Stress (Takotsubo) cardiomyopathy—a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning

Arising from: Lyon AR et al. (2008) Stress (Takotsubo) cardiomyopathy–a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning. Nat Clin Prac Cardiovasc Med 5: 22–29 [doi:10.1038/ncpcardio1066]

Authors' response: Lyon AR et al. (2008) Stress (Takotsubo) cardiomyopathy—a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning. Nat Clin Prac Cardiovasc Med [doi:10.1038/ncpcardio1236]

Lyon et al.'s article on “stress-induced” cardiomyopathy proposed that stress would be the essence of the Takotsubo apical ballooning transient cardiomyopathy, and it would be mediated by a high epinephrine blood level.¹

We have recently generated substantial evidence in a hypothesis-generating, initial study that seems to support a novel, alternative, “multivessel spasm” theory.² Specifically, we conducted an initial series of acetylcholine provocation tests, in a continuous series of patients recovering from Takotsubo. We were able to document the presence of endothelial dysfunction, as characterized by severe, diffuse spasm of all coronary distal branches, leading to transient, subtotal stoppage of coronary flow to most of the myocardium. Besides such angiographic findings, the accompanying symptoms were identical to the spontaneous initial ones, experienced by each patient. Additionally and revealingly, we found that such liability to extreme spasticity is transient (varying from a few hours to a few weeks) and accompanied by the recurrence of apical ballooning at simultaneous echocardiographic monitoring. In this setting, all manifestations promptly receded after intracoronary administration of nitroglycerin. We proposed that prior studies with acetylcholine testing in Takotsubo were substantially inconclusive because of the variable timing and protocols of testing, which allowed the disappearance of the unusual spasticity in a substantial percentage of the patients. We also demonstrated that the initially positive testing returns to negative, after a period of antispastic medication.

We hypothesized that in Takotsubo a spontaneous, diffuse, and severe spastic event occurs and it sustains for more than 15 min, but likely less than 45-60 min (otherwise death or permanent thrombotic occlusion would ensue, and Takotsubo would not be recognizable), leading to the onset of persistent apical ballooning, as a manifestation of myocardial stunning.³ Myocardial stunning is well known to occur both following typical Prinzmetal angina, as well as during prolonged balloon angioplasty, and in acute myocardial infarction followed by early reperfusion.² It is likely that Takotsubo occurs in variable clinical and biochemical contexts, definable by the degree of pre-existing endothelial dysfunction and the intensity of the precipitating factors. A catecholamine surge would function as one of many possible precipitating factors acting on labile, endothelially dysfunctional patients, but it would not be sufficient explanation of the Takotsubo crisis, by itself.

Our current challenge and project include extending the protocol to a large, continuous multicenter series, in order to definitely confirm the theory, and to establish sound clinical recommendations.