Phenylephrine and the Pathophysiology of Takotsubo Syndrome: Drug Effects on the Cardiomyocytes vs. the Central Nervous System

I read with much interest the report by Lee et al., published online ahead of print on July 19, 2016, in the Journal [ ], about the 27-year-old woman who suffered apical and subsequently mid-ventricular variants of Takotsubo syndrome (TTS), in the setting of therapy with phenylephrine (PL) initially as eye drops, and subsequently as an intraocular PL injection, for persisting recurrent anterior uveitis. I agree with the authors that probably the PL eye drops have led to some “priming” for the emergence of TTS that culminated to “full blown” TTS, after the intraocular injection. The authors expressed puzzlement about a plausible pathophysiologic mechanism of TTS via the α1-adrenergic receptor stimulation mediated by the pure α1-adrenergic agonist PL, instead of the currently prevailing postulated causation of TTS via the stimulation of β2-mediated agonist of epinephrine (EPI) [ ]. Catecholamines have been detected at high levels in patients with TTS [ ], and it would have been instructive if the authors have tested their patient for EPI, norepinephrine (NEPI), and even PL. An estimated calculation of the PL from the eye drops, and the intraocular injection over the course of the three days of therapy, could be based on an approach used previously [ ]. Another popular theory supports the view that TTS is due to NEPI released locally at the cardiac autonomic nerve endings with harmful effects on the cardiomyocytes, and not due to the blood-borne catecholamines [ ]. Thinking about “alternative mechanisms of myocardial injury” [ ], one cannot discard the physical/emotional stress induced in a patient with persisting acute recurrent anterior uveitis, who received an intraocular injection, even if the patient stated that the procedure had not caused her distress, and she had previous uneventful experiences with the procedure.