Divergent cardiac and renal effects of miR-181c-5p inhibition in a rodent heart failure model.

Aims: MiR-181c-5p overexpression associates with heart failure (HF) and cardiac damage, but the underlying pathophysiology remains unclear. This study investigated the effect of miR-181c-5p inhibition on cardiac function and fibrosis in a rodent model of diastolic dysfunction, and evaluated additional effects on kidney as relevant comorbid organ. Methods and results: Diastolic dysfunction was induced in male C57/BL6J mice (n = 20) by combining high-fat diet, L-NG-nitroarginine methyl ester, and angiotensin II administration, and was compared to sham controls (n = 18). Mice were randomized to subcutaneous miR-181c-5p antagomiR (INH) or scrambled antagomiR injections (40 mg/kg/week). HF mice demonstrated diastolic dysfunction and increased fibrosis, which was attenuated by INH treatment. Remarkably, HF + INH animals had a threefold higher mortality rate (60%) compared to HF controls (20%). Histological examination revealed increased glomerular damage in all INH treated mice, and signs of thrombotic microangiopathy (TMA) in mice who died prematurely. Quantitative polymerase chain reaction demonstrated a miR-181c-5p-related downregulation of cardiac but not renal Tgfbr1 in HF + INH mice, while INH treatment reduced renal but not cardiac Vegfa expression in all mice. Conclusion: This study demonstrates cardiac anti-fibrotic effects of miR-181c-5p inhibition in a rodent HF model through targeting of Tgfbr1 in the heart. Despite improved diastolic function, HF + INH mice had higher mortality due to increased predisposition for TMA, increased renal fibrosis and glomerular damage, associated with Vegfa downregulation in kidneys.

Pathophysiology and clinical relevance of atrial myopathy.

Atrial myopathy is a condition that consists of electrical, structural, contractile, and autonomic remodeling of the atria and is the substrate for development of atrial fibrillation, the most common arrhythmia. Pathophysiologic mechanisms driving atrial myopathy are inflammation, oxidative stress, atrial stretch, and neurohormonal signals, e.g., angiotensin-II and aldosterone. These mechanisms initiate the structural and functional remodeling of the atrial myocardium. Novel therapeutic strategies are being developed that target the pathophysiologic mechanisms of atrial myopathy. In this review, we will discuss the pathophysiology of atrial myopathy, as well as diagnostic and therapeutic strategies.

Peripheral Microvascular Dysfunction in Children and Adults with Congenital Heart Disease: A Literature Review.

Although there is a continually growing number of patients with congenital heart disease (CHD) due to medical and surgical advances, these patients still have a poorer prognosis compared to healthy individuals of similar age. In patients with heart failure, microvascular dysfunction (MVD) has recently emerged as a crucial modulator of disease initiation and progression. Because of the substantial pathophysiological overlap between CHD and heart failure induced by other etiologies, MVD could be important in the pathophysiology of CHD as well. MVD is believed to be a systemic disease and may be manifested in several vascular beds. This review will focus on what is currently known about MVD in the peripheral vasculature in CHD. Therefore, a search on the direct assessment of the vasodilatory capacity of the peripheral microcirculation in patients with CHD was conducted in the PubMed database. Since there is little data available and the reported studies are also very heterogeneous, peripheral MVD in CHD is not sufficiently understood to date. Its exact extent and pathophysiological relevance remain to be elucidated in further research.

Elevated oxidative stress in patients with congenital heart disease and the effect of cyanosis: a meta-analysis.

Oxidative stress is an important pathophysiological mechanism in the development of numerous cardiovascular disorders. To improve therapy and preventive strategies, clinicians need a better understanding of the underlying pathophysiological mechanisms of congenital heart diseases (CHD). The objective of this meta-analysis was to determine whether oxidative stress is elevated in patients with CHD compared to healthy controls, and to evaluate whether a difference in oxidative stress parameters can be observed between patients with cyanotic (cCHD) and acyanotic CHD (aCHD). Therefore, 21 studies investigating oxidative stress in peripheral blood of both children and adults with CHD were reviewed. Different methods to assess the oxidant status were compared and divided into three categories: pro-oxidative or anti-oxidative stress markers and the ratio of pro-to-anti oxidative stress markers. This meta-analysis showed elevated oxidative stress levels in patients with CHD, and more specifically in patients with cCHD. Moreover, this indicates that there could be potential in oxidative stress measurements as a new biomarker of disease severity. Further research will be needed to clarify the exact role of oxidative stress and its contributors in CHD in order to get a better and more in-depth understanding of the underlying pathophysiology of CHD, especially the higher susceptibility of the right ventricle (RV) to progress to heart failure (HF). This could facilitate the development of antioxidant treatments and RV-specific HF therapies, which are necessary to improve survival in these patients and could be of particular importance in cCHD.

Fluorescent In Situ Hybridization for miRNA Combined with Staining of Proteins.

The last decades have illustrated the importance of microRNAs (miRNAs) in various biological and pathological processes. The combined visualization of miRNAs using fluorescent in situ hybridization (FISH) and proteins using immunofluorescence (IF) can reveal their spatiotemporal distribution in relation to the cell and tissue morphology and can provide interesting insights into miRNA-protein interactions. However, standardized protocols for co-localization of miRNAs and proteins are currently lacking, and substantial technical obstacles still need to be addressed. In particular, the incompatibility of protein IF protocols with steps required for miRNA FISH, such as proteolytic pretreatments and ethylcarbodiimide post-fixation, as well as hurdles related to low signal intensity of low-copy miRNAs, remains challenging. Our technique may considerably enhance miRNA-based research, as current detection techniques lack the ability to elucidate cellular and subcellular localization. Here, we describe an optimized 2-day protocol for combined detection of low-abundant miRNAs and proteins in cryosections of cardiac tissue, without the need for protease-dependent pretreatment or post-fixation treatment. We successfully demonstrate endothelial-specific localization of low-abundant miR-181c-5p in cardiac tissue. © 2023 Wiley Periodicals LLC. Basic Protocol: Fluorescent in situ hybridization for miRNA combined with staining of proteins.

Endothelial dysfunction at the cellular level in three dimensions: severity, acuteness, and distribution.

Dysfunction or failure of the endothelial organ is a heterogenous and often ill-described feature of both cardiovascular and noncardiovascular disorders. Although seldom recognized as a separate clinical condition, endothelial cell dysfunction (ECD) is an established catalyst of disease. However, even in recent pathophysiological studies, ECD is frequently oversimplified as a binary state without gradation, based on the assessment of a single function (e.g., synthesis or activity of nitric oxide) and without considering spatiotemporal dimensions (local vs. generalized, acute vs. chronic). In this article, we suggest a simple scale to grade the severity of ECD and a definition of ECD in three dimensions: space, time, and severity. We also adopt a broader perspective on ECD by integrating and comparing gene expression data of endothelial cells from different organs and diseases and propose a concept that links common pathophysiological mechanisms. We hope that this will enhance the understanding of the pathophysiology of ECD and stimulate discussion in this field.

Coronary Microvascular Dysfunction in Patients with Congenital Heart Disease.

Congenital heart diseases represent a wide range of cardiac malformations. Medical and surgical advances have dramatically increased the survival of patients with congenital heart disease, leading to a continuously growing number of children, adolescents, and adults with congenital heart disease. Nevertheless, congenital heart disease patients have a worse prognosis compared to healthy individuals of similar age. There is substantial overlap in the pathophysiology of congenital heart disease and heart failure induced by other etiologies. Among the pathophysiological changes in heart failure, coronary microvascular dysfunction has recently emerged as a crucial modulator of disease initiation and progression. Similarly, coronary microvascular dysfunction could be important in the pathophysiology of congenital heart diseases as well. For this systematic review, studies on maximal vasodilatory capacity in the coronary microvascular bed in patients with congenital heart disease were searched using the PubMed database. To date, coronary microvascular dysfunction in congenital heart disease patients is incompletely understood because studies on this topic are rare and heterogeneous. The prevalence, extent, and pathophysiological relevance of coronary microvascular dysfunction in congenital heart diseases remain to be elucidated. Herein, we discuss what is currently known about coronary microvascular dysfunction in congenital heart disease and future directions.

Circulating Reactive Oxygen Species in Adults with Congenital Heart Disease.

Oxidative stress is an important pathophysiological mechanism in the development of numerous cardiovascular disorders, but few studies have examined the levels of oxidative stress in adults with congenital heart disease (CHD). The objective of this study was to investigate oxidative stress levels in adults with CHD and the association with inflammation, exercise capacity and endothelial function. To this end, 36 adults with different types of CHD and 36 age- and gender-matched healthy controls were enrolled. Blood cell counts, hs-CRP, NT-proBNP, fasting glucose, cholesterol levels, iron saturation and folic acid concentrations were determined in venous blood samples. Levels of superoxide anion radical in whole blood were determined using electron paramagnetic resonance spectroscopy in combination with the spin probe CMH. Physical activity was assessed with the IPAQ-SF questionnaire. Vascular function assessment (EndoPAT) and cardiopulmonary exercise testing were performed in the patient group. Superoxide anion radical levels were not statistically significantly different between adults with CHD and the matched controls. Moreover, oxidative stress did not correlate with inflammation, or with endothelial function or cardiorespiratory fitness in CHD; however, a significant negative correlation with iron saturation was observed. Overall, whole blood superoxide anion radical levels in adults with CHD were not elevated, but iron levels seem to play a more important role in oxidative stress mechanisms in CHD than in healthy controls. More research will be needed to improve our understanding of the underlying pathophysiology of CHD.

Cardiac electrophysiology studies in mice via the transjugular route: a comprehensive practical guide.

Cardiac arrhythmias are associated with cardiovascular morbidity and mortality. Cardiac electrophysiology studies (EPS) use intracardiac catheter recording and stimulation for profound evaluation of the heart's electrical properties. The main clinical application is investigation and treatment of rhythm disorders. These techniques have been translated to the murine setting to open opportunities for detailed evaluation of the impact of different characteristics (including genetics) and interventions on cardiac electrophysiology and -pathology. Currently, a detailed description of the technique of murine transjugular EPS (which is the standard route of catheter introduction) is lacking. This article provides detailed information on EPS in mice via the transjugular route. This includes catheter placement, stimulation protocols, intracardiac tracing interpretation, artifact reduction, and surface ECG recording. In addition, reference values as obtained in C57BL/6N mice are presented for common electrophysiological parameters. This detailed methodological description aims to increase accessibility and standardization of EPS in mice. Ultimately, also human research and patient care may benefit from translation of the knowledge obtained in preclinical models using this technique.NEW & NOTEWORTHY Electrophysiology studies (EPS) allow in-depth evaluation of cardiac electrophysiology and -pathology. These techniques have been adapted to the murine setting for (translational) studies, mainly focusing on arrhythmogenesis. Despite the frequent application of EPS via the transjugular route, a thorough description of the technique is currently lacking. This article aims to function as a comprehensive guide, also elaborating (for the first time) on nonsurgical aspects such as catheter positioning, tracing artifacts, stimulation protocols, and reference values.

Intracoronary Lithotripsy in Calcified Coronary Lesions: A Multicenter Observational Study.

OBJECTIVES: The aim of this study was to evaluate the feasibility, effectiveness, and safety of coronary intravascular lithotripsy (IVL; Shockwave Medical) in the treatment of severe coronary artery calcification (CAC) in a real-world setting. BACKGROUND: Severe CAC can be an arduous obstacle in interventional cardiology, often leading to suboptimal results of percutaneous coronary interventions (PCI). Coronary IVL is a novel technique that modulates severe CAC, thereby facilitating stent implantation. METHODS AND RESULTS: In this multicenter observational study, data from 134 IVL procedures in 5 Belgian hospitals were prospectively obtained. Successful delivery of the IVL catheter was achieved in all cases but 1 (99.3%). The primary endpoint was final overall procedural success, which was obtained in 88.1% of cases, an aggregate of 92.6% in de novo lesions and 77.5% in stent underexpansion or in-stent restenosis (ISR). IVL therapy effect was considered successful by the operators in 94% of cases, with 68.7% achieving optimal and 25.3% achieving suboptimal results. The 1-month major adverse cardiovascular event rate was 3%, including 2 cardiovascular deaths (1 in-stent thrombosis and 1 coronary artery perforation). CONCLUSIONS: This real-world experience suggests that Shockwave IVL is a feasible, effective, and safe technique for the treatment of heavily calcified coronary lesions.

The coronary and microcirculatory measurements in patients with aortic valve stenosis study: rationale and design.

Although concomitant coronary artery disease (CAD) is frequent in patients with severe aortic stenosis (AS), hemodynamic assessment of CAD severity in patients undergoing valve replacement for severe AS is challenging. Myocardial hypertrophic remodeling interferes with coronary blood flow and may influence the values of fractional flow reserve (FFR) and nonhyperemic pressure ratios (NHPRs). The aim of the current study is to investigate the effect of the AS and its treatment on current indices used for evaluation of CAD. We will compare intracoronary hemodynamics before, immediately after, and 6 mo after aortic valve replacement (AVR) when it is expected that microvascular function has improved. Furthermore, we will compare FFR and resting full-cycle ratio (RFR) with myocardial perfusion single-photon emission-computed tomography (SPECT) as indicators of myocardial ischemia in patients with AS and CAD. One-hundred consecutive patients with AS and intermediate CAD will be prospectively included. Patients will undergo pre-AVR SPECT and intracoronary hemodynamic assessment at baseline, immediately after valve replacement [if transcatheter AVR (TAVR) is chosen], and 6 mo after AVR. The primary end point is the change in FFR 6 mo after AVR. Secondary end points include the acute change of FFR after TAVR, the diagnostic accuracy of FFR versus RFR compared with SPECT for the assessment of ischemia, changes in microvascular function as assessed by the index of microcirculatory resistance (IMR), and the effect of these changes on FFR. The present study will evaluate intracoronary hemodynamic parameters before, immediately after, and 6 mo after AVR in patients with AS and intermediate coronary stenosis. The understanding of the impact of AVR on the assessment of FFR, NHPR, and microvascular function may help guide the need for revascularization in patients with AS and CAD planned for AVR.

Sterile Pericarditis in Aachener Minipigs As a Model for Atrial Myopathy and Atrial Fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia caused by structural remodeling of the atria, also called atrial myopathy. Current therapies only target the electrical abnormalities and not the underlying atrial myopathy. For the development of novel therapies, a reproducible large animal model of atrial myopathy is necessary. This paper presents a model of sterile pericarditis-induced atrial myopathy in Aachener minipigs. Sterile pericarditis was induced by spraying sterile talcum and leaving a layer of sterile gauze over the atrial epicardial surface. This led to inflammation and fibrosis, two crucial components of the pathophysiology of atrial myopathy, making the atria susceptible to the induction of AF. Two pacemaker electrodes were positioned epicardially on each atrium and connected to two pacemakers from different manufacturers. This strategy allowed for repeated non-invasive atrial programmed stimulation to determine the inducibility of AF at specified time points after surgery. Different protocols to test AF inducibility were used. The advantages of this model are its clinical relevance, with AF inducibility and the rapid induction of inflammation and fibrosis-both present in atrial myopathy-and its reproducibility. The model will be useful in the development of novel therapies targeting atrial myopathy and AF.

ERBB4 and Multiple MicroRNAs That Target ERBB4 Participate in Pregnancy-Related Cardiomyopathy.

BACKGROUND: Peripartum cardiomyopathy (PPCM) is a life-threatening disease in women without previously known cardiovascular disease. It is characterized by a sudden onset of heart failure before or after delivery. Previous studies revealed that the generation of a 16-kDa PRL (prolactin) metabolite, the subsequent upregulation of miR-146a, and the downregulation of the target gene Erbb4 is a common driving factor of PPCM. METHODS: miRNA profiling was performed in plasma of PPCM patients (n=33) and postpartum-matched healthy CTRLs (controls; n=36). Elevated miRNAs in PPCM plasma, potentially targeting ERBB4 (erythroblastic leukemia viral oncogene homolog 4), were overexpressed in cardiomyocytes using lentiviral vectors. Next, cardiac function, cardiac morphology, and PPCM phenotype were investigated after recurrent pregnancies of HZ (heterozygous) cardiomyocyte-specific Erbb4 mice (Erbb4F/+ αMHC-Cre+, n=9) with their age-matched nonpregnant CTRLs (n=9-10). RESULTS: Here, we identify 9 additional highly conserved miRNAs (miR-199a-5p and miR-199a-3p, miR-145a-5p, miR-130a-3p, miR-135a-5p, miR-221-3p, miR-222-3p, miR-23a-3p, and miR19b-3p) that target tyrosine kinase receptor ERBB4 and are over 4-fold upregulated in plasma of PPCM patients at the time of diagnosis. We confirmed that miR-146a, miR-199a-5p, miR-221-3p, miR-222-3p, miR-23a-3p, miR-130a-5p, and miR-135-3p overexpression decreases ERBB4 expression in cardiomyocytes (-29% to -50%; P<0.05). In addition, we demonstrate that genetic cardiomyocyte-specific downregulation of Erbb4 during pregnancy suffices to induce a variant of PPCM in mice, characterized by left ventricular dilatation (postpartum second delivery: left ventricular internal diameter in diastole, +19±7% versus HZ-CTRL; P<0.05), increased atrial natriuretic peptide (ANP) levels (4-fold increase versus HZ-CTRL mice, P<0.001), decreased VEGF (vascular endothelial growth factor) and VE-cadherin levels (-33±17%, P=0.07; -27±20%, P<0.05 versus HZ-CTRL), and histologically enlarged cardiomyocytes (+20±21%, versus HZ-CTRL, P<0.05) but without signs of myocardial apoptosis and inflammation. CONCLUSIONS: ERBB4 is essential to protect the maternal heart from peripartum stress. Downregulation of ERBB4 in cardiomyocytes induced by multiple miRNAs in the peripartum period may be crucial in PPCM pathophysiology. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00998556.

Neuregulin-1 compensates for endothelial nitric oxide synthase deficiency.

Endothelial cells (ECs) secrete different paracrine signals that modulate the function of adjacent cells; two examples of these paracrine signals are nitric oxide (NO) and neuregulin-1 (NRG1), a cardioprotective growth factor. Currently, it is undetermined whether one paracrine factor can compensate for the loss of another. Herein, we hypothesized that NRG1 can compensate for endothelial NO synthase (eNOS) deficiency. We characterized eNOS null and wild-type (WT) mice by cardiac ultrasound and histology and we determined circulating NRG1 levels. In a separate experiment, eight groups of mice were divided into four groups of eNOS null mice and WT mice; half of the mice received angiotensin II (ANG II) to induce a more severe phenotype. Mice were randomized to daily injections with NRG1 or vehicle for 28 days. eNOS deficiency increased NRG1 plasma levels, indicating that ECs increase their NRG1 expression when NO production is deleted. eNOS deficiency also increased blood pressure, lowered heart rate, induced cardiac fibrosis, and affected diastolic function. In eNOS null mice, ANG II administration not only increased cardiac fibrosis but also induced cardiac hypertrophy and renal fibrosis. NRG1 administration prevented cardiac and renal hypertrophy and fibrosis caused by ANG II infusion and eNOS deficiency. Moreover, Nrg1 expression in the myocardium is shown to be regulated by miR-134. This study indicates that administration of endothelium-derived NRG1 can compensate for eNOS deficiency in the heart and kidneys.NEW & NOTEWORTHY ECs compensate for eNOS deficiency by increasing the secretion of NRG1. NRG1 administration prevents cardiac and renal hypertrophy and fibrosis caused by ANG II infusion and eNOS deficiency. NRG1 expression is regulated by miR-134.

Autocrine Signaling in Cardiac Remodeling: A Rich Source of Therapeutic Targets.

The myocardium consists of different cell types, of which endothelial cells, cardiomyocytes, and fibroblasts are the most abundant. Communication between these different cell types, also called paracrine signaling, is essential for normal cardiac function, but also important in cardiac remodeling and heart failure. Systematic studies on the expression of ligands and their corresponding receptors in different cell types showed that for 60% of the expressed ligands in a particular cell, the receptor is also expressed. The fact that many ligand-receptor pairs are present in most cells, including the major cell types in the heart, indicates that autocrine signaling is a widespread phenomenon. Autocrine signaling in cardiac remodeling and heart failure is involved in all pathophysiological mechanisms generally observed: hypertrophy, fibrosis, angiogenesis, cell survival, and inflammation. Herein, we review ligand-receptor pairs present in the major cardiac cell types based on RNA-sequencing expression databases, and we review current literature on extracellular signaling proteins with an autocrine function in the heart; these include C-type natriuretic peptide, fibroblast growth factors 2, F21, and 23, macrophage migration inhibitory factor, heparin binding-epidermal growth factor, angiopoietin-like protein 2, leptin, adiponectin, follistatin-like 1, apelin, neuregulin 1, vascular endothelial growth factor, transforming growth factor ß, wingless-type integration site family, member 1-induced secreted protein-1, interleukin 11, connective tissue growth factor/cellular communication network factor, and calcitonin gene‒related peptide. The large number of autocrine signaling factors that have been studied in the literature supports the concept that autocrine signaling is an essential part of myocardial biology and disease.

The role of endothelial autocrine NRG1/ERBB4 signaling in cardiac remodeling.

Neuregulin-1 (NRG1) is a paracrine growth factor, secreted by cardiac endothelial cells (ECs) in conditions of cardiac overload/injury. The current concept is that the cardiac effects of NRG1 are mediated by activation of erythroblastic leukemia viral oncogene homolog (ERBB)4/ERBB2 receptors on cardiomyocytes. However, recent studies have shown that paracrine effects of NRG1 on fibroblasts and macrophages are equally important. Here, we hypothesize that NRG1 autocrine signaling plays a role in cardiac remodeling. We generated EC-specific Erbb4 knockout mice to eliminate endothelial autocrine ERBB4 signaling without affecting paracrine NRG1/ERBB4 signaling in the heart. We first observed no basal cardiac phenotype in these mice up to 32 wk. We next studied these mice following transverse aortic constriction (TAC), exposure to angiotensin II (ANG II), or myocardial infarction in terms of cardiac performance, myocardial hypertrophy, myocardial fibrosis, and capillary density. In general, no major differences between EC-specific Erbb4 knockout mice and control littermates were observed. However, 8 wk following TAC both myocardial hypertrophy and fibrosis were attenuated by EC-specific Erbb4 deletion, albeit these responses were normalized after 20 wk. Similarly, 4 wk after ANG II treatment, myocardial fibrosis was less pronounced compared with control littermates. These observations were supported by RNA-sequencing experiments on cultured endothelial cells showing that NRG1 controls the expression of various hypertrophic and fibrotic pathways. Overall, this study shows a role of endothelial autocrine NRG1/ERBB4 signaling in the modulation of hypertrophic and fibrotic responses during early cardiac remodeling. This study contributes to understanding the spatiotemporal heterogeneity of myocardial autocrine and paracrine responses following cardiac injury.NEW & NOTEWORTHY The role of NRG1/ERBB signaling in endothelial cells is not completely understood. Our study contributes to the understanding of spatiotemporal heterogeneity of myocardial autocrine and paracrine responses following cardiac injury and shows a role of endothelial autocrine NRG1/ERBB4 signaling in the modulation of hypertrophic and fibrotic responses during early cardiac remodeling.

INSPIRE: A European training network to foster research and training in cardiovascular safety pharmacology.

Safety pharmacology is an essential part of drug development aiming to identify, evaluate and investigate undesirable pharmacodynamic properties of a drug primarily prior to clinical trials. In particular, cardiovascular adverse drug reactions (ADR) have halted many drug development programs. Safety pharmacology has successfully implemented a screening strategy to detect cardiovascular liabilities, but there is room for further refinement. In this setting, we present the INSPIRE project, a European Training Network in safety pharmacology for Early Stage Researchers (ESRs), funded by the European Commission's H2020-MSCA-ITN programme. INSPIRE has recruited 15 ESR fellows that will conduct an individual PhD-research project for a period of 36 months. INSPIRE aims to be complementary to ongoing research initiatives. With this as a goal, an inventory of collaborative research initiatives in safety pharmacology was created and the ESR projects have been designed to be complementary to this roadmap. Overall, INSPIRE aims to improve cardiovascular safety evaluation, either by investigating technological innovations or by adding mechanistic insight in emerging safety concerns, as observed in the field of cardio-oncology. Finally, in addition to its hands-on research pillar, INSPIRE will organize a number of summer schools and workshops that will be open to the wider community as well. In summary, INSPIRE aims to foster both research and training in safety pharmacology and hopes to inspire the future generation of safety scientists.

The role of ErbB4 in cancer.

BACKGROUND: The epidermal growth factor receptor family consists of four members, ErbB1 (epidermal growth factor receptor-1), ErbB2, ErbB3, and ErbB4, which all have been found to play important roles in tumor development. ErbB4 appears to be unique among these receptors, because it is the only member with growth inhibiting properties. ErbB4 plays well-defined roles in normal tissue development, in particular the heart, the nervous system, and the mammary gland system. In recent years, information on the role of ErbB4 in a number of tumors has emerged and its general direction points towards a tumor suppressor role for ErbB4. However, there are some controversies and conflicting data, warranting a review on this topic. CONCLUSIONS: Here, we discuss the role of ErbB4 in normal physiology and in breast, lung, colorectal, gastric, pancreatic, prostate, bladder, and brain cancers, as well as in hepatocellular carcinoma, cholangiocarcinoma, and melanoma. Understanding the role of ErbB4 in cancer is not only important for the treatment of tumors, but also for the treatment of other disorders in which ErbB4 plays a major role, e.g. cardiovascular disease.

Coronary-subclavian steal syndrome, an easily overlooked entity in interventional cardiology.

Coronary-subclavian steal syndrome (CSSS) is a severe complication of coronary artery bypass graft (CABG) surgery with internal mammary artery grafting. It is caused by functional graft failure due to a hemodynamically significant proximal subclavian artery stenosis. In this manuscript, we provide a comprehensive review of literature and we report a series of five consecutive CSSS cases. This case series illustrates the variable clinical presentation, thereby emphasizing the importance of raised awareness concerning this pathology in CABG patients.