title: Deletion of the Serotonin Receptor Type 3A in Mice Leads to Sudden Cardiac Death During Pregnancy.
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.
  
  
  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.
authors.affiliation: Division of Cardiology, Yonsei University College of Medicine.
authors.forename: Hyewon
authors.initials: H
authors.lastname: Park
authors.forename: Chang-Myung
authors.initials: CM
authors.lastname: Oh
authors.forename: Junbeom
authors.initials: J
authors.lastname: Park
authors.forename: Hyelim
authors.initials: H
authors.lastname: Park
authors.forename: Shanyu
authors.initials: S
authors.lastname: Cui
authors.forename: Hyung Suk
authors.initials: HS
authors.lastname: Kim
authors.forename: Jun
authors.initials: J
authors.lastname: Namkung
authors.forename: Sang-kyu
authors.initials: SK
authors.lastname: Park
authors.forename: Hui-Nam
authors.initials: HN
authors.lastname: Pak
authors.forename: Moon-Hyoung
authors.initials: MH
authors.lastname: Lee
authors.forename: Hail
authors.initials: H
authors.lastname: Kim
authors.forename: Boyoung
authors.initials: B
authors.lastname: Joung
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism; D016757:Death, Sudden, Cardiac; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000235:genetics / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3 / Q000172:deficiency*; D012701:Serotonin / Q000096:biosynthesis* / Q000235:genetics; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism*
chemical_list: C511230:Htr3a protein, mouse; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin; C487801:Tph1 protein, mouse; D014365:Tryptophan Hydroxylase