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. 2019 Jun;30(6):941-949.
doi: 10.1111/jce.13942. Epub 2019 Apr 21.

Progesterone pretreatment reduces the incidence of drug-induced torsades de pointes in atrioventricular node-ablated isolated perfused rabbit hearts

James E Tisdale  1   2 , Heather A Jaynes  1 , Brian R Overholser  1   2 , Kevin M Sowinski  1   2 , Richard J Kovacs  3
Affiliations

Progesterone pretreatment reduces the incidence of drug-induced torsades de pointes in atrioventricular node-ablated isolated perfused rabbit hearts

James E Tisdale et al. J Cardiovasc Electrophysiol. 2019 Jun.

Abstract

Introduction: Higher progesterone concentrations are protective against drug-induced prolongation of ventricular repolarization. We tested the hypothesis that pretreatment with progesterone reduces the incidence of drug-induced torsades de pointes (TdP).

Methods and results: Female New Zealand white rabbits (2.5-3.2 kg) underwent ovariectomy and were randomized to undergo implantation with subcutaneous 21-day sustained release pellets containing progesterone 50 mg (n = 22) or placebo (n = 23). After 20 days, hearts were excised, mounted, and perfused with modified Krebs-Henseleit solution. The atrioventricular (AV) node was destroyed manually. Following a 15-minute equilibration period, hearts were perfused with dofetilide 100 nM for 30 minutes, during which the electrocardiogram was recorded continuously. Incidences of spontaneous TdP, other ventricular arrhythmias and mean QTc intervals were compared. Median serum progesterone concentrations were higher in progesterone vs placebo-treated rabbits (3.8 [range, 2.8-5.1] vs 0.7 [0.4-1.7] ng/mL, P < 0.0001). Median serum estradiol concentrations were similar (58 [22-72] vs 53 [34-62] pg/mL), P = 0.79). The incidence of TdP was lower in hearts from progesterone-treated rabbits (27% vs 61%, P = 0.049). The incidences of bigeminy (36% vs 74%, P = 0.03) and trigeminy (18% vs 57%, P = 0.01) were also lower in hearts from progesterone-treated rabbits. There was no significant difference between groups in incidence of couplets (59% vs 74%, P = 0.54) or monomorphic ventricular tachycardia (14% vs 30%, P = 0.28). Maximum QT c interval and short-term beat-to-beat QT interval variability during dofetilide perfusion were significantly shorter in hearts from progesterone-treated rabbits.

Conclusions: Pretreatment with progesterone reduces the incidence of drug-induced TdP, bigeminy, and trigeminy in isolated perfused AV node-ablated rabbit hearts.

Keywords: QT interval; beat-to-beat variability; dofetilide; isolated perfused heart; progesterone; rabbit; torsades de pointes; ventricular arrhythmias.

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Figures

Figure 1
Figure 1
Incidence of Torsades de Pointes and Other Ventricular Arrhythmias During Dofetilide Perfusion in Hearts From Progesterone and Placebo-Treated Rabbits
Figure 2
Figure 2
Spontaneous Torsades de Pointes During Dofetilide Perfusion in an Isolated Perfused Rabbit Heart Pretreated with Placebo
Figure 3
Figure 3
Ventricular Arrhythmia Burden During Dofetilide Perfusion in Hearts From Progesterone and Placebo-Treated Rabbits 3a. Median (range) Number of Total Ventricular Arrhythmia Complexes During Dofetilide Perfusion in Hearts From Progesterone and Placebo-Treated Rabbits 3b. Mean (±SD) Number of Ventricular Arrhythmia Complexes During a 5-Minute Period (from 10–15 Minutes Following Initiation of Perfusion) During Dofetilide Perfusion in Hearts From Progesterone and Placebo-Treated Rabbits SD = Standard deviation
Figure 3
Figure 3
Ventricular Arrhythmia Burden During Dofetilide Perfusion in Hearts From Progesterone and Placebo-Treated Rabbits 3a. Median (range) Number of Total Ventricular Arrhythmia Complexes During Dofetilide Perfusion in Hearts From Progesterone and Placebo-Treated Rabbits 3b. Mean (±SD) Number of Ventricular Arrhythmia Complexes During a 5-Minute Period (from 10–15 Minutes Following Initiation of Perfusion) During Dofetilide Perfusion in Hearts From Progesterone and Placebo-Treated Rabbits SD = Standard deviation
Figure 4
Figure 4
Mean (±SD) QTc Intervals Prior to and During Dofetilide Perfusion in Hearts From Progesterone and Placebo-Treated Rabbits 4a. Mean (±SD) Baseline (pre-dofetilide) QTc Intervals During Modified Krebs-Henseleit Perfusion in Hearts From Progesterone and Placebo-Treated Rabbits 4b. Mean (±SD) Maximum QTc Intervals During Dofetilide Perfusion in Hearts From Progesterone and Placebo-Treated Rabbits SD = Standard deviation
Figure 4
Figure 4
Mean (±SD) QTc Intervals Prior to and During Dofetilide Perfusion in Hearts From Progesterone and Placebo-Treated Rabbits 4a. Mean (±SD) Baseline (pre-dofetilide) QTc Intervals During Modified Krebs-Henseleit Perfusion in Hearts From Progesterone and Placebo-Treated Rabbits 4b. Mean (±SD) Maximum QTc Intervals During Dofetilide Perfusion in Hearts From Progesterone and Placebo-Treated Rabbits SD = Standard deviation
Figure 5
Figure 5
Mean (± SEM) QT intervals During the 30-minute Period of Dofetilide Perfusion formula image Progesterone formula image Placebo Overall p value = 0.04 *Tukey’s post-hoc p = 0.04 **Tukey’s post-hoc p = 0.008 SEM = Standard error of the mean
See this image and copyright information in PMC

Comment in

  • Sex hormones and jumping heart beats.
    van der Heyden MAG, Vos MA. van der Heyden MAG, et al. J Cardiovasc Electrophysiol. 2019 Jun;30(6):950-951. doi: 10.1111/jce.13939. Epub 2019 Apr 21. J Cardiovasc Electrophysiol. 2019. PMID: 31006915 No abstract available.

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