Pathophysiology and treatment of Takotsubo Syndrome - insights from preclinical studies

Sammanfattning: ABSTRACT Background: Takotsubo syndrome (TTS), also recognized as “stress-induced cardiomyopathy (SIC)” and “broken heart syndrome”, is an acute cardiac failure syndrome characterized by transient regional ventricular akinesia or hypokinesia, and often presents similarly to acute myocardial infarction (AMI). In contrast to AMI, the characteristic regional myocardial akinesia in TTS does not involve a culprit coronary artery. Although the associated cardiac dysfunction is potentially reversible, TTS is no longer regarded as benign. Today we know that TTS can lead to deleterious complications including death. Because physical and/or emotional stress often precedes TTS, acute sympathetic stimulation is understood to play a central role in pathophysiology of TTS, but the detailed mechanisms are still unclear. There are no clinical randomized studies in patients with TTS. Therefore, we currently lack guidelines for treatment. Aims: The aims of this thesis were to study the reproducibility of our rat model, to unravel TTS pathophysiology and to explore possible prevention and treatment strategies in TTS. We aimed to investigate whether exogenous catecholamines can induce TTS-like cardiac dysfunction in rats. Methods: We used 10-week-old Sprague Dawley rats in these preclinical studies. We based this work on our experimental TTS rat model which is based on exogenous isoprenaline. We tested whether different catecholamines, given intraperitoneally in titrated doses, could induce TTS. We studied possible preventive roles of β-blockers, ivabradine, sacubitril/valsartan and cardiostimulants in our rat model. Blood pressure and heart rate were recorded via cannulation of right carotid artery. Small animal echocardiography was used to study cardiac morphology and function, and cardiac tissues were collected for histopathological studies. Results: In Study I, we reproduced our isoprenaline-based rat model of TTS and showed that exogenous catecholamines can induce different patterns of TTS, depending on the associated blood pressure rather than their adrenergic receptor affinities. In Study II, we observed that phosphodiesterase inhibitor milrinone can induce typical TTS. We demonstrated that pretreatment with either β-non-selective antagonist or β1-selective antagonist, but not β2-selective antagonist, can prevent isoprenaline-induced TTS. Cardiostimulants failed to prevent isoprenaline-induced apical TTS. In fact, pretreatment with levosimendan worsened the degree of left ventricular apical akinesia. In Study III, we showed that ivabradine as well as heart block could prevent isoprenaline-induced TTS. Finally, in Study IV, we showed that pretreatment with sacubitril/valsartan can reduce mortality and prevent isoprenaline-induced TTS. Conclusion: Our isoprenaline-based rat model of TTS is reproducible. Exogenous catecholamines can cause different variants of TTS depending on the associated haemodynamic profiles rather than catecholamine adrenergic receptor affinities. Hypotension and tachycardia precede isoprenaline-induced LV apical TTS in rats. Phenylephrine, ivabradine and β1-selective antagonists could prevent typical TTS. These drugs mitigate the unique isoprenaline-associated haemodynamic profile. Takotsubo syndrome should, therefore, be regarded as an acute sympathetic stimulation-induced haemo-neuro-cardiac syndrome rather than a cardiomyopathy per se. Inotrope and cardiostimulants such as milrinone and levosimendan can be deleterious in TTS. Key words: Takotsubo syndrome, milrinone, levosimendan, echocardiography, isoprenaline, sacubitril/valsartan, ivabradine, stress-induced cardiomyopathy.