Natural history and pathogenesis of Takotsubo cardiomyopathy

Introduction: Takotsubo cardiomyopathy (TTC) is a transient left ventricular (LV) systolic dysfunction of uncertain pathogenesis, which occurs predominantly in ageing women. Although there is considerable uncertainty about the pathogenesis of TTC, pronounced catecholamine release and an acute inflammatory process is implicated. Furthermore, natural history of TTC is unknown and correlates of acute complications and incomplete recovery have not been evaluated. Methods: In the 5 experimental chapters, this thesis examines aspects of (a) pathogenesis and (b) natural history of TTC. As regard the pathogenesis, we hypothesized that increased release of nitric oxide (NO) in patients with TTC potentially induces the formation of peroxynitrite (ONOO⁻) anion with associated redox stress, protein nitration and downstream activation of thioredoxin interacting protein (TXNIP). Evaluation of presence of nitrosative stress was performed in a rat model of TTC in parallel with human experiments looking at the local and systemic rise in the 3-nitrotyrosine (3-NT) as a footmark of ONOO⁻ formation. As a part of clinical investigations, we evaluated the role of RV involvement in early hemodynamic derangement. We performed a meta-analysis to assess the impact of “secondary” TTC, male gender, advancing age and catecholamine use on mortality in TTC. We used a similar approach to assess the correlates of recurrence rate of TTC. Results: A. Pathogenesis: In rat model of TTC, there was substantially increased myocardial 3-NT (2.9 ± 0.6 % and 0.3 ± 0.1 %; p< 0.01) and TXNIP content (16.5 ± 5.2 vs 0.5± 0.2%; p < 0.01). Furthermore, use of poly (ADP) ribose polymerase (PARP)-1 inhibitor attenuated the isoprenaline induced LV systolic dysfunction. In human experiments, plasma concentrations of 3-NT did not differ significantly between TTC (2.26 ± 0.22 nmol/L) and control subjects (2.20 ± 0.25 nmol/L). However, myocardial 3-NT and TxNIP content were increased 4-fold and 10-fold respectively. Furthermore, myocardial content for poly (ADP) ribose (PAR) activity was increased 4 folds. B. Clinical investigations: RV involvement occurred in 1/3rd of TTC patients. Hypotension was noted in 21% of TTC patients, while shock occurred in 16%. RV involvement was a univariate but not a multivariate correlate of either hypotension or shock and did not result in prolonged hospital stay. RV involvement predicted more extensive LV hypokinesis and LV systolic dysfunction. C. Meta-Analysis: In-hospital mortality among patients with TTC was 4.5% (95% CI, 3.1%- 6.2%). Male gender was associated with higher mortality (OR 2.6, 95% CI, 1.5-4.6, p=0.0008) so was “secondary” TTC (RD-0.11, 95%CI; -0.18 to -0.04, p=0.003). TTC had 1-2% annual recurrence rate, which was independent of clinic utilization of betablocker prescription, but inversely correlated (r =-0.45, p = 0.016) with ACEi/ARB prescription. Patients with severe TTC at index admission were noted to have more recurrences. Conclusion: A. TTC is associated with evidence of nitrosative stress within left ventricular myocardium. B. RV involvement is not an independent predictor of hemodynamic derangement. C. Male gender and “secondary” TTC are associated with higher mortality and use of ACEi might reduce recurrence rate.Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2015