Cardiac Sympathetic Nerve Terminals in the Pathogenesis of Takotsubo Syndrome: A Brief Review and Novel Analytical Approach.

Takotsubo syndrome (TS) is an acute cardiac condition that clinically resembles acute coronary syndrome; however, TS is not caused by acute coronary obstruction. Moreover, TS is characterized by a distinctive regional, often circumferential, and typically reversible left ventricular wall motion abnormality, which can also involve the right ventricle. In addition to the takotsubo sign, the disease has several other characteristic features, including a history of an emotional or physical trigger, repolarization changes on electrocardiography, moderate elevations of biomarkers of myocardial cell necrosis, and histopathological myocardial changes in the form of contraction band necrosis (coagulative myocytolysis) with characteristic time-related evolutionary changes. Several pathophysiologic mechanisms underlying the disease process remain under debate. However, there is evidence of sympathetic nervous system involvement, including local cardiac sympathetic hyperactivation and disruption at cardiac sympathetic nerve terminals, with excessive norepinephrine release and spillover. Hence, the pathogenetic term autonomic neurocardiogenic syndrome (ANCA), with or without a takotsubo phenotype, has been introduced. For decades, the histopathological cardiac lesions of focal or multifocal coagulative myocytolysis and focal or multifocal "myocarditis" in TS/ANCA syndrome have been described as diagnostic terms in the medical literature. However, the circumferential and multifocal nature of this disease, along with the characteristic time-related histopathological changes and its presence within normal myocardium, provide further evidence that TS/ANCA syndrome is a disorder of the cardiac sympathetic nerve terminals. Therefore, this review presents evidence supporting the previously unquestioned pathogenetic mechanism, with a focus on the specific role of cardiac sympathetic nerve terminals in this syndrome.