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Abstract Background Ventricular arrhythmias (VA) are common complications of acute coronary syndromes (ACS) and can cause cardiac arrest and adverse outcomes. However, the prognostic impact of VA according to their timing in relation to percutaneous coronary intervention (PCI) remains unclear. Purpose To assess the prognostic significance of VA in patients with ACS undergoing PCI according to the timing of occurrence (before, during, or after PCI). Methods We performed a systematic review and meta-analysis of observational studies reporting all-cause mortality with and without VA (sustained VT/VF) in ACS patients undergoing PCI. Pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated using random-effects models for short-term (30 days/in-hospital) and long-term (1 year) mortality. Between-study heterogeneity was assessed using the I² statistic. We conducted subgroup analyses for studies that stratified VA according to timing, defined as VA before PCI (prior to arrival in the catheterization laboratory), VA during PCI (in the catheterization laboratory or immediately after reperfusion), VA after PCI (following completion of PCI). Each timing category was compared to patients who did not develop VA within the same time window (before, during or after PCI). Results Twelve studies comprising 49306 patients were included, of whom 4320 (8.76%) experienced VA. The mean age of the patients ranged from 60 to 70 years, and the follow-up ranged from hospital discharge to 8 years. VA was associated with increased short-term (OR 5.02 [3.91-6.44]) and long-term mortality (OR 3.00 [2.86-3.82]). However, in patients alive at discharge/30 days, subsequent long-term mortality risk did not differ between those with and without VA (OR 1.21 [0.70-2.09]) (Figure 1). The subgroup analyses showed that patients with VA were associated with higher short-term mortality compared to patients without VA within each time window: before (OR 4.32 [3.29-5.66]), during (OR 4.29 [2.08-8.84]), and after PCI (OR 9.29 [3.12-27.63]) (Figure 2). VA after PCI was associated with the highest OR for short-term mortality. Conclusions VA significantly worsens short-term outcomes in ACS patients undergoing PCI. Subgroup analysis shows that VA increases mortality in each timing category, before, during and after PCI, with the poorest prognosis observed for arrhythmias developed after reperfusion, in whom reversible acute ischemia may play a lesser role and underlying arrhythmic substrate may predominate.Figure 1Figure 2

Abstract Introduction Despite its prevalence, risk stratification for tachycardia-induced cardiomyopathy remains poorly understood. A deep learning model developed at Mayo Clinic uses standard 12-lead electrocardiograms (ECGs) to predict reduced LVEF (≤35%) in the general population with high accuracy (AUC 0.93) Purpose We investigated the performance of AI-ECG in predicting systolic dysfunction among patients with atrial fibrillation and rapid ventricular response, and compared it with NT-proBNP. Methods We conducted a retrospective study (IRB approval #25-000904) of adult patients (age ≥ 18 years) evaluated across our Clinic enterprise with atrial fibrillation and rapid ventricular response (heart rate >100 bpm), including AF occurring in-hospital and AF at presentation, between January 2017 and May 2025. We excluded patients with a known history of heart failure with reduced EF (<50%). We also collected data on NT-proBNP levels when available within one week of the ECG and echocardiogram. Results A total of 11,801 patients were included, with a mean age of 73.2 +- 12.6 years, 48.6% female and 94.8% White. A combination of AI ECG low EF probability cutoff of 75% had specificity of 96% and 98% NPV in ruling out LVEF < 35%. A combination of AI ECG low EF probability cutoff of 17% and LVEF <35% provided the best balance of sensitivity and specificity, 66% and 78%, respectively with an accuracy of 78%. NT-proBNP data was available on 5,279 patients (48%). Mean NT-proBNP level was 4090 pg/mL. Based on ROC curve analysis, AI ECG was superior to NT-proBNP in predicting LVEF <35% (AUC 0.72 vs 0.59), with accuracy of 77% versus 47% at Youden’s cutpoints of AI-ECG probability of 17% and NT-proBNP level of 1767 pg/mL, respectively Conclusions Our study demonstrates the utility of AI-ECG in predicting reduced LVEF among patients with AF RVR. AI-ECG demonstrated excellent specificity and NPV in ruling out reduced LVEF, serving as a powerful clinical screening tool to assist with the pharmacologic choice of rate control and could change the timing of further echocardiographic evaluation. Our study offers novel insights paving the way for future investigations to help fine-tune and further delineate the role of AI ECG in risk stratifying patients with suspected tachycardia-induced cardiomyopathy, guiding therapeutic and diagnostic clinical decisions

Abstract Background Calcium release channel deficiency syndrome (CRCDS) arises from loss-of-function variants in the RYR2-encoded type 2 ryanodine receptor (RyR2), predisposing patients to sudden cardiac arrest/death (SCA/SCD) despite normal exercise testing. Previously, a novel homozygous RYR2 duplication causing ~ 80% RyR2 reduction was associated with exertion-related SCD. However, how Ca2+ homeostasis is maintained despite RyR2-loss remains unknown, as RYR2-/- animals are non-viable. Purpose To generate a RYR2-knockout (RYR2-KO-/-) induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model to dissect compensatory mechanisms sustaining Ca2+ homeostasis and identify arrhythmogenic pathways predisposing to SCD. Methods CRISPR/Cas9 editing was used to introduce a homozygous c.163delT variant into a wild-type iPSC line (control), generating a RYR2-KO-/- model. A patient-derived RYR2-duplication (RYR2-DUP+/+) iPSC line was used for comparison. RyR2 expression was assessed by western blot (WB) and immunofluorescence (IF). Proteome and phospho-proteome were assessed using omics approaches. Intracellular Ca2+ handling was evaluated by Fluo-4 AM imaging (0.5 Hz and long-burst–long-pause [LBLP] protocol). Electrophysiological properties (action potential [AP], and sarcolemmal currents [ICaL, INa and INCX]) were assessed by patch-clamp. Results Despite complete RyR2-loss in RYR2-KO-/- iPSC-CMs as confirmed by WB and IF, contractility and contractile machinery expression was preserved. Ca2+ transient amplitude (ΔF/F0) was reduced markedly in RYR2-KO (0.14±0.01, p<0.01) and RYR2-DUP (0.27±0.2, p<0.01) compared to control (0.52±0.02). Proteomics revealed a significant NCX1 up-regulation and IP3R-interacting protein (ITPRIP) down-regulation in RYR2-KO compared to control, with pathway-analyses showing significant up-regulation of IP3-related pathways. Pharmacological IP3Rs block (2-APB, 10μM) abolished Ca2+ transient generation in RYR2-KO iPSC-CMs (Amplitude: baseline: 0.15±0.01, 2-APB: 0.06±0.01, p<0.01). RyR2-ablation induced electrical remodeling (pA/pF), including ICaL reduction, INCX up-regulation and hyperpolarization of the INa window current in RYR2-KO (ICaL [at 0mV]: -8.5±1.6; INCX [at -110mV]: -4.1±1.1) as compared to control (ICaL:-7.5±3.7, p<0.01; INCX:-1.5±0.5, p=0.02). RYR2-KO CMs demonstrated increased delayed after-depolarizations and beat-to-beat variability as compared to control. Despite Ca2+ sparks abolishment, RYR2-KO CMs displayed higher erratic beating (at 0.5Hz) and arrhythmogenic propensity than control, showing ventricular tachycardia-like events during LBLP stimulation. Conclusions Genetic RYR2-ablation disrupts physiological Ca2+ cycling and triggers electrical remodeling, including INCX up-regulation, overall promoting arrhythmogenesis. Compensatory IP3Rs activation sustains Ca2+ transient generation, revealing a mechanism preserving excitation-contraction coupling that may paradoxically promote arrhythmogenesis in CRCDS.RYR2-KO: Generation and CharacterizationElectrophysiological Assessment

Introduction Correct inhaler technique is of utmost importance in the optimal delivery of therapeutics utilized for respiratory illnesses. Previous research suggests that the ability of both patients and providers to correctly use these inhalers is sub-optimal and is associated with poorer patient outcomes. Further education about inhaler types and technique as part of residency education could serve to correct these trends. Methods Family medicine residents were taught correct inhaler technique with an inhaler training device (In-Check TM DIAL G16) using a didactic lecture with hands-on teaching exercise utilizing pharmacy interprofessional teaching. We assessed pre- and post-intervention comfort and knowledge of correct inhaler technique. Results Twenty of twenty-seven eligible family medicine residents attended an interdisciplinary workshop with clinical pharmacists with the purpose of improving inhaler technique comfort level and knowledge. A pre- and post-knowledge test and comfort questionnaire were provided to those participating. Comfort levels with prescribing different inhaler types increased after the intervention and knowledge of different inhalers improved. Conclusion Use of an inhaler training device coupled with an interdisciplinary lecture format improved provider knowledge of correct inhaler technique and comfort with prescribing inhalers.

Abstract Introduction Energy harvesters that convert biomechanical energy into electrical power could be used for implantable devices, providing a near-infinite energy solution. While various energy harvesters with piezoelectric or triboelectric elements have been designed and applied to the cardiac environment, none have been successfully integrated into leadless pacemakers due to their size constraints or insufficient energy generation. Purpose This study aimed to test the performance of a novel self-sustaining leadless pacemaker, which operates on a proprietary inertial piezoelectric energy harvester (PEH) capable of generating the energy required for VVI therapy from the beating of the heart. Method A novel autonomous Leadless Pacing System (ALPS), including a leadless implant, a customized delivery tool catheter, and a home monitor, was developed. The leadless implant was designed to operate on the energy generated by a specially designed PEH that could fit inside the implant. The harvester’s energy was used to charge a small rechargeable backup battery, which provided the energy for a VVI single-chamber therapy. The leadless device and its dedicated delivery tool were then tested in vivo in an ovine model, adhering to the principles of laboratory animal care and with local ethical approval. Results The heart contractility creates harmonic movement in the heart tissue, which is transmitted into the PEH, resulting in the PEH acceleration. The leadless PEH components transform these mechanical forces into electric energy. In pre-clinical testing on an AV block ovine model (n=7), the device was able to pace the animals for 3 months, at 100% pacing, with an average pacing capture threshold of 0.9 (+/-0.5)V, with a pulse width of 0.366 msec, an average impedance of 570 (+/- 115) Ohm, and daily communication with the home monitor device. Conclusion This work demonstrates that a novel leadless pacemaker that utilizes a piezoelectric element to harvest the heart's mechanical energy to generate electrical energy successfully sustains VVI therapy. This approach is able to produce enough energy to maintain device longevity and support additional functionality, such as daily wireless communication with a home monitor, overcoming major limitations of leadless cardiac devices.

Brexucabtagene-autoleucel (brexu-cel) produces high rates of measurable residual disease-negative (MRD-) complete response (CR) in adults with Philadelphia-chromosome positive (Ph+) acute lymphoblastic leukemia (ALL); however, subsequent relapses remain frequent. It is unclear whether maintenance with tyrosine kinase inhibitors (TKIs) can enhance remission durability. We evaluated outcomes among adults with relapsed/refractory Ph+ ALL who received commercial brexu-cel and achieved MRD- CR across 19 U.S. institutions. Considering TKI maintenance as a time-varying covariate, we analyzed outcomes based on receipt of subsequent TKI maintenance versus no maintenance. Patients receiving consolidative transplantation or non-TKI maintenance were excluded. Fifty-one patients were included: 20 received TKI maintenance and 31 received no maintenance. The use of TKI maintenance was associated with a significantly lower 1-year cumulative incidence of relapse (HR 0.12; 95% CI, 0.02-0.88; p=0.037) which translated into improved progression-free survival (PFS, HR 0.19; 95% CI, 0.04-0.85; p=0.029) and a trend towards improved overall survival (OS, HR 0.34; 95% CI, 0.07-1.62; p=0.18). There was no difference in non-relapse mortality (NRM, HR 0.83; 95% CI, 0.12-5.87; p=0.85). This real-world analysis supports the administration of TKI maintenance in Ph+ ALL following achievement of MRD- CR with brexu-cel as a strategy to improve PFS following chimeric antigen receptor T cell therapy.

Abstract Background New-onset atrial fibrillation (AF) is common in patients who are hospitalized with acute illness and is associated with overall poor outcomes. Current clinical and demographic predictors of new-onset AF have limitations. Electrocardiogram (ECG) waveforms, combined with these factors as part of multimodal approach could help improve prediction of new-onset AF. Purpose The purpose of our study was to develop a multimodal, deep-learning system that combines ECG waveforms with clinical data for prediction of new-onset AF in hospitalized patients. Methods We developed and compared two separate 1-dimensional models with a fusion model for prediction of new-onset AF. (a): one-dimensional convolutional neural network (1D-CNN) that learns patterns from the raw ECG waveforms. (b): a Multi-Layer Perceptron (MLP), unsupervised machine learning model which utilizes data from structured variables such as: age, heart rate, routinely obtained laboratory data and medications. The two modules each produce latent feature vectors, which are then placed end-to-end and fed into a final Multi- MLP head that outputs the probability of New-onset AF during hospitalization. We then compared this fused MLP model with the two simpler unimodal models based solely on ECG waveforms and clinical data respectively. Results On the held-out test set data, the feature-level fused model achieved an Area Under the Curve (AUC) of 0.81. This significantly outperformed both the ECG-alone model (0.77) and the clinical-alone model (0.74). By adjusting the threshold, we can fine-tune the tool at a threshold of 0.5, it flags 83% of patients who later develop AF (207 of 248) with a precision of 10%, a setting that could be useful for wider screening. By adjusting the threshold of 0.98 for a high-precision alert configuration, it has the ability to predict 46% of future occurrence of AF cases (113 of 248) while reducing false alarms by 81% (from 1,797 to 328), increasing precision to 26% and achieving an overall accuracy of 89%, a setting useful when resources for follow-up are limited. Conclusions Combining ECG signals with clinical data significantly enhances the model’s ability to detect new-onset AF in hospitalized patients as compared to a uni-dimensional CNN model. The dynamic nature of ML model also allows for adjustment of its decision threshold which can aid in broader screening and improving adverse outcomes related to occurrence of AF.ROC Curve for Fusion model

Abstract Introduction Atrial fibrillation (AF) is a major contributor to stroke risk, yet many cases remain undiagnosed due to its silent and paroxysmal nature. To address this, multiple risk scores have been developed to predict incident AF. This study aimed to evaluate the predictive accuracy of five widely used clinical AF prediction tools (i.e., CHARGE-AF, CHA2DS2-VASc, mC2HEST, HATCH, and HAVOC) among patients undergoing long-term continuous monitoring with implantable loop recorders (ILRs). Methods We conducted a retrospective cohort study across three major US academic medical centers, including patients with ILRs and no prior diagnosis or ECG evidence of AF. Clinical variables used to calculate each risk score were extracted from electronic health records. Discrimination was assessed using the area under the receiver operating characteristic curve (AUC). Kaplan-Meier survival analysis and Cox proportional hazards models were used to evaluate the association between each score’s risk categories and incident AF (defined as any episode lasting ≥6 minutes). Calibration was assessed using calibration plots and Brier scores. Results A total of 3,895 patients were included (mean age 61 ± 17 yrs.; 51% male). Incident AF was detected in 879 patients (22%) over a median follow up of 17 months (IQR 8-35). Table 1 presents baseline characteristics and device detected AF event data during follow up. CHARGE-AF had the highest AUC (0.68) but also the highest Brier score (Fig. 1). Failure curves showed clear risk stratification across all tools (Fig. 2). Calibration plots (Fig. 3) demonstrated modest agreement between predicted and observed risk across all models. Using CHARGE-AF as the reference, pairwise comparisons of Brier scores via the Wilcoxon signed-rank test showed lower calibration accuracy than CHA2DS2-VASc (p = 0.03), mC2HEST (p = 0.001), and HAVOC (p = 0.001), with no significant difference compared to HATCH (p = 0.15). Conclusions In patients undergoing continuous rhythm monitoring with ILRs, commonly used AF prediction scores demonstrated modest discriminatory ability and similar calibration performance. These findings suggest that existing risk models, which were largely developed in cohorts with clinically diagnosed AF, may not optimally translate to continuously monitored populations. Future work is needed to develop and validate AF prediction models specifically in cohorts undergoing long-term continuous cardiac monitoring.Figure 1Figure 2-3

Abstract Background/Introduction Atrial fibrillation (AF) is a common finding in patients with wild-type TTR amyloidosis. AF ablation represents a cornerstone of rhythm control in this population; however, the role of pulsed field ablation (PFA) remains unclear. Purpose This study aimed to describe the safety and efficacy of PFA for the treatment of atrial fibrillation in patients with wild-type TTR amyloidosis. Methods We conducted a prospective data collection of consecutive patients who underwent PFA for AF and had a confirmed diagnosis of wild-type TTR amyloidosis. The study included three centres within a major US health system. All procedures were performed between May 2024 and May 2025. A standardised follow-up strategy was applied, including 48-hour Holter monitoring between 90 and 180 days after ablation. The primary safety endpoint was the occurrence of procedural complications. The primary efficacy outcomes were acute procedural success and AF-free survival at six months after a blanking period of 30 days. AF recurrence was defined as any electrocardiographically documented episode lasting more than 30 seconds. Results A total of 13 patients were included in the study. The mean age was 72.6 ± 4.8 years, and all patients were male. Three patients (23.1%) underwent an index "redo" ablation. Seven patients (53.8%) had paroxysmal atrial fibrillation (AF). The median CHA2DS2-VASc score was 3 [2, 4.5], with a mean ejection fraction of 50.4 ± 14.8% and a mean left atrial volume index of 47.6 ± 15.7 mL/m². Eleven patients underwent PFA with the pentaspline Farawave catheter, and two with the focal Sphere-9 catheter. Additional extra-pulmonary vein lesions were performed in 11 patients, including posterior wall ablation in ten patients, cavotricuspid isthmus ablation in five, and mitral isthmus ablation in four patients. The primary endpoint occurred in one patient (7.7%) who developed acute respiratory failure complicated by pulseless electrical activity (PEA) arrest. The patient was successfully resuscitated but required prolonged hospital admission. All patients achieved acute pulmonary vein isolation, and six-month atrial fibrillation-free survival was 54.4%. Conclusion In this multicentre experience, pulsed field ablation (PFA) in patients with cardiac amyloidosis was feasible and acutely safe; however, the mid-term efficacy was suboptimal, with a relatively low six-month arrhythmia-free survival despite complete acute pulmonary vein isolation. These findings suggest that the current PFA strategies may not provide durable rhythm control in this population, underscoring the need for tailored ablation approaches and further research to improve long-term outcomes in patients with cardiac amyloidosis and atrial fibrillation.Figure 1