孕酮预处理可降低房室结消融的离体灌注兔心脏中药物诱导的尖端扭转型室性心动过速的发生率。
Progesterone pretreatment reduces the incidence of drug-induced torsades de pointes in atrioventricular node-ablated isolated perfused rabbit hearts.
作者信息
Tisdale James E, Jaynes Heather A, Overholser Brian R, Sowinski Kevin M, Kovacs Richard J
机构信息
Department of Pharmacy Practice, College of Pharmacy, Purdue University, Indianapolis, Indiana.
Department of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana.
出版信息
J Cardiovasc Electrophysiol. 2019 Jun;30(6):941-949. doi: 10.1111/jce.13942. Epub 2019 Apr 21.
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 QT 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 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.
引言
较高的孕酮浓度可预防药物引起的心室复极延长。我们检验了孕酮预处理可降低药物诱发尖端扭转型室性心动过速（TdP）发生率的假设。
方法与结果
对体重2.5 - 3.2千克的雌性新西兰白兔实施卵巢切除术，并随机分为两组，一组皮下植入含50毫克孕酮的21天缓释微丸（n = 22），另一组植入安慰剂（n = 23）。20天后，取出心脏，固定，并灌注改良的克雷布斯 - 亨塞尔特溶液。手动破坏房室（AV）结。经过15分钟的平衡期后，用100纳摩尔的多非利特灌注心脏30分钟，在此期间持续记录心电图。比较自发性TdP、其他室性心律失常的发生率以及平均QT间期。孕酮处理组兔子的血清孕酮浓度中位数高于安慰剂处理组（3.8 [范围，2.8 - 5.1] 对0.7 [0.4 - 1.7] 纳克/毫升，P < 0.0001）。血清雌二醇浓度中位数相似（58 [22 - 72] 对53 [34 - 62] 皮克/毫升），P = 0.79）。孕酮处理组兔子心脏中TdP的发生率较低（27% 对61%，P = 0.049）。孕酮处理组兔子心脏中室性早搏（36% 对74%，P = 0.03）和室性三联律（18% 对57%，P = 0.01）的发生率也较低。两组间成对室性早搏（59% 对74%，P = 0.54）或单形性室性心动过速（14% 对30%，P = 0.28）的发生率无显著差异。在多非利特灌注期间，孕酮处理组兔子心脏的最大QT间期和短期逐搏QT间期变异性显著缩短。
结论
孕酮预处理可降低离体灌注的房室结消融兔心脏中药物诱发的TdP、室性早搏和室性三联律的发生率。
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