Response to Association of Prolonged QTc Interval With Takotsubo Cardiomyopathy: A Neurocardiac Syndrome Inside the Mystery of the Insula of Reil

“It has often been argued that absolute scepticism is self-contradictory; […] even if it would be no argument against the absolute sceptic”,1 we would like to refute the comments adduced by Josef Finsterer MD on the mystery of the pathogenesis of Takotsubo cardiomyopathy (TC).2 First of all, the International Takotsubo Registry, a consortium of 26 centers in Europe and the United States has demonstrated that the TC occurred with high in-hospital mortality of 4.7% patient per year and evident emotional or physical triggers (71.5%).3 Using the proposition that there are 28.5% patients without any evident trigger, the author of the letter concludes that stress hypotesis could be not valid. This is an error in inference. Second, the following objection to the stress hypotesis is that the plasma catecholamines in the majority of patients with TC show normal or near normal values, as highlighted in our review, and that TC may occur in patients with neuropathies and diabetes. These premises are true and do not, in the least, contradict the fact that the cardiac lesions in patients with TC have a neural etiology due to intracardiac release of catecholamines. This reasoning is fallacious. If we knew that adrenalectomy does not protect the heart and that the decreased cardiac activity on 123I-mIBG or 11C-HED PET often described in some patients with dysautonomia is not a true cardiac denervation, then the inference against the stress hypotesis would lose all its validity. Third, in the next topic Dr. Finsterer dismisses the role of the insular cortex (IC), as proposed in our review2, by citing and quoting various papers, which, on the contrary, collectively favor an important role for the insula in TC. In particular, the study by Klein et al.,4 while strongly supporting a heart-brain interaction in the pathogenesis of TC, highlights that distinct areas of the limbic system, located in the dominant or non-dominant hemisphere and normally involved in driving activation of sympathetic and parasympathetic systems, show substantial structural changes between patients with TC and healthy controls. However, throughout the paper, the aforementioned authors underline the important role of the IC in regulating top-down autonomic responses. Further, Wood et al.5 investigated age-dependent dysregulation of autonomic control in a sample of 55 healthy individuals and reported positive relationship with cortical thickness, concluding that “both cardiovascular and sympathetic autonomic functions correlated with cortical thickness at the left medial prefrontal cortex and the left insula”. Finally, Dr. Finsterer criticizes that ischemic stroke, involving IC could play a role in the pathogenesis of cerebrogenic long QTc interval. This reasoning is an amphibology. Reviewing the clinical and experimental literature, physicians have known for more than half a century that stroke may produce QTc prolongation6 and the significant evidence that the insular cortex may play an important role in this respect is much more recent. Oppenheimer et al.7 in 1991 stated as QTc interval prolongation can be generated by phasic microstimulation of the rat left insula. Regarding the assertion that QTc is particularly associated with ischemic stroke in the posterior circulation, we reply with the words of the authors, saying that “the prevalence of QTc prolongation in our study is comparable to that of patients with insular strokes”.8 Although infarction confined to the IC in humans is somewhat rare, according to our previous report, at bivariate analysis insular involvement showed significant association with QTc.9 In addition, regarding the statement that “ventricular arrhythmias should be a frequent complication of ischemic stroke in the median [sic] cerebral artery territory, which supplies the IC”, the point is that not all ischemic strokes in the middle cerebral artery (MCA) territory involve the IC. While we are unaware of studies supporting Finsterer's conclusion, a recent study of 1311 patients with ischemic stroke in the MCA territory, disapproves this assertion, since only 112 patients (8.5%) showed IC involvement.10 As such, MCA stroke is not synonymous with IC involvement. The authors declare no potential conflicts of interest.