There has been a rapid growth of individual case reports and larger series describing a new syndrome of acute and severe, but reversible, heart failure – Takotsubo cardiomyopathy (TC). This syndrome usually follows an identifiable emotional, psychological or physical stress and mimics symptoms of acute myocardial infarction. It is characterised by regional wall motion abnormalities, classically an apical ballooning due to a hypercontractile base of the heart but poorly contracting or “stunned” apex. However, its most surprising characteristic is the rapid (days to weeks) recovery of many patients, usually from severe impairment to full health with subsequent good prognosis. For such a profound depression of contraction, deaths are relatively infrequent (1-3%) and, in that small percentage of patients in which the syndrome recurs, recovery is again complete. It is this ability to recover which makes the syndrome of such interest, since equivalent changes in chronic heart failure would be considered end-stage. This begins to lead us to the hypothesis that the cardiodepression is linked to some physiological strategy of benefit to the organism. Evidence points to adrenaline as the precipitating factor. Catecholamine levels in TC patients 1-2 days after presentation are higher than those MI: adrenaline falls back to MI levels only after 7-9 days. Particularly, the reproduction of the signs of TC by accidental administration of adrenaline (including single intramuscular 1mg doses from an ‘Epi-pen’) is most indicative of its central role. Adrenaline activates beta2AR as well as beta1ARs and the beta2AR is pleiotropic, having the potential to couple through Gs-AC-cAMP (like the beta1AR) but also though Giapha, Gbetagamma and non-G-protein pathways. The ability of different agonists to drive the beta2AR towards one or other coupling partners is known as biased agonism or stimulus trafficking. We had found in other circumstances that adrenaline at high concentrations could show biased agonism towards Gi coupling, with switch from a positive to negative inotropic response, and hypothesised that this was underlying the depression of contraction. In order to investigate this hypothesis and the underlying pathophysiological mechanisms, we have developed a model of TC in which an anaesthetised rat receives an intravenous (jugular) bolus of adrenaline (equivalent to ~5mg in an adult human) (Paur et al Circulation 2012). Intravenous bolus delivery was selected to mimic the human physiological response to sudden high stress. Adrenaline bolus triggered a marked decrease in cardiac contraction initiating at 15 min and reversing within an hour: this was localised to apex and mid-LV, a hallmark of TC. We showed that isolated apical cardiomyocytes demonstrated an increased beta2:beta1 ratio and greater beta2AR-specific contractile responses compared to paired basal cardiomyocytes isolated from the same heart. Importantly noradrenaline, which has a lower affinity at the beta2AR and is far weaker at producing beta2AR -Gi signalling, did not reproduce the effect of adrenaline. The negative effect of adrenaline was completely abolished by pertussis toxin, providing strong evidence for a Gi-dependent mechanism of action. Importantly, beta-blockers which demonstrate biased agonism of the beta2AR to Gi have an additive negative inotropic effect when added at the peak of the adrenaline-induced cardiodepression. The downstream mediator of negative inotropism appeared to be through p38 MAP kinase. We found evidence that the Gi/p38 negative inotropic signalling was cardioprotective as well as cardiodepressant, since blocking beta2AR or p38 MAPK precipitated a significantly increased incidence of sudden death in the adrenaline-treated animals. In summary, we have evidence that Takotsubo Cardiomyopathy is a result of beta2AR biased agonism to Gi pathways at high adrenaline levels. We hypothesise that this is part of a protective strategy to prevent catecholamine damage but that transient cardiodepression can be a consequence in particular individuals. .