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Title: Animal models of Takotsubo syndrome : a multi-level experimental approach
Author: Tranter, Matthew
ISNI:       0000 0004 7233 1300
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Takotsubo syndrome, also known as Takotsubo cardiomyopathy, broken heart syndrome and stress cardiomyopathy, is a form of acquired cardiac failure that typically occurs after a period of intense emotional or physical stress. Patients typically present with symptoms indicative of acute coronary syndrome, but angiography shows no culprit pathology. Ventricular imaging shows a hypokinetic apical, and often mid-LV, myocardium coupled with a hyperkinetic basal myocardium, although inverted Takotsubo variants with or without mid-LV sparing have also been described. The majority of reported Takotsubo syndrome cases are in post-menopausal females, although it can occur in both males and females across a wide range of ages. Using a previously-described method of inducing transient apical dysfunction in male rats by administering IV high-dose adrenaline, ovariectomised females showed a far greater sensitivity to the same adrenaline dose than non-ovariectomised females, showing a higher mortality rate. 2-week estrogen replacement did ameliorate this increase in mortality, although vehicle-only minipumps also had some effect in reducing mortality in ovariectomised female rats. 2-week estrogen administration to male rats did not result in a significantly-different mortality rate. Attempts to recapitulate another Takotsubo syndrome model by administering IP high-dose isoprenaline demonstrated that choice of anaesthetic was crucial in allowing a necessary condition, hyperthermia, to occur, as maintenance of anaesthesia with isoflurane rather than ketamine-midazolam prevented this rise in body temperature caused by the administration of isoprenaline. Hyperthermia was found to be an essential condition for the induction of apical dysfunction in this model, although the removal of hyperthermia after the initiation of contractile dysfunction did not reverse the Takotsubo-like contractility pattern. Attempts to recreate the contractile dysfunction in the isolated heart were unsuccessful. However, imaging studies showed that adrenaline can induce a mitochondrial dysfunction in the isolated rat heart, with hyperthermia augmenting this effect.
Supervisor: Harding, Sian Sponsor: National Heart and Lung Institute
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral