Asirvatham, Samuel J.

Abstract Background Many patients with atrial fibrillation (AF) suffer life-limiting symptoms and heart failure. Although enormous advances in rhythm control have been made, device-based therapies for treating recurrent episodes are limited. Using pulsed electric fields (PEF) to induce reversible electroporation of cardiac tissue may effectively terminate AF. Purpose To assess the feasibility of PEF delivery for converting atrial arrhythmias via reversible electroporation. Methods Four swine models were used in this acute study. Custom-made decapolar catheters for PEF delivery were deployed with the following configurations: 1. Endocardial right atrium (RA) and coronary sinus (CS), n=2; 2. Endocardial RA and epicardial left atrium (epiLA), n=2. AF and atrial flutter (AFL) were induced with programmed stimulation. PEF delivery was performed using the BTX 830 generator. For each attempt, a single monophasic pulse at 10 or 20µs pulse width was administered, with voltage varied across attempts (range 750-3000V). Successful (type 1 and 2 breaks) and unsuccessful conversion attempts were recorded. Post-PEF signal changes and arrhythmias were identified. Results A total of 58 AF/AFL (28 and 30 respectively) episodes were induced. Of the 37 successful conversion attempts, 33 (89.1%) were type 1 breaks. Conversion success probabilities generally increased with higher voltages for both configurations. >70% conversion success was seen with ≥1500V for the RA/CS configuration and ≥2000V for the RA/epiLA configuration. Arrhythmias including intra-atrial delay and high-grade atrioventricular block were seen, usually following successive PEF deliveries. Significant muscle stimulation was provoked with the current experimental setup. Conclusion Termination of atrial arrhythmias with PEF delivery is feasible, although further work is required to optimize its efficacy and safety.

Abstract Background Ventricular fibrillation (VF) is a leading cause of sudden cardiac death worldwide. Defibrillation via direct current shocks is effective but associated with significant pain and morbidity, prompting the need for alternative approaches. Reversible electroporation of cardiac tissue with pulsed electric fields (PEF) may be an effective means of terminating VF. Purpose To assess the feasibility of PEF delivery for terminating VF. Methods 5 acute swine models were used. Mechanical circulatory support with peripheral veno-arterial extracorporeal membrane oxygenation +/- percutaneous left ventricular assist device (Impella 5.5 L) was implemented and titrated to a mean arterial pressure ≥65 mmHg. Decapolar catheters were introduced into the endocardial right and/or left ventricle as well as epicardium. VF was induced with R on T shocks or rapid ventricular pacing. PEF was delivered with the endocardial catheter as the cathode and epicardial catheter as the anode; monophasic pulses (5-10) at 3000V, 100µs, and 200ms inter-pulse intervals were used. If VF persisted post-PEF, catheters were repositioned into regions of intact voltages for repeat delivery. Results 10 VF episodes were induced, 7 of which were successfully terminated with PEF delivery (70.0%). The median number of attempts to achieve VF termination was 2 (range 1-5). The post-VF rhythm was complete heart block with ventricular asystole in all successful defibrillation attempts, with no recovery after 30 minutes of observation. Significant muscle stimulation was seen with the utilized PEF parameters and catheter configurations. Conclusion Termination of VF using PEF – pulsed field defibrillation – is possible. However, further study is required to optimize delivery parameters/configurations to improve effectiveness and avoid muscle stimulation as well as conduction abnormalities.

ABSTRACT Gain-of-function mutations in the transient receptor potential 6 (TRPC6) channel have recently been recognized as risk factors for both doxorubicin (DOX)-induced cardiomyopathy. Functional evaluation of TRPC6 missense variants is therefore important for cancer patients undergoing anthracycline treatment. However, traditional electrophysiological methods are labor-intensive and time-consuming. In this study, we compared the functional responses of TRPC6 missense variants to 1-oleoyl-2-acetyl-sn-glycerol (OAG), a TRPC6 agonist, using molecular docking and patch clamp recording techniques. For the wild-type (WT) TRPC6 structure (PDB ID: 6UZ8), OAG exhibited a binding energy of -4.49 kcal/mol and a dissociation constant (Kd) of 0.511 mM. Twenty TRPC6 missense variants were identified from cancer patients in the Mayo Clinic database. Of these, fifteen variants had resolvable structures, nine of which displayed increased Kd values and six decreased Kd values compared to WT in molecular docking analysis. Patch clamp recordings revealed that TRPC6 WT and mutant channels were inactive at baseline but were activated upon 50 μM OAG stimulation, except two loss-of-function variants. Moreover, a 24-h treatment with 0.5 μM DOX significantly enhanced OAG-induced channel activation. All three variants identified in patients with heart failure demonstrated gain-of-function properties in both electrophysiological measurements and in-silico predictions. Importantly, the results obtained from molecular docking and patch clamp recordings were strongly correlated, showing an 82% concordance, higher than the predictions from AlphaMissense. These findings indicate that our computational analysis provides a rapid and reliable method for predicting the functional impact of TRPC6 missense variants, which may aid clinical decision-making in cancer patients receiving chemotherapy.

BACKGROUND: Cardiac radioablation is emerging as a treatment modality for refractory ventricular tachycardia. This study aimed to evaluate the effects of radiation on the coronary arteries in a swine model of proton beam cardiac radioablation. METHODS: Eighteen swine underwent single-fraction 30 to 40 Gy pencil-beam scanning proton therapy targeting the left ventricle and were euthanized 12 to 40 weeks later. Treatment planning was performed without restricting the dose to the coronary arteries. The maximum point dose (D max ) to the epicardial coronary arteries was calculated. In secondary analyses, the mean (D mean ) and minimum dose received by the highest irradiated 0.01 cm 3 (D 0.01 ) of each coronary artery were also calculated. Coronary artery segments were harvested from the D max sites for histological analysis, and the D max was correlated with stenosis severity. RESULTS: Ninety-six coronary arteries were analyzed. No stenoses were observed by computed tomography imaging preirradiation. By histological analysis posteuthanasia, 25/96 (26%) coronaries sampled at their D max sites had ≥75% stenosis. The median D max was 4.7 Gy for the <75% stenosis group and 29.7 Gy for the ≥75% stenosis group ( P <0.001). The AUC-ROC for the association between D max and stenosis ≥75% was 92.2%. A D max value of 20.1 Gy best predicted stenosis ≥75%, with sensitivity 92.3% and specificity 87.1%. The AUC-ROCs for the associations of D mean and D 0.01 with stenosis ≥75% were 84.8% and 91.6%, respectively. In histopathologic analysis, intimal hyperplasia was the most common coronary artery abnormality at the D max sites, and it was present in 61.5% of all arteries and in 93.9% of arteries with D max ≥20 Gy. CONCLUSIONS: In this preclinical model of proton beam cardiac radioablation, coronary stenoses occurred in a dose-dependent manner, with D max showing the closest correlation with stenosis ≥75%. These data provide for the first time a framework for dose constraint considerations for the coronary arteries during treatment planning for cardiac radioablation and thoracic malignancy radiation.

ABSTRACT Background Pulsed‐field ablation (PFA) offers myocardial selectivity with minimal thermal injury, but depth for ventricular lesions may be insufficient or heterogeneous at clinically tolerable field strengths. Calcium electroporation—local calcium chloride (CaCl₂) infusion after PFA—may amplify electroporation‐mediated cell death while maintaining low energy settings. Objective To determine whether immediate post‐PFA CaCl₂ infusion enhances acute and chronic ventricular lesion formation in vivo. Methods Nine swine underwent focal ventricular PFA (750–1000 V, biphasic, 20 μs × 50 pulses, 200 ms interpulse) via an irrigated focal catheter and benchtop electroporator. Immediately post‐PFA, lesions were randomized to saline, 0.2 g Ca, or 0.4 g Ca infused locally through the catheter tip. Acute hearts were explanted for TTC analysis; surviving animals were studied at 7 days for chronic lesion geometry. Results Among 41 acute lesions (17 control, 12 Ca 0.2 g, 12 Ca 0.4 g), Ca 0.4 g increased dark‐zone depth (3.5 ± 1.4 vs. 2.3 ± 0.8 mm; p = 0.038) and pale‐zone depth (2.6 ± 1.3 vs. 1.3 ± 0.8 mm; p = 0.011) versus control. At 7 days ( n = 33 lesions), Ca 0.4 g produced larger scars than control (width 11.6 ± 2.1 vs. 10.0 ± 1.9 mm; p = 0.027; depth 4.2 ± 1 vs. 3.0 ± 0.8 mm; p < 0.001; volume 193.6.4 ± 82.3 vs. 109.4 ± 48.2 mm³; p = 0.001). Conclusions Local CaCl₂ infusion after ventricular PFA significantly augments acute electroporation effect and chronic lesion size at low output, supporting facilitated PFA as a strategy for deeper, more durable ventricular ablation.

ABSTRACT Background Optimal management in patients presenting with persistent atrial fibrillation, cardiomyopathy, and atrial as well as ventricular dyssynchrony with left bundle branch block is unclear. Results and Methods A 67‐year‐old female patient presented with persistent atrial fibrillation, cardiomyopathy with a newly reduced ejection fraction (EF), increased P wave duration on electrocardiogram (ECG) and left bundle branch block. After shared decision making, the patient elected to proceed with Bachman bundle/left bundle branch area pacing plus atrioventricular (AV) node ablation. At 6‐month follow‐up post procedure, a repeat echocardiogram showed normalized atrial size and EF (65%). Device interrogation demonstrated no recurrent atrial fibrillation with the patient off antiarrhythmic and heart failure medical therapy. Conclusions Integrated atrial and ventricular synchronization through Bachmann bundle and left bundle branch area pacing may help break the cycle of dyssynchrony, remodeling, and arrhythmia. In combination with AV node ablation, it may be considered as an alternative treatment option in certain cases after shared decision making.

Abstract Background Elevated left ventricular filling pressure (LVFP) is associated with an increased risk of heart failure and mortality. Pulmonary artery wedge pressure (PAWP) is considered the gold standard for assessing LVFP. Recently, we validated an artificial intelligence-enabled electrocardiogram (AI-ECG) to assess LV diastolic function (LVDF) and LVFP. Herein, we compare AI-ECG with PAWP in predicting long-term mortality. Methods We included adults who had comprehensive echocardiography with available ECG within 14-days and right-heart-catheterization (RHC) within 30-days of echocardiography. Elevated-LVFP was defined as PAWP&gt;15 mmHg by RHC, grades 2-3 LVDF by echocardiography, or as adjudicated by the AI-ECG algorithm. Prognosis by AI-ECG was compared to that by echocardiography and PAWP. Results Among 4,168 patients (median age 64 years, 47.7% female), 1,841 had normal-LVFP, and 2,327 had elevated-LVFP by RHC. Echocardiography classified 1,502 patients as normal-LVFP, 1,643 as elevated-LVFP, and 1,023 as indeterminate-LVFP. AI-ECG demonstrated an area-under-the-curve of 0.879 (95%-confidence-interval 0.867-0.891) for predicting elevated-LVFP as determined by echocardiography and 0.742 (95%-confidence-interval 0.724-0.759) for predicting elevated-LVFP as determined by RHC. Over a median follow-up of 7.7 years, 2,735 (34.4%) patients died. In multivariable models, elevated-LVFP by any modality was associated with an increased risk of death (AI-ECG: adjusted-hazard-ratio 1.80, 95% confidence-interval 1.55-2.09; echocardiography: adjusted-hazard-ratio 1.74, 95% confidence-interval 1.51-2.02; PAWP: adjusted-hazard-ratio 1.26, 95% confidence-interval 1.11-1.43). AI-ECG-derived LVFP provided incremental prognostic discrimination compared to echocardiography- or RHC-derived LVFP. Conclusions AI-ECG-derived LVFP offers an accessible, affordable, and noninvasive alternative for detecting elevated LVFP, with potential independent prognostic value beyond traditional echocardiographic and invasive assessments.Survival across LVFP concordance

Background: Dofetilide, a commonly prescribed class III antiarrhythmic for atrial fibrillation (AF), currently requires a 3-month amiodarone washout period per FDA guidelines. We evaluated the safety of initiating dofetilide within this 3-month washout period. Methods: We performed a retrospective cohort study across all Mayo Clinic sites and identified patients using centralized datamart that were transitioned from amiodarone to dofetilide in less than 90 days. Patients were included and confirmed by manual chart review if they had been on amiodarone for ≥ 12 weeks and if available amiodarone level >0.3 mg/ml at the time of dofetilide initiation. Serial ECGs were assessed during the hospitalization for dofetilide initiation and at 3-, 6-, and 12-months follow-up to evaluate QT interval. Primary safety end point was torsade de pointes. Results: The final cohort included 66 patients with a mean age of 65 ±14 years; 71.0% were male; and the average BMI was 29.6 ±5.1 kg/m 2 . Of the 66 patients, 65 had a history of AF: 31.8% paroxysmal, 54.5% persistent, and 12.1% long-standing persistent. Permanent pacemakers and ICDs were present in 27.3% and 22.7% of patients. Patients received amiodarone for a median of 7.8 months at a mean daily dose of 187.1±48.3 mg (range: 100 – 400 mg), with a mean transition period of 44.2±20.3 days. Of 66 patients, 16 (24 %) transitioned within 30 days of stopping amiodarone—including 5 (8 %) within 14 days—while the remaining 50 (76 %) was between 30 and 90 days. A total of 24.2% (16/66) patients required dofetilide dose reduction due to QT prolongation and 10.6% of patients (7/66) required drug discontinuation. There was no difference in either discontinuation rate or dose reduction rate in patients with a transition period ≤30 days vs > 30 days [6.25% vs. 12% (p=0.85) and 12.5% vs. 28% (p=0.36), respectively]. No cases of torsades de pointes were observed during dofetilide initiation or follow up. Conclusion: In this cohort, dofetilide initiation less than 90 days after amiodarone discontinuation was not associated with increased torsades de pointes risk. These data challenge and support reconsideration of the blanket 3-month washout and suggest that a monitored, expedited rhythm-control transition is feasible and safe.