Development of a small animal model replicating core characteristics of takotsubo syndrome in humans.

Aims: Adequate animal models are necessary to understand human conditions, such as takotsubo syndrome (TS) characterized by the heart's transient regional wall motion abnormalities. This study aims to develop a reproducible, low-mortality TS model that closely mimics the human condition and addresses the limitations of existing models. Methods and results: We conducted six experiments using 309 Sprague Dawley rats, each approximately 300 g and aged 7-8 weeks. Initially, we replicated an established model using intraperitoneal isoprenaline injections. Subsequent experiments varied the doses and infusion durations of intravenous isoprenaline and assessed the effects of sex, strain, and breeder on the development of reversible akinetic segments. High-resolution echocardiography monitored the regional wall motion over 30 days to correlate with histological changes. Increasing the isoprenaline dose and the infusion time significantly enhanced akinesia (P < 0.01), resulting in pronounced apical ballooning observed in three-dimensional imaging. Akinesia peaked at 6 h post-infusion, with recovery observed at 24 h; most rats recovered from akinetic segments within 48-72 h. Optimizing the mode of administration, dose, and duration achieved a TS-like phenotype in 90% of cases, with a 16.7% mortality rate. Histological examinations confirmed that myocardial injury occurred, independent of apical ballooning. Conclusion: This study presents a refined TS model that reliably replicates the syndrome's key features, including morphological and electrocardiographic changes, demonstrating its transient nature with high fidelity and reduced mortality. The model's reproducibility, evidenced by consistent results across trials, suggests its potential for broader application pending further validation.

Animal models of Takotsubo syndrome: bridging the gap to the human condition.

Modelling human diseases serves as a crucial tool to unveil underlying mechanisms and pathophysiology. Takotsubo syndrome (TS), an acute form of heart failure resembling myocardial infarction, manifests with reversible regional wall motion abnormalities (RWMA) of the ventricles. Despite its mortality and clinical similarity to myocardial infarction, TS aetiology remains elusive, with stress and catecholamines playing central roles. This review delves into current animal models of TS, aiming to assess their ability to replicate key clinical traits and identifying limitations. An in-depth evaluation of published animal models reveals a variation in the definition of TS among studies. We notice a substantial prevalence of catecholamine-induced models, particularly in rodents. While these models shed light on TS, there remains potential for refinement. Translational success in TS research hinges on models that align with human TS features and exhibit the key features, including transient RWMA. Animal models should be comprehensively evaluated regarding the various systemic changes of the applied trigger(s) for a proper interpretation. This review acts as a guide for researchers, advocating for stringent TS model standards and enhancing translational validity.

Ischemic preconditioning affects phosphosites and accentuates myocardial stunning while reducing infarction size in rats.

Background and aims: Ischemic preconditioning (IPC), i.e., brief periods of ischemia, protect the heart from subsequent prolonged ischemic injury, and reduces infarction size. Myocardial stunning refers to transient loss of contractility in the heart after myocardial ischemia that recovers without permanent damage. The relationship between IPC and myocardial stunning remains incompletely understood. This study aimed primarily to examine the effects of IPC on the relationship between ischemia duration, stunning, and infarct size in an ischemia-reperfusion injury model. Secondarily, this study aimed to examine to which extent the phosphoproteomic changes induced by IPC relate to myocardial contractile function. Methods and results: Rats were subjected to different durations of left anterior descending artery (LAD) occlusion, with or without preceding IPC. Echocardiograms were acquired to assess cardiac contraction in the affected myocardial segment. Infarction size was evaluated using triphenyl tetrazolium chloride staining. Phosphoproteomic analysis was performed in heart tissue from preconditioned and non-preconditioned animals. In contrast to rats without IPC, reversible akinesia was observed in a majority of the rats that were subjected to IPC and subsequently exposed to ischemia of 13.5 or 15 min of ischemia. Phosphoproteomic analysis revealed significant differential regulation of 786 phosphopeptides between IPC and non-IPC groups, with significant associations with the sarcomere, Z-disc, and actin binding. Conclusion: IPC induces changes in phosphosites of proteins involved in myocardial contraction; and both accentuates post-ischemic myocardial stunning and reduces infarct size.

Inter- and intra-observer variability in the echocardiographic evaluation of wall motion abnormality in patients with ST-elevation myocardial infarction or takotsubo syndrome - A novel approach.

INTRODUCTION AND OBJECTIVES: Using existing transthoracic echocardiographic indices to quantify left ventricular wall motion abnormalities (WMAs) can be difficult due to the variations in the location of the abnormalities within the left ventricle, the quality of examinations, and the inter-/intra-observer variability of available indices. This study aimed to evaluate a new approach for measuring the extent of WMA by calculating the percentage of abnormal wall motion and comparing it to the wall motion score index (WMSI). The study also sought to assess inter- and intra-observer variability. METHODS: The study included 140 echocardiograms from 54 patients presenting with ST-elevation myocardial infarction or Takotsubo syndrome. All patients underwent an echocardiographic examination according to a standard protocol and the images were used to measure the extent of akinesia (proportion akinesia, PrA), akinesia and hypokinesia (proportion akinesia/hypokinesia, PrAH), and WMSI. The inter-observer variability between the two operators was analyzed. The intra-observer analysis was performed by one observer using the same images at least 1 month after the first measurement. The agreement was analyzed using the Pearson correlation coefficient and Bland-Altman plots. RESULTS: Inter- and intra-observer variability for PrA and PrAH were low and comparable to those for WMSI. CONCLUSION: PrA and PrAH are reliable and reproducible echocardiographic methods for the evaluation of left ventricular wall motion.

Temporal electrocardiographic changes in anterior ST elevation myocardial infarction versus the Takotsubo syndrome.

Background: Electrocardiography (ECG) on admission is similar in ST elevation myocardial infarction (STEMI) and Takotsubo syndrome (TTS). ECG on admission has been extensively investigated and compared between STEMI and TTS, however, only a few studies have compared temporal ECG. Our aim was to compare ECG in anterior STEMI versus female TTS from admission to day 30. Methods: Adult patients with anterior STEMI or TTS treated at Sahlgrenska University Hospital (Gothenburg, Sweden) from December 2019 to June 2022 were prospectively enrolled. Baseline characteristics, clinical variables and ECGs from admission to day 30 were analyzed. Using a mixed effects model, we compared temporal ECG between female patients with anterior STEMI or TTS, as well as between female and male patients with anterior STEMI. Results: A total of 101 anterior STEMI patients (31 female, 70 male) and 34 TTS patients (29 female, 5 male) were included. The temporal pattern of T wave inversion was similar between female anterior STEMI and female TTS, as well as between female and male anterior STEMI. ST elevation was more common, whereas QT prolongation was less common, in anterior STEMI compared with TTS. Q wave pathology was more similar between female anterior STEMI and female TTS than between female and male anterior STEMI. Conclusions: The pattern of T wave inversion and Q wave pathology from admission to day 30 was similar in female patients with anterior STEMI and female patients with TTS. Temporal ECG in female patients with TTS may be interpreted as following a "transient ischemic" pattern.

Differences between cardiac troponin I vs. T according to the duration of myocardial ischaemia.

AIMS: Cardiac troponin T (cTnT) and troponin I (cTnI) are expressed as an obligate 1:1 complex in the myocardium. However, blood levels of cTnI often rise much higher than that of cTnT in myocardial infarction (MI), whereas cTnT is often higher in patients with stable conditions such as atrial fibrillation. Here we examine high-sensitive (hs) cTnI and hs-cTnT after different durations of experimental cardiac ischaemia. METHODS AND RESULTS: hs-cTnI, hs-cTnT, and the hs-cTnT/hs-cTnI ratio were measured in plasma samples from rats before and at 30 and 120 min after 5, 10, 15, and 30 min of myocardial ischaemia. The animals were killed after 120 min of reperfusion, and the infarct volume and volume at risk were measured. hs-cTnI, hs-cTnT, and the hs-cTnT/hs-cTnI ratio were also measured in plasma samples collected from patients with ST-elevation myocardial infarction (STEMI). hs-cTnT and hs-cTnI increased over 10-fold in all rats subjected to ischaemia. The increase of hs-cTnI and hs-cTnT after 30 min was similar, resulting in a hs-cTnI/hs-cTnT ratio around 1. The hs-cTnI/hs-cTnT ratio was also around 1 in blood samples collected at 120 min in rats subjected to 5 or 10 min of ischaemia where no localized necrosis was observed. In contrast, the hs-cTnI/hs-cTnT ratio at 2 h was 3.6-5.5 after longer ischaemia that induced cardiac necrosis. The large hs-cTnI/hs-cTnT ratio was confirmed in patients with anterior STEMI. CONCLUSION: Both hs-cTnI and hs-cTnT increased similarly after brief periods of ischaemia that did not cause overt necrosis, whereas the hs-cTnI/hs-cTnT ratio tended to increase following longer ischaemia that induced substantial necrosis. A low hs-cTnI/hs-cTnT ratio around 1 may signify non-necrotic cTn release.

ECG differences and ECG predictors in patients presenting with ST segment elevation due to myocardial infarction versus takotsubo syndrome.

Background: Previous studies comparing electrocardiogram (ECG) in Takotsubo syndrome (TS) versus ST elevation myocardial infarction (STEMI) included TS patients without ST elevation, did not consider the culprit lesion in STEMI or had groups that were unbalanced regarding sex and age. Accounting for these factors, we sought to conduct a more reliable comparison of ECG in TS with ST-elevation (STE-TS) versus STEMI. The secondary aim was to investigate if ST segment changes, T wave inversion or prolonged QT interval predicted ventricular arrhythmia or death in STE-TS and STEMI. Methods: All STE-TS patients who presented at Sahlgrenska University Hospital between 2008 and 2019 were matched by sex and age to STEMI patients. STEMI patients were subcategorized according to whether or not the culprit lesion was located in the left anterior descending artery (LAD). Baseline characteristics, in-hospital outcomes and admission ECGs were analyzed. Results: 104 STE-TS patients were sex- and age-matched with 274 STEMI patients (113 LAD-STEMI, 161 non-LAD STEMI). Admission ECG in STE-TS was more similar to LAD STEMI than non-LAD STEMI. Reciprocal ST depression was less common in STE-TS (7/104, 6.7%) compared with STEMI (112/274, 41%; p= < 0.001). The sum of all ST elevations and the sum of all ST-deviations predicted life-threatening ventricular arrhythmia (LTVA) or death in LAD STEMI but not in STE-TS. Conclusions: In conclusion, admission ECG in STE-TS was similar to LAD STEMI but reciprocal ST depression was less common in STE-TS compared with STEMI overall. ST segment changes predicted LTVA or death in STEMI but not in STE-TS.

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.

Risk of in-hospital life-threatening ventricular arrhythmia or death after ST-elevation myocardial infarction vs. the Takotsubo syndrome.

AIMS: The risk of life-threatening ventricular arrhythmias (LTVA) has been reported to be lower in Takotsubo syndrome (TS) compared with ST-elevation myocardial infarction (STEMI). However, the extent to which these differences relate to the fact that most patients with TS are women (who have a lower risk of LTVA) and a relatively larger proportion of patients with STEMI are men is incompletely understood. We aimed to investigate the risk of LTVA or death in sex-matched and age-matched patients with TS, anterior STEMI, and non-anterior STEMI. METHODS AND RESULTS: We systematically reviewed the charts of all patients with TS who were treated at Sahlgrenska University Hospital (Gothenburg, Sweden) between 2008 and 2019. A total of 155 patients with confirmed TS (according to the European Society of Cardiology diagnostic criteria for TS) were sex-matched and age-matched 1:1:1 to patients with anterior and non-anterior STEMI. Baseline characteristics and in-hospital outcomes were recorded directly from the patient charts for all patients, and all admission electrocardiographs were analysed. The primary outcome was the composite of death or LTVA [defined as sustained ventricular tachycardia (>30 s) or ventricular fibrillation] within 72 h. The risk of LTVA or death within 72 h after admission was considerably lower in TS (2.6%) vs. anterior STEMI (14%; P = 0.002) and non-anterior STEMI (9.0%; P = 0.02), despite similar or greater risks of acute heart failure, and similar risks of cardiogenic shock. Compared with STEMI, TS was associated with a lower risk of sustained and non-sustained ventricular tachycardia and ventricular fibrillation. CONCLUSIONS: In a predominantly female age-matched and sex-matched cohort of patients with TS, anterior STEMI, and non-anterior STEMI, the adjusted risk of in-hospital LTVA or death was considerably lower in TS compared with STEMI, despite similar or greater risk of acute heart failure and similar risk of cardiogenic shock.

Electrocardiographic predictors of adverse in-hospital outcomes in the Takotsubo syndrome.

BACKGROUND: Takotsubo syndrome (TS) is a life-threatening acute heart failure syndrome. However, little is known about risk factors for worse outcomes in TS and no high-risk ECG criteria have been defined. We sought to identify ECG predictors of life-threatening in-hospital complications in TS. METHOD AND RESULT: Using the nationwide Swedish Angiography and Angioplasty Registry (SCAAR) we obtained data on all consecutive patients undergoing coronary angiography at Sahlgrenska University Hospital between June 2008 and February 2019. For all patients with TS we conducted in-depth chart reviews to confirm the TS diagnosis. For those with confirmed TS we then evaluated all ECGs obtained during the index hospitalization. The primary endpoint was the occurrence of in-hospital major adverse cardiac event (MACE), defined as the composite of death, ventricular tachycardia or fibrillation (VT/VF), or atrioventricular block ≥2 or asystole ≫10 s. We identified 215 patients with TS (mean age 69 ±â€¯13 years; 93% women). MACE occurred in 34 patients (16%), of whom 20 had VT/VF (9,3%). Patients with MACE were less likely than those without MACE to have sinus rhythm (85% versus 96%, p = 0.025) or T-wave inversion (29% versus 51%, p = 0.025). After propensity score adjustment T-wave inversion was independently associated with lower MACE risk (adjusted odds ratio [AdjOR] 0.28, 95% confidence interval [CI] 0.10-0.76, p = 0.012) and VT/VF (AdjOR 0.24, 95% CI 0.06-0.94, p = 0.041). CONCLUSION: T-wave inversion is common in TS and is associated with lower risk of MACE, driven by a lower risk of VT/VF.

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.