Author + information
- Ken Kato, MD, PhD,
- Davide Di Vece, MD,
- Victoria L. Cammann, MD,
- Jozef Micek,
- Konrad A. Szawan, MD,
- Beatrice Bacchi, MD,
- Thomas F. Lüscher, MD,
- Frank Ruschitzka, MD,
- Jelena R. Ghadri, MD,
- Christian Templin, MD, PhD∗ (, )@UZH_Science,
- on behalf of the InterTAK Collaborators
- ↵∗University Heart Center, Department of Cardiology, Raemistrasse 100, 8091 Zurich, Switzerland
Takotsubo syndrome (TTS) is associated with a substantial risk of recurrence (1). However, clinical features including triggers and ballooning patterns and predictors of recurrence have not yet been fully evaluated.
Patients were enrolled from the International Takotsubo Registry (2,3). Recurrence was defined as a TTS event occurring after complete recovery of wall motion abnormality related to a previous TTS event. In this regard, patients whose follow-up lasted <4 weeks were excluded from the study population. TTS patients were categorized into 2 groups based on the presence or absence of recurrence. Clinical features at initial TTS event were compared between groups. A multiple Cox-regression analysis was performed to identify independent predictors of recurrence. Furthermore, clinical characteristics including triggering factors and regional wall motion abnormality patterns of index and recurrent events were compared among patients with recurrence.
Overall, 1,402 patients with TTS were enrolled in the study, with a mean follow-up duration of 921 ± 883 days. Recurrent TTS events were observed in 66 patients (4.7%) at time intervals varying from 30 days to 9.9 years after index admission. The overall incidence rate of recurrence was 18.7 cases per 1,000 patient-years.
There was no significant difference in sex (female 97.0% vs. 90.6%; p = 0.081) and age (65.8 ± 11.1 years vs. 66.4 ± 12.6 years; p = 0.72) between patients with and without recurrence. No significant differences were observed in symptoms at onset, triggers, vital signs on admission, ballooning pattern, left ventricular ejection fraction, and medications at discharge. The prevalence of diabetes mellitus (4.6% vs. 15.7%; p = 0.012) and hypercholesterolemia (23.1% vs. 35.2%; p = 0.045) was significantly lower in patients with recurrence, whereas prevalence of other major cardiovascular risk factors was not significantly different between groups. Regarding comorbidities, psychiatric disorders such as affective, anxiety, and adjustment disorders (42.6% vs. 32.5%; p = 0.10) and neurologic disorders such as seizure, cerebrovascular disease, and migraine (37.1% vs. 24.7%; p = 0.028) were observed more frequently in patients with recurrence. In-hospital complications including cardiogenic shock and ventricular tachycardia were not different between both groups. Multiple Cox regression analysis demonstrated that neurologic disorders (hazard ratio: 1.76; 95% confidence interval: 1.01 to 3.07; p = 0.048) and psychiatric disorders (hazard ratio: 1.77; 95% confidence interval: 1.05 to 3.00; p = 0.033) emerged as independent predictors of recurrence.
Among patients with recurrence (n = 66), 23 patients (34.8%) showed different ballooning patterns between index and recurrent event (Figure 1A). In addition, 31 patients (47%) had different trigger types (Figure 1B). The intake of β-blockers was more frequent before a recurrent TTS event than before index admission (59.6% vs. 19.6%; p < 0.001). Multiple recurrent events of TTS were documented in 5 patients. All these patients experienced 3 distinct TTS events, and interestingly, had coexisting neurologic and/or psychiatric disorders.
In our cohort, one-third of patients with recurrence showed different ballooning patterns between different TTS events. Therefore, the proposed concept highlighting the involvement of the opposing apical–basal gradients of sympathetic nerve endings and β-adrenoceptor density explaining the pathophysiology of TTS might be questionable (4). Rather, our results indicate that an activation of different central pathways affecting different parts of the myocardium and/or the coronary microcirculation might be responsible for the pathogenesis in TTS.
Prevention of recurrence of TTS has not yet been established (5). Of note, in the present study, 59.6% of patients were on regular β-blocker therapy on admission related to TTS recurrence, most of which were β1-selective compounds (84.6%). Given our results, it is conceivable that β1-selective antagonists might not prevent TTS recurrence. Notwithstanding, these findings should be considered solely as hypothesis-generating owing to the observational nature of the study.
The study demonstrates a significant risk of recurrence associated with TTS. It is important to note that triggering factors and ballooning patterns can change in recurrence. Furthermore, neurologic and psychiatric disorders might be considered as predisposing factors for developing recurrence. Of note, a considerable number of recurrences occurred several years after the index event. Therefore, the present results emphasize the importance of long-term follow-up in TTS patients and identifying effective preventive strategies.
Please note: The InterTAK Registry (International Takotsubo Registry; NCT01947621) is supported by the Biss Davies Charitable Trust. Dr. Ghadri has received a research grant “Filling the gap” from the University of Zurich. Dr. Templin has been supported by the H.H. Sheikh Khalifa bin Hamad Al-Thani Research Programme. Dr. Templin has received fees for serving on advisory boards from Abbott Vascular, AstraZeneca, Boston Scientific, Fresenius Medical Care, and The Medicines Company; has received fees for serving on steering boards from Sanofi; has served as a consultant for Schnell Medical; has received travel support from Abbott Vascular, Biosensors, Boston Scientific, Edwards Lifesciences, and Medtronic; and has received research grant support from Abbott Vascular and Biosensors.
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