Macrophages enhance sodium channel expression in cardiomyocytes.

Cardiac macrophages facilitate electrical conduction through the atrioventricular-node (AV) in mice. A possible role for cardiomyocyte-macrophage coupling on the effect of antiarrhythmic therapy has not been investigated yet. Holter monitoring was conducted in LysMCrexCsf1rLsL-DTR mice (MMDTR) under baseline conditions and after an elctrophysiological stress test by flecainide. In vivo effects were recapitulated in vitro by patch-clamp experiments. The underlying mechanism was characterized by expression and localization analysis of connexin43 (Cx43) and voltage-gated-sodium-channel-5 (Nav1.5). ECG monitoring in MMDTR mice did not show any significant conduction abnormalities but a significantly attenuated flecainide-induced extension of RR- and PP-intervals. Patch-clamp analysis revealed that the application of flecainide to neonatal rat ventricular cardiomyocytes (CMs) changed their resting-membrane-potential (RMP) to more negative potentials and decreased action-potential-duration (APD50). Coupling of macrophages to CMs significantly enhances the effects of flecainide, with a further reduction of the RMP and APD50, mediated by an upregulation of Cx43 and Nav1.5 surface expression. Macrophage depletion in mice does not correlate with cardiac electric conduction delay. Cardiac macrophages amplify the effects of flecainide on electrophysiological properties of cardiomyocytes in vivo and in vitro. Mechanistically, formation of macrophage-cardiomyocyte cell-cell-contacts via Cx43 facilitates the recruitment of Nav1.5 to the cell membrane increasing flecainide effects.

[Morphological and functional diagnostics of coronary artery disease by computed tomography]. / Morphologische und funktionelle Diagnostik der koronaren Herzkrankheit mittels Computertomographie.

Computed tomography coronary angiography (cCTA) is a safe option for the noninvasive exclusion of significant coronary stenoses in patients with a low or moderate pretest probability for coronary artery disease (CAD). Furthermore, it also allows functional and morphological assessment of coronary stenoses. The European Society of Cardiology (ESC) guidelines on the diagnosis and management of chronic coronary syndrome published in 2019 have strengthened the importance of cCTA in this context and for this reason it has experienced a considerable upgrade. The determination of the Agatston score is a clinically established method for quantifying coronary calcification and influences the initiation of drug treatment. With technologies, such as the introduction of electrocardiography (ECG)-controlled dose modulation and iterative image reconstruction, cCTA can be performed with high image quality and low radiation exposure. Anatomic imaging of coronary stenoses alone is currently being augmented by innovative techniques, such as myocardial CT perfusion imaging or CT-fractional flow reserve (FFR) but the clinical value of these methods merits further investigation. The cCTA could therefore develop into a gatekeeper with respect to the indications for invasive coronary diagnostics and interventions.

Recurrence of atrial fibrillation after pulmonary vein isolation in dependence of arterial stiffness.

BACKGROUND: Arterial stiffness (AS) has emerged as a strong predictor of cardiovascular (CV) diseases. Although increased AS has been described as a predictor of atrial fibrillation (AF), its role as a risk marker for AF recurrence has not yet been elucidated. METHODS: Patients with AF who underwent pulmonary vein isolation (PVI) were included in this study. Presence of AS was evaluated by measuring aortic distensibility (AD) of the descending aorta by transoesophageal echocardiography. RESULTS: In total, 151 patients (mean ± standard deviation (SD) age 71.9 ± 9.8 years) were enrolled and followed for a median duration of 21 months (interquartile range 15.0-31.0). During follow-up, AF recurred in 94 (62.3%) patients. AF recurrence was seen more frequently in patients with permanent AF (27% vs 46%, p = 0.03) and in those who had undergone prior PVI (9% vs 23%, p = 0.02). AD was significantly reduced in patients with AF recurrence (mean ± SD 2.6 ± 2.3 vs 1.5 ± 0.7â€¯× 10-3 mm Hg-1, p < 0.0001), as well as left atrial volume index (LAVI) (mean ± SD 29 ± 12 vs 44 ± 15 ml/m2, p < 0.0001). Multivariable analysis revealed LAVI (odds ratio (OR) 2.9, 95% confidence interval (CI) 1.2-3.4) and AS (OR 3.6, 95% CI 2.8-4.1) as independent risk factors of AF recurrence. CONCLUSION: Increased AS and left atrial size were independent predictors of AF recurrence after PVI. AD as surrogate marker of AS seemed to reflect the overall CV risk. In addition, AD was significantly correlated with left atrial size, which suggests that increased AS leads to atrial remodelling and thus to AF recurrence. TRIAL REGISTRATION: German registry for clinical studies (DRKS), DRKS00019007.

Abnormal thyroid function is common in takotsubo syndrome and depends on two distinct mechanisms: results of a multicentre observational study.

BACKGROUND: Several reports have described Takotsubo syndrome (TTS) secondary to thyrotoxicosis. A complex interaction of central and peripheral catecholamines with thyroid homeostasis has been suggested. In this study, we analysed sequential thyroid hormone profiles during the acute phase of TTS. METHODS: Thyrotropin (TSH), free T4 (FT4) and free T3 (FT3) concentrations were analysed at predefined time points in 32 patients presenting with TTS or acute coronary syndrome (ACS, n = 16 in each group) in a 2-year period in two German university hospitals. Data were compared to age- and sex-matched controls (10 samples, each of 16 subjects), and an unsupervised machine learning (ML) algorithm identified patterns in the hormone signature. Subjects with thyroid disease and patients receiving amiodarone were excluded from follow-up. RESULTS: Among patients with TTS, FT4 concentrations were significantly higher when compared to controls or ACS. Four subjects (25%) suffered from subclinical or overt thyrotoxicosis. Two additional patients developed subclinical or overt thyrotoxicosis during stay in hospital. In four subjects (25%), FT4 concentrations were increased, despite nonsuppressed TSH concentration, representing an elevated set point of thyroid homeostasis. The thyroid hormone profile was normal in only six patients (38%) presenting with TTS. CONCLUSION: Abnormal thyroid function is frequent in patients with TTS. Primary hyperthyroidism and an elevated set point of thyroid homeostasis are common in TTS, suggesting a stress-dependent endocrine response or type 2 thyroid allostasis. Thyroid function may be a worthwhile target in treating or preventing TTS.

[Troponin elevation in acute ischemic stroke-unspecific or acute myocardial infarction? : Diagnostics and clinical implications]. / Troponinerhöhung beim akuten ischämischen Schlaganfall ­ unspezifisch oder Ausdruck eines akuten Myokardinfarkts? : Diagnostik und klinische Implikationen.

Routine determination of troponin levels is recommended for all patients with acute ischemic stroke. In 20-55% of these patients the troponin levels are elevated, which may be caused by ischemic as well as non-ischemic myocardial damage and particularly neurocardiogenic myocardial damage. In patients with acute ischemic stroke, the prevalence of previously unknown coronary heart disease is reported to be up to 27% and is prognostically relevant for these patients; however, relevant coronary stenoses are less frequently detected in stroke patients with troponin elevation compared to patients with non-ST elevation myocardial infarction. The risk of secondary intracerebral hemorrhage due to the necessity for dual platelet aggregation inhibition illustrates the challenging indication for invasive coronary diagnostics and revascularization. Therefore, a diagnostic work-up and interdisciplinary risk evaluation appropriate to the urgency are necessary in order to be able to determine a reasonable treatment approach with timing of the intervention, type and duration of blood thinning. In addition to conventional examination methods, multimodal cardiac imaging is increasingly used for this purpose. This review article aims to provide a pragmatic and clinically oriented approach to diagnostic and therapeutic procedures, taking into account the available evidence.

[ARENA-Project atrial fibrillation in the Rhein-Neckar region]. / ARENA ­ Projekt Vorhofflimmern in der Rhein-Neckar-Region.

Atrial fibrillation (AF) is the most common form of cardiac tachyarrhythmia. It is estimated that in the Rhein-Neckar region approximately 40,000-50,000 out of 2 million people are affected. Due to demographic changes in the near future there will be a significant increase in the prevalence of AF within the next decades. The ARENA project was initiated by the Foundation Institute for Cardiac Infarction Research (IHF) Ludwigshafen in cooperation with cardiological and neurological departments of neighboring hospitals, resident doctors and pharmacies to improve the awareness and care of patients with AF. The particular aim is the prevention of stroke as one of the most dreaded complications. The project focusses on the following three subtopics: interventions, medication, migration. The aim of the intervention project is to raise awareness of AF as a risk factor for stroke and to improve the diagnostic work-up and care for patients with diagnosed or unknown AF. The subproject medication focusses on the adherence of patients with AF to the prescribed antithrombotic medication. To evaluate differences concerning patients with and without a migration background the subproject migration was initiated.

Correction to: Occlusion of left atrial appendage affects metabolomic profile: focus on glycolysis, tricarboxylic acid and urea metabolism.

The article Occlusion of left atrial appendage aff ects metabolomic profile:focus on glycolysis, tricarboxylic acid and urea metabolism, written by K. Sattler, M. Behnes, C. Barth, A. Wenke, B. Sartorius, I. El-Battrawy, K. Mashayekhi, J. Kuschyk, U. Hoffmann, T. Papavasiliu, C. Fastner, S. Baumann, S. Lang, X. Zhou, G. Yücel, M. BorggrefeI, Akin, was originally published Online First without open access.

[Instantaneous wave-free ratio (iFR®) in patients with coronary artery disease]. / "Instantaneous wave-free ratio" (iFR®) bei Patienten mit koronarer Herzkrankheit.

Coronary angiography is considered as the gold standard in the morphological representation of coronary artery stenosis. Coronary angiography is often performed without preprocedural non-invasive proof of ischemia and the assessment of the severity of a coronary lesion by morphology is very subjective. Thus, invasive fractional flow reserve (FFR) measurement represents the current standard for estimation of the hemodynamic relevance of coronary artery stenosis and facilitates decision making for percutaneous coronary intervention (PCI) and stenting. The FFR-guided revascularization strategy has been classified as a class IA recommendation in the 2014 ESC/EACTS guidelines on myocardial revascularization. Both the DEFER and the FAME studies showed no treatment advantage of hemodynamically irrelevant stenosis. By use of FFR (and targeted interventions), clinical results could be improved as well as the procedure costs were reduced; however, the use in clinical practice is still limited due to the need of adenosine administration and a significant prolongation of the procedure. Instantaneous wave-free ratio (iFR®) is a new innovative approach for the determination of the hemodynamic relevance of coronary stenosis which can be obtained at rest without the use of vasodilators. Regarding periprocedural complications as well as prognosis, iFR® showed non-inferiority compared to FFR in the SWEDEHEART and DEFINE-FLAIR trials.

[Cardiac contractility modulation]. / Kardiale Kontraktilitätsmodulation.

Cardiac contractility modulation (CCM) is a device-based electrical therapy for the additive treatment of chronic drug-refractory heart insufficiency. High-amplitude signals are applied during the absolute refractory period and have been shown to enhance the strength of left ventricular (LV) contraction and improve exercise tolerance and quality of life. The mechanisms of action appear to involve effects on myocardial gene expression and on normalization of key myocardial proteins. So far, more than 3500 CCM devices have been implanted worldwide. For patients with therapy refractory heart insufficiency and narrow QRS complex, CCM is together with baroreceptor activation the only additive electrical therapy which had been approved in Germany. For the first time CCM has been referenced in the current guidelines on cardiac insufficiency. Prognostic data with respect to mortality have been evaluated in case series. Ongoing randomized trials and registries will address these specific endpoints and have to a significant extent already been recently published. A Food and Drug Administration (FDA) approval is expected within the next few months.

[Interaction between heart and brain in sudden cardiac death]. / Interaktion zwischen Herz und Hirn bei plötzlichem Herztod.

The heart and brain are constantly interacting under normal physiological conditions. This interaction is under the control of the autonomic nervous system with parasympathetic and sympathetic nerve fibers including the participating brain structures. Pathological conditions, such as epilepsy and ischemic cerebral stroke influence heart function, especially the frequency and may result in severe arrhythmia. An asymmetric influence of the left and right brain hemispheres on the heart rate is still under debate. Conversely, the influence of the heart in cases of acute cardiac arrest on brain function is equally relevant and a common clinical problem after resuscitation. We review the damaging cascade of global cerebral hypoxia and the value of different diagnostic procedures as well as the ethical problem of the point in time of termination of consciousness and the instruments for estimating the prognosis.

[Coronary artery disease : Interventional and operative therapeutic options after cardiac arrest]. / Koronare Herzerkrankung : Interventionelle und operative Therapiemöglichkeiten nach Herzstillstand.

Coronary artery disease (CAD) represents a common structural cause for developing cardiac arrest in older patients, whereas in young adults cardiac arrest is more often caused by cardiomyopathies and cardiac channelopathies. A structural heart disease is known in almost 50% of patients prior to cardiac arrest. The present review outlines current interventional and operative therapeutic options for patients surviving cardiac arrest. The focus is on associations between epidemiological data on the incidence of malignant arrhythmias causing cardiac arrest depending on the presence or absence of CAD. Furthermore, the potential benefits of an early coronary revascularization as well as of a prompt complete coronary revascularization compared to the individual treatment of the so-called culprit lesion only are described. Finally, the advantages of invasive therapies for patients surviving cardiac arrest, such as targeted temperature management and mechanical cardiac assist devices, are elucidated. Cardiac assist devices comprise the use of the intra-aortic balloon pump (IABP) and devices for extracorporeal life support (ECLS) for peripheral and central support of the right and left heart chambers.

[Current impact of cardiac implantable electronic devices]. / Aktueller Stellenwert der Device-Therapie.

Sudden cardiac death and chronic heart failure are among the main contributors to persisting high mortality rates in Germany. In addition to removal of causal factors and guideline-conform pharmacological therapy, therapy with cardiac implantable electronic devices (CIED) is of undisputed importance. Subcutaneous defibrillators have the advantage that they do not have intracardiac electrodes but still have the same efficacy and safety. For patients with a wide QRS complex and reduced ejection fraction, cardiac resynchronization has led to a reduction of morbidity and mortality. For patients with a normal QRS complex, cardiac contractility modulation had been shown to improve the quality of life, exercise capacity and left ventricular function. As a procedure for autonomic modulation in patients with reduced cardiac strength, the data for baroreceptor stimulation are the most convincing.

[Sudden cardiac death : Epidemiology, pathophysiology and risk stratification]. / Plötzlicher Herztod : Epidemiologie, Pathophysiologie und Risikostratifizierung.

Sudden cardiac death (SCD) remains a major public health burden despite revolutionary progress in the last three decades in the treatment of ventricular tachyarrhythmia with the use of implantable cardioverter defibrillator (ICD) therapy. Survivors of sudden cardiac arrest are at high risk for recurrent tachyarrhythmia events. Early recognition of low left ventricular ejection fractions (≤35%) as a strong predictor of mortality and the causal association between ventricular tachyarrhythmia and SCD has led to a significant development of not only pharmacological antiarrhythmic therapy but also device-based prevention of SCD. The ICD therapy is nowadays routinely used for primary prevention of SCD in patients with significant structural cardiomyopathy and primary electrical arrhythmia syndromes, which are associated with high a risk and secondary prevention in survivors of sudden cardiac arrest. Additionally, effective approaches exist to significantly reduce the recurrence rate of ventricular tachyarrhythmia of various origins by complex electrophysiological endocardial and epicardial catheter ablation procedures.

[Computed tomography in patients with chronic stable angina : Fractional flow reserve measurement]. / Computertomographie bei Patienten mit stabiler Angina Pectoris : Messung der fraktionellen Flussreserve.

Coronary computed tomography angiography (cCTA) has been established for the non-invasive diagnosis of coronary artery disease (CAD). Previous studies demonstrated the high diagnostic accuracy of cCTA, particularly for ruling out CAD. As a known limitation of cCTA a large number of visually significant coronary stenoses are found to be hemodynamically not relevant by invasive fractional flow reserve (FFR). CT-based FFR (CT-FFR) builds on recent advances in computational fluid dynamics and image simulation techniques. Along with CT myocardial perfusion imaging, CT-FFR is a promising approach towards a more accurate estimation of the hemodynamic relevance of coronary artery stenoses. CT-FFR is derived from regular CT datasets without additional image acquisitions, contrast material, or medication. Two CT-FFR techniques can be differentiated. The initial method requires external use of supercomputers and has gained approval for clinical use in the USA. Furthermore, a prototype-software has been introduced which is less computationally demanding via integration of reduced-order models for on-site calculation of CT-FFR. The present article reviews these methods in the context of available study results and meta-analyses. Furthermore, limitations and future concepts of CT-FFR are discussed.

[Dyspnea and skin rash in a 49-year-old male patient]. / Dyspnoe und Hautausschlag bei einem 49-jährigen Patienten.

We report on the case of a 49-year-old man who presented with increasing dyspnea and a skin rash. The community-acquired pneumonia was initially treated with broad spectrum antibiotics. The patient's respiratory condition rapidly worsened and the clinical picture of Waterhouse-Friderichsen syndrome developed with disseminated intravasal coagulopathy and necrosis of the toes. An infection with Capnocytophaga canimorsus, which had been caused by an initially unmentioned dog bite was confirmed. In view of the fulminant course and the high risk of operative treatment of the ubiquitous necroses in all limbs, a joint decision for deescalation of therapy was made together with relatives. The patient died 14 days after admission to hospital.

[Chronic cervical vagal stimulation. Mechanisms of action and clinical relevance for heart failure]. / Chronische zervikale vagale Stimulation. Mechanismen und momentaner klinischer Stellenwert bei der Herzinsuffizienz.

Increased sympathetic nerve activity and reduced vagal activity are associated with increased mortality in patients after myocardial infarction and patients with chronic heart failure; furthermore, vagal withdrawal has been documented to precede acute decompensation. Experimental studies have indicated that increased parasympathetic activity by means of vagal stimulation may reduce mortality in animal models of postinfarction sudden cardiac death and of chronic heart failure. First clinical results have demonstrated that chronic vagus nerve stimulation in heart failure patients with severe systolic dysfunction appears to be safe and tolerable and may improve the quality of life and left ventricular (LV) function. Vagus nerve stimulation gives rise to these potential clinical benefits by multiple mechanisms of action, including reduced heart rate, restoration of heart rate variability and baroreflex sensitivity, suppression of proinflammatory cytokines and antiarrhythmic effects. First clinical results suggest that vagal nerve stimulation is safe and tolerable and could lead to a marked clinical improvement but discrepancies in the findings due to different study designs warrant further discussion.

[Subcutaneous cervical and left thoracic emphysema in a 49-year-old woman on ventilation]. / Zervikales und linksthorakales Weichteilemphysem bei einer 49-jährigen beatmeten Patientin.

We report the case of a 49-year-old woman who was admitted with community-acquired pneumonia. The medical state worsened despite administration of antibiotics. She was intubated and ventilated because of respiratory distress. Several hours after intubation, she developed massive subcutaneous emphysema. The bronchoscopy showed tracheal transmural rupture 3 cm long on the posterior wall of the trachea. The high-risk surgery and massive doses of catecholamine favoured conservative treatment with bilateral endobronchial intubation and veno-venous extracorporeal membrane oxygenation. The patient made a full recovery.

Effects of adenoid/tonsillectomy on inflammatory response in snoring children with witnessed apnoea.

OBJECTIVE: The aim of this study was to investigate the clinical significance of preoperative serum C-reactive protein (CRP), interleukin-6 (IL-6), fetuin-A, cystatin C, adiponectin and tumour necrosis factor-alpha (TNF-α) levels in children with adenoid/tonsillar hypertrophy and compare these results with postoperative values. STUDY DESIGN: Prospective clinical trial. SETTING: Single tertiary care centre. PARTICIPANTS: Thirty-five children (14 boys and 21 girls) participated in this study. MAIN OUTCOME MEASURES: The operations were performed with the indication of sleep-disordered breathing (SDB). Blood samples were taken preoperatively and at 6 months postoperatively to determine the changes in serum high-sensitivity CRP (hs-CRP), IL-6, fetuin-A, cystatin C, adiponectin and TNF-α levels. Pre- and postoperative values of body weights and heights of the participants were recorded preoperatively and at postoperative 6 months. RESULTS: Patients underwent adenoidectomy (n = 21) or adenotonsillectomy (n = 21). The mean age at surgery was 8.74 ± 3.33 years (range 3-16 years). Mean serum levels of parameters measured preoperatively and at postoperative 6 months. The observed differences between pre- and postoperative values were statistically significant (P < 0.05), excluding cystatin C levels (P > 0.05). CONCLUSION: High levels of IL-6, hs-CRP and TNF-α and low levels of fetuin-A in serum might have a clinical significance in patients with sleep-disordered breathing. Levels of cytokines in children with sleep-disordered breathing because of adenotonsillar disease decreased after surgical treatment. The risks of development of cardiovascular disease are decreased in association with lower levels of cytokines, which are also closely associated with many disease states.

[Severe pain and livid discoloration in the left leg of a 32-year-old patient after intravascular heroin injection]. / Massive Schmerzen und livide Verfärbung des linken Beins nach intravaskulärer Heroininjektion bei einem 32-jährigen Patienten.

Acute leg ischemia after intra-arterial drug injection represents a critical vascular emergency scenario. Due to lack of evidence-based standards therapeutic strategies are oriented to the underlying pathomechanisms. For a sufficient therapy a close clinical monitoring and laboratory analyses as well as treatment with analgesics, anticoagulants, anti-inflammatory and spasmolytic agents are of utmost importance. This article reports on the diagnostic and therapeutic approaches in a 32-year-old patient with acute leg ischemia after intra-arterial administration of heroin and secondary infection with Peptostreptococcus and Peptoniphilus species.

Exploring PKG signaling as a therapeutic avenue for pressure overload, ischemia, and HFpEF.

INTRODUCTION: Heart failure (HF) is a complex and heterogeneous syndrome resulting from any diastolic or systolic dysfunction of the cardiac muscle. In addition to comorbid conditions, pressure overload, and myocardial ischemia are associated with cardiac remodeling which manifests as extracellular matrix (ECM) perturbations, impaired cellular responses, and subsequent ventricular dysfunction. AREAS COVERED: The current review discusses the main aspects of the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway (cGMP-PKG) pathway modulators and highlights the promising outcomes of its novel pharmacological boosters. EXPERT OPINION: Among several signaling pathways involved in the pathogenesis of pressure overload, ischemia and HF with preserved ejection fraction (HFpEF) is cGMP-PKG pathway. This pathway plays a pivotal role in the regulation of cardiac contractility, and modulation of cGMP-PKG signaling, contributing to the development of the diseases. Ventricular cardiomyocytes of HF patients and animal models are known to exhibit reduced cGMP levels and disturbed cGMP signaling including hypophosphorylation of PKG downstream targets. However, restoration of cGMP-PKG signaling improves cardiomyocyte function and promotes cardioprotective effects.