Electromechanical Window and Spontaneous Ventricular Tachyarrhythmias in Takotsubo Syndrome.

QT interval prolongation is common in patients hospitalized with Takotsubo syndrome (TTS), however, only a minority experience ventricular tachyarrhythmias. Our aim was to characterize the electromechanical window (EMW) in patients with TTS and to evaluate its association with ventricular tachyarrhythmias. We preformed aretrospective analysis of 84 patients hospitalized with TTS in the Tel-Aviv Medical Center between 2013 and 2022. All patients underwent a comprehensive echocardiographic evaluation and the EMW was calculated by subtracting the QT interval from the QRS onset to the aortic valve closure obtained from a continuous-wave Doppler for the same beat. Of the 84 patients with TTS, 74 (88%) were female and the mean age was 70 ± 11 years. The mean left ventricular ejection fraction was 42 ± 8%. The EMW was negative in 81 patients (96%), and the mean EMW was -69 ± 50 ms. Ventricular tachyarrhythmias occurred in 7 patients (8%). The EMW of patients who experienced ventricular tachyarrhythmias was more negative than patients who did not (-133 ± 23 ms vs -63 ± 48 ms, p = 0.001). In the univariate analysis, EMW and QT were associated with ventricular tachyarrhythmias (univariate odds ratio [OR]EMW 1.03, 95% confidence interval [CI] 1.01 to 1.05, p = 0.003 and univariate ORQTc 1.02, 95% CI 1.01 to 1.03, p = 0.02); however, only EMW remained significant in the multivariate analysis (OREMW 1.03 95% CI 1.03 to 1.05, p = 0.023). EMW was more effective than corrected QT interval in identifying patients who had ventricular tachyarrhythmias (AUCEMW: 0.89, 95% CI 0.82 to 0.97 vs AUCQTc 0.77, 95% CI 0.61 to 0.93, p = 0.02), and a cut-off value of -108 ms was predictive of ventricular tachyarrhythmias with a sensitivity of 86% and a specificity of 79%. In conclusion, EMW is negative in patients with TTS and is associated with increased risk for ventricular tachyarrhythmias. The role of EMW in the risk stratification of patients with TTS warrants further investigation.

Comparison of electrographic changes, clinical features and outcomes in different variants of Takotsubo syndrome.

BACKGROUND: Dysfunction of the left ventricular (LV) apex (apical variant) is the most common form in Takotsubo syndrome (TS). Several less common non-apical variants have been described - mid-ventricular, basal and focal. We hypothesised that the clinical presentation, and electrocardiographic (ECG) findings may vary between apical and non-apical TS. METHODS: We prospectively identified 194 consecutive patients with TS presenting to Middlemore Hospital, Auckland and obtained clinical, echocardiography, coronary angiography, and long-term follow-up data. ECGs at admission and Day 1 were compared. RESULTS: Of 194 patients with TS, 168 (86.6%) had apical TS, and 26 (13.4%) non-apical TS (11 mid-ventricular TS, 5 basal TS, 10 focal TS). Apical TS patients had more significant LV systolic impairment (p = 0.001) and longer length of stay (p = 0.001). The extent of T-wave inversion (TWI) was similar for both groups on admission (p = 0.88). By Day 1 the extent of TWI was greater in apical TS group (median number of leads 5 vs. 1, p = 0.02). The change in QTc interval between admission and Day 1 was greater in apical TS group (29.7 ms vs. 2.77 ms, p < 0.001). Composite in-hospital complication rate was similar for both groups (13.7% vs. 15.4%, p = 0.77). CONCLUSIONS: Compared with non-apical variants, apical TS patients develop more extensive TWI and greater QT prolongation on ECG, and more significant LV systolic impairment, but in-hospital complications were similar. Clinicians should be aware that there is a sub-group of TS patients who have non-apical regional wall motion abnormalities and who don't develop ECG changes typical of the more common apical variant.

An update on the mechanisms of Takotsubo syndrome: "At the end an acute coronary syndrome".

Takotsubo syndrome (TTS) is an acute reversible form of myocardial dysfunction, often preceded by a physical or emotional stressful event, that acts as a trigger. Despite, recent advances in the comprehension of the mechanisms leading to TTS, its pathophysiology is far from being completely understood. However, several studies seem to suggest that an acute coronary microvascular dysfunction may represent a crucial pathogenic mechanism involved in TTS occurrence. In this article, we aim to review the complex pathophysiology of TTS and the possible different mechanisms underlying this clinical condition, focusing on the role of coronary microvascular dysfunction and the remaining knowledge's gaps in the field.

Renal impairment and outcome in Takotsubo syndrome: Insights from a national multicentric cohort.

INTRODUCTION: Data on the association between kidney function and Takotsubo syndrome (TTS) outcomes are scarce and conflictive. OBJECTIVE: To assess the impact of chronic kidney disease (CKD) and acute renal failure (ARF) in patients with TTS. MATERIAL AND METHODS: Patients from the prospective nation-wide (RETAKO) registry were included and divided into quartiles of maximum creatinine (Cr) level during hospitalization. RESULTS: The prevalence of CKD and ARF in the whole RETAKO cohort was 5.4% and 11.7%, respectively. Compared to Q1 (Cr <0.71), patients within Q4 (Cr > 1.1) had lower left ventricular ejection fraction on admission (38.5 ± 12 vs 43.3 ± 11.3, p = 0.002) and higher bleeding rates during hospitalization (6.7% vs 2%, p = 0.005). In addition, compared to Q1, Q4 patients have a greater incidence of cardiogenic shock (17.3% vs 5.6%, p < 0.001), and a higher rate of 5-year all-cause death and major adverse cardiovascular events (31.5% vs 15.8%, p < 0.001 and 22.5% vs 9.3%, p < 0.001, respectively). CONCLUSIONS: TTS patients with CKD have a higher incidence of ARF and exhibit greater Cr on admission, which were linked with higher rates of cardiogenic shock, bleeding during hospitalization as well as major adverse cardiovascular events and all-cause death during a 5-year follow-up.

Insulin resistance in Takotsubo syndrome.

AIMS: Takotsubo syndrome (TTS) is an acute heart failure (AHF) syndrome mimicking the symptoms of acute myocardial infarction. Impaired outcome has been shown, making risk stratification and novel therapeutic concepts a necessity. We hypothesized insulin resistance with elevated plasma glucose and potentially myocardial glucose deprivation to contribute to the pathogenesis of TTS and investigated the therapeutic benefit of insulin in vivo. METHODS AND RESULTS: First, we retrospectively analysed patient data of n = 265 TTS cases (85.7% female, mean age 71.1 ± 14.1 years) with documented initial plasma glucose from the Department of Cardiology of the University Hospital Heidelberg in Germany (May 2011 to May 2021). Median split of the study population according to glucose levels (≤123 mg/dL vs. >123 mg/dL) yielded significantly elevated mean heart rate (80.75 ± 18.96 vs. 90.01 ± 22.19 b.p.m., P < 0.001), left ventricular end-diastolic pressure (LVEDP, 18.51 ± 8.35 vs. 23.09 ± 7.97 mmHg, P < 0.001), C-reactive protein (26.14 ± 43.30 vs. 46.4 ± 68.6 mg/L, P = 0.006), leukocyte count (10.12 ± 4.29 vs. 15.05 ± 9.83/nL, P < 0.001), peak high-sensitive Troponin T (hs-TnT, 515.44 ± 672.15 vs. 711.40 ± 736.37 pg/mL, P = 0.005), reduced left ventricular ejection fraction (EF, 34.92 ± 8.94 vs. 31.35 ± 8.06%, P < 0.001), and elevated intrahospital mortality (2.3% vs. 12.1%, P = 0.002) in the high-glucose group (Student's t-test, Mann-Whitney U test, or chi-squared test). Linear regression indicated a significant association of glucose with HR (P < 0.001), LVEDP (P = 0.014), hs-TnT kinetics from admission to the next day (P < 0.001), hs-TnT the day after admission (P < 0.001), as well as peak hsTnT (P < 0.001). Logistic regression revealed significant association of glucose with a composite intrahospital outcome including catecholamine use, respiratory support, and resuscitation [OR 1.010 (1.004-1.015), P = 0.001]. To further investigate the potential role of glucose in TTS pathophysiology experimentally, we utilized an in vivo murine model of epinephrine (EPI)-driven reversible AHF. For this, male mice underwent therapeutic injection of insulin (INS, 1 IU/kg) or/and glucose (GLU, 0.5 g/kg) after EPI (2.5 mg/kg), both of which markedly improved mean EF (EPI 34.3% vs. EPI + INS + GLU 43.7%, P = 0.025) and significantly blunted mean hs-TnT (EPI 14 393 pg/mL vs. EPI + INS 6864 pg/mL at 24 h, P = 0.039). Particularly, insulin additionally ameliorated myocardial pro-inflammatory gene expression, suggesting an anti-inflammatory effect of acute insulin therapy. CONCLUSIONS: Elevated initial plasma glucose was associated with adverse outcome-relevant parameters in TTS and may present a surrogate parameter of heightened catecholaminergic drive. In mice, insulin- and glucose injection both improved EPI-induced AHF and myocardial damage, indicating insulin resistance rather than detrimental effects of hyperglycaemia itself as the underlying cause. Future studies will investigate the role of HbA1c as a risk stratifier and of insulin-based therapy in TTS.

Valor pronóstico del intervalo Tpeak-Tend en el desarrollo de arritmias ventriculares subagudas intrahospitalarias en el síndrome de tako-tsubo / Prognostic value of the Tpeak-Tend interval for in-hospital subacute ventricular arrhythmias in tako-tsubo syndrome

Introducción y objetivos El valor de los parámetros del electrocardiograma (ECG) de repolarización asociados al riesgo de arritmias ventriculares (AVs) en el síndrome de tako-tsubo es controvertido. Nuestro objetivo fue identificar predictores ECG de AVs subagudas, definidas como aquellas ocurridas después de las primeras 48 horas desde el ingreso. Métodos Estudio observacional unicéntrico de pacientes ingresados en el servicio de cardiología entre 2012 y 2018 con diagnóstico de síndrome de tako-tsubo. La recogida de datos incluyó el ECG de 12 derivaciones al ingreso y a las 48 horas, registros de telemetría continua, analíticas, ecocardiografía transtorácica y angiografía coronaria durante la hospitalización. Los eventos de AVs se definieron como: extrasístoles ventriculares ≥ 2.000 en registros de telemetría de 24 horas, fibrilación ventricular, taquicardia ventricular (TV) sostenida, TV polimórfica y TV no sostenida. Resultados Se incluyeron 87 pacientes (edad 72±12 años). Durante una hospitalización mediana de 8 días se registraron AVs subagudas en 22 pacientes (25%) tras una mediana de 91 horas desde el ingreso. Las AVs subagudas se asociaron a aumento de la mortalidad hospitalaria (p=0,030). El intervalo Tpeak-Tend corregido global (promedio de las 12 derivaciones del ECG) a las 48 horas del ingreso fue un predictor independiente de AVs subagudas, superior al intervalo QT corregido (p=0,040). Un valor de corte 108ms en el Tpeak-Tend corregido global mostró una sensibilidad del 71% y especificidad del 72% para AVs subagudas. Conclusiones En pacientes con síndrome de tako-tsubo, las AVs subagudas se asocian a alteraciones de la repolarización que pueden detectarse en el ECG convencional mediante el intervalo Tpeak-Tend (AU)

Introduction and objectives The clinical value of electrocardiogram (ECG) repolarization parameters associated with ventricular arrhythmias (VAs) in tako-tsubo syndrome is still under debate. We aimed to evaluate ECG predictors of subacute VAs, defined as those occurring after the first 48hours from admission. Methods This single-center observational study enrolled patients admitted to the cardiology department between 2012 and 2018 with a confirmed diagnosis of tako-tsubo syndrome. Data collection included a 12-lead ECG on admission and at 48hours, continuous telemetry monitoring, blood testing, transthoracic echocardiography, and coronary angiography during hospitalization. VAs events were defined as: premature ventricular contractions ≥ 2000 within a 24-hour window of telemetry monitoring, ventricular fibrillation, sustained ventricular tachycardia (VT), polymorphic VT, and non-sustained VT. Results A total of 87 patients (age 72±12 years) were enrolled. During a median of 8 days of hospitalization, subacute VAs were documented in 22 patients (25%) after a median of 91hours from admission. Subacute VAs were associated with an increase in mortality during hospitalization (P=.030). The corrected global (mean of the 12-lead ECG values) Tpeak-Tend interval at 48hours from admission was an independent predictor of subacute VAs and was statistically superior to the standard corrected QT interval (Z test, P=.040). A cut-off of 108 msec for the corrected global Tpeak-Tend yielded a 71% sensitivity and 72% specificity for subacute VAs. Conclusions In patients with tako-tsubo syndrome, subacute VAs are associated with repolarization alterations that can be identified on conventional ECG using the Tpeak-Tend interval (AU)

Takotsubo cardiomyopathy in the setting of a myasthenic crisis.

BACKGROUND: Myasthenic crisis is characterized by severe weakness in bulbar and respiratory muscles leading to respiratory failure and can be a natural result of myasthenia gravis or precipitate due to infections, surgeries, and pregnancy. It has been shown that stressful emotional events can lead to stress, or takotsubo cardiomyopathy. Takotsubo cardiomyopathy is characterized by transient reversible left ventricular dysfunction in the absence of obstructive artery disease with hypo- or akinesis of the apex with hypercontractility of the base. METHODS: Case report and review of literature. RESULTS: We report a 77-year old man with myasthenia gravis that was admitted to the neurological intensive care unit due to a myasthenic crisis. During the course of his treatment with plasma exchange, he developed hypotension with a reduced cardiac ejection fraction found on transthoracic electrocardiography. Repeat echocardiography 2 and 8 days later showed a normal ejection fraction and resolved cardiac function. CONCLUSION: While takotsubo cardiomyopathy rarely presents concurrently with a myasthenic crisis, its consideration is warranted in the face of cardiovascular decompensation. Given that several cardiac complications are known to be associated with myasthenic crisis, cardiac monitoring is advised. Nine reports describe takotsubo cardiomyopathy occurring concurrently with a myasthenic crisis; however, only one report demonstrates this association in the absence of concomitant comorbidities or significant emotional distress.

Catecholamine-induced cardiotoxicity: A critical element in the pathophysiology of stroke-induced heart injury.

Cerebrovascular diseases such as ischemic stroke, brain hemorrhage, and subarachnoid hemorrhage provoke cardiac complications such as heart failure, neurogenic stress-related cardiomyopathy and Takotsubo cardiomyopathy. With regards to the pathophysiology of stroke-induced heart injury, several mechanisms have been postulated to contribute to this complex interaction between brain and heart, including damage from gut dysbiosis, immune and systematic inflammatory responses, microvesicle- and microRNA-mediated vascular injury and damage from a surge of catecholamines. All these cerebrovascular diseases may trigger pronounced catecholamine surges through diverse ways, including stimulation of hypothalamic-pituitary adrenal axis, dysregulation of autonomic system, and secretion of adrenocorticotropic hormone. Primary catecholamines involved in this pathophysiological response include norepinephrine (NE) and epinephrine. Both are important neurotransmitters that connect the nervous system with the heart, leading to cardiac damage via myocardial ischemia, calcium (Ca2+) overload, oxidative stress, and mitochondrial dysfunction. In this review, we will aim to summarize the molecular mechanisms behind catecholamine-induced cardiotoxicity including Ca2+ overload, oxidative stress, apoptosis, cardiac hypertrophy, interstitial fibrosis, and inflammation. In addition, we will focus on how synchronization among these pathways evokes cardiotoxicity.

Takotsubo syndrome as an overlooked and elusive cause of a single episode of dyspnea in young women: a case report.

BACKGROUND: Dyspnea is a common symptom in patients presenting to the emergency department. It has a variety of causes that range from non-urgent to life-threatening. One episode of dyspnea in a healthy young person is easy to overlook. However, if the symptoms occur after physically or emotionally stressful events, careful evaluation needs to be undertaken because it may be associated with Takotsubo syndrome, which is rarely expected but can be fatal. Herein, we report the case of Takotsubo syndrome in a healthy young woman who arrived at the emergency department after experiencing a short single episode of dyspnea following a minor surgery. CASE PRESENTATION: A 23-year old woman with no underlying chronic disease underwent closed reduction surgery for a nasal bone fracture under general anesthesia (with sevoflurane as the anesthetic). Approximately 5 h later, she presented to the emergency department with dyspnea, which improved soon upon arrival at the emergency department. There were no other symptoms. The dyspnea occurred about 5 h after being discharged on observation, with an uneventful postoperative course. Her electrocardiogram and chest X-ray findings were unremarkable. On testing, troponin I and creatine kinase myocardial band levels were elevated at 6.122 ng/mL and 11.2 µg/L (reference ranges: 0.000-0.046 ng/mL and 0.0-5.0 µg/L), respectively. Bedside echocardiography revealed an ejection fraction of 25%, with mid-ventricular and apical akinesia and basal hyperkinesia. The pulmonary and coronary angiographic computed tomographic scans were unremarkable. Hence, apical Takotsubo syndrome was suspected. A follow-up echocardiogram taken 5 days after admission showed full recovery with a normalized ejection fraction (60%) and no regional wall motion abnormality. The patient was discharged on the sixth day with no other complications. CONCLUSION: When atypical symptoms, such as transient dyspnea, manifest, it becomes necessary to suspect and diagnose Takotsubo syndrome to ensure timely and appropriate medical management, especially when a preceding stressful event, such as minor surgery has occurred. It might be helpful to perform bedside point-of-care echocardiography to check for regional wall motion abnormalities that are typically associated with Takotsubo syndrome.

Pathophysiology of Takotsubo Cardiomyopathy: Reopened Debate.

Takotsubo cardiomyopathy (TTC), a persistently obscure dysfunctional condition of the left ventricle, is uniquely transient but nevertheless dangerous. It features variable ventricular patterns and is predominant in women. For 30 years, pathophysiologic investigations have progressed only slowly and with inadequate focus. It was initially proposed that sudden-onset spastic obliteration of coronary flow induced myocardial ischemia with residual stunning and thus TTC. Later, it was generally accepted without proof that, in the presence of pain or emotional stress, the dominant mechanism for TTC onset was a catecholamine surge that had a direct, toxic myocardial effect. We think that the manifestations of TTC are more dynamic and complex than can be assumed from catecholamine effects alone. In addition, after reviewing the recent medical literature and considering our own clinical observations, especially on spasm, we theorize that atherosclerotic coronary artery disease modulates and physically opposes obstruction during spasm. This phenomenon may explain the midventricular variant of TTC and the lower incidence of TTC in men. We continue to recommend and perform acetylcholine testing to reproduce TTC and to confirm our theory that coronary spasm is its initial pathophysiologic factor. An improved understanding of TTC is especially important because of the condition's markedly increased incidence during the ongoing COVID-19 pandemic.

Reverse Takotsubo Cardiomyopathy Precipitated by Chronic Cocaine and Cannabis Use.

This case report describes a 31-year-old man with 10 years of cocaine and cannabis dependence who developed reverse Takotsubo cardiomyopathy (rTC), a rare variant of Takotsubo cardiomyopathy. He presented to the Emergency Department (ED) with severe left temporal headache and vomiting which began whilst smoking cannabis and several hours after smoking methamphetamine and using cocaine via insufflation. Computed tomography and angiography of the brain was normal, and the headache resolved with analgesia. Urine drug screen was positive for benzodiazepines, cannabinoids, cocaine, opiates (attributed to morphine administered in ED) and amphetamines. Three hours later he had a seizure and within 10 min developed cardiogenic shock with antero-inferior ST segment depression on electrocardiogram and troponin-T rise to 126 ng/L. Coronary angiography demonstrated normal coronary arteries. Transthoracic echocardiogram demonstrated severely impaired left ventricular (LV) systolic function with ejection fraction 15-20% and hypokinesis sparing the apex. Thyrotoxicosis, nutritional, vasculitic, autoimmune and viral screens were negative. Cardiac magnetic resonance imaging demonstrated severe LV functional impairment with dilated and hypocontractile basal segments, and T2 hyperintensity consistent with myocardial oedema and rTC. He received supportive management. Proposed mechanisms of rTC include catecholamine cardiotoxicity and coronary artery vasospasm. In this case, multiple insults including severe headache, cannabis hyperemesis and cocaine and methamphetamine-induced serotonin toxicity culminated in a drug-induced seizure which led to catecholamine cardiotoxicity resulting in rTC. Clinicians should be cognizant of stress cardiomyopathy as a differential diagnosis in patients with substance use disorders.

Incidence and Clinical Impact of Right Ventricular Involvement (Biventricular Ballooning) in Takotsubo Syndrome: Results From the GEIST Registry.

BACKGROUND: The short- and long-term prognosis of Takotsubo syndrome (TTS) presenting with right ventricular (RV) involvement remains poorly understood. RESEARCH QUESTION: What is the incidence and clinical outcome of RV involvement in TTS? STUDY DESIGN AND METHODS: This study analyzed 839 consecutive patients with TTS (758 female subjects and 81 male subjects) in a multicenter registry. RV involvement was defined as wall motion abnormality of the RV free wall, with or without apical involvement. The median long-term follow-up was 2.1 years (interquartile range, 0.3-4.5 years). The primary outcome was in-hospital and out-of-hospital all-cause mortality. The secondary end point was a composite of in-hospital death, thromboembolic events, cardiogenic shock, pulmonary edema, and malignant arrhythmias. RESULTS: The incidence of RV involvement in TTS was 11% (n = 93). More often patients with RV involvement were male compared with patients without RV involvement (P = .02). There was a slight difference in the left ventricular ejection fraction measured in patients with RV involvement vs those patients with isolated left ventricular TTS (38 ± 10% vs 40 ± 10%; P = .03). No major differences in terms of comorbidities were observed between groups except regarding a history of cancer, which was significantly more prevalent in patients with TTS presenting with RV involvement (P = .03). Physical stressors were more prevalent in the RV group (P < .01), whereas emotional stressors were less prevalent (P < .01). Patients with RV involvement had a higher incidence of in-hospital cardiogenic shock (P = .02). The primary outcome (in- and out-of-hospital all-cause mortality) was observed in 12.8% of patients without RV involvement compared with 29% of patients with RV involvement. Although the in-hospital mortality rate was similar in both groups, a higher out-of-hospital all-cause mortality rate (log-rank test, P = .008) was observed in the RV involvement group. The Cox multivariable regression analysis showed that physical triggers were independent predictors of RV involvement. INTERPRETATION: RV involvement defines a high-risk cohort of patients with TTS. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04361994; URL: www.clinicaltrials.gov.