Medetomidine/midazolam/fentanyl narcosis alters cardiac autonomic tone leading to conduction disorders and arrhythmias in mice

Figures

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  Fig. 1. Study design. A total of n = 29 C57BL/6N mice were randomly assigned to telemetry (without narcosis) or ECG/invasive EP study with MMF or IF narcosis. Basic ECG parameters, HRV parameters, sinus node and AV node function, refractory periods, susceptibility to arrhythmias and spontaneous arrhythmias were assessed. Figure created with BioRender.com.

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  Fig. 2. ECG parameters. a–e, ECG measurements obtained from awake mice were compared with those obtained under MMF or IF narcosis. a, Heart rate. b, PR interval. c, P wave duration. d, QRS duration. e, QTc (calculation was done according to Mitchell60). n = 7 for awake, n = 10 for MMF and n = 12 for IF, values presented as mean ± s.e.m.*P < 0.05, **P < 0.01, ****P < 0.0001, using one-way analysis of variance with Tukey’s multiple comparison test.

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  Fig. 3. HRV analysis. a–j, HRV parameters obtained from awake mice were compared with those obtained under MMF or IF narcosis. a, Median RR interval. b, SDRR. c, RMSSD. d, pRR50. e, Percentage of the VLF oscillation (0.00–0.15 Hz). f, Percentage of the LF oscillation (0.15–1.50 Hz). g, Percentage of the HF oscillation (1.5–5.0 Hz). h, LF/HF. i, SD1. j, SD2. n = 7 for awake, n = 10 for MMF and n = 12 for IF, values presented as mean ± s.e.m.*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, using one-way analysis of variance with Tukey’s multiple comparison test.

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  Fig. 4. EP study. a–g, EP study was performed in mice under MMF or IF narcosis. a, SNRT, corrected by subtraction of the individual atrial basic cycle length. b, WB CL. c, 2:1 CL. d, VA CL. e, AVERP. f, AERP. g, VERP. n = 10 for MMF and n = 12 for IF, values presented as mean ± s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 Mann–Whitney test.

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  Fig. 5. Arrhythmia inducibility and quantification. a–f, Arrhythmogenesis was assessed in mice under MMF or IF narcosis. a, Atrial inducibility. b, Atrial mean episode duration. c, Mean burden of atrial arrhythmia per animal. d, Ventricular inducibility. e, Ventricular mean episode duration. f, Mean burden of ventricular arrhythmia per animal. NS, not significant. n = 10 for MMF and n = 12 for IF, values are presented as mean ± s.e.m. *P < 0.05 chi-square test (for d). *P < 0.05 Mann–Whitney test (for b), ****P < 0.0001 unpaired Student’s t-test (for e).

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  Fig. 6. Spontaneous arrhythmias. a–d, Spontaneous occurrence of arrhythmia was analyzed from ECGs of awake mice and mice under MMF or IF narcosis. a, Quantification of sinus arrhythmia calculated as the percentage of animals per group showing the occurrence in the surface ECG (left) and a corresponding representative trace from MMF group (right). b, Quantification of intermittent AV block (AVB) type II Wenckebach (left) calculated as the percentage of animals per group showing the occurrence and a corresponding representative trace from MMF group (right). c, Quantification of intermittent AV block III (left) calculated as the percentage of animals per group showing the occurrence and a corresponding representative trace from MMF group (right). d, Quantification of abnormal spontaneous ventricular activity (left) calculated as the percentage of animals per group showing the occurrence and a corresponding representative trace from MMF group (right). Red, non-conducted atrial beats and spontaneous ventricular activity. A, atrial beat; F, fusion beat; T, spontaneous ventricular activity; V, ventricular beat. n = 7 for awake, n = 10 for MMF and n = 12 for IF, *P < 0.05, ****P < 0.001…