Ventricular electromechanics in a cardiac glycoside arrhythmia model in isoflurane-anaesthetised New Zealand White (NZW) rabbits

Abstract

Cardiac glycoside (CG) intoxication models are well-established tools to evaluate non-torsadogenic arrhythmic liabilities in vivo. However, preparations using practical inhalant anesthetics, particularly in rabbits, a highly translational species for preclinical electrophysiology and functional assessments, are seldom described. In this study, we characterize CG-induced cardiovascular responses under isoflurane anesthesia in an optimized in vivo rabbit preparation. Ventilated male NZW rabbits (n = 4–6/group, 6-month old) were administered either digoxin (DIG, 40 μg/kg/min IV) or ouabain (OUA, 15 μg/kg/min IV) after anesthetic stabilization under isoflurane inhalant (1.5–2 %) and butorphanol (0.2 mg/kg/h IV). Animals were vagotomized and instrumented for lead-II ECG, catheter-based arterial (MAP) and left-ventricular pressures (LVP), and pericardiectomized to permit electrophysiological mapping. Electromechanical window (EMW) was derived from ECG and LVP signals. The effects of concurrent beta-adrenergic stimulation with dobutamine (+DOB: 2.5 μg/kg/min) were evaluated in a subset of OAU rabbits. At baseline (BL), heart rate (HR: 266 ± 44 bpm), hemodynamics (MAP: 60 ± 10 mmHg), ECG intervals (QT: 146 ± 21 msec), and electromechanical indices (dPdtmax: 2551 ± 1144 mmHg/s, EMW: 46 ± 11 ms) were reflective of normal physiology in rabbits. Under CG administration, sustained ventricular ectopy (SVE, >30 s) and ventricular fibrillation (VF) were reliably and successively induced (DIG SVE: 22.2 ± 3 min, VF: 34.7 ± 5 min; OUA SVE: 8.5 ± 2 min, VF: 16 ± 2 min). Prior to SVE and consistent with CG toxicity, animals demonstrated robust increases in indices of inotropy (dPdtmax: DIG: +92 ± 47 %, OUA: +116 ± 43 %), afterload (MAP: DIG: +58 ± 34 %; OUA:+50 ± 14 %), and serum potassium ([K+]: DIG: +40 ± 11 %; OUA: +47 ± 15 %). Heart rate was equivalent to baseline in both preparations, aligning to pre-existing vagal withdrawal (DIG: +2 ± 11 %, OUA: -0.4 ± 3 %). EMW was variable but remained positive in all animals before SVE (EMW DIG: 44 ± 21 msec; OUA: 40 ± 11 msec) with nominal QT change (DIG: -2 ± 11 %, OUA: +5 ± 6 % vs. BL). Beta-adrenergic stimulation accelerated the time to OUA-induced SVE and VF (+DOB: −19 % and − 10 %, respectively vs. OUA). Taken together, these data strongly suggest that rabbits instrumented under a contemporary isoflurane anesthetic regimen constitute a viable model of cardiac glycoside induced ventricular arrhythmias, characterized by predictable and progressive ectopy that is sensitive to pharmacological modulation.