BACKGROUND: We investigate if renin--angiotensin and endothelin--1 response pathways follow the same pattern of recovery as left ventricular ejection fraction in patients with takotsubo cardiomyopathy. METHODS AND RESULTS: Ninety patients with takotsubo cardiomyopathy (n=30 in each of "acute," "convalescent" [3[symbol]-5 months] and "recovered" [>1 year] groups) who were on minimal or no medication and were free of any significant cardiac/metabolic comorbidities, and 30 controls were studied. Serum concentrations of renin, angiotensin--converting enzyme, angiotensin II, big endothelin--1, endothelin--1 were measured using commercially available ELISA, and B--type natriuretic peptide was meas- ured using an immunoassay. Mean left ventricular ejection fraction was <40% during the acute phase in all groups, but recov- ered to 63% in convalescent and 64% in the recovered groups, respectively. Serum renin concentrations remain persistently elevated after a episode of takotsubo cardiomyopathy (P=0.03 versus controls). Angiotensin converting enzyme levels are significantly depressed during the acute phase compared with convalescent (P=0.004), recovered takotsubo cardiomyopathy (P=0.02) or controls (P=0.03). Angiotensin II is increased in patients with takotsubo cardiomyopathy (P<0.001 versus controls) remaining persistently elevated in the chronically recovered group alone (P=0.03 versus controls). Big endothelin--1 levels are unchanged, but endothelin--1 is significantly lower after takotsubo cardiomyopathy compared with controls (P=0.03). CONCLUSIONS: Despite "normalization" of the left ventricular ejection fraction, there is long--term maladaptive activation of renin-- angiotensin system in patients with takotsubo cardiomyopathy.