BACKGROUND: In patients with nonischemic cardiomyopathy and no late gadolinium enhancement (LGE) on cardiac magnetic resonance, risk prediction for the occurrence of sustained ventricular arrhythmias (VA) is challenging. Global and regional sympathetic denervation has been associated with VA in patients with ischemic cardiomyopathy. Its prognostic relevance in nonischemic cardiomyopathy is unknown. METHODS: Consecutive patients from the Leiden Nonischemic Cardiomyopathy Study who underwent programmed electrical stimulation, LGE-cardiac magnetic resonance, and 123-iodine meta-iodobenzylguanidine imaging between 2011 and 2019 were included. The presence of LGE and global and regional sympathetic denervation on 123-iodine meta-iodobenzylguanidine were evaluated, and patients were followed for the occurrence of VA. Global denervation was assessed using the heart-to-mediastinum ratio. Regional denervation was evaluated by calculating the number of denervated segments (DS), the ratio of DS, the summed defect score, and the weighted denervation size. RESULTS: Of 75 included patients (median age 63 years [25th-75th interquartile range (IQR) 54-68], 79% male, left ventricular ejection fraction 36% [IQR, 27-44], 37% inducible for VA), 35 had no LGE. During 4.5±1.6 years of mean follow-up, VA occurred in 8 of 35 (23%) patients without LGE and in 18 of 40 (45%) patients with LGE. Among patients without LGE, those with VA had greater regional sympathetic denervation (median number of DS 8 [IQR, 7-10] versus 2 [IQR, 1-5], P=0.004; median ratio of DS 0.5 [IQR, 0.5-0.7] versus 0.2 [IQR, 0.1-0.4], P=0.007; median defect score 36 [IQR, 30-41] versus 18 [IQR, 14-24], P=0.01; median weighted denervation size 47 [IQR, 38-54] versus 22 [IQR, 14-30]; P=0.01). In bivariate analysis, the number of DS (hazard ratio, 1.25 [95% CI, 1.06-1.46]; P=0.006) was associated with the occurrence of VA in patients without LGE. Denervation of ≥7 segments identified patients without LGE at risk for VA (area under the curve, 0.83; sensitivity, 88%; specificity, 89%). Among patients with LGE, the innervation state was not associated with VA during follow-up. CONCLUSIONS: In patients with nonischemic cardiomyopathy without LGE the extent of regional denervation may contribute to risk stratification for VA.

Background: Electroanatomical voltage mapping (EAVM) has been compared with late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR), which cannot delineate diffuse fibrosis. T1-mapping CMR overcomes the limitations of LGE-CMR, but it has not been directly compared against EAVM. Objectives: This study aims to assess the relationship between left ventricular (LV) endocardial voltage obtained by EAVM and extracellular volume (ECV) obtained by T1 mapping. Methods: The study investigated patients who underwent endocardial EAVM for ventricular arrhythmias (CARTO 3, Biosense Webster) together with preprocedural contrast-enhanced T1 mapping (Ingenia 3T, Philips Healthcare). After image integration, EAVM datapoints were projected onto LGE-CMR and ECV-encoded images. Average values of unipolar voltage (UV), bipolar voltage (BV), LGE transmurality, and ECV were merged from corresponding cardiac segments (6 per slice) and pooled for analysis. Results: The analysis included data from 628 segments from 18 patients (57 ± 13 years of age, 17% females, LV ejection fraction 48% ± 14%, nonischemic/ischemic cardiomyopathy/controls: 8/6/4 patients). Based on the 95th and 5th percentile values obtained from the controls, ECV >33%, BV <2.9 mV, and UV <6.7 mV were considered abnormal. There was a significant inverse association between voltage and ECV, but only in segments with abnormal ECV. Increased ECV could predict abnormal BV and UV with acceptable accuracy (area under the curve of 0.78 [95% CI: 0.74-0.83] and 0.84 [95% CI: 0.79-0.88]). Conclusions: This study found a significant inverse relationship between LV endocardial voltage and ECV. Real-time integration of T1 mapping may guide catheter mapping and may allow identification of areas of diffuse fibrosis potentially related to ventricular arrhythmias.

AIMS: Ventricular tachyarrhythmias (VTs) are common in the pathologically remodelled heart. These arrhythmias can be lethal, necessitating acute treatment like electrical cardioversion to restore normal rhythm. Recently, it has been proposed that cardioversion may also be realized via optically controlled generation of bioelectricity by the arrhythmic heart itself through optogenetics and therefore without the need of traumatizing high-voltage shocks. However, crucial mechanistic and translational aspects of this strategy have remained largely unaddressed. Therefore, we investigated optogenetic termination of VTs (i) in the pathologically remodelled heart using an (ii) implantable multi-LED device for (iii) in vivo closed-chest, local illumination. METHODS AND RESULTS: In order to mimic a clinically relevant sequence of events, transverse aortic constriction (TAC) was applied to adult male Wistar rats before optogenetic modification. This modification took place 3 weeks later by intravenous delivery of adeno-associated virus vectors encoding red-activatable channelrhodopsin or Citrine for control experiments. At 8-10 weeks after TAC, VTs were induced ex vivo and in vivo, followed by programmed local illumination of the ventricular apex by a custom-made implanted multi-LED device. This resulted in effective and repetitive VT termination in the remodelled adult rat heart after optogenetic modification, leading to sustained restoration of sinus rhythm in the intact animal. Mechanistically, studies on the single cell and tissue level revealed collectively that, despite the cardiac remodelling, there were no significant differences in bioelectricity generation and subsequent transmembrane voltage responses between diseased and control animals, thereby providing insight into the observed robustness of optogenetic VT termination. CONCLUSION: Our results show that implant-based optical cardioversion of VTs is feasible in the pathologically remodelled heart in vivo after local optogenetic targeting because of preserved optical control over bioelectricity generation. These findings add novel mechanistic and translational insight into optical ventricular cardioversion.

Because of suboptimal therapeutic strategies, restoration of sinus rhythm in symptomatic atrial fibrillation (AF) often requires in-hospital delivery of high-voltage shocks, thereby precluding ambulatory AF termination. Continuous, rapid restoration of sinus rhythm is desired given the recurring and progressive nature of AF. Here, we present an automated hybrid bioelectronic system for shock-free termination of AF that enables the heart to act as an electric current generator for autogenous restoration of sinus rhythm. We show that local, right atrial delivery of adenoassociated virus vectors encoding a light-gated depolarizing ion channel results in efficient and spatially confined transgene expression. Activation of an implanted intrathoracic light-emitting diode device allows for termination of AF by illuminating part of the atria. Combining this newly obtained antiarrhythmic effector function of the heart with the arrhythmia detector function of a machine-based cardiac rhythm monitor in the closed chest of adult rats allowed automated and rapid arrhythmia detection and termination in a safe, effective, repetitive, yet shock-free manner. These findings hold translational potential for the development of shock-free antiarrhythmic device therapy for ambulatory treatment of AF.