Left Ventricular Thrombi and Embolic Events in Takotsubo Syndrome despite Therapeutic Anticoagulation.

INTRODUCTION: Takotsubo syndrome (TTS) may be complicated by left-ventricular (LV) thrombus formation in 1.3-5.3% of patients. Risk factors for thrombi comprise apical TTS, elevated levels of C-reactive protein and troponine, thrombocytosis, persisting ST segment elevation and right-ventricular involvement. Embolic risk appears high, and anticoagulation is recommended. CASE PRESENTATION: We present 3 females, aged 60-82 years, with TTS-associated LV thrombi and cerebral embolism despite therapeutic anticoagulation. Two patients showed apical and 1 patient midventricular ballooning. In 2 patients LV thrombi had not been present at the first echocardiographic examination. LV thrombi were multiple and highly mobile in 2 patients; 1 patient had a single immobile thrombus associated with spontaneous echocardiographic contrast (SEC). In each case, 3 of the described risk factors for LV thrombus formation were identified. The embolic stroke occurred 41-120 h after TTS symptom onset and 21-93 h after the initiation of therapeutic anticoagulation. Two patients were discharged with a neurological deficit, and 1 of them eventually died as a consequence of the stroke. LV thrombectomy to prevent embolism, which has been reported in a small number of cases, had not been considered in our patients. CONCLUSION: At present, the management of patients with TTS-related thrombi is still unclear, and further studies are urgently needed to assess the best methods for imaging and anticoagulation and to determine the role of thrombolysis and cardiac surgery. Until these studies are available, we suggest the following approach: patients with a TTS-related thrombus should be monitored by echocardiography while receiving anticoagulation. In case of highly mobile LV thrombi, the heart team may consider cardiac surgery to prevent systemic embolism. The role of SEC in TTS remains to be determined.

Influence of Age and Gender in Takotsubo Syndrome.

Takotsubo syndrome (TTS) occurs predominantly in elderly females but young individuals and children may also be affected. There are no consistent differences between men and women regarding age, symptoms, prehospital delay, or clinical course. Mortality has been reported to be higher in males. The QTc interval may be disproportionately prolonged in male patients in the days after admission predisposing them to ventricular arrhythmias. The higher level of cardiac markers in males with TTS may be related to the greater frequency of physical stress before the onset of TTS. Understanding the pathogenetic background may lead to preventive/therapeutic means against this life-threatening disease.

Interactions between antiepileptic drugs and direct oral anticoagulants for primary and secondary stroke prevention.

INTRODUCTION: Direct oral anticoagulants (DOAC) are the guideline-recommended therapy for prevention of stroke in atrial fibrillation (AF) and venous thromboembolism. Since approximately 10% of patients using antiepileptic drugs (AED) also receive DOAC, aim of this review is to summarize data about drug-drug interactions (DDI) of DOAC with AED by using data from PubMed until December 2023. AREAS COVERED: Of 49 AED, only 16 have been investigated regarding DDI with DOAC by case reports or observational studies. No increased risk for stroke was reported only for topiramate, zonisamide, pregabalin, and gabapentin, whereas for the remaining 12 AED conflicting results regarding the risk for stroke and bleeding were found. Further 16 AED have the potential for pharmacodynamic or pharmacokinetic DDI, but no data regarding DOAC are available. For the remaining 17 AED it is unknown if they have DDI with DOAC. EXPERT OPINION: Knowledge about pharmacokinetic and pharmacodynamic DDI of AED and DOAC is limited and frequently restricted to in vitro and in vivo findings. Since no data about DDI with DOAC are available for 67% of AED and an increasing number of patients have a combined medication of DOAC and AED, there is an urgent need for research on this topic.

Gender-related differences in takotsubo cardiomyopathy.

Takotsubo cardiomyopathy (TTC) predominantly occurs in elderly women. Men comprise 10% of the patients, with a similar clinical profile. In contrast to myocardial infarction, age distribution; symptoms, such as angina; and prehospital delay in TTC are not different between genders. In men, physical stress as a triggering event and shock or cardiac arrest on presentation are more frequent. Gender-related differences in TTC need to be carefully investigated at the clinical and experimental levels to explain the evident gender discrepancy in the prevalence of TTC, to clarify the pathogenetic background, and to develop preventive and therapeutic means against this life-threatening disease.

Role of cardiovascular magnetic resonance in takotsubo cardiomyopathy.

Cardiac MRI (CMR) has become an important tool in the diagnosis of cardiomyopathies. CMR is a unique tool for further evaluating and characterizing patients with takotsubo cardiomyopathy (TTC) and studying the underlying causes and pathophysiologic mechanisms of TTC. Using CMR, regional wall motion abnormalities, right ventricular involvement, intraventricular thrombi, and reversible myocardial injury (inflammation or ischemic edema) or irreversible myocardial injury (necrosis or fibrosis) can be detected in patients presenting with TTC. CMR imaging can distinguish between acute myocardial infarction and TTC.

Drug-drug interactions with direct oral anticoagulants for the prevention of ischemic stroke and embolism in atrial fibrillation: a narrative review of adverse events.

INTRODUCTION: In randomized trials, direct oral anticoagulants (DOAC) were non-inferior to the vitamin-K-antagonist (VKA) warfarin in preventing stroke/embolism in patients with atrial fibrillation (AF). DOAC are substrates for P-glycoprotein (P-gp), CYP3A4 and CYP2C9. The activity of these enzymes is modulated by several drugs which might induce pharmacokinetic drug-drug interactions (DDI). Drugs affecting platelet function have the potential for pharmacodynamic DDI of DOAC. AREAS COVERED: The literature was searched for: 'dabigatran,' 'rivaroxaban,' 'edoxaban,' or 'apixaban' and drugs affecting platelet function, CYP3A4-, CYP2C9- or P-gp-activity. Reports about bleeding and embolic events attributed to DDI with DOAC in AF-patients were found for 43 of 171 drugs with interacting potential (25%), most frequently with antiplatelet and nonsteroidal anti-inflammatory drugs. Whereas a co-medication of platelet-affecting drugs is invariably reported to increase the bleeding risk, the findings regarding P-gp-, CYP3A4- and CYP2C9- activity-affecting drugs are ambiguous. EXPERT OPINION: Tests for plasma DOAC-levels and information about DDI of DOAC should be widely available and user-friendly. If advantages and disadvantages of DOAC and VKA can be investigated exhaustively, individualized anticoagulant therapy can be offered to patients, considering co-medication, comorbidities, genetic and geographic factors and the health care system.

Stroke prevention in an octogenarian with atrial fibrillation, cerebral amyloid angiopathy and intracerebral hemorrhage.

Left-atrial-appendage-closure (LAAC) is suggested as alternative to antiplatelet/anticoagulant therapy (AP/AC) for stroke-prevention in patients with cerebral-amyloid-angiopathy (CAA), intracerebral hemorrhage (ICH) and atrial fibrillation (AF). Disadvantages of LAAC are the need for postinterventional AP and impairment of left atrial function, thus promoting heart-failure. Therefore, in an 83-year-old edoxaban-treated AF-patient with ICH and CAA, only antihypertensive therapy with neither AP/AC nor LAAC was recommended. Twenty-seven months without stroke/ICH support this strategy, which needs confirmation by a randomized-trial.

Adverse events and drug-drug interactions of sodium glucose co-transporter 2 inhibitors in patients treated for heart failure.

INTRODUCTION: Sodium glucose co-transporter 2-inhibitors (SGLT2-I), antihyperglycemic agents, are increasingly prescribed in chronic heart failure (CHF). Their risk for drug-drug interactions (DDI) seems low. Safety-data derive mainly from diabetes-patients. This review aims to summarize adverse-events (AE) and DDI of the SGLT2-I dapagliflozin, empagliflozin and sotagliflozin in patients with CHF. AREAS COVERED: Literature-search-terms in PubMed were 'adverse event/drug-drug interaction' and 'heart failure AND 'dapagliflozin' OR 'empagliflozin' OR 'sotagliflozin.'AEreported in randomized controlled trials (RCT) comprisegenitaland urinary-tract infections, hypotension, ketoacidosis, renal impairment, hypoglycemia, limb-amputations, Fournier's gangrene, bone-fractures, hepatopathy, pancreatitis, diarrhea, malignancy and venous thromboembolism. Their incidence is largely unknown, since they were not consistently evaluated in RCT of CHF. Further AE from meta-analyses, pharmacovigilance reports, case-series and case-reports include erythrocytosis, hypertriglyceridemia, myopathy, sarcopenia, skin problems, ventricular tachycardia, and urinary retention. The maximal observation period of RCT in CHF was 26 months.DDI were mainly studied in healthy volunteers for 3-8 days. In CHF or diabetes-patients, DDI were reported with interleukin-17-inhibitors, linezolid, lithium, tacrolimus, valproate, angiotensin-receptor-neprilysin-inhibitors and intravenous iron. EXPERT OPINION: Guidelines recommend treatment with SGLT2-I for CHF but no data on AE during long-term therapy and only little information on DDI are available, which stresses the need for further research. Evidence-based recommendations for ketoacidosis-prevention are desirable.

Pathophysiology of Takotsubo syndrome - a joint scientific statement from the Heart Failure Association Takotsubo Syndrome Study Group and Myocardial Function Working Group of the European Society of Cardiology - Part 2: vascular pathophysiology, gender and sex hormones, genetics, chronic cardiovascular problems and clinical implications.

While the first part of the scientific statement on the pathophysiology of Takotsubo syndrome was focused on catecholamines and the sympathetic nervous system, in the second part we focus on the vascular pathophysiology including coronary and systemic vascular responses, the role of the central and peripheral nervous systems during the acute phase and abnormalities in the subacute phase, the gender differences and integrated effects of sex hormones, genetics of Takotsubo syndrome including insights from microRNA studies and inducible pluripotent stem cell models of Takotsubo syndrome. We then discuss the chronic abnormalities of cardiovascular physiology in survivors, the limitations of current clinical and preclinical studies, the implications of the knowledge of pathophysiology for clinical management and future perspectives and directions of research.

Pathophysiology of Takotsubo syndrome - a joint scientific statement from the Heart Failure Association Takotsubo Syndrome Study Group and Myocardial Function Working Group of the European Society of Cardiology - Part 1: overview and the central role for catecholamines and sympathetic nervous system.

This is the first part of a scientific statement from the Heart Failure Association (HFA) of the European Society of Cardiology focused upon the pathophysiology of Takotsubo syndrome and is complimentary to the previous HFA position statement on Takotsubo syndrome which focused upon clinical management. In part 1 we provide an overview of the pathophysiology of Takotsubo syndrome and fundamental questions to consider. We then review and discuss the central role of catecholamines and the sympathetic nervous system in the pathophysiology, and the direct effects of high surges in catecholamines upon myocardial biology including ß-adrenergic receptor signalling, G-protein coupled receptor kinases, cardiomyocyte calcium physiology, myofilament physiology, cardiomyocyte gene expression, myocardial electrophysiology and arrhythmogenicity, myocardial inflammation, metabolism and energetics. The integrated effects upon ventricular haemodynamics are discussed and integrated into the pathophysiological model.

Effect of music on patients with cardiovascular diseases and during cardiovascular interventions : A systematic review.

BACKGROUND: The therapeutic effects of music have been known for thousands of years. Recently, studies with music interventions in patients with cardiovascular diseases yielded controversial results. The aim of this review is to provide an overview of the effects of receptive music intervention on the cardiovascular system. METHODS: We searched in PubMed, SCOPUS and CENTRAL for publications between January 1980 and May 2018. Primary endpoints were heart rate, heart rate variability and blood pressure. Secondary endpoints comprised respiratory rate, anxiety and pain. The quality of the studies was assessed by using the CONSORT statement and the Cochrane risk of bias assessment tool. A meta-analysis and subgroup analyses concerning music style, gender and region were planned. RESULTS: A total of 29 studies comprising 2579 patients were included and 18 studies with 1758 patients investigated the effect of music on patients undergoing coronary angiography or open heart surgery. Other studies applied music to children with congenital heart diseases, pregnant women with hypertension or patients with unstable angina. Due to high methodological study heterogeneity, a meta-analysis was not performed. The study quality was assessed as medium to low. In ten studies with higher quality comprising 1054 patients, music intervention was not associated with significant changes in the cardiovascular endpoints compared to the control group. The subgroup analyses did not demonstrate any relevant results. CONCLUSION: Currently no definite effect of receptive music intervention on the cardiovascular system can be verified. Further research is needed to assess music as an inexpensive and easy applicable form of therapy.

Pathophysiology of Takotsubo Syndrome: JACC State-of-the-Art Review.

Takotsubo syndrome (TTS) has been a recognized clinical entity for 31 years, since its first description in 1990. TTS is now routinely diagnosed in patients who present with acute chest pain, electrocardiographic changes, troponin elevation, unobstructed coronary arteries, and a typical pattern of circumferential left ventricular wall motion abnormalities that usually involve the apical and midventricular myocardium. Increasing understanding of this intriguing syndrome stems from wider recognition, possible increasing frequency, and a rising number of publications focused on the pathophysiology in clinical and laboratory studies. A comprehensive understanding of TTS pathophysiology and evidence-based treatments are lacking, and specific and effective treatments are urgently required. This paper reviews the pathophysiology of this fascinating syndrome; what is known from both clinical and preclinical studies, including review of the evidence for microvascular dysfunction, myocardial beta-adrenergic signaling, inflammation, and electrophysiology; and where focused research needs to fill gaps in understanding TTS.

Assault-induced Takotsubo cardiomyopathy associated with persisting anterograde amnesia and myopathy.

Takotsubo cardiomyopathy is characterized by transient left ventricular dysfunction, electrocardiographic changes, and minimal release of myocardial enzymes that mimic acute myocardial infarction in patients without coronary artery disease. Takotsubo cardiomyopathy is frequently triggered by emotional or physical stress and occurs primarily in post-menopausal women. The pathomechanism of Takotsubo cardiomyopathy is, so far, unknown. Stress-induced amnesia is probably induced by perturbation of the hippocampal function. Assault-induced Takotsubo cardiomyopathy associated with amnesia has not been reported so far. In a 77-year-old Caucasian female, hospitalized because of confusion, anterograde amnesia, and hypertension after she had been assaulted by a female who sneaked up to her when she was unlocking the door of her apartment, Takotsubo cardiomyopathy was diagnosed based on clinical findings, electrocardiography, echocardiography, and coronary angiography. Follow-up after 8 weeks showed a regression of electrocardiographic and echocardiographic abnormalities; the amnesia for the assault, however, remained unchanged. This case shows that Takotsubo cardiomyopathy may be triggered by emotional stress induced during an assault. Assault-induced stress may not only induce Takotsubo cardiomyopathy but also amnesia for some of the events that occurred during the act.

Reversible myocardial oedema due to acute myocardial infarction as differential diagnosis of cardiac transthyretin amyloidosis.

Using bone-avid radiotracers, cardiac transthyretin (TTR) amyloidosis can be diagnosed by scintigraphy, thus obviating endomyocardial biopsy. Radiotracer accumulation, however, may also be due to other causes. A 68-year-old male with acute myocardial infarction underwent recanalization of the left anterior descending coronary artery (LAD). Postinterventionally, transthoracic echocardiography showed hypokinesia of the septum and anterior wall and a thickened myocardium with granular sparkling appearance. Cardiac amyloidosis was suspected. A 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid whole-body scan 4 days after LAD recanalization showed Perugini 2 myocardial tracer uptake. Monoclonal gammopathy was excluded, and cardiac TTR amyloidosis was diagnosed. Three months later, 99m-Tc-hydroxydiphosphate scan showed no myocardial tracer uptake. Cardiac magnetic resonance imaging revealed late gadolinium enhancement within the LAD supply area. No mutation of the TTR gene was found. Suspicion of amyloidosis should consider not only echocardiography but also history and clinical findings. Myocardial oedema due to reperfusion should be acknowledged as a differential diagnosis for cardiac uptake of bone-avid radiotracers.

A 79-year-old woman with atrial fibrillation and new onset of heart failure.

As an alternative to oral anticoagulation, percutaneous left atrial appendage (LAA) closure is an increasingly performed procedure to prevent arterial embolism in patients with non-valvular atrial fibrillation. Besides procedure-related complications, residual leaks, device-related thrombus formation, and dislocation of the LAA occluder have been observed during follow-up. Heart failure as a consequence of interventional LAA closure has not been reported so far. This case report describes a 79-year-old lady with permanent non-valvular atrial fibrillation presenting with New York Heart Association Class IV heart failure. Symptoms had started immediately after attempted LAA closure 11 months before. Transoesophageal echocardiography demonstrated two devices in the LAA, a large peri-device leak, a mobile LAA thrombus, a right atrial appendage thrombus, and shunting via a patent foramen ovale. Under a maximally tolerated dose of heart failure medication and edoxaban, the patient remains without bleeding or embolism in New York Heart Association Class II. Because of its unique anatomical and endocrine properties, the LAA plays an important role in situations of pressure and volume overload. Interventional LAA closure interacts unfavourably with left atrial compliance and reservoir function. Atrial and brain natriuretic peptide secretion is known to be significantly reduced after LAA closure. Both mechanisms may result in the development of heart failure. Attempted LAA closure-instead of being the solution-may create new serious problems. Development of heart failure should be assessed, and a systematic search for late leaks after LAA closure should be performed in trials investigating safety and efficacy of this intervention.