Takotsubo syndrome (TTS) is identified as an acute severe ventricular systolic dysfunction, which is usually characterized by reversible and transient akinesia of walls of the ventricle in the ...absence of a significant obstructive coronary artery disease (CAD). Patients present with chest pain, ST-segment elevation or ischemia signs on ECG and increased troponin, similar to myocardial infarction. Currently, the known mechanisms associated with the development of TTS include elevated levels of circulating plasma catecholamines and their metabolites, coronary microvascular dysfunction, sympathetic hyperexcitability, inflammation, estrogen deficiency, spasm of the epicardial coronary vessels, genetic predisposition and thyroidal dysfunction. However, the real etiologic link remains unclear and seems to be multifactorial. Currently, the elusive pathogenesis of TTS and the lack of optimal treatment leads to the necessity of the application of experimental models or platforms for studying TTS. Excessive catecholamines can cause weakened ventricular wall motion at the apex and increased basal motion due to the apicobasal adrenoceptor gradient. The use of beta-blockers does not seem to impact the outcome of TTS patients, suggesting that signaling other than the beta-adrenoceptor-associated pathway is also involved and that the pathogenesis may be more complex than it was expected. Herein, we review the pathophysiological mechanisms related to TTS; preclinical TTS models and platforms such as animal models, human-induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) models and their usefulness for TTS studies, including exploring and improving the understanding of the pathomechanism of the disease. This might be helpful to provide novel insights on the exact pathophysiological mechanisms and may offer more information for experimental and clinical research on TTS.
Severe infections like sepsis lead frequently to cardiomyopathy. The mechanisms are unclear and an optimal therapy for septic cardiomyopathy still lacks. The aim of this study is to establish an ...endotoxin-induced inflammatory model using human induced pluripotent stem cell (hiPSC) derived cardiomyocytes (hiPSC-CMs) for mechanistic and therapeutic studies. hiPSC-CMs were treated by lipopolysaccharide (LPS) in different concentrations for different times. ELISA, FACS, qPCR, and patch-clamp techniques were used for the study. TLR4 (Toll-like receptor 4) and its associated proteins, CD14, LBP (lipopolysaccharide binding protein), TIRAP (toll-interleukin 1 receptor domain containing adaptor protein), Ly96 (lymphocyte antigen 96) and nuclear factor kappa B as well as some pro-and anti-inflammatory factors are expressed in hiPSC-CMs. LPS-treatment for 6 hours increased the expression levels of pro-inflammatory and chemotactic cytokines (TNF-a, IL-1ß, IL-6, CCL2, CCL5, IL-8), whereas 48 hour-treatment elevated the expression of anti-inflammatory factors (IL-10 and IL-6). LPS led to cell injury resulting from exaggerated cell apoptosis and necrosis. Finally, LPS inhibited small conductance Ca
-activated K
channel currents, enhanced Na
/Ca
-exchanger currents, prolonged action potential duration, suggesting cellular electrical dysfunctions. Our data demonstrate that hiPSC-CMs possess the functional reaction system involved in endotoxin-induced inflammation and can model some bacterium-induced inflammatory responses in cardiac myocytes.
In view of low prevalence rates, diabetes is discussed as a protective factor for the occurrence of Takotsubo syndrome (TTS). Furthermore, it was associated with improved outcome in a small ...single-center analysis. Therefore, this study assessed the prevalence and prognostic relevance of concomitant diabetes in TTS.
A total of 826 patients with TTS were enrolled in an international, multicenter, registry-based study (eight centers in Italy and Germany). All-cause mortality was compared between patients with diabetes and patients without diabetes, and the independent predictive value of diabetes was evaluated in multivariate regression analysis.
The prevalence of diabetes was 21.1% (
= 174). TTS patients with diabetes were older (
< 0.001), were more frequently male (
= 0.003), had a higher prevalence of hypertension (
< 0.001), physical triggers (
= 0.041), and typical apical ballooning (
= 0.010), had a lower left ventricular ejection fraction (
= 0.008), had a higher rate of pulmonary edema (
= 0.032), and had a longer hospital stay (
= 0.009). However, 28-day all-cause mortality did not differ between patients with diabetes and patients without diabetes (6.4% vs. 5.7%; hazard ratio HR 1.11 95% CI 0.55-2.25;
= 0.772). Longer-term follow-up after a median of 2.5 years revealed a significantly higher mortality among TTS patients with diabetes (31.4% vs. 16.5%;
< 0.001), and multivariate regression analysis identified diabetes as an independent predictor of adverse outcome (HR 1.66 95% CI 1.16-2.39;
= 0.006).
Diabetes is not uncommon in patients with TTS, is associated with increased longer-term mortality rates, and is an independent predictor of adverse outcome irrespective of additional risk factors.
Brugada syndrome (BrS) is an inherited and rare cardiac arrhythmogenic disease associated with an increased risk of ventricular fibrillation and sudden cardiac death. Different genes have been linked ...to BrS. The majority of mutations are located in the
gene, and the typical abnormal ECG is an elevation of the ST segment in the right precordial leads V1 to V3. The pathophysiological mechanisms of BrS were studied in different models, including animal models, heterologous expression systems, and human-induced pluripotent stem cell-derived cardiomyocyte models. Currently, only a few BrS studies have used human-induced pluripotent stem cell-derived cardiomyocytes, most of which have focused on genotype-phenotype correlations and drug screening. The combination of new technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 (CRISPR associated protein 9)-mediated genome editing and 3-dimensional engineered heart tissues, has provided novel insights into the pathophysiological mechanisms of the disease and could offer opportunities to improve the diagnosis and treatment of patients with BrS. This review aimed to compare different models of BrS for a better understanding of the roles of human-induced pluripotent stem cell-derived cardiomyocytes in current BrS research and personalized medicine at a later stage.
Background Current literature only reports variable information from single-center studies on the recurrence rate, the complications, and the outcome of patients with Takotsubo syndrome ( TTS) ...experiencing recurrent TTS . Therefore, a detailed description of clinical characteristics, predictors, and the prognostic impact of patients with TTS and recurrences in a multicenter registry is needed. Methods and Results We analyzed 749 patients with TTS from 9 European centers being part of the international, multicenter GEIST (German Italian Stress Cardiomyopathy) Registry. Patients were divided into the recurrence group and the nonrecurrence group. The recurrence rate at a median follow-up of 830 days (interquartile range, 118-1701 days) was 4%. Most recurrences were documented in the first 5 years after the index TTS episode. Up to 2 TTS recurrences were documented in 2 of 30 patients (6%). A variable ballooning pattern (n=6, 0.8%) with, in particular, involvement of the right ventricular occurred in 3 cases (0.4%) at the recurrence event. Except for the higher presence of arterial hypertension (86.7% versus 68.3%; P=0.03) in the recurrence group, no other baseline characteristics were different between groups. Observation of TTS complications during follow-up, including stroke, thromboembolic events, in-hospital death, and cardiogenic shock, revealed no significant differences between groups ( P>0.05), except the higher presence of pulmonary edema in the recurrence group versus the nonrecurrence group (13.3% versus 4.9%; P=0.04). Conclusions The incidence of TTS recurrence is estimated to be 4% in this multicenter TTS registry. A variable TTS pattern at recurrence is common in up to 20% of recurrence cases.
The development of innovative interventional strategies and materials, primarily attributed to rapid strides in healthcare technology and education, has helped position interventional cardiology as ...one of the foremost disciplines in cardiovascular medicine. Patients diagnosed with inoperable conditions, including complex structural heart disease, have found renewed hope with the practice of these path-breaking therapeutic techniques. Nevertheless, the growing complexity of these procedures has also necessitated a close cooperation with different specialists, such as cardiothoracic surgeons, vascular surgeons, anesthesiologists, and interventional radiologists. There is an urgent need to further explore the use of such alternative strategies of clinical management of cardiac disease, while limiting or potentially eliminating any procedural risks for the patient. This book is oriented to readers interested in learning the basic principles of interventional cardiology and offers a brief insight into the potential use of such treatments in routine clinical practice.
An increase in post-COVID patients with late sequelae of acute COVID-19 infection is emerging as an ongoing challenge for physicians and healthcare professionals. Since the beginning of the pandemic, ...it has rapidly become evident that the acute infection is not limited to the respiratory tract but that several organs, including the cardiovascular system, can be affected. Moreover, in a significant proportion of patients (ranging from about 10 to up to 50%) with former COVID-19, cardiopulmonary symptoms such as dyspnea, palpitations, restricted physical capacity, and cardiac arrhythmias can persist weeks and months after the acute SARS-CoV-2 infection. The spectrum of COVID-19-associated arrhythmias is rather wide, most likely due to various pathomechanisms. In this article, the prevalence of cardiac arrhythmias and underlying pathologies are reviewed, including direct myocardial injury and abnormal consequences with an impact on cardiac electric instability. The hyperinflammatory reaction of the host immune system is specifically considered. Moreover, several distinct rhythm disorders occurring in post-COVID patients are discussed with regard to their clinical management.
Abstract
Cardiovascular diseases are the main cause of sudden cardiac death (SCD) in developed and developing countries. Inherited cardiac channelopathies are linked to 5–10% of SCDs, mainly in the ...young. Short QT syndrome (SQTS) is a rare inherited channelopathy, which leads to both atrial and ventricular tachyarrhythmias, syncope, and even SCD. International European Society of Cardiology guidelines include as diagnostic criteria: (i) QTc ≤ 340 ms on electrocardiogram, (ii) QTc ≤ 360 ms plus one of the follwing, an affected short QT syndrome pathogenic gene mutation, or family history of SQTS, or aborted cardiac arrest, or family history of cardiac arrest in the young. However, further evaluation of the QTc ranges seems to be required, which might be possible by assembling large short QT cohorts and considering genetic screening of the newly described pathogenic mutations. Since the mechanisms underlying the arrhythmogenesis of SQTS is unclear, optimal therapy for SQTS is still lacking. The disease is rare, unclear genotype–phenotype correlations exist in a bevy of cases and the absence of an international short QT registry limit studies on the pathophysiological mechanisms of arrhythmogenesis and therapy of SQTS. This leads to the necessity of experimental models or platforms for studying SQTS. Here, we focus on reviewing preclinical SQTS models and platforms such as animal models, heterologous expression systems, human-induced pluripotent stem cell-derived cardiomyocyte models and computer models as well as three-dimensional engineered heart tissues. We discuss their usefulness for SQTS studies to examine genotype–phenotype associations, uncover disease mechanisms and test drugs. These models might be helpful for providing novel insights into the exact pathophysiological mechanisms of this channelopathy and may offer opportunities to improve the diagnosis and treatment of patients with SQT syndrome.
Recent studies have highlighted that takotsubo syndrome (TTS) is associated with a poor clinical outcome. Our study was conducted to determine the short- and long-term prevalence, recurrence rate and ...impact of life-threatening arrhythmias (LTA) on the clinical outcome of TTS.
Our institutional database constituted a collective of 114 patients diagnosed with TTS between 2003 and 2015. The patient groups, divided according to the presence (n = 13, 11.4%) or absence (n = 101, 88.6%) of LTAs, were followed-up over a period of 3 years so as to determine the clinical outcome. Our analyses suggest that patients comprising the LTA group suffered significantly more often from an acute cardiovascular event including cases of a newly diagnosed atrial fibrillation (38.4% vs. 2.9%), cardiogenic shock with use of inotropic agents (53.8% vs. 14.8%) and cardiopulmonary resuscitation (61.5% vs. 1%). The short-term recurrence rate of a LTA episode was 15.3%, while the long-term recurrence rate of any LTA was around 5%. Whereas, in-hospital mortality was significantly higher in TTS associated with LTAs, the overall survival rate over 3 years was similar. A multivariate Cox regression analysis suggested atrial fibrillation, EF ≤ 35%, cardiogenic shock, and glomerular filtration rate <60 mL/min. as independent predictors of adverse outcome.
The short- as well as the long-term prevalence and recurrence of LTAs in TTS patients is high. The long-term mortality rates were similar to the TTS patients presenting without any LTAs. LTAs in TTS could be triggered by a concomitant atrial fibrillation.
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