an endoscopic approach only. The older patient group showed a trend toward a higher fatality.

BACKGROUND:Premature atrial contractions (PACs) are independently associated with atrial fibrillation, stroke, and heart failure, yet no pharmacological therapy is approved for PAC suppression. Experimental studies have identified a functional cardiac glutamatergic system in which N-methyl-D-aspartate receptors regulate atrial electrophysiology. Preclinical studies show that pharmacological antagonism of N-methyl-D-aspartate receptors with memantine suppresses atrial arrhythmias. METHODS:We conducted an investigator-initiated, phase 2, multicenter, randomized, double-blind, placebo-controlled trial. Symptomatic adults with frequent PACs (≥1000/24 h) were randomly assigned to receive memantine or placebo for 6 weeks. The primary end point was the percentage change in mean 24-hour PAC count from baseline to the end of treatment. The primary analysis was performed in the intention-to-treat population. Prespecified secondary end points included the responder rate (≥50% PAC reduction), percentage change in nonsustained atrial tachycardia burden, and cumulative incidence of new-onset atrial fibrillation. RESULTS:Among 241 patients included in the efficacy analysis, memantine resulted in a greater reduction in PAC count than placebo (between-group difference, 47.1 percentage points; P=0.0045). The responder rate was higher with memantine than with placebo (52.4% versus 23.1%; P<0.0001). Memantine also reduced nonsustained atrial tachycardia burden (between-group difference, 30.98 percentage points; P=0.0043) and was associated with a lower cumulative incidence of new-onset atrial fibrillation (4.8% versus 23.9%; P<0.0001). No clinically meaningful differences were observed in electrocardiographic intervals or left ventricular function, and no drug-related serious adverse events occurred. CONCLUSIONS:In patients with frequent symptomatic PACs, memantine reduced atrial ectopy and atrial tachyarrhythmia burden and demonstrated a favorable safety profile. These findings provide proof of concept for a novel, non-ion channel-based therapeutic strategy targeting the cardiac glutamatergic system. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT06501638.

Background The Dietary Approaches to Stop Hypertension (DASH) diet reduces blood pressure and cardiovascular disease risk, but its impact on later coronary artery calcium (CAC) progression is unclear. This study aimed to identify DASH score trajectories from early to middle adulthood and assess their association with CAC progression in middle age, exploring the potential mediating factors. Methods We conducted a prospective analysis of 2238 Black and White adults who were aged 18 to 30 years at CARDIA (Coronary Artery Risk Development in Young Adults) baseline and were followed from study year 20 to year 25. DASH score trajectories from early to middle adulthood were determined using latent class analysis. The primary end point was CAC progression, a validated measure of plaque progression, defined as a >2.5 square root increase in CAC score between years 20 and 25. Results Two distinct DASH score trajectories were identified: the low‐increasing and high‐decreasing trajectories. In the fully adjusted model, participants in the high‐decreasing trajectory had a 21% lower risk of CAC progression compared with those in the low‐increasing trajectory (hazard ratio, 0.79 [95% CI, 0.65–0.98]; P =0.028). The association was partially mediated by diastolic blood pressure, insulin, uric acid, and lipid profiles. Conclusions DASH score trajectories vary from early to middle adulthood. Maintaining high adherence to the DASH diet from early to middle adulthood is associated with reduced CAC progression in middle age, partially mediated by cardiometabolic risk factors. These findings support the importance of long‐term adherence to a healthy dietary pattern for cardiovascular disease primary prevention. REGISTRATION: URL: https://www.clinicaltrials.gov ; unique identifier: NCT00005130.

The aim of this study was to investigate the associations between sleep duration, sleep disturbances and falls in different cardiovascular disease (CVD) states in a Chinese middle-aged and older adult population. This study used two waves (2011 wave1 and 2013 wave2) of data from the China Health and Retirement Longitudinal Study (CHARLS) to collect information on social, economic, and health status by tracking Chinese individuals aged 45 and above. The study used a logistic regression model to examine the association between sleep parameters and falls. Restricted cubic spline was used to analyze the association of sleep duration with falls in the overall population, and in the population with or without CVD. The overall incidence of new falls among all subjects was 18.35

Background and aimsData on the safety of direct current cardioversion (DCCV) in patients with left atrial appendage occlusion (LAAO) devices and its impact on thromboembolic prevention are limited. This study aimed to investigate the safety and efficacy of DCCV in patients with LAAO devices.MethodsThis single-center, ambispective cohort included patients undergoing one-stop procedures [LAAO combined with radiofrequency catheter ablation (RFCA)], where LAAO was performed first. DCCV was performed to restore sinus rhythm after LAAO. Patients were divided into the DCCV group and the no-DCCV group. Safety endpoints included DCCV-related death, device dislodgment, device embolization, and major bleeding events. Efficacy endpoints contained all-cause death, cardiovascular death, stroke/transient ischemic attack, and systemic embolism.ResultsA total of 196 patients (age 72.5 ± 7.4 years, 51.0% male) were enrolled, with 95 patients undergoing DCCV after LAAO. No DCCV-related death, device dislodgement, or device embolism was observed. At 12 months, the safety endpoints occurred in 3.2% of the DCCV group vs. 6.9% of the no-DCCV group (p = 0.238). Similarly, the efficacy endpoints were observed in 1.1% of the DCCV group vs. 4.0% of the no-DCCV group (p = 0.339). By performing pre- and post-DCCV transesophageal echocardiography (TEE) in the prospective cohort, a significant increase in device diameter at 45° and 90° (p = 0.044; 0.027), and an insignificant decline trend of peri-device leak and shoulder at 135° were noted (p = 0.051; 0.103).ConclusionsNo signal of excess risk was observed when performing DCCV in patients with LAAO devices. Tiny changes in device diameter after DCCV were noted on TEE at 45° and 90°, but these were not associated with adverse effects.

Presents corrections to the paper, Corrections to “CardioGPT: An ECG Interpretation Generation Model”.

Presents corrections to the paper, Corrections to “CardioGPT: An ECG Interpretation Generation Model”.

Background Inflammation and the nervous system play pivotal roles in cardiac remodeling after myocardial infarction (MI). Recent study showed renal denervation (RDN) could reduce cardiac inflammation, however, the specific mechanism remains unclear. Methods We firstly reanalyzed the previous heart single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics to examine the alterations in immune cell subsets following MI. Subsequently, we carried out diverse denervation procedures to explore the relationship between the nerve axis and the inflammatory response. Finally, we performed bulk RNA-seq and neurotransmitter analysis to explore the molecular mechanisms implicated in the migration of splenic myeloid cells after MI. Results Myeloid cells manifested the most substantial changes following MI and accumulated in the vicinity of the infarct area. The afferent renal nerve - splenic nerve axis regulates the migratory capacities of splenic myeloid cells after MI. RDN decreased the norepinephrine (NE) levels in the spleen after MI and attenuated the expression of ITGA9 on splenic myeloid cells, which impaired their interaction with VCAM-1 on cardiac endothelial cells and thereby reduced their migration to the heart. Conclusions Our study highlights the crucial role of the afferent renal nerve-splenic nerve axis in regulating cardiac inflammation and provides a interventional target for improving cardiac function after myocardial ischemic injury.

BACKGROUND Arrhythmogenic cardiomyopathy (ACM) patients in China exhibit unique genetic and clinical charac-teristics. There is a lack of prognostic models specific to Chinese ACM patients. OBJECTIVES This study aims to establish a large, national ACM patient cohort with uniformly collected, high-quality data for future risk prediction. METHODS This study includes patients with definite or borderline ACM diagnoses, along with their genotype-positive relatives. At baseline, comprehensive data collection includes medical history, electrocardiograms, imaging data, genetic testing, and laboratory evaluations. Outcome data include heart failure events and malignant ventricular arrhythmias. RESULTS As of September 2024, the registry has enrolled 622 participants, including 552 probands (88.7%) and 70 family members (11.3%) carrying ACM-related variants. Preliminary cohort includes 577 patients (92.8%), of whom 495 were diagnosed with definite arrhythmogenic right ventricular cardiomyopathy. The median age of symptom onset was 33.0 years (Q1-Q3: 22.0-45.0 years), with 41.6% experiencing arrhythmia-related symptoms. Abnormal electrocardio-gram findings included T-wave inversion (72.7%) and epsilon waves (24.8%) in leads V1 to V3. Imaging evaluation revealed RV dilatation in 44.6% and left ventricular dilatation in 29.8%, with a mean left ventricular ejection fraction of 53.0% f 14.5%. Regarding outcomes, malignant ventricular arrhythmias occurred in 255 (40.1%) individuals, while 21.9% developed end-stage heart failure, including 35 individuals who died of heart failure and 101 patients who un-derwent heart transplantation. CONCLUSIONS The ChinaCORE ACM (China Multi-Center Cohort Study on Risk Evaluation of Arrhythmogenic Cardiomyopathy) registry is a national, longitudinal, observational cohort study. This study contributes to expanding the understanding of the disease spectrum of Chinese ACM patients and improving prognostic predictions. (JACC Asia. 2025;5:914-923) (c) 2025 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Green tea and black tea have shown beneficial effects on cardiovascular health, and they are recommended for the prevention of cardiovascular disease (CVD) events. However, the impact of herbal tea on cardiovascular health remains unclear. This study aims to evaluate the potential benefits of herbal tea consumption in reducing the risk of incident CVD events in the general population. Data for this study were derived from the Multi-Ethnic Study of Atherosclerosis (MESA). The primary outcome was incident CVD events, while secondary outcomes included all-cause and cardiovascular mortality. Cox proportional hazards regression models were used to examine the relationship between herbal tea consumption and the risk of incident CVD events. Kaplan-Meier survival curves were employed to assess the timing of incident CVD events, all-cause mortality and cardiovascular mortality. A total of 4711 participants were included in the analysis, with 1834 (38.9