Pathophysiology of Takotsubo Syndrome

Abstract

Takotsubo syndrome (TTS), also known as takotsubo cardiomyopathy, stress cardiomyopathy and apical ballooning syndrome, is an acute, reversible heart failure (HF) syndrome that has increasingly come to medical attention over the past 24 years with wider access to early diagnostic coronary angiography for patients with acute chest pain and ECG abnormalities. 1 The typical case is a postmenopausal woman with an extremely stressful emotional or physical trigger, who presents with chest pain and breathlessness, ECG changes and acute hypokinesia of the apical and middle segments of the left ventricle (LV) in a circumferential pattern extending beyond a single coronary territory, and in the absence of culprit obstructive coronary artery disease (CAD). 2,3 Providing the patient survives the acute event, the dysfunctional segments recover, at least macroscopically, within days to weeks. 4 Many other variations on this "typical case" exist, including different demographics (men, younger women), different anatomical variants (basal/inverted, mid-LV, biventricular), spontaneous cases without a triggering stressor, cases triggered by other medical, surgical or psychiatric emergencies and permanent cardiac abnormalities (permanent "new" left bundle branch block, apical transmural necrosis).One common feature appears to be an extreme surge in catecholamines in response to the triggering stress or coexisting medical condition (eg, subarachnoid hemorrhage, pheochromocytoma, and thyrotoxicosis). 5-7 Animal models can replicate the features of this HF syndrome in order to dissect its mechanisms. 8-11 In contrast to the reductionist approach in most modern pathophysiological research, the more that is understood about TTS, the more it is apparent that a number of processes may result in the final common pathway of acute apical dysfunction. There are a number of mediators that may modify the severity and course of a particular episode. Defining the precise pathophysiology is challenging, and we suggest that an integrated approach to studying the cardiovascular responses to extreme surges in catecholamines is appropriate.Here we use a novel approach to reviewing the pathophysiology of TTS. Animal and clinical studies have reported findings at different phases through the development of this condition, and it is intuitive that the observed integrated cardiovascular responses to surges in serum catecholamines and sympathetic neural outflow would change over time. We discuss the pathophysiology in a sequential fashion describing effects as they occur at different time-points, integrating the observations and explaining the negative inotropic response and potential activation of cardioprotective mechanisms.Before discussing the temporal sequence of events, it is important to note a growing body of evidence that TTS is not a form of acute myocardial infarction (MI). Firstly, the epide- Takotsubo syndrome (TTS), also known as takotsubo cardiomyopathy, is an acute heart failure syndrome that typically occurs after a period of great emotion...

Clinical Impact of Left Ventricular Outflow Tract Obstruction in Takotsubo Cardiomyopathy

“…LVOT obstruction is known to induce systolic anterior motion of the anterior mitral leaflet and subsequent significant MR 33 In the most reliable hypothesis of catecholamine-mediated myocardial stunning, elevated catecholamines, especially epinephrine, switch β-adrenergic receptors from stimulatory G protein to inhibitory G protein. 30,31 The difference in the distribution of the adrenergic receptors between the base vs. the mid-portion and apex of the LV may induce LV dysfunction that does not closely fit with any coronary artery territory. 27,33 It was convincing that in the current study the prevalence of recurrent TC, which is associated with elevated plasma catecholamine levels, was more frequent in patients with LVOT obstruction, which might be prevented by β-blockers, than in patients without LVOT obstruction.…”

Isoprenaline induced Takotsubo syndrome: Histopathological analyses of female rat hearts

“…In the literature, several hypotheses have been proposed. TTS may result from multivessel epicardial coronary spasm, or may be associated with coronary microvasculature impairment, or may reflect activation of central neurogenic mechanisms analogous to those evoked by subarachnoid hemorrhage, or finally it can be related to catecholamine cardiotoxicity [8][9][10]. The last hypothesis presents as the most interesting, because in these patients elevated plasma catecholamine concentrations were observed.…”

Comprehensive Histological and Immunochemical Forensic Studies in Deaths Occurring in Custody

“…The pathophysiology in stress cardiomyopathy involves high levels of circulating catecholamines from the adrenal glands and local catecholamines (especially norepinephrine) released by sympathetic nerves in the myocardium. High levels of catecholamines shift beta receptor function from a Gs stimulatory pathway to a Gi inhibitory pathway to produce a negative inotropic, noncontractile state (i.e., myocardial stunning) [45, 46]. The Gi pathway is associated with myocardial cell protection through the activation of antiapoptotic cellular processes.…”

“…The Gi pathway is associated with myocardial cell protection through the activation of antiapoptotic cellular processes. Consequently, the pathophysiology of stress cardiomyopathy likely reflects differences in local concentrations of catecholamines in the myocardium, the location and density of beta receptors, and receptor sensitivity to catecholamines [46]. There does not appear to be any difference in beta receptor polymorphisms in patients with stress cardiomyopathy when compared to patients with ischemic cardiac events [47, 48].…”