Recent Cardiovascular Research highlights from Europe

The Top of Europe is the highest European railway station in the Swiss Alps. The view from the Jungfraujoch 3454 m above sea level is really breathtaking (Figure 1). If you think about Cardiovascular Research, the Top of Europe might be defined differently. View from the Top of Europe, the highest European railway station at the Jungfraujoch 3454 m above sea level in the Swiss Alps. What have endothelial glycocalyx breakdown,1 experimental peripartum cardiomyopathy,2 exosomes in cardiac allograft rejection,3 and in ischaemia4 and the impact of diabetes on heart failure5 in common? They all reflect cutting-edge top research from the five most downloaded original research papers submitted to Cardiovascular Research in 2017 originating from Europe. If you have invested a lot of hard work in your cardiovascular research project and have achieved exiting new data Cardiovascular Research should be the perfect journal of choice. It is especially encouraging the submission of high-quality original research and reviews from Europe.6 Some figures may support this. Cardiovascular Research has a global readership, with over 2 million downloads per year. From 2018, the average primary review time is 29 days. After acceptance, your article gets a swift production process and online publication. Articles are available on Advanced Access online in an average of 10 days from sending to production. Why it is especially for European scientists attractive to submit their best papers to Cardiovascular Research? Cardiovascular Research is the international journal for basic and translational research of the European Society of Cardiology (ESC). The ESC has more than 95 000 members from 56 member national cardiac societies and organizes the world’s largest cardiovascular congress. Cardiovascular Research accepts papers from all topics within cardiology and cardiovascular biology. Its impact factor has increased to 6.29 in 2017 resulting in rank 16 out of 128 journals in the field of Cardiac & Cardiovascular Systems. Almost 40% of all original research papers received by Cardiovascular Research in 2017 were from Europe. Almost 60% of papers accepted in 2017 were from Europe. This shows the excellent quality of the submissions from European basic and clinical cardiovascular research. So what are the scientific subjects of the most downloaded European papers in Cardiovascular Research in 2017? The endothelial glycocalyx is the carbohydrate-rich layer lining the luminal surface of the endothelium. It provides a vasoprotective barrier against vascular leakage and adhesion in sepsis and vascular inflammation. While there is a rapidly growing interest in the vascular field in the role of the endothelial glycocalyx, the molecular mechanisms of its formation and degradation are not well-understood. Alexander Lukasz, Philipp Kümpers, and their colleagues from the University Hospital Münster, Germany, have studied the mechanisms of breakdown of the endothelial glycocalyx.1 Using confocal atomic force microscopy they can show that exogenous angiopoietin-2 induces a rapid loss of the endothelial glycocalyx in endothelial cells in vitro. The process involves specific loss of the main constituent heparan sulfate. This is accompanied by secretion of heparan sulfate-specific heparanase from endosomal/lysosomal stores. This mechanism has been confirmed by in vivo experiments. These findings support a crucial role of angiopietin-2 in heparanase-dependent endothelial glycocalyx breakdown contributing to plasma leakage and leucocyte recruitment. It makes an important contribution to the growing understanding of the role of the glycocalyx in microvascular function highlighted in the corresponding editorial by FitzRoy E. Curry from the University of California, Davis, CA, USA.7 The paper initiates new directions of research like advancing our understanding of the balance between Angiopoietin-1 and -2 signalling in the endothelium to modulate microvascular function, the structure and stability of the layers of the glycocalyx and establishing early changes in glycocalyx thickness as a marker of microvascular structure and function in inflammatory vascular diseases.7 The paper has raised a lot of interest in the field and initiated further studies like the contribution of the disintegrin and metalloproteinase 15-mediated glycocalyx shedding to vascular leakage during inflammation.8 The group of Denise Hilfiker-Kleiner from the Hannover Medical School, Germany, studies an important pregnancy-induced cardiovascular disease, the peripartum cardiomyopathy.9 In the highlighted study in Cardiovascular Research, Justus Nonhoff, Denise Hilfiker-Kleiner, and their colleagues evaluated the pregnancy hormone Relaxin-2 as a potential diagnostic marker and/or therapeutic target in peripartum cardiomyopathy.2 In healthy peripartum women, serum Relaxin-2 levels in the second half of pregnancy were elevated showing a decreasing trend in the first postpartum week and returned to non-pregnant levels thereafter. In peripartum cardiomyopathy patients diagnosed in the first postpartum week, serum Relaxin-2 levels were lower compared to healthy postpartum stage-matched controls. In mice, serum Relaxin-1 as the functional equivalent of human Relaxin-2 was increased late in pregnancy and rapidly cleared in the first postpartum week. In mice with peripartum cardiomyopathy due to a cardiomyocyte-specific knockout of STAT3 neither low nor high dose of recombinant Relaxin-2 (serelaxin) affected cardiac fibrosis, inflammation and heart failure but increased capillary/cardiomyocyte ratio. High-dose serelaxin increased heart/body weight ratio and cardiomyocyte cross-sectional area in postpartum cardiomyocyte-specific knockout of STAT3 and wild type mice. It further augmented plasma Prolactin levels in both genotypes, which induced cardiac activation of STAT5. Finally, in vitro analyses showed that Prolactin induces cardiomyocyte hypertrophy via activation of STAT5. In summary, the high pregnancy-related variance does not support the use of serum Relaxin-2 levels as biomarker for peripartum cardiomyopathy. However, supplementation with serelaxin may contribute to angiogenesis and compensatory hypertrophy in the diseased heart without preventing heart failure in an experimental model of this disease.2 Future directions of research could be the potential therapeutic effects of serelaxin in peripartum cardiomyopathy and the development of different biomarkers in gestational cardiac hypertrophy.10 Two excellent studies analysed novel roles of exosomes in cardiovascular diseases. The study by Teresa M. Ribeiro-Rodrigues, Henrique Girão, and their colleagues from the University of Coimbra, the Universidade do Porto, the University of Lisbon, Portugal, the Imperial College London, UK, and the University of Geneva, Switzerland, analysed exosomes excreted by cardiomyocytes subjected to ischaemia and their impact on cardiac angiogenesis.4 They can show that cardiomyocytes subjected to ischaemia release exosomes support protection against oxidative-induced lesion, promote proliferation and sprouting of endothelial cells, stimulate the formation of capillary-like structures, and strengthen adhesion complexes and barrier function. Ischaemic exosomes contain high levels of metalloproteinases and promotes their secretion from endothelial cells. The most abundant microRNAs in ischaemic exosomes miR-222 and miR-143 mediate the angiogenic effects of exosomes leading to new functional vessels in vivo. Furthermore, intramyocardial transfer of ischaemic exosomes improves neovascularization after myocardial infarction.4 This study establishes a new concept that exosomes secreted by ischaemic cardiomyocytes may promote heart angiogenesis and enhance myocardial blood supply. This may open new options to use exosomes as cell-free therapeutic agent for the induction of neovascularization after myocardial infarction. Ihdina Sukma Dewi, Olof Gidlöf, and their colleagues from Lund University, Sweden and Vancouver, BC, Canada, investigated the role of exosomal microRNAs in the crosstalk between T cells and endothelial cells and its implications for acute cellular rejection in heart transplantation.3 By profiling they identified microRNAs enriched in serum samples of heart transplant patients with acute cardiac allograft rejection. They explored a novel mechanism how miR-142-3p, a microRNA enriched in exosomes during acute cellular rejection, is transferred to endothelial cells and compromises endothelial barrier function via down-regulation of its target gene RAB11FIP2.3 This study sheds new light on the interaction between host immune system and cardiac allograft endothelium during acute cellular rejection and could have also important clinical implications by stimulating novel studies to understand the molecular mechanisms of allograft rejection. The corresponding editorial by Shashi K. Gupta and Thomas Thum from the Hannover Medical School, Germany, and the Imperial College London, UK, highlights the underlying molecular mechanisms and the diagnostic and therapeutic potential of miR-142-3p to improve allograft outcome.11 Diabetes mellitus is an important risk factor of cardiovascular diseases. Different experimental model of diabetes might show specific functional responses to therapeutic agents12 or to cardiovascular risk factors. In the highlighted Cardiovascular Research paper by Desiree Abdurrachim, Jeanine J. Prompers, and their colleagues from the Eindhoven University of Technology, the Maastricht University, the University of Groningen, The Netherlands, the University Hospital of Münster and the Jena University Hospital, Germany, analysed the impact of pressure overload in diabetic db/db mice on cardiac function, energy status, lipid content, glucose uptake and changes in protein expression.5 They induced pressure overload by transverse aortic constriction in non-diabetic and diabetic db/db mice. In non-diabetic mice, transverse aortic constriction induced progressive cardiac hypertrophy and dysfunction, which correlated with increased protein kinase D-1 phosphorylation and increased glucose uptake. These changes in glucose utilization preceded a reduction in cardiac energy status. The cardiac metabolic adaptations in diabetic mice seem to prevent heart failure upon pressure overload, suggesting that restoring the balance between glucose and fatty acid utilization is beneficial for cardiac function.5 In the corresponding editorial, Craig A. Lygate from the University of Oxford, UK, highlights that the diabetic hearts were relatively protected following transverse aortic constriction, developed less severe hypertrophy and only mild dysfunction, which was associated with near normalization of glucose uptake, energy status, and mitochondrial fatty acid oxidation, and discusses the underlying molecular mechanisms.13 More recent studies found that chronic elevation of fatty acid oxidation has a relatively subtle impact on cardiac function under baseline conditions.14 The findings may provide novel insights into the obesity paradox and suggest novel therapeutic approaches that mimic the positive aspects of the diabetic heart. In conclusion, the five most downloaded original research papers submitted to Cardiovascular Research in 2017 originating from Europe cover hot topics of current cardiovascular research and reflect the excellent quality of European research. We are looking forward to new submissions to Cardiovascular Research from our European colleagues. Conflict of interest: none declared. This work was supported by the Deutsche Forschungsgemeinschaft (DFG) (MO 1695/4-1, MO 1695/5-1, and the Excellence Initiative by the German Federal and State Governments, Institutional Strategy, measure ‘support the best’, grant 3-2, F-03661-553-41B-1250000 to H.M.). Biography: Henning Morawietz is Professor and Chief of the Division of Vascular Endothelium and Microcirculation at the Technische Universität Dresden, Germany. He is Consulting Editor of Cardiovascular Research, Secretary General of the German Society for Microcirculation and Vascular Biology, Joint Chair of the Strategy Committee of the European Society for Microcirculation and Fellow of the American Heart Association.