Takotsubo syndrome as an outcome of the use of checkpoint inhibitor therapy in patients with COVID-19.

Takotsubo Syndrome (TS) is a heart disease caused by extreme exposure of the body to physical or psychological stress. In the context of COVID-19, the virus can be a significant source of stress, with particular attention being paid to the cytokine storm as a cause of damage to the body. New research shows that the production of specific cytokines is linked to the activation of immune checkpoint proteins such as PD-1, PD-L1, and CTLA-4 on T cells. Although initially beneficial in combating infections, it can suppress defense and aid in disease progression. Therefore, checkpoint inhibitor therapy has been highlighted beyond oncological therapies, given its effectiveness in strengthening the immune system. However, this treatment can lead to excessive immune responses, inflammation, and stress on the heart, which can cause Takotsubo Syndrome in patients. Several studies investigate the direct link between this therapy and cardiac injuries in these patients, which can trigger TS. From this perspective, we must delve deeper into this treatment and consider its effects on the prognosis against SARS-CoV-2 infection.

Ginsenoside Rb1 mitigates acute catecholamine surge-induced myocardial injuries in part by suppressing STING-mediated macrophage activation.

Stress cardiomyopathy (SCM) is associated with cardiovascular mortality rates similar to acute coronary syndrome. Myocardial injuries driven by inflammatory mechanisms may in part account for the dismal prognosis of SCM. Currently, no inflammation-targeted therapies are available to mitigate SCM-associated myocardial injuries. In this study, acute catecholamine surge-induced SCM was modeled by stimulating the ovariectomized (OVX) mice with isoproterenol (ISO). The effects of ginsenoside Rb1 (Rb1) on SCM-associated myocardial injuries were assessed in the OVX-ISO compound mice. RAW 264.7 macrophages stimulated with calf thymus DNA (ctDNA) or STING agonist DMXAA were adopted to further understand the anti-inflammatory mechanisms of Rb1. The results show that estrogen deprivation increases the susceptibility to ISO-induced myocardial injuries. Rb1 mitigates myocardial injuries and attenuates cardiomyocyte necrosis as well as myocardial inflammation in the OVX-ISO mice. Bioinformatics analysis suggests that cytosolic DNA-sensing pathway is closely linked with ISO-triggered inflammatory responses and cell death in the heart. In macrophages, Rb1 lowers ctDNA-stimulated production of TNF-α, IL-6, CCL2 and IFN-ß. RNA-seq analyses uncover that Rb1 offsets DNA-stimulated upregulation in multiple inflammatory response pathways and cytosolic DNA-sensing pathway. Furthermore, Rb1 directly mitigates DMXAA-stimulated STING activation and inflammatory responses in macrophages. In conclusion, the work here demonstrates for the first time that Rb1 protects against SCM-associated myocardial injuries in part by counteracting acute ISO stress-triggered cardiomyocyte necrosis and myocardial inflammation. Moreover, by evidencing that Rb1 downregulates cytosolic DNA-sensing machineries in macrophages, our findings warrant further investigation of therapeutic implications of the anti-inflammatory Rb1 in the treatment of SCM.

Takotsubo syndrome: Impact of medical therapies on prognosis. A state of art review.

Tako-Tsubo syndrome (TTS) presents as transient ventricular dysfunction, yet its underlying pathophysiology remains enigmatic. The prognosis of patients presenting with TTS appears to be impaired as compared to the general population and is similar to patients with acute coronary syndromes. Recent investigations have predominantly focused on elucidating therapeutic strategies associated with improved outcomes, particularly among post-menopausal female patients. Current evidence suggests that angiotensin-converting enzyme inhibitors (ACEi) may confer a survival advantage in TTS. Notably, ACEi emerges as the sole therapeutic modality demonstrating efficacy in both acute and chronic clinical courses of TTS. Despite this, the magnitude of survival benefit remains less pronounced than anticipated. This underscores the need for further research to explore additional therapeutic pathways and optimize management strategies for this unique patient cohort. Randomized clinical trials and meta-analysis are paramount in discerning the most effective therapeutic interventions aimed at enhancing survival and ameliorating outcomes in TTS. This review aims to comprehensively synthesize evidence pertaining to the prognostic implications of cardiovascular medications in TTS management.

Effects of pharmacological interventions on mortality in patients with Takotsubo syndrome: a report from the SWEDEHEART registry.

AIMS: Takotsubo syndrome (TS) is a heart condition mimicking acute myocardial infarction. TS is characterized by a sudden weakening of the heart muscle, usually triggered by physical or emotional stress. In this study, we aimed to investigate the effect of pharmacological interventions on short- and long-term mortality in patients with TS. METHODS AND RESULTS: We analysed data from the SWEDEHEART (the Swedish Web System for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies) registry, which included patients who underwent coronary angiography between 2009 and 2016. In total, we identified 1724 patients with TS among 228 263 individuals in the registry. The average age was 66 ± 14 years, and 77% were female. Nearly half of the TS patients (49.4%) presented with non-ST-elevation acute coronary syndrome, and a quarter (25.9%) presented with ST-elevation myocardial infarction. Most patients (79.1%) had non-obstructive coronary artery disease on angiography, while 11.7% had a single-vessel disease and 9.2% had a multivessel disease. All patients received at least one pharmacological intervention; most of them used beta-blockers (77.8% orally and 8.3% intravenously) or antiplatelet agents [aspirin (66.7%) and P2Y12 inhibitors (43.6%)]. According to the Kaplan-Meier estimator, the probability of all-cause mortality was 2.5% after 30 days and 16.6% after 6 years. The median follow-up time was 877 days. Intravenous use of inotropes and diuretics was associated with increased 30 day mortality in TS [hazard ratio (HR) = 9.92 (P < 0.001) and HR = 3.22 (P = 0.001), respectively], while angiotensin-converting enzyme inhibitors and statins were associated with decreased long-term mortality [HR = 0.60 (P = 0.025) and HR = 0.62 (P = 0.040), respectively]. Unfractionated and low-molecular-weight heparins were associated with reduced 30 day mortality [HR = 0.63 (P = 0.01)]. Angiotensin receptor blockers, oral anticoagulants, P2Y12 antagonists, aspirin, and beta-blockers did not statistically correlate with mortality. CONCLUSIONS: Our findings suggest that some medications commonly used to treat TS are associated with higher mortality, while others have lower mortality. These results could inform clinical decision-making and improve patient outcomes in TS. Further research is warranted to validate these findings and to identify optimal pharmacological interventions for patients with TS.

A rare case of Takotsubo cardiomyopathy.

BACKGROUND: The recent advent of the cyclin-dependent kinase (CDK) 4/6 inhibitors has considerably evolved hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer treatment. Palbociclib, an orally administered pyridopyrimidine derivative, was the first CDK4/6 inhibitor to be introduced into daily clinical practice in combination with classic endocrine backbone, based on progression-free survival (PFS) benefit assessed in the pivotal PALOMA series of randomized clinical trials. Regarding its safety profile, neutropenia and leukopenia are the most common and well-defined adverse effects, while cardiac complications are rather scarce. CASE REPORT: We present the rare case of a middle-aged female patient with HR+/HER2- metastatic breast cancer, without prior exposure to cardiotoxic antineoplastic agents, who developed Takotsubo cardiomyopathy (TTC) in the context of systemic therapy with palbociclib plus letrozole combination. CONCLUSIONS: Pharmacovigilance and experimental studies are warranted to confirm any causative relationship and to explore the underlying pathophysiology, respectively.

Statin therapy and outcome in Takotsubo syndrome patients: Results from the multicenter international GEIST registry.

BACKGROUND AND AIMS: Several studies have shown that endothelial dysfunction plays a role in the pathogenesis of Takotsubo syndrome (TTS). Given the potential benefit of statin therapy on endothelial dysfunction, we hypothesized that such treatment could improve outcome. Aim of our study was to evaluate clinical characteristics and outcome of TTS patients treated with statin therapy. METHODS: Patients were enrolled in the international multicenter GEIST (GErman Italian Spanish Takotsubo) registry. Demographic data, clinical features and drug therapy at discharge were recorded. Primary study outcome was the occurrence of all-cause death at follow-up. RESULTS: Study population included 2429 consecutive TTS patients: 1293 (53.2%) discharged on statin and 1136 (46.8%) without statin. Patients with statin were older (age 72 ± 11 vs 69 ± 13 years, p < 0.001), with higher prevalence of hypertension (74.3% vs 60.3%, p < 0.001), diabetes (21.1% vs 14.7%, p < 0.001), dyslipidemia (56.1% vs 23.3%, p < 0.001), history of coronary artery disease (13.3% vs 6.3%, p < 0.001) and lower rates of in-hospital complications (14.7% vs 19.3%, p = 0.003). Survival analysis showed similar mortality rates between groups (log rank p = 0.803). At univariable analysis, statin therapy at discharge was not associated with lower mortality (HR: 0.97, 95% CI 0.74-1.26, p = 0.803). At multivariable analysis age (HR: 1.06 95% CI 1.04-1.08, p < 0.001), male sex (HR: 1.83, 95% CI 1.20-2.80, p = 0.005), diabetes (HR: 2.55, 95% CI 1.83-3.54 p < 0.001), malignancies (HR: 2.41, 95% CI 1.68-3.44, p < 0.001) and physical trigger (HR: 2.24, 95% CI 1.62-3.10, p < 0.001) were associated with increased mortality. CONCLUSIONS: Statin therapy after a TTS event was not associated with better prognosis at follow-up.

Haemodynamic effects of acute intravenous landiolol in Takotsubo cardiomyopathy with dynamic left ventricular outflow tract obstruction.

Takotsubo cardiomyopathy (TCM) leads to serious left ventricular outflow tract (LVOT) obstruction with cardiogenic shock in 6%-20% of cases. The onset of LVOT obstruction, coupled with mitral regurgitation resulting from systolic anterior motion of mitral valve leaflets, can lead to haemodynamic instability in addition to severely impaired systolic function. We describe three patients who experienced chest discomfort following emotional stress. These patients displayed pronounced abnormalities on ECGs, insignificant obstructive coronary disease and haemodynamic instability due to LVOT obstruction. The infusion of landiolol, a short-acting beta blocker, was effective in releasing the gradient. Dynamic outflow obstruction is the major predictor of haemodynamic collapse. We suggested that an early identification of this complication in hypotensive patients with suspected TCM could be of utmost importance to optimise the therapeutic approach in the acute setting.

An Opportune Time to Consider Glucose-Insulin-Potassium Therapy for Takotsubo Syndrome.

This viewpoint takes the position that the management of takotsubo syndrome (TTS) should not wait the elucidation of the pathophysiology of this mysterious malady but should move along the direction currently implemented for acute coronary syndromes (ACS). Accordingly, and since there is a current rekindled interest in the salutary effect of glucose-insulin-potassium (GIK) for the management of acute myocardial infarction, and in general of the broad domain of ACS, it is the opinion of this author that it is an opportune time for the same therapeutic principles, including GIK, applied for the broad domain of suspected ACS (in view of the prospective phase 3 IMMEDIATE-2 trial), to be considered for TTS.

Arterial hypertension in patients with takotsubo syndrome: prevalence, long-term outcome, and secondary preventive strategies: a report from the Takotsubo Italian Network register.

AIMS: The aim of this study was to investigate the long-term outcome of takotsubo syndrome (TTS) patients with and without hypertension (HT) and to evaluate the effectiveness of treatment with beta-blockers (BBs) and/or renin-angiotensin-aldosterone system inhibitors (RAASi). METHODS AND RESULTS: The study population includes a register-based, multicentre cohort of consecutive patients with TTS, divided into two groups according to the history of HT. Further stratification was performed for BB/RAASi prescription at discharge. The primary outcome was the composite of all-cause death and TTS recurrence at the longest available follow-up. The propensity score weighting technique was used to account for potential confounding. In the overall population (903 patients, mean age 70 ± 11 years), HT was reported in 66% of cases. At a median 2-year follow-up, there was no difference in the risk of the primary composite outcome between patients with and without HT. The adjusted Cox regression analysis showed a significantly lower risk for the primary outcome [adjusted hazard ratio (aHR): 0.69; 95% confidence interval (CI): 0.49-0.99] in patients who received BB vs. those who did not. Renin-angiotensin-aldosterone system inhibitors treatment was not associated with the primary study outcome. The lower risk for the primary outcome with BB treatment was confirmed in patients with HT (aHR: 0.37; 95% CI: 0.24-0.56) but not in patients without (aHR: 1.83; 95% CI: 0.92-3.64; Pinteraction < 0.001). CONCLUSION: In this TTS study, HT did not affect the long-term risk of adverse events but increased the probability of benefit from BB treatment after discharge. Owing to the favourable outcome impact of BB prescription in TTS patients with HT, a tailored pharmacological therapy should be considered in this cohort.

Although not associated with clinical outcomes, hypertension (HT) seems to modify the long-term effectiveness of pharmacological treatment in patients with takotsubo syndrome (TTS). Beta-blockers improved the overall survival of TTS patients with HT and should be considered as first-line therapy in this patient population. The effectiveness of renin­angiotensin­aldosterone system inhibitors on long-term outcome was not significant regardless of the history of HT.

Successful treatment of a severe Takotsubo syndrome case complicated by liver abscess.

The main manifestations of Takotsubo syndrome (TTS) are a spherical expansion of the left ventricle or near the apex and decreased systolic function. TTS is mostly thought to be induced by emotional stress, and the induction of TTS by severe infection is not often reported. A 72-year-old female patient with liver abscess reported herein was admitted due to repeated fever with a history of hypertension and impaired glucose tolerance. Her severe infection caused TTS, and her blood pressure dropped to 80/40 mmHg. IABP treatment was performed immediately and continued for 10 days, and comprehensive medication was administered. Based on her disease course and her smooth recovery, general insights and learnings may be: Adding to mental and other pathological stress reaction, serious infections from pathogenic microorganism could be of great important causation of stress reaction leading to TTS, while basic diseases such as coronary heart disease, hypertension, and diabetes were be of promoting factors; In addition to effective drug therapies for TTS, the importance of the timely using of IABP should be emphasized.

Can Breaking Heroin Addiction Lead to a Broken Heart? A Case of Reverse Takotsubo Cardiomyopathy in a Patient With Heroin Withdrawal.

Reverse takotsubo cardiomyopathy is triggered by emotional or physical stress and has a presentation similar to that of acute coronary syndrome. A 39-year-old woman with a history of heroin use disorder presented with intractable nausea, vomiting, and diarrhea. She was diagnosed with heroin withdrawal and started on buprenorphine-naloxone. On day 2 of her hospitalization, she developed chest heaviness and had an elevated troponin I level of 3.2 ng/mL (reference range, 0.015-0.045 ng/mL); electrocardiography showed new T-wave inversions in the anterior and inferior leads. Emergent coronary angiography showed patent coronary arteries, and left ventriculography showed basal hypokinesis and apical hyperkinesis, consistent with reverse takotsubo cardiomyopathy secondary to heroin withdrawal. She was started on antihypertensive agents, and her buprenorphine-naloxone dose was increased. At her 3-month follow-up visit, she reported no symptoms consistent with angina or heart failure. This appears to be the first report of heroin withdrawal causing reverse takotsubo cardiomyopathy. Awareness of this association can lead to earlier recognition and treatment of reverse takotsubo cardiomyopathy.

Can Significant Coronary Artery Disease Coexist With Transient Takotsubo Cardiomyopathy, and How Does Spasm Interrelate?

An 86-year-old woman being treated for metastatic breast cancer developed severe chest pain at rest during a follow-up visit at a hospital's outpatient oncology clinic. An electrocardiogram showed severe ST-segment elevation. The patient was given sublingual nitroglycerin and was transferred to the emergency department. Diagnostic coronary angiography revealed moderate coronary artery disease with calcific stenoses and transient spastic occlusion of the left anterior descending coronary artery. For this patient, sublingual nitroglycerin aborted the spastic event and apparent transient takotsubo cardiomyopathy. Chemotherapy can potentially cause endothelial dysfunction and increased coronary spasticity, which could result in takotsubo cardiomyopathy.

Takotsubo cardiomyopathy with left ventricle thrombus caused by subacute thyroiditis.

We report a rare case of takotsubo cardiomyopathy caused by subacute thyroiditis in a man in his 50s. He went to the doctor with complaints of loss of appetite, diarrhoea, chills and general malaise. He had consciousness disturbance, thyrotoxicosis and thyroid-stimulating hormone (TSH) suppression. Thyroglobulin and C reactive protein levels in the blood were elevated, but TSH receptor antibody, thyroid-stimulating antibody, antithyroglobulin antibody and antithyroid peroxidase antibody were not. We began treatment with prednisolone and propranolol after he was diagnosed with thyroid storm caused by subacute thyroiditis. The ECG revealed inverted T waves on the fifth day after admission. He was newly diagnosed with takotsubo cardiomyopathy on the day. A large thrombus was detected in the left ventricle, requiring anticoagulation therapy. Thus, even if there are no findings of takotsubo cardiomyopathy or thrombus at the onset of thyroid storm, appropriate monitoring is required because they can develop during the treatment course.

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).

Iatrogenic adrenaline induced mid-ventricular Takotsubo cardiomyopathy: a case-based review.

Takotsubo cardiomyopathy (TCM) is regarded as an acute and often reversible cardiac syndrome characterised by apical ballooning of the left ventricle that occurs in the absence of coronary artery obstruction and myocarditis. The underlying pathophysiology remains largely unknown, but the most widely accepted theory is catecholamine toxicity.More recently, atypical variants of TCM have been described, and are characterised by the regional wall motion abnormalities that are observed. Mid-ventricular Takotsubo cardiomyopathy (MVTCM) is characterised by hypokinesia/akinesia of the mid left ventricular wall segments with hyperdynamic basal and apical function. This report describes the first documented case of a patient who developed MVTCM after receiving a dose of intravenous adrenaline. This case provides further evidence to support the notion that catecholamine toxicity is implicated in the pathogenesis of TCM.