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.

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.

[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.

[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.

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.

[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.

Gender-based comparison of takotsubo syndrome versus myocardial infarction.

BACKGROUND: Takotsubo Syndrome (TTS) is an acute reversible left ventricular dysfunction. Recently published studies have highlighted a similar mortality rate as acute coronary syndrome (ACS). We compared the impact of gender differences on the outcome of TTS patients as compared to ACS patient. DESIGN AND METHODS: We included a collective of 138 patients TTS between 2003 and 2016 at our institution. Patients were divided according to their gender into two groups (Males n=21, 15% and females, n=117, 85%). They were compared with a cohort of 300 patients with a diagnosis of ACS. RESULTS: On the acute phase, in male patients with TTS, a treatment with inotropic was more often required (33.3 vs. 11.5%, P<0.01), were more susceptible to cardiogenic shock (28.6 vs. 12.5%, P<0.04). Concerning the long-term prognosis after the acute event, male patients had higher all-cause mortality over long-term follow-up. A Kaplan-Meier analysis indicated that the mortality of male patients with TTS was significantly higher compared to male patients with ACS (log-rank <0.01), while there was no significant difference between female patients with TTS and ACS (log-rank =0.60, P=0.45). In a multivariate cox regression analysis, male gender (HR 2.7, 95% CI: 1.1-6.5, P=0.02) GFR <60 ml/min (HR 2.8, 95% CI: 1.2-6.0, P=0.01) and history of cancer (HR 3.6, 95% CI 1.4-9.3, P<0.01) were independent predictors of 5-year mortality. CONCLUSIONS: Considerable evidence suggests that TTS compared to ACS implicates more significant clinical short-term events on male patients and it may be associated with poorer long-term prognosis.

[Cardiac contractility modulation for treatment of chronic heart failure]. / Kardiale Kontraktilitätsmodulation zur Behandlung der chronischen Herzinsuffizienz.

The worldwide prevalence of heart failure is 1-2% with a portion of >10% in patients older than 70 years. In addition to treatment of causal determined factors and lifestyle modification, basic treatment consists of guideline-directed medical therapy with angiotensin-converting enzyme inhibitors (ACE), ß­blockers (BB), mineralocorticoid receptor antagonists (MRA), diuretics, digitalis (class IIb recommendation), angiotensin receptor blockers (ARB), Iƒ-channel blockers plus recently recommended in the guidelines angiotensin receptor neprilysin inhibitor (ARNI) to substitute the ACE inhibitor (class I b). Cardiac contractility modulation (CCM) is a device-based electrical therapy for the treatment of refractory heart failure symptoms. CCM signals are relatively high intensity, nonexcitatory signals applied during the absolute refractory period that 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 normalization of myocardial key-proteins. So far, more than 3500 CCM devices have been implanted worldwide. For patients with symptomatic heart failure and narrow QRS complex, CCM is together with baroreceptor activation the only additive electrical therapy which had been approved in Germany. Actually, for the first time, CCM has been referenced in the current Heart Failure Guidelines. Prognostic data with regard to mortality are currently being evaluated in case series; some of which have since been published. Approval by the US Food and Drug Administration (FDA) is expected within the next months.

[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.

Interventional left atrial appendage closure may affect metabolism of essential amino acids and bioenergetic efficacy.

BACKGROUND: Interventional closure of left atrial appendage (LAAC) represents an alternative for stroke prevention in patients with non-valvular atrial fibrillation. Whether LAAC may affect metabolomic pathways has not been investigated yet. This study evaluates the impact of LAAC on the metabolism of essential amino acids, kynurenine and creatinine. METHODS: Peripheral blood samples of prospectively enrolled patients undergoing successful LAAC were taken before (T0) and 6 months after (T1, mid-term follow-up). Targeted metabolomic profiling was performed using electrospray ionization liquid chromatography-mass spectrometry (ESI-LC-MS/MS) and MS/MS measurements focusing on metabolism of essential amino acids. RESULTS: 44 patients with non-valvular AF (mean CHA2DS2-VASc score 4, mean HAS-BLED score 4) were enrolled. Changes in metabolites of essential amino acids, myocardial contraction and bioenergetic efficacy, such as phenylalanine (percentage change 8.2%, p = 0.006), tryptophan (percentage change 20.3%, p = 0.0006), tyrosine (percentage change 20.2%, p = 0.0001), creatinine (percentage change 7.2%, p > 0.05) and kynurenine (percentage change 8.3%, p = 0.0239) were found at mid-term follow-up. CONCLUSIONS: LAAC may affect the metabolism of essential amino acids and bioenergetic efficacy. ClinicalTrials.gov Identifier: NCT02985463.

Long term outcome of patients suffering from cancer and Takotsubo syndrome or myocardial infarction.

BACKGROUND: The pathophysiology of takotsubo syndrome (TTS) is unclear so far. There is strong association of the occurrence of TTS and malignant diseases. An association between malignant diseases and myocardial infarction (MI) was found recently and ascribed to common molecular and lifestyle mechanisms. AIM: To compare the outcome of patients with MI or TTS and malignant diseases in a matched cohort. METHODS: Patients with TTS or with MI (n = 138 per group) were matched for age and sex and assessed retrospectively and prospectively. Occurrence of malignant diseases and clinical outcome was followed up over 4 years. RESULTS: At the time of the index event, 8 (5.8%) MI patients and 17 (12.3%) TTS patients were already diagnosed with cancer. During follow up, the rate of patients who developed cancer was significantly higher in the TTS group than in the MI group (log rank P = 0.01). Mortality was higher in the TTS group, but also in the subgroup of TTS patients with cancer (log rank P < 0.05). In the multivariate analysis, male gender, renal impairment and the history of cancer was associated with an increased risk for death. CONCLUSIONS: Patients with TTS have more often malignant diseases than patients with MI. Cancer patients with TTS have a worse clinical outcome. The underlying mechanism is unclear yet, but the results point at TTS being the syndrome of an extracardiac disease rather than a disease of cardiac origin. Longer and closer follow up of patients with TTS and further studies addressing the mechanism of TTS are needed.

Percutaneous Closure of Left Atrial Appendage significantly affects Lipidome Metabolism.

Patients with non-valvular atrial fibrillation (AF) and a high risk for oral anticoagulation can be treated by percutaneous implantation of left atrial appendage occlusion devices (LAAC) to reduce the risk of cardio-embolic stroke. This study evaluates whether LAAC may influence lipid metabolism, which has never been investigated before. Patients with successful LAAC were included consecutively. Venous peripheral blood samples of patients were collected immediately before (T0, baseline) and 6 months after (T1, mid-term) LAAC. A targeted metabolomics approach based on electrospray ionization liquid chromatography-mass spectrometry (ESI-LC-MS/MS) and MS/MS measurements was performed. A total of 34 lipids revealed a significant change from baseline to mid-term follow-up after successful LAAC. Subgroup analysis revealed confounding influence by gender, age, diabetes mellitus type II, body mass index, left ventricular ejection fraction, creatinine and NT-proBNP. After multivariable adjustment within logistic regression models, these 34 lipids were still significantly altered after LAAC. Successful percutaneous LAAC may affect lipid metabolism and thereby may potentially affect pro-atherogenic and cardio-toxic effects.

Risk stratification in Takotsubo syndrome: a role of mitral annular plane systolic excursion.

AIM: Takotsubo syndrome (TTS) patients have a higher mortality rate than the general population. Our study was conducted to determine the short- and long-term outcome of TTS patients associated with a significantly compromised mitral annular plane systolic excursion (MAPSE) on hospital admission. METHODS AND RESULTS: Our institutional database constituted a collective of 53 patients diagnosed with TTS between 2003 and 2016. The patients were classified into two groups based on the MAPSE, with those presenting with an MAPSE <1 cm on admission categorized into one group (n = 20, 38%) and those presenting with MAPSE ≥1 cm (n = 33, 62%) categorized into another group. Preliminary results indicated that patients with an MAPSE < 1 cm had a greater risk of developing thromboembolic events. The long-term mortality was significantly higher in TTS patients with an MAPSE < 1 cm. In the multivariate Cox regression analysis, cardiogenic shock (hazard ratio 3.5; 95% confidence interval: 1.2-10.7; P = 0.02) and MAPSE < 1 cm (hazard ratio 5.1; 95% confidence interval: 1.3-19.2; P = 0.01) figured as independent predictors of the mortality. CONCLUSION: Although the short-term mortality rates among TTS patients diagnosed with a reduced MAPSE on admission were as similar as without reduced MAPSE, the long-term mortality rates among TTS patients diagnosed with a reduced MAPSE on admission were significantly higher. There is an urgent need for randomized trials, which could help define uniform clinical management strategies for high-risk TTS patients.

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.

[Bedside implantation of a new temporary vena cava inferior filter : German results from the European ANGEL registry]. / Bettseitige Implantation eines neuen passageren V.-cava-inferior-Filters : Deutsche Daten aus dem europäischen ANGEL-Register.

BACKGROUND: Pulmonary embolism (PE) is a frequently occurring complication in critically ill patients, and the simultaneous occurrence of PE and life-threatening bleeding is a therapeutic dilemma. Inferior vena cava filters (IVCF) may represent an important therapeutic alternative in these cases. The Angel® catheter (Bio2 Medical Inc., San Antonio, TX, USA) is a novel IVCF that provides temporary protection from PE and is implanted at bedside without fluoroscopy. MATERIAL AND METHODS: The European Angel® Catheter Registry is an observational, multicenter study. In our German substudy, we investigated patients from three German hospitals and four intensive care units, who underwent Angel® catheter implantation between February 2016 and December 2016. RESULTS: A total of 23 critically ill patients (68 ± 9 years, 43% male) were included. The main indication for implantation was a high risk for or an established PE, combined with contraindications for prophylactic or therapeutic anticoagulation due to either an increased risk of bleeding (81%) or active bleeding (13%). The Angel® catheter was successfully inserted in all patients at bedside. No PE occurred in patients with an indwelling Angel® catheter. Clots with a diameter larger the 20 mm, indicating clot migration, were detected in 5% of the patients by cavography before filter retrieval. Filter retrieval was uneventful in all of our cases, while filter dislocation occurred in 3% of the patients. CONCLUSION: The German data from the multicenter European Angel® Catheter Registry show that the Angel® catheter is a safe and effective approach for critically ill patients with a high risk for the development of PE or an established PE, when an anticoagulation therapy is contraindicated.

Sex differences of in-hospital outcome and long-term mortality in patients with Takotsubo cardiomyopathy.

BACKGROUND: Previous studies revealed that patients with Takotsubo cardiomyopathy (TTC) have a higher mortality rate than the general population. It is still unclear whether sex differences may influence long-term prognosis of TTC patients. The purpose of this study was to determine whether sex differences do influence the short- and long-term outcomes of TTC. METHODS AND RESULTS: A total of 114 patients with TTC were admitted to the University Medical Centre Mannheim from January 2003 to September 2015 and entered into the TTC database of the University Medical Centre Mannheim, and retrospectively analyzed. Patients were diagnosed by the Mayo Clinic criteria. All-cause mortality over mean follow-up of 1,529±1,121 days was revealed. Significantly more male patients died within long-term follow-up compared to female TTC patients (log-rank test; P=0.01). Most males died of noncardiac causes. In multivariate Cox regression analysis, the male sex (P=0.02, hazard ratio [HR] 2.8, 95% CI 1.1-7.2), the ejection fraction ≤35% (P=0.01, HR 3.3, 95% CI 1.2-9.2) and glomerular filtration rate <60 mL/min (P<0.01, HR 3.1, 95% CI 1.4-7.0) figured out as independent predictors of the adverse outcome. CONCLUSION: This study shows that males suffering from TTC reveal a higher long-term all-cause mortality rate than females over a 5 year follow-up period.