ABC | Volume 114, Nº3, March 2020

Original Article Campos et al. Takotsubo syndrome recurrence Arq Bras Cardiol. 2020; 114(3):477-483 compared to women aged 50 years old or older (16 versus 3%, respectively; p = 0.017). This suggests that younger women tend to have recurrence of the syndrome more often. However, in this study, women younger than 50 years of age had higher rate of psychiatric disorders, leaving in doubt whether the higher rate of TTS recurrence was due to lower age or to association with psychiatric disorders. Vriz et al. 12 reported higher recurrence rate in older patients – patients who had recurrence had a mean age of 71.4 years, while those with only one episode had a mean age of 65.7 years. A systematic review with meta-analysis, composed of 31 studies, 6 found an average age of 65.5 years among patients who presented recurrence, most of themwomen. These data show the divergence between different studies in relation to the age group that would be more predisposed to an episode of TTS recurrence. Cohorts with greater samples, covering larger age groups, are necessary to better clarify this association. Four studies of this systematic review reported the time between the first and second episodes. Episodes of recurrence have been reported for about 22 days 12 until slightly more than nine years after the first episode. 3 Although there is a recurrence report up to ten years after the initial episode, 15 cases like this are extremely rare. Looi et al. 9 found that recurrence was more frequent in the first year after the initial episode. Elesber et al. 11 showed higher annual recurrence rate in the first four years compared to subsequent years (2.9  versus 1.3% per year, respectively). Vriz et al. 12 reported in their study a higher recurrence of the syndrome in the first three months after the first episode. Another study, published in 2017, 16 reported TTS recurrence in five patients, with the second episode occurring in an average of 2.1 years. All these data corroborate the idea that a person’s likelihood of TTS recurrence decreases over time, being more likely in the first few months following the first episode, and there is a gradual decrease in the chances of a second episode over the years, reducing significantly after four years. To date, the only study identified in this review that conducted an association between TTS recurrence and BMI was the one by Nishida et al. 13 In this study, low BMI was a risk factor for TTS recurrence. The higher the BMI of the individual the lower his chances of recurrence, with a HR of 0.75 (for each 1kg/m 2 increase). A clear explanation for this association was not possible, but recent studies 17,18 have suggested that the hemodynamic response to mental stress is more intense in people with lower BMI, while the basal activity of the sympathetic nervous system of these individuals is lower than in individuals with higher BMI. Thus, one may suggest that the greater sensitivity of the sympathetic nervous system in people with lower BMI would reduce their threshold to emotional stress, triggering potential TTS. Regarding the clinical presentation of the patients who presented TTS, Looi et al. 9 described an absolute higher rate of recurrence in patients presenting ST elevation in their ECG when compared to patients who did not present it, with a recurrence rate of 7.4 versus 6.3%, respectively; there was no statistical significance, p = 1.00. Another study by Dib et al. 19 reported that there was no difference in the 5-year recurrence rate related to ECG presentation, 13% in those who presented ST segment elevation, 5% in those who presented with T wave inversion, and 17% in those whit non-specific changes in the ST segment and T wave (p = 0.25). Such data do not suggest that a specific electrocardiographic alteration changes the prognosis of those affected by TTS with respect to its recurrence. The study by Nishida et al. 13 initially showed an association between biventricular involvement and recurrence, but no statistical significance was reached in this analysis, p = 0.06. Another study, by Kagiyama et al., 20 also analyzed this relationship with the morphological pattern of the syndrome manifested by the patients, being the recurrence rate in patients with biventricular involvement greater when compared to those with classic morphology, that is, 4.8 and 0%, respectively. Nishida et al. 13 found higher recurrence rate in patients with medium ventricular obstruction, which corresponds to hypercontractility of the middle third of the left ventricle, which occurred in patients with apical ballooning, probably as a compensatory mechanism. No further studies were found to evaluate this relationship. Four studies of this systematic review analyzed the use of BB as a possible method of preventing TTS recurrence. In the Looi et al. 9 study, four (57%) of the patients were in use of BB on recurrence; Templin et al. 3 reported that 29 patients (50.8%) were in use of BB during the second episode; in the study by Vriz et al., 12 BB therapy did not prevent recurrence; Elesber et al. 11 showed a recurrence rate of 80% among patients on BB and 52% in patients who did not use this medication, without statistical significance (p = 0.10). Together, these data suggest that BB therapy is not associated to prevention of episodes of TTS recurrence. Elesber et al. 11 also compared recurrence among patients in and without use of aspirin, ACEI/ARB, and statins. In their study, patients taking aspirin had a recurrence rate of 60%, whereas those who did not use this medication had a 67% recurrence rate, with no statistical significance (p = 0.67). The recurrence rate between patients who did and those who did not use ACEI/ARB was 60 and 51%, respectively (p = 0.59). From the patients who presented recurrence, 40% used statins and 33% did not, nor was there any statistical significance (p = 0.67). Given the above, none of the studies of this systematic review suggested specific drug therapy to prevent TTS recurrence. In several studies, the use of BB showed no efficacy in TTS prevention. This medication was also not useful for this purpose in a systematic review with a meta-analysis of 31 studies 6 . However, this same study 6 showed a negative association between the use of ACE inhibitors or ARB and the recurrence rate, that is, the use of these medications decreased recurrence rates, different from those found by Elesber et al. 11 Long-term segmental cohorts with a greater number of patients who presented TTS and made use of ACEI/ARB are necessary to better clarify this association. The largest study in this reviewwas the one by Templin et al. 3 This was a case-control study with 1,750 TTS patients according to the Mayo criteria and 57 recurrences cases were found in the long term follow up. The authors aimed to evaluate clinical features, prognostic predictors, clinical course, and outcomes of TTS in a wide population. However, as they did not focus specifically on recurrence predictors, the article does not bring specific insights about this subgroup apart from the use of BB. This article updates and complements the systematic review by Singh et al. 6 Some data could be confirmed in 481