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Title: Molecular mechanisms for fetal cardiac arrhythmia in intrahepatic cholestasis of pregnancy
Author: Sheikh Abdul Kadir, Siti Hamimah
ISNI:       0000 0004 2694 0383
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2010
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Intrahepatic cholestasis in pregnancy (ICP) is characterized by raised serum bile acids which can cause fetal complications, including preterm labour and intrauterine death. The fetal death in ICP is not well understood. In this thesis, the mechanisms of bile-acid induced arrhythmia were studied extensively using in vitro models of the fetal heart. Addition of the bile acid taurocholate (TC) to cardiomyocytes led to a reduction in the rate and amplitude of contraction, dysregulation of beating and desynchronization of intracellular calcium release. The results obtained from both differentiated mouse and human embryonic stem cell-derived cardiomyocytes (ESC-CM) demonstrated that immature cardiomyocytes are more susceptible to TC-induced arrhythmias than more mature cardiomyocytes. Although classical hepatic bile acid transporters such as ntcp, mrp2 and mdr2 are expressed in neonatal rat cardiomyocytes, the results suggest that they are unlikely to play role in TC-induced arrhythmia. They also suggest that the bile acid nuclear receptor FXR is not involved as uptake of radioactively labelled TC into the cells is minimal and that there is no functional involvement of the classical hepatic FXR pathways in neonatal rat cardiomyocytes. Similarly, the membrane bile acid receptor TGR5 showed neither immunoreactivity nor functional effects in cardiomyocytes. TC binds to the muscarinic M2 receptor and serves as a partial agonist of this receptor in terms of receptor activation and its inhibitory effect on cAMP in neonatal rat cardiomyocytes. Inhibition of the M2 muscarinic receptor by antagonist and the knockdown of the receptor with siRNA completely abolished the negative effect of TC on cardiomyocyte contraction, calcium transient amplitude and synchronisation in small cell clusters. In conclusion, immature ESC-CMs are more susceptible to TC and this effect is lost as cells progress to more mature phenotypes. Moreover, the findings suggest the arrhythmogenic effect of TC in neonatal cardiomyocytes is mediated by the muscarinic M2 receptor. This mechanism might serve as a promising new therapeutic target for fetal arrhythmia.
Supervisor: Gorelik, Julia ; Williamson, Catherine Sponsor: Universiti Teknologi Mara ; Malaysia Higher Education
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral