Background-Takotsubo cardiomyopathy is an acute heart failure syndrome characterized by myocardial hypocontractility from the mid left ventricle to the apex. It is precipitated by extreme stress and can be triggered by intravenous catecholamine administration, particularly epinephrine. Despite its grave presentation, Takotsubo cardiomyopathy is rapidly reversible, with generally good prognosis. We hypothesized that this represents switching of epinephrine signaling through the pleiotropic ␤ 2 -adrenergic receptor (␤ 2 AR) from canonical stimulatory G-protein-activated cardiostimulant to inhibitory G-protein-activated cardiodepressant pathways. Methods and Results-We describe an in vivo rat model in which a high intravenous epinephrine, but not norepinephrine, bolus produces the characteristic reversible apical depression of myocardial contraction coupled with basal hypercontractility. The effect is prevented via G i inactivation by pertussis toxin pretreatment. ␤ 2 AR number and functional responses were greater in isolated apical cardiomyocytes than in basal cardiomyocytes, which confirmed the higher apical sensitivity and response to circulating epinephrine. In vitro studies demonstrated high-dose epinephrine can induce direct cardiomyocyte cardiodepression and cardioprotection in a ␤ 2 AR-Gi-dependent manner. Preventing epinephrine-G i effects increased mortality in the Takotsubo model, whereas ␤-blockers that activate ␤ 2 AR-G i exacerbated the epinephrine-dependent negative inotropic effects without further deaths. In contrast, levosimendan rescued the acute cardiac dysfunction without increased mortality. Conclusions-We suggest that biased agonism of epinephrine for ␤ 2 AR-G s at low concentrations and for G i at high concentrations underpins the acute apical cardiodepression observed in Takotsubo cardiomyopathy, with an apical-basal gradient in ␤ 2 ARs explaining the differential regional responses. We suggest this epinephrine-specific ␤ 2 AR-G i signaling may have evolved as a cardioprotective strategy to limit catecholamine-induced myocardial toxicity during acute stress. (Circulation. 2012;126:697-706.)Key Words: acute heart failure Ⅲ catecholamines Ⅲ receptors, adrenergic, beta Ⅲ Takotsubo syndrome T here has been a rapid increase in the recognition of a syndrome of acute and severe but reversible heart failure called Takotsubo or stress cardiomyopathy, 1-3 also known as broken heart syndrome, which usually follows within hours of an identifiable emotional, psychological, or physical stress. Takotsubo cardiomyopathy mimics symptoms of acute myocardial infarction but is distinguished by the lack of coronary occlusion and by characteristic regional wall-motion abnormalities, classically a virtual apical ballooning appearance caused by a hypercontractile base of the heart relative to hypokinetic or akinetic apical and mid left ventricular myocardium, the latter extending beyond a single coronary artery territory. Clinical Perspective on p 706The pathophysiological mechanisms for this increasingly recogn...

In Takotsubo cardiomyopathy, the left ventricle shows apical ballooning combined with basal hypercontractility. Both clinical observations in humans and recent experimental work on isolated rat ventricular myocytes suggest the dominant mechanisms of this syndrome are related to acute catecholamine overload. However, relating observed differences in single cells to the capacity of such alterations to result in the extreme changes in ventricular shape seen in Takotsubo syndrome is difficult. By using a computational model of the rat left ventricle, we investigate which mechanisms can give rise to the typical shape of the ventricle observed in this syndrome. Three potential dominant mechanisms related to effects of β-adrenergic stimulation were considered: apical-basal variation of calcium transients due to differences in L-type and sarco(endo)plasmic reticulum Ca2+-ATPase activation, apical-basal variation of calcium sensitivity due to differences in troponin I phosphorylation, and apical-basal variation in maximal active tension due to, e.g., the negative inotropic effects of p38 MAPK. Furthermore, we investigated the interaction of these spatial variations in the presence of a failing Frank-Starling mechanism. We conclude that a large portion of the apex needs to be affected by severe changes in calcium regulation or contractile function to result in apical ballooning, and smooth linear variation from apex to base is unlikely to result in the typical ventricular shape observed in this syndrome. A failing Frank-Starling mechanism significantly increases apical ballooning at end systole and may be an important additional factor underpinning Takotsubo syndrome.

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...