Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/120498
Type: Thesis
Title: [EMBARGOED] Nitrosative Stress and the Pathogenesis of Takotsubo Syndrome: Insights from a Novel Female Rat Model
Author: Surikow, Sven Yuri
Issue Date: 2018
School/Discipline: Adelaide Medical School
Abstract: Introduction: Takotsubo Syndrome (TS), also known as Takotsubo Cardiomyopathy or Broken Heart Syndrome, is a poorly recognised condition presenting with similar symptoms to an acute coronary syndrome. Characterised by what appears to be transient dysfunction and inflammation of the left ventricle, TS was initially thought to be relatively rare and benign, however as more is understood about the condition this has found to be untrue. It has now been established that TS shares a similar in-hospital mortality to acute myocardial infarction and there is development of a heart failure phenotype that persists after the index admission. The pathogenesis remains uncertain, although substantial evidence now suggests that catecholamines and associated β2-adrenoceptor activation play a critical role. Furthermore, the biochemical pathways that result in myocardial inflammation and energetic impairment in this condition are still yet to be elucidated. Methods: In four experimental chapters, this thesis examines the evidence for, and role of, nitrosative stress in the pathogenesis of TS. Initial investigations were conducted in myocardial biopsy tissue recovered from patients dying of TS, with immunohistochemistry utilised to assess myocardial content of 3-NT, TXNIP and PAR. Subsequent experiments revolved around the creation and use of a rodent model of TS, using echocardiography to assess functional parameters, and immunohistochemistry and Western blot to assess myocardial content of 3-NT, TXNIP, PAR, CD68, CD45, PARP-1, iNOS, eNOS and NFκB. Results: Initial experiments from a pilot human post-mortem study revealed the presence of nitrosative stress within the myocardium of patients dying from TS, which was in contrast to investigations in patient plasma during the acute phase of TS. A female rodent model of TS was developed using a bolus intra-peritoneal (IP) administration of isoprenaline, in Sprague-Dawley rats aged 4-5 months, mimicking the characteristics of human TS. There was significant apical left ventricular dysfunction, infiltration of inflammatory cells and evidence of nitrosative stress. Mortality was consistent with that seen in other catecholamine rodent models of TS. The role of activation of PARP-1 in TS, the “energetic sink” enzyme, was investigated in our female rodent model, using bolus IP administration of the PARP-1 inhibitor 3-aminobenzamide. Results showed that inhibition of PARP-1 was successful in reducing the apical dysfunction associated with isoprenaline administration. Intriguingly, mortality and left ventricular function were not linked, with mortality in this group comparable to isoprenaline alone. As β2-adrenoceptor activation is linked to nitric oxide synthases, the role of NOS was investigated, using the NOS inhibitor L-NAME. Inhibition of NOS was unsuccessful in reversing isoprenaline-associated LV dysfunction, but reduced mortality in this model, providing further evidence that function and mortality are not intimately related. Conclusions: In summary, nitrosative stress has been found to play a significant role in the pathogenesis of TS. Downstream activation of PARP-1 and associated energetic impairment appears to be related to left ventricular dysfunction, while mortality is linked to NOS activation. Further investigations involving peroxynitrite formation/decomposition or suppression of inflammation may provide incremental therapeutic targets, in a condition which currently has no definitive therapeutic strategy.
Advisor: Horowitz, John D.
Nguyen, Thanh Ha
Chirkov, Yuliy
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2019
Keywords: Takotsubo
broken heart
inflammation
nitrosative stress
animal model
catecholamine
nitric oxide
Provenance: This thesis is currently under Embargo and not available.
Appears in Collections:Research Theses

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