ORCID Profile
0000-0002-5287-9016
Current Organisation
University of Oxford
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Publisher: Springer Science and Business Media LLC
Date: 08-2016
DOI: 10.1038/NG.3627
Publisher: Elsevier BV
Date: 07-2014
Publisher: Oxford University Press (OUP)
Date: 28-04-2023
Abstract: Hypertrophic cardiomyopathy (HCM) is characterized by hypercontractility and diastolic dysfunction, which alter blood flow haemodynamics and are linked with increased risk of adverse clinical events. Four-dimensional flow cardiac magnetic resonance (4D-flow CMR) enables comprehensive characterization of ventricular blood flow patterns. We characterized flow component changes in non-obstructive HCM and assessed their relationship with phenotypic severity and sudden cardiac death (SCD) risk. Fifty-one participants (37 non-obstructive HCM and 14 matched controls) underwent 4D-flow CMR. Left-ventricular (LV) end-diastolic volume was separated into four components: direct flow (blood transiting the ventricle within one cycle), retained inflow (blood entering the ventricle and retained for one cycle), delayed ejection flow (retained ventricular blood ejected during systole), and residual volume (ventricular blood retained for & two cycles). Flow component distribution and component end-diastolic kinetic energy/mL were estimated. HCM patients demonstrated greater direct flow proportions compared with controls (47.9 ± 9% vs. 39.4 ± 6%, P = 0.002), with reduction in other components. Direct flow proportions correlated with LV mass index (r = 0.40, P = 0.004), end-diastolic volume index (r = −0.40, P = 0.017), and SCD risk (r = 0.34, P = 0.039). In contrast to controls, in HCM, stroke volume decreased with increasing direct flow proportions, indicating diminished volumetric reserve. There was no difference in component end-diastolic kinetic energy/mL. Non-obstructive HCM possesses a distinctive flow component distribution pattern characterised by greater direct flow proportions, and direct flow-stroke volume uncoupling indicative of diminished cardiac reserve. The correlation of direct flow proportion with phenotypic severity and SCD risk highlight its potential as a novel and sensitive haemodynamic measure of cardiovascular risk in HCM.
Publisher: Public Library of Science (PLoS)
Date: 10-03-2011
Publisher: BMJ
Date: 10-07-2014
DOI: 10.1136/BMJ.G4164
Publisher: Public Library of Science (PLoS)
Date: 29-06-2016
Publisher: Research Square Platform LLC
Date: 10-03-2022
DOI: 10.21203/RS.3.RS-1409164/V1
Abstract: Hypertension is a leading cause of premature death affecting more than a billion in iduals worldwide. Here we report on the genetic determinants of blood pressure (BP) traits (systolic, diastolic, and pulse pressure) in the largest single-stage genome-wide analysis to date (N = 1,028,980 European-descent in iduals). We identified 2,103 independent genetic signals (P 5x10 − 8 ) for BP traits, including 113 novel loci. These associations explain ~ 40% of common SNP heritability of systolic and diastolic BP. Comparison of top versus bottom deciles of polygenic risk scores (PRS) based on these results reveal clinically meaningful differences in BP (12.9 mm Hg for systolic BP, 95% CI 11.5–14.2 mm Hg, p = 9.08×10 − 73 ) and hypertension risk (OR 5.41 95% CI 4.12 to 7.10 P = 9.71×10 − 33 ) in an independent dataset. Compared with the area under the curve (AUC) for hypertension discrimination for a model with sex, age, BMI, and genetic ancestry, adding systolic and diastolic BP PRS increased discrimination from 0.791 (95% CI = 0.781–0.801) to 0.814 (95% CI = 0.805–0.824, ∆AUC = 0.023, P = 2.27x10 − 22 ). Our transcriptome-wide association study detected 2,793 BP colocalized associations with genetically-predicted expression of 1,070 genes in five cardiovascular tissues, of which 500 are previously unreported for BP traits. These findings represent an advance in our understanding of hypertension and highlight the role of increasingly large genomic studies for development of more accurate PRS, which may inform precision health research.
Publisher: Elsevier BV
Date: 03-2013
Publisher: Springer Science and Business Media LLC
Date: 05-10-2014
DOI: 10.1038/NG.3097
Publisher: Springer Science and Business Media LLC
Date: 12-08-2012
DOI: 10.1038/NG.2385
Publisher: Public Library of Science (PLoS)
Date: 10-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-08-2021
DOI: 10.1161/CIRCULATIONAHA.121.054432
Abstract: Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging is the gold standard for noninvasive myocardial tissue characterization but requires intravenous contrast agent administration. It is highly desired to develop a contrast agent–free technology to replace LGE for faster and cheaper CMR scans. A CMR virtual native enhancement (VNE) imaging technology was developed using artificial intelligence. The deep learning model for generating VNE uses multiple streams of convolutional neural networks to exploit and enhance the existing signals in native T1 maps (pixel-wise maps of tissue T1 relaxation times) and cine imaging of cardiac structure and function, presenting them as LGE-equivalent images. The VNE generator was trained using generative adversarial networks. This technology was first developed on CMR datasets from the multicenter Hypertrophic Cardiomyopathy Registry, using hypertrophic cardiomyopathy as an exemplar. The datasets were randomized into 2 independent groups for deep learning training and testing. The test data of VNE and LGE were scored and contoured by experienced human operators to assess image quality, visuospatial agreement, and myocardial lesion burden quantification. Image quality was compared using a nonparametric Wilcoxon test. Intra- and interobserver agreement was analyzed using intraclass correlation coefficients (ICC). Lesion quantification by VNE and LGE were compared using linear regression and ICC. A total of 1348 hypertrophic cardiomyopathy patients provided 4093 triplets of matched T1 maps, cines, and LGE datasets. After randomization and data quality control, 2695 datasets were used for VNE method development and 345 were used for independent testing. VNE had significantly better image quality than LGE, as assessed by 4 operators (n=345 datasets P .001 [Wilcoxon test]). VNE revealed lesions characteristic of hypertrophic cardiomyopathy in high visuospatial agreement with LGE. In 121 patients (n=326 datasets), VNE correlated with LGE in detecting and quantifying both hyperintensity myocardial lesions ( r =0.77–0.79 ICC=0.77–0.87 P .001) and intermediate-intensity lesions ( r =0.70–0.76 ICC=0.82–0.85 P .001). The native CMR images (cine plus T1 map) required for VNE can be acquired within 15 minutes and producing a VNE image takes less than 1 second. VNE is a new CMR technology that resembles conventional LGE but without the need for contrast administration. VNE achieved high agreement with LGE in the distribution and quantification of lesions, with significantly better image quality.
Publisher: Oxford University Press (OUP)
Date: 15-05-2015
DOI: 10.1093/IJE/DYV074
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2022
DOI: 10.1161/CIRCGEN.121.003598
Abstract: A key goal of precision medicine is to disaggregate common, complex diseases into discrete molecular subtypes. Rare coding variants in the low-density lipoprotein receptor gene ( LDLR ) are identified in 1% to 2% of coronary artery disease (CAD) patients, defining a molecular subtype with risk driven by hypercholesterolemia. To search for additional subtypes, we compared the frequency of rare, predicted loss-of-function and damaging missense variants aggregated within a given gene in 41 081 CAD cases versus 217 115 controls. Rare variants in LDLR were most strongly associated with CAD, present in 1% of cases and associated with 4.4-fold increased CAD risk. A second subtype was characterized by variants in endothelial nitric oxide synthase gene ( NOS3 ), a key enzyme regulating vascular tone, endothelial function, and platelet aggregation. A rare predicted loss-of-function or damaging missense variants in NOS3 was present in 0.6% of cases and associated with 2.42-fold increased risk of CAD (95% CI, 1.80–3.26 P =5.50×10 −9 ). These variants were associated with higher systolic blood pressure (+3.25 mm Hg [95% CI, 1.86–4.65] P =5.00×10 −6 ) and increased risk of hypertension (adjusted odds ratio 1.31 [95% CI, 1.14–1.51] P =2.00×10 −4 ) but not circulating cholesterol concentrations, suggesting that, beyond lipid pathways, nitric oxide synthesis is a key nonlipid driver of CAD risk. Beyond LDLR , we identified an additional nonlipid molecular subtype of CAD characterized by rare variants in the NOS3 gene.
Publisher: Springer Science and Business Media LLC
Date: 23-12-2012
DOI: 10.1038/NG.2500
Publisher: Springer Science and Business Media LLC
Date: 08-2016
DOI: 10.1038/NATURE19057
Publisher: Springer Science and Business Media LLC
Date: 1995
DOI: 10.1038/NG0195-75
Abstract: Nemaline myopathies are diseases characterized by the presence in muscle fibres of pathognomonic rod bodies. These are composed largely of alpha-actinin and actin. We have identified a missense mutation in the alpha-tropomyosin gene, TPM3, which segregates completely with the disease in a family whose autosomal dominant nemaline myopathy we had previously localized to chromosome 1p13-q25. The mutation substitutes an arginine residue for a highly conserved methionine in a putative actin-binding site near the N terminus of the alpha-tropomyosin. The mutation may strengthen tropomyosin - actin binding, leading to rod body formation, by adding a further basic residue to the postulated actin-binding motif.
Publisher: Public Library of Science (PLoS)
Date: 05-06-2009
Publisher: Springer Science and Business Media LLC
Date: 25-01-2021
Publisher: Elsevier BV
Date: 02-2014
Publisher: Elsevier BV
Date: 11-2012
Publisher: Springer Science and Business Media LLC
Date: 07-04-2013
DOI: 10.1038/NG.2606
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2014
DOI: 10.1161/STROKEAHA.113.002707
Abstract: Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases. Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance ( P .01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 in iduals with the ischemic large artery stroke (LAS) subtype. Common variants associated with CAD at P .01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance ( P ×10 −8 ) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 ( P IS =1.62×10 −7 ) and ABO ( P IS =2.6×10 −4 ), as well as at HDAC9 ( P LAS =2.32×10 −12 ), 9p21 ( P LAS =3.70×10 −6 ), RAI1-PEMT-RASD1 ( P LAS =2.69×10 −5 ), EDNRA ( P LAS =7.29×10 −4 ), and CYP17A1-CNNM2-NT5C2 ( P LAS =4.9×10 −4 ). Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.
Publisher: Elsevier BV
Date: 03-2014
Publisher: American Medical Association (AMA)
Date: 07-2009
Publisher: American Association for the Advancement of Science (AAAS)
Date: 2014
DOI: 10.1126/SCITRANSLMED.AAT1199
Abstract: Mutations in MYBPC3 disrupt myosin states of relaxation, and manipulating myosin therapeutically abates the effects of MYBPC3 mutations.
Publisher: Springer Science and Business Media LLC
Date: 10-05-2009
DOI: 10.1038/NG.361
Publisher: Elsevier BV
Date: 03-2012
Publisher: Oxford University Press (OUP)
Date: 28-11-2022
Abstract: Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by dynamic obstruction of the left ventricular (LV) outflow tract (LVOT). Although this may be mediated by interplay between the hypertrophied septal wall, systolic anterior motion of the mitral valve, and papillary muscle abnormalities, the mechanistic role of LV shape is still not fully understood. This study sought to identify the LV end-diastolic morphology underpinning oHCM. Cardiovascular magnetic resonance images from 2398 HCM in iduals were obtained as part of the NHLBI HCM Registry. Three-dimensional LV models were constructed and used, together with a principal component analysis, to build a statistical shape model capturing shape variations. A set of linear discriminant axes were built to define and quantify (Z-scores) the characteristic LV morphology associated with LVOT obstruction (LVOTO) under different physiological conditions and the relationship between LV phenotype and genotype. The LV remodelling pattern in oHCM consisted not only of basal septal hypertrophy but a combination with LV lengthening, apical dilatation, and LVOT inward remodelling. Salient differences were observed between obstructive cases at rest and stress. Genotype negative cases showed a tendency towards more obstructive phenotypes both at rest and stress. LV anatomy underpinning oHCM consists of basal septal hypertrophy, apical dilatation, LV lengthening, and LVOT inward remodelling. Differences between oHCM cases at rest and stress, as well as the relationship between LV phenotype and genotype, suggest different mechanisms for LVOTO. Proposed Z-scores render an opportunity of redefining management strategies based on the relationship between LV anatomy and LVOTO.
Publisher: Public Library of Science (PLoS)
Date: 26-06-2009
Publisher: Public Library of Science (PLoS)
Date: 31-07-2014
Publisher: Cold Spring Harbor Laboratory
Date: 24-02-2016
DOI: 10.1101/041111
Abstract: The accurate interpretation of variation in Mendelian disease genes has lagged behind data generation as sequencing has become increasingly accessible. Ongoing large sequencing efforts present huge interpretive challenges, but also provide an invaluable opportunity to characterize the spectrum and importance of rare variation. Here we analyze sequence data from 7,855 clinical cardiomyopathy cases and 60,706 ExAC reference s les to better understand genetic variation in a representative autosomal dominant disorder. We show that in some genes previously reported as important causes of a given cardiomyopathy, rare variation is not clinically informative and there is a high likelihood of false positive interpretation. By contrast, in other genes, we find that diagnostic laboratories may be overly conservative when assessing variant pathogenicity. We outline improved interpretation approaches for specific genes and variant classes and propose that these will increase the clinical utility of testing across a range of Mendelian diseases.
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1038/GIM.2016.90
Publisher: Springer Science and Business Media LLC
Date: 12-09-2016
DOI: 10.1038/NG.3667
Publisher: Springer Science and Business Media LLC
Date: 18-05-2201
DOI: 10.1038/NG.3304
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Hugh Watkins.