Are the different patterns of stress-induced (Takotsubo) cardiomyopathy explained by regional mechanical overload and demand: Supply mismatch in selected ventricular regions?

Abstract

Takotsubo cardiomyopathy (TCM) or stress-induced cardiomyopathy is an increasingly recognized syndrome characterized by severe regional left ventricular dysfunction in the absence of an explanatory coronary lesion. TCM may lead to lethal complications but is completely reversible if the patient survives the acute phase. The pathogenesis of TCM and the mechanism behind this remarkable recovery are unknown.Plasma levels of catecholamine are elevated in many TCM patients and exogenously administered catecholamine induces TCM-like cardiac dysfunction in both humans and rats. A catecholamine excess increases myocardial metabolic demand by increasing the force of contraction as well as the heart rate, and also alters cardiac depolarization patterns.We propose that an altered spatiotemporal pattern of cardiac contraction and excessive force of contraction may lead to a redistribution of wall stresses in the left ventricle. This redistribution of wall stress causes regional mechanical overload of regions where wall tension becomes disproportionately great and renders these cardiomyocytes “metabolically insufficient”. In other words, these cardiomyocytes experience a demand: supply mismatch on the basis of excessive metabolic demand. In order to prevent the death of these cardiomyocytes and to prevent excessive wall tension from developing in neighboring regions, a protective metabolic shutdown occurs in the affected cardiomyocytes. This metabolic shutdown, i.e., acute down regulation of non-vital cellular functions, serves to protect the affected regions from necrosis and explains the apparently complete recovery observed in TCM. We propose that this phenomenon may share important characteristics with phenomena such as ischemic conditioning, stunning and hibernation. In this manuscript, we discuss our hypothesis in the context of available knowledge and discuss important experiments that would help to corroborate or refute the hypothesis.