Clinical perspectives: Takotsubo cardiomyopathy.

Takotsubo syndrome is a condition characterised by temporary acute left ventricular dysfunction with regional wall abnormalities extending beyond a single coronary artery territory. Initially thought to be benign, this condition, which is challenging to distinguish from acute coronary syndrome, has substantial morbidity and mortality. The mechanism behind this condition remains elusive, but multiple theories have been proposed. Although beta blockers and angiotensin-converting enzyme inhibitors are used as treatments for left ventricular dysfunction, currently, there are no randomised controlled trials to support their use. In this paper, we review the latest evidence regarding aetiologies, pathophysiology, diagnostic criteria, prognosis, complications and management of Takotsubo syndrome.

Takotsubo syndrome is a coronary microvascular disease: experimental evidence.

BACKGROUND AND AIMS: Takotsubo syndrome (TTS) is a conundrum without consensus about the cause. In a murine model of coronary microvascular dysfunction (CMD), abnormalities in myocardial perfusion played a key role in the development of TTS. METHODS AND RESULTS: Vascular Kv1.5 channels connect coronary blood flow to myocardial metabolism and their deletion mimics the phenotype of CMD. To determine if TTS is related to CMD, wild-type (WT), Kv1.5-/-, and TgKv1.5-/- (Kv1.5-/- with smooth muscle-specific expression Kv1.5 channels) mice were studied following transaortic constriction (TAC). Measurements of left ventricular (LV) fractional shortening (FS) in base and apex, and myocardial blood flow (MBF) were completed with standard and contrast echocardiography. Ribonucleic Acid deep sequencing was performed on LV apex and base from WT and Kv1.5-/- (control and TAC). Changes in gene expression were confirmed by real-time-polymerase chain reaction. MBF was increased with chromonar or by smooth muscle expression of Kv1.5 channels in the TgKv1.5-/-. TAC-induced systolic apical ballooning in Kv1.5-/-, shown as negative FS (P < 0.05 vs. base), which was not observed in WT, Kv1.5-/- with chromonar, or TgKv1.5-/-. Following TAC in Kv1.5-/-, MBF was lower in LV apex than in base. Increasing MBF with either chromonar or in TgKv1.5-/- normalized perfusion and function between LV apex and base (P = NS). Some genetic changes during TTS were reversed by chromonar, suggesting these were independent of TAC and more related to TTS. CONCLUSION: Abnormalities in flow regulation between the LV apex and base cause TTS. When perfusion is normalized between the two regions, normal ventricular function is restored.

Rationale and design of BROKEN-SWEDEHEART: a registry-based, randomized, parallel, open-label multicenter trial to test pharmacological treatments for broken heart (takotsubo) syndrome.

BACKGROUND: Takotsubo syndrome (TS) is a life-threatening acute heart failure syndrome without any evidence-based treatment options. No treatment for TS has been examined in a randomized trial. STUDY DESIGN AND OBJECTIVES: BROKEN-SWEDEHEART is a multicenter, randomized, open-label, registry-based 2 × 2 factorial clinical trial in patients with TS designed to test whether treatment with adenosine and dipyridamole accelerates cardiac recovery and improves clinical outcomes compared to standard care (study 1); and apixaban reduces the risk of thromboembolic events compared to no treatment with antithrombotic drugs (study 2). The trial will enroll 1,000 patients. Study 1 (adenosine hypothesis) will evaluate 2 coprimary end points: (1) wall motion score index at 48 to 96 hours (evaluated in the first 200 patients); and (2) the composite of death, cardiac arrest, need for mechanical assist device or heart failure hospitalization within 30 days or left ventricular ejection fraction <50% at 48 to 96 hours (evaluated in 1,000 patients). The primary end point in study 2 (apixaban hypothesis) is the composite of death or thromboembolic events within 30 days or the presence of intraventricular thrombus on echocardiography at 48 to 96 hours. CONCLUSIONS: BROKEN-SWEDEHEART will be the first prospective randomized multicenter trial in patients with TS. It is designed as 2 parallel studies to evaluate whether adenosine accelerates cardiac recovery and improves cardiac function in the acute phase and the efficacy of anticoagulation therapy for preventing thromboembolic complications in TS. If either of its component studies is successful, the trial will provide the first evidence-based treatment recommendation in TS. CLINICAL TRIALS IDENTIFIER: The trial has been approved by the Swedish Medicinal Product Agency and the Swedish Ethical Board and is registered at ClinicalTrials.gov (NCT04666454).

Takotsubo Syndrome: The Secret Crosstalk between Heart and Brain.

An acute, transient episode of left ventricular dysfunction characterizes Takotsubo syndrome. It represents about 2% of all cases of acute coronary syndrome (ACS), and occurs predominantly in postmenopausal women, generally following a significant physical or emotional stressor. It can be diagnosed based on clinical symptoms and the absence of coronary artery disease on angiography. Ventriculography remains the gold standard for the diagnosis. Despite its transitory characteristic Takotsubo syndrome should not be considered a benign condition since complications occur in almost half of the patients, and the mortality rate reaches 4-5%. Lately, it has been revealed that Takotsubo syndrome can also lead to permanent myocardial damage due to the massive release of catecholamines that leads to myocardial dysfunction. Different mechanisms have been advanced to explain this fascinating syndrome, such as plaque rupture and thrombosis, coronary spasm, microcirculatory dysfunction, catecholamine toxicity, and activation of myocardial survival pathways. Here are still several issues with Takotsubo syndrome that need to be investigated: the complex relationship between the heart and the brain, the risk of permanent myocardial damage, and the impairment of cardiomyocyte. Our review aims to elucidate the pathophysiology and the mechanisms underlying this complex disease to manage the diagnostic and therapeutic algorithms to create a functional synergy between physicians and patients.

Prognostic impact of antiplatelet therapy in Takotsubo syndrome: a systematic review and meta-analysis of the literature.

While the most recent evidence suggests a lack of benefit, antithrombotic therapy is still extensively prescribed in patients with Takotsubo syndrome (TTS). The objective of this study was to determine whether patients with TTS benefit from anti-aggregation, in terms of either short-term or long-term outcomes. A systematic review and meta-analysis was conducted. A comprehensive search of the literature included MEDLINE, Cochrane Library, Clinicaltrials.gov, EU Clinical Trial Register, References, and contact with the authors. Methodological quality assessment and data extraction were systematically performed. The review adhered to the PRISMA framework guidelines. A total of 86 citations were identified, six being eligible for inclusion, for a total of 1997 patients. One of them considered both short-term and long-term outcomes. One reported outcomes during the index event, while the remaining four focused on potential long-term benefits. They were all retrospective cohort studies.Based on our data, the long-term use of antiplatelet therapy (AT) led to a significantly higher incidence of the composite outcome (OR: 1.54; 95% CI 1.09-2.17; p = 0.014) and overall mortality (OR 1.72; 95% CI 1.07-2.77; p = 0.027). The analysis did not show a statistically significant difference in TTS recurrences, stroke/TIA, and MI or CAD worsening with AT compared with no anti-aggregation. The AT in this settings did not show any clear benefit in improving the long-term outcomes, and it may be even detrimental and it may be detrimental. These results warrant further future research and the design of adequately powered randomized controlled trials focusing on the impact of aspirin on the outcomes in patients presenting with TTS.

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.

A rare case of permanent pacemaker-induced takotsubo cardiomyopathy in a male patient.

Takotsubo cardiomyopathy is a type of non-ischemic cardiomyopathy that usually appears after a stressful event or in a woman and is rarely seen after pacemaker implantation (PMI). Herein, we present the case of a 65-year-old man with PMI because of a 2:1 atrioventricular nodal block who had a syncopal episode later in the day of the procedure. Echocardiography showed septal and apical hypokinesis with reduced ejection fraction suggestive of takotsubo cardiomyopathy. Before PMI, echocardiography showed normal left ventricular function with no wall-motion abnormality. Coronary angiography showed no coronary artery stenosis. The patient was seen again in the clinic 1 month later, and repeat echocardiography showed improvement of ejection fraction to 55% with no wall-motion abnormality. Generally, the complication rate after PMI is very low and includes infection, hematoma, lead dislocation, or allergic reaction at the site. The clinicians must be aware of potentially rare complications that can occur after PMI, such as takotsubo cardiomyopathy.

Aneurysmal subarachnoid hemorrhage as a trigger for Takotsubo syndrome: a comprehensive review.

Takotsubo syndrome (TTS) can result in acute heart failure and lead to a potentially life-threatening complication of aneurysmal subarachnoid hemorrhage (aSAH). The incidence of TTS in aSAH is less than 10% of all patients with aSAH, with a preponderance of postmenopausal women. Early indicators of TTS include elevated serum troponin levels and electrocardiographic abnormalities. The key finding is left ventricular wall motion abnormality. Echocardiography and coronary angiography help to establish the diagnosis. Vasopressors, milrinone, levosimendan, insulin, and anticoagulation may be required. The value of beta-blockers is a matter of controversy. TTS must not delay the treatment of a ruptured aneurysm. The clinical outcome in patients with aSAH and TTS is mostly determined by the aSAH and not the TTS.

Takotsubo Syndrome: Uncovering Myths and Misconceptions.

PURPOSE OF REVIEW: Takotsubo syndrome (TTS) was described in Japan 3 decades ago to affect predominately postmenopausal women after emotional stress. This history is the basis of commonly held beliefs which may contribute to the underdiagnosis and misperception of TTS. RECENT FINDINGS: TTS affects not only women, but can be present in both sexes, and can appear in children as well as in the elderly. TTS is characterized by unique clinical characteristics with morphological variants, and incurs a substantial risk for recurrent events and adverse outcomes. Physical triggers are more common than emotional triggers and are major disease determinants. TTS seems not to be completely transient as patients report ongoing chest pain, dyspnea, or fatigue even after months of the acute event. Knowledge of the clinical features and outcomes of TTS patients has evolved substantially over the past decades. The heterogeneous appearance of TTS needs to be recognized in all medical disciplines to maximize therapy and improve outcomes.

The effects of beta-blockers in patients with stress cardiomyopathy.

Beta-blockers are often used in the treatment of patients with stress cardiomyopathy without firm evidence of benefit. We conducted a retrospective case note review investigating the effects of beta-blockers on QT interval and heart rate in patients with stress cardiomyopathy over 3 days of hospital admission. We found no evidence of effects on QT interval from beta-blocker treatment in this condition.

Takotsubo Syndrome-Is There a Need for CMR?

PURPOSE OF REVIEW: Takotsubo syndrome (TTS) is a transient but severe myocardial dysfunction that has been known for decades and is still to be fully understood regarding its clinical presentations and pathophysiological mechanisms. Cardiac magnetic resonance (CMR) imaging plays a key role in the comprehensive analysis of patients with TTS in acute and follow-up examinations. In this review, we focus on the major advantages and latest evolutions of CMR in diagnosis and prognostication of TTS and discuss future perspectives and needs in the field of research and cardiovascular imaging in TTS. RECENT FINDINGS: Specific CMR criteria for TTS diagnosis at the time of acute presentation are established. In addition to identifying the typical regional wall motion abnormalities, CMR allows for precise quantification of right ventricular and left ventricular (LV) function, the assessment of additional abnormalities/complications (e.g. pericardial and/or pleural effusion, LV thrombi), and most importantly myocardial tissue characterization (myocardial oedema, inflammation, necrosis/fibrosis). CMR enables a comprehensive assessment of the entire spectrum of functional and structural changes that occur in patients with TTS and may have also a prognostic impact. CMR can distinguish between TTS and other important differential diagnoses (myocarditis, myocardial infarction) with direct consequences on medical therapy.

Cardiac arrest in takotsubo syndrome: results from the InterTAK Registry.

AIMS: We aimed to evaluate the frequency, clinical features, and prognostic implications of cardiac arrest (CA) in takotsubo syndrome (TTS). METHODS AND RESULTS: We reviewed the records of patients with CA and known heart rhythm from the International Takotsubo Registry. The main outcomes were 60-day and 5-year mortality. In addition, predictors of mortality and predictors of CA during the acute TTS phase were assessed. Of 2098 patients, 103 patients with CA and known heart rhythm during CA were included. Compared with patients without CA, CA patients were more likely to be younger, male, and have apical TTS, atrial fibrillation (AF), neurologic comorbidities, physical triggers, and longer corrected QT-interval and lower left ventricular ejection fraction on admission. In all, 57.1% of patients with CA at admission had ventricular fibrillation/tachycardia, while 73.7% of patients with CA in the acute phase had asystole/pulseless electrical activity. Patients with CA showed higher 60-day (40.3% vs. 4.0%, P < 0.001) and 5-year mortality (68.9% vs. 16.7%, P < 0.001) than patients without CA. T-wave inversion and intracranial haemorrhage were independently associated with higher 60-day mortality after CA, whereas female gender was associated with lower 60-day mortality. In the acute phase, CA occurred less frequently in females and more frequently in patients with AF, ST-segment elevation, and higher C-reactive protein on admission. CONCLUSIONS: Cardiac arrest is relatively frequent in TTS and is associated with higher short- and long-term mortality. Clinical and electrocardiographic parameters independently predicted mortality after CA.

Persistent Long-Term Structural, Functional, and Metabolic Changes After Stress-Induced (Takotsubo) Cardiomyopathy.

BACKGROUND: Takotsubo cardiomyopathy is an increasingly recognized acute heart failure syndrome precipitated by intense emotional stress. Although there is an apparent rapid and spontaneous recovery of left ventricular ejection fraction, the long-term clinical and functional consequences of takotsubo cardiomyopathy are ill-defined. METHODS: In an observational case-control study, we recruited 37 patients with prior (>12-month) takotsubo cardiomyopathy, and 37 age-, sex-, and comorbidity-matched control subjects. Patients completed the Minnesota Living with Heart Failure Questionnaire. All participants underwent detailed clinical phenotypic characterization, including serum biomarker analysis, cardiopulmonary exercise testing, echocardiography, and cardiac magnetic resonance including cardiac 31P-spectroscopy. RESULTS: Participants were predominantly middle-age (64±11 years) women (97%). Although takotsubo cardiomyopathy occurred 20 (range 13-39) months before the study, the majority (88%) of patients had persisting symptoms compatible with heart failure (median of 13 [range 0-76] in the Minnesota Living with Heart Failure Questionnaire) and cardiac limitation on exercise testing (reduced peak oxygen consumption, 24±1.3 versus 31±1.3 mL/kg/min, P<0.001; increased VE/Vco2 slope, 31±1 versus 26±1, P=0.002). Despite normal left ventricular ejection fraction and serum biomarkers, patients with prior takotsubo cardiomyopathy had impaired cardiac deformation indices (reduced apical circumferential strain, -16±1.0 versus -23±1.5%, P<0.001; global longitudinal strain, -17±1 versus -20±1%, P=0.006), increased native T1 mapping values (1264±10 versus 1184±10 ms, P<0.001), and impaired cardiac energetic status (phosphocreatine/γ-adenosine triphosphate ratio, 1.3±0.1 versus 1.9±0.1, P<0.001). CONCLUSIONS: In contrast to previous perceptions, takotsubo cardiomyopathy has long-lasting clinical consequences, including demonstrable symptomatic and functional impairment associated with persistent subclinical cardiac dysfunction. Taken together our findings demonstrate that after takotsubo cardiomyopathy, patients develop a persistent, long-term heart failure phenotype. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT02989454.

Takotsubo syndrome in patients with myasthenia gravis: a systematic review of previously reported cases.

BACKGROUND: Myasthenia gravis associated takotsubo syndrome is a rare condition. This study aimed to explore its typical presentation, investigations and treatment through a systematic review of previously reported cases. METHODS: Databases and reference lists of the selected articles were searched for case reports on Myasthenia gravis associated takotsubo syndrome. CARE guidelines were used for the quality assessment of the selected articles. RESULTS: Sixteen cases were selected out of 580 search results. Western Pacific, American and European regions contributed to 88% of the cases. Females were most affected (81%). Features of both myasthenia gravis and takotsubo syndrome were the common clinical presentations. All cases had a myasthenic crisis. Half of the cases had no prior diagnosis of myasthenia gravis. Pyridostigmine and prednisolone were useful for myasthenia gravis while dobutamine was most commonly used for takotsubo syndrome. All cases survived except four (25%). CONCLUSIONS: Myasthenia gravis associated takotsubo syndrome via a myasthenic crisis is rare but life-threatening. Therefore, predisposition due to emotional and physical triggers needs to be avoided for its prevention. The rare entity should be suspected even in patients without a prior diagnosis of Myasthenia gravis.

Oral anticoagulation in high risk Takotsubo syndrome: when should it be considered and when not?

Standard pharmacological therapy in Takotsubo syndrome (TTS) is still debated and there is a lack of prospective data. In their recent work in BMC Cardiovascular Disorders Abanador-Kamper et al. found that stroke in TTS has an event rate of 2.8% after 30 days and 4.2% after 12 months and they question which patients need oral anticoagulation. According to our clinical data, TTS patients with LV thrombi may be at high risk of stroke. These patients are characterized by apical ballooning pattern, high prevalence of ST-elevation and higher troponin I levels. We have recently proposed a therapeutic algorithm for oral anticoagulation in TTS. In case of apical ballooning pattern and increased admission levels of troponin-I (> 10 ng/mL), oral anticoagulation should be considered, while in case of midventricular/basal ballooning or apical ballooning associated with troponin-I levels < 10 ng/ml, oral anticoagulation should not be considered. A simple combination of echocardiographic parameters (apical ballooning pattern),ECG data (ST-elevation at admission and persistent after 72 h) and laboratory values (troponin serum levels) could be useful for an appropriate therapeutic management of oral anticoagulation in TTS.

Epidemiology, pathogenesis, and management of takotsubo syndrome.

Takotsubo syndrome is a recently recognized acute cardiac disease entity with a clinical presentation resembling that of an acute coronary syndrome. The typical takotsubo syndrome patient has a unique circumferential left (bi-) ventricular contraction abnormality profile that extends beyond a coronary artery supply territory and appears to follow the anatomical cardiac sympathetic innervation. The syndrome predominantly affects postmenopausal women and is often preceded by emotional or physical stress. Patients with predisposing factors such as malignancy and other chronic comorbidities are more prone to suffer from takotsubo syndrome. The pathogenesis of takotsubo syndrome is elusive. Several pathophysiological mechanisms involving myocardial ischemia (multivessel coronary artery spasm, microvascular dysfunction, aborted myocardial infarction), left ventricular outlet tract obstruction, blood-borne catecholamine myocardial toxicity, epinephrine-induced switch in signal trafficking, and autonomic nervous system dysfunction have been proposed. The syndrome is usually reversible; nevertheless, during the acute stage, a substantial number of patients develop severe complications such as arrhythmias, heart failure including pulmonary edema and cardiogenic shock, thromboembolism, cardiac arrest, and rupture. Treatment of precipitating factors, predisposing diseases, and complications is fundamental during the acute stage of the disease. The epidemiology, pathogenesis, and management of takotsubo syndrome are reviewed in this paper.

Respiratory insufficiency from myasthenia gravis and polymyositis due to malignant thymoma triggering Takotsubo syndrome.

BACKGROUND: Takotsubo syndrome (TTS) is a non-ischaemic cardiomyopathy with sudden but transient systolic dysfunction. TTS mimics myocardial infarction clinically, chemically, and electrocardiographically but echocardiography typically shows apical ballooning and coronary angiography is normal. TTS has not been reported in a patient with myasthenia gravis (MG) and polymyositis due to a malignant thymoma. CASE REPORT: Two weeks prior to admission, a 76-year-old female developed dysarthria, chronic coughing and disabling myalgias of the entire musculature. Since there was hyper-CKemia and elevated troponin, myocardial infarction was suspected. During swallowing of the antithrombotic medication on admission, she experienced apnoea, requiring cardio-pulmonary resuscitation with intubation and mechanical ventilation. Further diagnostic work-up precluded coronary heart disease but revealed TTS. Upon neurologic work-up, MG and polymyositis were diagnosed but the response to cholinergic drugs and plasmapheresis was poor. TTS was attributed to stress and anxiety from MG-associated respiratory insufficiency. The further course was complicated by recurrent supraventricular bradyarrhythmias and respiratory insufficiency. Upon thoracic CT a thymoma was suspected. Two months after admission, the mediastinal tumour was resected and malignant thymoma WHO BII infiltrating the mediastinum (modified Masaoka-Koga II/2) was diagnosed. CONCLUSIONS: This case shows that TTS may be triggered by stress from respiratory insufficiency during a myasthenic crisis, MG may be associated with polymyositis, cholinergic medication may trigger bradyarrhythmias, and cholinergic drugs and plasmapheresis may exhibit a poor effect if malignant thymoma and polymyositis are present.

Takotsubo cardiomyopathy: A known unknown foe of asthma.

INTRODUCTION: Patients with uncontrolled asthma are at a greater risk of asthma attacks requiring emergency room visits or hospital admissions. Takotsubo cardiomyopathy is potentially a significant complication in a course of status asthmaticus. CASE STUDY: We describe a 43-year-old female patient who presented with status asthmaticus that was further complicated with takotsubo cardiomyopathy. RESULTS: Recognizing apical ballooning syndrome is challenging in patients with a history of respiratory disease because the symptoms of the last entity may complicate the diagnostic approach. It is difficult to distinguish clinically apical ballooning syndrome from the acute airway exacerbation itself. Both asthma and takotsubo cardiomyopathy share the same clinical presentation with dyspnea and chest tightness. In our patient, the electrocardiographic abnormalities, the rapidly reversible distinctive characteristics of echocardiography, and the modest elevation of serum cardiac biomarkers levels, in combination with the presence of a stress trigger (severe asthma attack), strongly supported the diagnosis of broken heart syndrome. CONCLUSIONS: Clinicians should re-evaluate asthma management and be aware of the complications associated with asthma attacks such as stress-induced cardiomyopathy.

Happy heart syndrome: role of positive emotional stress in takotsubo syndrome.

AIMS: Takotsubo syndrome (TTS) is typically provoked by negative stressors such as grief, anger, or fear leading to the popular term 'broken heart syndrome'. However, the role of positive emotions triggering TTS remains unclear. The aim of the present study was to analyse the prevalence and characteristics of patients with TTS following pleasant events, which are distinct from the stressful or undesirable episodes commonly triggering TTS. METHODS AND RESULTS: Takotsubo syndrome patients with preceding pleasant events were compared to those with negative emotional triggers from the International Takotsubo Registry. Of 1750 TTS patients, we identified a total of 485 with a definite emotional trigger. Of these, 4.1% (n = 20) presented with pleasant preceding events and 95.9% (n = 465) with unequivocal negative emotional events associated with TTS. Interestingly, clinical presentation of patients with 'happy heart syndrome' was similar to those with the 'broken heart syndrome' including symptoms such as chest pain [89.5% (17/19) vs. 90.2% (412/457), P = 1.0]. Similarly, electrocardiographic parameters, laboratory findings, and 1-year outcome did not differ. However, in a post hoc analysis, a disproportionate higher prevalence of midventricular involvement was noted in 'happy hearts' compared with 'broken hearts' (35.0 vs. 16.3%, P = 0.030). CONCLUSION: Our data illustrate that TTS can be triggered by not only negative but also positive life events. While patient characteristics were similar between groups, the midventricular TTS type was more prevalent among the 'happy hearts' than among the 'broken hearts'. Presumably, despite their distinct nature, happy and sad life events may share similar final common emotional pathways, which can ultimately trigger TTS.