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Aims Takotsubo syndrome (TTS) is a form of acute myocardial inflammation, often triggered by catecholamine release surges, which accounts for approximately 10% of ‘myocardial infarctions’ in female patients above the age of 50. Its associated substantial risk of in‐hospital mortality is mainly driven by the development of hypotension and shock. While hypotension is induced largely by factors other than low cardiac output, its precise cause is unknown, and clinical parameters associated with hypotension have not been identified previously. We therefore sought to identify the incidence and clinical/laboratory correlates of early hypotension in TTS. Methods and results We analysed the in‐hospital data of patients recruited to the South Australian TTS Registry. Associations between the development of hypotension, patient demographics, severity of the acute TTS attack, and key biochemical markers were sought. One hundred thirteen out of 319 patients (35%) were hypotensive (median systolic blood pressure 80 mmHg) during their index hospitalization. Development of hypotension preceded all in‐hospital deaths (n = 8). On univariate analyses, patients who developed hypotension had lower left ventricular ejection fraction (P = 0.009), and higher plasma N‐terminal pro brain natriuretic peptide and troponin‐T concentrations (P = 0.046 and 0.008, respectively), all markers of severity of the TTS attack; hypotension also occurred less commonly in male than in female patients (P = 0.014). On multivariate linear regression analysis, female sex and lower left ventricular ejection fraction were independent correlates of the development of hypotension (P = 0.009 and 0.010, respectively). Conclusions Early development of hypotension is very common in TTS, and its presence is associated with a substantial risk of in‐hospital mortality. Hypotension is a marker of severe TTS attacks and occurs more commonly in female TTS patients.

Refereed/Peer-reviewed Since its initial description by Japanese investigators 30 years ago, TakoTsubo Syndrome (TTS) has variously been regarded as a form of acute coronary syndrome and also as a form of cardiomyopathy (or more accurately, a myocarditis). There is actually good evidence that TTS embodies both of these concepts, and the main purpose of this review is to present data that they occur sequentially. The initial phase of the disorder (over perhaps the first 48 hours post onset of symptoms) represents a form of vasculitis, with associated damage to the endothelial glycocalyx and associated permeabilization of blood vessels. This is followed by a more prolonged phase of myocardial inflammation and oedema, associated with inflammatory activation and energetic impairment within the entire myocardium. Although this phase subsides after several months, it may be followed by longstanding impairment of myocardial function, reflecting residual fibrosis. Understanding of this gradual transition in TTS pathogenesis from vasculature towards myocardium remains an important limitation of patient management, especially as many patients are still told that their hearts have “recovered” within 1–2 weeks. A number of important uncertainties remain. These include development of specific early and ongoing therapeutic strategies to be used to match the sequential pathogenesis of TTS. “And so these men of Indostan disputed loud and long, each in his own opinion exceeding stiff and strong, though each was partly in the right, and all were in the wrong!” From: Six wise men of Hindustan

It is now 30 years since Japanese investigators first described Takotsubo Syndrome (TTS) as a disorder occurring mainly in ageing women, ascribing it to the impact of multivessel coronary artery spasm. During the intervening period, it has become clear that TTS involves relatively transient vascular injury, followed by prolonged myocardial inflammatory and eventually fibrotic changes. Hence symptomatic recovery is generally slow, currently an under-recognised issue. It appears that TTS is induced by aberrant post-β2-adrenoceptor signalling in the setting of “surge” release of catecholamines. Resultant activation of nitric oxide synthases and increased inflammatory vascular permeation lead to prolonged myocardial infiltration with macrophages and associated oedema formation. Initially, the diagnosis of TTS was made via exclusion of relevant coronary artery stenoses, plus the presence of regional left ventricular hypokinesis. However, detection of extensive myocardial oedema on cardiac MRI imaging offers a specific basis for diagnosis. No adequate methods are yet available for definitive diagnosis of TTS at hospital presentation. Other major challenges remaining in this area include understanding of the recently demonstrated association between TTS and antecedent cancer, the development of effective treatments to reduce risk of short-term (generally due to shock) and long-term mortality, and also to accelerate symptomatic recovery. Refereed/Peer-reviewed

Background Although Takotsubo syndrome (TTS) was once considered to be rare and largely benign, it is now recognised to represent a major cause of cardiac morbidity and mortality, especially in aging women. The biochemical precipitant of attacks of TTS is an increase in catecholamine concentrations within the myocardium, engendering inflammatory activation via biased post-receptor signalling at myocardial β2-adrenoceptor level. Cases of TTS have been reported in patients treated with catecholamines, and with antidepressants which limit catecholamine re-uptake. In the current investigation, we sought to delineate the extent and potential impact of this “iatrogenic” form of TTS. Methods/Results Patients' data from a regional registry of 272 consecutive cases of TTS were evaluated. After exclusion of patients (n=14) in whom TTS has occurred in association with life threatening extracardiac disease states, a total of 47 (18%) of patients were identified as having antecedent exposure to potentially “iatrogenic” agents (antidepressants in 29 cases, β2-adrenoceptor agonists in 14). Demographics, including proportion of male patients, did not differ significantly between patients with and without “iatrogenic” TTS, but plasma concentrations of the catecholamine metabolite normetanephrine tended to be greater (median 1160 vs. 950 pmol/L; p=0.07). Long-term survival (median follow-up 3.5 years) was marginally (p=0.09) worse for patients with “iatrogenic” TTS. Conclusion (1) A potentially iatrogenic component of precipitation (via iatrogenic elevation of catecholamine levels and β2-adrenoceptor stimulation) is present in a substantial proportion of patients. (2) In such patients there is an implication of increased long-term mortality risk, potentially accentuated by continued administration of the precipitating agent(s).

It is not known how clinicians assess polypharmacy or the medication-related characteristics that influence their assessment. The aim of this study was to examine the level of agreement between clinicians when assessing polypharmacy and to identify medication-related characteristics that influence their assessment. Twenty cases of patients with varying levels of comorbidity and polypharmacy were used to examine clinician assessment of polypharmacy. Medicine-related factors within the cases included Beers and STOPP Criteria medicines, falls-risk medicines, drug burden index (DBI) medicines, medicines causing postural hypotension, and pharmacokinetic drug–drug interactions. Clinicians were asked to rate cases on the degree of polypharmacy, likelihood of harm, and potential for the medication list to be simplified. Inter-rater reliability analysis, correlations, and multivariate logistic regression analyses were conducted to identify medicine factors associated with clinicians' assessment. Eighteen expert clinicians were recruited (69.2% response rate). Strong agreement was observed in clinicians' assessment of polypharmacy (intraclass correlation coefficients [ICC] = 0.94), likelihood to cause harm (ICC = 0.89), and ability to simplify medication list (ICC = 0.90). Multivariate analyses demonstrated number of medicines (P < 0.0001) and DBI scores (P = 0.047) were significantly associated with assessment of polypharmacy. Medicines associated with harm were significantly associated with the number of medicines (P = 0.01) and Beers criteria medicines (P = 0.003). Ability to simplify the medication regimen was significantly associated with number of medicines (P = 0.03) and medicines f rom the STOPP criteria (P = 0.018). Among clinicians, strong consensus exists with regard to assessment of polypharmacy, medication harm, and ability to simplify medications. Definitions of polypharmacy need to take into account not only the numbers of medicines but also potential for medicines to cause harm or be inappropriate, and validate them against clinical outcomes. Refereed/Peer-reviewed