Critical Reappraisal of Takotsubo Syndrome (TS) and Myocarditis Association: “The Myocarditis-Like Features” Seen in TS Are Secondary Changes and not True Myocarditis

Takotsubo syndrome (TS) is an acute cardiac disease entity characterized by a reversible regional, usually circumferential, left ventricular wall motion abnormality in patients presenting with a clinical picture resembling that of acute coronary syndrome with non-obstructive coronary arteries. Overwhelming evidence supports the involvement of sympathetic nervous system hyperactivation in the pathogenesis of TS. Therefore, the diagnostic pathogenic term of autonomic neurocardiogenic (ANCA) syndrome has also been introduced. An association between TS or ANCA syndrome and "myocarditis" has been reported. The definitive histopathological diagnosis of acute "myocarditis" is based on myocardial infiltration with mainly mononuclear cells and signs of non-ischemic myocyte necrosis with or without fibrosis. The radiological diagnosis of myocarditis is based on the cardiac magnetic resonance (CMR) imaging findings of hyperemia, myocardial oedema, and non-ischemic myocardial necrosis/fibrosis. These endomyocardial biopsy and CMR imaging findings may also be seen in TS or ANCA syndrome and have been interpreted as true "myocarditis". However, histopathological changes in TS or ANCA syndrome begin with hypercontraction of sarcomeres, and myocardial cells may die in a tonic state if hypercontraction is severe and persistent. This myocardial cell necrosis elicits mononuclear cell infiltration, followed by fibrosis and scarring. Mononuclear cell infiltration occurs as a response or secondary process following the development of myocardial cell necrosis. Regrettably, these histopathological "secondary myocarditis-like changes" and the consequent CMR imaging findings have been, and at times remain, misdiagnosed as true "myocarditis" for many decades. These misinterpretations have been critically reviewed, analyzed, and illustrated with revealing images and with a novel conclusion.