Effect of anisotropy on ventricular vulnerability to unidirectional block and reentry by single premature stimulation during normal sinus rhythm in rat heart

Abstract

Single high-intensity premature stimuli when applied to the ventricles during ventricular drive of an ectopic site, as in Winfree's "pinwheel experiment," usually induce reentry arrhythmias in the normal heart, while single low-intensity stimuli barely do. Yet ventricular arrhythmia vulnerability during normal sinus rhythm remains largely unexplored. With a view to define the role of anisotropy on ventricular vulnerability to unidirectional conduction block and reentry, we revisited the pinwheel experiment with reduced constraints in the in situ rat heart. New features included single premature stimulation during normal sinus rhythm, stimulation and unipolar potential mapping from the same high-resolution epicardial electrode array, and progressive increase in stimulation strength and prematurity from diastolic threshold until arrhythmia induction. Measurements were performed with 1-ms cathodal stimuli at multiple test sites ( = 26) in seven rats. Stimulus-induced virtual electrode polarization during sinus beat recovery phase influenced premature ventricular responses. Specifically, gradual increase in stimulus strength and prematurity progressively induced make, break, and graded-response stimulation mechanisms. Hence unidirectional conduction block occurred as follows: ) along fiber direction, on right and left ventricular free walls ( = 23), initiating figure-eight reentry ( = 17) and tachycardia ( = 12), and ) across fiber direction, on lower interventricular septum ( = 3), initiating spiral wave reentry ( = 2) and tachycardia ( = 1). Critical time window (55.1 ± 4.7 ms, 68.2 ± 6.0 ms) and stimulus strength lower limit (4.9 ± 0.6 mA) defined vulnerability to reentry. A novel finding of this study was that ventricular tachycardia evolves and is maintained by episodes of scroll-like wave and focal activation couplets. We also found that single low-intensity premature stimuli can induce repetitive ventricular response ( = 13) characterized by focal activations. We performed ventricular cathodal point stimulation during sinus rhythm by progressively increasing stimulus strength and prematurity. Virtual electrode polarization and recovery gradient progressively induced make, break, and graded-response stimulation mechanisms. Unidirectional conduction block occurred along or across fiber direction, initiating figure-eight or spiral wave reentry, respectively, and tachycardia sustained by scroll wave and focal activations.

Multimodal imaging shows fibrosis architecture and action potential dispersion are predictors of arrhythmic risk in spontaneous hypertensive rats

“…Following capture loss, stimulation was then reduced in steps of 0.1 Hz to determine the maximum pacing frequency. Two‐second bursts of 2 ms pulse trains with increasing frequencies (×4) and amplitudes (×3) were applied until VT or VF (>15 sustained complexes on the electrogram following cessation of stimulation) was induced (Rossi et al., 2017; Yang et al., 2007). The total stimulus current, I S (mA), was used to assign VT/VF risk index integer values from 12 (high risk: low total current) to 1 (low risk: high total current) according to the following relationship: $$\begin{equation*}{I_{\rm{S}}} \propto {{\sigma}}\left( f \right)fV.\end{equation*}$$Here, σ is the local tissue conductivity (mS/mm) and a function of stimulus frequency, f is the pulse train frequency (10, 20, 50, 100 Hz) and V is the pulse amplitude (3, 5, 7.5 V).…”

“…Following capture loss, stimulation was then reduced in steps of 0.1 Hz to determine the maximum pacing frequency. Two-second bursts of 2 ms pulse trains with increasing frequencies (×4) and amplitudes (×3) were applied until VT or VF (>15 sustained complexes on the electrogram following cessation of stimulation) was induced (Rossi et al, 2017;Yang et al, 2007). The total stimulus current, I S (mA), was used to assign VT/VF risk index integer values from 12 (high risk: low total current) to 1 (low risk: high total current) according to the following relationship:…”