We thank Dr. Madias for his interest and thoughtful comments on our report assessing the natural history of cardiac arrest (CA) in patients diagnosed with takotsubo cardiomyopathy (TTC). In this report, we reviewed 77 published cases of TTC complicated by CA to assess if TTC was a precipitant or a consequence of CA. Clinical characteristics of patients with “primary or typical” TTC were different from the “secondary” TTC group. Patients with typical TTC were older, had relatively longer QTc interval at the time of CA, and had polymorphic ventricular tachycardia. The underlying cause of CA in typical TTC is delayed repolarization leading to polymorphic ventricular tachycardia. We believe that in this subgroup of patients, the risk of recurrence of CA is extremely rare because the risk of TTC recurrence itself is 3% to 5%. In contrast, the etiology of CA in patients with secondary TTC is not that clear. This subgroup of patients appears to comprise subjects who either had TTC and experienced a CA in the very acute phase of their illness or had a CA because of non–TTC-related cardiac cause and, after resuscitation, developed TTC.

The etiology of CA in the very acute phase of TTC, when the QTc interval is relatively normal, is unknown. We tried to understand the pathophysiology behind this by evaluating the information available on patients who experienced CA under anesthesia while being monitored. There was evidence suggestive of development of hypotension before CA. Hypotension and shock, an acute complication of TTC with multifactorial etiology, is one of main causes of morbidity and mortality in patients with TTC. Given that we relied on information available in the published data, details on hemodynamics after CA were not available. The information on excessive use of adrenaline during resuscitation was also unavailable. We agree with Dr. Madias that hypotension is a common accompaniment after resuscitation even when CA is not related to TTC. From our experience and from the data available, we believe that acute hypotension in patients with TTC clearly precedes CA. These patients tend to remain hypotensive for 48 to 72 hours and gradually improve. Certainly, the use of adrenaline and noradrenaline during and after resuscitation worsens the myocardial injury related to TTC. These patients with hypotension are well compensated; we currently argue against intervention with vasoactive treatment or intra-aortic balloon pump (IABP) unless there is development of shock. In patients who develop shock with hypotensive hepatic or renal injury, we have used levosimendan and even calcium infusion for treatment in the absence of any clear evidence-based guidelines.

Supporting evidence of acute hypotension and CA comes from the animal model of TTC. We and the others have used intraperitoneal injection of isoprenaline to induce TTC in rat hearts. TTC-inducing dose of isoprenaline is associated with high mortality approaching nearly 25%. It has been previously observed that most of the rats die within the first 2 hours of isoprenaline injection most likely because of hypotension and ventricular arrhythmias. The study by Redfors et al, demonstrated that although adrenaline, noradrenaline, and dopamine produced high blood pressure and atypical changes of TTC, isoprenaline induced typical apical TTC and hypotension. In other words, typical apical TTC was associated with hypotension, whereas atypical variants had higher blood pressure. Although speculative at the moment, these findings could be helpful to differentiate typical TTC from postresuscitation “iatrogenic” TTC. We and other investigators have noticed greater prevalence of atypical TTC variants in out-of-hospital CA survivors. However, at the moment, it is just an observation, and future studies will clarify this issue.

Overall, these issues argue strongly for not only an active lookout for TTC in out-of-hospital CA survivors but also development of short- and long-term management strategies in such patients.