Electrophysiology and Arrhythmogenesis in the Human Right Ventricular Outflow Tract

Abstract

Background: Right ventricular outflow tract (RVOT) is a common source of ventricular tachycardia, which often requires ablation. However, the mechanisms underlying the RVOT’s unique arrhythmia susceptibility remain poorly understood due to lack of detailed electrophysiological and molecular studies of the human RVOT. Methods: We conducted optical mapping studies in 16 nondiseased donor human RVOT preparations subjected to pharmacologically induced adrenergic and cholinergic stimulation to evaluate susceptibility to arrhythmias and characterize arrhythmia dynamics. Results: We found that under control conditions, RVOT has shorter action potential duration at 80% repolarization relative to the right ventricular apical region. Treatment with isoproterenol (100 nM) shortened action potential duration at 80% repolarization and increased incidence of premature ventricular contractions ( P =0.003), whereas acetylcholine (100 μM) stimulation alone had no effect on action potential duration at 80% repolarization or premature ventricular contractions. However, acetylcholine treatment after isoproterenol stimulation reduced the incidence of premature ventricular contractions ( P =0.034) and partially reversed action potential duration at 80% repolarization shortening ( P =0.029). Immunolabeling of RVOT (n=4) confirmed the presence of cholinergic marker VAChT (vesicular acetylcholine transporter) in the region. Rapid pacing revealed RVOT susceptibility to both concordant and discordant alternans. Investigation into transmural arrhythmia dynamics showed that arrhythmia wave fronts and phase singularities (rotors) were relatively more organized in the endocardium than in the epicardium ( P =0.006). Moreover, there was a weak but positive spatiotemporal autocorrelation between epicardial and endocardial arrhythmic wave fronts and rotors. Transcriptome analysis (n=10 hearts) suggests a trend that MAPK (mitogen-activated protein kinase) signaling, calcium signaling, and cGMP-PKG (protein kinase G) signaling are among the pathways that may be enriched in the male RVOT, whereas pathways of neurodegeneration may be enriched in the female RVOT. Conclusions: Human RVOT electrophysiology is characterized by shorter action potential duration relative to the right ventricular apical region. Cholinergic right ventricular stimulation attenuates the arrhythmogenic effects of adrenergic stimulation, including increase in frequency of premature ventricular contractions and shortening of wavelength. Right ventricular arrhythmia is characterized by positive spatial-temporal autocorrelation between epicardial-endocardial arrhythmic wave fronts and rotors that are relatively more organized in the endocardium.

Rationale and study design for empirical additional lesions for premature ventricular complex from the outflow tract: a multi-center, prospective randomized trial (EASE-PVC study)

“…Catheter ablation was introduced into the clinical practice for the treatment of OT-PVCs over two decades ago [10]. There is a wide consensus that an extra heart beat is caused by one time of electrical impulse from a focus formed by a cluster of cells with abnormal automaticity [11]. Consequently, the ablation strategy for these idiopathic ventricular arrhythmias is to find the site exhibiting the earliest activation, or a site which demonstrates a perfect match compared with the clinical arrhythmia.…”

Verification of the Efficacy of Mexiletine Treatment for the A1656D Mutation on Downgrading Reentrant Tachycardia Using a 3D Cardiac Electrophysiological Model

“…Results may be different when simulated using other cell types. However, recent studies [ 36 , 37 , 38 ] showed that the epicardial could exhibit more alternants than other regions (myocardial and endocardial), which may be related to the buildup of fat on the epicardial surface. Therefore, we may assume that the results from the epicardial cell are sufficient to describe the occurrence of a spiral breakup.…”

Hardware‐Mappable Cellular Neural Networks for Distributed Wavefront Detection in Next‐Generation Cardiac Implants

“…However, these results were directly applicable to electrically recorded data, as shown in Figure 2b , c . [ 24 ] Studies into the resolution required to extract any possible chaotic rotors in human tissue are still under investigation and higher-resolution setups are being developed.…”

“…2b,c are reproduced with permission. [24] Copyright 2022, American Heart Association. Due to the unavoidable interrupts during the hour-long experiments and the underlying condition of the available human heart tissue, noise was an inevitable occurrence in the dataset.…”

“…b) Simultaneous optical and electrical cardiac mapping. c) Corresponding representative electrical and optical signals.Figure2b,c are reproduced with permission [24]. Copyright 2022, American Heart Association.…”