Improving translational research in sex-specific effects of comorbidities and risk factors in ischaemic heart disease and cardioprotection: position paper and recommendations of the ESC Working Group on Cellular Biology of the Heart
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Abstract
Ischaemic heart disease (IHD) is a complex disorder and a leading cause of death and
morbidity in both men and women. Sex, however, affects several aspects of IHD, including
pathophysiology, incidence, clinical presentation, diagnosis as well as treatment
and outcome. Several diseases or risk factors frequently associated with IHD can modify
cellular signalling cascades, thus affecting ischaemia/reperfusion injury as well
as responses to cardioprotective interventions. Importantly, the prevalence and impact
of risk factors and several comorbidities differ between males and females, and their
effects on IHD development and prognosis might differ according to sex. The cellular
and molecular mechanisms underlying these differences are still poorly understood,
and their identification might have important translational implications in the prediction
or prevention of risk of IHD in men and women. Despite this, most experimental studies
on IHD are still undertaken in animal models in the absence of risk factors and comorbidities,
and assessment of potential sex-specific differences are largely missing. This ESC
WG Position Paper will discuss: (i) the importance of sex as a biological variable
in cardiovascular research, (ii) major biological mechanisms underlying sex-related
differences relevant to IHD risk factors and comorbidities, (iii) prospects and pitfalls
of preclinical models to investigate these associations, and finally (iv) will provide
recommendations to guide future research. Although gender differences also affect
IHD risk in the clinical setting, they will not be discussed in detail here.
Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
There is limited information describing the presenting characteristics and outcomes of US patients requiring hospitalization for coronavirus disease 2019 (COVID-19).
In the last decade the number of bioscience journals has increased enormously, with many filling specialised niches reflecting new disciplines and technologies. The emergence of open-access journals has revolutionised the publication process, maximising the availability of research data. Nevertheless, a wealth of evidence shows that across many areas, the reporting of biomedical research is often inadequate, leading to the view that even if the science is sound, in many cases the publications themselves are not “fit for purpose,” meaning that incomplete reporting of relevant information effectively renders many publications of limited value as instruments to inform policy or clinical and scientific practice [1]–[21]. A recent review of clinical research showed that there is considerable cumulative waste of financial resources at all stages of the research process, including as a result of publications that are unusable due to poor reporting [22]. It is unlikely that this issue is confined to clinical research [2]–[14],[16]–[20]. Failure to describe research methods and to report results appropriately therefore has potential scientific, ethical, and economic implications for the entire research process and the reputation of those involved in it. This is particularly true for animal research, one of the most controversial areas of science. The largest and most comprehensive review of published animal research undertaken to date, to our knowledge, has highlighted serious omissions in the way research using animals is reported [5]. The survey, commissioned by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), a UK Government-sponsored scientific organisation, found that only 59% of the 271 randomly chosen articles assessed stated the hypothesis or objective of the study, and the number and characteristics of the animals used (i.e., species/strain, sex, and age/weight). Most of the papers surveyed did not report using randomisation (87%) or blinding (86%) to reduce bias in animal selection and outcome assessment. Only 70% of the publications that used statistical methods fully described them and presented the results with a measure of precision or variability [5]. These findings are a cause for concern and are consistent with reviews of many research areas, including clinical studies, published in recent years [2]–[22]. Good Reporting Is Essential for Peer Review and to Inform Future Research Scrutiny by scientific peers has long been the mainstay of “quality control” for the publication process. The way that experiments are reported, in terms of the level of detail of methods and the presentation of key results, is crucial to the peer review process and, indeed, the subsequent utility and validity of the knowledge base that is used to inform future research. The onus is therefore on the research community to ensure that their research articles include all relevant information to allow in-depth critique, and to avoiding duplicating studies and performing redundant experiments. Ideally scientific publications should present sufficient information to allow a knowledgeable reader to understand what was done, why, and how, and to assess the biological relevance of the study and the reliability and validity of the findings. There should also be enough information to allow the experiment to be repeated [23]. The problem therefore is how to ensure that all relevant information is included in research publications. Using Reporting Guidelines Measurably Improves the Quality of Reporting Evidence provided by reviews of published research suggests that many researchers and peer reviewers would benefit from guidance about what information should be provided in a research article. The CONSORT Statement for randomised controlled clinical trials was one of the first guidelines developed in response to this need [24],[25]. Since publication, an increasing number of leading journals have supported CONSORT as part of their instructions to authors [26],[27]. As a result, convincing evidence is emerging that CONSORT improves the quality and transparency of reports of clinical trials [28],[29]. Following CONSORT, many other guidelines have been developed—there are currently more than 90 available for reporting different types of health research, most of which have been published in the last ten years (see http://www.equator-network.org and references [30],[31]). Guidelines have also been developed to improve the reporting of other specific bioscience research areas including metabolomics and gene expression studies [32]–[37]. Several organisations support the case for improved reporting and recommend the use of reporting guidelines, including the International Committee of Medical Journal Editors, the Council of Science Editors, the Committee on Publication Ethics, and the Nuffield Council for Bioethics [38]–[41]. Improving the Reporting of Animal Experiments—The ARRIVE Guidelines Most bioscience journals currently provide little or no guidance on what information to report when describing animal research [42]–[50]. Our review found that 4% of the 271 journal articles assessed did not report the number of animals used anywhere in the methods or the results sections [5]. Reporting animal numbers is essential so that the biological and statistical significance of the experimental results can be assessed or the data reanalysed, and is also necessary if the experimental methods are to be repeated. Improved reporting of these and other details will maximise the availability and utility of the information gained from every animal and every experiment, preventing unnecessary animal use in the future. To address this, we led an initiative to produce guidelines for reporting animal research. The guidelines, referred to as ARRIVE (Animals in Research: Reporting In Vivo Experiments), have been developed using the CONSORT Statement as their foundation [24],[25]. The ARRIVE guidelines consist of a checklist of 20 items describing the minimum information that all scientific publications reporting research using animals should include, such as the number and specific characteristics of animals used (including species, strain, sex, and genetic background); details of housing and husbandry; and the experimental, statistical, and analytical methods (including details of methods used to reduce bias such as randomisation and blinding). All the items in the checklist have been included to promote high-quality, comprehensive reporting to allow an accurate critical review of what was done and what was found. Consensus and consultation are the corner-stones of the guideline development process [51]. To maximise their utility, the ARRIVE guidelines have been prepared in consultation with scientists, statisticians, journal editors, and research funders. We convened an expert working group, comprising researchers and statisticians from a range of disciplines, and journal editors from Nature Cell Biology, Science, Laboratory Animals, and the British Journal of Pharmacology (see Acknowledgments). At a one-day meeting in June 2009, the working group agreed the scope and broad content of a draft set of guidelines that were then used as the basis for a wider consultation with the scientific community, involving researchers, and grant holders and representatives of the major bioscience funding bodies including the Medical Research Council, Wellcome Trust, Biotechnology and Biological Sciences Research Council, and The Royal Society (see Table 1). Feedback on the content and wording of the items was incorporated into the final version of the checklist. Further feedback on the content utility of the guidelines is encouraged and sought. 10.1371/journal.pbio.1000412.t001 Table 1 Funding bodies consulted. Name of Bioscience Research Funding Body Medical Research Council Biotechnology and Biological Sciences Research Council Wellcome Trust The Royal Society Association of Medical Research Charities British Heart Foundation Parkinson's Disease Society The ARRIVE guidelines (see Table 2) can be applied to any area of bioscience research using laboratory animals, and the inherent principles apply not only to reporting comparative experiments but also to other study designs. Laboratory animal refers to any species of animal undergoing an experimental procedure in a research laboratory or formal test setting. The guidelines are not intended to be mandatory or absolutely prescriptive, nor to standardise or formalise the structure of reporting. Rather they provide a checklist that can be used to guide authors preparing manuscripts for publication, and by those involved in peer review for quality assurance, to ensure completeness and transparency. 10.1371/journal.pbio.1000412.t002 Table 2 Animal Research: Reporting In Vivo experiments: The ARRIVE guidelines. ITEM RECOMMENDATION TITLE 1 Provide as accurate and concise a description of the content of the article as possible. ABSTRACT 2 Provide an accurate summary of the background, research objectives (including details of the species or strain of animal used), key methods, principal findings, and conclusions of the study. INTRODUCTION Background 3 a. Include sufficient scientific background (including relevant references to previous work) to understand the motivation and context for the study, and explain the experimental approach and rationale.b. Explain how and why the animal species and model being used can address the scientific objectives and, where appropriate, the study's relevance to human biology. Objectives 4 Clearly describe the primary and any secondary objectives of the study, or specific hypotheses being tested. METHODS Ethical statement 5 Indicate the nature of the ethical review permissions, relevant licences (e.g. Animal [Scientific Procedures] Act 1986), and national or institutional guidelines for the care and use of animals, that cover the research. Study design 6 For each experiment, give brief details of the study design, including:a. The number of experimental and control groups.b. Any steps taken to minimise the effects of subjective bias when allocating animals to treatment (e.g., randomisation procedure) and when assessing results (e.g., if done, describe who was blinded and when).c. The experimental unit (e.g. a single animal, group, or cage of animals).A time-line diagram or flow chart can be useful to illustrate how complex study designs were carried out. Experimental procedures 7 For each experiment and each experimental group, including controls, provide precise details of all procedures carried out. For example:a. How (e.g., drug formulation and dose, site and route of administration, anaesthesia and analgesia used [including monitoring], surgical procedure, method of euthanasia). Provide details of any specialist equipment used, including supplier(s).b. When (e.g., time of day).c. Where (e.g., home cage, laboratory, water maze).d. Why (e.g., rationale for choice of specific anaesthetic, route of administration, drug dose used). Experimental animals 8 a. Provide details of the animals used, including species, strain, sex, developmental stage (e.g., mean or median age plus age range), and weight (e.g., mean or median weight plus weight range).b. Provide further relevant information such as the source of animals, international strain nomenclature, genetic modification status (e.g. knock-out or transgenic), genotype, health/immune status, drug- or test-naïve, previous procedures, etc. Housing and husbandry 9 Provide details of:a. Housing (e.g., type of facility, e.g., specific pathogen free (SPF); type of cage or housing; bedding material; number of cage companions; tank shape and material etc. for fish).b. Husbandry conditions (e.g., breeding programme, light/dark cycle, temperature, quality of water etc. for fish, type of food, access to food and water, environmental enrichment).c. Welfare-related assessments and interventions that were carried out before, during, or after the experiment. Sample size 10 a. Specify the total number of animals used in each experiment and the number of animals in each experimental group.b. Explain how the number of animals was decided. Provide details of any sample size calculation used.c. Indicate the number of independent replications of each experiment, if relevant. Allocating animals to experimental groups 11 a. Give full details of how animals were allocated to experimental groups, including randomisation or matching if done.b. Describe the order in which the animals in the different experimental groups were treated and assessed. Experimental outcomes 12 Clearly define the primary and secondary experimental outcomes assessed (e.g., cell death, molecular markers, behavioural changes). Statistical methods 13 a. Provide details of the statistical methods used for each analysis.b. Specify the unit of analysis for each dataset (e.g. single animal, group of animals, single neuron).c. Describe any methods used to assess whether the data met the assumptions of the statistical approach. RESULTS Baseline data 14 For each experimental group, report relevant characteristics and health status of animals (e.g., weight, microbiological status, and drug- or test-naïve) before treatment or testing (this information can often be tabulated). Numbers analysed 15 a. Report the number of animals in each group included in each analysis. Report absolute numbers (e.g. 10/20, not 50%a).b. If any animals or data were not included in the analysis, explain why. Outcomes and estimation 16 Report the results for each analysis carried out, with a measure of precision (e.g., standard error or confidence interval). Adverse events 17 a. Give details of all important adverse events in each experimental group.b. Describe any modifications to the experimental protocols made to reduce adverse events. DISCUSSION Interpretation/scientific implications 18 a. Interpret the results, taking into account the study objectives and hypotheses, current theory, and other relevant studies in the literature.b. Comment on the study limitations including any potential sources of bias, any limitations of the animal model, and the imprecision associated with the resultsa.c. Describe any implications of your experimental methods or findings for the replacement, refinement, or reduction (the 3Rs) of the use of animals in research. Generalisability/translation 19 Comment on whether, and how, the findings of this study are likely to translate to other species or systems, including any relevance to human biology. Funding 20 List all funding sources (including grant number) and the role of the funder(s) in the study. a Schulz, et al. (2010) [24]. Improved Reporting Will Maximise the Output of Published Research These guidelines were developed to maximise the output from research using animals by optimising the information that is provided in publications on the design, conduct, and analysis of the experiments. The need for such guidelines is further illustrated by the systematic reviews of animal research that have been carried out to assess the efficacy of various drugs and interventions in animal models [8],[9],[13],[52]–[55]. Well-designed and -reported animal studies are the essential building blocks from which such a systematic review is constructed. The reviews have found that, in many cases, reporting omissions, in addition to the limitations of the animal models used in the individual studies assessed in the review, are a barrier to reaching any useful conclusion about the efficacy of the drugs and interventions being compared [2],[3]. Driving improvements in reporting research using animals will require the collective efforts of authors, journal editors, peer reviewers, and funding bodies. There is no single simple or rapid solution, but the ARRIVE guidelines provide a practical resource to aid these improvements. The guidelines will be published in several leading bioscience research journals simultaneously [56]–[60], and publishers have already endorsed the guidelines by including them in their journal Instructions to Authors subsequent to publication. The NC3Rs will continue to work with journal editors to extend the range of journals adopting the guidelines, and with the scientific community to disseminate the guidelines as widely as possible (http://www.nc3rs.org.uk/ARRIVE).
[1
]Department of Advanced Biomedical Sciences, Federico II University, Via Pansini 5,
80131 Naples, Italy
[2
]Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvárad tér
4, 1089 Budapest, Hungary
[3
]Pharmahungary Group, Hajnoczy str. 6., H-6722 Szeged, Hungary
[4
]Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Blvd. 161,
8200 Aarhus, Denmark
[5
]Department of Physiology, Amsterdam UMC, Vrije Universiteit, Amsterdam Cardiovascular
Sciences, De Boelelaan 1117, Amsterdam, 1108 HV, the Netherlands
[6
]Imperial College, Faculty of Medicine, National Heart & Lung Institute, South Kensington
Campus, London SW7 2AZ, UK
[7
]Royal Brompton Hospital, Sydney St, Chelsea, London SW3 6NP, UK
[8
]The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, WC1E
6HX London, UK
[9
]Experimental Cardiology Laboratory, Department of Cardiology, University Medical Center
Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
[10
]Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute
of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Muscle Research
Center Erlangen (MURCE), Schwabachanlage 12, 91054 Erlangen, Germany
[11
]Department for Clinical Science, University of Bergen, PO Box 7804, 5020 Bergen, Norway
[12
]Faculty of Medicine, Coimbra Institute for Clinical and Biomedical Research (iCBR),
University of Coimbra, Azinhaga Santa Comba, Celas, 3000-548 Coimbra, Portugal
[13
]Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra,
and Clinical Academic Centre of Coimbra (CACC), 3000-548 Coimbra, Portugal
[14
]Department of Cardiology, Medical University of Vienna, Waehringer Guertel 18-20,
A-1090 Vienna, Austria
[15
]Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore
Medical School, 8 College Road, 169857, Singapore
[16
]National Heart Research Institute Singapore, National Heart Centre Singapore, 5 Hospital
Drive, 169609, Singapore
[17
]Yong Loo Lin School of Medicine, National University Singapore, 1E Kent Ridge Road,
119228, Singapore
[18
]The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London
WC1E 6HX, UK
[19
]Cardiovascular Research Center, College of Medical and Health Sciences, Asia University,
500, Lioufeng Rd., Wufeng, Taichung 41354, Taiwan
[20
]Hatter Institute for Cardiovascular Research in Africa, Faculty of Health Sciences,
Chris Barnard Building, University of Cape Town, Private Bag X3 7935 Observatory,
Cape Town, South Africa
[21
]Institute of Cardiology, University of Pisa, Lungarno Antonio Pacinotti 43, 56126
Pisa, Italy
[22
]Department of Internal Medicine, University of Texas Medical School in Houston, 6410
Fannin St #1014, Houston, TX 77030, USA
[23
]King’s College London BHF Centre, The Rayne Institute, St Thomas’ Hospital, Westminster
Bridge Road, London SE1 7EH, UK
[24
]Laboratory of Cardiac Physiology, Cardiovascular Branch, NHLBI, NIH, 10 Center Drive,
Bethesda, MD 20892, USA
[25
]Unità di Ingegneria Tissutale Cardiovascolare, Centro Cardiologico Monzino, IRCCS
Via Parea, 4, I-20138 Milan, Italy
[26
]Berlin Institute of Gender in Medicine, Center for Cardiovascular Research, DZHK,
partner site Berlin, Geschäftsstelle Potsdamer Str. 58, 10785 Berlin, Germany
[27
]University of Zürich, Rämistrasse 71, 8006 Zürich, Germany
[28
]Experimental Cardiology Laboratory, Department of Cardiology, University Medical Center
Utrecht, Utrecht University, Heidelberglaan 8, 3584 CS Utrecht, the Netherlands
[29
]Circulatory Health Laboratory, Regenerative Medicine Center, University Medical Center
Utrecht, Utrecht University, Heidelberglaan 8, 3584 CS Utrecht, the Netherlands
[30
]Institute for Cardiovascular Prevention and German Centre for Cardiovascular Research
(DZHK), partner site Munich Heart Alliance, Pettenkoferstr. 9, Ludwig-Maximilians-University,
80336 Munich, Germany
[31
]Department of Cardiac Surgery, Medical University of Innsbruck, Anichstr.35, A – 6020
Innsbruck, Austria
[32
]Cardiology and UMC Utrecht Regenerative Medicine Center, University Medical Center
Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
[33
]Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité, University
Medicine Berlin, 10178 Berlin, Germany
[34
]Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité, University Medicine
Berlin, 10178 Berlin, Germany
[35
]German Centre for Cardiovascular Research (DZHK), partner site Berlin, Berlin, Germany
[36
]Institute of Physiology, Justus-Liebig University Giessen, Ludwigstraße 23, 35390
Giessen, Germany
[37
]Department of Medical Biology, UiT The Arctic University of Norway, Hansine Hansens
veg 18, 9037 Tromsø, Norway
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