Takotsubo Syndrome: Precipitants, Clinical Course and Emerging Treatments

Abstract

Introduction Clinically, patients with Takotsubo Syndrome(TTS) presents similarly to that of acute coronary syndromes(ACS). Recent evidence has demonstrated that not only is TTS a common condition, like ACS, it is also associated with significant morbidity and mortality in the short- and long-term. It is now also recognised that there are various precipitants and risk factors of TTS, and like ACS, this list continues to grow. However, the exact pathophysiology, natural history, as well as treatment options for TTS remain incompletely understood. The studies described in this thesis were carried out to delineate a number of aspects of the precipitation, complications and potential treatment of TTS. Methods We investigated (a)novel risk/precipitating factors for ACS and TTS, (b)prognostic impact of variability in severity of attacks of acute TTS and the rate of myocardial recovery, and (c)pharmacological strategies for limiting severity of acute attacks, as well as accelerating the recovery in TTS. We sought correlations of high ambient temperatures, pollution, and proximity to bushfires(as individual and cumulative stressors) with the incidence of ACS and TTS. We also investigated the impacts of exogenous catecholamines and catecholamine-potentiating drugs(CPD) on TTS. In regards to the impacts of variable severity of acute attacks of TTS, we sought correlations between severity of TTS attacks and the incidence of hypotension acutely, as well as the recovery in quality of life at 3 months’ follow up. Finally, we designed a double-blinded randomised controlled trial to help determine pharmacological strategies for the treatment of TTS. Novel risk/precipitating factors: Incidence of ACS increased with not only increased ambient temperatures in warmer months of the year(rs=0.26, p=0.005), but also in the presence of high ambient temperatures, pollution and bushfires in combination(rs=0.25,p=0.005). We found no significant analogous correlations with TTS presentations however, with the caveat of small numbers. We also found that precipitation of TTS in association with drug-induced incremental catecholamine exposure was common(18% of total case-load), and associated with a non-significant trend(log rank X2=2.3, p=0.13) towards increased long-term mortality. Impacts of variable severity of acute attacks of TTS: Hypotension/shock occurred commonly(35%) in TTS patients acutely, and correlated with markers of attack severity including lower LVEF(p=0.009), higher plasma troponin-T(p=0.008) and NT-proBNP concentrations(p=0.046). Hypotension/shock was also a strong predictor of in-hospital mortality(p<0.001). However, the magnitude of acute TTS attacks did not significantly correlate with quality of life after 3 months. Design of randomised controlled trial: We utilised N-acetylcysteine(NAC) acutely, a potent anti-oxidant and a source of hydrogen sulphide to limit nitrosative stress, and then an ACE inhibitor(ramipril), due to its anti-inflammatory properties. Recruitment for NACRAM is now advanced, but treatment allocation remains blinded. Conclusions Our understanding of the differential pathophysiology of ACS and TTS continue to evolve and grow. We have confirmed that TTS is not only associated with both substantial mortality in the short-(especially in the presence of hypotension) and long-term, and also that TTS leads to significant morbidity in the long-term. Whilst the NACRAM clinical trial represents the first prospective therapeutic investigation in TTS, additional future studies are also needed to develop interventions to prevent the occurrence and recurrence of TTS.