Publications by authors named "Paul Leeson"

147 Publications

Target-Based Evaluation of "Drug-Like" Properties and Ligand Efficiencies.

J Med Chem 2021 06 13;64(11):7210-7230. Epub 2021 May 13.

European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SD, United Kingdom.

Physicochemical descriptors commonly used to define "drug-likeness" and ligand efficiency measures are assessed for their ability to differentiate marketed drugs from compounds reported to bind to their efficacious target or targets. Using ChEMBL version 26, a data set of 643 drugs acting on 271 targets was assembled, comprising 1104 drug-target pairs having ≥100 published compounds per target. Taking into account changes in their physicochemical properties over time, drugs are analyzed according to their target class, therapy area, and route of administration. Recent drugs, approved in 2010-2020, display no overall differences in molecular weight, lipophilicity, hydrogen bonding, or polar surface area from their target comparator compounds. Drugs are differentiated from target comparators by higher potency, ligand efficiency (LE), lipophilic ligand efficiency (LLE), and lower carboaromaticity. Overall, 96% of drugs have LE or LLE values, or both, greater than the median values of their target comparator compounds.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610969PMC
June 2021

Association of Systolic Blood Pressure Elevation With Disproportionate Left Ventricular Remodeling in Very Preterm-Born Young Adults: The Preterm Heart and Elevated Blood Pressure.

JAMA Cardiol 2021 May 12. Epub 2021 May 12.

Oxford Cardiovascular Clinical Research Facility, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, England.

Importance: Preterm-born individuals have higher blood pressure with an increased risk of hypertension by young adulthood, as well as potentially adverse cardiac remodeling even when normotensive. To what extent blood pressure elevation affects left ventricular (LV) structure and function in adults born preterm is currently unknown.

Objective: To investigate whether changes observed in LV structure and function in preterm-born adults make them more susceptible to cardiac remodeling in association with blood pressure elevation.

Design, Setting, And Participants: This cross-sectional cohort study, conducted at the Oxford Cardiovascular Clinical Research Facility and Oxford Centre for Clinical Magnetic Resonance Research, included 468 adults aged 18 to 40 years. Of these, 200 were born preterm (<37 weeks' gestation) and 268 were born at term (≥37 weeks' gestation). Cardiac magnetic resonance imaging was used to characterize LV structure and function, with clinical blood pressure readings measured to assess hypertension status. Demographic and anthropometric data, as well as birth history and family medical history information, were collected. Data were analyzed between January 2012 and February 2021.

Main Outcomes And Measures: Cardiac magnetic resonance measures of LV structure and function in response to systolic blood pressure elevation.

Results: The cohort was primarily White (>95%) with a balanced sex distribution (51.5% women and 48.5% men). Preterm-born adults with and without hypertension had higher LV mass index, reduced LV function, and smaller LV volumes compared with term-born individuals both with and without hypertension. In regression analyses of systolic blood pressure with LV mass index and LV mass to end-diastolic volume ratio, there was a leftward shift in the slopes in preterm-born compared with term-born adults. Compared with term-born adults, there was a 2.5-fold greater LV mass index per 1-mm Hg elevation in systolic blood pressure in very and extremely preterm-born adults (<32 weeks' gestation) (0.394 g/m2 vs 0.157 g/m2 per 1 mm Hg; P < .001) and a 1.6-fold greater LV mass index per 1-mm Hg elevation in systolic blood pressure in moderately preterm-born adults (32 to 36 weeks' gestation) (0.250 g/m2 vs 0.157 g/m2 per 1 mm Hg; P < .001). The LV mass to end-diastolic volume ratio per 1-mm Hg elevation in systolic blood pressure in the very and extremely preterm-born adults was 3.4-fold greater compared with those born moderately preterm (3.56 × 10-3 vs 1.04 × 10-3 g/mL per 1 mm Hg; P < .001) and 3.3-fold greater compared with those born at term (3.56 × 10-3 vs 1.08 × 10-3 g/mL per 1 mm Hg; P < .001).

Conclusions And Relevance: Preterm-born adults have a unique LV structure and function that worsens with systolic blood pressure elevation. Additional primary prevention strategies specifically targeting cardiovascular risk reduction in this population may be warranted.
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http://dx.doi.org/10.1001/jamacardio.2021.0961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117059PMC
May 2021

Preeclampsia and the Brain-A Long-term View.

JAMA Netw Open 2021 Apr 1;4(4):e215364. Epub 2021 Apr 1.

Cardiovascular Clinical Research Facility, RDM Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom.

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http://dx.doi.org/10.1001/jamanetworkopen.2021.5364DOI Listing
April 2021

The Preterm Heart-Brain Axis in Young Adulthood: The Impact of Birth History and Modifiable Risk Factors.

J Clin Med 2021 Mar 19;10(6). Epub 2021 Mar 19.

Oxford Cardiovascular Clinical Research Facility, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK.

People born preterm are at risk of developing both cardiac and brain abnormalities. We aimed to investigate whether cardiovascular physiology may directly affect brain structure in young adulthood and whether cardiac changes are associated with modifiable biomarkers. Forty-eight people born preterm, followed since birth, underwent cardiac MRI at age 25.1 ± 1.4 years and brain MRI at age 33.4 ± 1.0 years. Term born controls were recruited at both time points for comparison. Cardiac left and right ventricular stroke volume, left and right ventricular end diastolic volume and right ventricular ejection fraction were significantly different between preterm and term born controls and associated with subcortical brain volumes and fractional anisotropy in the corpus callosum in the preterm group. This suggests that cardiovascular abnormalities in young adults born preterm are associated with potentially adverse future brain health. Associations between left ventricular stroke volume indexed to body surface area and right putamen volumes, as well as left ventricular end diastolic length and left thalamus volumes, remained significant when adjusting for early life factors related to prematurity. Although no significant associations were found between modifiable biomarkers and cardiac physiology, this highlights that cardiovascular health interventions may also be important for brain health in preterm born adults.
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http://dx.doi.org/10.3390/jcm10061285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003804PMC
March 2021

Personalized exercise prescription in the prevention and treatment of arterial hypertension: a Consensus Document from the European Association of Preventive Cardiology (EAPC) and the ESC Council on Hypertension.

Eur J Prev Cardiol 2021 Mar 24. Epub 2021 Mar 24.

Oxford Cardiovascular Clinical Research Facility, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK.

Treatment of hypertension and its complications remains a major ongoing health care challenge. Around 25% of heart attacks in Europe are already attributed to hypertension and by 2025 up to 60% of the population will have hypertension. Physical inactivity has contributed to the rising prevalence of hypertension, but patients who exercise or engage in physical activity reduce their risk of stroke, myocardial infarction, and cardiovascular mortality. Hence, current international guidelines on cardiovascular disease prevention provide generic advice to increase aerobic activity, but physiological responses differ with blood pressure (BP) level, and greater reductions in BP across a population may be achievable with more personalized advice. We performed a systematic review of meta-analyses to determine whether there was sufficient evidence for a scientific Consensus Document reporting how exercise prescription could be personalized for BP control. The document discusses the findings of 34 meta-analyses on BP-lowering effects of aerobic endurance training, dynamic resistance training as well as isometric resistance training in patients with hypertension, high-normal, and individuals with normal BP. As a main finding, there was sufficient evidence from the meta-review, based on the estimated range of exercise-induced BP reduction, the number of randomized controlled trials, and the quality score, to propose that type of exercise can be prescribed according to initial BP level, although considerable research gaps remain. Therefore, this evidence-based Consensus Document proposes further work to encourage and develop more frequent use of personalized exercise prescription to optimize lifestyle interventions for the prevention and treatment of hypertension.
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http://dx.doi.org/10.1093/eurjpc/zwaa141DOI Listing
March 2021

Impact of COVID-19 on UK stress echocardiography practice: insights from the EVAREST sites.

Echo Res Pract 2021 Mar;8(1):1-8

Cardiovascular Clinical Research Facility, RDM Division of Cardiovascular Medicine, University of Oxford, Oxford, UK.

Introduction: Healthcare delivery is being transformed by COVID-19 to reduce transmission risk but continued delivery of routine clinical tests is essential. Stress echocardiography is one of the most widely used cardiac tests in the NHS. We assessed the impact of the first (W1) and second (W2) waves of the pandemic on the ability to deliver stress echocardiography.

Methods: Clinical echocardiography teams in 31 NHS hospitals participating in the EVAREST study were asked to complete a survey on the structure and delivery of stress echocardiography as well as its impact on patients and staff in July and November 2020. Results were compared to stress echocardiography activity in the same centre during January 2020.

Results: 24 completed the survey in July, and 19 NHS hospitals completed the survey in November. A 55% reduction in the number of studies performed was reported in W1, recovering to exceed pre-COVID rates in W2. The major change was in the mode of stress delivery. 70% of sites stopped their exercise stress service in W1, compared to 19% in W2. In those still using exercise during W1, 50% were wearing FFP3/N95 masks, falling to 38% in W2. There was also significant variability in patient screening practices with 7 different pre-screening questionnaires used in W1 and 6 in W2.

Conclusion: Stress echocardiography delivery restarted effectively after COVID-19 with adaptations to reduce transmission that means activity has been able to continue, and exceed, pre-COVID-19 levels during the second wave. Further standardization of protocols for patient screening and PPE may help further improve consistency of practice within the United Kingdom.
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http://dx.doi.org/10.1530/ERP-20-0043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111306PMC
March 2021

Changes in the Preterm Heart From Birth to Young Adulthood: A Meta-analysis.

Pediatrics 2020 08 7;146(2). Epub 2020 Jul 7.

Oxford Cardiovascular Clinical Research Facility, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom;

Context: Preterm birth is associated with incident heart failure in children and young adults.

Objective: To determine the effect size of preterm birth on cardiac remodeling from birth to young adulthood.

Data Sources: Data sources include Medline, Embase, Scopus, Cochrane databases, and clinical trial registries (inception to March 25, 2020).

Study Selection: Studies in which cardiac phenotype was compared between preterm individuals born at <37 weeks' gestation and age-matched term controls were included.

Data Extraction: Random-effects models were used to calculate weighted mean differences with corresponding 95% confidence intervals.

Results: Thirty-two observational studies were included (preterm = 1471; term = 1665). All measures of left ventricular (LV) and right ventricular (RV) systolic function were lower in preterm neonates, including LV ejection fraction ( = .01). Preterm LV ejection fraction was similar from infancy, although LV stroke volume index was lower in young adulthood. Preterm LV peak early diastolic tissue velocity was lower throughout development, although preterm diastolic function worsened with higher estimated filling pressures from infancy. RV longitudinal strain was lower in preterm-born individuals of all ages, proportional to the degree of prematurity ( = 0.64; = .002). Preterm-born individuals had persistently smaller LV internal dimensions, lower indexed LV end-diastolic volume in young adulthood, and an increase in indexed LV mass, compared with controls, of 0.71 g/m per year from childhood ( = .007).

Limitations: The influence of preterm-related complications on cardiac phenotype could not be fully explored.

Conclusions: Preterm-born individuals have morphologic and functional cardiac impairments across developmental stages. These changes may make the preterm heart more vulnerable to secondary insults, potentially underlying their increased risk of early heart failure.
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http://dx.doi.org/10.1542/peds.2020-0146DOI Listing
August 2020

The effects of an aerobic training intervention on cognition, grey matter volumes and white matter microstructure.

Physiol Behav 2020 09 29;223:112923. Epub 2020 May 29.

FMRIB Centre, Wellcome Centre for Integrative Neuroimaging, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK, OX3 9DU. Electronic address:

While there is strong evidence from observational studies that physical activity is associated with reduced risk of cognitive decline and dementia, the extent to which aerobic training interventions impact on cognitive health and brain structure remains subject to debate. In a pilot study of 46 healthy older adults (66.6 years ± 5.2 years, 63% female), we compared the effects of a twelve-week aerobic training programme to a waitlist control condition on cardiorespiratory fitness, cognition and magnetic resonance imaging (MRI) outcomes. Cardiorespiratory fitness was assessed by VO max testing. Cognitive assessments spanned executive function, memory and processing speed. Structural MRI analysis included examination of hippocampal volume, and voxel-wise assessment of grey matter volumes using voxel-based morphometry. Diffusion tensor imaging analysis of fractional anisotropy, axial diffusivity and radial diffusivity was performed using tract-based spatial statistics. While the intervention successfully increased cardiorespiratory fitness, there was no evidence that the aerobic training programme led to changes in cognitive functioning or measures of brain structure in older adults. Interventions that are longer lasting, multi-factorial, or targeted at specific high-risk populations, may yield more encouraging results.
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http://dx.doi.org/10.1016/j.physbeh.2020.112923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378567PMC
September 2020

The UK Biobank imaging enhancement of 100,000 participants: rationale, data collection, management and future directions.

Nat Commun 2020 05 26;11(1):2624. Epub 2020 May 26.

Nuffield Department of Population Health, University of Oxford, Oxford, UK.

UK Biobank is a population-based cohort of half a million participants aged 40-69 years recruited between 2006 and 2010. In 2014, UK Biobank started the world's largest multi-modal imaging study, with the aim of re-inviting 100,000 participants to undergo brain, cardiac and abdominal magnetic resonance imaging, dual-energy X-ray absorptiometry and carotid ultrasound. The combination of large-scale multi-modal imaging with extensive phenotypic and genetic data offers an unprecedented resource for scientists to conduct health-related research. This article provides an in-depth overview of the imaging enhancement, including the data collected, how it is managed and processed, and future directions.
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http://dx.doi.org/10.1038/s41467-020-15948-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250878PMC
May 2020

Prenatal and Postnatal Cardiac Development in Offspring of Hypertensive Pregnancies.

J Am Heart Assoc 2020 05 30;9(9):e014586. Epub 2020 Apr 30.

Division of Cardiovascular Medicine Oxford Cardiovascular Clinical Research Facility Oxford United Kingdom.

Background Pregnancy complications such as preterm birth and fetal growth restriction are associated with altered prenatal and postnatal cardiac development. We studied whether there were changes related specifically to pregnancy hypertension. Methods and Results Left and right ventricular volumes, mass, and function were assessed at birth and 3 months of age by echocardiography in 134 term-born infants. Fifty-four had been born to mothers who had normotensive pregnancy and 80 had a diagnosis of preeclampsia or pregnancy-induced hypertension. Differences between groups were interpreted, taking into account severity of pregnancy disorder, sex, body size, and blood pressure. Left and right ventricular mass indexed to body surface area (LVMI and RVMI) were similar in both groups at birth (LVMI 20.9±3.7 versus 20.6±4.0 g/m, =0.64, RVMI 17.5±3.7 versus 18.1±4.7 g/m, =0.57). However, right ventricular end diastolic volume index was significantly smaller in those born to hypertensive pregnancy (16.8±5.3 versus 12.7±4.7 mL/m, =0.001), persisting at 3 months of age (16.4±3.2 versus 14.4±4.8 mL/m, =0.04). By 3 months of age these infants also had significantly greater LVMI and RVMI (LVMI 24.9±4.6 versus 26.8±4.9 g/m, =0.04; RVMI 17.1±4.2 versus 21.1±3.9 g/m, <0.001). Differences in RVMI and right ventricular end diastolic volume index at 3 months, but not left ventricular measures, correlated with severity of the hypertensive disorder. No differences in systolic or diastolic function were evident. Conclusions Infants born at term to a hypertensive pregnancy have evidence of both prenatal and postnatal differences in cardiac development, with right ventricular changes proportional to the severity of the pregnancy disorder. Whether differences persist long term as well as their underlying cause and relationship to increased cardiovascular risk requires further study.
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http://dx.doi.org/10.1161/JAHA.119.014586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428573PMC
May 2020

Variations in Cardiovascular Structure, Function, and Geometry in Midlife Associated With a History of Hypertensive Pregnancy.

Hypertension 2020 06 20;75(6):1542-1550. Epub 2020 Apr 20.

From the Oxford Cardiovascular Clinical Research Facility, Division of Cardiovascular Medicine, Radcliffe Department of Medicine (H.B., M.L., A.V., R.U., A.B., R.D., C.S., Y.K., C.Y.L.A., W.W., O.H., A.J.L., P. Leeson), University of Oxford, United Kingdom.

Hypertensive pregnancy is associated with increased maternal cardiovascular risk in later life. A range of cardiovascular adaptations after pregnancy have been reported to partly explain this risk. We used multimodality imaging to identify whether, by midlife, any pregnancy-associated phenotypes were still identifiable and to what extent they could be explained by blood pressure. Participants were identified by review of hospital maternity records 5 to 10 years after pregnancy and invited to a single visit for detailed cardiovascular imaging phenotyping. One hundred seventy-three women (age, 42±5 years, 70 after normotensive and 103 after hypertensive pregnancy) underwent magnetic resonance imaging of the heart and aorta, echocardiography, and vascular assessment, including capillaroscopy. Women with a history of hypertensive pregnancy had a distinct cardiac geometry with higher left ventricular mass index (49.9±7.1 versus 46.0±6.5 g/m; =0.001) and ejection fraction (65.6±5.4% versus 63.7±4.3%; =0.03) but lower global longitudinal strain (-18.31±4.46% versus -19.94±3.59%; =0.02). Left atrial volume index was also increased (40.4±9.2 versus 37.3±7.3 mL/m; =0.03) and E:A reduced (1.34±0.35 versus 1.52±0.45; =0.003). Aortic compliance (0.240±0.053 versus 0.258±0.063; =0.046) and functional capillary density (105.4±23.0 versus 115.2±20.9 capillaries/mm; =0.01) were reduced. Only differences in functional capillary density, left ventricular mass, and atrial volume indices remained after adjustment for blood pressure (<0.01, =0.01, and =0.04, respectively). Differences in cardiac structure and geometry, as well as microvascular rarefaction, are evident in midlife after a hypertensive pregnancy, independent of blood pressure. To what extent these phenotypic patterns contribute to cardiovascular disease progression or provide additional measures to improve risk stratification requires further study.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682801PMC
June 2020

Impaired myocardial reserve underlies reduced exercise capacity and heart rate recovery in preterm-born young adults.

Eur Heart J Cardiovasc Imaging 2021 Apr;22(5):572-580

Oxford Cardiovascular Clinical Research Facility, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Headley Way, John Radcliffe Hospital, Oxford OX39DU, UK.

Aims : We tested the hypothesis that the known reduction in myocardial functional reserve in preterm-born young adults is an independent predictor of exercise capacity (peak VO2) and heart rate recovery (HRR).

Methods And Results : We recruited 101 normotensive young adults (n = 47 born preterm; 32.8 ± 3.2 weeks' gestation and n = 54 term-born controls). Peak VO2 was determined by cardiopulmonary exercise testing (CPET), and lung function assessed using spirometry. Percentage predicted values were then calculated. HRR was defined as the decrease from peak HR to 1 min (HRR1) and 2 min of recovery (HRR2). Four-chamber echocardiography views were acquired at rest and exercise at 40% and 60% of CPET peak power. Change in left ventricular ejection fraction from rest to each work intensity was calculated (EFΔ40% and EFΔ60%) to estimate myocardial functional reserve. Peak VO2 and per cent of predicted peak VO2 were lower in preterm-born young adults compared with controls (33.6 ± 8.6 vs. 40.1 ± 9.0 mL/kg/min, P = 0.003 and 94% ± 20% vs. 108% ± 25%, P = 0.001). HRR1 was similar between groups. HRR2 decreased less in preterm-born young adults compared with controls (-36 ± 13 vs. -43 ± 11 b.p.m., P = 0.039). In young adults born preterm, but not in controls, EFΔ40% and EFΔ60% correlated with per cent of predicted peak VO2 (r2 = 0.430, P = 0.015 and r2 = 0.345, P = 0.021). Similarly, EFΔ60% correlated with HRR1 and HRR2 only in those born preterm (r2 = 0.611, P = 0.002 and r2 = 0.663, P = 0.001).

Conclusions : Impaired myocardial functional reserve underlies reductions in peak VO2 and HRR in young adults born moderately preterm. Peak VO2 and HRR may aid risk stratification and treatment monitoring in this population.
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http://dx.doi.org/10.1093/ehjci/jeaa060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081423PMC
April 2021

The 'Digital Twin' to enable the vision of precision cardiology.

Eur Heart J 2020 12;41(48):4556-4564

Department of Engineering Science, University of Oxford, Oxford, UK.

Providing therapies tailored to each patient is the vision of precision medicine, enabled by the increasing ability to capture extensive data about individual patients. In this position paper, we argue that the second enabling pillar towards this vision is the increasing power of computers and algorithms to learn, reason, and build the 'digital twin' of a patient. Computational models are boosting the capacity to draw diagnosis and prognosis, and future treatments will be tailored not only to current health status and data, but also to an accurate projection of the pathways to restore health by model predictions. The early steps of the digital twin in the area of cardiovascular medicine are reviewed in this article, together with a discussion of the challenges and opportunities ahead. We emphasize the synergies between mechanistic and statistical models in accelerating cardiovascular research and enabling the vision of precision medicine.
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http://dx.doi.org/10.1093/eurheartj/ehaa159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774470PMC
December 2020

Cardiac remodelling and exercise: What happens with ultra-endurance exercise?

Eur J Prev Cardiol 2020 09 13;27(14):1464-1466. Epub 2020 Feb 13.

Oxford Cardiovascular Clinical Research Facility, University of Oxford, Oxford, UK.

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http://dx.doi.org/10.1177/2047487320904511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521004PMC
September 2020

Cardiac abnormalities identified with echocardiography in anorexia nervosa: systematic review and meta-analysis.

Br J Psychiatry 2020 Feb 6:1-10. Epub 2020 Feb 6.

Professor of Cardiovascular Medicine, Cardiovascular Clinical Research Facility, Oxford University Hospitals NHS Foundation Trust, UK.

Background: Anorexia nervosa affects most organ systems, with 80% suffering from cardiovascular complications.

Aims: To define echocardiographic abnormalities in anorexia nervosa through systematic review and meta-analysis.

Method: Two reviewers independently assessed eligibility of publications from Medline, EMBASE and Cochrane Database of Systematic Reviews registries. Studies were included if anorexia nervosa was the primary eating disorder and the main clinical association in described cardiac abnormalities. Data was extracted in duplicate and quality-assessed with a modified Newcastle-Ottawa scale. For continuous outcomes we calculated mean and standardised mean difference (SMD), and corresponding 95% confidence interval. For dichotomous outcomes we calculated proportion and corresponding 95% confidence interval. For qualitative data we summarised the studies.

Results: We identified 23 eligible studies totalling 960 patients, with a mean age of 17 years and mean body mass index of 15.2 kg/m2. Fourteen studies (469 participants) reported data suitable for meta-analysis. Cardiac abnormalities seen in anorexia nervosa compared with healthy controls were reduced left ventricular mass (SMD 1.82, 95% CI 1.32-2.31, P < 0.001), reduced cardiac output (SMD 1.92, 95% CI 1.38-2.45, P < 0.001), increased E/A ratio (SMD -1.10, 95% CI -1.67 to -0.54, P < 0.001), and increased incidence of pericardial effusions (25% of patients, P < 0.01, 95% CI 17-34%, I2 = 80%). Trends toward improvement were seen with weight restoration.

Conclusions: Patients with anorexia nervosa have structural and functional cardiac changes, identifiable with echocardiography. Further work should determine whether echocardiography can help stratify severity and guide safe patient location, management and effectiveness of nutritional rehabilitation.
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http://dx.doi.org/10.1192/bjp.2020.1DOI Listing
February 2020

Blood pressure monitoring in high-risk pregnancy to improve the detection and monitoring of hypertension (the BUMP 1 and 2 trials): protocol for two linked randomised controlled trials.

BMJ Open 2020 01 23;10(1):e034593. Epub 2020 Jan 23.

Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.

Introduction: Self-monitoring of blood pressure (BP) in pregnancy could improve the detection and management of pregnancy hypertension, while also empowering and engaging women in their own care. Two linked trials aim to evaluate whether BP self-monitoring in pregnancy improves the detection of raised BP during higher risk pregnancies (BUMP 1) and whether self-monitoring reduces systolic BP during hypertensive pregnancy (BUMP 2).

Methods And Analyses: Both are multicentre, non-masked, parallel group, randomised controlled trials. Participants will be randomised to self-monitoring with telemonitoring or usual care. BUMP 1 will recruit a minimum of 2262 pregnant women at higher risk of pregnancy hypertension and BUMP 2 will recruit a minimum of 512 pregnant women with either gestational or chronic hypertension. The BUMP 1 primary outcome is the time to the first recording of raised BP by a healthcare professional. The BUMP 2 primary outcome is mean systolic BP between baseline and delivery recorded by healthcare professionals. Other outcomes will include maternal and perinatal outcomes, quality of life and adverse events. An economic evaluation of BP self-monitoring in addition to usual care compared with usual care alone will be assessed across both study populations within trial and with modelling to estimate long-term cost-effectiveness. A linked process evaluation will combine quantitative and qualitative data to examine how BP self-monitoring in pregnancy is implemented and accepted in both daily life and routine clinical practice.

Ethics And Dissemination: The trials have been approved by a Research Ethics Committee (17/WM/0241) and relevant research authorities. They will be published in peer-reviewed journals and presented at national and international conferences. If shown to be effective, BP self-monitoring would be applicable to a large population of pregnant women.

Trial Registration Number: NCT03334149.
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http://dx.doi.org/10.1136/bmjopen-2019-034593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044851PMC
January 2020

Setting Our Sights on Infectious Diseases.

ACS Infect Dis 2020 01 6;6(1):3-13. Epub 2019 Dec 6.

Global Health Institute of Merck, Ares Trading S.A. , a subsidiary of Merck KGaA Darmstadt Germany , Route de Crassier 1 , 1262 Eysins , Switzerland.

In May 2019, the Wellcome Centre for Anti-Infectives Research (CAIR) at the University of Dundee, UK, held an international conference with the aim of discussing some key questions around discovering new medicines for infectious diseases and a particular focus on diseases affecting Low and Middle Income Countries. There is an urgent need for new drugs to treat most infectious diseases. We were keen to see if there were lessons that we could learn across different disease areas and between the preclinical and clinical phases with the aim of exploring how we can improve and speed up the drug discovery, translational, and clinical development processes. We started with an introductory session on the current situation and then worked backward from clinical development to combination therapy, pharmacokinetic/pharmacodynamic (PK/PD) studies, drug discovery pathways, and new starting points and targets. This Viewpoint aims to capture some of the learnings.
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http://dx.doi.org/10.1021/acsinfecdis.9b00371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958537PMC
January 2020

Does self-reported pregnancy loss identify women at risk of an adverse cardiovascular phenotype in later life? Insights from UK Biobank.

PLoS One 2019 23;14(10):e0223125. Epub 2019 Oct 23.

Oxford Cardiovascular Clinical Research Facility, Radcliffe Department of Medicine, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe, Oxford, United Kingdom.

Introduction: Cardiovascular disease (CVD) is more common in women who have had pregnancy complications such as spontaneous pregnancy loss. We used cross-sectional data from the UK Biobank Imaging Enhancement Study to determine whether pregnancy loss is associated with cardiac or vascular remodelling in later life, which might contribute to this increased risk.

Methods: Pregnancy history was reported by women participating in UK Biobank between 2006 and 2010 at age 40-69 years using a self-completed touch-screen questionnaire. Associations between self-reported spontaneous pregnancy loss and cardiovascular measures, collected in women who participated in the Imaging Enhancement Study up to the end of 2015, were examined. Cardiac structure and function were assessed by magnetic resonance (CMR) steady-state free precession imaging at 1.5 Tesla. Carotid intima-media thickness (CIMT) measurements were taken for both common carotid arteries using a CardioHealth Station. Statistical associations with CMR and carotid measures were adjusted for age, BMI and other cardiovascular risk factors.

Results: Data were available on 2660 women of whom 111 were excluded because of pre-existing cardiovascular disease and 30 had no pregnancy information available. Of the remaining 2519, 446 were nulligravid and 2073 had a history of pregnancies, of whom 622 reported at least one pregnancy loss (92% miscarriages and 8% stillbirths) and 1451 reported no pregnancy loss. No significant differences in any cardiac or carotid parameters were evident in women who reported pregnancy loss compared to other groups (Table 1).

Conclusion: Women who self-report pregnancy loss do not have significant differences in cardiac structure, cardiac function, or carotid structure in later life to explain their increased cardiovascular risk. This suggests any cardiovascular risks associated with pregnancy loss operate through other disease mechanisms. Alternatively, other characteristics of pregnancy loss, which we were not able to take account of, such as timing and number of pregnancy losses may be required to identify those at greatest cardiovascular risk.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223125PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6808447PMC
March 2020

Preeclampsia: Risk Factors, Diagnosis, Management, and the Cardiovascular Impact on the Offspring.

J Clin Med 2019 Oct 4;8(10). Epub 2019 Oct 4.

Oxford Cardiovascular Clinical Research Facility, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK.

Hypertensive disorders of pregnancy affect up to 10% of pregnancies worldwide, which includes the 3%-5% of all pregnancies complicated by preeclampsia. Preeclampsia is defined as new onset hypertension after 20 weeks' gestation with evidence of maternal organ or uteroplacental dysfunction or proteinuria. Despite its prevalence, the risk factors that have been identified lack accuracy in predicting its onset and preventative therapies only moderately reduce a woman's risk of preeclampsia. Preeclampsia is a major cause of maternal morbidity and is associated with adverse foetal outcomes including intra-uterine growth restriction, preterm birth, placental abruption, foetal distress, and foetal death in utero. At present, national guidelines for foetal surveillance in preeclamptic pregnancies are inconsistent, due to a lack of evidence detailing the most appropriate assessment modalities as well as the timing and frequency at which assessments should be conducted. Current management of the foetus in preeclampsia involves timely delivery and prevention of adverse effects of prematurity with antenatal corticosteroids and/or magnesium sulphate depending on gestation. Alongside the risks to the foetus during pregnancy, there is also growing evidence that preeclampsia has long-term adverse effects on the offspring. In particular, preeclampsia has been associated with cardiovascular sequelae in the offspring including hypertension and altered vascular function.
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http://dx.doi.org/10.3390/jcm8101625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832549PMC
October 2019

Towards a personalised approach in exercise-based cardiovascular rehabilitation: How can translational research help? A 'call to action' from the Section on Secondary Prevention and Cardiac Rehabilitation of the European Association of Preventive Cardiology.

Eur J Prev Cardiol 2020 09 4;27(13):1369-1385. Epub 2019 Oct 4.

Department of Cardiology, Charité Universitätsmedizin, Germany.

The benefit of regular physical activity and exercise training for the prevention of cardiovascular and metabolic diseases is undisputed. Many molecular mechanisms mediating exercise effects have been deciphered. Personalised exercise prescription can help patients in achieving their individual greatest benefit from an exercise-based cardiovascular rehabilitation programme. Yet, we still struggle to provide truly personalised exercise prescriptions to our patients. In this position paper, we address novel basic and translational research concepts that can help us understand the principles underlying the inter-individual differences in the response to exercise, and identify early on who would most likely benefit from which exercise intervention. This includes hereditary, non-hereditary and sex-specific concepts. Recent insights have helped us to take on a more holistic view, integrating exercise-mediated molecular mechanisms with those influenced by metabolism and immunity. Unfortunately, while the outline is recognisable, many details are still lacking to turn the understanding of a concept into a roadmap ready to be used in clinical routine. This position paper therefore also investigates perspectives on how the advent of 'big data' and the use of animal models could help unravel inter-individual responses to exercise parameters and thus influence hypothesis-building for translational research in exercise-based cardiovascular rehabilitation.
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http://dx.doi.org/10.1177/2047487319877716DOI Listing
September 2020

Combining Artificial Intelligence With Human Insight to Automate Echocardiography.

Circ Cardiovasc Imaging 2019 09 16;12(9):e009727. Epub 2019 Sep 16.

Department of Cardiac Physiology, Royal Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom (A.J.F.).

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http://dx.doi.org/10.1161/CIRCIMAGING.119.009727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099860PMC
September 2019

(Deep) Learning Your Left From Your Right.

Authors:
Paul Leeson

JACC Cardiovasc Imaging 2020 02 15;13(2 Pt 1):382-384. Epub 2019 May 15.

Radcliffe Department of Medicine, Division of Cardiovascular Medicine, Oxford Cardiovascular Clinical Research Facility, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.jcmg.2019.03.015DOI Listing
February 2020

Artificial Intelligence in Cardiovascular Imaging: JACC State-of-the-Art Review.

J Am Coll Cardiol 2019 03;73(11):1317-1335

Baker Heart and Diabetes Research Institute, Melbourne, Australia. Electronic address:

Data science is likely to lead to major changes in cardiovascular imaging. Problems with timing, efficiency, and missed diagnoses occur at all stages of the imaging chain. The application of artificial intelligence (AI) is dependent on robust data; the application of appropriate computational approaches and tools; and validation of its clinical application to image segmentation, automated measurements, and eventually, automated diagnosis. AI may reduce cost and improve value at the stages of image acquisition, interpretation, and decision-making. Moreover, the precision now possible with cardiovascular imaging, combined with "big data" from the electronic health record and pathology, is likely to better characterize disease and personalize therapy. This review summarizes recent promising applications of AI in cardiology and cardiac imaging, which potentially add value to patient care.
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http://dx.doi.org/10.1016/j.jacc.2018.12.054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474254PMC
March 2019

Neurohumoral and ambulatory haemodynamic adaptations following isometric exercise training in unmedicated hypertensive patients.

J Hypertens 2019 04;37(4):827-836

School of Human and Life Sciences, Canterbury Christ Church University, Kent.

Objective: Hypertension remains the leading modifiable risk factor for cardiovascular disease. Isometric exercise training (IET) has been shown to be a useful nonpharmacological intervention for reducing resting blood pressure (BP). This study aimed to measure alterations in office BP, ambulatory BP, cardiac autonomic modulation and inflammatory and vascular biomarkers following a programme of IET in unmedicated hypertensive patients.

Methods: Twenty-four unmedicated stage 1 hypertensive patients (age 43.8 ± 7.3 years; height, 178.1 ± 7 cm; weight 89.7 ± 12.8 kg) were randomly assigned in a cross-over study design, to 4-weeks of home-based IET and control period, separated by a 3-week washout period. Office and ambulatory BP, cardiac autonomic modulation, and inflammatory and vascular biomarkers were recorded pre and post-IET and control periods.

Results: Clinic and 24-h ambulatory BP significantly reduced following IET by 12.4/6.2 and 11.8/5.6 mmHg in SBP/DBP, respectively (P < 0.001 for both), compared with the control. The BP adaptations were associated with a significant (P = 0.018) reduction in the average real variability of 24-h ambulatory BP following IET, compared with control. Cardiac autonomic modulation improved by 11% (P < 0.001), baroreceptor reflex sensitivity improved by 47% (P < 0.001), and IL-6 and asymmetric dimethylarginine reduced by 10% (P = 0.022) and 19% (P = 0.023), respectively, which differed significantly to the control period.

Conclusion: This is the first evidence of durable BP reduction and wider cardiovascular disease risk benefits of IET in a relevant patient population. Our findings support the role of IET as a safe and viable therapeutic and preventive intervention in the treatment of hypertension.
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http://dx.doi.org/10.1097/HJH.0000000000001922DOI Listing
April 2019

Automated Myocardial Wall Motion Classification using Handcrafted Features vs a Deep CNN-based mapping.

Annu Int Conf IEEE Eng Med Biol Soc 2018 Jul;2018:3140-3143

Compared to other modalities such as computed tomography or magnetic resonance imaging, the appearance of ultrasound images is highly dependent on the expertise of the sonographer or clinician making the image acquisition, as well as the machine used, making it a challenge to analyze due to the frequent presence of artefacts, missing boundaries, attenuation, shadows, and speckle. In addition, manual contouring of the epicardial and endocardial walls exhibits large inconsistencies and variations as it is strongly dependent on the sonographer's training and expertise. Hence, in this paper we propose a fully automated image analysis framework to ultimately perform wall motion abnormality classification in 2D+T images. We explore both traditional Random Forests classification with handcrafted features and spatio-temporal hierarchical aggregation of information with a deep learning CNN-based approach. Regarding the later classifier, we also investigate the effect of local phase information retrieval through the use of Feature Asymmetry (FA), and demonstrate that pre-processing videos with FA enables the spatio-temporal CNN to better discover relevant left ventricle endocardial abstractions from low-level features to high-level representations automatically.
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http://dx.doi.org/10.1109/EMBC.2018.8513063DOI Listing
July 2018

Improving Visual Detection of Wall Motion Abnormality with Echocardiographic Image Enhancing Methods.

Annu Int Conf IEEE Eng Med Biol Soc 2018 Jul;2018:1128-1131

Analysis of wall motion abnormality using echocardiography is an established method for detecting myocardial ischemia. We describe a hybrid approach of enhancing 2D+T echo datasets with border detection and Eulerian motion magnification to improve the visual assessment of wall motion. We implemented a local phase-based approach using the monogenic signal and its derived features, either feature asymmetry (FA) or oriented feature symmetry (OFS), to detect boundaries of the heart structure. We enhanced the 2D+T datasets using either an intensity-based or phase-based Eulerian Motion Magnification (EMM) video processing technique, and identified among eight different types of enhancements the best performing method as OFS with an accuracy of 78% versus the original B-Mode with an accuracy of 71%.
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http://dx.doi.org/10.1109/EMBC.2018.8512537DOI Listing
July 2018

Trial of exercise to prevent HypeRtension in young adults (TEPHRA) a randomized controlled trial: study protocol.

BMC Cardiovasc Disord 2018 11 6;18(1):208. Epub 2018 Nov 6.

Oxford Cardiovascular Clinical Research Facility, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK.

Background: Hypertension prevalence in young adults has increased and is associated with increased incidence of cerebrovascular and cardiovascular events in middle age. However, there is significant debate regards how to effectively manage young adult hypertension with recommendation to target lifestyle intervention. Surprisingly, no trials have investigated whether lifestyle advice developed for blood pressure control in older adults is effective in these younger populations.

Methods/design: TEPHRA is an open label, parallel arm, randomised controlled trial in young adults with high normal and elevated blood pressure. The study will compare a supervised physical activity intervention consisting of 16 weeks structured exercise, physical activity self-monitoring and motivational coaching with a control group receiving usual care/minimal intervention. Two hundred young adults aged 18-35 years, including a subgroup of preterm born participants will be recruited through open recruitment and direct invitation. Participants will be randomised in a ratio of 1:1 to either the exercise intervention group or control group. Primary outcome will be ambulatory blood pressure monitoring at 16 weeks with measure of sustained effect at 12 months. Study measures include multimodal cardiovascular assessments; peripheral vascular measures, blood sampling, microvascular assessment, echocardiography, objective physical activity monitoring and a subgroup will complete multi-organ magnetic resonance imaging.

Discussion: The results of this trial will deliver a novel, randomised control trial that reports the effect of physical activity intervention on blood pressure integrated with detailed cardiovascular phenotyping in young adults. The results will support the development of future research and expand the evidence-based management of blood pressure in young adult populations.

Trial Registration: Clinicaltrials.gov registration number NCT02723552 , registered on 30 March, 2016.
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http://dx.doi.org/10.1186/s12872-018-0944-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220491PMC
November 2018

Neonatal Micro-RNA Profile Determines Endothelial Function in Offspring of Hypertensive Pregnancies.

Hypertension 2018 10 20;72(4):937-945. Epub 2018 Aug 20.

Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

Offspring of hypertensive pregnancies are at increased risk of developing hypertension in adulthood. In the neonatal period they display endothelial cell dysfunction and altered microvascular development. MicroRNAs, as important endothelial cellular regulators, may play a role in this early endothelial dysfunction. Therefore we identified differential microRNA patterns in endothelial cells from offspring of hypertensive pregnancies and determined their role in postnatal vascular cell function. Studies were performed on human umbilical vein endothelial cell (HUVECs) samples from 57 pregnancies. Unbiased RNA-sequencing identified 30 endothelial-related microRNAs differentially expressed in HUVECs from hypertensive compared to normotensive pregnancies. Quantitative reverse transcription PCR (RT-qPCR) confirmed a significant higher expression level of the top candidate, miR-146a. Combined miR-146a targeted gene expression and pathway analysis revealed significant alterations in genes involved in inflammation, angiogenesis and immune response in the same HUVECs. Elevated miR-146a expression level at birth identified cells with reduced ability for vascular tube formation, which was rescued by miR-146a inhibition. In contrast, miR-146a overexpression significantly reduced vascular tube formation in HUVECs from normotensive pregnancies. Finally, we confirmed that mir146a levels at birth predicted microvascular development during the first three postnatal months. Offspring of hypertensive pregnancy have a distinct endothelial regulatory microRNA profile at birth, which is related to altered endothelial cell behaviour, and predicts patterns of microvascular development during the first three months of life. Modification of this microRNA profile can restore impaired vascular cell function.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.11343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166786PMC
October 2018

The Role of Neuropeptide Y in Cardiovascular Health and Disease.

Front Physiol 2018 19;9:1281. Epub 2018 Sep 19.

Department of Physiology, Anatomy and Genetics, Burdon Sanderson Cardiac Science Centre, University of Oxford, Oxford, United Kingdom.

Neuropeptide Y (NPY) is an abundant sympathetic co-transmitter, widely found in the central and peripheral nervous systems and with diverse roles in multiple physiological processes. In the cardiovascular system it is found in neurons supplying the vasculature, cardiomyocytes and endocardium, and is involved in physiological processes including vasoconstriction, cardiac remodeling, and angiogenesis. It is increasingly also implicated in cardiovascular disease pathogenesis, including hypertension, atherosclerosis, ischemia/infarction, arrhythmia, and heart failure. This review will focus on the physiological and pathogenic role of NPY in the cardiovascular system. After summarizing the NPY receptors which predominantly mediate cardiovascular actions, along with their signaling pathways, individual disease processes will be considered. A thorough understanding of these roles may allow therapeutic targeting of NPY and its receptors.
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http://dx.doi.org/10.3389/fphys.2018.01281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157311PMC
September 2018