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| 2. |
- Gasim Elsied, Anwar Ali, et al.
(författare)
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Effects of pretreatment with cardiostimulants and beta-blockers on isoprenaline-induced takotsubo-like cardiac dysfunction in rats
- 2019
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Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273. ; 281, s. 99-104
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Tidskriftsartikel (refereegranskat)abstract
- 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 carclio-simulative and cardio-clepressing drugs on the development of isoprenaline-inclucal lakolsubo-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 levosiniendan 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 ino tropes and that selective betai-blockade may be beneficial in the treatment of TS-patients. C 2018 Elsevier B.V. All rights reserved.
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- Gasim Elsied, Anwar Ali
(författare)
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Pathophysiology and treatment of Takotsubo Syndrome - insights from preclinical studies
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 5. |
- Gasim Elsied, Anwar Ali, et al.
(författare)
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Sacubitril/valsartan decreases mortality in the rat model of the isoprenaline-induced takotsubo-like syndrome
- 2021
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Ingår i: ESC Heart Failure. - : Wiley. - 2055-5822. ; 8:5, s. 4130-4138
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 6. |
- Gasim Elsied, Anwar Ali, et al.
(författare)
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The importance of heart rate in isoprenaline-induced takotsubo-like cardiac dysfunction in rats
- 2020
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Ingår i: Esc Heart Failure. - : Wiley. - 2055-5822. ; 7:5, s. 2690-2699
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Tidskriftsartikel (refereegranskat)abstract
- 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 8792, 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.
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| 7. |
- Oras, Jonatan, 1978, et al.
(författare)
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Early treatment with isoflurane attenuates left ventricular dysfunction and improves survival in experimental Takotsubo
- 2017
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Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172. ; 61:4, s. 399-407
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundTakotsubo syndrome (TS) is an acute cardiac condition, often triggered by critical illness, for which no specific treatment exists. Previously, we showed that isoflurane can prevent experimental TS. The aim of this study was to evaluate the potential treatment effects of isoflurane. Our primary hypothesis was that early treatment with isoflurane attenuates left ventricular akinesia in experimental TS. MethodIn propofol-sedated animals, TS was induced by an intraperitoneal bolus of isoprenaline (50 mg/kg). Animals were randomized to one of six groups (n = 15 in each group), and 1% isoflurane was administered for 90 min in all groups. Isoflurane treatment was started at 0, 10, 30 (early treatment) or 120 (late treatment) minutes after isoprenaline injection. One additional late treatment group received isoflurane 0.5% for 180 min. A control group did not receive isoflurane. Left ventricular (LV) echocardiographic examination was performed at 90 min and 48 h after isoprenaline. Mortality was assessed at 48 h. ResultsMedian degree of LV akinesia at 90 min was 24% in the control group and 0% in the early treatment groups (P < 0.001). Stroke volume, cardiac output and LV ejection fraction were higher in the early treatment groups vs. controls (P < 0.01). Mortality was lower in the early treatment groups (24%) vs. controls (86%) (P < 0.001). Mortality did not differ between the late treatment groups and controls. ConclusionEarly treatment with isoflurane attenuates the LV akinesia and improves survival in experimental TS. Isoflurane sedation in patients at risk of developing Takotsubo syndrome could be a subject for future studies.
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| 9. |
- Redfors, Björn, et al.
(författare)
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Are the different patterns of stress-induced (Takotsubo) cardiomyopathy explained by regional mechanical overload and demand: Supply mismatch in selected ventricular regions?
- 2013
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Ingår i: Medical hypotheses. - : Elsevier BV. - 1532-2777 .- 0306-9877. ; 81:5, s. 954-960
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Tidskriftsartikel (refereegranskat)abstract
- Takotsubo cardiomyopathy (TCM) or stress-induced cardiomyopathy is an increasingly recognized syndrome characterized by severe regional left ventricular dysfunction in the absence of an explanatory coronary lesion. TCM may lead to lethal complications but is completely reversible if the patient survives the acute phase. The pathogenesis of TCM and the mechanism behind this remarkable recovery are unknown. Plasma levels of catecholamine are elevated in many TCM patients and exogenously administered catecholamine induces TCM-like cardiac dysfunction in both humans and rats. A catecholamine excess increases myocardial metabolic demand by increasing the force of contraction as well as the heart rate, and also alters cardiac depolarization patterns. We propose that an altered spatiotemporal pattern of cardiac contraction and excessive force of contraction may lead to a redistribution of wall stresses in the left ventricle. This redistribution of wall stress causes regional mechanical overload of regions where wall tension becomes disproportionately great and renders these cardiomyocytes "metabolically insufficient". In other words, these cardiomyocytes experience a demand: supply mismatch on the basis of excessive metabolic demand. In order to prevent the death of these cardiomyocytes and to prevent excessive wall tension from developing in neighboring regions, a protective metabolic shutdown occurs in the affected cardiomyocytes. This metabolic shutdown, i.e., acute down regulation of non-vital cellular functions, serves to protect the affected regions from necrosis and explains the apparently complete recovery observed in TCM. We propose that this phenomenon may share important characteristics with phenomena such as ischemic conditioning, stunning and hibernation. In this manuscript, we discuss our hypothesis in the context of available knowledge and discuss important experiments that would help to corroborate or refute the hypothesis.
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| 10. |
- Redfors, Björn, et al.
(författare)
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Rat models reveal differences in cardiocirculatory profile between Takotsubo syndrome and acute myocardial infarction.
- 2015
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Ingår i: Journal of cardiovascular medicine (Hagerstown, Md.). - 1558-2035. ; 16:9, s. 632-638
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Tidskriftsartikel (refereegranskat)abstract
- Takotsubo syndrome, also known as stress-induced cardiomyopathy, is an important differential diagnosis in patients presenting with chest pain and is associated with significant morbidity and mortality. Beyond adrenergic overstimulation the pathophysiology behind Takotsubo is poorly known and the syndrome cannot be differentiated from acute myocardial infarction (AMI) by non-invasive tests. Despite the facts that Takotsubo syndrome and AMI may differ in many important aspects and that potential mechanistic similarities and/or differences between Takotsubo syndrome and AMI have not been established, Takotsubo syndrome patients are treated according to guidelines developed for AMI and acute heart failure. The aim of this article was to assess whether cardiac function and hemodynamic indices differ between rat models of Takotsubo syndrome and AMI.
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