Interventricular Differences in Action Potential Duration Restitution Contribute to Dissimilar Ventricular Rhythms in ex vivo Perfused Hearts

Abstract

Background: Dissimilar ventricular rhythms refer to the occurrence of different ventricular tachyarrhythmias in the right and left ventricles or different rates of the same tachyarrhythmia in the two ventricles. Objective: We investigated the inducibility of dissimilar ventricular rhythms, their underlying mechanisms, and the impact of anti-arrhythmic drugs (lidocaine and amiodarone) on their occurrence. Methods: Ventricular tachyarrhythmias were induced with burst pacing in 28 Langendorff-perfused Sprague Dawley rat hearts (14 control, 8 lidocaine, 6 amiodarone) and bipolar electrograms recorded from the right and left ventricles. Fourteen (6 control, 4 lidocaine, 4 amiodarone) further hearts underwent optical mapping of transmembrane voltage to study interventricular electrophysiological differences and mechanisms of dissimilar rhythms. Results: In control hearts, dissimilar ventricular rhythms developed in 8/14 hearts (57%). In lidocaine treated hearts, there was a lower cycle length threshold for developing dissimilar rhythms, with 8/8 (100%) hearts developing dissimilar rhythms in comparison to 0/6 in the amiodarone group. Dissimilar ventricular tachycardia (VT) rates occurred at longer cycle lengths with lidocaine vs. control (57.1 ± 7.9 vs. 36.6 ± 8.4 ms, p < 0.001). The ratio of LV:RV VT rate was greater in the lidocaine group than control (1.91 ± 0.30 vs. 1.76 ± 0.36, p < 0.001). The gradient of the action potential duration (APD) restitution curve was shallower in the RV compared with LV (Control - LV: 0.12 ± 0.03 vs RV: 0.002 ± 0.03, p = 0.015), leading to LV-to-RV conduction block during VT. Conclusion: Interventricular differences in APD restitution properties likely contribute to the occurrence of dissimilar rhythms. Sodium channel blockade with lidocaine increases the likelihood of dissimilar ventricular rhythms.

Keywords: action potential duration restitution; antiarrhythmic drugs; dissimilar rhythms; dissimilar ventricular rhythms; implantable cardioverter-defibrillator; lidocaine; ventricular fibrillation; ventricular tachycardia.

Figure 1

Dissimilar ventricular rhythms recorded on a CRTD. An example of a CRT-D trace showing a patient with VF recorded on a surface ECG, and a regular slow RV activation rate compared to a dissimilar irregular LV activation rate (recorded as LVS) from the LV sensing lead.

Figure 2

Dissimilar rhythms are inducible in ex-vivo perfused hearts: (A) Type of ventricular rhythm induced in control hearts (B) Type of dissimilar rhythm induced (C) Ratio of LV to RV rate in VT and VF (D) Representative graph of a single experiment showing CL of RV and LV conduction in different ventricular rhythms with dissimilar VT CLs. (E) Representative electrogram trace for a single heart in VT showing 2:1 LV to RV rate (F) and 1–1 LV to RV rate in VF. LV, left ventricle; RV, right ventricle; CL, cycle length(s); SR, sinus rhythm; VT, ventricular tachycardia; VF, ventricular fibrillation [Data from control hearts (n = 14), ***p < 0.001, 1-way ANOVA, post-hoc Bonferroni test].

Figure 3

Lidocaine lowers threshold for dissimilar VT rates: Representative bipolar electrograms of LV and RV in VT in (A) a control heart (B) a heart perfused with 10 μM Lidocaine showing dissimilar VT rates occurring at longer LV CLs with lidocaine. (C) Increased propensity to develop dissimilar rhythms with 10 μM lidocaine compared to control and 10 μM amiodarone treated hearts (D) LV CL of VT is longer with lidocaine 10 μM (E) LV to RV conduction ratio in VT with dissimilar interventricular rates is higher in control and lidocaine 10 μM perfused hearts. [Data from control (n = 14), 10 μM lidocaine (n = 8), and 10 μM amiodarone (n = 6) hearts, **p < 0.01, ***p < 0.001, t-test (D), and 1-way ANOVA with post-hoc Bonferroni (E)]. Abbreviations as per Figure 2.

Figure 4

LV APD shortens more than RV at shorter pacing cycle lengths. LV and RV APD restitution curves at different paced cycle lengths showing that the LV APD restitution curve has a steeper gradient than the RV APD restitution curves in (A) control, (B) lidocaine, and (C) amiodarone hearts. □/° showing LV and RV APD in sample VT data set with dissimilar rhythms. (D) Representative APD90 maps from control (left), lidocaine (middle), and amiodarone (right) hearts. [Data from control (n = 6), lidocaine (n = 4), and amiodarone (n = 4) hearts, linear regression].

Figure 5

Interventricular conduction block in dissimilar ventricular VT rates. Representative LV and RV bipolar electrograms (top), optical mapping signals (bottom) with corresponding sampling sites (right) in (A) control and (B) lidocaine perfused hearts showing interventricular rate differences in VT. Corresponding activation maps and optical fluorescence data showing interventricular conduction block as the mechanism of 2:1 LV to RV VT rate in control (C) and lidocaine (D) perfused hearts.

Figure 6

VF phase maps. (A) Representative LV and RV bipolar electrograms (top) and optical mapping signals (bottom) with corresponding sampling sites (left) in a control heart showing dissimilar ventricular tachyarrhythmias (VT and VF). (B) Corresponding VF phase map of (A) showing regular periodic RV activation and contrasting more disorganized LV activation (Supplementary Data–Video 1). (C) Representative LV and RV bipolar electrograms (top) and optical mapping signals (bottom) with corresponding sampling sites (left) in an amiodarone perfused heart, and the corresponding VF phase map (D) showing disorganized VF with similar rates.