Twenty-five-year trends in incidence, angiographic appearance, and management of spontaneous coronary artery dissection.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) has been described as an infrequent cause of acute coronary syndrome (ACS). Knowledge about the disease is still limited and SCAD might still be underdiagnosed. OBJECTIVES: Trends in incidence, presentation, angiographic appearance, management, and outcomes of SCAD over 25 years were analyzed. METHODS: Patients with SCAD between 1997 and 2021 at the University Hospital Zurich, Switzerland, were included. Incidences were assessed as total numbers and proportions of ACS cases. Clinical data were collected from medical records and angiographic findings were reviewed. Major adverse cardiac events (MACE) were defined as the composite of all-cause death, cardiac arrest, SCAD recurrence or progression, other myocardial infarction, and stroke. RESULTS: One hundred fifty-six SCAD cases were included in this study. The incidence increased significantly in total (p < 0.001) and relative to ACS cases (p < 0.001). This was based on an increase of shorter lesions (p = 0.004), SCAD type 2 (p < 0.001), and lesions in side branches (p = 0.014), whereas lesions in the left main coronary artery and proximal segments were decreasing (p-values 0.029 and < 0.001, respectively). There was an increase in conservative therapy (p < 0.001). The rate of MACE (24%) was stable, however, there was a reduced proportion of patients with a need for intensive care treatment (p = 0.017). CONCLUSIONS: SCAD represents an important entity of ACS that still might be underappreciated. The increasing incidence of SCAD is likely based on better awareness and familiarity with the disease. A lower need for intensive care treatment suggests positive effects of the increasing implementation of conservative management.

Takotsubo syndrome: getting closer to its causes.

Takotsubo syndrome (TTS) accounts for between 1 and 4% of cases presenting clinically as an acute coronary syndrome. It typically presents as a transient cardiac phenotype of left ventricular dysfunction with spontaneous recovery. More dramatic presentations may include cardiogenic shock or cardiac arrest. Despite progress in the understanding of the condition since its first description in 1990, considerable questions remain into understanding underlying pathomechanisms. In this review article, we describe the current published data on potential underlying mechanisms associated with the onset of TTS including sympathetic nervous system over-stimulation, structural and functional alterations in the central nervous system, catecholamine secretion, alterations in the balance and distribution of adrenergic receptors, the additive impact of hormones including oestrogen, epicardial coronary or microvascular spasm, endothelial dysfunction, and genetics as potentially contributing to the cascade of events leading to the onset. These pathomechanisms provide suggestions for novel potential therapeutic strategies in patients with TTS including the role of cognitive behavioural therapy, beta-blockers, and endothelin-A antagonists. The underlying mechanism of TTS remains elusive. In reality, physical or emotional stressors likely trigger through the amygdala and hippocampus a central neurohumoral activation with the local and systemic secretion of excess catecholamine and other neurohormones, which exert its effect on the myocardium through a metabolic switch, altered cellular signalling, and endothelial dysfunction. These complex pathways exert a regional activation in the myocardium through the altered distribution of adrenoceptors and density of autonomic innervation as a protective mechanism from myocardial apoptosis. More research is needed to understand how these different complex mechanisms interact with each other to bring on the TTS phenotype.

Clinical characteristics and outcomes of patients with takotsubo syndrome versus spontaneous coronary artery dissection.

BACKGROUND: Takotsubo syndrome (TTS) and spontaneous coronary artery dissection (SCAD) are now increasingly recognized. Both conditions predominantly affect females; however, the exact pathophysiology remains unclear. Large multi-center databases can help elucidate the underlying mechanism and optimize treatments to improve outcomes by allowing us to compare features and outcomes of patients with TTS and patients with SCAD. METHODS: Takotsubo syndrome patients were enrolled from the International Takotsubo Registry and compared to SCAD patients from the Canadian Spontaneous Coronary Artery Dissection Cohort Study. In total 2098 TTS patients and 750 SCAD patients were included in the present study. RESULTS: More than 85% of patients in both groups were females. TTS patients were older compared to SCAD patients. Physical triggers were more common in TTS patients, while emotional triggers and non-identifiable triggering events were more common in SCAD patients. Left ventricular ejection fraction was more impaired in TTS compared to SCAD. TTS patients had more major cardiovascular risk factors, while SCAD patients had a higher rate of migraines and anxiety disorders than TTS patients. Thirty-day mortality was significantly higher in TTS patients, while 30-day stroke rates were comparable between groups. CONCLUSIONS: These findings suggest that women are at higher risk for TTS and SCAD compared to men, which should be considered in the differential diagnosis of those presenting with acute coronary syndrome. Additionally, emotional stressors play a significant role in triggering events particularly in younger women suffering from SCAD. The present findings may help clinicians better differentiate these two entities and aid in the appropriate risk stratification, diagnosis, and management. TRIAL REGISTRATION: ClinicalTrials.gov no. NCT01947621.

Psychosocial and clinical characteristics of a patient with Takotsubo syndrome and her healthy monozygotic twin: a case report.

Background: Takotsubo syndrome (TTS) is an acute heart failure syndrome characterized by transient left ventricular dysfunction, increased myocardial biomarkers, and electrocardiographic changes. Symptoms of TTS are similar to those of acute coronary syndromes, but there is often no significant coronary stenosis. Although emotional and physical stressors are often reported as having triggered TTS, the pathogenesis is largely unknown. To address this issue, we comprehensively characterized a monozygous pair of twin sisters, one of whom experienced TTS. Case summary: The 60-year-old Caucasian monozygotic female twins with and without TTS were examined at the University Hospital Zurich in Switzerland. The twins completed questionnaires and clinical interviews assessing several sociopsychological factors. The twin sister with TTS exhibited higher levels of anxiety, vital exhaustion, social inhibition, and alexithymia, and lower levels of quality of and meaning in life. She was given the diagnoses of social phobia, adjustment disorder, specific anxiety disorder, obsessive-compulsive personality disorder, and an accentuated anxiety-avoidant personality disorder. Additionally, the twin with TTS experienced more-and also more severe-stressors involving life-threatening and dangerous situations over the life course. Discussion: These monozygous female twins with and without TTS differed in several notable aspects of their psychological functioning, psychiatric status, personality, and lifetime stressor exposure. The results thus highlight several factors, besides genetic components, that may play an important role in the pathogenesis of TTS. Looking forward, larger studies using experimental and longitudinal designs are needed to elucidate the role that psychosocial factors play in TTS.

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.

Spontaneous Coronary Artery Dissection: A Rare Event?

Spontaneous coronary artery dissection is an infrequent cause of acute coronary syndrome with comparable clinical features. Previously considered a rare disease, recent scientific interest has revealed spontaneous coronary artery dissection as an important differential diagnosis of acute coronary syndrome, especially in young women, during pregnancy or postpartum, and in patients with fibromuscular dysplasia or other arteriopathies. However, there remain many uncertainties regarding pathophysiology, risk factors, acute treatment, and optimal long-term management. The aim of this review is to summarize current scientific evidence on epidemiology, management, and outcomes.

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.

Clinical correlates and prognostic impact of neurologic disorders in Takotsubo syndrome.

Cardiac alterations are frequently observed after acute neurological disorders. Takotsubo syndrome (TTS) represents an acute heart failure syndrome and is increasingly recognized as part of the spectrum of cardiac complications observed after neurological disorders. A systematic investigation of TTS patients with neurological disorders has not been conducted yet. The aim of the study was to expand insights regarding neurological disease entities triggering TTS and to investigate the clinical profile and outcomes of TTS patients after primary neurological disorders. The International Takotsubo Registry is an observational multicenter collaborative effort of 45 centers in 14 countries (ClinicalTrials.gov, identifier NCT01947621). All patients in the registry fulfilled International Takotsubo Diagnostic Criteria. For the present study, patients were included if complete information on acute neurological disorders were available. 2402 patients in whom complete information on acute neurological status were available were analyzed. In 161 patients (6.7%) an acute neurological disorder was identified as the preceding triggering factor. The most common neurological disorders were seizures, intracranial hemorrhage, and ischemic stroke. Time from neurological symptoms to TTS diagnosis was ≤ 2 days in 87.3% of cases. TTS patients with neurological disorders were younger, had a lower female predominance, fewer cardiac symptoms, lower left ventricular ejection fraction, and higher levels of cardiac biomarkers. TTS patients with neurological disorders had a 3.2-fold increased odds of in-hospital mortality compared to TTS patients without neurological disorders. In this large-scale study, 1 out of 15 TTS patients had an acute neurological condition as the underlying triggering factor. Our data emphasize that a wide spectrum of neurological diseases ranging from benign to life-threatening encompass TTS. The high rates of adverse events highlight the need for clinical awareness.

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.

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.

Prognostic value of texture analysis from cardiac magnetic resonance imaging in patients with Takotsubo syndrome: a machine learning based proof-of-principle approach.

Cardiac magnetic resonance (CMR) imaging has become an important technique for non-invasive diagnosis of takotsubo syndrome (TTS). The long-term prognostic value of CMR imaging in TTS has not been fully elucidated yet. This study sought to evaluate the prognostic value of texture analysis (TA) based on CMR images in patients with TTS using machine learning. In this multicenter study (InterTAK Registry), we investigated CMR imaging data of 58 patients (56 women, mean age 68 ± 12 years) with TTS. CMR imaging was performed in the acute to subacute phase (median time after symptom onset 4 days) of TTS. TA of the left ventricle was performed using free-hand regions-of-interest in short axis late gadolinium-enhanced and on T2-weighted (T2w) images. A total of 608 TA features adding the parameters age, gender, and body mass index were included. Dimension reduction was performed removing TA features with poor intra-class correlation coefficients (ICC ≤ 0.6) and those being redundant (correlation matrix with Pearson correlation coefficient r > 0.8). Five common machine-learning classifiers (artificial neural network Multilayer Perceptron, decision tree J48, NaïveBayes, RandomForest, and Sequential Minimal Optimization) with tenfold cross-validation were applied to assess 5-year outcome including major adverse cardiac and cerebrovascular events (MACCE). Dimension reduction yielded 10 TA features carrying prognostic information, which were all based on T2w images. The NaïveBayes machine learning classifier showed overall best performance with a sensitivity of 82.9% (confidence interval (CI) 80-86.2), specificity of 83.7% (CI 75.7-92), and an area-under-the receiver operating characteristics curve of 0.88 (CI 0.83-0.92). This proof-of-principle study is the first to identify unique T2w-derived TA features that predict long-term outcome in patients with TTS. These features might serve as imaging prognostic biomarkers in TTS patients.

Correction to: Multimodality imaging in takotsubo syndrome: a joint consensus document of the European Association of Cardiovascular Imaging (EACVI) and the Japanese Society of Echocardiography (JSE).

In the original publication of the article, the first and the second authors' names should be changed as follows.

Multimodality imaging in takotsubo syndrome: a joint consensus document of the European Association of Cardiovascular Imaging (EACVI) and the Japanese Society of Echocardiography (JSE).

Takotsubo syndrome (TTS) is a complex and still poorly recognized heart disease with a wide spectrum of possible clinical presentations. Despite its reversibility, it is associated with serious adverse in-hospital events and high complication rates during follow-up. Multimodality imaging is helpful for establishing the diagnosis, guiding therapy, and stratifying prognosis of TTS patients in both the acute and post-acute phase. Echocardiography plays a key role, particularly in the acute care setting, allowing for the assessment of left ventricular (LV) systolic and diastolic function and the identification of the typical apical-midventricular ballooning pattern, as well as the circumferential pattern of wall motion abnormalities. It is also useful in the early detection of complications (i.e. LV outflow tract obstruction, mitral regurgitation, right ventricular involvement, LV thrombi, and pericardial effusion) and monitoring of systolic function recovery. Left ventriculography allows the evaluation of LV function and morphology, identifying the typical TTS patterns when echocardiography is not available or wall motion abnormalities cannot be properly assessed with ultrasound. Cardiac magnetic resonance provides a more comprehensive depiction of cardiac morphology and function and tissue characterization and offers additional value to other imaging modalities for differential diagnosis (myocardial infarction and myocarditis). Coronary computed tomography angiography has a substantial role in the diagnostic workup of patients with acute chest pain and a doubtful TTS diagnosis to rule out other medical conditions. It can be considered as a non-invasive appropriate alternative to coronary angiography in several clinical scenarios. Although the role of nuclear imaging in TTS has not yet been well established, the combination of perfusion and metabolic imaging may provide useful information on myocardial function in both the acute and post-acute phase.

Multimodality imaging in takotsubo syndrome: a joint consensus document of the European Association of Cardiovascular Imaging (EACVI) and the Japanese Society of Echocardiography (JSE).

Takotsubo syndrome (TTS) is a complex and still poorly recognized heart disease with a wide spectrum of possible clinical presentations. Despite its reversibility, it is associated with serious adverse in-hospital events and high complication rates during follow-up. Multimodality imaging is helpful for establishing the diagnosis, guiding therapy, and stratifying prognosis of TTS patients in both the acute and post-acute phase. Echocardiography plays a key role, particularly in the acute care setting, allowing for the assessment of left ventricular (LV) systolic and diastolic function and the identification of the typical apical-midventricular ballooning pattern, as well as the circumferential pattern of wall motion abnormalities. It is also useful in the early detection of complications (i.e. LV outflow tract obstruction, mitral regurgitation, right ventricular involvement, LV thrombi, and pericardial effusion) and monitoring of systolic function recovery. Left ventriculography allows the evaluation of LV function and morphology, identifying the typical TTS patterns when echocardiography is not available or wall motion abnormalities cannot be properly assessed with ultrasound. Cardiac magnetic resonance provides a more comprehensive depiction of cardiac morphology and function and tissue characterization and offers additional value to other imaging modalities for differential diagnosis (myocardial infarction and myocarditis). Coronary computed tomography angiography has a substantial role in the diagnostic workup of patients with acute chest pain and a doubtful TTS diagnosis to rule out other medical conditions. It can be considered as a non-invasive appropriate alternative to coronary angiography in several clinical scenarios. Although the role of nuclear imaging in TTS has not yet been well established, the combination of perfusion and metabolic imaging may provide useful information on myocardial function in both the acute and post-acute phase.

Diagnostic criteria for left ventricular non-compaction in cardiac computed tomography.

PURPOSE: Left ventricular non-compaction (LVNC) is characterized by a 2-layered myocardium composed of a noncompacted (NC) and a compacted (C) layer. The echocardiographic NC:C ratio is difficult to assess in many patients. The aim of the study was to assess the value of cardiac computed tomography (CCT) for the diagnosis of LVNC. METHODS: In this prospective controlled study, segmental analysis of transthoracic echocardiography (TTE) and prospective ECG-triggered CCT was performed in 17 patients with LVNC and 19 healthy controls. In TTE maximal NC and C thickness was measured at enddiastole and endsystole in the segment with most prominent trabeculation in short axis views. In CCT, maximal segmental NC and C thickness was measured during diastole, and NC:C ratio was determined. Spearman's correlation coefficient and receiver operating characteristic curves were calculated. RESULTS: The median [IQR] radiation dose was 1.3[1.2-1.5]mSv. The CCT thickness of the C layer was significantly lower in patients with LVNC as compared to controls in the inferolateral, midventricular, lateral-, inferior-, and septal-apical segments. The CCT NC:C ratio differed significantly between LVNC and controls in the inferior-midventricular and all the apical segments. NC:C ratio correlated significantly between TTE and CCT at enddiastole (σ = 0.8) and endsystole (σ = 0.9). Using a CCT NC:C ratio ≥1.8, all LVNC patients could be identified. CONCLUSION: LVNC can be diagnosed with ECG-triggered low-dose CCT and discriminated from normal individuals using a NC:C ratio of ≥1.8 in diastole. There is a very good correlation of NC:C ratio in TTE and CCT.

Generation of iPSC-lines from two independent Takotsubo syndrome patients with recurrent Takotsubo events.

The Takotsubo syndrome (TTS) is characterized by acute transient left ventricular dysfunction in the absence of obstructive coronary lesions. An enhanced ß-adrenergic signaling and higher sensitivity to catecholamine-induced-toxicity were identified as mechanisms associated with TTS. It is still elusive, whether TTS patients with recurrent events show similar underlying signaling pathomechanism. Induced pluripotent stem cell (iPSC)-lines were generated from skin fibroblasts of two independent female Takotsubo syndrome patients with a severe phenotype characterized by recurrent TTS events. For reprogramming, a non-integrative plasmid technique was used. All generated iPSCs maintained full pluripotency, genomic integrity, and spontaneous in vitro and in vivo differentiation capacity.