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Little is known about the efficacy and safety of rivaroxaban in patients with atrial fibrillation (AF) who underwent percutaneous coronary intervention (PCI) in clinical practice. We therefore conducted a prospective observational study to determine the rate of ischemic, embolic, and bleeding events in patients with AF and PCI treated with rivaroxaban in a real-world experience. The RIVA-PCI ("rivaroxaban in patients with AF who underwent PCI") (clinicaltrials.gov NCT03315650) is a prospective, noninterventional, multicenter study with a follow-up until 14 months, including patients with AF who underwent PCI discharged with rivaroxaban. Between January 2018 and March 2020, 700 patients with PCI treated with rivaroxaban (elective in 50.1%, non-ST-elevation acute coronary syndrome 43.0%, ST-elevation myocardial infarction in 6.9%) were enrolled at 51 German hospitals. After PCI, a dual antithrombotic therapy consisting of rivaroxaban and a P2Y12 inhibitor was administered in 70.7% and triple antithrombotic therapy in 27.9%, respectively. Follow-up information could be obtained in 695 patients (99.3%). Rivaroxaban has been stopped prematurely in 21.6% of patients. Clinical events under rivaroxaban during the 14-month follow-up compared with those observed in the PIONEER-AF PCI trial included cardiovascular death (2.0% % vs 2.0%), myocardial infarction (0.9% vs 3.0%), stent thrombosis (0.2% vs 0.8%), stroke (1.3% vs 1.3%), International Society on Thrombosis and Haemostasis major (4.2% vs 3.9%), and International Society on Thrombosis and Haemostasis nonmajor clinically relevant bleeding (15.3% vs 12.9%). Therefore, in this real-world experience, rivaroxaban in patients with AF who underwent PCI is associated with ischemic and bleeding event rates comparable with those observed in the randomized PIONEER-AF PCI trial.

Background Acute kidney injury (AKI) affects increasing numbers of hospitalized patients, the prog-nosis remains poor. The diagnosis is still based on the 2012 published KDIGO criteria. Numerous new AKI biomarkers have been identified in recent years, they either reflect impaired excretory function or structural damage. The majority of markers are useful for AKI recognition under certain circumstances. Fewer data are available on the role of biomarkers in the prediction of in-hospital survival and renal recovery post-AKI. The current article is intended to provide information about these two aspects. Summary The following databases were screened: PubMed, Web of Science, Cochrane Library, Scopus. The period lasted from 2000 until 2022. The following terms were applied: ´AKI´ AND ´biomarker´ AND ´survival´ OR ´mortality´ OR ´recovery of kidney function´ OR ´renal recovery´ OR ´kidney recovery´. The following terms were used for additional literature search: ´TIMP-2´ AND ´IGFBP7´ and ´RNA biomarker´ AND ´hematology´. Regarding mortality, exclusively those studies were selected, that addressed the in-hospital mortality. Nine (9) studies were identified that evaluated biomarker-based pre-diction of in-hospital mortality and/or of recovery of kidney function (ROKF). A homoge-nous definition of ROKF is however missing yet. Currently, some biomarkers, meas-ured early during the course of the disease are associated with increased mortality risk and/or with a higher chance of renal recovery. Key messages • The literature provides only a few biomarker-related studies that address the is-sues of mortality and recovery. • The definition of ROKF needs to be homogenized.

BackgroundWe investigated the pleiotropic effects of an angiotensin receptor-neprilysin inhibitor (ARNi) on collateral-dependent myocardial perfusion in a rat model of coronary arteriogenesis, and performed comprehensive analyses to uncover the underlying molecular mechanisms.MethodsA rat model of coronary arteriogenesis was established by implanting an inflatable occluder on the left anterior descending coronary artery followed by a 7-day repetitive occlusion procedure (ROP). Coronary collateral perfusion was measured by using a myocardial particle infusion technique. The putative ARNi-induced pro-arteriogenic effects were further investigated and compared with an angiotensin-converting enzyme inhibitor (ACEi). Expression of the membrane receptors and key enzymes in the natriuretic peptide system (NPS), renin-angiotensin-aldosterone system (RAAS) and kallikrein-kinin system (KKS) were analyzed by quantitative polymerase chain reaction (qPCR) and immunoblot assay, respectively. Protein levels of pro-arteriogenic cytokines were measured by enzyme-linked immunosorbent assay, and mitochondrial DNA copy number was assessed by qPCR due to their roles in arteriogenesis. Furthermore, murine heart endothelial cells (MHEC5-T) were treated with a neprilysin inhibitor (NEPi) alone, or in combination with bradykinin receptor antagonists. MHEC5-T proliferation was analyzed by colorimetric assay.ResultsThe in vivo study showed that ARNis markedly improved coronary collateral perfusion, regulated the gene expression of KKS, and increased the concentrations of relevant pro-arteriogenic cytokines. The in vitro study demonstrated that NEPis significantly promoted MHEC5-T proliferation, which was diminished by bradykinin receptor antagonists.ConclusionARNis improve coronary collateral perfusion and exert pro-arteriogenic effects via the bradykinin receptor signaling pathway.

Summary: Background: Angiotensin-converting-enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) are widely used as a first-line therapy for the treatment of cardiovascular disease. Here, ACEI modulate the bradykinin receptor (BDKRB1 and BDKRB2) system and NO-dependent endothelial function, thus determining cardiovascular health and regenerative arteriogenesis. The current study aims at evaluating nitric oxide-dependent endothelial function, and gene expression of bradykinin receptors in peripheral blood mononuclear cells (PBMC) from patients with ACEI or ARB treatment. Patients and methods: The WalkByLab has been established to screen cardiovascular patients for peripheral artery disease and coronary artery disease. In total 177 patients from WalkByLab with heterogenous disease and risk status were randomly selected, divided according to their medication history into the following groups: 1. ACEI group, 2. ARB group or 3. non-ACE/ARB group. Total plasma nitrite/nitrate (NO) levels were measured, endothelial function was evaluated by assessing flow meditated dilation (FMD). PBMC were isolated from peripheral whole blood, and gene expression (qRT-PCR) of bradykinin receptors and angiotensin converting enzyme were assessed. Results: Plasma total NO concentration in the ACEI group (24.66±16.28, µmol/l) was increased as compared to the ARB group (18.57±11.58, µmol/l, P=0.0046) and non-ACE/ARB group (16.83±8.64, µmol/l, P=0.0127) in patients between 40 to 90 years of age. However, FMD values (%) in the ACEI group (7.07±2.40, %) were similar as compared to the ARB (6.35±2.13, %) and non-ACE/ARB group (6.51±2.15, %), but significantly negatively correlated with age. Interestingly, BDKRB1 mRNA level was significantly higher and BDKRB2 mRNA level lower in the ACEI group (BDKRB1 3.88-fold±1.05, BDKRB2 0.22-fold±0.04) as compared to the non-ACE/ARB group (BDKRB1 1.00-fold±0.39, P

Background Left atrial appendage (LAA) closure with the WATCHMAN device is an alternative to anticoagulation therapy for the prevention of stroke in selected patients with atrial fibrillation (AF). Infrequently, left atrial (LA) device-related thrombus formation occurs and it is poorly understood. Thrombus formation due to incomplete covering of the LAA is even rarer and may occur within the first few months after device implantation. Case summary Here, we present a case of a 68-year-old male patient with permanent AF, drug- and hepatitis induced liver cirrhosis (CILD Score B), and prior aortic valve replacement. The patient had a history of percutaneous LAA closure using a WATCHMAN device. He developed massive peri-device leak and thrombus arising from the space between the device and appendage cleft 2 years after implantation. Because of the high bleeding risk with a HAS-BLED score of 5 points, surgery was chosen as the therapy of choice instead of long-term anticoagulation. The patient was discharged in good clinical condition and has been scheduled for a yearly follow-up. Discussion This case emphasizes the importance of choosing appropriately sized LAA occluder devices and planning for regular post-interventional follow-ups to minimize the risk of per-device leaks and thrombi.

Background The function of high-density lipoprotein (HDL) cholesterol may play a more important role in the prevention of cardiovascular disease compared to the concentration of the HDL. Cardiovascular diseases such as coronary artery disease (CAD) and atrial fibrillation (AF) have been linked to impaired HDL function. Purpose The aim of the present study is to assess a biochemical measure of the antioxidant function of HDL and its association with presence of CAD and AF. Methods Patients admitted for elective cardiac catheterization were recruited in this cross-sectional study. Out of 1231 participants that were included in the analyses, 727 patients had confirmed CAD (CAD group), 369 patients had no CAD (no CAD group) and 129 persons were included as a control group. HDL function was measured in sera by determination of HDL-lipid peroxidation content (HDLox) assessed by a validated fluorometric cell-free biochemical assay and was normalized for the levels of HDL cholesterol (normalized HDLox/HDL-C ratio or nHDLox; no units). Results are expressed as median with interquartile range. Associations of nHDLox with presence of CAD and AF were assessed by univariate and multivariate analyses. Results Participants in the CAD group had higher levels of nHDLox (0.80, 0.61–1.03) compared to the no CAD (0.70, 0.55–0.93) and control (0.66, 0.55–1.03, no units, p0.05) Conclusions Reduced antioxidant function of HDL (increased HDLox measured by a biochemical assay), a metric of HDL function, is increased in patients with atherosclerosis and manifested CAD and is also associated with the presence of atrial fibrillation independent of the presence of CAD. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Medical School of Brandenburg-MHB Fontane

Background 35.3% of deaths in 2019 in Germany are caused by cardiovascular diseases (Destatis). 95% of these people were 60 years and older. To increase survival rate in elderly patients we investigate the relevance of altered expression of neuronal nitric oxide synthase 1 (NOS1) adaptor protein (NOS1AP) acting as an L-type calcium channel (CaV1.2) modulator via directing NOS1 to CaV1.2 on cardiac electrophysiology. Genome-wide association studies have linked genetic polymorphisms in NOS1AP to variations in QT interval duration (QTc). The QT interval reflects ventricular de- and repolarization. It may predispose individuals to ventricular tachycardia and sudden cardiac death (SCD) if prolonged, shortened or otherwise unregularly. In addition, about 20% of families with a clinically proven diagnosis of long QT syndrome (LQTS) host no mutation in any of the 16 associated genes. Methods and results Transgenic mice with conditional overexpression of NOS1AP in cardiac myocytes were used as model organism. We confirmed the interaction of NOS1AP with NOS1 and CaV1.2. Electrocardiography in NOS1AP overexpressing mice showed atrial and ventricular tachycardia both spontaneously and upon programmed stimulation associated with a significant decrease in QTc. Heart rates in NOS1AP overexpressing mice were similar to non-induced animals. Survival was significantly reduced (only 60% after 12 weeks vs. 100% in non-induced mice). Induced QTc alterations and accompanied deaths subsided upon re-administration of doxycycline. Whole-cell patch-clamp measurements in isolated adult ventricular myocytes were performed and action potential duration at 90% of repolarization (APD90) was significantly reduced in induced transgenic NOS1AP overexpressing mice compared to control littermates. In addition, we investigated the functional effect of the human SNP rs16847548 (T/C) located within the NOS1AP promoter. The SNP was found to decrease the transcriptional activity of NOS1AP in vitro and therefore, potentially leading to a decrease in NOS1AP expression in humans. Conclusion Myocardial overexpression of NOS1AP leads to short QT syndrome with increased susceptibility to atrial and ventricular arrhythmias and cardiac death. In accordance, APD90 is significantly shortened in overexpressing animals. The human SNP rs16847548, which is located in the promoter region of NOS1AP, results in a reduced NOS1AP promoter activity in vitro, hereby providing an explanation for the frequently published elongation of QT intervals. In summary, not only mutations in ion channels themselves but also genetic alterations in the expression of ion channel modulators such as NOS1AP, have an impact on QTc and arrhythmogenesis and represent a promising therapeutic target for LQTS patients. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Gesundheitscampus Brandenburg (MWFK)

Background ICD therapy in elderly patients is controversially discussed, since survival benefits might be attenuated by non-arrhythmic causes of death. Purpose This study aimed to investigate the outcome of septua- and octogenarians after ICD generator exchange (GE). Methods 506 patients undergoing elective GE were analysed to determine the incidence of ICD shocks and survival after GE. For further analysis, patients were divided according to age (70 – 79 or ≥80 years) and previous ICD therapy: patients that did not experience a shock and patients that received at least one shock from prior ICDs. Results The effect of the ICD on all-cause mortality and arrhythmic death was determined for two groups (patients with 70 – 79 and ≥80 years). Comparing septua- with octogenarians, similar left ventricular ejection fraction (35.6±11.2% vs. 32.4±8.9%) and baseline prevalence of NYHA class 3 or 4 heart failure (17.1% vs. 14.7%) was found. Older patients were more likely to die of non-arrhythmic death (22% per year vs. 8% per year, p Conclusion Decision making for ICD generator exchange among elderly patients should be considered carefully for an individual patient during clinical practice. Funding Acknowledgement Type of funding sources: None.

Notwithstanding a decrease in the incidence and mortality of cardiovascular diseases during the last decades, notable disparities in health outcomes depending on a patient´s socioeconomic position persist and are most visible in acute myocardial infarction and ischemic heart disease. Education is a pivotal indicator of the socioeconomic position. Effects of the social determinants of health on the incidence, prevalence and mortality of cardiovascular diseases were previously effectually investigated and shown to be inversely associated but evidence on non-fatal health outcomes such as heart failure, ability to return to work or rehospitalizations still remain insufficiently examined. We provide a literature review dealing with the impact that formal education has on non-fatal health outcomes including major adverse cardiovascular events, clinical outcomes, depression, use of cardiac rehabilitation, quality of life, self-perceived health and social participation after a myocardial infarction from a global and comprehensive perspective.

Little is known about current patterns of antithrombotic therapy in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) in clinical practice in Germany.The RIVA-PCI is a prospective, non-interventional, multicenter study with follow-up until hospital discharge including consecutive patients with AF undergoing PCI.Between January 2018 and March 2020, 1636 patients (elective in 52.6%, non-ST elevation acute coronary syndrome [NSTE-ACS] in 39.3%, ST-elevation myocardial infarction in 8.2%) from 51 German hospitals were enrolled in the study. After PCI a dual antithrombotic therapy (DAT) consisting of OAC and a P2Y12 inhibitor was given to 66.0%, triple antithrombotic therapy (TAT) to 26.0%, dual antiplatelet therapy to 5.5%, and a mono-therapy to 2.5% of the patients. Non-vitamin K antagonist oral anticoagulants (NOACs) were given to 82.4% and vitamin K antagonists to 11.5% of the patients. In-hospital events included death in 12 cases (0.7%), myocardial infarction, stent thrombosis, and ischemic stroke in four (0.2%) patients each, while 2.8% of patients had bleeding complications. The recommended durations for DAT or TAT at discharge were 1 month (1.5%), 3 months (2.1%), 6 months (43.1%), and 12 months (45.6%), with a 6-month course of DAT (47.7%) most often recommended after elective PCI and a 12-month course of DAT (40.1%) after ACS.The preferred therapy after PCI in patients with AF is DAT with a NOAC and clopidogrel. In-hospital ischemic and bleeding events were rare. The recommended durations for combination therapy vary considerably.HINTERGRUND: Über die aktuellen, im klinischen Alltag in Deutschland angewandten Schemata zur antithrombotischen Therapie bei Patienten mit Vorhofflimmern (VF), bei denen eine perkutane Koronarintervention (PCI) durchgeführt wird, ist nur wenig bekannt.Das RIVA-PCI-Register („Rivaroxaban in patients with atrial fibrillation undergoing PCI“) stellt eine prospektive nichtinterventionelle Multizenterstudie mit Nachbeobachtung bis zur Krankenhausentlassung dar und bezieht aufeinanderfolgende Patienten mit VF ein, bei denen eine PCI erfolgt.Zwischen Januar 2018 und März 2020 wurden 1636 Patienten (elektiv in 52,6%, akutes Koronarsyndrom ohne ST-Strecken-Hebung [NSTE-ACS] in 39,3%, ST-Hebungs-Myokardinfarkt in 8,2% der Fälle) aus 51 deutschen Krankenhäusern in die Studie aufgenommen. Nach PCI wurde eine duale antithrombotische Therapie (DAT) mit oralen Antikoagulanzien (OAK) und einem P2Y12-Inhibitor bei 66,0%, eine dreifache („triple“) antithrombotische Therapie (TAT) bei 26,0%, eine duale Plättchenhemmung bei 5,5% und eine Monotherapie bei 2,5% der Patienten durchgeführt. Nicht-Vitamin-K-abhängige orale Antikoagulanzien (NOAC) wurden 82,4% und Vitamin-K-Antagonisten 11,5% der Patienten verordnet. Zu den Ereignissen während des stationären Aufenthalts zählten Tod in 12 Fällen (0,7%), Myokardinfarkt, Stentthrombose und ischämischer Schlaganfall jeweils bei 4 (0,2%) Patienten, während 2,8% der Patienten Blutungskomplikationen aufwiesen. Die empfohlene Dauer für die DAT oder TAT bei Entlassung betrug einen Monat (1,5%), 3 Monate (2,1%), 6 Monate (43,1%) bzw. 12 Monate (45,6%), dabei wurde meistens (47,7%) eine 6‑monatige DAT nach elektiver PCI und eine 12-monatige DAT (40,1%) nach ACS empfohlen.Die bevorzugte Therapie nach PCI bei Patienten mit VF besteht in einer DAT mit einem NOAK und Clopidogrel. Ischämische und Blutungsereignisse während des stationären Aufenthalts waren selten. Die empfohlenen Dauern für die Kombinationstherapie variieren beträchtlich.

Aims Anxiety, depression, and reduced quality of life (QoL) are common in patients with implantable cardioverter-defibrillators (ICDs). Treatment options are limited and insufficiently defined. We evaluated the efficacy of a web-based intervention (WBI) vs. usual care (UC) for improving psychosocial well-being in ICD patients with elevated psychosocial distress. Methods and results This multicentre, randomized controlled trial (RCT) enrolled 118 ICD patients with increased anxiety or depression [≥6 points on either subscale of the Hospital Anxiety and Depression Scale (HADS)] or reduced QoL [≤16 points on the Satisfaction with Life Scale (SWLS)] from seven German sites (mean age 58.8 ± 11.3 years, 22% women). The primary outcome was a composite assessing change in heart-focused fear, depression, and mental QoL 6 weeks after randomization to WBI or UC, stratified for age, gender, and indication for ICD placement. Web-based intervention consisted of 6 weeks’ access to a structured interactive web-based programme (group format) including self-help interventions based on cognitive behaviour therapy, a virtual self-help group, and on-demand support from a trained psychologist. Linear mixed-effects models analyses showed that the primary outcome was similar between groups (η p 2 = 0.001). Web-based intervention was superior to UC in change from pre-intervention to 6 weeks (overprotective support; P = 0.004, η p 2 = 0.036), pre-intervention to 1 year (depression, P = 0.004, η p 2 = 0.032; self-management, P = 0.03, η p 2 = 0.015; overprotective support; P = 0.02, η p 2 = 0.031), and 6 weeks to 1 year (depression, P = 0.02, η p 2 = 0.026; anxiety, P = 0.03, η p 2 = 0.022; mobilization of social support, P = 0.047, η p 2 = 0.018). Conclusion Although the primary outcome was neutral, this is the first RCT showing that WBI can improve psychosocial well-being in ICD patients.

Background: Arrhythmia and sudden cardiac death (SCD) are known complications of acute viral myocarditis, regardless of ejection fraction (EF) at presentation. Whether such complications confer long-term risk is unknown, especially in those who present with preserved left ventricular (LV) function. No guidelines exist to the long-term reduction of arrhythmic death in such patients. Method: In this retrospective study, we analyzed the long-term results of implantable cardioverter defibrillator (ICD) treatment in patients after an acute phase of myocarditis with life-threatening arrhythmia. Results: We identified 51 patients who had ICDs implanted following life-threatening arrhythmia presentation of confirmed acute viral myocarditis, despite preserved LVEF. Overall, 72.5% of patients had a clinical history of chest pain and viral infection with fever. Viral myocarditis was confirmed by cardiac magnetic resonance imaging (all had late enhancement) plus endomyocardial biopsies (most frequent were Epstein-Barr virus 29.4%, adenovirus 17.6%, and Coxsackie 17.6%), and 88.2% were discharged on anti-arrhythmic drugs. Overall, 12 patients (23.5%) required ICD intervention within the first 3 months, a further 7 patients (37.3% overall) between 3 and 12 months, and a further 12 patients (60.8% overall) until 58 months. During the follow-up, 3 of 51 patients (5.9%) died—deaths were due to cardiac events (n = 1), fatal infection (n = 1), and car accidents (n = 1). Of the 31 patients who had ventricular tachycardias after the acute phase of myocarditis, 11 needed radiofrequency ablation due to a high number of events or electrical storm. No baseline variables were identified that would serve as a basis for risk stratification. Conclusion: Malignant arrhythmic events due to viral myocarditis are potential predictors of future SCD in patients not only with a reduced but also with a preserved EF.

The function of high-density lipoprotein (HDL) cholesterol may play a more important role in the prevention of cardiovascular disease compared to the concentration of the HDL. The aim of the present study is to assess a novel cell-free test to quantify oxidation of HDL and its association to coronary artery disease (CAD). We performed a prospective trial by including patients undergoing elective cardiac catheterization and healthy controls. A total of 895 subjects were included. In 483 patients CAD was confirmed (CAD group) and in 241 patients CAD was ruled-out (no CAD). Control patients (n=171) had no known CAD, had no diabetes and were not smokers. HDL function was measured in serum samples by determining its HDL-lipid peroxidation by a novel fluorometric cell-free biochemical assay. HDL lipid peroxide content (HDLox) is adjusted for the HDL cholesterol and has no units. Patients with confirmed CAD had higher levels of HDLox (0.92±0.58, no units) compared to patients with no CAD (0.8±0.46, no units) and controls (0.78±0.41, no units, p=0.003). HDL-Cholesterol was lower in the CAD group (50.7±17.7mg/dl) compared to no CAD (58.4±17.6mg/dl) and healthy subjects (59.1±15.9mg/dl, p Oxidation of HDL, a metric of HDL function, measured by a cell-free biochemical assay, is increased in patients with CAD and is a predictor of the disease. Logistic Regression analysis Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Medical School of Brandenburg

Background Exercise training increases high-density lipoprotein (HDL) cholesterol, but its effect on HDL function is unclear. In hypertensives, exercise improves endothelial dysfunction, which is related to HDL function. In the present study, we assess for the first time the effects of different exercise modalities on two cell-free assays of HDL function. Design The study was conducted as a prospective randomized controlled trial in 75 hypertensive patients. Methods Patients were randomized in three groups: (a) handgrip isometric training five times weekly; (b) placebo-handgrip; and (c) aerobic exercise training at least three times per week. HDL function was assessed in serum samples at baseline and after 12 weeks of training by two independent assays that determine the proinflammatory phenotype (haptoglobin content) of a specific amount of HDL (Haptoglobin-HDL [HPHDL]) and oxidized HDL (HDLox) as a measure of reduced antioxidant function of HDL. HDL function measures were normalized by the measures of a pooled control of sera from healthy participants and by HDL-C levels (normalized ratio, no units). Results Aerobic exercise led to significant reduction of the HDLox from 0.99 ± 0.27 to 0.90 ± 0.29 (no units, p = 0.03). The HPHDL did not change in any training group. Changes of HDLox correlated with reduction of the systolic blood pressure only after aerobic exercise ( R = 0.64, p = 0.03). Conclusions Aerobic but not isometric exercise improves the antioxidant function of HDL in patients with hypertension. This improvement correlates positively with reductions of blood pressure.

Background: Loop diuretics (LD) are widely used in emergency and intensive care medicine. Summary: The substances increase the clearance of electrolytes and water; thus, they allow us to control hypervolemia and to prevent patients from pulmonary edema. LD are also frequently applied to patients with an acute decrease in glomerular filtration rate, namely, acute kidney injury (AKI). Nevertheless, volume depletion may be associated with reduced renal perfusion and possibly slower restitution or even aggravation of kidney dysfunction. Several trials on the preventive or therapeutic efficacy of LD have been published since the early 1970s. Our review article is intended to summarize the most important references related to this topic. In addition, we discuss the diagnostic value of the so-called furosemide stress test. The currently available data indicate that LD may act in a beneficial manner as long as euvolemia is maintained (matched hydration). Key Massages: LD are not beneficial for AKI treatment if kidney-related endpoints are considered. In certain situations, AKI prevention with LD can be associated with favorable outcomes as long as euvolemia is maintained. LD can help to identify AKI subjects at a higher risk of AKI progression, but the exact clinical consequences need to be determined.

Aims Elevated levels of inositol 1,4,5-trisphosphate (IP3) in adult cardiac myocytes are typically associated with the development of cardiac hypertrophy, arrhythmias, and heart failure. IP3 enhances intracellular Ca2+ release via IP3 receptors (IP3Rs) located at the sarcoplasmic reticulum (SR). We aimed to determine whether IP3-induced Ca2+ release affects mitochondrial function and determine the underlying mechanisms. Methods and results We compared the effects of IP3Rs- and ryanodine receptors (RyRs)-mediated cytosolic Ca2+ elevation achieved by endothelin-1 (ET-1) and isoproterenol (ISO) stimulation, respectively, on mitochondrial Ca2+ uptake and adenosine triphosphate (ATP) generation. Both ET-1 and isoproterenol induced an increase in mitochondrial Ca2+ (Ca2 +m) but only ET-1 led to an increase in ATP concentration. ET-1-induced effects were prevented by cell treatment with the IP3 antagonist 2-aminoethoxydiphenyl borate and absent in myocytes from transgenic mice expressing an IP3 chelating protein (IP3 sponge). Furthermore, ET-1-induced mitochondrial Ca2+ uptake was insensitive to the mitochondrial Ca2+ uniporter inhibitor Ru360, however was attenuated by RyRs type 1 inhibitor dantrolene. Using real-time polymerase chain reaction, we detected the presence of all three isoforms of IP3Rs and RyRs in murine ventricular myocytes with a dominant presence of type 2 isoform for both receptors. Conclusions Stimulation of IP3Rs with ET-1 induces Ca2+ release from the SR which is tunnelled to mitochondria via mitochondrial RyR leading to stimulation of mitochondrial ATP production.

Thrombus-in-transit crossing an interatrial communication is a rare but potentially serious clinical condition, which has so far not been described after implantation of left atrial appendage (LAA) closure devices. Here, we describe the case of a 76-year-old woman with permanent atrial fibrillation and contraindication for oral anticoagulation therapy, who developed pericardial tamponade and acute pulmonary embolism with visible thrombus-in-transit formation following LAA closure. Most likely manipulation of the Watchman device in the LAA during two failed attempts in device positioning led to pericardial tamponade and venous puncture, manual compression after completion of the procedure and further immobilization resulted in deep vein thrombosis with consecutive pulmonary embolism and thrombus-in-transit formation. This case highlights the value of echocardiography after LAA closure.

Background— E193, a heterozygous truncating mutation in the human transcription cofactor Eyes absent 4 (Eya4), causes hearing impairment followed by dilative cardiomyopathy. Methods and Results— In this study, we first show Eya4 and E193 alter the expression of p27 kip1 in vitro, suggesting Eya4 is a negative regulator of p27. Next, we generated transgenic mice with cardiac-specific overexpression of Eya4 or E193. Luciferase and chromatin immunoprecipitation assays confirmed Eya4 and E193 bind and regulate p27 expression in a contradictory manner. Activity and phosphorylation status of the downstream molecules casein kinase-2α and histone deacetylase 2 were significantly elevated in Eya4- but significantly reduced in E193-overexpressing animals compared with wild-type littermates. Magnetic resonance imaging and hemodynamic analysis indicate Eya4-overexpression results in an age-dependent development of hypertrophy already under baseline conditions with no obvious functional effects, whereas E193 animals develop onset of dilative cardiomyopathy as seen in human E193 patients. Both cardiac phenotypes were aggravated on pressure overload. Finally, we identified a new heterozygous truncating Eya4 mutation, E215, which leads to similar clinical features of disease and a stable myocardial expression of the mutant protein as seen with E193. Conclusions— Our results implicate Eya4/Six1 regulates normal cardiac function via p27/casein kinase-2α/histone deacetylase 2 and indicate that mutations within this transcriptional complex and signaling cascade lead to the development of cardiomyopathy.

Introduction: We previously reported that E193, a heterozygous truncating mutation in the transcription cofactor “Eyes absent” (Eya4) leads to late-onset familial DCM and heart failure. Yet a precise role for Eya4 in the myocardium has not been identified. It appears to regulate normal cardiac function via p27 kip1 , a protein shown to be involved in regulating hypertrophic responses in the adult cardiomyocyte. This study was aimed to explore the role of Eya4 in angiotensin II (ATII)-induced cardiac hypertrophy. Methods and results: We used our transgenic mouse model with a constitutive myocardial overexpression of HA-tagged Eya4. Wildtype and Eya4 overexpressing mice were challenged with ATII via osmotic minipumps for four weeks to induce cardiac hypertrophy. Analysis of these animals using magnetic resonance imaging to visualize cardiac structures in detail showed that in response to the sustained ATII stimulation, the Eya4 overexpressing mice exhibited a phenotype with significantly increased parameters of hypertrophy. LV free wall diameter as measured in 7T MRI was 1,7±0,2 in Eya4 mice with ATII compared to 1,3±0,2 mm in WT mice with ATII. This was also confirmed by HW/BW ratio, hemodynamic measurements and cell size measurements. Histology also affirmed the results of the MR imaging. Moreover, Eya4 overexpression induced a significant suppression of p27 protein expression which is in agreement with our in vitro data. This confirmed our hypothesis that Eya4 negatively acts upon p27 expression which facilitates development of myocardial hypertrophy. Conclusion: In summary, we previously described a mutation in Eya4 to disturb cardiac physiology. We now provide evidence that Eya4 is also involved in forms of acquired heart disease. It seems to suppress p27 kip1 , thereby augmenting ATII induced cardiac hypertrophy.

Information about a real patient is presented in stages (boldface type) to expert clinicians (Dr Oliver Ritter and Dr Ralf Michael Muellenbach), who respond to the information, sharing their reasoning with the reader (regular type). A discussion by the authors follows. A 63-year-old white male was admitted with recurring chest pain of increasing intensity for ≈3 days. He had a known history of arterial hypertension and was obese, with a body mass index of 29.4 kg/m2. After seeking help at his family physician he was immediately transferred to our hospital using emergency medical services because of ST-segment elevations. On arrival he had severe chest pain with dyspnea and a lowered blood pressure of 90/60 mm Hg. On auscultation moist rales could be heard over both lungs, whereas heart sounds were normal. The abdomen was nondistended with normal bowel sounds and no palpable organomegaly. His extremities were warm and exhibited peripheral edemas on both sides. The ECG displayed sinus tachycardia at 102/min with posteroinferior ST-segment elevations and reciprocal ST-segment depressions in leads I, aVL, V2 and V3. Bedside echocardiographic assessment showed severely depressed biventricular function with a left ventricular ejection fraction of ≈15% and a dilated right ventricle measuring a tricuspid annular plane systolic excursion (TAPSE) of ≈1 cm. All heart valves were normal, and no signs of pericardial effusion could be observed. Dr Ritter: The presentation of patients with severe chest pain and impaired hemodynamic parameters is always suggestive of myocardial infarction. However, intense pain accompanied by vegetative symptoms such as nausea, vomiting, dyspnea, or sweating should always prompt rapid diagnostic evaluation of an array of possible diagnoses. Life-threatening conditions include an acute myocardial infarction as well as aortic dissection, pulmonary embolism, Boerhaave syndrome, or pneumothorax. The first step of diagnostic evaluation is …

A decrease in the supply of ATP from the creatine kinase (CK) system is thought to contribute to the evolution of heart failure. However, previous studies on mice with a combined knockout of the mitochondrial and cytosolic CK (CK−/−) have not revealed overt left ventricular dysfunction. The aim of this study was to employ novel MRI techniques to measure maximal myocardial velocity ( Vmax) and myocardial perfusion and thus determine whether abnormalities in the myocardial phenotype existed in CK−/− mice, both at baseline and 4 wk after myocardial infarction (MI). As a result, myocardial hypertrophy was seen in all CK−/− mice, but ejection fraction (EF) remained normal. Vmax, however, was significantly reduced in the CK−/− mice [wild-type, 2.32 ± 0.09 vs. CK−/−, 1.43 ± 0.16 cm/s, P < 0.05; and wild-type MI, 1.53 ± 0.11 vs. CK−/− MI, 1.26 ± 0.11 cm/s, P = not significant (NS), P < 0.05 vs. baseline]. Myocardial perfusion was also lower in the CK−/− mice (wild-type, 6.68 ± 0.27 vs. CK−/−, 4.12 ± 0.63 ml/g·min, P < 0.05; and wild-type MI, 3.97 ± 0.65 vs. CK−/− MI, 3.71 ± 0.57 ml/g·min, P = NS, P < 0.05 vs. baseline), paralleled by a significantly reduced capillary density (histology). In conclusion, myocardial function in transgenic mice may appear normal when only gross indexes of performance such as EF are assessed. However, the use of a combination of novel MRI techniques to measure myocardial perfusion and mechanics allowed the abnormalities in the CK−/− phenotype to be detected. The myocardium in CK-deficient mice is characterized by reduced perfusion and reduced maximal contraction velocity, suggesting that the myocardial hypertrophy seen in these mice cannot fully compensate for the absence of the CK system.

OBJECTIVE: Creatine kinase (CK) is responsible for the transport of high-energy phosphates in excitable tissue and is of central importance in myocardial energy homeostasis. Significant changes in myocardial energetics have been reported in mice lacking the various CK isoenzymes. Our hypothesis was that ablation of CK isoenzymes leads to cardiac hypertrophy, impaired function, and aggravation of left ventricular remodeling post-myocardial infarction. METHODS: CK-deficient mice (CK KO) were examined by cardiac magnetic resonance imaging (MRI) to determine left ventricular volumes, ejection fraction, and mass: ten wild-type (WT), 6 mitochondrial CK KO (Mito-CK-/-), 10 cytosolic CK KO (M-CK-/-), and 10 mice with combined KO (M/Mito-CK-/-). RESULTS: While ejection fraction was similar in all groups, there was significant LV dilatation with a approximately 30% increase in LV end-diastolic volumes in Mito-CK-/- and in M/Mito-CK-/-. Compared to WT, there was a striking 73% and 64% increase of LV mass in Mito-CK-/- and in M/Mito-CK-/- mice, respectively, but no significant increase of LV mass (+33%; p=n.s.) in M-CK-/-. Furthermore, significant re-expression of beta-MHC, a marker of myocardial hypertrophy, was found in all CK-deficient hearts. LV remodeling was investigated by MRI in hearts of 7 WT and 10 M/Mito-CK-/- mice 4 weeks postmyocardial infarction (MI). Four weeks post-LAD ligation (MI size approximately 32%), WT and M/Mito-CK-/- showed a similar degree of cardiac dysfunction, dilatation, and hypertrophy. CONCLUSION: Mito-CK-/- and M/Mito-CK-/- mice show significant LV dilatation and marked LV hypertrophy, but LV remodeling post-MI is not aggravated. CK ablation leads to substantial adaptational changes in heart.

The serine–threonine phosphatase calcineurin is activated in cardiac myocytes in the diseased heart and induces pathological hypertrophy. Calcineurin activity is mainly triggered by calcium/calmodulin binding but also through calpain mediated cleavage. How controlled calcineurin activation is possible in cardiac myocytes, which typically show a 10-fold difference in cytosolic calcium concentration with every heartbeat, has remained enigmatic. It is now emerging that calcineurin activation and signaling occur in subcellular microdomains, in which it is brought together with target proteins and exceedingly high concentrations of calcium in order to induce downstream signaling. We review current evidence of subcellular calcineurin mainly at the sarcolemma and the nucleus, but also in association with the sarcoplasmic reticulum and mitochondria. We also suggest that knowledge about subcellular signaling could help to develop inhibitors of calcineurin in specific microdomains to avoid side-effects that may arise from complete calcineurin inhibition.

Two sons of a consanguineous marriage developed biventricular cardiomyopathy. One boy died of severe heart failure at the age of 6 years, the other was transplanted because of severe heart failure at the age of 10 years. In addition, focal palmoplantar keratoderma and woolly hair were apparent in both boys. As similar phenotypes have been described in Naxos disease and Carvajal syndrome, respectively, the genes for plakoglobin (JUP) and desmoplakin (DSP) were screened for mutations using direct genomic sequencing. A novel homozygous 2 bp deletion was identified in an alternatively spliced region of DSP. The deletion 5208_5209delAG led to a frameshift downstream of amino acid 1,736 with a premature truncation of the predominant cardiac isoform DSP-1. This novel homozygous truncating mutation in the isoform-1 specific region of the DSP C-terminus caused Carvajal syndrome comprising severe early-onset heart failure with features of non-compaction cardiomyopathy, woolly hair and an acantholytic form of palmoplantar keratoderma in our patient. Congenital hair abnormality and manifestation of the cutaneous phenotype in toddler age can help to identify children at risk for cardiac death. Electronic supplementary material The online version of this article (doi:10.1007/s00392-011-0345-9) contains supplementary material, which is available to authorized users.

Background— Imaging of myocardial ablation lesions during electrophysiology procedures would enable superior guidance of interventions and immediate identification of potential complications. The aim of this study was to establish clinically suitable MRI-based imaging techniques for intraprocedural lesion visualization in interventional electrophysiology. Methods and Results— Interventional electrophysiology was performed under magnetic resonance guidance in an animal model, using a custom setup including magnetic resonance–conditional catheters. Various pulse sequences were explored for intraprocedural lesion visualization after radiofrequency ablation. The developed visualization techniques were then used to investigate lesion formation in patients immediately after ablation of atrial flutter. The animal studies in 9 minipigs showed that gadolinium-DTPA–enhanced T1-weighted and nonenhanced T2-weighted pulse sequences are particularly suitable for lesion visualization immediately after radiofrequency ablation. MRI-derived lesion size correlated well with autopsy ( R 2 =0.799/0.709 for contrast-enhanced/nonenhanced imaging). Non–contrast agent–enhanced techniques were suitable for repetitive lesion visualization during electrophysiological interventions, thus allowing for intraprocedural monitoring of ablation success. The patient studies in 24 patients with typical atrial flutter several minutes to hours after cavotricuspid isthmus ablation confirmed the results from the animal experiments. Therapeutic lesions could be visualized in all patients using contrast-enhanced and also nonenhanced MRI with high contrast-to-noise ratio (94.6±35.2/111.1±32.6 versus 48.0±29.0/68.0±37.3 for ventricular/atrial lesions and contrast-enhanced versus nonenhanced imaging). Conclusions— MRI allows for precise lesion visualization in electrophysiological interventions just minutes after radiofrequency ablation. Nonenhanced T2-weighted MRI is particularly feasible for intraprocedural delineation of lesion formation as lesions are detectable within minutes after radiofrequency delivery and imaging can be repeated during interventions.

Hemodynamic improvement from biventricular pacing is well documented; however, its electrophysiologic effects have not been systematically studied. In this study, incidence and risk factors for electrical storm (ES) were investigated in 729 ICD and biventricular defibrillator (CRT-D) heart failure patients.168 consecutive CRT-D and 561 ICD patients were retrospectively analyzed for the occurrence of VT/VF and predisposing factors. Electrical storm was defined as ventricular tachycardia or fibrillation ≥3 times during 24 h. Mean follow-up was 41 months.In 168 CRT-D patients only one patient experienced electrical storm compared to 39 patients out of 561 ICD patients (0.6% vs. 7%, p0.01). 33% of the patients with electrical storm died within one year. In the CRT-D group 81 patients (48%) developed VT or VF and received at least one appropriate therapy, compared to 281 patients (50%) in the ICD group. Mean ejection fraction was 21.7% in the CRT-D group and 34.7% (p0.01) in the ICD group. Stratifying the patients according to primary or secondary prevention and ejection fraction demonstrated that VT/VF clusters were significantly associated with ICD indication for secondary prevention, previous myocardial infarction and LVEF30%.The development of electrical storm is accompanied with a highly increased mortality risk even if an ICD/CRT-D is implanted. In CRT-D patients electrical storm is much less common than in ICD patients. Secondary prevention and ejection fraction30% are predictors of electrical storm. Beside hemodynamic improvements cardiac resynchronization therapy may reduce the arrhythmia burden in heart failure patients.

Introduction of a cardiac pacing lead via the subclavian artery is a rare complication in the process of pacemaker implantation. Removal of the lead from the arterial system imposes an increased risk of cerebral thrombembolism and, in case of arterial puncture, an increased risk of bleeding. Methods and results Here we describe an acute coronary syndrome caused by a pacing lead inserted via the subclavian artery with the tip implanted close to the ostium of the left coronary artery. We further describe the successful removal of the lead and give a short overview of the literature. ConclusionIn cases where a pacemaker or ICD lead has already been placed in the left ventricle for an extended period of time and there is no indication for replacement like insufficient threshold levels, infection, or thrombembolic events, the lead can be left in place and the patient be treated with anticoagulants. In asymptomatic patients with additional indications for cardiac surgery simultaneous lead extraction should be considered. In patients with a history of thrombembolic events, or in patients with other indications for lead replacement, lead extraction should preferably be performed by cardiac surgery, rather than by percutaneous extraction.

This review article summarizes results of a number of new clinical trials and registries in the field of cardiovascular medicine. Key presentations made at the 74th annual meeting of the German Cardiac Society, held in Mannheim, Germany, in March 2008 are reported. The data were presented by leading experts in the field with relevant positions in the trials and registries. These comprehensive summaries should provide the readers with the most recent data on diagnostic and therapeutic developments in cardiovascular medicine.

Rationale: The QT interval duration (QTc) reflects cardiac depolarization. It may predispose individuals to ventricular tachycardia and sudden cardiac death if prolonged (long QTc), shortened (short QTc) or otherwise unregularly. Whole-genome association studies have linked genetic variations in the neuronal nitric oxide synthase adapter protein NOS1AP to variations in QTc intervals and sudden cardiac death. Hypothesis: We hypothesize NOS1AP functions as an L-type-Ca2+ channel modulator via its interaction with the neuronal nitric oxide synthase NOS1. Therefore, alterations in myocardial NOS1AP expression should temper with QTc intervals and increase susceptibility to rhythm disorders. Methods and results: We generated conditional double transgenic mice by crossbreeding pTRE-6xHN-Nos1AP animals with α-MHC-tTA mice; NOS1AP expression is therefore restricted to cardiomyocytes and under control of doxycycline (Tet-Off system). NOS1AP overexpressing animals were investigated with the main focus upon electrophysiology. Heart rates were similar in induced and non-induced animals. NOS1AP overexpression resulted in arrhythmia already under basal conditions; we observed ventricular fibrillation and tachycardia. There was a clear decrease of QTc intervals in NOS1AP overexpressing mice paralleled by a significantly reduced survival (only 56% after 12 weeks vs 100% in non-induced mice. QTc alterations and accompanied deaths subsided upon readministration of doxycycline. We also investigated the functional effect of the human SNP rs16847548 (T/C). We found that this SNP decreased NOS1AP transcriptional activity in vitro and therefore suggest this leads to a decrease in NOS1AP expression in humans. Conclusion: Myocardial overexpression of NOS1AP leads to short QTc syndrome with increased susceptibility to atrial and ventricular rhythm disorders and cardiac death. SNP rs16847548 in NOS1AP resulted in less NOS1AP promoter activity in vitro which could explain the alteration in QTc intervals. In summary, not only mutations in ion channels themselves but also genetic alterations in the expression of ion channel modulators such as NOS1AP, have an impact on QTc intervals.

Rationale: The QT interval duration (QTc) reflects cardiac depolarization. It may predispose individuals to ventricular tachycardia and sudden cardiac death if prolonged (long QTc), shortened (short QTc) or otherwise unregularly. Whole-genome association studies have linked genetic variations in the neuronal nitric oxide synthase adapter protein NOS1AP to variations in QTc intervals and sudden cardiac death. Hypothesis: We hypothesize NOS1AP functions as an L-type-Ca2+ channel modulator via its interaction with the neuronal nitric oxide synthase NOS1. Therefore, alterations in myocardial NOS1AP expression should temper with QTc intervals and increase susceptibility to rhythm disorders. Methods and results: We generated conditional double transgenic mice by crossbreeding pTRE-6xHN-Nos1AP animals with α-MHC-tTA mice; NOS1AP expression is therefore restricted to cardiomyocytes and under control of doxycycline (Tet-Off system). Double transgenic animals were investigated with the main focus upon electrical alterations. Heart rates were similar in NOS1AP overexpressing and non-induced animals. Atrial programmed stimulation repeatedly caused atrial tachycardia, while ventricular programmed stimulation caused VT in NOS1AP overexpressing mice. There was a clear decrease of QTc intervals in NOS1AP overexpressing mice paralleld by a significantly reduced survival (only 56% after 12 weeks vs 100% in non-induced mice. Induced QTc alterations and accompanied deaths subsided upon readministration of doxycycline. We also investigated the functional effect of the human SNP rs16847548 (T/C). We found that this SNP decreased NOS1AP transcriptional activity in vitro and therefore suggest this leads to a decrease in NOS1AP expression in humans. Conclusion: Myocardial overexpression of NOS1AP leads to short QTc syndrome with increased susceptibility to atrial and ventricular rhythm disorders and cardiac death. SNP rs16847548 in NOS1AP resulted in less NOS1AP promoter activity in vitro which could explain the alteration in QTc intervals. In summary, not only mutations in ion channels themselves but also genetic alterations in the expression of ion channel modulators such as NOS1AP, have an impact on QTc intervals.

Rationale: We previously identified a mutation in the human transcriptional cofactor Eya4 as cause of familial dilated cardiomyopathy (DCM). We now provide evidence that the Eya4/Six1 signalling cascade also is crucial in acquired heart disease. Hypothesis: We hypothesize that the transcriptional complex Eya4/Six1 regulates targets relevant in normal cardiac function. We speculate it, amongst others, regulates expression of p27kip1, a known inhibitor of hypertrophy in adult cardiomyocytes, upon hypertrophic stimuli. Methods and results: We first examined the correlation of Eya4 and p27 in regards to phosphorylation and cellular distribution in failing and normal human hearts. Immunhistology revealed Eya4 is mainly distributed in the cytoplasm while p27 predominantly resides in the nucleus of healthy myocardial tissue. In sections of failing human hearts, Eya4 accumulated in the perinuclear and nuclear region; nuclear p27 levels were significantly diminished, phosphorylated p27 was evenly distributed in the cytoplasm. In a murine model of MI, IH showed Eya4 translocates in a time-dependent manner. WB analyses for p27 showed an age dependent decrease in p27 protein levels upon MI compared to control littermates. We generated transgenic mice with constitutive myocardial overexpression of Eya4 and E193. As judged by MRI, hemodynamic and morphometric analysis both transgenic mouse models developed cardiac phenotypes compared to age-matched wildtype littermates already under basal conditions in an age dependent manner. p27 expression and downstream factors were also altered in both transgenic lines as a result of Eya4, and accordingly, E193 overexpression. In summary, we provide evidence that the Eya4/Six1 signalling cascade is not only relevant in a rare version of heritable DCM but also in more common forms of acquired heart disease. Eya4/Six1 seems to regulate p27, which was shown to be an important regulator of cardiac physiology in postmitotic cardiomyocytes.

We thank Drs Reddy and Leesar for their interest in our article1 and their informative letter on the complementary use of venoarterial extracorporeal membrane oxygenation (vaECMO) and intra-aortic balloon counterpulsation (IABP). In clinical practice, IABP is frequently used as the primary method of mechanical support for patients experiencing a myocardial infarction and cardiogenic shock. This choice is often based on years of experience with the device, whereas extracorporeal support is added only if IABP support does not suffice. Recent studies suggest that the concomitant use of IABP and vaECMO can …

Background— Calcineurin (CnA) is important in the regulation of myocardial hypertrophy. We demonstrated that targeted proteolysis of the CnA autoinhibitory domain under pathological myocardial workload leads to increased CnA activity in human myocardium. Here, we investigated the proteolytic mechanism leading to activation of CnA. Methods and Results— In patients with diseased myocardium, we found strong nuclear translocation of CnA. In contrast, in normal human myocardium, there was a cytosolic distribution of CnA. Stimulation of rat cardiomyocytes with angiotensin (Ang) II increased calpain activity significantly (433±11%; P P P P =NS; n=6) after removal of Ang II. Ang II stimulation of cardiomyocytes also translocated CnA into the nucleus as demonstrated by immunohistochemical staining and transfection assays with GFP-tagged CnA. Calpain inhibition and therefore suppression of calpain-mediated proteolysis of CnA enabled CnA exit from the nucleus. Conclusions— Ang II stimulation of cardiomyocytes increased calpain activity, leading to proteolysis of the autoinhibitory domain of CnA. This causes an increase in CnA activity and results in nuclear translocation of CnA. Loss of the autoinhibitory domain renders CnA constitutively nuclear and active, even after removal of the hypertrophic stimulus.

Influenza is a common disease in the population. Influenza vaccination is performed routinely and is usually well tolerated. Minor local or systemic side effects like fever and myalgia are described. Rarely there are more severe adverse events. Systemic vasculitis has been reported in some cases. In this case we report on a female patient with secondary vasculitis and myocardial infarction after influenza vaccination. The patient received cortisol and recovered. The literature about influenza vaccination, its side effects and recommendations about vaccination in patients with coronary artery disease is reviewed.

Background — In animal models, increased signaling through the calcineurin pathway has been shown to be sufficient for the development of cardiac hypertrophy. Calcineurin activity has been reported to be elevated in the myocardium of patients with congestive heart failure. In contrast, few data are available about calcineurin activity in patients with pressure overload or cardiomyopathic hypertrophy who are not in cardiac failure. Methods and Results — We investigated calcineurin activity and protein expression in 2 different forms of cardiac hypertrophy: hypertrophic obstructive cardiomyopathy (HOCM) and aortic stenosis (AS). We found that the C-terminus of calcineurin A protein containing the autoinhibitory domain was less abundant in myocardial hypertrophy than in normal heart, which suggests the possibility of proteolysis. No new splice variants could be detected by reverse-transcription polymerase chain reaction. This resulted in a significant elevation of calcineurin enzymatic activity in HOCM and AS compared with 6 normal hearts. Increased calcineurin phosphatase activity caused increased migration of NF-AT2 (nuclear factor of activated T cells 2) in SDS-PAGE compatible with pronounced NF-AT dephosphorylation in hypertrophied myocardial tissue. Conclusions — Hypertrophy in HOCM and AS without heart failure is characterized by a significant increase in calcineurin activity. This might occur by (partial) proteolysis of the calcineurin A C-terminus containing the autoinhibitory domain. Increased calcineurin activity has functional relevance, as shown by altered NF-AT phosphorylation state. Although hypertrophy in AS and HOCM may be initiated by different upstream triggers (internal versus external fiber overload), in both cases, there is activation of calcineurin, which suggests an involvement of this pathway in the pathogenesis of human cardiac hypertrophy.

Background: Congenital long- or short-QT syndrome may lead to life-threatening ventricular tachycardia and sudden cardiac death. Apart from rare disease-causing mutations in ion channels, common genetic variations in the neuronal nitric oxide synthase (NOS1) regulator NOS1AP, have recently been associated with QT interval variations in a human whole-genome association study. In fact, NOS1AP SNPs have been linked to increases in QTc intervals and sudden cardiac death. We therefore speculate that myocardial NOS1AP overexpression may lead to a decrease of the QTc interval and an increased susceptibility to rhythm disorders. Methods and Results: We generated transgenic mice (TG) with a conditional myocardial NOS1AP overexpression and focused on electrical alterations. Conditional overexpression of NOS1AP resulted in a 147% ventricular increase in TG mice compared to WT littermates. NOS1AP was mainly located at the sarcolemma where it interacted with NOS1 and the L-type Ca2+- channel. HW/BW ratio, ventricular ANP expression, ventricular cross-sectional area and collagen deposition were not altered in NOS1AP mice under baseline conditions. However, NOS1AP overexpressing mice showed a clear decrease of QTc intervals (33 vs. 48 ms). They were more prone to bradycardia (resting heart rate 467 bpm vs. 666 bpm). Atrial programmed stimulation repeatedly caused atrial tachycardia. Ventricular programmed stimulation caused VT in some mice with NOS1AP overexpression. We also investigated the functional effect of the human rs16847548 (T/C). We found that this SNP decreased NOS1AP promoter activity in a viral NOS1AP luciferase assay, suggesting that this SNP downregulates NOS1AP expression in humans. Conclusion: Myocardial overexpression of NOS1AP leads to a significant shortening of the QTc interval with an increased susceptibility to atrial and ventricular rhythm disorders. SNP rs16847548 in NOS1AP resulted in downregulation of NOS1AP expression which provides an explanation for elongation of QTc intervals. In summary, not only a mutation in ion channels itself but also genetic alterations in expression of ion channel modifiers, such as NOS1AP, have an impact on QTc intervals.

Introduction: E193, a human mutation in the transcription cofactor Eyes absent 4 (EYA4) causes hearing impairment followed by terminal heart failure, defining an important role for Eya4 in maintaining normal cardiac function. METHODS AND RESULTS: First, in-vitro experiments show that overexpression of Eya4 and the mutant isoform alter the expression of p27kip1 on both, transcript and protein levels. Next, we generated transgenic mice with cardiomyocyte-specific Eya4 or E193 overexpression to elucidate the in vivo function of Eya4 upon cardiac physiology. Luciferase and CHIP assays revealed that Eya4 and E193 bind to and regulate p27 expression in a contradictory manner, as already seen in vitro. Activity and phoshorylation of the downstream molecules CK2α and HDAC2 were significantly elevated in Eya4 mice, whereas they were significantly reduced in E193 animals compared to WT littermates. MRI and hemodynamic analysis indicate that a constitutive overexpression of Eya4 results in the age-dependent development of hypertrophy already under baseline conditions with no obvious functional effects, whereas E193 overexpressing animals develop onset of dilative cardiomyopathy as seen in human patients carrying the E193 mutation. Morphometric analysis proved ventricular hypertrophy or dilation of the LV associated with a thinning of the myocardial wall, interstitial fibrosis of myocardial tissue and alterations in cell size. Re-activation of fetal genes also occured in both TG models, characteristic for cardiac disease. Both cardiac phenotypes were aggravated upon pressure overload. Finally, we identified a new human heterozygous truncating Eya4 mutation, E215, which leads to similar clinical features of disease and a stable myocardial expression of the mutant protein. Conclusion: Our results implicate that Eya4 plays a critical role in regulating normal cardiac physiology and function via Six1/p27/CK2α/HDAC2 and that an imbalance within the Eya4/Six1 transcriptional complex leads to an age dependent onset of cardiomyopthy and heart failure.

Magnetic resonance imaging (MRI) has long been regarded a general contraindication in patients with cardiovascular implanted electronic devices such as cardiac pacemakers or cardioverter defibrillators (ICDs) due to the risk of severe complications and even deaths caused by interactions of the magnetic resonance (MR) surrounding and the electric devices. Over the last decade, a better understanding of the underlying mechanisms responsible for such potentially life-threatening complications as well as technical advances have allowed an increasing number of pacemaker and ICD patients to safely undergo MRI. This review lists the key findings from basic research and clinical trials over the last 20 years, and discusses the impact on current day clinical practice. With ‘MR-conditional’ devices being the new standard of care, MRI in pacemaker and ICD patients has been adopted to clinical routine today. However, specific precautions and specifications of these devices should be carefully followed if possible, to avoid patient risks which might appear with new MR technology and further increasing indications and patient numbers.

Introduction: Eyes absent 4 (Eya4) is a transcription cofactor involved in a number of cellular and developmental processes. We have previously shown that a truncating mutation in Eya4, E193, causes hearing impairment followed by terminal heart failure suggesting Eya4 is a regulator in cardiac physiology. Methods and Results: Transgene- or adenovirus mediated overexpression of Eya4 or E193 altered the expression of p27kip1, a critical mediator of cardiac hypertrophy in adult cardiomyocytes. Luciferase reporter and EMSA assays revealed that Eya4 directly binds to and suppresses p27kip1 promoter activity, while E193 exerts an opposing effect, respectively. Activity and phosphorylation of downstream molecules were significantly altered in Eya4 and E193 transgenic (TG) mice in a contradictory manner. Cardiac phenotypes evolved in both TG models already under basal conditions. Eya4 TG hearts developed hypertrophy as judged by increases in heart weight and cross-sectional cell surfaces and re-activation of fetal genes as well as fibrosis. E193 TG animals showed onset of DCM along with wall thinning, ventricular dilation, fibrosis and slightly compromised cardiac function. These two distinct cardiac phenotypes were even more aggravated upon pressure overload or Angiotensin II infusion. Finally, we just recently identified a new mutation in Eya4, E215, which also causes hearing impairment and heart failure. Conclusion: Our data indicate that Eya4, in a physical complex with Six1, plays a critical role in regulating normal cardiac function via p27/CK2-α/HDAC2 and allude that mutations within the Exa4/Six1 transcriptional complex interfere with this newly established signalling pathway, finally leading to age-related onset of cardiomyopathy. Clinical Perspective: Gaining a better understanding of this disease mechanism could help identify new treatment options for heart failure patients.

Introduction: E193, a truncating mutation in the transcription cofactor Eyes absent 4 (Eya4) causes hearing impairment followed by heart failure. Here we identified the Eya4 dependent molecular mechanisms leading to the cardiac phenotype in the E193 mutation. Methods and Results: First we showed in vitro that the cyclin-dependent kinase inhibitor protein p27kip1 is a direct target of Eya4/Six1 and is suppressed upon Eya4 overexpression, whereas E193 has a dominant negative effect, releasing Eya4 mediated suppression of p27. We next generated transgenic mice with cardiac specific constitutive overexpression of full-length Eya4 or the mutant form E193. While E193 transgenic mice developed age-dependent DCM, Eya4 mice displayed cardiac hypertrophy already under basal conditions as judged by increases in heart weight and cardiomyocyte cross-sectional areas along with increases in myocardial dimension and mass. These two distinct cardiac phenotypes were even more aggravated upon pressure overload suggesting Eya4 is a regulator of cardiac hypertrophy. We also observed that the activity of Casein Kinase 2-α and the phosphorylation status of HDAC2 were significantly upregulated in the Eya4 transgenic mice, while they were significantly reduced in E193 mice, under baseline conditions and pressure overload. We were also able to identify a new human mutation (E215) with a phenotype comparable to the one seen in E193 patients. Conclusion: Our results implicate that Eya4/Six1 regulates cardiac hypertrophic reactions via p27/CK2-α/HDAC2 and indicate that truncating mutations in Eya4 interfere with this newly established signalling pathway.

Background: Surgical procedures in small animal models of heart disease, such as artificial ligation of the coronary arteries for experimental myocardial infarction, can evoke alterations in cardiac morphology and function. Such alterations might induce artificial early or long term effects in vivo that might account for a significant bias in basic cardiovascular research, and, therefore, could potentially question the meaning of respective studies in small animal models of heart disease. Methods: Female Wistar rats were matched for weight and distributed to sham left coronary artery ligation or untreated control. Cardiac parameters were then investigated in vivo by high-field MRI over time after the surgical procedure, determining left and right ventricular morphology and function. Additionally, the time course of several metabolic and inflammatory blood parameters was determined. Results: Rats after sham surgery showed a lower body weight for up to 8 weeks after the intervention compared to healthy controls. Left and right ventricular morphology and function were not different in absolute measures in both groups 1 week after surgery. However, there was a confined difference in several cardiac parameters normalized to the body weight (bw), such as myocardial mass (2.19±0.30/0.83±0.13 vs. 1.85±0.22/0.70±0.07 mg left/right per g bw, p Conclusion: There is a small distinct impact of cardio-thoracic surgical procedures on the global integrity of the organism, which in the long term also includes circumscribed repercussions on cardiac morphology and function. This impact has to be considered when analyzing data from respective studies and transferring the findings to conditions in patients.

Chagas disease and its causative agent Trypanosoma cruzi are endemic in almost all countries in South and Middle America. Currently, there are more than 10 million affected people. It is the most common reason for heart failure and a frequent cause of intestinal problems in Latin America. The phenotype of the Chagas cardiomyopathy is varying. Dilative cardiomyopathy, often accompanied by an apical aneurysm is the most common finding in the end stage heart failure, but rhythm disorders like conduction blocks, ventricular or supraventricular forms of tachycardia or repolarization changes occur as well, mainly in the early stages. Migration of infected people leads to a distribution from the endemic countries to North America and Europe. Although more than 500,000 people of Latin American origin are currently living in Europe, Chagas disease is not considered as a public health problem, yet. Cases of transmission via blood donation, organ transplantation or from mother-to-child are reported for several European countries but there is no database for Germany. Current epidemiological data are mostly available from regional surveys from other countries or are extrapolated. Hence, there is a large variation in the estimated numbers on the incidence of Chagas. Robust and reliable data are lacking. This review gives an overview on the currently available data and calls for a German Chagas surveillance.

Introduction: Eyes absent 4 (Eya4) is a transcription cofactor involved in a number of cellular and developmental processes. We have previously shown that a mutation in Eya4 (E193) leads to late-onset familial dilated cardiomyopathy and heart failure. A precise role for Eya4 in the myocardium has not yet been identified. It appears to regulate the cyclin dependent kinase inhibitor p27 kip1 (p27), a protein shown to regulate hypertrophic responses in the adult cardiomyocyte. This study was aimed to explore the role of Eya4 in induced cardiac hypertrophy. Methods and results: We generated transgenic mice with cardiac-specific overexpression of HA-tagged Eya4 or E193 to elucidate the function of these proteins in the development of heart failure in vivo . These and wildtype littermates were challenged with angiotensin II (ATII) or subjected to transaortic constriction (TAC). Magnetic resonance imaging to visualize cardiac structures in detail showed that in response to sustained ATII stimulation and TAC, Eya4 mice exhibited a phenotype with significantly increased parameters of hypertrophy compared to WT and E193 overexpressing animals as judged by increases in heart weight and LV free wall diameter, cross-sectional cell surface areas and fibrosis. MRI also showed mild cardiac hypertrophy in Eya4 transgenic mice already under baseline conditions in an age dependent fashion. Moreover, Eya4 overexpression induced a significant suppression of p27 protein expression and resulted in increased levels of phosphorylated histone deacetylase 2 (HDAC2). E193 overexpression induced age dependent wall thinning and ventricular dilation under baseline conditions with no obvious structural or functional defects. ATII or TAC induced significant changes in HW/BW ratio, IVS, fibrosis, hemodynamic and cell size measurements, albeit to a lesser extent than seen with Eya4 mice. p27 expression and pHDAC2 levels were only slightly altered. Conclusion: In summary, we have demonstrated a mutation in Eya4 to disturb cardiac physiology. We now provide evidence that Eya4 is also involved in forms of acquired heart disease. It seems to suppress p27, which leads to phosphorylation and activation of HDAC2 and results in the development of cardiac hypertrophy.