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Dive into the research topics where Declan P. O’Regan is active.

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Featured researches published by Declan P. O’Regan.


Science Translational Medicine | 2015

Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease

Angharad M. Roberts; James S. Ware; Daniel S. Herman; Sebastian Schafer; John Baksi; Alexander G. Bick; Rachel Buchan; Roddy Walsh; Shibu John; Samuel Wilkinson; Francesco Mazzarotto; Leanne E. Felkin; Sungsam Gong; Jacqueline A. L. MacArthur; Fiona Cunningham; Jason Flannick; Stacey B. Gabriel; David Altshuler; P. Macdonald; Matthias Heinig; Anne Keogh; Christopher S. Hayward; Nicholas R. Banner; Dudley J. Pennell; Declan P. O’Regan; Tan Ru San; Antonio de Marvao; Timothy Dawes; Ankur Gulati; Emma J. Birks

Truncating variants of the giant protein titin cause dilated cardiomyopathy when they occur toward the protein’s carboxyl terminus and in highly expressed exons. What Happens When Titins Are Trimmed? The most common form of inherited heart failure, dilated cardiomyopathy, can be caused by mutations in a mammoth heart protein, appropriately called titin. Now, Roberts et al. sort out which titin mutations cause disease and why some people can carry certain titin mutations but remain perfectly healthy. In an exhaustive survey of more than 5200 people, with and without cardiomyopathy, the authors sequenced the titin gene and measured its corresponding RNA and protein levels. The alterations in titin were truncating mutations, which cause short nonfunctional versions of the RNA or protein. These defects produced cardiomyopathy when they occurred closer to the protein’s carboxyl terminus and in exons that were abundantly transcribed. The titin-truncating mutations that occur in the general population tended not to have these characteristics and were usually benign. This new detailed understanding of the molecular basis of dilated cardiomyopathy penetrance will promote better disease management and accelerate rational patient stratification. The recent discovery of heterozygous human mutations that truncate full-length titin (TTN, an abundant structural, sensory, and signaling filament in muscle) as a common cause of end-stage dilated cardiomyopathy (DCM) promises new prospects for improving heart failure management. However, realization of this opportunity has been hindered by the burden of TTN-truncating variants (TTNtv) in the general population and uncertainty about their consequences in health or disease. To elucidate the effects of TTNtv, we coupled TTN gene sequencing with cardiac phenotyping in 5267 individuals across the spectrum of cardiac physiology and integrated these data with RNA and protein analyses of human heart tissues. We report diversity of TTN isoform expression in the heart, define the relative inclusion of TTN exons in different isoforms (using the TTN transcript annotations available at http://cardiodb.org/titin), and demonstrate that these data, coupled with the position of the TTNtv, provide a robust strategy to discriminate pathogenic from benign TTNtv. We show that TTNtv is the most common genetic cause of DCM in ambulant patients in the community, identify clinically important manifestations of TTNtv-positive DCM, and define the penetrance and outcomes of TTNtv in the general population. By integrating genetic, transcriptome, and protein analyses, we provide evidence for a length-dependent mechanism of disease. These data inform diagnostic criteria and management strategies for TTNtv-positive DCM patients and for TTNtv that are identified as incidental findings.


Hypertension | 2013

Body Fat Is Associated With Reduced Aortic Stiffness Until Middle Age

Ben Corden; Niall G. Keenan; Antonio de Marvao; Timothy Dawes; Alain DeCesare; Tamara Diamond; Giuliana Durighel; Alun D. Hughes; Stuart A. Cook; Declan P. O’Regan

Obesity is a major risk factor for cardiometabolic disease, but the effect of body composition on vascular aging and arterial stiffness remains uncertain. We investigated relationships among body composition, blood pressure, age, and aortic pulse wave velocity in healthy individuals. Pulse wave velocity in the thoracic aorta, an indicator of central arterial stiffness, was measured in 221 volunteers (range, 18–72 years; mean, 40.3±13 years) who had no history of cardiovascular disease using cardiovascular MRI. In univariate analyses, age (r=0.78; P<0.001) and blood pressure (r=0.41; P<0.001) showed a strong positive association with pulse wave velocity. In multivariate analysis, after adjustment for age, sex, and mean arterial blood pressure, elevated body fat% was associated with reduced aortic stiffness until the age of 50 years, thereafter adiposity had an increasingly positive association with aortic stiffness (&bgr;=0.16; P<0.001). Body fat% was positively associated with cardiac output when age, sex, height, and absolute lean mass were adjusted for (&bgr;=0.23; P=0.002). These findings suggest that the cardiovascular system of young adults may be capable of adapting to the state of obesity and that an adverse association between body fat and aortic stiffness is only apparent in later life.


medical image computing and computer assisted intervention | 2013

Cardiac Image Super-Resolution with Global Correspondence Using Multi-Atlas PatchMatch

Wenzhe Shi; Jose Caballero; Christian Ledig; Xiahai Zhuang; Wenjia Bai; Kanwal K. Bhatia; Antonio de Marvao; Tim Dawes; Declan P. O’Regan; Daniel Rueckert

The accurate measurement of 3D cardiac function is an important task in the analysis of cardiac magnetic resonance (MR) images. However, short-axis image acquisitions with thick slices are commonly used in clinical practice due to constraints of acquisition time, signal-to-noise ratio and patient compliance. In this situation, the estimation of a high-resolution image can provide an approximation of the underlaying 3D measurements. In this paper, we develop a novel algorithm for the estimation of high-resolution cardiac MR images from single short-axis cardiac MR image stacks. First, we propose to use a novel approximate global search approach to find patch correspondence between the short-axis MR image and a set of atlases. Then, we propose an innovative super-resolution model which does not require explicit motion estimation. Finally, we build an expectation-maximization framework to optimize the model. We validate the proposed approach using images from 19 subjects with 200 atlases and show that the proposed algorithm significantly outperforms conventional interpolation such as linear or B-spline interpolation. In addition, we show that the super-resolved images can be used for the reproducible estimation of 3D cardiac functional indices.


medical image computing and computer assisted intervention | 2016

Multi-input Cardiac Image Super-Resolution Using Convolutional Neural Networks

Ozan Oktay; Wenjia Bai; Matthew C. H. Lee; Ricardo Guerrero; Konstantinos Kamnitsas; Jose Caballero; Antonio de Marvao; Stuart A. Cook; Declan P. O’Regan; Daniel Rueckert

3D cardiac MR imaging enables accurate analysis of cardiac morphology and physiology. However, due to the requirements for long acquisition and breath-hold, the clinical routine is still dominated by multi-slice 2D imaging, which hamper the visualization of anatomy and quantitative measurements as relatively thick slices are acquired. As a solution, we propose a novel image super-resolution (SR) approach that is based on a residual convolutional neural network (CNN) model. It reconstructs high resolution 3D volumes from 2D image stacks for more accurate image analysis. The proposed model allows the use of multiple input data acquired from different viewing planes for improved performance. Experimental results on 1233 cardiac short and long-axis MR image stacks show that the CNN model outperforms state-of-the-art SR methods in terms of image quality while being computationally efficient. Also, we show that image segmentation and motion tracking benefits more from SR-CNN when it is used as an initial upscaling method than conventional interpolation methods for the subsequent analysis.


Medical Image Analysis | 2015

A bi-ventricular cardiac atlas built from 1000+ high resolution MR images of healthy subjects and an analysis of shape and motion

Wenjia Bai; Wenzhe Shi; Antonio de Marvao; Timothy Dawes; Declan P. O’Regan; Stuart A. Cook; Daniel Rueckert

Atlases encode valuable anatomical and functional information from a population. In this work, a bi-ventricular cardiac atlas was built from a unique data set, which consists of high resolution cardiac MR images of 1000+ normal subjects. Based on the atlas, statistical methods were used to study the variation of cardiac shapes and the distribution of cardiac motion across the spatio-temporal domain. We have shown how statistical parametric mapping (SPM) can be combined with a general linear model to study the impact of gender and age on regional myocardial wall thickness. Finally, we have also investigated the influence of the population size on atlas construction and atlas-based analysis. The high resolution atlas, the statistical models and the SPM method will benefit more studies on cardiac anatomy and function analysis in the future.


Magnetic Resonance Materials in Physics Biology and Medicine | 2013

Impact of number of channels on RF shimming at 3T

Alexander S. Childs; Shaihan J. Malik; Declan P. O’Regan; Joseph V. Hajnal

ObjectAt high-field strengths (≥3T) inhomogeneity of the radio frequency (RF) field and RF power deposition become increasingly problematic. Parallel Transmission (PTx)—the use of segmented transmission arrays with independently driven elements—affords the ability to combat both of these issues. There are a variety of existing designs for PTx coils, ranging from systems with two channels to systems with eight or more. In this work, we have investigated the impact of the number of independent channels on the achievable results for both homogeneity improvement and power reduction in vivo.Materials and methodsA 3T Philips Achieva MRI system fitted with an 8-channel PTx body coil was driven so as to emulate configurations with 1, 2 4 and 8 independent channels. RF shimming was used in two different anatomies in order to assess improvements in RF homogeneity.ResultsSignificant homogeneity improvements were observed when increasing from 1 to 2, 2 to 4, and 4 to 8 channel configurations. Reductions in RF power requirements and local SAR were predicted for increasing numbers of channels.ConclusionIncreasing the number of RF transmit channels adds extra degrees of freedom which can be used to benefit homogeneity improvement or power reduction for body imaging at 3T.


Science Translational Medicine | 2017

Inhibition of pyruvate dehydrogenase kinase improves pulmonary arterial hypertension in genetically susceptible patients

Evangelos D. Michelakis; Vikram Gurtu; Linda Webster; Gareth Barnes; Geoffrey Watson; Luke Howard; John Cupitt; Ian Paterson; Richard B. Thompson; Kelvin Chow; Declan P. O’Regan; Lan Zhao; John Wharton; David G. Kiely; Adam Kinnaird; Aristeidis Boukouris; C.W. White; Darren H. Freed; Stephen J. Wort; J. Simon R. Gibbs; Martin R. Wilkins

Metabolic modulation with dichloroacetate improves hemodynamics in genetically susceptible patients with idiopathic pulmonary arterial hypertension. Progress for PAH In addition to thickening and occlusion of the pulmonary arteries, mitochondrial respiration is suppressed in pulmonary arterial hypertension (PAH). Michelakis et al. treated lungs from patients with PAH with dichloroacetate (DCA), a drug used to treat cancer and congenital mitochondrial disease that inhibits the mitochondrial enzyme pyruvate dehydrogenase kinase. DCA increased mitochondrial function; however, the response was variable, and this variable response was mirrored in a phase 1 trial, with some patients showing improved hemodynamics and functional capacity. The authors determined that patients with inactivating mutations in two genes encoding mitochondrial proteins were less responsive to DCA. This work highlights the importance of considering patient genotype in clinical trial design and identifies a drug target for PAH. Pulmonary arterial hypertension (PAH) is a progressive vascular disease with a high mortality rate. It is characterized by an occlusive vascular remodeling due to a pro-proliferative and antiapoptotic environment in the wall of resistance pulmonary arteries (PAs). Proliferating cells exhibit a cancer-like metabolic switch where mitochondrial glucose oxidation is suppressed, whereas glycolysis is up-regulated as the major source of adenosine triphosphate production. This multifactorial mitochondrial suppression leads to inhibition of apoptosis and downstream signaling promoting proliferation. We report an increase in pyruvate dehydrogenase kinase (PDK), an inhibitor of the mitochondrial enzyme pyruvate dehydrogenase (PDH, the gatekeeping enzyme of glucose oxidation) in the PAs of human PAH compared to healthy lungs. Treatment of explanted human PAH lungs with the PDK inhibitor dichloroacetate (DCA) ex vivo activated PDH and increased mitochondrial respiration. In a 4-month, open-label study, DCA (3 to 6.25 mg/kg b.i.d.) administered to patients with idiopathic PAH (iPAH) already on approved iPAH therapies led to reduction in mean PA pressure and pulmonary vascular resistance and improvement in functional capacity, but with a range of individual responses. Lack of ex vivo and clinical response was associated with the presence of functional variants of SIRT3 and UCP2 that predict reduced protein function. Impaired function of these proteins causes PDK-independent mitochondrial suppression and pulmonary hypertension in mice. This first-in-human trial of a mitochondria-targeting drug in iPAH demonstrates that PDK is a druggable target and offers hemodynamic improvement in genetically susceptible patients, paving the way for novel precision medicine approaches in this disease.


Journal of Cardiovascular Magnetic Resonance | 2014

Population-based studies of myocardial hypertrophy: high resolution cardiovascular magnetic resonance atlases improve statistical power

Antonio de Marvao; Timothy Dawes; Wenzhe Shi; Christopher Minas; Niall G. Keenan; Tamara Diamond; Giuliana Durighel; Giovanni Montana; Daniel Rueckert; Stuart A. Cook; Declan P. O’Regan

BackgroundCardiac phenotypes, such as left ventricular (LV) mass, demonstrate high heritability although most genes associated with these complex traits remain unidentified. Genome-wide association studies (GWAS) have relied on conventional 2D cardiovascular magnetic resonance (CMR) as the gold-standard for phenotyping. However this technique is insensitive to the regional variations in wall thickness which are often associated with left ventricular hypertrophy and require large cohorts to reach significance. Here we test whether automated cardiac phenotyping using high spatial resolution CMR atlases can achieve improved precision for mapping wall thickness in healthy populations and whether smaller sample sizes are required compared to conventional methods.MethodsLV short-axis cine images were acquired in 138 healthy volunteers using standard 2D imaging and 3D high spatial resolution CMR. A multi-atlas technique was used to segment and co-register each image. The agreement between methods for end-diastolic volume and mass was made using Bland-Altman analysis in 20 subjects. The 3D and 2D segmentations of the LV were compared to manual labeling by the proportion of concordant voxels (Dice coefficient) and the distances separating corresponding points. Parametric and nonparametric data were analysed with paired t-tests and Wilcoxon signed-rank test respectively. Voxelwise power calculations used the interstudy variances of wall thickness.ResultsThe 3D volumetric measurements showed no bias compared to 2D imaging. The segmented 3D images were more accurate than 2D images for defining the epicardium (Dice: 0.95 vs 0.93, P < 0.001; mean error 1.3 mm vs 2.2 mm, P < 0.001) and endocardium (Dice 0.95 vs 0.93, P < 0.001; mean error 1.1 mm vs 2.0 mm, P < 0.001). The 3D technique resulted in significant differences in wall thickness assessment at the base, septum and apex of the LV compared to 2D (P < 0.001). Fewer subjects were required for 3D imaging to detect a 1 mm difference in wall thickness (72 vs 56, P < 0.001).ConclusionsHigh spatial resolution CMR with automated phenotyping provides greater power for mapping wall thickness than conventional 2D imaging and enables a reduction in the sample size required for studies of environmental and genetic determinants of LV wall thickness.


Jacc-cardiovascular Imaging | 2015

Precursors of Hypertensive Heart Phenotype Develop in Healthy Adults: A High-Resolution 3D MRI Study

Antonio de Marvao; Timothy Dawes; W Shi; Giuliana Durighel; Daniel Rueckert; Stuart A. Cook; Declan P. O’Regan

Objectives This study used high-resolution 3-dimensional cardiac magnetic resonance to define the anatomical and functional left ventricular (LV) properties associated with increasing systolic blood pressure (SBP) in a drug-naive cohort.Objectives This study used high-resolution 3-dimensional cardiac magnetic resonance to define the anatomical and functional left ventricular (LV) properties associated with increasing systolic blood pressure (SBP) in a drug-naïve cohort. Background LV hypertrophy and remodeling occur in response to hemodynamic stress but little is known about how these phenotypic changes are initiated in the general population. Methods In this study, 1,258 volunteers (54% women, mean age 40.6 ± 12.8 years) without self-reported cardiovascular disease underwent 3-dimensional cardiac magnetic resonance combined with computational modeling. The relationship between SBP and wall thickness (WT), relative WT, end-systolic wall stress (WS), and fractional wall thickening were analyzed using 3-dimensional regression models adjusted for body surface area, sex, race, age, and multiple testing. Significantly associated points in the LV model (p < 0.05) were identified and the relationship with SBP reported as mean β coefficients. Results There was a continuous relationship between SBP and asymmetric concentric hypertrophic adaptation of the septum and anterior wall that was associated with normalization of wall stress. In the lateral wall an increase in wall stress with rising SBP was not balanced by a commensurate hypertrophic relationship. In normotensives, SBP was positively associated with WT (β = 0.09) and relative WT (β = 0.07) in the septal and anterior walls, and this regional hypertrophic relationship was progressively stronger among pre-hypertensives (β = 0.10) and hypertensives (β = 0.30). Conclusions These findings show that the precursors of the hypertensive heart phenotype can be traced to healthy normotensive adults and that an independent and continuous relationship exists between adverse LV remodeling and SBP in a low-risk population. These adaptations show distinct regional variations with concentric hypertrophy of the septum and eccentric hypertrophy of the lateral wall, which challenge conventional classifications of LV remodeling.


Radiology | 2017

Machine Learning of Three-dimensional Right Ventricular Motion Enables Outcome Prediction in Pulmonary Hypertension: A Cardiac MR Imaging Study

Timothy Dawes; Antonio de Marvao; Wenzhe Shi; Tristan Fletcher; Geoffrey Watson; John Wharton; Christopher J. Rhodes; Luke Howard; J. Simon R. Gibbs; Daniel Rueckert; Stuart A. Cook; Martin R. Wilkins; Declan P. O’Regan

Applying machine learning of complex motion phenotypes obtained from cardiac MR images allows more accurate prediction of patient outcomes in pulmonary hypertension.

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Stuart A. Cook

National University of Singapore

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Wenzhe Shi

Imperial College London

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Wenjia Bai

Imperial College London

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Luke Howard

Imperial College Healthcare

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