Diane Gal

Identifying circulating microRNAs as biomarkers of cardiovascular disease: a systematic review

The aim of the present study is to identify microRNAs (miRs) with high potential to be used as biomarkers in plasma and/or serum to clinically diagnose, or provide accurate prognosis for survival in, patients with atherosclerosis, coronary artery disease, and acute coronary syndrome (ACS). A systematic search of published original research yielded a total of 72 studies. After review of the risk of bias of the published studies, according to Cochrane Collaboration and the QUADUAS Group standards, 19 studies were selected. Overall 52 different miRs were reported. In particular, miR-133a/b (5 studies), miR-208a/b (6 studies), and miR-499 (7 studies) were well studied and found to be significant diagnostic and/or prognostic markers across different cardiovascular disease progression stages. miR-1 and miR-145b are potential biomarkers of ACS; miR-1 with higher sensitivity for all acute myocardial infarction (AMI), and miR-145 for STEMI and worse outcome of AMI. But when miRs were studied across different ACS study populations, patients had varying degrees of coronary stenosis, which was identified as an important confounder that limited the ability to quantitatively pool the study results. The identified miRs were found to regulate endothelial function and angiogenesis (miR-1, miR-133), vascular smooth muscle cell differentiation (miR-133, miR-145), communication between vascular smooth muscle and endothelial cell to stabilize plaques (miR-145), apoptosis (miR-1, miR-133, miR-499), cardiac myocyte differentiation (miR-1, miR-133, miR-145, miR-208, miR-499), and to repress cardiac hypertrophy (miR-133). Their role in these processes may be explained by regulation of shared RNA targets such as cyclin-dependent kinase inhibitor 1A (or p21), ETS proto-oncogene 1, fascin actin-bundling protein 1, hyperpolarization-activated cyclic nucleotide-gated potassium channel 4, insulin-like growth factor 1 receptor LIM and SH3 protein 1, purine nucleoside phosphorylase, and transgelin 2. These mechanistic data further support the clinical relevance of the identified miRs. miR-1, miR-133a/b, miR-145, miR-208a/b, and miR-499(a) in plasma and/or serum show some potential for diagnosis of cardiovascular disease. However, biased selection of miRs in most studies and unexplained contrasting results are major limitations of current miR research. Inconsistencies need to be addressed in order to definitively identify clinically useful miRs. Therefore, this paper presents important aspects to improve future miR research, including unbiased selection of miRs, standardization/normalization of reference miRs, adjustment for patient comorbidities and medication, and robust protocols of data-sharing plans that could prevent selective publication and selective reporting of miR research outcomes.

Mapping cross-border collaboration and communication in cardiovascular research from 1992 to 2012

Aims The growing burden of cardiovascular disease requires growth in research and innovation. We examine world-wide participation and citation impact across the cardiovascular research landscape from 1992 to 2012; we investigate cross-fertilization between countries and examine whether cross-border collaboration affects impact. Methods and Results State-of-the-art bibliometric methods and indicators are used to identify cardiovascular publications from the Web of Science, and to map trends over time in output, citation impact, and collaboration. The publication output in cardiovascular research has grown steadily from 1992 to 2012 with increased participation worldwide. China has the highest growth as relative share. The USA share initially predominated yet has reduced steadily. Over time, the EU-27 supra-national region has increased its participation above the USA, though on average it has not had greater citation impact than the USA. However, a number of European countries, as well as Australia and Canada, have improved their absolute and relative citation impact above that of the USA by 2006–2012. Europe is a hub of cross-fertilization with strengthening collaborations and strong citation links; the UK, Germany, and France remain central in this network. The USA has the highest number of strong citation links with other countries. All countries, but especially smaller, highly collaborative countries, have higher citation impact for their internationally collaborative research when compared with their domestic publications. Conclusion Participation in cardiovascular research is growing but growth and impact show wide variability between countries. Cross-border collaboration is increasing, in particular within the EU, and is associated with greater citation impact.

Cardiovascular Research turns the spotlight onto the right ventricle

This month’s issue of Cardiovascular Research is dedicated to the right ventricle. As introduced by the guest editors, this has long been considered the ‘lesser’ ventricle. A PubMed search for ‘left ventricle’ (LV) shows 25 217 publications since 2010, whereas a search for ‘right ventricle’ (RV) results in 21 684 publications in the same time period. However, most documents include both terms, so if we compare the publications that exclusively cover the ‘left ventricle’ we get 6 270 documents, and in contrast there are only 2 737 publications specifically on the ‘right ventricle’. Even if this is a crude approximation, it aligns with a message that is present in several of the review articles of this Spotlight Issue, namely that our knowledge of the RV is less than that of the LV. At the same time, available knowledge clearly indicates the particularities of the RV and underscores that we cannot simply ‘copy-paste’ insights from the LV to the RV. In the past years, we also noticed that the RV was less often the topic of submitted manuscripts but seemed to gain attention. We have browsed the recent issues of Cardiovascular Research, bringing together relevant publications in this virtual issue including selected articles from Europace and European Heart Journal, to complement the series of reviews. Filling of the RV and diastolic functions were studied by Pérez Del Villar et al., focusing on the restoring forces and the role of suction. The interaction between LV and RV function, focusing on diastolic dysfunction, was recently underscored in a study on HFpEF patients demonstrating impaired RV functional reserve. The causes and mechanisms underlying arrhythmogenic RV disease are still being unravelled, and diagnostic testing presents challenges. The power of advanced and next generation sequencing can support differential diagnosis and positioning within the group of cardiomyopathies. Mechanisms of remodeling and targets for treatment are mostly studied in models of RV hypertrophy and failure consequent on pulmonary hypertension (PHT). Within the RV, apoptosis and loss of myocytes may temporarily be compensated by the remaining myocytes. Targeting pathways that reduce PHT and vascular remodelling are associated with improved RV remodelling. While this could be due to the reduced haemodynamic load, some of these approaches may involve some direct effects on the RV, as e.g. the neuregulin pathway. Other mechanistic studies emphasize the tight link between the vascular remodelling and RV remodelling, as for miR-223-IGF-IR. Thrombospondin-1 may be important in signalling within the lungs and pulmonary vascular smooth muscle cells in response to hypoxia, but interrupting this pathway benefits cardiac function as well. Conflict of interest: none declared.

Functional Role of Cardiovascular Exosomes in Myocardial Injury and Atherosclerosis

Extracellular vesicles are now widely recognized as key players in the prevention, repair or progression of cardiovascular disease. Here we first focus on the functional roles of extracellular vesicles in the cross-talk between cardiomyocytes and endothelial cells, important for maintaining normal development and function of the heart. Second, we discuss the role of extracellular vesicles secreted by embryonic and non-embryonic stem cells in repairing cardiomyocyte function and in restoring angiogenic potential after myocardial ischemia-reperfusion injury. Third, we focus on the role of extracellular vesicles in Endothelial to Mesenchymal Transition (EndMT), leading to conversion of endothelial cells to fibroblasts, secretion of extracellular proteins collagen and fibronectin, and fibrosis. Finally, we discuss the role of extracellular vesicles secreted under stress by endothelial cells, macrophages and vascular smooth muscle cells in atherosclerosis. On aggregate, the reviewed preclinical studies present evidence that extracellular vesicles secreted by cardiomyocytes, fibroblasts, endothelial cells, immune-system-related cells, vascular smooth muscle cells and stem cells play an important role in the pathogenesis of cardiovascular disease. However, further studies are needed to gain better insight into the mechanisms used to select specific content to transfer to specific target cells, and to induce or repress signaling pathways in their target cells.

Hot topics and networks in Cardiovascular Research.

‘Publish or perish’ refers to the essence of journals as instruments for sharing novel and reliable information to advance scientific knowledge. Editors are expected to present high-quality, novel, and relevant studies to the community by a process of review and selection from submitted manuscripts. Peer review is an essential part of this selection process providing expert input on all three aspects for the final editorial decision. In addition, regular evaluation of the outcome of the editorial work is essential to guide the process. ISI provides metrics of which the impact factor is best-known, but there are many others. All of these give single numerical value to the aggregate of the articles but do not inform about the content of the journal. Here, after 3 years in office, we wanted to take stock of the research published in Cardiovascular Research in 2013 and 2014. Are we on track for the impact and visibility we aim to achieve? What topics are emerging? Have publication policies provided more visibility to these publications? Taking a global view of the results of the first 2 years, the topics of the papers published and their visibility in the research community, is a useful step in analysing the decisions made in the past. Overall, 379 original research articles and 80 reviews were published in Cardiovascular Research in 2013 and 2014. One of the main indicators of visibility of these publications is the number of citations obtained from Web of Science online on 21 September 2015, totalling 3199 citations. Publications in Cardiovascular Research enjoy a high visibility, with an average citation rate of 7 citations per publication, a low percentage of only 7% that have …

A Changing Landscape in Cardiovascular Research Publication Output: Bridging the Translational Gap

The concern about predominance of basic discovery research and lack of translation into clinical medicine, and segregation between these research communities, led the authors to study these research communities through mapping networks of publications and cross-references. Cardiovascular research from 1993 to 2013 was published in 565 journals, including 104 new journals. Only 50% were published in core cardiovascular journals, such as the Journal of the American College of Cardiology, whereas one-half of cardiovascular publications were found in broader biomedical/multidisciplinary journals. The growth of the clinical journal community and merging into one broad journal community suggests a decreasing dichotomy between basic/preclinical and clinical research, potentially contributing to bridging the translational gap.

Cardiovascular Research as a forum for publications from China: present, past and future

There has been a rapid growth of publications from China over the last 20 years, with China becoming the second largest producer of scientific papers across all disciplines in the year 2007.1 Focused investment in building scientific capacity in China has significantly contributed to the growth in publication output. In 1998, the launch of the ‘985’ project increased Chinas commitment to improve the global standing and publication activities of a select group of 24 universities.2 Research performance has also gained from the commitment of the Chinese government to increase the Gross Domestic Expenditure on Research and Development (GERD). A common indicator used is the ratio of GERD to Gross Domestic Product (GDP) and in China, this ratio has grown steadily from 1.07% in 2002 to reach 1.84% in 2011.3 More specifically, the funding provided through the National Natural Science Foundation of China (NSFC; http://www.nsfc.gov.cn/publish/portal1/tab293/) and the National Basic Research Program of China (NBRPC) have had a significant impact in fuelling basic research, for example with almost 40 million Euros [312 million Chinese Renminbi (RMB)] being assigned by the NSFC to experimental cardiovascular studies in 2013 alone.4 These policy and funding commitments in China have affected the submissions to Cardiovascular Research over the past 40 years. The number of publications from Chinese authors in Cardiovascular Research has grown progressively from one article being published in the 1970s, three in the 1980s, and seven being published from 1990 to 1994, before finally seeing more than one publication per year starting from 1998 onwards. Cardiovascular Research has experienced a steady increase in the submissions resulting from research based in China, which has raised the interest of …

Editorial highlights from Cardiovascular Research

In the past years, the editorial office has regularly taken stock of what the journal published and how papers fared. We have been particularly interested in the impact of the editorial choices and the evolution in the field. Following up on our 2015 editorial report, we have now examined the papers published in 2015 and 2016, identifying topics and zooming in on papers highlighted as editors’ choice, mostly papers accompanied by an editorial. We then compared the outcome to the previous analysis.