Deletion of the serotonin receptor type 3A in mice leads to sudden cardiac death during pregnancy

Hyewon Park, Chang Myung Oh, Junbeom Park, Hyelim Park, Shanyu Cui, Hyung Suk Kim, Jun Namkung, Sang Kyu Park, Hui Nam Pak, Moon Hyoung Lee, Hail Kim, Boyoung Joung

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Background: The serotonin receptor type 3 (Htr3) blocker is associated with QT prolongation and torsades de pointes. However, little is known about effects of Htr3 on the heart arrhythmia. Methods and Results: An electrophysiological study Involving knock-out (KO) female mice lacking functional Htr3a (Htr3a–/–) and their wild-type littermates during non-pregancy (NP) and late pregnancy (LP) was performed. Htr3a mRNA was present in the wild-type, but not in the Htr3a–/– mouse hearts. Serotonin and tryptophan hydroxylase 1 (Tph1), a rate-limiting enzyme of serotonin synthesis in hearts, is increased during pregnancy. The heart weight and size were increased in the pregnant mice regardless of a mutation. The QTc intervals were prolonged after pregnancy in both the wild (NP: 171.2 ±16.8 vs. LP: 247.7±14.3 ms; P<0.001) and Htr3a–/– mice (NP: 187.9±18.7 vs. LP: 275.6±11.0 ms, P<0.001). Compared with wild-type LP mice, Htr3a–/– LP mice had increased spontaneous ventricle tarchycardia (VT; 56% vs. 0%, P=0.002), VT inducibility (66% vs. 25%, P=0.002) and mortality (56% vs. 0%, P=0.002). Pharmacologic administration of serotonin and Htr3 agonists (m-CPBG) decreased the QT interval in wild mice, but not in Htr3a–/– mice. Conclusions: Htr3a is present in mouse hearts. Serotonin and Tph1 were increased during pregnancy. The deletion of Htr3a was related to fatal arrhythmias and sudden cardiac death during pregnancy, and its activation reversed the QT prolongation.

Original languageEnglish
Pages (from-to)1807-1815
Number of pages9
JournalCirculation Journal
Volume79
Issue number8
DOIs
StatePublished - 24 Jul 2015

Keywords

  • Fatal arrhythmia
  • Pregnancy
  • QT prolongation
  • Serotonin receptor type 3

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