Are ischemic stunning, conditioning, and “takotsubo” different sides to the same coin?

Abstract

In the normally contracting heart, the contractile apparatus consumes the great majority of myocardial energy metabolites and oxygen. In fact, non-contractile myocardial functions, including cardiac action potentials as well as maintenance of cellular homeostasis, require less than 20% as much oxygen [1]. It is therefore apparent that shutting down the hearts' mechanical activities during severe oxygen deprivation could preserve energy metabolites. In fact, this is what happens during ischemic stunning. We believe that the same mechanisms are at play in takotsubo, another conditions in which the cardiomyocytes sense relative oxygen deprivation. The heart relies almost entirely on aerobic metabolism and is dependent on a continuous supply of oxygen. In healthy subjects the heart can increase regional blood flow at least 5-fold through socalled autoregulatory mechanisms and can therefore tolerate fluctuations in myocardial oxygen demand. However, situations can arise where autoregulatory mechanisms fail to maintain adequate tissue perfusion. This leads to myocardial ischemia. If the supply:demand mismatch is of sufficient magnitude and duration cardiomyocyte cell death ensues. Following complete occlusion of a coronary artery, cardiomyocytes supplied by that artery stop contracting within seconds. Energy metabolites decrease to 50% of their initial levels within 10 min and within 20 min irreversible cell injury ensues. Thus, contractile activities cease well before the cell is depleted of energy, a phenomenon coined “ischemic stunning”. Such a hierarchical order of cellular functions is reasonable from an evolutionary perspective and is common in biology. By downprioritizing contractile activities the cell preserves energy and is able to sustain longer periods of oxygen deprivation. Hence, although it inherently leads to impaired cardiac function with potential complications, ischemic stunning is likely an important protective mechanism in acute ischemic syndromes, including acute myocardial infarction. Pre-, perand postconditioning are terms used to describe the protective effect on the myocardium of brief episodes of ischemia against subsequent, simultaneous, or preceding greater ischemic insults. A great myriad of molecules have been postulated to mediate conditioning but none have been successfully translated to clinical praxis. It is clear from earlier studies that ischemic conditioning phenomena entail more thanmerely ischemic stunning, i.e. preservation of energy metabolites otherwise destined to be consumed by the contractile apparatus. Studies have shown that brief episodes of ischemia preceding an ischemic event are associated with cardioprotection independent on the degree of functional impairment still present at the onset of the indexevent [2]. This is not surprising since ischemic stunning likely ensues immediately upon coronary artery occlusion. Thus, since little energy is lost before stunning ensues, little if any benefit would be expected if the myocardium was already stunned beforehand. Instead, conditioning more likely probes the heart towards more efficient “stunning” once the ischemic insult occurs. This is most likely accomplished by complex intracellular alterations, some of which have been thoroughly studied. Takotsubo is characterized by regional contractile dysfunction that develops in the absence of an explanatory vascular culprit lesion and that often extends beyond the territory supplied by a single main coronary artery. Catecholamines are strongly implicated in the pathogenesis and a strong emotional and/or physical stressor can be identified in the majority of patients [3]. Although the mechanisms underlying takotsubo are incompletely understood, there is indirect support in the literature for a causative role of relative ischemia. First, microvascular resistance has been shown to be increased in patients with takotsubo [4]. Second, and more important, left ventricular outflow obstruction can be observed at the time of echocardiographic assessment in approximately 1/4 of patients that present with typical takotsubo, i.e. apical akinesia with preserved basal function [5]. The combination of strong inotropic drive and outflow obstruction could be expected to greatly increase LV afterload, particularly in apical regions. Cardiomyocytes within