Ketamine's love story with the heart: A Takotsubo twist.

INTRODUCTION: Ketamine is a dissociative anesthetic with N-methyl-d-aspartate and glutamate receptor antagonist properties. It has been the most popular agent to facilitate emergency department procedures for three decades. Considered a safe and effective option for procedural sedation, ketamine has rapid onset, short effective sedation time, and a low risk profile. Ketamine's sympathomimetic effects could theoretically induce stress-related cardiac dysfunction, including cardiomyopathy. A review of the literature demonstrates one prior report of stress (Takotsubo) cardiomyopathy after ketamine sedation. CASE REPORT: In this case report, we present a case of Takotsubo cardiomyopathy after ketamine sedation for distal radius fracture reduction. The patient presented hemodynamically normal with an unremarkable cardiac ultrasound and progressed to hypoxia from bilateral pulmonary edema, eventually requiring intubation. Inpatient evaluation revealed elevated high sensitivity troponin, non-obstructive coronary arteries on catheterization, and echocardiogram findings of Takotsubo cardiomyopathy. She received operative fixation of her radius fracture by orthopedics and was discharged home on hospital day 9. She had an unremarkable follow up with cardiology but had no echocardiogram to determine full resolution. CONCLUSION: Although ketamine has robust evidence of safety and efficacy, physicians should be aware of the potential complications of its sympathomimetic effects, from hypertension and tachycardia to overt Takotsubo cardiomyopathy.

Mitochondrial damage in a Takotsubo syndrome-like mouse model mediated by activation of ß-adrenoceptor-Hippo signaling pathway.

Takotsubo syndrome (TTS) is characterized by short-term contractile dysfunction with its mechanism undefined. We showed that activation of cardiac Hippo pathway mediates mitochondrial dysfunction and that stimulation of ß-adrenoceptors (ßAR) activates Hippo pathway. Here, we investigated the role of ßAR-Hippo signaling in mediating mitochondrial dysfunction in isoproterenol (Iso)-induced TTS-like mouse model. Elderly postmenopausal female mice were administered with Iso (1.25 mg/kg/h for 23 h). Cardiac function was determined by serially echocardiography. At days 1 and 7 post-Iso exposure, mitochondrial ultrastructure and function were examined by electron microscopy and various assays. Alterations in cardiac Hippo pathway and effects of genetic inactivation of Hippo kinase (Mst1) on mitochondrial damage and dysfunction in the acute phase of TTS were investigated. Isoproterenol exposure induced acute increase in biomarkers of cardiac damage and ventricular contractile dysfunction and dilation. At day 1 post-Iso, we observed extensive abnormalities in mitochondrial ultrastructure, downregulation of mitochondrial marker proteins, and mitochondrial dysfunction evidenced by lower ATP content, increased lipid droplets, higher contents of lactate, and augmented reactive oxygen species (ROS). All changes were reversed by day 7. ßAR stimulation led to activation of cardiac Hippo pathway with enhanced expression of Hippo kinase Mst1 and inhibitory YAP phosphorylation, as well as reduced nuclear YAP-TEAD1 interaction. In mice with cardiac expression of inactive mutant Mst1 gene, acute mitochondrial damage and dysfunction were mitigated. Stimulation of cardiac ßAR activates Hippo pathway that mediates mitochondrial dysfunction with energy insufficiency and enhanced ROS, promoting acute but short-term ventricular dysfunction.NEW & NOTEWORTHY Takotsubo syndrome (TTS) is featured by activation of sympatho-ß-adrenoceptor (ßAR) system leading to acute loss of ventricular contractile performance. However, the molecular mechanism remains undefined. We demonstrated, in an isoproterenol-induced murine TTS-like model, extensive mitochondrial damage, metabolic dysfunction, and downregulated mitochondrial marker proteins, changes temporarily associated with cardiac dysfunction. Mechanistically, stimulation of ßAR activated Hippo signaling pathway and genetic inactivation of Mst1 kinase ameliorated mitochondrial damage and metabolic dysfunction at the acute phase of TTS.

Pediatric Takotsubo cardiomyopathy resulting from clonidine overdose.

Takotsubo cardiomyopathy is a syndrome characterized by localized apical dysfunction of the left ventricle. It is rarely seen in pediatric patients, but can carry significant morbidity and mortality. While most commonly associated with psychosocial stressors or physical exertion, a growing number of cases are being attributed to medications. We describe a case of a six-month-old male diagnosed with Takotsubo cardiomyopathy in the setting of an accidental clonidine overdose. The patient presented with altered mental status and hypertension. In the course of his broad workup, cardiac dysfunction was indicated by bedside ultrasound in the Emergency Department. The classic apical dyskinesis was seen on a follow-up, cardiology-based echocardiogram. The patient responded to high-dose naloxone and only briefly required an epinephrine infusion. His symptoms resolved in a few days and serial echocardiograms showed a return to normal LV function. Rates of pediatric clonidine overdoses are increasing in the setting of changing prescribing practices. Our case illustrates some key features of the clinical presentation, as well as demonstrates a rare sequelae to this common toxic exposure. To our knowledge, this is the first reported pediatric case of Takotsubo cardiomyopathy secondary to a clonidine overdose.

Dobutamine-induced Takotsubo syndrome in a paediatric heart transplant patient.

Takotsubo syndrome is a potentially reversible cause of acute systolic dysfunction. Takotsubo syndrome is rare in children, with no reported dobutamine-induced cases to date. We present a 14-year-old male with prior history of heart transplantation, who developed Takotsubo syndrome during dobutamine stress echocardiography. We highlight the importance of its early recognition to ensure supportive measures with avoidance of inotropic medications.

Transfusion double whammy? Adrenaline-takotsubo-anaphylaxis-Kounis complex post transfusion?

BACKGROUND AND OBJECTIVES: The adrenaline-takotsubo-anaphylaxis-Kounis, or the ATAK complex, where there are clinical and pathophysiological overlaps between takotsubo and Kounis syndromes, in which histaminergic, adrenergic and other mediators may play roles, was recently described. The objective of this report was to describe three cases where the ATAK complex was suspected to have occurred after transfusion. MATERIALS AND METHODS: Three cases were recently reported to the New Zealand Blood Service haemovigilance programme that appeared to have features in common suggestive of the ATAK complex. RESULTS: All three patients had had a blood component transfused, an initial severe allergic reaction, treatment with adrenaline or a congener, subsequent acute left ventricular failure or transfusion-associated circulatory overload, and features suggestive of takotsubo cardiomyopathy. CONCLUSIONS: Although rarely described, transfusion-associated ATAK complex may be occurring more often than believed. Circumstances during a transfusion may predispose to it. It should be suspected if the sequence of events described above occur. Its characteristics need to be better understood. Risk factors for it may be modifiable.

Takotsubo Cardiomyopathy and ß-Blocker Poisoning: A Case Report.

ß-blocker poisoning is frequently observed because of its primary use for the treatment of cardiovascular diseases. The management of ß-blocker toxicity is dependent on the cardiovascular response and the severity of presentation. The present study describes the case of a patient with combined drug intoxication, ß-blocker, digoxin, benzodiazepines, acetaminophen and opiates in a suicidal attempt. A 63-year-old female was found somnolent and in a confused state at her residence following intentional poly-drug ingestion. Upon presentation, she was found to be hemodynamically unstable and was thus treated with vasopressors. The toxicological screening performed upon presentation was positive for polydrug ingestion. On day 3, the patient developed chest pain and ST-segment elevation in anterior leads, while transthoracic echocardiographic assessment disclosed a non-dilated left ventricle with moderate dysfunction and akinesia of the apex. Coronary angiogram revealed normal coronary arteries and, subsequently, the diagnosis of Takotsubo cardiomyopathy (TTC) was suspected. Supportive treatment was initiated with favorable evolution and left ventricular ejection fraction normalization. The management of hemodynamic instability with vasopressors should be judiciously administered in the treatment of ß-blocker poisoning, in view of the adverse effects on cardiac functions, including stress cardiomyopathy.

Takotsubo Cardiomyopathy as Epiphenomenon of Cardiotoxicity in Patients With Cancer: A Meta-summary of Case Reports.

ABSTRACT: Many antitumoral drugs have been linked to takotsubo cardiomyopathy, with no clear pathogenetic mechanisms. Data about this condition are lacking in literature. The aim of this meta-summary is to summarize the characteristics of patients with antitumoral drug-induced takotsubo cardiomyopathy, described in case reports available in literature. We searched for published case reports in PubMed, Google Scholar, EMBASE, and Scopus from 2009 about stress cardiomyopathy and antiblastic drugs. We selected 41 case reports. All cases underwent chemotherapy/immunotherapy for different types of cancer. The median age was 58 years, and 61% of them were women. The most common comorbidities were hypertension (12.2%) and dyslipidemia (4.9%), but most of the population had no cardiological clinical history. Takotsubo cardiomyopathy is associated to the 5-fluorouracil (36.5%), capecitabine (9.7%), trastuzumab (9.7%), and immune check point inhibitor (9.7%) treatment. The median time of onset was 2 days (1-150). Cardiogenic shock was the first manifestation in 11 patients (26.8%). Left ventricle ejection fraction recovery was showed in 33 patients (89%) with mean ejection fraction 57.7 ± 7%, after a median of 30-day (4-300) follow-up. Patients with cancer experienced takotsubo cardiomyopathy within few days from the beginning of therapy, and the most of them normalized the heart function in few weeks. Cardiogenic shock showed high prevalence in this setting of patients. Larger studies are needed to better understand the pathological mechanisms of antiblastic drug-induced stress cardiomyopathy, to find risk factors associated and preventive strategies for limit this type of cardiotoxicities.

What the Cardiologist Needs to Know About Cancer Immunotherapies and Complications.

OPINION STATEMENT: Immunotherapies have transformed the current landscape for cancer treatment and demonstrated unparalleled improvements in survival rates. Now, a third of cancer patients are eligible for treatment with the most widely used class of immunotherapy, immune checkpoint inhibitors (ICIs). As more patients are treated with these novel agents, it is critical for both oncologists and subspecialists to establish a better understanding of the adverse events which can occur. The incidence of myocarditis associated with ICI therapy has been reported to be between 0.27 and 1.14%, 5 times that of myocarditis from other cancer therapies, and, of those patients, 20-50% develop a fulminant form. However, because of unclear risk factors, a broad clinical spectrum, and lack of specific noninvasive studies for diagnosis, the care of patients with ICI-associated cardiotoxicity can be challenging. Here, we have provided a brief overview of the current immunotherapy agents with a focus on the emerging evidence regarding diagnosis and management of cardiac adverse events.

New Insights into Mechanisms of Immune Checkpoint Inhibitor-Induced Cardiovascular Toxicity.

PURPOSE OF REVIEW: The review aims to summarize the present knowledge about cardiovascular toxicities associated with immune checkpoint inhibitors (ICI) and dissect underlying mechanism associated with individual cardiovascular toxicity. RECENT FINDINGS: Widespread use of ICI therapy has allowed for increasing recognition of a wide spectrum of immune-related adverse events that leave all organ systems vulnerable. Immune-mediated cardiovascular toxicities, initially thought to be rare, are more often being reported and present considerable challenges due to their non-specific clinical presentation, potential to have a fulminant progression, and overlap with other cardiovascular and general medical illnesses. Myocarditis is the most common manifestation of ICI-associated cardiovascular toxicity. Pericardial diseases, vasculitis, Takotsubo syndrome, conduction abnormalities, and destabilization of atherosclerotic lesions constitute other significant adverse events. At this stage, mechanisms underlying fundamental biology of cardiac toxicity have not been studied comprehensively and there remain gaps of knowledge in the current literature concerning the underlying pathomechanisms. It is hypothesized that immune-mediated myocarditis is a result of an exaggerated adaptive immune response against shared epitopes in the myocardium and tumor cells. Further, underlying mechanism of other cardiovascular toxicities is still unclear, further compounded by sparsity of epidemiological data. It is paramount to understand the mechanisms behind ICI-induced cardiovascular toxicities to develop appropriate treatment and prevention strategies and minimize the morbidity and mortality of cancer patients undergoing ICI therapy.

Incremental "Therapeutic" Myocardial Exposure to Catecholamines: Incidence and Impact in Takotsubo Syndrome.

BACKGROUND: Although Takotsubo syndrome (TS) was once considered to be rare and largely benign, it is now recognized to represent a major cause of cardiac morbidity and mortality, especially in ageing women. The biochemical precipitant of attacks of TS is an increase in catecholamine concentrations within the myocardium, engendering inflammatory activation via biased post-receptor signalling at myocardial ß2-adrenoceptor level. Cases of TS have been reported in patients treated with catecholamines, and with antidepressants which limit catecholamine re-uptake. In the current investigation, we sought to delineate the extent and potential impact of this "iatrogenic" form of TS. METHODS/RESULTS: Patients' data from a regional registry of 301 consecutive cases of TS were evaluated after exclusion of patients (n = 20) in whom TS had occurred in association with life threatening extracardiac disease states. A total of 55 (18%) of patients were identified as having antecedent exposure to potentially "iatrogenic" agents (tricyclic antidepressants in 24 cases, ß2-adrenoceptor agonists in 15). Demographics, including proportion of male patients, did not differ significantly between patients with and without "iatrogenic" TS, but plasma concentrations of the catecholamine metabolite normetanephrine tended to be greater (median 1149 pmol/L vs 938 pmol/L; p = 0.03). Long-term survival (median follow-up 3 years) was marginally (p = 0.13) worse for patients with "iatrogenic" TS. CONCLUSION: Potentially iatrogenic precipitation of TS attacks (via iatrogenic elevation of catecholamine levels and ß2-adrenoceptor stimulation) is common, associated with greater elevation of plasma normetanephrine concentrations, and also with a trend towards increased long-term mortality when compared to the remainder of TS patients.

Iatrogenic Takotsubo Cardiomyopathy Following Overdose Norepinephrine Administration During Percutaneous Coronary Intervention.

Takotsubo cardiomyopathy (TTC) is characterized by reversible ventricular dysfunction induced by endogenous and, occasionally, exogenous catecholamine. We present a report on a patient who developed TTC and cardiogenic shock during percutaneous coronary intervention (PCI) secondary to inadvertent norepinephrine administration. His hemodynamic status and cardiac function were totally restored within 1 week after hemodynamic support using intra-aortic balloon pump without sequela. Thus, TTC should be considered once a patient presents with symptoms mimicking acute coronary syndrome (ACS) after catecholamine administration.

Takotsubo Cardiomyopathy Induced by Epinephrine Infiltration for Liposuction: Broken Heart Syndrome.

Broken heart syndrome, more commonly known as Takotsubo cardiomyopathy (TCM), is an acute cardiac condition. It is characterized by regional cardiac wall motion abnormalities triggered by physical or emotional stress or administration of catecholamines such as epinephrine. The initial clinical presentation is similar to an acute coronary syndrome and must be ruled out. Visualization of the characteristic wall motion will trigger the diagnosis of TCM. In this case report, we present a 50-year-old woman with additional liposuction and fat grafting after autologous breast reconstruction. Shortly after infiltration with a solution containing epinephrine to achieve vasoconstriction, hypotension and bradycardia was noticed. This escalated into full asystole for which cardiac resuscitation was required. ST-elevations and a decrease in systolic function were clear indicators for urgent coronarography and ventriculography. These confirmed the diagnosis of TCM. Infiltration with epinephrine-containing products to achieve local vasoconstriction is used routinely. Medical professionals should be aware that this can trigger a TCM with an estimated mortality rate of 5%. No evidence of a specific preventive measure currently exists. We know that women with a neurologic or psychiatric comorbidity and high levels of stress are more at risk. Reducing stress and anxiolytic medication prior to surgery could be useful. We also know that the cardiac wall motion abnormality is mainly related to ß-adrenoreceptors. The use of a selective α-adrenoreceptor agonist could be considered. Further research in the pathophysiology and incidence of TCM could improve identification of patients at risk and lead to more effective prevention and treatment.

Chemotherapy-Induced Takotsubo Syndrome.

Cardiovascular complications are a significant problem in systemically treated cancer patients. One such complication is Takotsubo cardiomyopathy, also known as Takotsubo syndrome. It is most frequently defined as a sudden and transient left or right ventricular systolic dysfunction; mimicking acute coronary syndrome, but without the associated changes in coronary arteries. Takotsubo syndrome is a relatively little known complication that appears in the course of oncological treatment, and its incidence has not yet been established. In this study, we reviewed Medline database according to case reports concerning takotsubo syndrome appearing after systemic treatment in oncological patients. We took into consideration all types of anticancer drugs. We reviewed the changes reported in the electrocardiography, echocardiography, and coronary angiography, and also the level of troponin, a marker of acute coronary syndrome elevation. In view of the increasing frequency of cardiac complications reported in patients receiving systemic oncological treatment, Takotsubo syndrome appears to be underdiagnosed. However, the syndrome may be linked to potentially fatal complications such as cardiogenic shock or cardiac arrest. Therefore, it seems essential to carry out appropriate diagnostic procedures for every patient experiencing clinical side effects of onco-pharmacotherapy. In patients with chest pain and dyspnea during or after treatment, Takotsubo syndrome should be considered, particularly that the syndrome requires a different therapy approach than that used in a coronary syndrome. Diagnostic procedures should include echocardiogram and the assessment of myocardial necrosis markers and natriuretic peptides.

[Takotsubo cardiomyopathy developing during anagrelide therapy in a patient with essential thrombocythemia].

A 76-year-old woman taking anagrelide (ANA) for essential thrombocythemia (ET) was rushed to the hospital by ambulance because of severe chest pain. Echocardiography revealed apical akinesis with basal and mid-hyperkinesis, and a coronary angiography revealed no significant stenosis in the dominant coronary artery. The patient was diagnosed with takotsubo cardiomyopathy (Tako). Tako is typically believed to be caused by stress; however, no stress was detected except that related to ANA therapy. ANA is useful in treating ET and is known to have severe cardiovascular effects. We must pay careful attention to Tako during ANA therapy.

A Case Report of Reversible Takotsubo Cardiomyopathy after Amphetamine/Dextroamphetamine Ingestion in a 15-Year-Old Adolescent Girl.

Stimulant medications are used in the treatment of attention deficit hyperactivity disorder and serious cardiac complications can occur when these medications are abused. We present a 15-year-old adolescent girl who was found to have a Takotsubo cardiomyopathy after acute amphetamine/dextroamphetamine ingestion.

Chemotherapy-induced Takotsubo cardiomyopathy, a case report and review of the literature.

BACKGROUND: Several chemotherapy molecules, monoclonal antibodies and tyrosine kinase inhibitors, have been linked to Takotsubo cardiomyopathy (TC). CASE PRESENTATION: In this article, we describe the case of a 45-year-old woman who developed TC after receiving an intra-arterial and intra-venous polychemotherapy for locally advanced epidermoid carcinoma of the anal canal. This is the first described case of TC associated with intra-arterial chemotherapy. CONCLUSIONS: A review of the literature points to 5-fluorouracil as the most common molecule associated with TC and highlights the potential risk associated with rechallenging patient with the same drug.

Hydrogen sulfide attenuates cardiac injury in takotsubo cardiomyopathy by alleviating oxidative stress.

Takotsubo cardiomyopathy (TCM) is characterized by transient left ventricular apical ballooning with the absence of coronary occlusion, which is an acute cardiac syndrome with substantial morbidity and mortality. It was reported that reduced endogenous hydrogen sulfide (H2S) levels may be related to various heart diseases. The present study investigated the mechanism by which H2S administration modulates and protects cardiac function in TCM rats. In order to establish a TCM model, Sprague Dawley (SD) rats were injected with a single dose of ß-adrenergic agonist isoprenaline (ISO). We found that ISO induced cardiac dysfunction, which was characterized by a significant decrease in left ventricular systolic pressure (LVSP), maximum contraction velocity (+dp/dtmax), maximum relaxation velocity (-dp/dtmax) and increased left ventricular end-diastolic pressure (LVEDP). Accordingly, we found that plasma and heart tissue H2S levels in TCM rats decreased significantly, and cardiac cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST) expression were lower. Moreover, cardiac dysfunction in TCM was associated with oxidative stress response and reactive oxygen species (ROS) formation. NADPH Oxidase 4 (NOX4) and p67 protein expressions significantly increased in TCM cardiac tissues. In addition, Sodium hydrosulfide (NaHS) ameliorated ISO-induced cardiac dysfunction and reversed ISO-induced oxidative stress. This study revealed that H2S exerted cardioprotective effects by reducing NADPH oxidase, which reduced ROS formation and prevented oxidative stress. Our study provided novel evidence that H2S is protective in myocardial dysfunction in TCM rats and could be a therapeutic target for alleviating ß-adrenergic system overstimulation-induced cardiovascular dysfunction.