Bernard Keavney

The University of Manchester, Manchester, England, United Kingdom

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Publications (151)1190 Total impact

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    ABSTRACT: Lymphocytes contribute to ischemia/reperfusion (I/R) injury in several organ systems, but their relevance in ST elevation myocardial infarction (STEMI) is unknown. Our goal was to characterize lymphocyte dynamics in individuals after primary percutaneous coronary intervention (PPCI), assess the prognostic relevance of these cells, and explore mechanisms of lymphocyte-associated injury. Lymphocyte counts were retrospectively analyzed in 1,377 STEMI patients, and the prognostic relevance of post-PPCI lymphopenia was assessed by Cox proportional hazards regression. Blood from 59 prospectively recruited STEMI patients undergoing PPCI was sampled, and leukocyte subpopulations were quantified. Microvascular obstruction (MVO), a component of I/R injury, was assessed using MRI. In the retrospective cohort, lymphopenia was associated with a lower rate of survival at 3 years (82.8% vs. 96.3%, lowest vs. highest tertile; hazard ratio 2.42). In the prospective cohort, lymphocyte counts fell 90 minutes after reperfusion, primarily due to loss of T cells. CD8+ T cells decreased more than CD4+ T cells, and effector subsets exhibited the largest decline. The early decrease in effector T cell levels was greater in individuals that developed substantial MVO. The drop in T cell subsets correlated with expression of the fractalkine receptor CX3CR1 (r2 = 0.99, P = 0.006). Serum fractalkine concentration peaked at 90 minutes after reperfusion, coinciding with the T cell count nadir. Lymphopenia following PPCI is associated with poor prognosis. Our data suggest that fractalkine contributes to lymphocyte shifts, which may influence development of MVO through the action of effector T cells. Not applicable. British Heart Foundation (FS/12/31/29533) and National Institute of Health Research (NIHR) Newcastle Biomedical Research Centre.
    The Journal of clinical investigation 07/2015; DOI:10.1172/JCI80055 · 13.77 Impact Factor
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    ABSTRACT: Genome-wide association studies (GWAS) have identified genetic variants in a number of chromosomal regions that are associated with atrial fibrillation (AF). The mechanisms underlying these associations are unknown, but are likely to involve effects of the risk haplotypes on expression of neighbouring genes. To investigate the association between genetic variants at AF-associated loci and expression of nearby candidate genes in human atrial tissue and peripheral blood. Right atrial appendage (RAA) samples were collected from 122 patients undergoing cardiac surgery, in 12 of whom left atrial appendage samples were also available. 22 patients had a history of AF. Peripheral blood samples were collected from 405 patients undergoing diagnostic cardiac catheterisation. In order to tag genetic variation at each of nine loci, a total of 367 single nucleotide polymorphisms (SNPs) were genotyped using the Sequenom platform. Total expression of 16 candidate genes in the nine AF-associated regions was measured by quantitative PCR. The relative expression of each allele of the candidate genes was measured on the Sequenom platform using one or more transcribed SNPs to distinguish between alleles in heterozygotes. We tested association between the SNPs of interest and gene expression using total gene expression (integrating cis and trans acting sources of variation), and allelic expression ratios (specific for cis acting influences), in atrial tissue and peripheral blood. We adjusted for multiple comparisons using a Bonferroni approach. In subsidiary analyses, we compared the expression of candidate genes between patients with and without a history of AF. Total expression of 15 transcripts of 14 genes and allelic expression ratio of 14 transcripts of 14 genes in genomic regions associated with AF were measured in right atrial appendage tissue. 8 of these transcripts were also expressed in peripheral blood. Risk alleles at AF-associated SNPs were associated in cis with an increased expression of PITX2a (2.01-fold, p=6.5x10(-4)); and with decreased expression of MYOZ1 (0.39 fold; p=5.5x10(-15)), CAV1 (0.89 fold; p=5.9x10(-8)), C9orf3 (0.91 fold; 1.5x10(-5)), and FANCC (0.94-fold; p=8.9x10(-8)) in right atrial appendage. Of these five genes, only CAV1 was expressed in peripheral blood; association between the same AF risk alleles and lower expression of CAV1 was confirmed (0.91 fold decrease; p=4.2x10(-5)). A history of AF was also associated with a decrease in expression of CAV1 in both right and left atria (0.84 and 0.85 fold, respectively; p=0.03), congruent with the magnitude of the effect of the risk SNP on expression, and independent of genotype. The analyses in peripheral blood showed association between AF risk SNPs and decreased expression of KCNN3 (0.85-fold; p=2.1x10(-4)); and increased expression of SYNE2 (1.12-fold; p=7.5x10(-24)); however, these associations were not detectable in atrial tissue. We identified novel cis-acting associations in atrial tissue between AF risk SNPs and increased expression of PITX2a/b; and decreased expression of CAV1 (an association also seen in peripheral blood), C9orf3 and FANCC. We also confirmed a previously described association between AF risk variants and MYOZ1 expression. Analyses of peripheral blood illustrated tissue-specificity of cardiac eQTLs and highlights the need for larger-scale genome-wide eQTL studies in cardiac tissue. Our results suggest novel aetiological roles for genes in four AF-associated genomic regions. Copyright © 2015. Published by Elsevier Ltd.
    Journal of Molecular and Cellular Cardiology 06/2015; 85. DOI:10.1016/j.yjmcc.2015.06.005 · 5.22 Impact Factor
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    ABSTRACT: Genetic cardiac diseases are major causes of morbidity and mortality. Although animal models have been created to provide some useful insights into the pathogenesis of genetic cardiac diseases, the significant species differences and the lack of genetic information for complex genetic diseases markedly attenuates the application values of such data. Generation of induced pluripotent stem cells (iPSC) from patient-specific specimens and subsequent derivation of cardiomyocytes offers novel avenues to study the mechanisms underlying cardiac diseases, to identify new causative genes and to provide insights into the disease aetiology. In recent years, the list of human iPSC-based models for genetic cardiac diseases has been expanding rapidly, although there are still remaining concerns on the level of functionality of iPSC derived cardiomyocytes and their ability to be used for modelling complex cardiac diseases in adults. The current review focuses on the development of cardiomyocyte induction from pluripotent stem cells, the recent progress in heart disease modelling using iPSC-derived cardiomyocytes and the challenges associated with understanding complex genetic diseases. To address these issues we examine the similarity between iPSC derived cardiomyocytes and their ex vivo counterparts and how this relates to the method used to differentiate the pluripotent stem cells into a cardiomyocyte phenotype. We progress to examine categories of congenital cardiac abnormalities that are suitable for iPSC based disease modelling. This article is protected by copyright. All rights reserved. © 2015 AlphaMed Press.
    Stem Cells 05/2015; DOI:10.1002/stem.2070 · 7.70 Impact Factor
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    ABSTRACT: This study aims to evaluate temporal changes in stroke complications and their association with mortality and MACE outcomes in a national cohort of patients undergoing percutaneous coronary interventions (PCIs) in England and Wales. A total of 426 046 patients who underwent PCI in England and Wales between 2007 and 2012 in the British Cardiovascular Intervention Society (BCIS) database were analysed. Statistical analyses were performed evaluating the rates of stroke complications according to the year of PCI and multiple logistic regressions were used to evaluate the odds of 30-day mortality and in-hospital major adverse cardiovascular events (MACE; a composite of in-hospital mortality, myocardial infarction or re-infarction, and revascularization) with stroke complications. Four hundred and thirty-six patients (0.1%) sustained an ischaemic stroke/TIA complication and 107 patients (0.03%) sustained a haemorrhagic stroke complication. Ischaemic stroke/TIA complications increased non-linearly from 0.67 (95% CI 0.47-0.87) to 1.14 (0.94-1.34) per 1000 patients between 2007 and 2012 (P = 0.006), whilst haemorrhagic stroke rates decreased non-linearly from 0.29 (0.19-0.39) to 0.15 (0.05-0.25) per 1000 patients in 2012 (P = 0.009). Following adjustment for baseline clinical and procedural demographics, ischaemic stroke was independently associated with both 30-day mortality (OR 4.92, 3.06-7.92) and in-hospital MACE (OR 3.11, 1.83-5.27). An even greater impact on prognosis was observed with haemorrhagic complications (30-day mortality: OR 13.87, 6.37-30.21), in-hospital MACE (OR 13.50, 6.30-28.92). Incident ischaemic stroke complications have increased over time, whilst haemorrhagic stroke complications have decreased, driven through changes in clinical, procedural, drug-treatment, and demographic factors. Both ischaemic and haemorrhagic strokes are rare but devastating complications with high 30-day mortality and in-hospital MACE rates. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.
    European Heart Journal 04/2015; 36(25). DOI:10.1093/eurheartj/ehv113 · 14.72 Impact Factor
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    ABSTRACT: Background Truncus arteriosus (TA) is characterised by failure of septation of the outflow tract into aortic and pulmonary trunks and is associated with high morbidity and mortality. Although ranked among the least common congenital heart defects, TA provides an excellent model for the role of individual genes in cardiac morphogenesis as exemplified by TBX1 deficiency caused by point mutations or, more commonly, hemizygosity as part of the 22q11.2 deletion syndrome. The latter genetic lesion, however, is only observed in a proportion of patients with TA, which suggests the presence of additional disease genes. Objective To identify novel genes that cause Mendelian forms of TA. Methods and results We exploited the occurrence of monogenic forms of TA in the Saudi population, which is characterised by high consanguinity, a feature conducive to the occurrence of Mendelian phenocopies of complex phenotypes as we and others have shown. Indeed, we demonstrate in two multiplex consanguineous families that we are able to map TA to regions of autozygosity in which whole-exome sequencing revealed homozygous truncating mutations in PRKD1 (encoding a kinase derepressor of MAF2) and NRP1 (encoding a coreceptor of vascular endothelial growth factor (VEGFA)). Previous work has demonstrated that Prkd1−/− is embryonic lethal and that its tissue-specific deletion results in abnormal heart remodelling, whereas Nrp1−/− develops TA. Surprisingly, molecular karyotyping to exclude 22q11.2 deletion syndrome in the replication cohort of 17 simplex TA cases revealed a de novo hemizygous deletion that encompasses PRDM1, deficiency of which also results in TA phenotype in mouse. Conclusions Our results expand the repertoire of molecular lesions in chromatin remodelling and transcription factors that are implicated in the pathogenesis of congenital heart disease in humans and attest to the power of monogenic forms of congenital heart diseases as a complementary approach to dissect the genetics of these complex phenotypes.
    Journal of Medical Genetics 02/2015; 52(5). DOI:10.1136/jmedgenet-2015-102992 · 5.64 Impact Factor
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    ABSTRACT: Objective We investigate adoption of the TRA in different age groups and study the relationship between age and access site related outcomes in a national cohort of patients undergoing PCI in the UK. Background Previous studies have reported conflicting data on radial access site adoption between different age groups, with age an independent predictor of failure of procedures undertaken through the radial approach. Methods Age and access site related outcomes (based on transradial (TRA) and transfemoral (TFA) access) were studied in 469,983 PCI procedures undertaken in the UK from 2006-2012 in the age groups; <60, 60-<70, 70-<80 and ≥80 in the British Cardiovascular Intervention Society database. Results We studied access site practice in 469,983 patients who underwent PCI procedures in the United Kingdom. TRA utilization increased from 17.5%to 65.6% in the age group <60, and 16.6% to 54.5% in the age group ≥80 between 2006-2012. TRA was independently associated with decreased 30 day mortality in all age groups (<60: OR 0.64; 95% CI 0.54-0.74, P<0.0001; 60 to <70: OR 0.65; 95% CI 0.57-75, P<0.0001,70 to <80: OR 0.58 (0.52-0.65, P<0.0001 and ≥80: OR 0.65 (0.57-0.73, P<0.0001). Conclusions Adoption of the TRA for PCI has occurred least in older patients in the UK despite similar associations between TRA use and decreased 30-day mortality observed in all age groups. This article is protected by copyright. All rights reserved. Copyright © 2015 Wiley Periodicals, Inc., a Wiley company.
    Catheterization and Cardiovascular Interventions 02/2015; DOI:10.1002/ccd.25896 · 2.40 Impact Factor
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    ABSTRACT: Our previous genome-wide association study (GWAS) identified two susceptibility loci for congenital heart disease (CHD) in Han Chinese. Here we identify additional loci by testing promising associations in an extended 3-stage validation consisting of 6,053 CHD cases and 7,410 controls. We find GW significant (P<5.0 × 10(-8)) evidence of 4 additional CHD susceptibility loci at 4q31.22 (rs1400558, upstream of EDNRA, Pall=1.63 × 10(-9)), 9p24.2 (rs7863990, close to SMARCA2, Pall=3.71 × 10(-14)), 12q24.13 (rs2433752, upstream of TBX3 and TBX5, Pall=1.04 × 10(-10)) and 20q12 (rs490514, in PTPRT, Pall=1.20 × 10(-13)). Moreover, the data from previous European GWAS supports that rs490514 is associated with the risk of CHD (P=3.40 × 10(-3)). These results enhance our understanding of CHD susceptibility.
    Nature Communications 01/2015; 6:8082. DOI:10.1038/ncomms9082 · 10.74 Impact Factor
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    ABSTRACT: Background The ZFHX3 gene, located in Chromosome 16q22.3, codes for a transcription factor which is widely expressed in human tissues. Genome-wide studies have identified associations between variants within the gene and Kawasaki disease and atrial fibrillation. ZFHX3 has two main transcripts that utilise different transcription start sites. We examined the association between genetic variants in the 16q22.3 region and expression of ZFHX3 to identify variants that regulate gene expression.ResultsWe genotyped 65 single-nucleotide polymorphisms to tag genetic variation at the ZFHX3 locus in two cohorts, 451 British individuals recruited in the North East of England and 310 mixed-ancestry individuals recruited in South Africa. Allelic expression analysis revealed that the minor (A) allele of rs8060701, a variant in the first intron of ZFHX3, was associated with a 1.16-fold decrease in allelic expression of both transcripts together, (p¿=¿4.87e-06). The minor (C) allele of a transcribed variant, rs10852515, in the second exon of ZFHX3 isoform A was independently associated with a 1.36-fold decrease in allelic expression of ZFHX3 A (p¿=¿7.06e-31), but not overall ZFHX3 expression. However, analysis of total gene expression of ZFHX3 failed to detect an association with genotype at any variant. Differences in linkage disequilibrium between the two populations allowed fine-mapping of the locus to a 7 kb region overlapping exon 2 of ZFHX3 A. We did not find any association between ZFHX3 expression and any of the variants identified by genome wide association studies.Conclusions ZFHX3 transcript levels are regulated in a transcript-specific fashion by independent cis-acting transcribed polymorphisms. Our results demonstrate the power of allelic expression analysis and trans-ethnic fine mapping to identify transcript-specific cis-acting regulatory elements .
    BMC Genetics 12/2014; 15(1):1. DOI:10.1186/s12863-014-0136-1 · 2.36 Impact Factor
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    ABSTRACT: Rationale: There is mounting evidence of a higher incidence of coronary heart disease (CHD) in cytomegalovirus (CMV) seropositive individuals. Objective: The aim of this study was to investigate whether acute MI triggers an inflammatory T-cell response that might lead to accelerated immunosenescence in CMV-seropositive patients. Methods and Results: Thirty-four patients with acute MI undergoing primary PCI (PPCI) were longitudinally studied within 3 months following reperfusion (Cohort A). In addition, 54 patients with acute and chronic MI were analyzed in a cross-sectional study (Cohort B). CMV-seropositive patients demonstrated a greater fall in the concentration of terminally differentiated CD8 effector memory T cells (TEMRA) in peripheral blood during the first 30 min of reperfusion compared with CMV-seronegative patients (-192 vs. -63 cells/µl; p=0.008), correlating with the expression of programmed cell death-1 (PD-1) before PPCI (r=0.8; p=0.0002). A significant proportion of TEMRA cells remained depleted for at least 3 months in CMV-seropositive patients. Using high-throughput 13-parameter flow cytometry and HLA class I CMV-specific dextramers, we confirmed an acute and persistent depletion of terminally differentiated TEMRA and CMV-specific CD8(+) cells in CMV-seropositive patients. Long-term reconstitution of the TEMRA pool in chronic CMV-seropositive post-MI patients was associated with signs of terminal differentiation including an increase in KLRG1 and shorter telomere length in CD8(+) T cells (2225 bp vs. 3397 bp; p<0.001). Conclusions: Myocardial ischemia and reperfusion in CMV-seropositive patients undergoing PPCI leads to acute loss of antigen-specific, terminally differentiated CD8 T-cells, possibly through PD-1-dependent programmed cell death. Our results suggest that acute MI and reperfusion accelerate immunosenescence in CMV-seropositive patients.
    Circulation Research 11/2014; 116(1). DOI:10.1161/CIRCRESAHA.116.304393 · 11.09 Impact Factor
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    ABSTRACT: Statins are one of the most potent drugs in delaying age-related inflammatory changes in the arterial vessel wall, slowing down the progression of atherosclerosis. Statins have also been shown to abrogate telomere-attributed cardiovascular risk. The goal of our study was to explore a potential effect of atorvastatin on telomerase activity in peripheral blood mononuclear cells (PBMCs) and T-lymphocytes (T cells). Methods and Results Treatment with pharmacologically relevant concentrations (0.1-0.3 μM) of atorvastatin resulted in a 6-fold increase of telomerase activity (TA) (p<0.0001) in human and mouse PBMCs and CD4 T cells, translating into moderate proliferation of T lymphocytes. In contrast, high doses of atorvastatin (2 - 5 μM) or the addition of LDL cholesterol completely inhibited proliferation, thereby abrogating telomerase activity. The proliferative effect of atorvastatin was ablated by the absense of the catalytic subunit of telomerase, telomerase reverse transcriptase (TERT). Using transgenic GFP-mTert reporter mice, we observed a decrease in telomerase-positive lymphocytes from 30% to 15% during the first 5 months of age (p<0.01). This suggests that the decrease in immune cell turnover during normal development and maturation is mirrored by a reduction in telomerase activity in lymphocytes in-vivo. Conclusion Atorvastatin and cholesterol have opposing effects on telomerase in mononuclear cells and T-lymphocytes. Our study suggests a link between cholesterol metabolism and telomere-related cardiovascular risk.
    Atherosclerosis 10/2014; 236(2). DOI:10.1016/j.atherosclerosis.2014.07.020 · 3.97 Impact Factor
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    ABSTRACT: Guidelines advocate using B-type natriuretic peptides in the diagnostic work-up of suspected heart failure (HF). Their main role is to limit echocardiography rates by ruling out HF/LV dysfunction where peptide level is low. Recommended rule-out cut points vary between guidelines. The utility of B-type natriuretic peptides in the very old (85+) requires further investigation, with optimal cut points yet to be established. We examined NT-proBNP's utility, alone and in combination with history of myocardial infarction (MI), as a rule-out test for LV dysfunction in very old people with limiting dyspnoea. Design: Cross-sectional analysis. Setting: Population-based sample; North-East England. Participants: 155 people (aged 87-89) with limiting dyspnoea. Measures: Dyspnoea assessed by questionnaire. Domiciliary echocardiography performed; LV systolic/diastolic function graded. NT-proBNP measured (Roche Diagnostics). Receiver operating characteristic analyses examined NT-proBNP's diagnostic accuracy for LV dysfunction. AUC for LVEF less than or equal to 50% was poor (0.58, 95% CI 0.49-0.65), but good for LVEF less than or equal to 40% (0.80, 95% CI 0.73-0.86). At ESC cut point (125ng/l), few cases of systolic dysfunction were missed (NPV 94-100%, depending on severity), but echocardiography (88%) and false positive rates (56-81 per 100 screened) were high. At NICE cut point (400ng/l), echocardiography (51%) and false positive rates (33-45) were lower; exclusionary performance was good for LVEF less than or equal to 40% (1 case missed per 100 screened, 15% of cases; NPV 97%), but poor for LVEF less than or equal to 50% (16 cases missed per 100 screened, 45% of cases; NPV 68%). Incorporating isolated moderate/severe diastolic dysfunction into target condition increased the proportion of cases missed (lower NPV), whilst improving case detection. Incorporating MI history as an additional referral prompt slightly reduced the number of cases missed at expense of higher echocardiography and false positive rates. High echocardiography rates and poor exclusionary performance for mild degrees of systolic dysfunction and for diastolic dysfunction limit NT-proBNP's utility as a rule-out test for LV dysfunction in very old people with limiting dyspnoea. Incorporating MI history as an additional echocardiography prompt yields no overall benefit compared to using NT-proBNP level alone.
    BMC Cardiovascular Disorders 09/2014; 14(1):128. DOI:10.1186/1471-2261-14-128 · 1.50 Impact Factor
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    ABSTRACT: Motivation: During the past 4 years, whole-exome sequencing has become a standard tool for finding rare variants causing Mendelian disorders. In that time, there has also been a proliferation of both sequencing platforms and approaches to analyse their output. This requires approaches to assess the performance of different methods. Traditionally, criteria such as comparison with microarray data or a number of known polymorphic sites have been used. Here we expand such approaches, developing a maximum likelihood framework and using it to estimate the sensitivity and specificity of whole-exome sequencing data. Results: Using whole-exome sequencing data for a panel of 19 individuals, we show that estimated sensitivity and specificity are similar to those calculated using microarray data as a reference. We explore the effect of frequency misspecification arising from using an inappropriately selected population and find that, although the estimates are affected, the rankings across procedures remain the same. Availability and implementation: An implementation using Perl and R can be found at busso.ncl.ac.uk (Username: igm101; Password: Z1z1nts). Contact: Darren.Houniet@ogt.com; mauro.santibanez-koref@newcastle.ac.uk
    Bioinformatics 09/2014; 31(1). DOI:10.1093/bioinformatics/btu606 · 4.62 Impact Factor
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    ABSTRACT: Alternative splicing-the production of multiple messenger RNA isoforms from a single gene-is regulated in part by RNA binding proteins. While the RBPs transformer2 alpha (Tra2α) and Tra2β have both been implicated in the regulation of alternative splicing, their relative contributions to this process are not well understood. Here we find simultaneous-but not individual-depletion of Tra2α and Tra2β induces substantial shifts in splicing of endogenous Tra2β target exons, and that both constitutive and alternative target exons are under dual Tra2α-Tra2β control. Target exons are enriched in genes associated with chromosome biology including CHEK1, which encodes a key DNA damage response protein. Dual Tra2 protein depletion reduces expression of full-length CHK1 protein, results in the accumulation of the DNA damage marker γH2AX and decreased cell viability. We conclude Tra2 proteins jointly control constitutive and alternative splicing patterns via paralog compensation to control pathways essential to the maintenance of cell viability.
    Nature Communications 09/2014; 5:4760. DOI:10.1038/ncomms5760 · 10.74 Impact Factor
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    ABSTRACT: Background Around one third of patients undergoing percutaneous coronary intervention (PCI) have left ventricular (LV) dysfunction. Whilst the prevalence of LV dysfunction is known to increase with age, the prevalence of LV dysfunction in different age groups in the PCI setting is not known and the effect of age on the prognostic value of LV function in the PCI setting has not been examined.Methods The relationship between LV function and 30-day mortality in patients undergoing PCI in different age groups (<60 years, 60 to <70 years, 70 to <80 years and ≥80 years) was studied in 246,840 patients in the UK between 2006 and 2011.ResultsPrevalent LV dysfunction in patients undergoing PCI increased with age; 25,106/83,161 (30.2%: <60 years), 24,114/76,895 (31.4%: 60 to <70 years), 23,580/64,711 36.4% (70 to <80 years) and 9,851/22,073 (44.6%) in patients aged 80 or over (P < 0.0001). Poor LV function was independently associated with increased risk of 30-day mortality outcomes in all age groups (OR 5.65:95% CI 4.21-7.58, age <60 years; OR 5.07: 95% CI 3.91-6.57, age 60 to <70 years; OR 4.50: 95% CI 3.64-5.57, 70 to <80 years and OR 4.83:95% CI 3.79-6.15, age ≥80 years).Conclusions Our analysis suggests that worsening LV function is an important independent predictor of worse 30-day mortality outcomes across all age groups and underscores the need for a measure of LV function in all patients for accurate risk stratification prior to PCI. © 2014 Wiley Periodicals, Inc.
    European Heart Journal 08/2014; 35(43). DOI:10.1093/eurheartj/ehu303 · 14.72 Impact Factor
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    ABSTRACT: Objective Rare variants in certain transcription factors involved in cardiac development cause Mendelian forms of congenital heart disease. The purpose of this study was to systematically assess the frequency of rare transcription factor variants in sporadic patients with the cardiac outflow tract malformation tetralogy of Fallot (TOF). Methods and Results We sequenced the coding, 5′UTR, and 3′UTR regions of twelve transcription factor genes implicated in cardiac outflow tract development (NKX2.5, GATA4, ISL1, TBX20, MEF2C, BOP/SMYD1, HAND2, FOXC1, FOXC2, FOXH, FOXA2 and TBX1) in 93 non-syndromic, non-Mendelian TOF cases. We also analysed Illumina Human 660W-Quad SNP Array data for copy number variants in these genes; none were detected. Four of the rare variants detected have previously been shown to affect transactivation in in vitro reporter assays: FOXC1 p.P297S, FOXC2 p.Q444R, FOXH1 p.S113T and TBX1 p.P43_G61del PPPPRYDPCAAAAPGAPGP. Two further rare variants, HAND2 p.A25_A26insAA and FOXC1 p.G378_G380delGGG, A488_491delAAAA, affected transactivation in in vitro reporter assays. Each of these six functionally significant variants was present in a single patient in the heterozygous state; each of the four for which parental samples were available were maternally inherited. Thus in the 93 TOF cases we identified six functionally significant mutations in the secondary heart field transcriptional network. Significance This study indicates that rare genetic variants in the secondary heart field transcriptional network with functional effects on protein function occur in 3–13% of patients with TOF. This is the first report of a functionally significant HAND2 mutation in a patient with congenital heart disease.
    PLoS ONE 08/2014; 9(8):e95453. DOI:10.1371/journal.pone.0095453 · 3.23 Impact Factor
  • Wu Bada · Mj Miossec · R Hussain · J Goodship · B Keavney
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    ABSTRACT: Introduction: Congenital heart disease (CHD) is the most common congenital abnormality, affecting approximately 7 in 1,000 live births. Transposition of the great arteries (TGA) is the most commonly diagnosed cyanotic heart defect in neonates. We propose that TGA has a genetic cause, likely to be de novo or in genes causing heterotaxy syndrome. Purpose: Exomes of 9 subjects diagnosed with TGA with no family history of CHD and their unaffected parents (trios) were subject to sequencing. The project aims were to: implement the exome bioinformatic analysis pipeline to identify de novo mutations (DNMs) and validate variants called by the pipeline. This is the first study investigating de novo changes in TGA patients. Methods: Bioinformatic pipeline was set up to analyse sequencing performed on Illumina GAIIX following exon capture. Programs used included Casava-Gerald after base calling, NovoAlign/BWA for alignment, SAMtools for variant calling. Integrated Genomics Viewer was used to inspect the variants. Polymerase chain reactions were performed prior to sending off for validation by Sanger sequencing. Results: Bioinformatic pipeline identified on average 188 DNMs per trio. 17 variants were chosen for validation. 1 trio had 2 de novo mutations: 1 nonsense in ZNF227 and 1 missense in PHLPP2. 1 trio had a de novo change in RBP5 gene. 1 trio had an inherited splice site change in RTTN, a candidate gene. Conclusions: The presence of de novo and inherited mutations suggests a complex polygenic cause of TGA.
    Cardiovascular Research 07/2014; 103(suppl 1):S59. DOI:10.1093/cvr/cvu091.15 · 5.81 Impact Factor
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    ABSTRACT: Objective The objective of this study is to evaluate the efficacy and safety of renal denervation in patients with resistant hypertension. Methods We searched MEDLINE and EMBASE for studies that evaluated the use of catheter-based renal sympathetic denervation compared to a control group and reported blood pressure results at follow-up. Data was extracted from relevant studies and pooled estimates for blood pressure were determined using the inverse variance method for meta-analysis with mean difference. Results We identified 12 studies (three randomised controlled trials (n=688), eight prospective observational studies (n=478) and one observational study with matched controls (n=310)). Data from SYMPLICITY HTN-3, the only high-quality blinded randomised control trial suggests that there is no significant difference in change in systolic (−2.30 95% CI −6.90 to 2.30 mm Hg) or diastolic (−1.96 95% CI −4.98 to 1.06 mm Hg) blood pressure at 6 months. The pooled data from two unblinded trials of lower quality showed significant reduction in change in systolic (−27.36 95% CI −37.08 to −24.61 mm Hg) and diastolic blood pressure (−9.62 95% CI −14.51 to −4.72 mm Hg). In terms of safety, SYMPLICITY HTN-3 found no significant differences between treatment and control group in terms of death, myocardial infarction, new onset renal disease, stroke and hypertensive emergencies. Conclusions In conclusion, while poor quality unblinded studies provide evidence that renal denervation using catheter-based systems is effective in reducing systolic and diastolic blood pressure in resistant hypertension, the largest randomised controlled trial to date (SYMPLICITY HTN-3) failed to demonstrate any benefit.
    07/2014; 1(1):e000092. DOI:10.1136/openhrt-2014-000092
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    ABSTRACT: Although it is widely believed that IL-27 is anti-inflammatory, its role in controlling human immune responses is not fully established. In particular, its interactions with Th17 cytokines are unclear. Our aims were to establish the relationships between IL-27 and pro-inflammatory cytokines, including IL-17A, in human sera and cultures of peripheral blood mononuclear cells. Plasma IL-27 levels in 879 healthy humans from 163 families varied widely, but with relatively low heritability (19%). Despite IL-27 including a subunit encoded by Epstein-Barr virus-induced gene 3 (EBI3), there was no correlation of levels with serological evidence of infection with the virus. Although IL-27 has been reported to inhibit IL-17A production, we demonstrated a strong positive correlation in sera, but lower correlations of IL-27 with other pro-inflammatory cytokines. We verified that IL-27 inhibited IL-17A production by human peripheral blood T cells in vitro, but not that it stimulated IL-10 secretion. Importantly, addition of IL-17A decreased IL-27 production by stimulated T cells but had the opposite effect on resting T cells. Together, these data suggest a model whereby IL-27 and IL-17A exerts complex reciprocal effects to boost inflammatory responses, but restrain resting cells to prevent inappropriate activation.
    Clinical & Experimental Immunology 06/2014; 178(2). DOI:10.1111/cei.12408 · 3.28 Impact Factor
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    ABSTRACT: Our understanding of genome biology, genomics, and disease, and even hu-man history, has advanced tremen-dously with the completion of the Human Genome Project. Technologi-cal advances coupled with significant cost reductions in genomic research have yielded novel insights into disease etiol-ogy, diagnosis, and therapy for some of the world's most intractable and devastat-ing diseases—including ma-laria, HIV/AIDS, tuberculosis, cancer, and diabetes. Yet, de-spite the burden of infectious diseases and, more recently, noncommunicable diseases (NCDs) in Africa, Africans have only par-ticipated minimally in genomics research. Of the thousands of genome-wide association studies (GWASs) that have been conducted globally, only seven (for HIV susceptibility, malaria, tuberculosis, and podoconiosis) have been conducted exclusively on Afri-can participants; four others (for prostate cancer, obsessive compulsive disorder, and anthropometry) included some African participants (www.genome.gov/gwastudies/). As discussed in 2011 (www.h3africa.org), if the dearth of genomics research involving Africans persists, the potential health and economic benefits emanating from genomic science may elude an entire continent. The lack of large-scale genomics studies in Africa is the result of many deep-seated issues, including a shortage of African scien-tists with genomic research expertise, lack of biomedical research infrastructure, lim-ited computational expertise and resources, lack of adequate support for biomedical research by African governments, and the participation of many African scientists in collaborative research at no more than the level of sample collection. Overcoming these limitations will, in part, depend on African Enabling the genomic revolution in Africa By The H3Africa Consortium * H3Africa is developing capacity for health-related genomics research in Africa Yet, roughly a decade ago, newly pro-posed DNA-based taxonomy (11) promised to solve the species debate. A Barcode of Life Data Systems (BOLD) (12) quickly emerged, seeking to provide a reliable, cost-effective solution to the problem of species identification (12) and a standard screening threshold of sequence differ-ence (10× average intraspecific difference) to speed the discovery of new animal spe-cies (13). Sometimes considered a "carica-ture of real taxonomy" (14), this approach failed to identify, perhaps not surprisingly, two American crow species and a number of members of the herring gull Larus ar-gentatus species assemblage above the set threshold (13). Furthermore, despite past (3) and present (6) sequencing projects, carrion crows and hooded crows can also not be differentiated from one another by means of DNA-barcode approaches. By contrast, Poelstra et al. show that much more DNA sequencing data are needed, combined with RNA expression data, to reconstruct the evolution of a reproductive barrier that culminated in the speciation of these two crow taxa. Armed with this new very detailed genetic informa-tion, it is clear that none of the currently formulated species concepts fully apply to these two crow taxa (unless one is willing relax some stringency in the various definitions). In-deed, the genomes of German carrion crows are much more similar to those of hooded crows than to Spanish car-rion crows. Put simply, apart from the few carrion crow type "speciation islands," German carrion crows could be con-sidered to represent hooded crows with a black (carrion crow) phenotype. There is a clear need for ad-ditional population genomic studies using a more dense sampling, especially among the fully black carrion crows, before the complexity of repro-ductive isolation and speciation among these two taxa can be fully understood. The specia-tion genomics strategy already proved itself in unraveling the complexities of mimicry among many Heliconius butterfly taxa (7) and, as in the study of Poelstra et al., stresses the im-portance of using RNA-based information in addition to DNA. Only time will tell if, and when, German carrion crows will adopt the "hooded phenotype," a fate that seems un-avoidable. Until then, we can only applaud these crows for defeating Linnaeus's curse.
    Science 06/2014; 344(6190):1346-1348. · 31.48 Impact Factor

Publication Stats

4k Citations
1,190.00 Total Impact Points

Institutions

  • 2015
    • The University of Manchester
      Manchester, England, United Kingdom
  • 2014
    • Masaryk University
      • Centre for Biomedical Image Analysis
      Brünn, South Moravian, Czech Republic
  • 2001–2014
    • Newcastle University
      • • Institute of Genetic Medicine
      • • Institute for Ageing and Health
      • • School of Mathematics and Statistics
      Newcastle-on-Tyne, England, United Kingdom
  • 2013
    • Academisch Medisch Centrum Universiteit van Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 2003–2008
    • The Newcastle upon Tyne Hospitals NHS Foundation Trust
      Newcastle-on-Tyne, England, United Kingdom
  • 2006
    • University of Newcastle
      Newcastle, New South Wales, Australia
  • 2002–2006
    • University of Cambridge
      • Department of Public Health and Primary Care
      Cambridge, ENG, United Kingdom
    • University of Aberdeen
      Aberdeen, Scotland, United Kingdom
  • 1996–2001
    • University of Oxford
      • Wellcome Trust Centre for Human Genetics
      Oxford, England, United Kingdom
  • 1995–2000
    • Oxford University Hospitals NHS Trust
      • • Department of Cardiovascular Medicine
      • • Nuffield Department of Medicine
      Oxford, England, United Kingdom