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. 2023 Apr 20;18(4):e0282943.
doi: 10.1371/journal.pone.0282943. eCollection 2023.

Epicardial electrical heterogeneity after amiodarone treatment increases vulnerability to ventricular arrhythmias under therapeutic hypothermia

Chin-Yu Lin  1   2 , Ting-Yung Chang  1   2 , Yu-Feng Hu  1   2   3 , Yu-Cheng Hsieh  4 , Yi-Jen Chen  5 , Hung-I Yeh  6 , Yenn-Jiang Lin  1   2 , Shih-Lin Chang  1   2 , Li-Wei Lo  1   2 , Tze-Fan Chao  1   2 , Fa-Po Chung  1   2 , Jo-Nan Liao  1   2 , Ta-Chuan Tuan  1   2 , Shih-Ann Chen  1   2   4   7
Affiliations

Epicardial electrical heterogeneity after amiodarone treatment increases vulnerability to ventricular arrhythmias under therapeutic hypothermia

Chin-Yu Lin et al. PLoS One. .

Abstract

Background: Amiodarone is commonly used during therapeutic hypothermia (TH) following cardiac arrest due to ventricular arrhythmias. However, electrophysiological changes and proarrhythmic risk after amiodarone treatment have not yet been explored in TH.

Methods: Epicardial high-density bi-ventricular mapping was performed in pigs under baseline temperature (BT), TH (32-34°C), and amiodarone treatment during TH. The total activation time (TAT), conduction velocity (CV), local electrogram (LE) duration, and wavefront propagation from pre-specified segments were analyzed during sinus rhythm (SR) or right ventricular (RV) pacing (RVP), along with tissue expression of connexin 43. The vulnerability to ventricular arrhythmias was assessed.

Results: Compared to BT, TH increased the global TAT, decreased the CV, and generated heterogeneous electrical substrate during SR and RVP. During TH, the CV reduction and LE duration prolongation were greater in the anterior mid RV than in the other areas, which changed the wavefront propagation in all animals. Compared to TH alone, amiodarone treatment during TH further increased the TAT and LE duration and decreased the CV. Heterogeneous conduction was partially attenuated after amiodarone treatment. After TH and amiodarone treatment, the connexin 43 expression in the anterior mid RV was lower than that in the other areas, compatible with the heterogeneous CV reduction. The animals under TH and amiodarone treatment had a higher incidence of inducible ventricular arrhythmias than those under BT or TH without amiodarone.

Conclusion: Electrical heterogeneity during amiodarone treatment and TH was associated with vulnerability to ventricular arrhythmias.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Sequential changes in the surface ECG parameters after TH and amiodarone treatment.
(A) Representative ECG parameters (QRS duration, QT interval, and TpTe interval) at BT (upper panel), TH (middle panel), and amiodarone/TH (lower panel) of pig 3 during SR. The ECG parameters analyzed included the following: (B) QRS durations, (C) QT intervals, (D) QTc intervals, and (E) TpTe intervals. TH increased all ECG parameters compared with BT. However, even under TH, amiodarone treatment further increased the durations of all ECG parameters. These data were derived from all the six pigs from this study. *P < 0.05, BT vs. TH; #P < 0.05, TH vs. Amiodarone/TH, both by the paired t-test. The data were presented as means ± standard deviations. BT, baseline temperature; ECG, electrocardiography; QTc, corrected QT; TH, therapeutic hypothermia; TpTe, T-peak to T-end interval.
Fig 2
Fig 2. Sequential changes in the TAT after TH and amiodarone treatment.
(A) Sequential changes in the TAT after the induction of TH and amiodarone infusion (amiodarone/TH) either during SR (left panel) or RVP (right panel). These data were derived from the six pigs from protocol I. (B) Representative isochronal map of pig 1 during SR (left panel: BT, middle panel: after TH, and right panel: after amiodarone infusion). The Panel B showed a left anterior-oblique (LAO) view to the heart. The upper part indicated anterior aspect of the heart and the lower part indicated the posterior aspect of the heart. From a LAO view, the LV was in the right side and RV in the left side. The landmark was highlighted in yellow color. The white color on the map indicated the earliest activation site and followed by red, orange, yellow, green, light blue, blue, and purple color. *P < 0.05, BT vs. TH; #P < 0.05, TH vs. Amiodarone/TH, both by the paired t-test. The data are presented as means ± standard deviations. BT, baseline temperature; LV, left ventricle; RV, right ventricle; RVP, right ventricular pacing; SR, sinus rhythm; TAT, total activation time; TH, therapeutic hypothermia.
Fig 3
Fig 3. Global and regional changes in the CV.
(A) Sequential changes in the CV after TH or amiodarone treatment during SR or RVP. A sequential reduction in the CVs was observed after TH and amiodarone treatment. These data were derived from all the six pigs from this study. *P < 0.05, BT vs. TH; #P < 0.05, TH vs. Amiodarone/TH, both by the paired t-test. (B) Interval changes between BT and TH (ΔCV between BT and TH) and between TH and amiodarone/TH (ΔCV between TH and amiodarone/TH) in the different epicardial segments. These data were derived from all the six pigs from this study. The interval changes in the CV in segment 8 (anterior mid right ventricle) were significantly greater than those in all the other segments. *P < 0.05, ΔCV between BT and TH in segment 8 vs. the other segments in the post-hoc analysis with the Bonferroni method. (C) The color-coded polar map of the interval changes between BT and TH (ΔCV between BT and TH) and between TH and amiodarone/TH (ΔCV between TH and amiodarone/TH) in the different epicardial segments. Each color indicated different degree of decrease in the CV.
Fig 4
Fig 4. Global and regional changes in the LE duration.
(A) Sequential changes in the LE duration after TH or amiodarone treatment during SR or RVP. These data were derived from all the six pigs from this study. A sequential reduction in the LE durations was observed after TH or amiodarone treatment. *P < 0.05, BT vs. TH; #P < 0.05, TH vs. Amiodarone/TH, both by the paired t-test. (B) Interval changes between BT and TH (ΔLE durations between BT and TH) and between TH and amiodarone/TH (ΔLE durations between TH and amiodarone/TH) in the different epicardial segments. These data were derived from all the six pigs from this study. The interval changes in the LE durations in segment 8 (anterior mid RV or posterior mid RV) were significantly greater than those in all the other segments. *P < 0.05, ΔLE durations between BT and TH in segment 8 or segment 9 vs. the other segments in the post-hoc analysis with the Bonferroni method. (C) Representative bipolar electrograms of segment 8 and segment 1 from pig 4 during BT, TH, and amiodarone/TH demonstrating sequential prolongation of the LE durations.
Fig 5
Fig 5. Changes in the wavelet activation pattern, the vulnerability to ventricular arrhythmias after amiodarone treatment during TH, and Regional differences in the connexin 43 expression during TH and amiodarone treatment.
(A) Representative isochronal activation from pig 1 according to the pre-specified segments. During SR, the earliest activated site was the apical area (segment 13), and the latest activated site was the outflow tract area (segment 1) at BT. After TH, the latest activated site changed to the anterior basal RV (segment 2). After amiodarone infusion during TH, the latest activated site moved back to the outflow tract area (segment 1). During RVP, the earliest activated site was the posterior basal right ventricle (segment 3), and the latest activated site was mostly (83.3%) the posterior basal LV (segment 5) at BT. At TH, the latest activated site mostly changed to the anterior basal LV (segment 6, 66.7%). At amiodarone/TH, the latest activated site moved to the posterior basal LV (segment 5, 50%) in half of the pigs. (B) The incidence of ventricular arrhythmias after burst RVP. The vulnerability to ventricular arrhythmias was tested in 4, 4, and 3 pigs with BT, TH, and amiodarone/TH respectively. The vulnerability to ventricular arrhythmias of pigs with amiodarone/TH group was higher than the pigs at BT and the pigs with TH (P = 0.021).
Fig 6
Fig 6. Regional differences in the connexin 43 expression during TH and amiodarone treatment.
(A) Left panel: Comparison of the connexin 43 expressions among segment 8 (anterior mid RV wall), segment 5 (posterior basal LV wall), and segment 12 (anterior mid LV wall). The data are presented as box plot. These data were derived from pig 3, pig 4, pig 5, and pig 6 from the protocol I. Right panel: Comparison of the connexin 43 lateralization among segment 8 (anterior mid RV wall), segment 5 (posterior basal LV wall), and segment 12 (anterior mid LV wall). The data are presented as box plot. These data were derived from pig 3, pig 4, pig 5, and pig 6 from the protocol I. (6 slides from each segment of each pig) The parameters between the three segments were compared using one-way ANOVA. (B) Presentative fluorescent images of the connexin 43 expressions. Left panel: anterior mid RV (segment 8 of pig 6); middle panel: posterior basal LV (segment 5 of pig 5); right panel: anterior mid LV (segment 12 of pig 4). Green fluorescence: connexin 43; blue fluorescence: 4,6-diamidino-2-phenylindole for nucleus. BT: baseline temperature; LV = left ventricle; RV = right ventricle; RVP = right ventricular pacing; TH = therapeutic hypothermia.
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References

    1. Callaway CW, Donnino MW, Fink EL, Geocadin RG, Golan E, Kern KB, et al.. Part 8: Post-Cardiac Arrest Care: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132:S465–482. doi: 10.1161/CIR.0000000000000262 - DOI - PMC - PubMed
    1. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al.. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346:557–563. doi: 10.1056/NEJMoa003289 - DOI - PubMed
    1. Hypothermia after Cardiac Arrest Study G. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549–556. doi: 10.1056/NEJMoa012689 - DOI - PubMed
    1. Piktel JS, Suen Y, Kouk S, Maleski D, Pawlowski G, Laurita KR, et al.. Effect of Amiodarone and Hypothermia on Arrhythmia Substrates During Resuscitation. J Am Heart Assoc. 2021;10:e016676. doi: 10.1161/JAHA.120.016676 - DOI - PMC - PubMed
    1. Fu XK, Liu YQ, Gao H, Wang GL, Li HY, Dai DJ. [Effects of hypothermia on the repolarization duration of ventricular myocytes in rats and its mechanism]. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2020;36:228–231. doi: 10.12047/j.cjap.5914.2020.050 - DOI - PubMed

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