Response to: Angelini P (2008) Stress (Takotsubo) cardiomyopathy—a novel pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning. Nat Clin Pract Cardiovasc Med [doi:10.1038/ncpcardio1235]

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]

We thank Dr Angelini for his letter in response to our article discussing a potential mechanism for Stress (Takotsubo) Cardiomyopathy. We propose an explanation for this syndrome based upon the direct negative inotropic effects of supraphysiological epinephrine levels upon the myocardium mediated via the [beta]2adrenoceptor, with an apical-basal [beta]adrenoceptor density gradient determining preferential apical stunning.1 Dr Angelini's group have assessed coronary vascular function and demonstrated inducible, diffuse and reversible vasospasm with provocation in patients with this syndrome. This adds important new physiological data to a field which is lacking thorough and consistent evaluation of these patients.

We would agree that the coronary vasculature is likely to respond to supraphysiological catecholamine surges with an abnormal vasoreactive response, and endothelial dysfunction is likely to persist for a variable period after the insult. The critical question is whether inducible diffuse coronary spasm, demonstrated by the findings of Dr Angelini's study, represents the underlying cause of the syndrome, or is a surrogate marker of abnormal coronary endothelial function in the aftermath of high catecholamine levels. Dobutamine infusion during both acute and short-term follow-up elicits an abnormal myocardial response in patients with stress (Takotsubo) cardiomyopathy,2 which differs from recoverable function after classical ischemia-induced myocardial stunning,3,4 but this cannot be taken as proof of direct myocardial effect as the primary cause of dysfunction. A minority of reported cases in published series provide evidence that coronary vasospasm at the time of presentation,5 and some patients have benefited from [beta]-blocker therapy during acute cardiogenic shock.6 This would be inconsistent with classical coronary vasospasm. However in the shocked patient with outflow tract obstruction, the beneficial effect of [beta]-blockers may outweigh any adverse effect upon vasospastic arteries.

In our article we comment that the vascular influence of high circulating catecholamine levels may also contribute stating that “norepinephrine-mediated coronary vasospasm may play an additional role”. A pragmatic approach to this syndrome, with an increasingly heterogeneous pattern of clinical and cardiac phenotypes, would be to conclude that a combination of both myocardial and coronary vascular responses to supraphysiological catecholamine levels may contribute to the final phenotype. Genetic and environmental factors may determine whether one mechanism contributes predominantly in a particular individual. What is clear is that further study with thorough evaluation of both vascular and myocardial pathophysiology, using structured and defined protocols such as that performed by Dr Angelini's team, is required for this syndrome which appears to be more prevalent than previously recognised.