Letter by Stiermaier and Eitel Regarding Article, "pathophysiology of Takotsubo Syndrome"

We have read with great interest the comprehensive review by Pelliccia et al1 regarding the still unknown pathophysiology of Takotsubo syndrome (TTS) and want to share some additional thoughts. Contrary to the depiction in the article, it should be noted that male sex has been linked to increased mortality in several TTS studies and was identified as an independent predictor of an adverse outcome.2 Furthermore, cardiogenic shock and ventricular arrhythmias are not rare complications in TTS. Both have been reported in >10% of patients and are therefore major determinants of morbidity and mortality.3,4 However, coming back to the main issue of the review, there is broad consensus in the medical community that increased catecholamine levels and sympathetic overdrive appear to play key roles in the pathogenesis of TTS. The multifaceted pathways and mediators that impact coronary vasculature—most likely on a microcirculatory level—and the myocardium are nicely illustrated in the present article.1 In our opinion, 2 major missing links are needed to complete this theory. First, everybody is exposed to stressors in daily life, but only a few people develop TTS, and most of these individuals were exposed to stressful events before without experiencing an episode of TTS. This fact could imply that a certain stress level is required for the onset of the disease and further points to an increased susceptibility in some people. As discussed by the authors, sex hormones and particularly estrogen deficiency are conceivable factors given the predominance of postmenopausal women. In addition, we would like to emphasize a potential role of genetically determined vulnerability. Recurrence of TTS, familial cases, and association with rare genetic disorders support this concept. Recently, the first genome-wide association study in TTS identified several candidate loci.5 These promising preliminary results are encouraging to further pursue this approach, which requires international collaboration to acquire a sufficient number of patients for valid genetic analyses. The second missing piece in the puzzle is the explanation for the characteristic distribution of regional contraction abnormalities. The entire cardiovascular system is exposed to catecholamine excess and sympathetic activity, but cardiac dysfunctions involve only certain segments while sparing other surrounding parts of the ventricle. Moreover, right ventricular involvement can be observed in some patients with TTS. Regional differences in adrenoceptor expression are certainly an appealing concept, as discussed in the review by Pelliccia and colleagues.1 However, different ballooning patterns in patients with recurrent episodes of TTS contradict this theory as a sole mechanism. Conclusive explanations for the determinants of disease onset and the restriction to some myocardial regions would be a large step toward clarification of the mechanisms underlying TTS. Currently, answers to these important questions need additional research.