Sacubitril/valsartan decreases mortality in the rat model of the isoprenaline-induced takotsubo-like syndrome.

AIMS: Takotsubo syndrome (TTS) is an acute potentially reversible cardiac syndrome characterized by variable regional myocardial akinesia that cannot be attributed to a culprit coronary artery occlusion. TTS is an important differential diagnosis of acute heart failure where brain natriuretic peptides are elevated. Sacubitril/valsartan is a novel and effective pharmacological agent for the treatment of patients with heart failure. Our aim was to explore whether treatment with sacubitril/valsartan could prevent isoprenaline-induced takotsubo-like phenotype in rats. METHODS AND RESULTS: A total number of 186 Sprague-Dawley male rats were randomized to receive pretreatment with water (CONTROL, n = 62), valsartan (VAL, n = 62), or sacubitril/valsartan (SAC/VAL, n = 62) before receiving isoprenaline for induction of TTS. We recorded heart rate and blood pressure invasively. Cardiac morphology and function were evaluated by high-resolution echocardiography 90 min after the administration of isoprenaline. We documented the survival rate at the time of echocardiography. Compared with the CONTROL group, the SAC/VAL group had less pronounced TTS-like cardiac dysfunction and lower mortality rate, while the VAL group did not differ. Heart rate and blood pressure were not significantly different between the groups. Analysis of cardiac lipids was performed with mass spectrometry. The VAL and SAC/VAL groups had significantly higher levels of lysophosphatidylcholine (LPC), in particular LPC 18:1 and LPC 16:0. CONCLUSIONS: Pretreatment with sacubitril/valsartan but not with valsartan reduces mortality and attenuates isoprenaline-induced apical akinesia in the TTS-like model in rats. Sacubitril/valsartan could be a potential treatment option in patients with TTS in humans.

The importance of heart rate in isoprenaline-induced takotsubo-like cardiac dysfunction in rats.

AIMS: Takotsubo syndrome (TS) is an acute cardiac syndrome characterized by regional myocardial akinesia that cannot be attributed to a culprit lesion in coronary arteries. Cardiac overstimulation by catecholamines in the setting of stress is implicated in the pathogenesis of TS. While catecholamine-induced alterations in cardiac contractility have been studied as part of the causal pathway in TS, the importance of catecholamine-mediated tachycardia has not been studied. Our aim was to explore whether the reduction in heart rate, either by pharmacological suppression of the sinoatrial node with ivabradine or by surgical induction of third-degree atrioventricular block, prevents isoprenaline-induced TS-like akinesia in an experimental animal model. METHODS AND RESULTS: We used 142 female Sprague-Dawley rats in two separate protocols. The TS-like phenotype was induced by an intraperitoneal bolus dose of isoprenaline (ISO) 50 mg/kg. In the first protocol, we randomized 54 rats to ivabradine 10 min before ISO (IVAB1), ivabradine 10 min after ISO (IVAB2), or saline 10 min before ISO (CONTROL). In the second protocol, we randomized 88 rats to surgically induced complete heart block (CHB) or sham operation (CTRL) 10 min before the administration of ISO. All drugs were administered intraperitoneally. We recorded heart rate and blood pressure invasively in the right carotid artery. Cardiac morphology and function were evaluated by high-resolution echocardiography (VisualSonics 770 VEVO, Toronto, Ontario, Canada) 90 min after ISO injection. IVAB1 and IVAB2 rats had significantly lower heart rate and less pronounced TS-like cardiac dysfunction than CONTROL. CHB rats had a lower (54%) heart rate, and no animal developed left ventricular akinesia. In the first protocol, the CONTROL group had a median degree of akinesia of 10.2 [inter-quartile range (IQR) 0.0-18.6]. The IVAB1 group showed a median of akinesia of 0% (IQR 0.0-0.0, P < 0.001 vs. CONTROL). In the IVAB2 group, 5% had TS-like dysfunction (P = 0.001). Ejection fraction was higher in both the IVAB1 (92%, IQR 89-95) and IVAB2 groups (93%, IQR 87-96) than in the CONTROL group (78%, IQR 63-87, P < 0.05). In the second protocol, the median degree of akinesia in the CTRL group was 21.9% (IQR 8.9-24.6). In the CHB group, no rat developed akinesia (median 0%; IQR 0.0-0.0, P < 0.001 vs. CONTROL). Ejection fraction was higher in the CHB group (90%, IQR 87-92) than in the CTRL group (51%, IQR 87-92, P < 0.05). CONCLUSIONS: Isoprenaline-induced TS-like cardiac dysfunction can be prevented by lowering heart rate. Tachycardia may be an important part of the causal pathway in TS.

Effects of pretreatment with cardiostimulants and beta-blockers on isoprenaline-induced takotsubo-like cardiac dysfunction in rats.

BACKGROUND: Takotsubo syndrome (TS) is an acute cardiac syndrome characterized by regional myocardial akinesia that is not caused by coronary artery occlusion. Exogenous as well as endogenous excess catecholamines can induce TS. The aim of this study was to explore the effects of pharmacological cardio-simulative and cardio-depressing drugs on the development of isoprenaline-induced takotsubo-like cardiac dysfunction, a rat model of TS. METHODS: We randomized 295 rats into twelve groups. The animals were randomized to pre-treatment with either a low or high dose of metoprolol, propranolol, ICI 118551 (beta2-receptor antagonists), milrinone (phosphodiesterase inhibitor), levosimendan or saline (control) before induction of TS with isoprenaline. In one additional group, high dose of milrinone was administered alone. We measured invasively blood pressure and heart rate over a period of 90 min. Cardiac function and morphology were evaluated with high-resolution echocardiography. RESULTS: Milrinone alone induced apical ballooning similar to isoprenaline. Pretreatment with propranolol and metoprolol but not with ICI 118551 attenuated takotsubo-like akinesia in a dose-dependent manner. Pretreatment with metoprolol decreased mortality. Pretreatment with levosimendan resulted in higher incidence of apical ballooning while pretreatment with milrinone did not change the degree of akinesia. CONCLUSION: The phosphodiesterase inhibitor milrinone induces takotsubo-like dysfunction in the absence of exogenous catecholamines. This finding challenges the concept that high levels of circulating catecholamines or excessive stimulation of adrenergic receptors are necessary for the development of takotsubo syndrome. Our study provides experimental evidence for the concept of avoidance of inotropes and that selective beta1-blockade may be beneficial in the treatment of TS-patients.

Clinical management in the takotsubo syndrome.

Introduction: Takotsubo syndrome (TS) is an increasingly recognized acute heart failure syndrome which is self-limiting in most cases but can result in life-threatening complications. TS is difficult to distinguish from acute myocardial infarction (AMI) early in the disease course and currently lacks evidence-based treatment recommendations. Areas covered: Based on the available literature this systematic review discusses the clinical management of patients with TS during (i) the diagnostic workup; (ii) acutely after establishing the TS diagnosis; and (iii) after recovery of cardiac function. Expert commentary: Since TS is self-limiting in most cases it is recommended to refrain from unnecessary treatment (the do no harm principle) when managing patients with TS. The management of patients with TS should focus on careful monitoring of ECG and hemodynamics, and on preventing and treating complications. Because catecholamine-mediated inotropic overstimulation is implicated in the pathogenesis of TS, and because inotropic drugs have been associated with worse outcomes for patients with TS, we recommend the treating physician to avoid these drugs. Instead, mechanical assist devices should be considered early for patients with TS who develop cardiogenic shock with signs of end-organ hypo-perfusion.