The Oxford Heart Vessels and Fat (ox-HVF) Cohort

Ischemic heart disease remains the leading cause of death in upper-middle and high income economies. Coronary artery disease (CAD) accounts for one in seven deaths in men and one in twelve deaths in women in England, responsible for over 53,000 deaths every year, with associated healthcare costs continuing to rise. Coronary artery bypass graft surgery (CABG) continues to be the optimum revascularisation strategy for most patients with multi-vessel coronary artery disease. Although the biological variability between patients should be crucial for the prediction of long-term outcome of patients undergoing cardiac surgery, the exact mechanism linking the biology of the heart, the vascular grafts used and the myocardium with clinical outcome are unclear. Furthermore, taking into account the fact that cardiovascular disease remains one of the top mortality causes in the developed world, there is an unmet need in developing new markers of disease development and progression.

The aim of the OxHVF cohort study is to discover new blood, genetic and imaging biomarkers that differ between patients with advanced coronary atherosclerosis and healthy individuals (controls). The ability of these biomarkers to predict clinical outcomes in patients and controls will be evaluated by analysing prospective data collected through hospital records and other sources such as NHS Digital. These new biomarkers could also serve as potential therapeutic targets, allowing the development of new therapeutic strategies for the prevention and treatment of cardiovascular disease.

The University of Oxford is requesting mortality and Hospital Episode Statistics (HES) data with the aim to progress understanding of cardiovascular disease pathogenesis leading to the development of novel markers for early disease detection, ultimately resulting in sooner, better and more efficient cardiovascular disease management in the interest of the 1.8 million people that are currently battling coronary heart disease in England.

Collection of outcomes data for the patients with atherosclerosis and healthy controls, will allow the University of Oxford to compare the predictive value of any new biomarker identified through the cross-sectional analyses, between patients with atherosclerosis and healthy individuals. For example, the University of Oxford will compare the ability of new blood, genetic and imaging biomarkers discovered in the ox-HVF cohort to predict cardiovascular and other clinical outcomes in individuals with or without advanced atherosclerosis.

The Oxford Heart, Vessels & Fat (Ox-HVF) cohort consists of participants recruited into one of the clinical sub-studies constituting the cohort: ART Vascular Study, Bypass Vascular Study, AdipoRedOx and ORFAN. Ox-HVF was designed to provide synergistic results allowing the deployment of a multi-level strategy to address the aforementioned issues (see www.oxhvf.com). The primary aim of the cohort is to discover new biomarkers and/or therapeutic targets for the prediction and prevention of cardiovascular events and other clinical outcomes. These biomarkers can be biochemical (measured in the blood of the patient), genetic (measured in the DNA) or imaging (measured in non-invasive imaging). The therapeutic targets can be at the level of the circulation or tissue (by studying human blood, arteries and veins, fat or myocardial samples collected during surgery).

In the Ox-HVF cohort, the patients with advanced cardiovascular disease are recruited through 3 main clinical sub-studies (ART Vascular Study, Bypass Vascular Study, AdipoRedOx), and the control individuals (with risk factors but no established cardiovascular disease) through ORFAN sub-study. The ORFAN study was designed from the beginning in collaboration with NHS Digital, to enable collection of control data for Ox-HVF. All Ox-HVF participants contribute blood and imaging data to the cohort, whereas patient participants also contribute tissue samples. Data are aggregated from all sub-studies in a single database (ox-HVF database) and analysed collectively, as a single cohort (ox-HVF cohort) comprising of both patients and controls.

In more detail, the participants of the cohort come from the following 4 sub-studies:

i) The Arterial Revascularisation Trial: Vascular sub-study (ART Vasc) (November 2004 to 2017; REC: MREC04/03/006) compares coronary artery bypass grafting with a single internal mammary artery (IMA) to surgery with bilateral internal mammary arteries. 258 patients undergoing coronary artery bypass grafting surgery at the John Radcliffe Hospital, Oxford were enrolled to the study. ART Vasc study is no longer recruiting. Data collection continues through access to patients’ medical records, extracting data from both the local Hospital archive and the NHS Digital records.

ii) The Vascular Properties of Bypass Grafts (Bypass Vascular study) (January 2005 to current; REC: 04/Q1605/95) aims to compare measures of vascular function with post-operative clinical outcome after cardiac surgery. The inner lining of a person’s arteries is made up of cells (specifically endothelial cells) that can control how the artery stretches or dilates. The measure of how well this mechanism works is called endothelial function. The term “endothelial dysfunction” is used to describe changes in the in the inner lining of the artery to a state that can lead to disease progression and atherosclerosis.

The Bypass Vascular Study invited patients undergoing coronary artery bypass graft surgery at the John Radcliffe Hospital to participate in further investigation of their endothelial function to help better understand why some bypass grafts work better than others and how the function of them could possibly be improved in the future. 231 patients were successfully enrolled to the study. The Bypass Vascular Study is no longer recruiting. Data collection continues through access to the patient’s medical records and extracting data from NHS Digital.

iii) The AdipoRedOx study (15/09/2011 to current; REC: 11/SC/140), aims to investigate the mechanisms by which the fat tissue, the vascular tissue and the heart muscle interact and the University of Oxford aim to explore whether aspects of this interaction can predict the outcomes of coronary artery bypass grafting operation (CABG). The AdipoRedOx study is actively recruiting and will follow participants up until 2030.

iv) The controls of the cohort come from the ORFAN sub-study (11/10/2015 to current; REC: 15/SC/0545). This aims to recruit individuals with risk factors but not advanced coronary artery disease, serving as controls to the heavily diseased populations of the other three sub-studies, and ultimately as the validation cohort for the predictive and prognostic value of any biomarker developed for early cardiovascular disease detection.

Participants were enrolled to ART Vasc, Bypass Vascular Study and the AdipoRedOx study before they underwent open-heart surgery at the John Radcliffe Hospital, Oxford. All four sub-studies have gained informed consent from each participant to access their medical records to collect long-term outcome data to provide information that may have a predictive value. Importantly, these studies aim to link the collected data (i.e. risk factors, data on vascular function, imaging data etc.) with patient clinical outcome data, producing the world’s most comprehensive resource comparing vascular, myocardial and adipose tissue biology and imaging with clinical outcomes.

Data is requested in line with Article 6(1)(e) –‘processing is necessary for the performance of a task carried out in the public interest’.

Public interest is in line with Article 9(2)(j) – ‘processing is necessary for archiving purposes in the public interest'.

The University of Oxford is the sole data controller and also processes the data for this study. The University of Oxford is seeking to collect health outcome data on these participants, namely Hospital Episode Statistics and civil registry mortality data (cause and date of death). No other organisations process the data for this purpose. The University of Oxford solely determines the purpose and outputs of the Ox-HVF cohort sub-studies.

The following organisations are involved in recruiting study participants for the ORFAN sub-study only:

- Milton Keynes University Hospital

- University Hospitals of Leicester NHS Trust

- Royal Brompton and Harefield NHS Foundation Trust

- Oxford University Hospitals NHS Foundation Trust

Oxford University Hospitals NHS Foundation Trust is the only organisation involved in recruiting study participants for the AdipoRedOx sub-study.

Jersey General Hospital, The Nuffield Health Manor Hospital and Milton Keynes University Hospital performed post-operative CT scans of participants already recruited in the "AdipoRedOx" sub-study from Oxford University Hospitals NHS Foundation Trust.

The "Art-Vasc" and "Bypass Vascular Grafts" sub-studies are NOT actively recruiting any participants. All participants in these sub-studies were recruited from Oxford University Hospitals NHS Foundation Trust.

The Oxford University Hospitals (OUH) NHS Foundation Trust's logo is displayed on the consent materials because all patients within the AdipoRedOx, "Art-Vasc" and "Bypass Vascular Grafts" sub-studies have been recruited in OUH.

For the ORFAN sub-study, the logo section and the contact information have been kept blank, to include details of the local site and the local PI (principal investigator). More specifically, participants recruited from the OUH will be given consent material with the OUH logo on them, whereas participants recruited at external sites, will be given consent material with the local Trust logo and local PI information. None of the local study investigators from the multiple recruitment sites or their respective organisations have any control over any of the Ox-HVF data.

The sites recruiting participants (for ORFAN sub-study only), perform tests outlined in the respective study protocols and collect demographic data (for all sub-studies), which they hand over to the sole data controller, i.e. the University of Oxford.

The University of Oxford is the sole data controller because the Chief Investigator in all 4 sub-studies constituting the Ox-HVF cohort is a full-time employee of the University of Oxford. All clinical researchers involved in data analysis within the Ox-HVF cohort are employed by the University of Oxford.

The primary objective of the study is to:

Develop and validate new blood, genetic, imaging and other biomarkers that allow good discrimination between patients with coronary artery disease and healthy individuals, and evaluate their ability to predict clinical outcomes. These biomarkers may also form therapeutic targets for the development of new strategies to prevent and treat cardiovascular diseases.

Secondary objectives are to:

i) Investigate the mechanisms by which adipose tissue derived molecules affects vascular/myocardial redox state, endothelial (inner lining of the artery) function and clinical outcomes of patients undergoing coronary artery bypass grafting operation (CABG) and validate their applicability in healthy individuals.

ii) Search for a possible signal from the myocardium/vascular wall to epicardial/perivascular adipose tissue that regulates the synthesis of adipokines and other signalling molecules and compare their blood levels between patients with cardiovascular disease and healthy individuals.

iii) Search for novel biomarkers/signalling molecules identified in peripheral blood or expressed in adipose tissue, that regulate vascular/myocardial redox state and/or predict vein graft patency and compare their blood levels between patients with cardiovascular disease and healthy individuals.

iv) Search for novel imaging biomarkers and signatures reflecting underlying biology, which have predictive and prognostic value and therefore have the potential to be used in large-scale population wide screenings for early cardiovascular disease detection.

In summary these objectives will then potentially result in the creation of patient risk models that the University of Oxford hope will improve health outcomes of patients with cardiovascular disease.

The University of Oxford is attempting to manage long-term, prospective cohorts in the cardiovascular field. Specifically, the University of Oxford would like to obtain information from participants who were or will be submitted to cardiac surgery (ART Vasc, Bypass Grafts Sub-study, AdipoRedOx Sub-study), or cardiac investigations (ORFAN study). In this regard, participants need to be categorised before, during and immediately after surgery, and at long-term follow-up.

The study will use NHS Digital's List Cleaning service to ascertain the current vital status and addresses of all participants in the four sub-studies before sending all living participants a newsletter to ensure they are fully informed of how their data is being used for the purposes of the Oxford Heart, Vessels & Fat (Ox-HVF) study and, in particular, how the specific sub-study they consented to participate in contributes to the overarching study. Once participants have been sent this newsletter, the University of Oxford will be permitted to request further data about the participants' health and vital status.

The study will then send participants' NHS numbers to NHS Digital in order to obtain pre-operative co-morbidities and medications, surgical procedure details and immediate post-operative outcomes, and at long-term, the study will check for recurrence of symptoms that motivate new hospital admissions, necessity of re-revascularizations, fatal and non-fatal coronary events and all-cause death.

The University of Oxford requires the following linked identifiable NHS Digital data:

i) Hospital Episode Statistics Outpatients, Critical Care, Admitted Patient Care and Accident and Emergency including date of hospital admission and reason for admission for each individual participant from the date of consent to the relevant research sub-study (provided) until the start date of this current Data Sharing Agreement

ii) Civil registry mortality data including date and cause of death from the date of consent to the relevant research sub-study (provided) until the start date of this current Data Sharing Agreement.

Following discussions with NHS Digital regarding the inclusion of the ORFAN sub-study, NHS Digital will provide data on all Ox-HVF cohort participants from the 23rd February 2016 (date that the first participant was enrolled to the ORFAN study). There will be a minimal overlap with the data already provided by NHS Digital to the University of Oxford team, under a previous version of this Data Sharing Agreement (DARS-NIC-392669T1F8B-v.1.3) for the period between 23rd February 2016 and 31st March 2017 (this is referred to those participants already included in the patient group of the cohort under the previous DSA). The University of Oxford will provide evidence that any duplicate records held on the older studies will be destroyed in order to minimise risk associated with data management and handling.

During the course of this Agreement, yearly extracts will be requested for up to date data on the current cohorts plus any additional participants that have been recruited in the meantime to the AdipoRedOx and ORFAN sub-studies.

Under previous iterations of this Data Sharing Agreement, the University of Oxford has received HES and linked mortality data for the cohorts from the ART Vascular, Bypass Vascular study and AdipoRedOx studies from 2003/04 to 2016/17.

Collection of this data is vital to obtaining the primary endpoint statistics linking the existing study data with post-surgery clinical outcome. Statistical analyses on time-to-event data are very dependent on number of events recorded and time to follow-up, with higher numbers providing higher statistical power. Given the heterogeneous nature of the cohort, a long follow-up period of at least ten years is deemed minimum for extracting reliable information. NHS Digital data for England and Wales will allow the study to analyse these events in different health care institutions within the NHS.

The research outputs will include peer reviewed publications in leading international journals, presentations in international and national scientific meetings and possible media reports.

In summary:

Journals being targeted to submit to/publish in:

i) The New England Journal of Medicine

ii) The Journal of the American Medical Association Family Journals

iii) The Lancet Family Journals

iv) Circulation

v) Journal of the American College of Cardiology

Vi) European Heart Journal

Congresses targeted to submit to:

i) Scientific sessions of the American Heart Association

ii) Scientific sessions of the European Society of Cardiology

iii) Scientific sessions of the American College of Cardiology

iv) Scientific sessions of the British Cardiac Society

The outputs from this work will be both immediate - with publications in high impact journals (please see below a list with the most up to date high impact publications), as well as long-term - when diagnostic biomarkers or new therapeutics are implemented in clinical practice. As the ox-HVF is expected to continue collecting outcomes data for at least the next 10 years, the cohort will continue to generate outputs as more events accumulate over time. These long-term impacts have the potential to change clinical practice worldwide and save lives. To target the lay audience, the ox-HVF team uses the following approaches:

a) Website (www.oxhvf.com); this is updated with all the most up to date information regarding the outputs of the research. This is a patient-facing website, and the patients have the ability to read the “For Patients” section of the website and understand the impact of the team’s research.

b) Newsletters; when major findings or general outputs are available, the ox-HVF team post newsletters both on the website and through the post, to the study participants (after confirming that the patients are still alive through the data collected through NHS Digital).

The ox-HVF team aims to keep study participants as up to date as possible. To do this, the publications section of the oxhvf.com website is routinely updated with all recent research papers (see link: https://oxhvf.com/publications/). For reference:

1. Kotanidis CP et al. Constructing custom-made radiotranscriptomic signatures of vascular inflammation from routine CT angiograms: a prospective outcomes validation study in COVID-19. The Lancet Digital Health (2022) – Impact Factor: 36.61

2. Akoumianakis I et al. Non-canonical WNT signalling in cardiovascular disease: mechanisms and therapeutic implications. Nature Reviews Cardiology (2022) – Impact Factor: 49.42

3. Badi I et al. Brown Adipose Tissue and the Take (12,13-di)HOME Message to the Heart. Circulation (2022) – Impact Factor: 39.92

4. Antoniades C et al. The year in cardiovascular medicine 2020: digital health and innovation. European Heart Journal (2021) – Impact Factor: 35.86

5. Oikonomou EK et al. Standardized measurement of coronary inflammation using cardiovascular computed tomography: integration in clinical care as a prognostic medical device. Cardiovascular Research – Impact Factor: 13.08

The oxHVF is a single cohort, so the updates are addressing all participants across the sub-studies. The last hard-copy newsletter was sent out by post in June 2020 to all oxHVF participants who were still alive, and included updates on new data processing activities that included processing of NHS Digital data, as well as news on the development of the ox-HVF team's novel biomarker, the Fat Attenuation Index (FAI), that gathered a lot of media attention including BBC News, The Guardian, The Financial Times and CBN and was published in the prestigious journal “Science Translational Medicine” (see example: https://test188076.files.wordpress.com/2018/01/newsletter-adiporedox-15-09-2017.pdf).

c) Press releases; the ox-HVF team have an active involvement in outreach activities of the University of Oxford, Oxford University Innovations and the British heart Foundation communications team, and the major findings from their studies lead to press releases, and from there they are distributed to the lay press. Examples of recent press releases and lay press articles are found below:

Press releases on the radiotranscriptomic work:

https://www.bhf.org.uk/what-we-do/news-from-the-bhf/news-archive/2021/june/ai-detects-life-threatening-blood-vessel-inflammation-from-covid-19-variants

https://www.rdm.ox.ac.uk/news/ai-detects-life-threatening-blood-vessel-inflammation-from-covid-19-variants

https://woodzog.com/ai-tool-to-track-vascular-inflammation-in-covid-19-patients/

1. Recent interview for the use of artificial intelligence in practice.

2. Press release on the validation of Fat Attenuation Index for prediction of mortality and morbidity (http://www.ox.ac.uk/news/2018-08-28-study-shows-new-technology-can-predict-fatal-heart-attacks). This led to a Reuters release (https://uk.reuters.com/article/us-health-heart-britain/tech-breakthrough-offers-early-warning-system-for-heart-attacks-idUKKCN1ME14F) and various articles in lay press (the Guardian, Times, Independent, Sky News etc)

3. Press release on the discovery of novel implications of insulin treatment for patients with cardiac diseases, that led to lay press coverage in iNews (https://inews.co.uk/news/health/diabetes-drug-prevent-heart-attacks-strokes/)

4. Press release on discovery of fat attenuation Index 2017 (https://oxfordbrc.nihr.ac.uk/oxford-researchers-develop-new-early-warning-scan-for-heart-attacks/) that led to wide coverage in lay press (BBC, NBC, Financial Times etc).

5. Press release on artificial intelligence (https://www.research.ox.ac.uk/Article/2018-10-15-making-healthcare-smarter-with-ai) and lay press coverage on how the team’s research can transform the NHS in the next years (https://inews.co.uk/news/health/the-ten-health-innovations-that-could-soon-be-on-the-nhs/)

6. UpToDate’s latest chapter on Noninvasive Coronary Imaging (https://www.uptodate.com/contents/noninvasive-coronary-imaging-with-cardiac-computed-tomography-and-cardiovascular-magnetic-resonance)

7. JAMA Network article (https://jamanetwork.com/journals/jama/article-abstract/2706117?utm_source=fbpage&utm_medium=social_jama&utm_term=1820946790&utm_content=followers-article_engagement-illustration_medical&utm_campaign=article_alert&linkId=57902365)

d) Documentaries: the ox-HVF team has participated in a Horizon BBC 1 documentary on “crashing diets” 2018, discussing how diet can affect blood pressure (https://www.bbc.co.uk/programmes/b0b53xqs).

e) Workshops and patient and public involvement; the ox-HVF team participate in workshops for patients as part of the Biomedical Research Centre in Oxford, and through that they inform the patients about their research and ask for their involvement in the design of protocols, feedback on research procedures and more, through Patient and Public involvement (PPI) panels (e.g. such panels were set for AdipoRedOx and ORFAN substudies).

First outputs are expected 6-12 months after the data is received, but as the cohort matures, new data is included and the outcomes data from previous years are populated with then newer data, leading to added value to the datasets.

Outputs already delivered:

Ox-HVF produces a wide range of outputs spanning basic, translational, and clinical cardiovascular research. The University of Oxford present below a narrative addressed to lay audiences of a selection of research landmarks derived from the cohort thus far. Please note that this only includes a fraction of the achieved outputs. For a full comprehensive list, please visit https://oxhvf.com/publications

In a landmark study published in Science Translational Medicine (https://www.science.org/doi/abs/10.1126/scitranslmed.aal2658), the University of Oxford discovered a bidirectional communication between the heart arteries and the fat surrounding them. The team found that the fat surrounding these arteries “senses” inflammation coming from the adjacent artery, resulting in altered fat composition. A new imaging technology, based on routine CTA, called “perivascular fat attenuation indexing” (FAI), tracked the changes in the fat surrounding inflamed arteries - even in the absence of visible plaques or narrowings. The technology also detected those “vulnerable” plaques that are prone to sudden blockages, flagging the individuals at highest risk for heart attacks.

This new biomarker, the Fat Attenuation Index (FAI), was then tested for the first time in a large study published in The Lancet (https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31114-0/fulltext), and was presented at the European Society of Cardiology congress in Munich in 2018. This validation involved 3,900 patients from Europe (Erlangen, Germany) and the United States (Cleveland Clinic), who were followed up for ten years after they had a CT coronary angiogram. The FAI technology was found to predict fatal heart attacks many years before they happen, with a significantly superior predictive accuracy compared with other methods. People with abnormal FAI had up to nine times higher risk of having a fatal heart attack in the next five years. Importantly, these patients would be the ideal candidates for aggressive medical therapy to prevent this from happening.

Onwards, the FAI was combined with other known risk factors and imaging characteristics to create a new risk score named CaRi-Heart®. This constitutes a novel CCTA-based risk stratification medical device, integrating the recently described FAI mapping with traditional cardiovascular risk factors and multi-dimensional, comprehensive CCTA coronary plaque analysis. The prognostic output produced by CaRi-Heart® demonstrated significant net clinical benefit in two large and independent CCTA populations over and above traditional cardiovascular risk factors in a study published in Cardiovascular Research (https://academic.oup.com/cardiovascres/article/117/13/2677/6358671?login=false).

Further, in a study published in the European Heart Journal (https://academic.oup.com/eurheartj/article/40/43/3529/5554432?login=false) the University of Oxford used fat biopsies from people undergoing cardiac surgery to analyse the expression of genes associated with inflammation, scarring and new blood vessel formation, which were matched to the CCTA scan images to determine which features best indicate changes to the fat surrounding the heart vessels, called perivascular fat. Next, the team compared the CCTA scans of the 101 people (from a pool of 5487 individuals), who went on to have a heart attack or cardiovascular death within five years of having a CCTA, versus similar 'matched' controls who did not. This helped the team understand the changes in the perivascular space which indicate that someone is at higher risk of a heart attack. Using machine learning, we developed the FRP fingerprint that captures the level of risk. Following validation of this perivascular fingerprint in 1,575 people in the SCOT-HEART trial, the University of Oxford found that the FRP had a striking value in predicting heart attacks, above what can be achieved with any of the tools currently used by doctors in clinics.

In addition, the University of Oxford observed that insulin itself can cause oxidative damage to human arteries, contrary to what has previously been found in mouse and cell studies. In this landmark study published in Science Translational Medicine (https://www.science.org/doi/10.1126/scitranslmed.aav8824), the University of Oxford found that a commonly used category of anti-diabetic tablets (which inhibit a key enzyme known as dipeptidyl peptidase 4-DPP4) can ameliorate this effect, restoring blood vessel health.

Finally, in the most recently published work in the Lancet Digital Health (https://www.thelancet.com/journals/landig/article/PIIS2589-7500(22)00132-7/fulltext), the University of Oxford developed a novel image analysis platform, which uses artificial intelligence to quantify cytokine-driven vascular inflammation from routine CT angiograms. The team was able to carry out ‘virtual biopsies’, by deriving a radiomic ‘signature’ from the angiogram images, and then using machine learning to train this signature against transcriptomic profiles (derived from RNA sequencing data) from tissue biopsies. Using this method, the University of Oxford developed C19-RS, a radiotranscriptomic signature of vascular cytokine-driven arterial inflammation. The University of Oxford tested this new radiotranscriptomic signature with data from routine CT angiograms of patients with COVID-19, to find that cytokine-driven vascular inflammation predicts thrombosis and the likelihood of patients dying in hospital. This method also identified patients who respond well to steroid treatment.

Recent data have shown that treatment of patients with diabetes with insulin, may lead to significant damage of the heart arteries if the treatment is not accompanied by a drug called insulin sensitizer. This could lead to major changes in the treatment of these patients globally (https://inews.co.uk/news/health/diabetes-drug-prevent-heart-attacks-strokes).

The University of Oxford team have previously shown that obesity may not be necessarily bad, and those patients with high body mass index may be “protected against cardiovascular mortality” because fat in the body may secrete protective substances. This is called obesity paradox and has major implications for the treatment of patients with heart diseases (Diabetes 2015, link to press coverage about the obesity paradox: https://www.telegraph.co.uk/news/science/science-news/11657811/Why-obesity-protects-against-heart-disease-and-heart-attack.html).

The University of Oxford has recently identified a major therapeutic target for the treatment of heart diseases, and that discovery led to intense research to develop new drugs to modify this target (presented in the last European Society of Cardiology 2018 Congress, and received the Best Poster Award).

The University of Oxford has recently develop a method to detect patients at risk for future heart attacks using the ox-HVF cohort (Science Transl Med 2017), which was validated in a recent publication (Lancet 2018). This method has been included into the recent Up-To-Date guidance (https://www.uptodate.com/contents/cardiac-imaging-with-computed-tomography-and-magnetic-resonance-in-the-adult) and can be used to detect patients who may need intense medical therapy to prevent future heart attacks.

The University of Oxford group has developed a novel imaging biomarker (see Antonopoulos et al Science Translational Medicine 2017), namely the Fat Attenuation Index (FAI), which has been shown to be a marker of vascular inflammation at early disease stages. Validation of this biomarker in large cohorts of patients with residual cardiovascular risk showed that FAI is able to detect patients at high risk for cardiac mortality and is also predictive of non-fatal heart attacks. This permits reclassification of an individual’s risk, above and beyond the current state-of-the-art diagnostic tools, with strong implications for guiding medical management in patients and guiding the use of primary and secondary prevention measures. The development of this technology is a significant example that highlights the strength and unique ability of the Ox-HVF cohort in combining data across different and diverse fields - from clinical and epidemiological data to basic science and imaging data to outcome data (requested in the current application)- to create new, boundary-pushing ideas that promote health and serve the public interest. Of note, FAI was featured by iNews as one of the ten health innovations that could soon be on the NHS (https://inews.co.uk/news/health/the-ten-health-innovations-that-could-soon-be-on-the-nhs/).

The University of Oxford has found that insulin treatment in diabetic people should be accompanied by medication targeting a specific molecule, which is regarded to be able to sensitize the human vessels to insulin signalling, in order to avoid damage to the heart arteries. Furthermore, they have shown that a molecule secreted from fat surrounding the human vessels, can trigger the development of damage and inflammation to them and therefore could constitute a promising therapeutic target.

Ischemic heart disease remains the leading cause of death in upper-middle and high income economies. Coronary artery disease (CAD) accounts for one in seven deaths in men and one in twelve deaths in women in England, responsible for over 53,000 deaths every year, with associated healthcare costs continuing to rise. Coronary artery bypass graft surgery (CABG) continues to be the optimum revascularisation strategy for most patients with multi-vessel coronary artery disease. Although the biological variability between patients should be crucial for the prediction of long-term outcome of patients undergoing cardiac surgery, the exact mechanism linking the biology of the heart, the vascular grafts used and the myocardium with clinical outcome are unclear. Furthermore, taking into account the fact that cardiovascular disease remains one of the top mortality causes in the developed world, there is an unmet need in developing new markers of disease development and progression.

The aim of the OxHVF cohort study is to discover new blood, genetic and imaging biomarkers that differ between patients with advanced coronary atherosclerosis and healthy individuals (controls). The ability of these biomarkers to predict clinical outcomes in patients and controls will be evaluated by analysing prospective data collected through hospital records and other sources such as NHS Digital. These new biomarkers could also serve as potential therapeutic targets, allowing the development of new therapeutic strategies for the prevention and treatment of cardiovascular disease.

The University of Oxford is requesting mortality and Hospital Episode Statistics (HES) data with the aim to progress understanding of cardiovascular disease pathogenesis leading to the development of novel markers for early disease detection, ultimately resulting in sooner, better and more efficient cardiovascular disease management in the interest of the 1.8 million people that are currently battling coronary heart disease in England.

Collection of outcomes data for the patients with atherosclerosis and healthy controls, will allow the University of Oxford to compare the predictive value of any new biomarker identified through the cross-sectional analyses, between patients with atherosclerosis and healthy individuals. For example, the University of Oxford will compare the ability of new blood, genetic and imaging biomarkers discovered in the ox-HVF cohort to predict cardiovascular and other clinical outcomes in individuals with or without advanced atherosclerosis.

The Oxford Heart, Vessels & Fat (Ox-HVF) cohort consists of participants recruited into one of the clinical sub-studies constituting the cohort: ART Vascular Study, Bypass Vascular Study, AdipoRedOx and ORFAN. Ox-HVF was designed to provide synergistic results allowing the deployment of a multi-level strategy to address the aforementioned issues (see www.oxhvf.com). The primary aim of the cohort is to discover new biomarkers and/or therapeutic targets for the prediction and prevention of cardiovascular events and other clinical outcomes. These biomarkers can be biochemical (measured in the blood of the patient), genetic (measured in the DNA) or imaging (measured in non-invasive imaging). The therapeutic targets can be at the level of the circulation or tissue (by studying human blood, arteries and veins, fat or myocardial samples collected during surgery).

In the Ox-HVF cohort, the patients with advanced cardiovascular disease are recruited through 3 main clinical sub-studies (ART Vascular Study, Bypass Vascular Study, AdipoRedOx), and the control individuals (with risk factors but no established cardiovascular disease) through ORFAN sub-study. The ORFAN study was designed from the beginning in collaboration with NHS Digital, to enable collection of control data for Ox-HVF. All Ox-HVF participants contribute blood and imaging data to the cohort, whereas patient participants also contribute tissue samples. Data are aggregated from all sub-studies in a single database (ox-HVF database) and analysed collectively, as a single cohort (ox-HVF cohort) comprising of both patients and controls.

In more detail, the participants of the cohort come from the following 4 sub-studies:

i) The Arterial Revascularisation Trial: Vascular sub-study (ART Vasc) (November 2004 to 2017; REC: MREC04/03/006) compares coronary artery bypass grafting with a single internal mammary artery (IMA) to surgery with bilateral internal mammary arteries. 258 patients undergoing coronary artery bypass grafting surgery at the John Radcliffe Hospital, Oxford were enrolled to the study. ART Vasc study is no longer recruiting. Data collection continues through access to patients’ medical records, extracting data from both the local Hospital archive and the NHS Digital records.

ii) The Vascular Properties of Bypass Grafts (Bypass Vascular study) (January 2005 to current; REC: 04/Q1605/95) aims to compare measures of vascular function with post-operative clinical outcome after cardiac surgery. The inner lining of a person’s arteries is made up of cells (specifically endothelial cells) that can control how the artery stretches or dilates. The measure of how well this mechanism works is called endothelial function. The term “endothelial dysfunction” is used to describe changes in the in the inner lining of the artery to a state that can lead to disease progression and atherosclerosis.

The Bypass Vascular Study invited patients undergoing coronary artery bypass graft surgery at the John Radcliffe Hospital to participate in further investigation of their endothelial function to help better understand why some bypass grafts work better than others and how the function of them could possibly be improved in the future. 231 patients were successfully enrolled to the study. The Bypass Vascular Study is no longer recruiting. Data collection continues through access to the patient’s medical records and extracting data from NHS Digital.

iii) The AdipoRedOx study (15/09/2011 to current; REC: 11/SC/140), aims to investigate the mechanisms by which the fat tissue, the vascular tissue and the heart muscle interact and the University of Oxford aim to explore whether aspects of this interaction can predict the outcomes of coronary artery bypass grafting operation (CABG). The AdipoRedOx study is actively recruiting and will follow participants up until 2030.

iv) The controls of the cohort come from the ORFAN sub-study (11/10/2015 to current; REC: 15/SC/0545). This aims to recruit individuals with risk factors but not advanced coronary artery disease, serving as controls to the heavily diseased populations of the other three sub-studies, and ultimately as the validation cohort for the predictive and prognostic value of any biomarker developed for early cardiovascular disease detection.

Participants were enrolled to ART Vasc, Bypass Vascular Study and the AdipoRedOx study before they underwent open-heart surgery at the John Radcliffe Hospital, Oxford. All four sub-studies have gained informed consent from each participant to access their medical records to collect long-term outcome data to provide information that may have a predictive value. Importantly, these studies aim to link the collected data (i.e. risk factors, data on vascular function, imaging data etc.) with patient clinical outcome data, producing the world’s most comprehensive resource comparing vascular, myocardial and adipose tissue biology and imaging with clinical outcomes.

Data is requested in line with Article 6(1)(e) –‘processing is necessary for the performance of a task carried out in the public interest’.

Public interest is in line with Article 9(2)(j) – ‘processing is necessary for archiving purposes in the public interest'.

The University of Oxford is the sole data controller and also processes the data for this study. The University of Oxford is seeking to collect health outcome data on these participants, namely Hospital Episode Statistics and civil registry mortality data (cause and date of death). No other organisations process the data for this purpose. The University of Oxford solely determines the purpose and outputs of the Ox-HVF cohort sub-studies.

The following organisations are involved in recruiting study participants for the ORFAN sub-study only:

- Milton Keynes University Hospital

- University Hospitals of Leicester NHS Trust

- Royal Brompton and Harefield NHS Foundation Trust

- Oxford University Hospitals NHS Foundation Trust

Oxford University Hospitals NHS Foundation Trust is the only organisation involved in recruiting study participants for the AdipoRedOx sub-study.

Jersey General Hospital, The Nuffield Health Manor Hospital and Milton Keynes University Hospital performed post-operative CT scans of participants already recruited in the "AdipoRedOx" sub-study from Oxford University Hospitals NHS Foundation Trust.

The "Art-Vasc" and "Bypass Vascular Grafts" sub-studies are NOT actively recruiting any participants. All participants in these sub-studies were recruited from Oxford University Hospitals NHS Foundation Trust.

The Oxford University Hospitals (OUH) NHS Foundation Trust's logo is displayed on the consent materials because all patients within the AdipoRedOx, "Art-Vasc" and "Bypass Vascular Grafts" sub-studies have been recruited in OUH.

For the ORFAN sub-study, the logo section and the contact information have been kept blank, to include details of the local site and the local PI (principal investigator). More specifically, participants recruited from the OUH will be given consent material with the OUH logo on them, whereas participants recruited at external sites, will be given consent material with the local Trust logo and local PI information. None of the local study investigators from the multiple recruitment sites or their respective organisations have any control over any of the Ox-HVF data.

The sites recruiting participants (for ORFAN sub-study only), perform tests outlined in the respective study protocols and collect demographic data (for all sub-studies), which they hand over to the sole data controller, i.e. the University of Oxford.

The University of Oxford is the sole data controller because the Chief Investigator in all 4 sub-studies constituting the Ox-HVF cohort is a full-time employee of the University of Oxford. All clinical researchers involved in data analysis within the Ox-HVF cohort are employed by the University of Oxford.

The primary objective of the study is to:

Develop and validate new blood, genetic, imaging and other biomarkers that allow good discrimination between patients with coronary artery disease and healthy individuals, and evaluate their ability to predict clinical outcomes. These biomarkers may also form therapeutic targets for the development of new strategies to prevent and treat cardiovascular diseases.

Secondary objectives are to:

i) Investigate the mechanisms by which adipose tissue derived molecules affects vascular/myocardial redox state, endothelial (inner lining of the artery) function and clinical outcomes of patients undergoing coronary artery bypass grafting operation (CABG) and validate their applicability in healthy individuals.

ii) Search for a possible signal from the myocardium/vascular wall to epicardial/perivascular adipose tissue that regulates the synthesis of adipokines and other signalling molecules and compare their blood levels between patients with cardiovascular disease and healthy individuals.

iii) Search for novel biomarkers/signalling molecules identified in peripheral blood or expressed in adipose tissue, that regulate vascular/myocardial redox state and/or predict vein graft patency and compare their blood levels between patients with cardiovascular disease and healthy individuals.

iv) Search for novel imaging biomarkers and signatures reflecting underlying biology, which have predictive and prognostic value and therefore have the potential to be used in large-scale population wide screenings for early cardiovascular disease detection.

In summary these objectives will then potentially result in the creation of patient risk models that the University of Oxford hope will improve health outcomes of patients with cardiovascular disease.

The University of Oxford is attempting to manage long-term, prospective cohorts in the cardiovascular field. Specifically, the University of Oxford would like to obtain information from participants who were or will be submitted to cardiac surgery (ART Vasc, Bypass Grafts Sub-study, AdipoRedOx Sub-study), or cardiac investigations (ORFAN study). In this regard, participants need to be categorised before, during and immediately after surgery, and at long-term follow-up.

The study will use NHS Digital's List Cleaning service to ascertain the current vital status and addresses of all participants in the four sub-studies before sending all living participants a newsletter to ensure they are fully informed of how their data is being used for the purposes of the Oxford Heart, Vessels & Fat (Ox-HVF) study and, in particular, how the specific sub-study they consented to participate in contributes to the overarching study. Once participants have been sent this newsletter, the University of Oxford will be permitted to request further data about the participants' health and vital status.

The study will then send participants' NHS numbers to NHS Digital in order to obtain pre-operative co-morbidities and medications, surgical procedure details and immediate post-operative outcomes, and at long-term, the study will check for recurrence of symptoms that motivate new hospital admissions, necessity of re-revascularizations, fatal and non-fatal coronary events and all-cause death.

The University of Oxford requires the following linked identifiable NHS Digital data:

i) Hospital Episode Statistics Outpatients, Critical Care, Admitted Patient Care and Accident and Emergency including date of hospital admission and reason for admission for each individual participant from the date of consent to the relevant research sub-study (provided) until the start date of this current Data Sharing Agreement

ii) Civil registry mortality data including date and cause of death from the date of consent to the relevant research sub-study (provided) until the start date of this current Data Sharing Agreement.

Following discussions with NHS Digital regarding the inclusion of the ORFAN sub-study, NHS Digital will provide data on all Ox-HVF cohort participants from the 23rd February 2016 (date that the first participant was enrolled to the ORFAN study). There will be a minimal overlap with the data already provided by NHS Digital to the University of Oxford team, under a previous version of this Data Sharing Agreement (DARS-NIC-392669T1F8B-v.1.3) for the period between 23rd February 2016 and 31st March 2017 (this is referred to those participants already included in the patient group of the cohort under the previous DSA). The University of Oxford will provide evidence that any duplicate records held on the older studies will be destroyed in order to minimise risk associated with data management and handling.

During the course of this Agreement, yearly extracts will be requested for up to date data on the current cohorts plus any additional participants that have been recruited in the meantime to the AdipoRedOx and ORFAN sub-studies.

Under previous iterations of this Data Sharing Agreement, the University of Oxford has received HES and linked mortality data for the cohorts from the ART Vascular, Bypass Vascular study and AdipoRedOx studies from 2003/04 to 2016/17.

Collection of this data is vital to obtaining the primary endpoint statistics linking the existing study data with post-surgery clinical outcome. Statistical analyses on time-to-event data are very dependent on number of events recorded and time to follow-up, with higher numbers providing higher statistical power. Given the heterogeneous nature of the cohort, a long follow-up period of at least ten years is deemed minimum for extracting reliable information. NHS Digital data for England and Wales will allow the study to analyse these events in different health care institutions within the NHS.

The research outputs will include peer reviewed publications in leading international journals, presentations in international and national scientific meetings and possible media reports.

In summary:

Journals being targeted to submit to/publish in:

i) The New England Journal of Medicine

ii) The Journal of the American Medical Association Family Journals

iii) The Lancet Family Journals

iv) Circulation

v) Journal of the American College of Cardiology

Vi) European Heart Journal

Congresses targeted to submit to:

i) Scientific sessions of the American Heart Association

ii) Scientific sessions of the European Society of Cardiology

iii) Scientific sessions of the American College of Cardiology

iv) Scientific sessions of the British Cardiac Society

The outputs from this work will be both immediate - with publications in high impact journals (please see below a list with the most up to date high impact publications), as well as long-term - when diagnostic biomarkers or new therapeutics are implemented in clinical practice. As the ox-HVF is expected to continue collecting outcomes data for at least the next 10 years, the cohort will continue to generate outputs as more events accumulate over time. These long-term impacts have the potential to change clinical practice worldwide and save lives. To target the lay audience, the ox-HVF team uses the following approaches:

a) Website (www.oxhvf.com); this is updated with all the most up to date information regarding the outputs of the research. This is a patient-facing website, and the patients have the ability to read the “For Patients” section of the website and understand the impact of the team’s research.

b) Newsletters; when major findings or general outputs are available, the ox-HVF team post newsletters both on the website and through the post, to the study participants (after confirming that the patients are still alive through the data collected through NHS Digital).

The ox-HVF team aims to keep study participants as up to date as possible. To do this, the publications section of the oxhvf.com website is routinely updated with all recent research papers (see link: https://oxhvf.com/publications/). For reference:

1. Kotanidis CP et al. Constructing custom-made radiotranscriptomic signatures of vascular inflammation from routine CT angiograms: a prospective outcomes validation study in COVID-19. The Lancet Digital Health (2022) – Impact Factor: 36.61

2. Akoumianakis I et al. Non-canonical WNT signalling in cardiovascular disease: mechanisms and therapeutic implications. Nature Reviews Cardiology (2022) – Impact Factor: 49.42

3. Badi I et al. Brown Adipose Tissue and the Take (12,13-di)HOME Message to the Heart. Circulation (2022) – Impact Factor: 39.92

4. Antoniades C et al. The year in cardiovascular medicine 2020: digital health and innovation. European Heart Journal (2021) – Impact Factor: 35.86

5. Oikonomou EK et al. Standardized measurement of coronary inflammation using cardiovascular computed tomography: integration in clinical care as a prognostic medical device. Cardiovascular Research – Impact Factor: 13.08

The oxHVF is a single cohort, so the updates are addressing all participants across the sub-studies. The last hard-copy newsletter was sent out by post in June 2020 to all oxHVF participants who were still alive, and included updates on new data processing activities that included processing of NHS Digital data, as well as news on the development of the ox-HVF team's novel biomarker, the Fat Attenuation Index (FAI), that gathered a lot of media attention including BBC News, The Guardian, The Financial Times and CBN and was published in the prestigious journal “Science Translational Medicine” (see example: https://test188076.files.wordpress.com/2018/01/newsletter-adiporedox-15-09-2017.pdf).

c) Press releases; the ox-HVF team have an active involvement in outreach activities of the University of Oxford, Oxford University Innovations and the British heart Foundation communications team, and the major findings from their studies lead to press releases, and from there they are distributed to the lay press. Examples of recent press releases and lay press articles are found below:

Press releases on the radiotranscriptomic work:

https://www.bhf.org.uk/what-we-do/news-from-the-bhf/news-archive/2021/june/ai-detects-life-threatening-blood-vessel-inflammation-from-covid-19-variants

https://www.rdm.ox.ac.uk/news/ai-detects-life-threatening-blood-vessel-inflammation-from-covid-19-variants

https://woodzog.com/ai-tool-to-track-vascular-inflammation-in-covid-19-patients/

1. Recent interview for the use of artificial intelligence in practice.

2. Press release on the validation of Fat Attenuation Index for prediction of mortality and morbidity (http://www.ox.ac.uk/news/2018-08-28-study-shows-new-technology-can-predict-fatal-heart-attacks). This led to a Reuters release (https://uk.reuters.com/article/us-health-heart-britain/tech-breakthrough-offers-early-warning-system-for-heart-attacks-idUKKCN1ME14F) and various articles in lay press (the Guardian, Times, Independent, Sky News etc)

3. Press release on the discovery of novel implications of insulin treatment for patients with cardiac diseases, that led to lay press coverage in iNews (https://inews.co.uk/news/health/diabetes-drug-prevent-heart-attacks-strokes/)

4. Press release on discovery of fat attenuation Index 2017 (https://oxfordbrc.nihr.ac.uk/oxford-researchers-develop-new-early-warning-scan-for-heart-attacks/) that led to wide coverage in lay press (BBC, NBC, Financial Times etc).

5. Press release on artificial intelligence (https://www.research.ox.ac.uk/Article/2018-10-15-making-healthcare-smarter-with-ai) and lay press coverage on how the team’s research can transform the NHS in the next years (https://inews.co.uk/news/health/the-ten-health-innovations-that-could-soon-be-on-the-nhs/)

6. UpToDate’s latest chapter on Noninvasive Coronary Imaging (https://www.uptodate.com/contents/noninvasive-coronary-imaging-with-cardiac-computed-tomography-and-cardiovascular-magnetic-resonance)

7. JAMA Network article (https://jamanetwork.com/journals/jama/article-abstract/2706117?utm_source=fbpage&utm_medium=social_jama&utm_term=1820946790&utm_content=followers-article_engagement-illustration_medical&utm_campaign=article_alert&linkId=57902365)

d) Documentaries: the ox-HVF team has participated in a Horizon BBC 1 documentary on “crashing diets” 2018, discussing how diet can affect blood pressure (https://www.bbc.co.uk/programmes/b0b53xqs).

e) Workshops and patient and public involvement; the ox-HVF team participate in workshops for patients as part of the Biomedical Research Centre in Oxford, and through that they inform the patients about their research and ask for their involvement in the design of protocols, feedback on research procedures and more, through Patient and Public involvement (PPI) panels (e.g. such panels were set for AdipoRedOx and ORFAN substudies).

First outputs are expected 6-12 months after the data is received, but as the cohort matures, new data is included and the outcomes data from previous years are populated with then newer data, leading to added value to the datasets.

Outputs already delivered:

Ox-HVF produces a wide range of outputs spanning basic, translational, and clinical cardiovascular research. The University of Oxford present below a narrative addressed to lay audiences of a selection of research landmarks derived from the cohort thus far. Please note that this only includes a fraction of the achieved outputs. For a full comprehensive list, please visit https://oxhvf.com/publications

In a landmark study published in Science Translational Medicine (https://www.science.org/doi/abs/10.1126/scitranslmed.aal2658), the University of Oxford discovered a bidirectional communication between the heart arteries and the fat surrounding them. The team found that the fat surrounding these arteries “senses” inflammation coming from the adjacent artery, resulting in altered fat composition. A new imaging technology, based on routine CTA, called “perivascular fat attenuation indexing” (FAI), tracked the changes in the fat surrounding inflamed arteries - even in the absence of visible plaques or narrowings. The technology also detected those “vulnerable” plaques that are prone to sudden blockages, flagging the individuals at highest risk for heart attacks.

This new biomarker, the Fat Attenuation Index (FAI), was then tested for the first time in a large study published in The Lancet (https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31114-0/fulltext), and was presented at the European Society of Cardiology congress in Munich in 2018. This validation involved 3,900 patients from Europe (Erlangen, Germany) and the United States (Cleveland Clinic), who were followed up for ten years after they had a CT coronary angiogram. The FAI technology was found to predict fatal heart attacks many years before they happen, with a significantly superior predictive accuracy compared with other methods. People with abnormal FAI had up to nine times higher risk of having a fatal heart attack in the next five years. Importantly, these patients would be the ideal candidates for aggressive medical therapy to prevent this from happening.

Onwards, the FAI was combined with other known risk factors and imaging characteristics to create a new risk score named CaRi-Heart®. This constitutes a novel CCTA-based risk stratification medical device, integrating the recently described FAI mapping with traditional cardiovascular risk factors and multi-dimensional, comprehensive CCTA coronary plaque analysis. The prognostic output produced by CaRi-Heart® demonstrated significant net clinical benefit in two large and independent CCTA populations over and above traditional cardiovascular risk factors in a study published in Cardiovascular Research (https://academic.oup.com/cardiovascres/article/117/13/2677/6358671?login=false).

Further, in a study published in the European Heart Journal (https://academic.oup.com/eurheartj/article/40/43/3529/5554432?login=false) the University of Oxford used fat biopsies from people undergoing cardiac surgery to analyse the expression of genes associated with inflammation, scarring and new blood vessel formation, which were matched to the CCTA scan images to determine which features best indicate changes to the fat surrounding the heart vessels, called perivascular fat. Next, the team compared the CCTA scans of the 101 people (from a pool of 5487 individuals), who went on to have a heart attack or cardiovascular death within five years of having a CCTA, versus similar 'matched' controls who did not. This helped the team understand the changes in the perivascular space which indicate that someone is at higher risk of a heart attack. Using machine learning, we developed the FRP fingerprint that captures the level of risk. Following validation of this perivascular fingerprint in 1,575 people in the SCOT-HEART trial, the University of Oxford found that the FRP had a striking value in predicting heart attacks, above what can be achieved with any of the tools currently used by doctors in clinics.

In addition, the University of Oxford observed that insulin itself can cause oxidative damage to human arteries, contrary to what has previously been found in mouse and cell studies. In this landmark study published in Science Translational Medicine (https://www.science.org/doi/10.1126/scitranslmed.aav8824), the University of Oxford found that a commonly used category of anti-diabetic tablets (which inhibit a key enzyme known as dipeptidyl peptidase 4-DPP4) can ameliorate this effect, restoring blood vessel health.

Finally, in the most recently published work in the Lancet Digital Health (https://www.thelancet.com/journals/landig/article/PIIS2589-7500(22)00132-7/fulltext), the University of Oxford developed a novel image analysis platform, which uses artificial intelligence to quantify cytokine-driven vascular inflammation from routine CT angiograms. The team was able to carry out ‘virtual biopsies’, by deriving a radiomic ‘signature’ from the angiogram images, and then using machine learning to train this signature against transcriptomic profiles (derived from RNA sequencing data) from tissue biopsies. Using this method, the University of Oxford developed C19-RS, a radiotranscriptomic signature of vascular cytokine-driven arterial inflammation. The University of Oxford tested this new radiotranscriptomic signature with data from routine CT angiograms of patients with COVID-19, to find that cytokine-driven vascular inflammation predicts thrombosis and the likelihood of patients dying in hospital. This method also identified patients who respond well to steroid treatment.

Recent data have shown that treatment of patients with diabetes with insulin, may lead to significant damage of the heart arteries if the treatment is not accompanied by a drug called insulin sensitizer. This could lead to major changes in the treatment of these patients globally (https://inews.co.uk/news/health/diabetes-drug-prevent-heart-attacks-strokes).

The University of Oxford team have previously shown that obesity may not be necessarily bad, and those patients with high body mass index may be “protected against cardiovascular mortality” because fat in the body may secrete protective substances. This is called obesity paradox and has major implications for the treatment of patients with heart diseases (Diabetes 2015, link to press coverage about the obesity paradox: https://www.telegraph.co.uk/news/science/science-news/11657811/Why-obesity-protects-against-heart-disease-and-heart-attack.html).

The University of Oxford has recently identified a major therapeutic target for the treatment of heart diseases, and that discovery led to intense research to develop new drugs to modify this target (presented in the last European Society of Cardiology 2018 Congress, and received the Best Poster Award).

The University of Oxford has recently develop a method to detect patients at risk for future heart attacks using the ox-HVF cohort (Science Transl Med 2017), which was validated in a recent publication (Lancet 2018). This method has been included into the recent Up-To-Date guidance (https://www.uptodate.com/contents/cardiac-imaging-with-computed-tomography-and-magnetic-resonance-in-the-adult) and can be used to detect patients who may need intense medical therapy to prevent future heart attacks.

The University of Oxford group has developed a novel imaging biomarker (see Antonopoulos et al Science Translational Medicine 2017), namely the Fat Attenuation Index (FAI), which has been shown to be a marker of vascular inflammation at early disease stages. Validation of this biomarker in large cohorts of patients with residual cardiovascular risk showed that FAI is able to detect patients at high risk for cardiac mortality and is also predictive of non-fatal heart attacks. This permits reclassification of an individual’s risk, above and beyond the current state-of-the-art diagnostic tools, with strong implications for guiding medical management in patients and guiding the use of primary and secondary prevention measures. The development of this technology is a significant example that highlights the strength and unique ability of the Ox-HVF cohort in combining data across different and diverse fields - from clinical and epidemiological data to basic science and imaging data to outcome data (requested in the current application)- to create new, boundary-pushing ideas that promote health and serve the public interest. Of note, FAI was featured by iNews as one of the ten health innovations that could soon be on the NHS (https://inews.co.uk/news/health/the-ten-health-innovations-that-could-soon-be-on-the-nhs/).

The University of Oxford has found that insulin treatment in diabetic people should be accompanied by medication targeting a specific molecule, which is regarded to be able to sensitize the human vessels to insulin signalling, in order to avoid damage to the heart arteries. Furthermore, they have shown that a molecule secreted from fat surrounding the human vessels, can trigger the development of damage and inflammation to them and therefore could constitute a promising therapeutic target.

Ischemic heart disease remains the leading cause of death in upper-middle and high income economies. Coronary artery disease (CAD) accounts for one in seven deaths in men and one in twelve deaths in women in England, responsible for over 53,000 deaths every year, with associated healthcare costs continuing to rise. Coronary artery bypass graft surgery (CABG) continues to be the optimum revascularisation strategy for most patients with multi-vessel coronary artery disease. Although the biological variability between patients should be crucial for the prediction of long-term outcome of patients undergoing cardiac surgery, the exact mechanism linking the biology of the heart, the vascular grafts used and the myocardium with clinical outcome are unclear. Furthermore, taking into account the fact that cardiovascular disease remains one of the top mortality causes in the developed world, there is an unmet need in developing new markers of disease development and progression.

The aim of the OxHVF cohort study is to discover new blood, genetic and imaging biomarkers that differ between patients with advanced coronary atherosclerosis and healthy individuals (controls). The ability of these biomarkers to predict clinical outcomes in patients and controls will be evaluated by analysing prospective data collected through hospital records and other sources such as NHS Digital. These new biomarkers could also serve as potential therapeutic targets, allowing the development of new therapeutic strategies for the prevention and treatment of cardiovascular disease.

The University of Oxford is requesting mortality and Hospital Episode Statistics (HES) data with the aim to progress understanding of cardiovascular disease pathogenesis leading to the development of novel markers for early disease detection, ultimately resulting in sooner, better and more efficient cardiovascular disease management in the interest of the 1.8 million people that are currently battling coronary heart disease in England.

Collection of outcomes data for the patients with atherosclerosis and healthy controls, will allow the University of Oxford to compare the predictive value of any new biomarker identified through the cross-sectional analyses, between patients with atherosclerosis and healthy individuals. For example, the University of Oxford will compare the ability of new blood, genetic and imaging biomarkers discovered in the ox-HVF cohort to predict cardiovascular and other clinical outcomes in individuals with or without advanced atherosclerosis.

The Oxford Heart, Vessels & Fat (Ox-HVF) cohort consists of participants recruited into one of the clinical sub-studies constituting the cohort: ART Vascular Study, Bypass Vascular Study, AdipoRedOx and ORFAN. Ox-HVF was designed to provide synergistic results allowing the deployment of a multi-level strategy to address the aforementioned issues (see www.oxhvf.com). The primary aim of the cohort is to discover new biomarkers and/or therapeutic targets for the prediction and prevention of cardiovascular events and other clinical outcomes. These biomarkers can be biochemical (measured in the blood of the patient), genetic (measured in the DNA) or imaging (measured in non-invasive imaging). The therapeutic targets can be at the level of the circulation or tissue (by studying human blood, arteries and veins, fat or myocardial samples collected during surgery).

In the Ox-HVF cohort, the patients with advanced cardiovascular disease are recruited through 3 main clinical sub-studies (ART Vascular Study, Bypass Vascular Study, AdipoRedOx), and the control individuals (with risk factors but no established cardiovascular disease) through ORFAN sub-study. The ORFAN study was designed from the beginning in collaboration with NHS Digital, to enable collection of control data for Ox-HVF. All Ox-HVF participants contribute blood and imaging data to the cohort, whereas patient participants also contribute tissue samples. Data are aggregated from all sub-studies in a single database (ox-HVF database) and analysed collectively, as a single cohort (ox-HVF cohort) comprising of both patients and controls.

In more detail, the participants of the cohort come from the following 4 sub-studies:

i) The Arterial Revascularisation Trial: Vascular sub-study (ART Vasc) (November 2004 to 2017; REC: MREC04/03/006) compares coronary artery bypass grafting with a single internal mammary artery (IMA) to surgery with bilateral internal mammary arteries. 258 patients undergoing coronary artery bypass grafting surgery at the John Radcliffe Hospital, Oxford were enrolled to the study. ART Vasc study is no longer recruiting. Data collection continues through access to patients’ medical records, extracting data from both the local Hospital archive and the NHS Digital records.

ii) The Vascular Properties of Bypass Grafts (Bypass Vascular study) (January 2005 to current; REC: 04/Q1605/95) aims to compare measures of vascular function with post-operative clinical outcome after cardiac surgery. The inner lining of a person’s arteries is made up of cells (specifically endothelial cells) that can control how the artery stretches or dilates. The measure of how well this mechanism works is called endothelial function. The term “endothelial dysfunction” is used to describe changes in the in the inner lining of the artery to a state that can lead to disease progression and atherosclerosis.

The Bypass Vascular Study invited patients undergoing coronary artery bypass graft surgery at the John Radcliffe Hospital to participate in further investigation of their endothelial function to help better understand why some bypass grafts work better than others and how the function of them could possibly be improved in the future. 231 patients were successfully enrolled to the study. The Bypass Vascular Study is no longer recruiting. Data collection continues through access to the patient’s medical records and extracting data from NHS Digital.

iii) The AdipoRedOx study (15/09/2011 to current; REC: 11/SC/140), aims to investigate the mechanisms by which the fat tissue, the vascular tissue and the heart muscle interact and the University of Oxford aim to explore whether aspects of this interaction can predict the outcomes of coronary artery bypass grafting operation (CABG). The AdipoRedOx study is actively recruiting and will follow participants up until 2030.

iv) The controls of the cohort come from the ORFAN sub-study (11/10/2015 to current; REC: 15/SC/0545). This aims to recruit individuals with risk factors but not advanced coronary artery disease, serving as controls to the heavily diseased populations of the other three sub-studies, and ultimately as the validation cohort for the predictive and prognostic value of any biomarker developed for early cardiovascular disease detection.

Participants were enrolled to ART Vasc, Bypass Vascular Study and the AdipoRedOx study before they underwent open-heart surgery at the John Radcliffe Hospital, Oxford. All four sub-studies have gained informed consent from each participant to access their medical records to collect long-term outcome data to provide information that may have a predictive value. Importantly, these studies aim to link the collected data (i.e. risk factors, data on vascular function, imaging data etc.) with patient clinical outcome data, producing the world’s most comprehensive resource comparing vascular, myocardial and adipose tissue biology and imaging with clinical outcomes.

Data is requested in line with Article 6(1)(e) –‘processing is necessary for the performance of a task carried out in the public interest’.

Public interest is in line with Article 9(2)(j) – ‘processing is necessary for archiving purposes in the public interest'.

The University of Oxford is the sole data controller and also processes the data for this study. The University of Oxford is seeking to collect health outcome data on these participants, namely Hospital Episode Statistics and civil registry mortality data (cause and date of death). No other organisations process the data for this purpose. The University of Oxford solely determines the purpose and outputs of the Ox-HVF cohort sub-studies.

The following organisations are involved in recruiting study participants for the ORFAN sub-study only:

- Milton Keynes University Hospital

- University Hospitals of Leicester NHS Trust

- Royal Brompton and Harefield NHS Foundation Trust

- Oxford University Hospitals NHS Foundation Trust

Oxford University Hospitals NHS Foundation Trust is the only organisation involved in recruiting study participants for the AdipoRedOx sub-study.

Jersey General Hospital and Milton Keynes University Hospital perfomed post-operative CT scans of participants already recruited in the "AdipoRedOx" sub-study from Oxford University Hospitals NHS Foundation Trust.

The "Art-Vasc" and "Bypass Vascular Grafts" sub-studies are NOT actively recruiting any participants. All participants in these sub-studies were recruited from Oxford University Hospitals NHS Foundation Trust.

The Oxford University Hospitals (OUH) NHS Foundation Trust's logo is displayed on the consent materials because all patients within the AdipoRedOx, "Art-Vasc" and "Bypass Vascular Grafts" sub-studies have been recruited in OUH.

For the ORFAN sub-study, the logo section and the contact information have been kept blank, to include details of the local site and the local PI (principal investigator). More specifically, participants recruited from the OUH will be given consent material with the OUH logo on them, whereas participants recruited at external sites, will be given consent material with the local Trust logo and local PI information. None of the local study investigators from the multiple recruitment sites or their respective organisations have any control over any of the Ox-HVF data.

The sites recruiting participants (for ORFAN sub-study only), perform tests outlined in the respective study protocols and collect demographic data (for all sub-studies), which they hand over to the sole data controller, i.e. the University of Oxford.

The University of Oxford is the sole data controller because the Chief Investigator in all 4 sub-studies constituting the Ox-HVF cohort is a full-time employee of the University of Oxford. All clinical researchers involved in data analysis within the Ox-HVF cohort are employed by the University of Oxford.

The primary objective of the study is to:

Develop and validate new blood, genetic, imaging and other biomarkers that allow good discrimination between patients with coronary artery disease and healthy individuals, and evaluate their ability to predict clinical outcomes. These biomarkers may also form therapeutic targets for the development of new strategies to prevent and treat cardiovascular diseases.

Secondary objectives are to:

i) Investigate the mechanisms by which adipose tissue derived molecules affects vascular/myocardial redox state, endothelial (inner lining of the artery) function and clinical outcomes of patients undergoing coronary artery bypass grafting operation (CABG) and validate their applicability in healthy individuals.

ii) Search for a possible signal from the myocardium/vascular wall to epicardial/perivascular adipose tissue that regulates the synthesis of adipokines and other signalling molecules and compare their blood levels between patients with cardiovascular disease and healthy individuals.

iii) Search for novel biomarkers/signalling molecules identified in peripheral blood or expressed in adipose tissue, that regulate vascular/myocardial redox state and/or predict vein graft patency and compare their blood levels between patients with cardiovascular disease and healthy individuals.

iv) Search for novel imaging biomarkers and signatures reflecting underlying biology, which have predictive and prognostic value and therefore have the potential to be used in large-scale population wide screenings for early cardiovascular disease detection.

In summary these objectives will then potentially result in the creation of patient risk models that the University of Oxford hope will improve health outcomes of patients with cardiovascular disease.

The University of Oxford is attempting to manage long-term, prospective cohorts in the cardiovascular field. Specifically, the University of Oxford would like to obtain information from participants who were or will be submitted to cardiac surgery (ART Vasc, Bypass Grafts Sub-study, AdipoRedOx Sub-study), or cardiac investigations (ORFAN study). In this regard, participants need to be categorised before, during and immediately after surgery, and at long-term follow-up.

The study will use NHS Digital's List Cleaning service to ascertain the current vital status and addresses of all participants in the four sub-studies before sending all living participants a newsletter to ensure they are fully informed of how their data is being used for the purposes of the Oxford Heart, Vessels & Fat (Ox-HVF) study and, in particular, how the specific sub-study they consented to participate in contributes to the overarching study. Once participants have been sent this newsletter, the University of Oxford will be permitted to request further data about the participants' health and vital status.

The study will then send participants' NHS numbers to NHS Digital in order to obtain pre-operative co-morbidities and medications, surgical procedure details and immediate post-operative outcomes, and at long-term, the study will check for recurrence of symptoms that motivate new hospital admissions, necessity of re-revascularizations, fatal and non-fatal coronary events and all-cause death.

The University of Oxford requires the following linked identifiable NHS Digital data:

i) Hospital Episode Statistics Outpatients, Critical Care, Admitted Patient Care and Accident and Emergency including date of hospital admission and reason for admission for each individual participant from the date of consent to the relevant research sub-study (provided) until the start date of this current Data Sharing Agreement

ii) Civil registry mortality data including date and cause of death from the date of consent to the relevant research sub-study (provided) until the start date of this current Data Sharing Agreement.

Following discussions with NHS Digital regarding the inclusion of the ORFAN sub-study, NHS Digital will provide data on all Ox-HVF cohort participants from the 23rd February 2016 (date that the first participant was enrolled to the ORFAN study). There will be a minimal overlap with the data already provided by NHS Digital to the University of Oxford team, under a previous version of this Data Sharing Agreement (DARS-NIC-392669T1F8B-v.1.3) for the period between 23rd February 2016 and 31st March 2017 (this is referred to those participants already included in the patient group of the cohort under the previous DSA). The University of Oxford will provide evidence that any duplicate records held on the older studies will be destroyed in order to minimise risk associated with data management and handling.

During the course of this Agreement, yearly extracts will be requested for up to date data on the current cohorts plus any additional participants that have been recruited in the meantime to the AdipoRedOx and ORFAN sub-studies.

Under previous iterations of this Data Sharing Agreement, the University of Oxford has received HES and linked mortality data for the cohorts from the ART Vascular, Bypass Vascular study and AdipoRedOx studies from 2003/04 to 2016/17.

Collection of this data is vital to obtaining the primary endpoint statistics linking the existing study data with post-surgery clinical outcome. Statistical analyses on time-to-event data are very dependent on number of events recorded and time to follow-up, with higher numbers providing higher statistical power. Given the heterogeneous nature of the cohort, a long follow-up period of at least ten years is deemed minimum for extracting reliable information. NHS Digital data for England and Wales will allow the study to analyse these events in different health care institutions within the NHS.

The research outputs will include peer reviewed publications in leading international journals, presentations in international and national scientific meetings and possible media reports.

In summary:

Journals being targeted to submit to/publish in:

i) The New England Journal of Medicine

ii) The Journal of the American Medical Association

iii) The Lancet

iv) Circulation

v) Journal of the American College of Cardiology or the British Medical Journal

Congresses targeted to submit to:

i) Scientific sessions of the American Heart Association

ii) Scientific sessions of the European Society of Cardiology

iii) Scientific sessions of the American College of Cardiology

iv) Scientific sessions of the British Cardiac Society

The outputs from this work will be both immediate - with publications in high impact journals (see Oikonomou et al Lancet 2018 and others) as well as long-term - when diagnostic biomarkers or new therapeutics are implemented in clinical practice. As the ox-HVF is expected to continue collecting outcomes data for at least the next 10 years, the cohort will continue to generate outputs as more events accumulate over time. These long-term impacts have the potential to change clinical practice worldwide and save lives. To target the lay audience, the ox-HVF team uses the following approaches:

a) Website (www.oxhvf.com); this is updated with all the most up to date information regarding the outputs of the research. This is a patient-facing website, and the patients have the ability to read the “For Patients” section of the website and understand the impact of the team’s research.

b) Newsletters; when major findings or general outputs are available, the ox-HVF team post newsletters both on the website and through the post, to the study participants (after confirming that the patients are still alive through the data collected through NHS Digital).

The ox-HVF team aims to keep study participants as up to date as possible. To do this, the publications section of the oxhvf.com website is routinely updated with all recent research papers (see link: https://oxhvf.com/publications/). The oxHVF is a single cohort, so the updates are addressing all participants across the sub-studies. The last hard-copy newsletter was sent out by post in September 2017 to all oxHVF participants who were still alive, and included updates on new data processing activities that included processing of NHS Digital data, as well as news on the development of the ox-HVF team's novel biomarker, the Fat Attenuation Index (FAI), that gathered a lot of media attention including BBC News, The Guardian, The Financial Times and CBN and was published in the prestigious journal “Science Translational Medicine” (see example: https://test188076.files.wordpress.com/2018/01/newsletter-adiporedox-15-09-2017.pdf).

c) Press releases; the ox-HVF team have an active involvement in outreach activities of the University of Oxford, Oxford University Innovations and the British heart Foundation communications team, and the major findings from their studies lead to press releases, and from there they are distributed to the lay press. Examples of recent press releases and lay press articles are found below:

1. Recent interview for the use of artificial intelligence in practice.

2. Press release on the validation of Fat Attenuation Index for prediction of mortality and morbidity (http://www.ox.ac.uk/news/2018-08-28-study-shows-new-technology-can-predict-fatal-heart-attacks). This led to a Reuters release (https://uk.reuters.com/article/us-health-heart-britain/tech-breakthrough-offers-early-warning-system-for-heart-attacks-idUKKCN1ME14F) and various articles in lay press (the Guardian, Times, Independent, Sky News etc)

3. Press release on the discovery of novel implications of insulin treatment for patients with cardiac diseases, that led to lay press coverage in iNews (https://inews.co.uk/news/health/diabetes-drug-prevent-heart-attacks-strokes/)

4. Press release on discovery of fat attenuation Index 2017 (https://oxfordbrc.nihr.ac.uk/oxford-researchers-develop-new-early-warning-scan-for-heart-attacks/) that led to wide coverage in lay press (BBC, NBC, Financial Times etc).

5. Press release on artificial intelligence (https://www.research.ox.ac.uk/Article/2018-10-15-making-healthcare-smarter-with-ai) and lay press coverage on how the team’s research can transform the NHS in the next years (https://inews.co.uk/news/health/the-ten-health-innovations-that-could-soon-be-on-the-nhs/)

6. UpToDate’s latest chapter on Noninvasive Coronary Imaging (https://www.uptodate.com/contents/noninvasive-coronary-imaging-with-cardiac-computed-tomography-and-cardiovascular-magnetic-resonance)

7. JAMA Network article (https://jamanetwork.com/journals/jama/article-abstract/2706117?utm_source=fbpage&utm_medium=social_jama&utm_term=1820946790&utm_content=followers-article_engagement-illustration_medical&utm_campaign=article_alert&linkId=57902365)

d) Documentaries: the ox-HVF team has participated in a Horizon BBC 1 documentary on “crashing diets” 2018, discussing how diet can affect blood pressure (https://www.bbc.co.uk/programmes/b0b53xqs).

e) Workshops and patient and public involvement; the ox-HVF team participate in workshops for patients as part of the Biomedical Research Centre in Oxford, and through that they inform the patients about their research and ask for their involvement in the design of protocols, feedback on research procedures and more, through Patient and Public involvement (PPI) panels (e.g. such panels were set for AdipoRedOx and ORFAN substudies).

First outputs are expected 6-12 months after the data is received, but as the cohort matures, new data is included and the outcomes data from previous years are populated with then newer data, leading to added value to the datasets.

Outputs already delivered:

Publications:

i) Oikonomou EK, Marwan M, Desai MY, Mancio J, Alashi A, Hutt Centeno E, et al. Non-invasive detection of coronary inflammation using computed tomography and prediction of residual cardiovascular risk (the CRISP CT study): a post-hoc analysis of prospective outcome data. Lancet. 2018;392(10151):929-39.

ii) Oikonomou EK, Antoniades C. The role of adipose tissue in cardiovascular health and disease. Nature reviews Cardiology. 2019;16(2):83-99.

iii) Antonopoulos AS, Antoniades C. Cardiac Magnetic Resonance Imaging of Epicardial and Intramyocardial Adiposity as an Early Sign of Myocardial Disease. Circulation Cardiovascular imaging. 2018;11(8):e008083.

iv) Antonopoulos AS, Antoniades C. Perivascular Fat Attenuation Index by Computed Tomography as a Metric of Coronary Inflammation. Journal of the American College of Cardiology. 2018;71(23):2708-9.

v) Mancio J, Oikonomou EK, Antoniades C. Perivascular adipose tissue and coronary atherosclerosis. Heart (British Cardiac Society). 2018;104(20):1654-62.

vi) Tarun A, Antoniades C. The era of cardiovascular epigenetics: histone deacetylases and vascular inflammation. Cardiovascular research. 2018;114(7):928-30.

Conference presentations:

i) AS Antonopoulos, L Herdman, S Thomas, I Akoumianakis, C Kotanidis, K Thomas, EK Oikonomou, K Psarros, R Sayeed, C Antoniades. 104Metabolically healthy obesity is associated with a distinct epicardial fat phenotype and low myocardial oxidative stress. ESC Congress, 25–29 August 2018, Munich, Germany.

ii) I Akoumianakis, L Herdman, M Margaritis, R Sayeed, G Krasopoulos, M Petrou, N Tennagels, P Wohlfart, KM Channon, C Antoniades. 2437 Insulin triggers oxidative stress in the vascular wall of patients with atherosclerosis, independently of systemic insulin resistance: the beneficial role of DPP-IV inhibition. ESC Congress, 25–29 August 2018, Munich, Germany.

iii) I Akoumianakis, F Sanna, M Margaritis, L Herdman, AS Antonopoulos, R Sayeed, G Krasopoulos, M Petrou, KM Channon, C Antoniades. P592 Perivascular adipose tissue-derived Wnt5a as a regulator of human vascular disease pathogenesis. ESC Congress, 25–29 August 2018, Munich, Germany.

iv) I Akoumianakis, AS Antonopoulos, L Herdman, M Margaritis, EK Oikonomou, G Krasopoulos, M Petrou, R Sayeed, KM Channon, C Antoniades. 3398 NADPH oxidase activity in internal mammary arteries predicts mortality in patients undergoing coronary bypass surgery. ESC Congress, 25–29 August 2018, Munich, Germany.

v) EK Oikonomou, S Thomas, J Mancio, AS Antonopoulos, N Sabharwal, A Kelion, S Neubauer, KM Channon, C Antoniades. 1182 Computed tomography-based perivascular fat phenotyping identifies unstable coronary lesions and active vascular calcification. ESC Congress, 25–29 August 2018, Munich, Germany.

vi) EK Oikonomou, S Thomas, S Kesavan, LM Fan, AS Antonopoulos, S Anthony, N Sabharwal, A Kelion, C Shirodaria, JP Langrish, AJ Lucking, RK Kharbanda, S Neubauer, KM Channon, C Antoniades. Perivascular fat imaging for unstable plaque detection and prediction of coronary plaque progression. BAS Annual Meeting, 6-7 September 2018, Cambridge, UK.

vii) I Akoumianakis, F Sanna, M Margaritis, L Herdman, AS Antonopoulos, R Sayeed, G Krasopoulos, M Petrou, KM Channon, C Antoniades. Perivascular adipose tissue-derived Wnt5a as a regulator of human vascular disease pathogenesis. BAS Annual Meeting, 6-7 September 2018, Cambridge, UK.

viii) C Kotanidis, AS Antonopoulos, L Herdman, S Thomas, I Akoumianakis, K Thomas, EK Oikonomou, K Psarros, R Sayeed, C Antoniades. Metabolically healthy obese individuals present a distinct epicardial data phenotype and low myocardial oxidative stress. BAS Annual Meeting, 6-7 September 2018, Cambridge, UK.

ix) EK Oikonomou, S Thomas, AS Antonopoulos, S Kesavan, LM Fan, L Herdman, S Anthony, N Sabharwal, A Kelion, RK Kharbanda, S Neubauer, KM Channon, C Antoniades. Computed tomography-derived perivascular Fat Attenuation Index (FAI) identifies culprit coronary lesions and predicts progression of vascular calcification. SCCT 13th Annual Scientific Meeting, 12 – 15 July 2018, Texas, USA.

x) EK Oikonomou, S Thomas, S Kesavan, LM Fan, AS Antonopoulos, S Anthony, N Sabharwal, A Kelion, C Shirodaria, JP Langrish, AJ Lucking, RK Kharbanda, S Neubauer, KM Channon, C Antoniades. Perivascular fat phenotyping predicts plaque progression and allows detection of unstable plaque using coronary computed tomography angiography. AHA Scientific Sessions, 10 – 12 November 2018, Chicago, Illinois.

xi) I Akoumianakis, L Herdman, M Margaritis, R Sayeed, G Krasopoulos, M Petrou, N Tennagels, P Wohlfart, KM Channon, C Antoniades. Insulin treatment induces oxidative stress in the vascular wall of patients with atherosclerosis, independently of diabetes or systemic insulin resistance: The protective effect of DPP-IV inhibition. Frontiers in CardioVascular Biology Congress, 20 – 22 April 2018, Vienna, Austria.

Recent data have shown that treatment of patients with diabetes with insulin, may lead to significant damage of the heart arteries if the treatment is not accompanied by a drug called insulin sensitizer. This could lead to major changes in the treatment of these patients globally (https://inews.co.uk/news/health/diabetes-drug-prevent-heart-attacks-strokes).

The University of Oxford team have previously shown that obesity may not be necessarily bad, and those patients with high body mass index may be “protected against cardiovascular mortality” because fat in the body may secrete protective substances. This is called obesity paradox and has major implications for the treatment of patients with heart diseases (Diabetes 2015, link to press coverage about the obesity paradox: https://www.telegraph.co.uk/news/science/science-news/11657811/Why-obesity-protects-against-heart-disease-and-heart-attack.html).

The University of Oxford has recently identified a major therapeutic target for the treatment of heart diseases, and that discovery led to intense research to develop new drugs to modify this target (presented in the last European Society of Cardiology 2018 Congress, and received the Best Poster Award).

The University of Oxford has recently develop a method to detect patients at risk for future heart attacks using the ox-HVF cohort (Science Transl Med 2017), which was validated in a recent publication (Lancet 2018). This method has been included into the recent Up-To-Date guidance (https://www.uptodate.com/contents/cardiac-imaging-with-computed-tomography-and-magnetic-resonance-in-the-adult) and can be used to detect patients who may need intense medical therapy to prevent future heart attacks.

The University of Oxford group has developed a novel imaging biomarker (see Antonopoulos et al Science Translational Medicine 2017), namely the Fat Attenuation Index (FAI), which has been shown to be a marker of vascular inflammation at early disease stages. Validation of this biomarker in large cohorts of patients with residual cardiovascular risk showed that FAI is able to detect patients at high risk for cardiac mortality and is also predictive of non-fatal heart attacks. This permits reclassification of an individual’s risk, above and beyond the current state-of-the-art diagnostic tools, with strong implications for guiding medical management in patients and guiding the use of primary and secondary prevention measures. The development of this technology is a significant example that highlights the strength and unique ability of the Ox-HVF cohort in combining data across different and diverse fields - from clinical and epidemiological data to basic science and imaging data to outcome data (requested in the current application)- to create new, boundary-pushing ideas that promote health and serve the public interest. Of note, FAI was featured by iNews as one of the ten health innovations that could soon be on the NHS (https://inews.co.uk/news/health/the-ten-health-innovations-that-could-soon-be-on-the-nhs/).

The University of Oxford has found that insulin treatment in diabetic people should be accompanied by medication targeting a specific molecule, which is regarded to be able to sensitize the human vessels to insulin signalling, in order to avoid damage to the heart arteries. Furthermore, they have shown that a molecule secreted from fat surrounding the human vessels, can trigger the development of damage and inflammation to them and therefore could constitute a promising therapeutic target.

Ischemic heart disease remains the leading cause of death in upper-middle and high income economies. Coronary artery disease (CAD) accounts for one in seven deaths in men and one in twelve deaths in women in England, responsible for over 53,000 deaths every year, with associated healthcare costs continuing to rise. Coronary artery bypass graft surgery (CABG) continues to be the optimum revascularisation strategy for most patients with multi-vessel coronary artery disease. Although the biological variability between patients should be crucial for the prediction of long-term outcome of patients undergoing cardiac surgery, the exact mechanism linking the biology of the heart, the vascular grafts used and the myocardium with clinical outcome are unclear. Furthermore, taking into account the fact that cardiovascular disease remains one of the top mortality causes in the developed world, there is an unmet need in developing new markers of disease development and progression.

The aim of the OxHVF cohort study is to discover new blood, genetic and imaging biomarkers that differ between patients with advanced coronary atherosclerosis and healthy individuals (controls). The ability of these biomarkers to predict clinical outcomes in patients and controls will be evaluated by analysing prospective data collected through hospital records and other sources such as NHS Digital. These new biomarkers could also serve as potential therapeutic targets, allowing the development of new therapeutic strategies for the prevention and treatment of cardiovascular disease.

Under a previous iteration of this Data Sharing Agreement, the University of Oxford obtained civil registration mortality and Hospital Episode Statistics (HES) data with the aim to progress understanding of cardiovascular disease pathogenesis leading to the development of novel markers for early disease detection, ultimately resulting in sooner, better and more efficient cardiovascular disease management in the interest of the 1.8 million people that are currently battling coronary heart disease in England.

Collection of outcomes data for the patients with atherosclerosis and healthy controls, will allow the University of Oxford to compare the predictive value of any new biomarker identified through the cross-sectional analyses, between patients with atherosclerosis and healthy individuals. For example, the University of Oxford will compare the ability of new blood, genetic and imaging biomarkers discovered in the ox-HVF cohort to predict cardiovascular and other clinical outcomes in individuals with or without advanced atherosclerosis.

The Oxford Heart, Vessels & Fat (Ox-HVF) cohort consists of participants recruited into one of the clinical sub-studies constituting the cohort: ART Vascular Study, Bypass Vascular Study, and AdipoRedOx. Ox-HVF was designed to provide synergistic results allowing the deployment of a multi-level strategy to address the aforementioned issues (see www.oxhvf.com). The primary aim of the cohort is to discover new biomarkers and/or therapeutic targets for the prediction and prevention of cardiovascular events and other clinical outcomes. These biomarkers can be biochemical (measured in the blood of the patient), genetic (measured in the DNA) or imaging (measured in non-invasive imaging). The therapeutic targets can be at the level of the circulation or tissue (by studying human blood, arteries and veins, fat or myocardial samples collected during surgery).

In the Ox-HVF cohort, the patients with advanced cardiovascular disease are recruited through 3 main clinical sub-studies (ART Vascular Study, Bypass Vascular Study, AdipoRedOx). All Ox-HVF participants contribute blood and imaging data to the cohort. Data are aggregated from all sub-studies in a single database (ox-HVF database) and analysed collectively, as a single cohort (ox-HVF cohort).

In more detail, the participants of the cohort come from the following 3 sub-studies:

i) The Arterial Revascularisation Trial: Vascular sub-study (ART Vasc) (November 2004 to 2017; REC: MREC04/03/006) compares coronary artery bypass grafting with a single internal mammary artery (IMA) to surgery with bilateral internal mammary arteries. 258 patients undergoing coronary artery bypass grafting surgery at the John Radcliffe Hospital, Oxford were enrolled to the study. ART Vasc study is no longer recruiting. Data collection continues through access to patient’s medical records, extracting data from both the local Hospital archive and the NHS Digital records.

ii) The Vascular Properties of Bypass Grafts (Bypass Vascular study) (January 2005 to current; REC: 04/Q1605/95) aims to compare measures of vascular function with post-operative clinical outcome after cardiac surgery. The inner lining of a person’s arteries is made up of cells (specifically endothelial cells) that can control how the artery stretches or dilates. The measure of how well this mechanism works is called “endothelial function”. The term “endothelial dysfunction” is used to describe changes in the in the inner lining of the artery to a state that can lead to disease progression and atherosclerosis.

The Bypass Vascular Study invited patients undergoing coronary artery bypass graft surgery at the John Radcliffe Hospital to participate in further investigation of their endothelial function to help better understand why some bypass grafts work better than others and how the function of them could possibly be improved in the future. 231 patients were successfully enrolled to the study. The Bypass Vascular Study is no longer recruiting. Data collection continues through access to the patient’s medical records and extracting data from NHS Digital.

iii) The AdipoRedOx study (15/09/2011 to current; REC: 11/SC/140), aims to investigate the mechanisms by which the fat tissue, the vascular tissue and the heart muscle interact and the University of Oxford aim to explore whether aspects of this interaction can predict the outcomes of coronary artery bypass grafting operation (CABG). The AdipoRedOx study is actively recruiting until 2020 and will follow participants up until 2030.

For information, there is intention to include a fourth cohort in this study which will consist of a controls cohort (ORFAN sub-study). This aims to recruit individuals with risk factors but not advanced coronary artery disease, serving as controls to the heavily diseased populations of the other three sub-studies, and ultimately as the validation cohort for the predictive and prognostic value of any biomarker developed for early cardiovascular disease detection. However, this is not in scope of this Agreement and its inclusion will be subject to a future application with NHS Digital.

Participants were enrolled to ART Vasc, Bypass Vascular Study and the AdipoRedOx study before they underwent open heart surgery at the John Radcliffe Hospital, Oxford. Each study has gained informed consent from each participant to access their medical records to collect long-term outcome data to provide information that may have a predictive value after cardiac surgery. Importantly, these studies aim to link the collected data (i.e. risk factors, data on vascular function etc.) with patient clinical outcome data, producing the world’s most comprehensive resource comparing vascular biology with clinical outcome post-cardiac surgery.

Data is requested in line with Article 6(1)(e) –‘processing is necessary for the performance of a task carried out in the public interest’.

Public interest is in line with Article 9(2)(j) – ‘processing is necessary for archiving purposes in the public interest'.

The University of Oxford is the sole data controller and also processes the data for this study. The University of Oxford is seeking to collect health outcome data on these participants, namely Hospital Episode Statistics and civil registry mortality data (cause and date of death). No other organisations process the data for this purpose. The University of Oxford solely determines the purpose and outputs of the Ox-HVF cohort sub-studies.

The primary objective of the study is to:

Develop and validate new blood, genetic, imaging and other biomarkers that allow good discrimination between patients with coronary artery disease and healthy individuals, and evaluate their ability to predict clinical outcomes. These biomarkers may also form therapeutic targets for the development of new strategies to prevent and treat cardiovascular diseases.

Secondary objectives are to:

i) Investigate the mechanisms by which adipose tissue derived molecules affects vascular/myocardial redox state, endothelial (inner lining of the artery) function and clinical outcomes of patients undergoing coronary artery bypass grafting operation (CABG) and validate their applicability in healthy individuals.

ii) Search for a possible signal from the myocardium/vascular wall to epicardial/perivascular adipose tissue that regulates the synthesis of adipokines and other signalling molecules and compare their blood levels between patients with cardiovascular disease and healthy individuals.

iii) Search for novel biomarkers/signalling molecules identified in peripheral blood or expressed in adipose tissue, that regulate vascular/myocardial redox state and/or predict vein graft patency and compare their blood levels between patients with cardiovascular disease and healthy individuals.

iv) Search for novel imaging biomarkers and signatures reflecting underlying biology, which have predictive and prognostic value and therefore have the potential to be used in large-scale population wide screenings for early cardiovascular disease detection.

In summary these objectives will then potentially result in the creation of patient risk models that the University of Oxford hope will improve health outcomes of patients with cardiovascular disease.

The University of Oxford is attempting to manage long-term, prospective cohorts in the cardiovascular field. Specifically, the University of Oxford would like to obtain information from participants who were or will be submitted to cardiac surgery (ART Vasc, Bypass Grafts Sub-study, AdipoRedOx Sub-study). In this regard, participants need to be categorised before, during and immediately after surgery, and at long-term follow-up. Under a previous iteration of this Agreement, the University of Oxford sent the participants' identifying details to NHS Digital in order to obtain pre-operative co-morbidities and medications, surgical procedure details and immediate post-operative outcomes, and at long-term, the study will check for recurrence of symptoms that motivate new hospital admissions, necessity of re-revascularizations, fatal and non-fatal coronary events and all-cause death.

Under previous iterations of this Data Sharing Agreement, the University of Oxford has received HES and linked mortality data for the cohorts from the ART Vascular, Bypass Vascular study and AdipoRedOx studies from 2003/04 to 2016/17.

Collection of this data is vital to obtaining the primary endpoint statistics linking the existing study data with post-surgery clinical outcome. Statistical analyses on time-to-event data are very dependent on number of events recorded and time to follow-up, with higher numbers providing higher statistical power. Given the heterogeneous nature of the cohort, a long follow-up period of at least ten years is deemed minimum for extracting reliable information.

NHS Digital data for England and Wales will allow the study to analyse these events in different health care institutions within the NHS.

All participants have given informed consent for the purpose of this research and the University of Oxford has determined therefore that there are no moral or ethical issues from dissemination of data for this purpose.

The research outputs will include peer reviewed publications in leading international journals, presentations in international and national scientific meetings and possible media reports.

In summary:

Journals being targeted to submit to/publish in:

i) The New England Journal of Medicine

ii) The Journal of the American Medical Association

iii) The Lancet

iv) Circulation

v) Journal of the American College of Cardiology or the British Medical Journal

Congresses targeted to submit to:

i) Scientific sessions of the American Heart Association

ii) Scientific sessions of the European Society of Cardiology

iii) Scientific sessions of the American College of Cardiology

iv) Scientific sessions of the British Cardiac Society

The outputs from this work will be both immediate - with publications in high impact journals, (see Oikonomou et al Lancet 2018 and others) as well as long-term - when diagnostic biomarkers or new therapeutics are implemented in clinical practice. As the ox-HVF is expected to continue collecting outcomes data for at least the next 10 years, the cohort will continue to generate outputs as more events accumulate over time. These long-term impacts have the potential to change clinical practice worldwide and save lives. To target the lay audience, the ox-HVF team uses the following approaches:

a) Website (www.oxhvf.com); this is updated with all the most up to date information regarding the outputs of the research. This is a patient-facing website, and the patients have the ability to read the “For Patients” section of the website and understand the impact of the team’s research.

b) Newsletters; when major findings or general outputs are available, the ox-HVF team post newsletters both on the website and through the post, to the study participants (after confirming that the patients are still alive through the data collected through NHS Digital).

c) Press releases; the ox-HVF team have an active involvement in outreach activities of the University of Oxford, Oxford University Innovations and the British heart Foundation communications team, and the major findings from their studies lead to press releases, and from there they are distributed to the lay press. Examples of recent press releases and lay press articles are found below:

The ox-HVF team aims to keep study participants as up to date as possible. To do this, the publications section of the oxhvf.com website is routinely updated with all recent research papers (see link: https://oxhvf.com/publications/). The oxHVF is a single cohort, so the updates are addressing all participants across the sub-studies. The last hard-copy newsletter was sent out by post in September 2017 to all oxHVF participants who were still alive, and included updates on new data processing activities that included processing of NHS Digital data, as well as news on the development of the ox-HVF team's novel biomarker, the Fat Attenuation Index (FAI), that gathered a lot of media attention including BBC News, The Guardian, The Financial Times and CBN and was published in the prestigious journal “Science Translational Medicine” (see example: https://test188076.files.wordpress.com/2018/01/newsletter-adiporedox-15-09-2017.pdf).

1. Recent interview for the use of artificial intelligence in practice (https://www.youtube.com/watch?v=ek3yGjLNk4A).

2. Press release on the validation of Fat Attenuation Index for prediction of mortality and morbidity (http://www.ox.ac.uk/news/2018-08-28-study-shows-new-technology-can-predict-fatal-heart-attacks). This led to a Reuters release (https://uk.reuters.com/article/us-health-heart-britain/tech-breakthrough-offers-early-warning-system-for-heart-attacks-idUKKCN1ME14F) and various articles in lay press (the Guardian, Times, Independent, Sky News etc)

3. Press release on the discovery of novel implications of insulin treatment for patients with cardiac diseases, that led to lay press coverage in iNews (https://inews.co.uk/news/health/diabetes-drug-prevent-heart-attacks-strokes/)

4. Press release on discovery of fat attenuation Index 2017 (https://oxfordbrc.nihr.ac.uk/oxford-researchers-develop-new-early-warning-scan-for-heart-attacks/) that led to wide coverage in lay press (BBC, NBC, Financial Times etc).

5. Press release on artificial intelligence (https://www.research.ox.ac.uk/Article/2018-10-15-making-healthcare-smarter-with-ai) and lay press coverage on how the team’s research can transform the NHS in the next years (https://inews.co.uk/news/health/the-ten-health-innovations-that-could-soon-be-on-the-nhs/)

6. UpToDate’s latest chapter on Noninvasive Coronary Imaging (https://www.uptodate.com/contents/noninvasive-coronary-imaging-with-cardiac-computed-tomography-and-cardiovascular-magnetic-resonance)

7. JAMA Network article (https://jamanetwork.com/journals/jama/article-abstract/2706117?utm_source=fbpage&utm_medium=social_jama&utm_term=1820946790&utm_content=followers-article_engagement-illustration_medical&utm_campaign=article_alert&linkId=57902365)

d) Documentaries: the ox-HVF team has participated in a Horizon BBC 1 documentary on “crashing diets” 2018, discussing how diet can affect blood pressure (https://www.bbc.co.uk/programmes/b0b53xqs).

e) Workshops and patient and public involvement; the ox-HVF team participate in workshops for patients as part of the Biomedical Research Centre in Oxford, and through that they inform the patients about their research and ask for their involvement in the design of protocols, feedback on research procedures and more, through Patient and Public involvement (PPI) panels (e.g. such panels were set for AdipoRedOx and ORFAN substudies).

First outputs are expected 6-12 months after the data is received, but as the cohort matures, new data is included and the outcomes data from previous years are populated with then newer data, leading to added value to the datasets.

Outputs already delivered:

Publications:

i) Oikonomou EK, Marwan M, Desai MY, Mancio J, Alashi A, Hutt Centeno E, et al. Non-invasive detection of coronary inflammation using computed tomography and prediction of residual cardiovascular risk (the CRISP CT study): a post-hoc analysis of prospective outcome data. Lancet. 2018;392(10151):929-39.

ii) Oikonomou EK, Antoniades C. The role of adipose tissue in cardiovascular health and disease. Nature reviews Cardiology. 2019;16(2):83-99.

iii) Antonopoulos AS, Antoniades C. Cardiac Magnetic Resonance Imaging of Epicardial and Intramyocardial Adiposity as an Early Sign of Myocardial Disease. Circulation Cardiovascular imaging. 2018;11(8):e008083.

iv) Antonopoulos AS, Antoniades C. Perivascular Fat Attenuation Index by Computed Tomography as a Metric of Coronary Inflammation. Journal of the American College of Cardiology. 2018;71(23):2708-9.

v) Mancio J, Oikonomou EK, Antoniades C. Perivascular adipose tissue and coronary atherosclerosis. Heart (British Cardiac Society). 2018;104(20):1654-62.

vi) Tarun A, Antoniades C. The era of cardiovascular epigenetics: histone deacetylases and vascular inflammation. Cardiovascular research. 2018;114(7):928-30.

Conference presentations:

i) AS Antonopoulos, L Herdman, S Thomas, I Akoumianakis, C Kotanidis, K Thomas, EK Oikonomou, K Psarros, R Sayeed, C Antoniades. 104Metabolically healthy obesity is associated with a distinct epicardial fat phenotype and low myocardial oxidative stress. ESC Congress, 25–29 August 2018, Munich, Germany.

ii) I Akoumianakis, L Herdman, M Margaritis, R Sayeed, G Krasopoulos, M Petrou, N Tennagels, P Wohlfart, KM Channon, C Antoniades. 2437 Insulin triggers oxidative stress in the vascular wall of patients with atherosclerosis, independently of systemic insulin resistance: the beneficial role of DPP-IV inhibition. ESC Congress, 25–29 August 2018, Munich, Germany.

iii) I Akoumianakis, F Sanna, M Margaritis, L Herdman, AS Antonopoulos, R Sayeed, G Krasopoulos, M Petrou, KM Channon, C Antoniades. P592 Perivascular adipose tissue-derived Wnt5a as a regulator of human vascular disease pathogenesis. ESC Congress, 25–29 August 2018, Munich, Germany.

iv) I Akoumianakis, AS Antonopoulos, L Herdman, M Margaritis, EK Oikonomou, G Krasopoulos, M Petrou, R Sayeed, KM Channon, C Antoniades. 3398 NADPH oxidase activity in internal mammary arteries predicts mortality in patients undergoing coronary bypass surgery. ESC Congress, 25–29 August 2018, Munich, Germany.

v) EK Oikonomou, S Thomas, J Mancio, AS Antonopoulos, N Sabharwal, A Kelion, S Neubauer, KM Channon, C Antoniades. 1182 Computed tomography-based perivascular fat phenotyping identifies unstable coronary lesions and active vascular calcification. ESC Congress, 25–29 August 2018, Munich, Germany.

vi) EK Oikonomou, S Thomas, S Kesavan, LM Fan, AS Antonopoulos, S Anthony, N Sabharwal, A Kelion, C Shirodaria, JP Langrish, AJ Lucking, RK Kharbanda, S Neubauer, KM Channon, C Antoniades. Perivascular fat imaging for unstable plaque detection and prediction of coronary plaque progression. BAS Annual Meeting, 6-7 September 2018, Cambridge, UK.

vii) I Akoumianakis, F Sanna, M Margaritis, L Herdman, AS Antonopoulos, R Sayeed, G Krasopoulos, M Petrou, KM Channon, C Antoniades. Perivascular adipose tissue-derived Wnt5a as a regulator of human vascular disease pathogenesis. BAS Annual Meeting, 6-7 September 2018, Cambridge, UK.

viii) C Kotanidis, AS Antonopoulos, L Herdman, S Thomas, I Akoumianakis, K Thomas, EK Oikonomou, K Psarros, R Sayeed, C Antoniades. Metabolically healthy obese individuals present a distinct epicardial data phenotype and low myocardial oxidative stress. BAS Annual Meeting, 6-7 September 2018, Cambridge, UK.

ix) EK Oikonomou, S Thomas, AS Antonopoulos, S Kesavan, LM Fan, L Herdman, S Anthony, N Sabharwal, A Kelion, RK Kharbanda, S Neubauer, KM Channon, C Antoniades. Computed tomography-derived perivascular Fat Attenuation Index (FAI) identifies culprit coronary lesions and predicts progression of vascular calcification. SCCT 13th Annual Scientific Meeting, 12 – 15 July 2018, Texas, USA.

x) EK Oikonomou, S Thomas, S Kesavan, LM Fan, AS Antonopoulos, S Anthony, N Sabharwal, A Kelion, C Shirodaria, JP Langrish, AJ Lucking, RK Kharbanda, S Neubauer, KM Channon, C Antoniades. Perivascular fat phenotyping predicts plaque progression and allows detection of unstable plaque using coronary computed tomography angiography. AHA Scientific Sessions, 10 – 12 November 2018, Chicago, Illinois.

xi) I Akoumianakis, L Herdman, M Margaritis, R Sayeed, G Krasopoulos, M Petrou, N Tennagels, P Wohlfart, KM Channon, C Antoniades. Insulin treatment induces oxidative stress in the vascular wall of patients with atherosclerosis, independently of diabetes or systemic insulin resistance: The protective effect of DPP-IV inhibition. Frontiers in CardioVascular Biology Congress, 20 – 22 April 2018, Vienna, Austria.

Recent data have shown that treatment of patients with diabetes with insulin, may lead to significant damage of the heart arteries if the treatment is not accompanied by a drug called insulin sensitizer. This could lead to major changes in the treatment of these patients globally (https://inews.co.uk/news/health/diabetes-drug-prevent-heart-attacks-strokes).

The University of Oxford team have previously shown that obesity may not be necessarily bad, and those patients with high body mass index may be “protected against cardiovascular mortality” because fat in the body may secrete protective substances. This is called obesity paradox and has major implications for the treatment of patients with heart diseases (Diabetes 2015, link to press coverage about the obesity paradox: https://www.telegraph.co.uk/news/science/science-news/11657811/Why-obesity-protects-against-heart-disease-and-heart-attack.html).

The University of Oxford has recently identified a major therapeutic target for the treatment of heart diseases, and that discovery led to intense research to develop new drugs to modify this target (presented in the last European Society of Cardiology 2018 Congress, and received the Best Poster Award).

The University of Oxford has recently develop a method to detect patients at risk for future heart attacks using the ox-HVF cohort (Science Transl Med 2017), which was validated in a recent publication (Lancet 2018). This method has been included into the recent Up-To-Date guidance (https://www.uptodate.com/contents/cardiac-imaging-with-computed-tomography-and-magnetic-resonance-in-the-adult) and can be used to detect patients who may need intense medical therapy to prevent future heart attacks.

The University of Oxford group has developed a novel imaging biomarker (see Antonopoulos et al Science Translational Medicine 2017), namely the Fat Attenuation Index (FAI), which has been shown to be a marker of vascular inflammation at early disease stages. Validation of this biomarker in large cohorts of patients with residual cardiovascular risk showed that FAI is able to detect patients at high risk for cardiac mortality and is also predictive of non-fatal heart attacks. This permits reclassification of an individual’s risk, above and beyond the current state-of-the-art diagnostic tools, with strong implications for guiding medical management in patients and guiding the use of primary and secondary prevention measures. The development of this technology is a significant example that highlights the strength and unique ability of the Ox-HVF cohort in combining data across different and diverse fields - from clinical and epidemiological data to basic science and imaging data to outcome data (requested in the current application)- to create new, boundary-pushing ideas that promote health and serve the public interest. Of note, FAI was featured by iNews as one of the ten health innovations that could soon be on the NHS (https://inews.co.uk/news/health/the-ten-health-innovations-that-could-soon-be-on-the-nhs/).

The University of Oxford has found that insulin treatment in diabetic people should be accompanied by medication targeting a specific molecule, which is regarded to be able to sensitize the human vessels to insulin signalling, in order to avoid damage to the heart arteries. Furthermore, they have shown that a molecule secreted from fat surrounding the human vessels, can trigger the development of damage and inflammation to them and therefore could constitute a promising therapeutic target.