Imperial College London

ProfessorDeclanO'Regan

Faculty of MedicineInstitute of Clinical Sciences

Professor of Imaging Sciences
 
 
 
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Contact

 

+44 (0)20 3313 1510declan.oregan

 
 
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Location

 

Imaging Sciences DepartmentHammersmith HospitalHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

139 results found

Mazzarotto F, Hawley MH, Beltrami M, Beekman L, De Marvao A, McGurk K, Statton B, Boschi B, Girolami F, Roberts AM, Lodder EM, Allouba M, Romeih S, Aguib Y, Baksi J, Pantazis A, Prasad SK, Cerbai E, Yacoub M, O'Regan D, Cook S, Ware J, Funke B, Olivotto I, Bezzina C, Barton P, Walsh Ret al., 2020, Systematic large-scale assessment of the genetic architecture of left ventricular non-compaction reveals diverse aetiologies, Genetics in Medicine, ISSN: 1098-3600

Journal article

Aguib Y, Allouba M, Afify A, Halawa S, El-Khatib M, Sous M, Galal A, Abdelrahman E, Shehata N, El Sawy A, Elmaghawry M, Anwer S, Kamel O, El Mozy W, Khedr H, Kharabish A, Thabet N, Theotokis P, Buchan R, Govind R, Whiffin N, Walsh R, Aguib H, ElGuindy A, O'Regan D, Cook S, Barton P, Ware J, Yacoub Met al., 2020, The Egyptian collaborative cardiac genomics (ECCO-GEN) Project: defining a healthy volunteer cohort, npj Genomic Medicine, Vol: 5, Pages: 1-8, ISSN: 2056-7944

The integration of comprehensive genomic and phenotypic data from diverse ethnic populations offers unprecedented opportunities towards advancements in precision medicine and novel diagnostic technologies. Current reference genomic databases are not representative of the global human population, making variant interpretation challenging, especially in underrepresented populations such as the North African population. To address this, the Egyptian Collaborative Cardiac Genomics (ECCO-GEN) Project launched a study comprising 1,000 individuals free of cardiovascular disease (CVD). Here, we present the first 391 Egyptian healthy volunteers (EHVols) recruited to establish a pilot phenotyped control cohort. All individuals underwent detailed clinical investigation, including cardiac MRI, and were sequenced using a targeted panel of 174 genes with reported roles in inherited cardiac conditions (ICC). We identified 1,262 variants in 27 cardiomyopathy genes of which 15.1% were not captured in current global and regional genetic reference databases (here: gnomAD and Great Middle Eastern (GME) Variome). The ECCO-GEN project aims at defining the genetic landscape of an understudied population and providing individual-level genetic and phenotypic data to support future studies in CVD and population genetics.

Journal article

Zhang X, Walsh R, Whiffin N, Buchan R, Midwinter W, Wilk A, Govind R, Li N, Ahmad M, Mazzarotto F, Roberts A, Theotokis P, Mazaika E, Allouba M, de Marvao A, Pua CJ, Day SM, Ashley E, Colan SD, Michels M, Pereira AC, Jacoby D, Ho CY, Olivotto I, Gunnarsson GT, Jefferies J, Semsarian C, Ingles J, ORegan DP, Aguib Y, Yacoub MH, Cook SA, Barton PJR, Bottolo L, Ware JSet al., 2020, Disease-specific variant pathogenicity prediction significantly improves variant interpretation in inherited cardiac conditions, Genetics in Medicine, ISSN: 1098-3600

Background: Accurate discrimination of benign and pathogenic rare variation remains a priority for clinical genome interpretation. State-of-the-art machine learning tools are useful for genome-wide variant prioritisation but remain imprecise. Since the relationship between molecular consequence and likelihood of pathogenicity varies between genes with distinct molecular mechanisms, we hypothesised that a disease-specific classifier may outperform existing genome-wide tools. Methods: We present a novel disease-specific variant classification tool, CardioBoost, that estimates the probability of pathogenicity for rare missense variants in inherited cardiomyopathies and arrhythmias, trained with variants of known clinical effect. To benchmark against state-of-the-art genome-wide pathogenicity classification tools, we assessed classification of hold-out test variants using both overall performance metrics, and metrics of high-confidence (>90%) classifications relevant to variant interpretation. We further evaluated the prioritisation of variants associated with disease and patient clinical outcomes, providing validations that are robust to potential mis-classification in gold-standard reference datasets.Results: CardioBoost has higher discriminating power than published genome-wide variant classification tools in distinguishing between pathogenic and benign variants based on overall classification performance measures with the highest area under the Precision-Recall Curve as 91% for cardiomyopathies and as 96% for inherited arrhythmias. When assessed at high-confidence (>90%) classification thresholds, prediction accuracy is improved by at least 120% over existing tools for both cardiomyopathies and arrhythmias, with significantly improved sensitivity and specificity. Finally, CardioBoost improves prioritisation of variants significantly associated with disease, and stratifies survival of patients with cardiomyopathies, confirming biologically relevant vari

Journal article

Meyer H, Dawes T, Serrani M, Bai W, Tokarczuk P, Cai J, Simoes Monteiro de Marvao A, Henry A, Lumbers T, Gierten J, Thumberger T, Wittbrodt J, Ware J, Rueckert D, Matthews P, Prasad S, Costantino M, Cook S, Birney E, O'Regan Det al., 2020, Genetic and functional insights into the fractal structure of the heart, Nature, Vol: 584, Pages: 589-594, ISSN: 0028-0836

The inner surfaces of the human heart are covered by a complex network of muscular strands that is thought to be a vestigeof embryonic development.1,2 The function of these trabeculae in adults and their genetic architecture are unknown. Toinvestigate this we performed a genome-wide association study using fractal analysis of trabecular morphology as animage-derived phenotype in 18,096 UK Biobank participants. We identified 16 significant loci containing genes associatedwith haemodynamic phenotypes and regulation of cytoskeletal arborisation.3,4 Using biomechanical simulations and humanobservational data, we demonstrate that trabecular morphology is an important determinant of cardiac performance. Throughgenetic association studies with cardiac disease phenotypes and Mendelian randomisation, we find a causal relationshipbetween trabecular morphology and cardiovascular disease risk. These findings suggest an unexpected role for myocardialtrabeculae in the function of the adult heart, identify conserved pathways that regulate structural complexity, and reveal theirinfluence on susceptibility to disease

Journal article

Bai W, Suzuki H, Huang J, Francis C, Wang S, Tarroni G, Guitton F, Aung N, Fung K, Petersen SE, Piechnik SK, Neubauer S, Evangelou E, Dehghan A, O'Regan DP, Wilkins MR, Guo Y, Matthews PM, Rueckert Det al., 2020, A population-based phenome-wide association study of cardiac and aortic structure and function, Nature Medicine, Vol: 26, Pages: 1654-1662, ISSN: 1078-8956

Differences in cardiac and aortic structure and function are associated with cardiovascular diseases and a wide range of other types of disease. Here we analyzed cardiovascular magnetic resonance images from a population-based study, the UK Biobank, using an automated machine-learning-based analysis pipeline. We report a comprehensive range of structural and functional phenotypes for the heart and aorta across 26,893 participants, and explore how these phenotypes vary according to sex, age and major cardiovascular risk factors. We extended this analysis with a phenome-wide association study, in which we tested for correlations of a wide range of non-imaging phenotypes of the participants with imaging phenotypes. We further explored the associations of imaging phenotypes with early-life factors, mental health and cognitive function using both observational analysis and Mendelian randomization. Our study illustrates how population-based cardiac and aortic imaging phenotypes can be used to better define cardiovascular disease risks as well as heart–brain health interactions, highlighting new opportunities for studying disease mechanisms and developing image-based biomarkers.

Journal article

Osimo EF, Brugger SP, de Marvao A, Pillinger T, Whitehurst T, Statton B, Quinlan M, Berry A, Cook SA, O'Regan DP, Howes ODet al., 2020, Cardiac structure and function in schizophrenia: cardiac magnetic resonance imaging study, British Journal of Psychiatry, Vol: 217, Pages: 450-457, ISSN: 0007-1250

BACKGROUND: Heart disease is the leading cause of death in schizophrenia. However, there has been little research directly examining cardiac function in schizophrenia. AIMS: To investigate cardiac structure and function in individuals with schizophrenia using cardiac magnetic resonance imaging (CMR) after excluding medical and metabolic comorbidity. METHOD: In total, 80 participants underwent CMR to determine biventricular volumes and function and measures of blood pressure, physical activity and glycated haemoglobin levels. Individuals with schizophrenia ('patients') and controls were matched for age, gender, ethnicity and body surface area. RESULTS: Patients had significantly smaller indexed left ventricular (LV) end-diastolic volume (effect size d = -0.82, P = 0.001), LV end-systolic volume (d = -0.58, P = 0.02), LV stroke volume (d = -0.85, P = 0.001), right ventricular (RV) end-diastolic volume (d = -0.79, P = 0.002), RV end-systolic volume (d = -0.58, P = 0.02), and RV stroke volume (d = -0.87, P = 0.001) but unaltered ejection fractions relative to controls. LV concentricity (d = 0.73, P = 0.003) and septal thickness (d = 1.13, P < 0.001) were significantly larger in the patients. Mean concentricity in patients was above the reference range. The findings were largely unchanged after adjusting for smoking and/or exercise levels and were independent of medication dose and duration. CONCLUSIONS: Individuals with schizophrenia show evidence of concentric cardiac remodelling compared with healthy controls of a similar age, gender, ethnicity, body surface area and blood pressure, and independent of smoking and activity levels. This could be contributing to the excess cardiovascular mortality observed in schizophrenia. Future studies should investigate the contribution of antipsychotic medication to these changes.

Journal article

Biffi C, Cerrolaza Martinez JJ, Tarroni G, Bai W, Simoes Monteiro de Marvao A, Oktay O, Ledig C, Le Folgoc L, Kamnitsas K, Doumou G, Duan J, Prasad S, Cook S, O'Regan D, Rueckert Det al., 2020, Explainable anatomical shape analysis through deep hierarchical generative models, IEEE Transactions on Medical Imaging, Vol: 39, Pages: 2088-2099, ISSN: 0278-0062

Quantification of anatomical shape changes currently relies on scalar global indexes which are largely insensitive to regional or asymmetric modifications. Accurate assessment of pathology-driven anatomical remodeling is a crucial step for the diagnosis and treatment of many conditions. Deep learning approaches have recently achieved wide success in the analysis of medical images, but they lack interpretability in the feature extraction and decision processes. In this work, we propose a new interpretable deep learning model for shape analysis. In particular, we exploit deep generative networks to model a population of anatomical segmentations through a hierarchy of conditional latent variables. At the highest level of this hierarchy, a two-dimensional latent space is simultaneously optimised to discriminate distinct clinical conditions, enabling the direct visualisation of the classification space. Moreover, the anatomical variability encoded by this discriminative latent space can be visualised in the segmentation space thanks to the generative properties of the model, making the classification task transparent. This approach yielded high accuracy in the categorisation of healthy and remodelled left ventricles when tested on unseen segmentations from our own multi-centre dataset as well as in an external validation set, and on hippocampi from healthy controls and patients with Alzheimer’s disease when tested on ADNI data. More importantly, it enabled the visualisation in three-dimensions of both global and regional anatomical features which better discriminate between the conditions under exam. The proposed approach scales effectively to large populations, facilitating highthroughput analysis of normal anatomy and pathology in largescale studies of volumetric imaging.

Journal article

Bhuva AN, Treibel TA, De Marvao A, Biffi C, Dawes TJW, Doumou G, Bai W, Patel K, Boubertakh R, Rueckert D, O'Regan DP, Hughes AD, Moon JC, Manisty CHet al., 2020, Sex and regional differences inmyocardial plasticity in aortic stenosis are revealed by 3D modelmachine learning, EUROPEAN HEART JOURNAL-CARDIOVASCULAR IMAGING, Vol: 21, Pages: 417-427, ISSN: 2047-2404

Journal article

Grapsa J, Tan TC, Nunes MCP, O'Regan DP, Durighel G, Howard LSGE, Gibbs JSR, Nihoyannopoulos Pet al., 2020, Prognostic impact of right ventricular mass change in patients with idiopathic pulmonary arterial hypertension, INTERNATIONAL JOURNAL OF CARDIOLOGY, Vol: 304, Pages: 172-174, ISSN: 0167-5273

Journal article

Jarral OA, Tan MKH, Salmasi MY, Pirola S, Pepper JR, O'Regan DP, Xu XY, Athanasiou Tet al., 2020, Phase-contrast magnetic resonance imaging and computational fluid dynamics assessment of thoracic aorta blood flow: a literature review, European Journal of Cardio-Thoracic Surgery, Vol: 57, Pages: 438-446, ISSN: 1010-7940

The death rate from thoracic aortic disease is on the rise and represents a growing global health concern as patients are often asymptomatic before acute events, which have devastating effects on health-related quality of life. Biomechanical factors have been found to play a major role in the development of both acquired and congenital aortic diseases. However, much is still unknown and translational benefits of this knowledge are yet to be seen. Phase-contrast cardiovascular magnetic resonance imaging of thoracic aortic blood flow has emerged as an exceptionally powerful non-invasive tool enabling visualization of complex flow patterns, and calculation of variables such as wall shear stress. This has led to multiple new findings in the areas of phenotype-dependent bicuspid valve flow patterns, thoracic aortic aneurysm formation and aortic prosthesis performance assessment. Phase-contrast cardiovascular magnetic resonance imaging has also been used in conjunction with computational fluid modelling techniques to produce even more sophisticated analyses, by allowing the calculation of haemodynamic variables with exceptional temporal and spatial resolution. Translationally, these technologies may potentially play a major role in the emergence of precision medicine and patient-specific treatments in patients with aortic disease. This clinically focused review will provide a systematic overview of key insights from published studies to date.

Journal article

Phua AIH, Le T-T, Tara SW, De Marvao A, Duan J, Toh D-F, Ang B, Bryant JA, O'Regan DP, Cook SA, Chin CWLet al., 2020, Paradoxical higher myocardial wall stress and increased cardiac remodeling despite lower mass in females, Journal of the American Heart Association, Vol: 9, Pages: 1-7, ISSN: 2047-9980

BackgroundIncreased left ventricular (LV) mass is characterized by increased myocardial wall thickness and/or ventricular dilatation that is associated with worse outcomes. We aim to comprehensively compare sex‐stratified associations between measures of LV remodeling and increasing LV mass in the general population.Methods and ResultsParticipants were prospectively recruited in the National Heart Center Singapore Biobank to examine health and cardiovascular risk factors in the general population. Cardiovascular magnetic resonance was performed in all individuals. Participants with established cardiovascular diseases and abnormal cardiovascular magnetic resonance scan results were excluded. Global and regional measures of LV remodeling (geometry, function, interstitial volumes, and wall stress) were performed using conventional image analysis and novel 3‐dimensional machine learning phenotyping. Sex‐stratified analyses were performed in 1005 participants (57% males; 53±13 years). Age and prevalence of cardiovascular risk factors were well‐matched in both sexes (P>0.05 for all). Progressive increase in LV mass was associated with increased concentricity in either sex, but to a greater extent in females. Compared with males, females had higher wall stress (mean difference: 170 mm Hg, P<0.0001) despite smaller LV mass (42.4±8.2 versus 55.6±14.2 g/m2, P<0.0001), lower blood pressures (P<0.0001), and higher LV ejection fraction (61.9±5.9% versus 58.6±6.4%, P<0.0001). The regions of increased concentric remodeling corresponded to regions of increased wall stress. Compared with males, females had increased extracellular volume fraction (27.1±2.4% versus 25.1±2.9%, P<0.0001).ConclusionsCompared with males, females have lower LV mass, increased wall stress, and concentric remodeling. These findings provide mechanistic insights that females are susceptible to particular cardiovascular complications.

Journal article

Esslinger U, Garnier S, Korniat A, Proust C, Kararigas G, Müller-Nurasyid M, Empana J-P, Morley MP, Perret C, Stark K, Bick AG, Prasad SK, Kriebel J, Li J, Tiret L, Strauch K, O'Regan DP, Marguiles KB, Seidman JG, Boutouyrie P, Lacolley P, Jouven X, Hengstenberg C, Komajda M, Hakonarson H, Isnard R, Arbustini E, Grallert H, Cook SA, Seidman CE, Regitz-Zagrosek V, Cappola TP, Charron P, Cambien F, Villard Eet al., 2020, Correction: Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy., PLoS One, Vol: 15, Pages: e0229472-e0229472, ISSN: 1932-6203

[This corrects the article DOI: 10.1371/journal.pone.0172995.].

Journal article

Mazzarotto F, Tayal U, Buchan RJ, Midwinter W, Wilk A, Whiffin N, Govind R, Mazaika E, de Marvao A, Dawes T, Felkin LE, Ahmad M, Theotokis PI, Edwards E, Ing AI, Thomson KL, Chan LLH, Sim D, Baksi AJ, Pantazis A, Roberts AM, Watkins H, Funke B, O'Regan D, Olivotto I, Barton PJR, Prasad SK, Cook SA, Ware JS, Walsh Ret al., 2020, Re-evaluating the genetic contribution of monogenic dilated cardiomyopathy, Circulation, Vol: 141, Pages: 387-398, ISSN: 0009-7322

Background: Dilated cardiomyopathy (DCM) is genetically heterogeneous, with >100 purported disease genes tested in clinical laboratories. However, many genes were originally identified based on candidate-gene studies that did not adequately account for background population variation. Here we define the frequency of rare variation in 2538 DCM patients across protein-coding regions of 56 commonly tested genes and compare this to both 912 confirmed healthy controls and a reference population of 60,706 individuals in order to identify clinically interpretable genes robustly associated with dominant monogenic DCM.Methods: We used the TruSight Cardio sequencing panel to evaluate the burden of rare variants in 56 putative DCM genes in 1040 DCM patients and 912 healthy volunteers processed with identical sequencing and bioinformatics pipelines. We further aggregated data from 1498 DCM patients sequenced in diagnostic laboratories and the ExAC database for replication and meta-analysis.Results: Truncating variants in TTN and DSP were associated with DCM in all comparisons. Variants in MYH7, LMNA, BAG3, TNNT2, TNNC1, PLN, ACTC1, NEXN, TPM1 and VCL were significantly enriched in specific patient subsets, with the last 2 genes potentially contributing primarily to early-onset forms of DCM. Overall, rare variants in these 12 genes potentially explained 17% of cases in the outpatient clinic cohort representing a broad range of adult DCM patients and 26% of cases in the diagnostic referral cohort enriched in familial and early-onset DCM. Whilst the absence of a significant excess in other genes cannot preclude a limited role in disease, such genes have limited diagnostic value since novel variants will be uninterpretable and their diagnostic yield is minimal.Conclusion: In the largest sequenced DCM cohort yet described, we observe robust disease association with 12 genes, highlighting their importance in DCM and translating into high interpretability in diagnostic testing. The

Journal article

de Marvao A, Dawes TJ, Howard JP, O'Regan DPet al., 2020, Artificial intelligence and the cardiologist: what you need to know for 2020., Heart, Vol: 106, Pages: 399-400, ISSN: 1355-6037

Journal article

de Marvao A, Dawes TJW, O'Regan DP, 2020, Artificial intelligence for cardiac imaging-genetics research, Frontiers in Cardiovascular Medicine, Vol: 6, Pages: 1-10, ISSN: 2297-055X

Cardiovascular conditions remain the leading cause of mortality and morbidity worldwide, with genotype being a significant influence on disease risk. Cardiac imaging-genetics aims to identify and characterize the genetic variants that influence functional, physiological, and anatomical phenotypes derived from cardiovascular imaging. High-throughput DNA sequencing and genotyping have greatly accelerated genetic discovery, making variant interpretation one of the key challenges in contemporary clinical genetics. Heterogeneous, low-fidelity phenotyping and difficulties integrating and then analyzing large-scale genetic, imaging and clinical datasets using traditional statistical approaches have impeded process. Artificial intelligence (AI) methods, such as deep learning, are particularly suited to tackle the challenges of scalability and high dimensionality of data and show promise in the field of cardiac imaging-genetics. Here we review the current state of AI as applied to imaging-genetics research and discuss outstanding methodological challenges, as the field moves from pilot studies to mainstream applications, from one dimensional global descriptors to high-resolution models of whole-organ shape and function, from univariate to multivariate analysis and from candidate gene to genome-wide approaches. Finally, we consider the future directions and prospects of AI imaging-genetics for ultimately helping understand the genetic and environmental underpinnings of cardiovascular health and disease.

Journal article

Mazzarotto F, Hawley M, Beltrami M, Beekman L, Boschi B, Girolami F, Roberts A, Lodder E, Cerbai E, Cook S, Ware J, Funke B, Olivotto I, Bezzina C, Barton PJR, Walsh Ret al., 2020, The genetic architecture of left ventricular non-compaction reveals both substantial overlap with other cardiomyopathies and a distinct aetiology in a subset of cases, Publisher: bioRxiv

Rationale: Left ventricular non-compaction (LVNC) is a condition characterised by trabeculations in the myocardial wall and is the subject of considerable conjecture as to whether it represents a distinct pathology or a secondary phenotype associated with other cardiac diseases, particularly cardiomyopathies. Objective: To investigate the genetic architecture of LVNC by identifying genes and variant classes robustly associated with disease and comparing these to other genetically characterised cardiomyopathies. Methods and Results: We performed rare variant association analysis using six different LVNC cohorts comprising 840 cases together with 125,748 gnomAD population controls and compared results to similar analyses with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) cases. We observed substantial overlap in genes and variant classes enriched in LVNC and DCM/HCM, indicating that in many cases LVNC belongs to a spectrum of more established cardiomyopathies, with non-compaction representing a phenotypic variation in patients with DCM- or HCM-causing variants. In contrast, five variant classes were uniquely enriched in LVNC cases, of which truncating variants in MYH7, ACTN2 and PRDM16 may represent a distinct LVNC aetiology. MYH7 truncating variants are generally considered as non-pathogenic but were detected in 2% of LVNC cases compared to 0.1% of controls, including a cluster of variants around a single splice region. Additionally, structural variants (exon deletions) in RYR2 and missense variants in the transmembrane region of HCN4 were enriched in LVNC cases, confirming prior reports regarding the association of these variant classes with combined LVNC and arrhythmia phenotypes. Conclusions: We demonstrated that genetic association analysis can clarify the relationship between LVNC and established cardiomyopathies, highlighted substantial overlap with DCM/HCM but also identified variant classes associated with distinct LVNC and with joint LVN

Working paper

Biffi C, Doumou G, Duan J, Prasad SK, Cook SA, O Regan DP, Rueckert D, Cerrolaza JJ, Tarroni G, Bai W, De Marvao A, Oktay O, Ledig C, Le Folgoc L, Kamnitsas Ket al., 2020, Explainable anatomical shape analysis through deep hierarchical generative models., Publisher: arXiv

Quantification of anatomical shape changes currently relies on scalar global indexes which are largely insensitive to regional or asymmetric modifications. Accurate assessment of pathology-driven anatomical remodeling is a crucial step for the diagnosis and treatment of many conditions. Deep learning approaches have recently achieved wide success in the analysis of medical images, but they lack interpretability in the feature extraction and decision processes. In this work, we propose a new interpretable deep learning model for shape analysis. In particular, we exploit deep generative networks to model a population of anatomical segmentations through a hierarchy of conditional latent variables. At the highest level of this hierarchy, a two-dimensional latent space is simultaneously optimised to discriminate distinct clinical conditions, enabling the direct visualisation of the classification space. Moreover, the anatomical variability encoded by this discriminative latent space can be visualised in the segmentation space thanks to the generative properties of the model, making the classification task transparent. This approach yielded high accuracy in the categorisation of healthy and remodelled left ventricles when tested on unseen segmentations from our own multi-centre dataset as well as in an external validation set, and on hippocampi from healthy controls and patients with Alzheimer's disease when tested on ADNI data. More importantly, it enabled the visualisation in three-dimensions of both global and regional anatomical features which better discriminate between the conditions under exam. The proposed approach scales effectively to large populations, facilitating highthroughput analysis of normal anatomy and pathology in largescale studies of volumetric imaging.

Working paper

O'Regan DP, 2020, Putting machine learning into motion: applications in cardiovascular imaging, Clinical Radiology, Vol: 75, Pages: 33-37, ISSN: 0009-9260

Heart and circulatory diseases cause a quarter of all deaths in the UK and cardiac imaging offers an effective tool for early diagnosis and risk-stratification to improve premature death and disability. This domain of radiology is unique in that assessing flow and motion is essential for understanding and quantifying normal physiology and disease processes. Conventional image interpretation relies on manual analysis but this often fails to capture important prognostic features in the complex disturbances of cardiovascular physiology. Machine learning (ML) in cardiovascular imaging promises to be a transformative tool and addresses an unmet need for patient-specific management, accurate prediction of future events, and the discovery of tractable molecular mechanisms of disease. This review discusses the potential of ML across every aspect of image analysis including efficient acquisition, segmentation and motion tracking, disease classification, prediction tasks and modelling of genotype–phenotype interactions; however, significant challenges remain in access to high-quality data at scale, robust validation, and clinical interpretability.

Journal article

Lee AWC, O'Regan DP, Gould J, Sidhu B, Sieniewicz B, Plank G, Warriner DR, Lamata P, Rinaldi CA, Niederer SAet al., 2019, Sex-dependent QRS guidelines for cardiac resynchronization therapy using computer model predictions, Biophysical Journal, Vol: 117, Pages: 2375-2381, ISSN: 0006-3495

Cardiac resynchronization therapy (CRT) is an important treatment for heart failure. Low female enrollment in clinical trials means that current CRT guidelines may be biased toward males. However, females have higher response rates at lower QRS duration (QRSd) thresholds. Sex differences in the left ventricle (LV) size could provide an explanation for the improved female response at lower QRSd. We aimed to test if sex differences in CRT response at lower QRSd thresholds are explained by differences in LV size and hence predict sex-specific guidelines for CRT. We investigated the effect that LV size sex difference has on QRSd between male and females in 1093 healthy individuals and 50 CRT patients using electrophysiological computer models of the heart. Simulations on the healthy mean shape models show that LV size sex difference can account for 50–100% of the sex difference in baseline QRSd in healthy individuals. In the CRT patient cohort, model simulations predicted female-specific guidelines for CRT, which were 9–13 ms lower than current guidelines. Sex differences in the LV size are able to account for a significant proportion of the sex difference in QRSd and provide a mechanistic explanation for the sex difference in CRT response. Simulations accounting for the smaller LV size in female CRT patients predict 9–13 ms lower QRSd thresholds for female CRT guidelines.

Journal article

Osimo E, Brugger S, De Marvao A, Pillinger T, Whitehurst T, Statton B, Quinlan M, Berry A, Cook SA, O'Regan D, Howes ODet al., 2019, Cardiac structure and function in schizophrenia: a cardiac MR imaging study, British Journal of Psychiatry, ISSN: 0007-1250

Background: Heart disease is the leading cause of death in schizophrenia. However, there has been little research directly examining cardiac function in schizophrenia.Aims:We investigated cardiac structure and function in patients with schizophrenia using cardiac magnetic resonance imaging (CMR) after excluding medical and metabolic comorbidity. Methods:80 participants underwent CMR to determine biventricular volumes and function and measures of blood pressure, physical activity, and glycated haemoglobin levels. Patients and controls were matched for age, sex, ethnicity, and body surface area. Results:Patients with schizophrenia had significantly smaller indexed left ventricular (LV) end-diastolic volume (effect size, d=-0.82, p=0.001), LV end-systolic volume (d=-0.58, p=0.02), LV stroke volume (d=-0.85, p=0.001), right ventricular (RV) end-diastolic volume (d=-0.79, p=0.002), RV end-systolic volume (d=-0.58, p=0.02), and RV stroke volume (d=-0.87, p=0.001) but unaltered ejection fractions relative to controls. LV concentricity (d=0.73, p=0.003) and septal thickness (d=1.13, p<0.001) were significantly larger in schizophrenia. Mean concentricity in patients was above the reference range. The findings were largely unchanged after adjusting for smoking and/or exercise levels and were independent of medication dose and duration. Conclusions:Patients with schizophrenia show evidence of concentric cardiac remodelling compared to healthy controls of a similar age, sex, ethnicity, body surface area and blood pressure, and independent of smoking and activity levels. This could be contributing to the excess cardiovascular mortality observed in patients. Future studies should investigate the contribution of antipsychotic medication to these changes.

Journal article

Osimo EF, Brugger SP, de Marvao A, Pillinger T, Whitehurst T, Statton B, Quinlan M, Berry A, Cook SA, ORegan DP, Howes ODet al., 2019, Cardiac structure and function in schizophrenia: a cardiac MR imaging study, Publisher: Cold Spring Harbor Laboratory

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Heart disease is the leading cause of death in schizophrenia.</jats:p></jats:sec><jats:sec><jats:title>Aims</jats:title><jats:p>We investigated cardiac structure and function in patients with schizophrenia using cardiac magnetic resonance imaging (CMR) after excluding medical and metabolic comorbidity.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>80 participants underwent CMR to determine biventricular volumes and function and measures of blood pressure, physical activity, and glycated haemoglobin levels. Patients and controls were matched for age, sex, ethnicity, and body surface area.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Patients with schizophrenia had significantly smaller indexed left ventricular (LV) end-diastolic volume, end-systolic volume, stroke volume, right ventricular (RV) end-diastolic volume, end-systolic volume, and stroke volume but unaltered ejection fractions relative to controls. LV concentricity and septal thickness were significantly larger in schizophrenia. The findings were largely unchanged after adjusting for smoking or exercise levels and were independent of medication dose and duration.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Patients with schizophrenia show evidence of prognostically-adverse cardiac remodelling compared to matched controls, independent of conventional risk factors.</jats:p></jats:sec>

Working paper

Orini M, Graham AJ, MartinezNaharro A, Andrews CM, de Marvao A, Statton B, Cook SA, O'Regan DP, Hawkins PN, Rudy Y, Fontana M, Lambiase PDet al., 2019, Noninvasive mapping of the electrophysiological substrate in cardiac amyloidosis and its relationship to structural abnormalities, Journal of the American Heart Association, Vol: 8, ISSN: 2047-9980

BackgroundThe relationship between structural pathology and electrophysiological substrate in cardiac amyloidosis is unclear. Differences between light‐chain (AL) and transthyretin (ATTR) cardiac amyloidosis may have prognostic implications.Methods and ResultsECG imaging and cardiac magnetic resonance studies were conducted in 21 cardiac amyloidosis patients (11 AL and 10 ATTR). Healthy volunteers were included as controls. With respect to ATTR, AL patients had lower amyloid volume (51.0/37.7 versus 73.7/16.4 mL, P=0.04), lower myocardial cell volume (42.6/19.1 versus 58.5/17.2 mL, P=0.021), and higher T1 (1172/64 versus 1109/80 ms, P=0.022) and T2 (53.4/2.9 versus 50.0/3.1 ms, P=0.003). ECG imaging revealed differences between cardiac amyloidosis and control patients in virtually all conduction‐repolarization parameters. With respect to ATTR, AL patients had lower epicardial signal amplitude (1.07/0.46 versus 1.83/1.26 mV, P=0.026), greater epicardial signal fractionation (P=0.019), and slightly higher dispersion of repolarization (187.6/65 versus 158.3/40 ms, P=0.062). No significant difference between AL and ATTR patients was found using the standard 12‐lead ECG. T1 correlated with epicardial signal amplitude (cc=−0.78), and extracellular volume with epicardial signal fractionation (cc=0.48) and repolarization time (cc=0.43). Univariate models based on single features from both cardiac magnetic resonance and ECG imaging classified AL and ATTR patients with an accuracy of 70% to 80%.ConclusionsIn this exploratory study cardiac amyloidosis was associated with ventricular conduction and repolarization abnormalities, which were more pronounced in AL than in ATTR. Combined ECG imaging–cardiac magnetic resonance analysis supports the hypothesis that additional mechanisms beyond infiltration may contribute to myocardial damage in AL amyloidosis. Further studies are needed to assess the clinical impact of this approach.

Journal article

Duan J, Schlemper J, Qin C, Ouyang C, Bai W, Biffi C, Bello G, Statton B, O’Regan DP, Rueckert Det al., 2019, VS-Net: variable splitting network for accelerated parallel MRI reconstruction, International Conference on Medical Image Computing and Computer-Assisted Intervention, Publisher: Springer International Publishing, Pages: 713-722, ISSN: 0302-9743

In this work, we propose a deep learning approach for parallel magnetic resonance imaging (MRI) reconstruction, termed a variable splitting network (VS-Net), for an efficient, high-quality reconstruction of undersampled multi-coil MR data. We formulate the generalized parallel compressed sensing reconstruction as an energy minimization problem, for which a variable splitting optimization method is derived. Based on this formulation we propose a novel, end-to-end trainable deep neural network architecture by unrolling the resulting iterative process of such variable splitting scheme. VS-Net is evaluated on complex valued multi-coil knee images for 4-fold and 6-fold acceleration factors. We show that VS-Net outperforms state-of-the-art deep learning reconstruction algorithms, in terms of reconstruction accuracy and perceptual quality. Our code is publicly available at https://github.com/j-duan/VS-Net.

Conference paper

Duan J, Bello G, Schlemper J, Bai W, Dawes TJW, Biffi C, Marvao AD, Doumou G, O'Regan DP, Rueckert Det al., 2019, Automatic 3D bi-ventricular segmentation of cardiac images by a shape-refined multi-task deep learning approach, IEEE Transactions on Medical Imaging, Vol: 38, Pages: 2151-2164, ISSN: 0278-0062

Deep learning approaches have achieved state-of-the-art performance incardiac magnetic resonance (CMR) image segmentation. However, most approaches have focused on learning image intensity features for segmentation, whereas the incorporation of anatomical shape priors has received less attention. In this paper, we combine a multi-task deep learning approach with atlas propagation to develop a shape-constrained bi-ventricular segmentation pipeline for short-axis CMR volumetric images. The pipeline first employs a fully convolutional network (FCN) that learns segmentation and landmark localisation tasks simultaneously. The architecture of the proposed FCN uses a 2.5D representation, thus combining the computational advantage of 2D FCNs networks and the capability of addressing 3D spatial consistency without compromising segmentation accuracy. Moreover, the refinement step is designed to explicitly enforce a shape constraint and improve segmentation quality. This step is effective for overcoming image artefacts (e.g. due to different breath-hold positions and large slice thickness), which preclude the creation of anatomically meaningful 3D cardiac shapes. The proposed pipeline is fully automated, due to network's ability to infer landmarks, which are then used downstream in the pipeline to initialise atlas propagation. We validate the pipeline on 1831 healthy subjects and 649 subjects with pulmonary hypertension. Extensive numerical experiments on the two datasets demonstrate that our proposed method is robust and capable of producing accurate, high-resolution and anatomically smooth bi-ventricular3D models, despite the artefacts in input CMR volumes.

Journal article

Biffi C, Cerrolaza JJ, Tarroni G, de Marvao A, Cook SA, O'Regan DP, Rueckert Det al., 2019, 3D high-resolution cardiac segmentation reconstruction from 2D views using conditional variational autoencoders, 16th IEEE International Symposium on Biomedical Imaging (ISBI), Publisher: IEEE, Pages: 1643-1646, ISSN: 1945-7928

Accurate segmentation of heart structures imaged by cardiac MR is key for the quantitative analysis of pathology. High-resolution 3D MR sequences enable whole-heart structural imaging but are time-consuming, expensive to acquire and they often require long breath holds that are not suitable for patients. Consequently, multiplanar breath-hold 2D cines sequences are standard practice but are disadvantaged by lack of whole-heart coverage and low through-plane resolution. To address this, we propose a conditional variational autoencoder architecture able to learn a generative model of 3D high-resolution left ventricular (LV) segmentations which is conditioned on three 2D LV segmentations of one short-axis and two long-axis images. By only employing these three 2D segmentations, our model can efficiently reconstruct the 3D high-resolution LV segmentation of a subject. When evaluated on 400 unseen healthy volunteers, our model yielded an average Dice score of 87.92 ± 0.15 and outperformed competing architectures (TL-net, Dice score = 82.60 ± 0.23, p = 2.2 · 10 -16 ).

Conference paper

Garcia-Pavia P, Kim Y, Restrepo-Cordoba MA, Lunde IG, Wakimoto H, Smith AM, Toepfer CN, Getz K, Gorham J, Patel P, Ito K, Willcox JA, Arany Z, Li J, Owens AT, Govind R, Nuñez B, Mazaika E, Bayes-Genis A, Walsh R, Finkelman B, Lupon J, Whiffin N, Serrano I, Midwinter W, Wilk A, Bardaji A, Ingold N, Buchan R, Tayal U, Pascual-Figal DA, de Marvao A, Ahmad M, Garcia-Pinilla JM, Pantazis A, Dominguez F, John Baksi A, O'Regan DP, Rosen SD, Prasad SK, Lara-Pezzi E, Provencio M, Lyon AR, Alonso-Pulpon L, Cook SA, DePalma SR, Barton PJR, Aplenc R, Seidman JG, Ky B, Ware JS, Seidman CEet al., 2019, Genetic variants associated with cancer therapy-induced cardiomyopathy, Circulation, Vol: 140, Pages: 31-41, ISSN: 0009-7322

BackgroundCancer therapy-induced cardiomyopathy (CCM) is associated with cumulative drug exposures and pre-existing cardiovascular disorders. These parametersincompletely account for substantial inter-individual susceptibility to CCM. We hypothesized that rare variants in cardiomyopathy genes contribute to CCM.MethodsWe studied 213 CCM patients from three cohorts: retrospectively recruited adults with diverse cancers (n=99), prospectively phenotyped breast cancer adults (n=73) and prospectively phenotyped children with acute myeloid leukemia (n=41). Cardiomyopathy genes, including nine pre-specified genes were sequenced. The prevalence of rare variants was compared between CCM cohorts and The Cancer Genome Atlas (TCGA) participants(n=2053), healthy volunteers(n=445), and ancestry-matchedreference population. Clinical characteristics and outcomes were assessed, stratified by genotypes. A prevalent CCM genotype was modeled in anthracycline-treated mice.ResultsCCM was diagnosed 0.4-9 years after chemotherapy; 90% of these patients received anthracyclines. Adult CCM patients had cardiovascular risk factors similar to the U.S. population. Among nine prioritized genes CCM patients had more rare protein-altering variants than comparative cohorts (p≤1.98e-04). Titin-truncating variants (TTNtv) predominated, occurring in 7.5% CCM patients versus 1.1% TCGA participants (p=7.36e-08), 0.7% healthy volunteers (p=3.42e-06), and 0.6% reference population (p=5.87e-14). Adult CCM patients with TTNtv experienced more heart failure and atrial fibrillation (p=0.003)and impaired myocardial recovery (p=0.03) than those without.Consistent with human data, anthracycline-treated TTNtv mice and isolated TTNtv cardiomyocytes showed sustained contractile dysfunction unlike wildtype (p=0.0004 and p<0.002, respectively).ConclusionsUnrecognized rare variants in cardiomyopathy-associated genes, particularly TTNtv, increased the risk for CCM in children and adults, and adverse cardiac events

Journal article

O'Regan D, Dawes T, 2019, UK-Digital-Heart-Project/AutoFD: Optimized UKBB parallel distribution

Optimized UKBB parallel distribution with default parameters.The files pft_ExtractMatchedAndShiftedImages.m and pft_ExtractMatchedAndShiftedImages.new exist to accommodate different naming conventions for i/p files.This is the code being used for the Nature submission.Windows, Linux and MacOS platforms should be supported, but have not been exhaustively tested.

Software

Pillinger T, Osimo EF, de Marvao A, Berry MA, Whitehurst T, Statton B, Quinlan M, Brugger S, Vazir A, Cook SA, O'Regan DP, Howes ODet al., 2019, Cardiac structure and function in patients with schizophrenia taking antipsychotic drugs: an MRI study, Translational Psychiatry, Vol: 9, ISSN: 2158-3188

Cardiovascular disease (CVD) is a major cause of excess mortality in schizophrenia. Preclinical evidence shows antipsychotics can cause myocardial fibrosis and myocardial inflammation in murine models, but it is not known if this is the case in patients. We therefore set out to determine if there is evidence of cardiac fibrosis and/or inflammation using cardiac MRI in medicated patients with schizophrenia compared with matched healthy controls. Thirty-one participants (14 patients and 17 controls) underwent cardiac MRI assessing myocardial markers of fibrosis/inflammation, indexed by native myocardial T1 time, and cardiac structure (left ventricular (LV) mass) and function (left/right ventricular end-diastolic and end-systolic volumes, stroke volumes, and ejection fractions). Participants were physically fit, and matched for age, gender, smoking, blood pressure, BMI, HbA1c, ethnicity, and physical activity. Compared with controls, native myocardial T1 was significantly longer in patients with schizophrenia (effect size, d = 0.89; p = 0.02). Patients had significantly lower LV mass, and lower left/right ventricular end-diastolic and stroke volumes (effect sizes, d = 0.86-1.08; all p-values < 0.05). There were no significant differences in left/right end-systolic volumes and ejection fractions between groups (p > 0.05). These results suggest an early diffuse fibro-inflammatory myocardial process in patients that is independent of established CVD-risk factors and could contribute to the excess cardiovascular mortality associated with schizophrenia. Future studies are required to determine if this is due to antipsychotic treatment or is intrinsic to schizophrenia.

Journal article

Attard M, Dawes T, Simoes Monteiro de Marvao A, Biffi C, Shi W, Wharton J, Rhodes C, Ghataorhe P, Gibbs J, Howard L, Rueckert D, Wilkins M, O'Regan Det al., 2019, Metabolic pathways associated with right ventricular adaptation to pulmonary hypertension: Three dimensional analysis of cardiac magnetic resonance imaging, EHJ Cardiovascular Imaging / European Heart Journal - Cardiovascular Imaging, Vol: 20, Pages: 668-676, ISSN: 2047-2412

AimsWe sought to identify metabolic pathways associated with right ventricular (RV) adaptation to pulmonary hypertension (PH). We evaluated candidate metabolites, previously associated with survival in pulmonary arterial hypertension, and used automated image segmentation and parametric mapping to model their relationship to adverse patterns of remodelling and wall stress.Methods and resultsIn 312 PH subjects (47.1% female, mean age 60.8 ± 15.9 years), of which 182 (50.5% female, mean age 58.6 ± 16.8 years) had metabolomics, we modelled the relationship between the RV phenotype, haemodynamic state, and metabolite levels. Atlas-based segmentation and co-registration of cardiac magnetic resonance imaging was used to create a quantitative 3D model of RV geometry and function—including maps of regional wall stress. Increasing mean pulmonary artery pressure was associated with hypertrophy of the basal free wall (β = 0.29) and reduced relative wall thickness (β = −0.38), indicative of eccentric remodelling. Wall stress was an independent predictor of all-cause mortality (hazard ratio = 1.27, P = 0.04). Six metabolites were significantly associated with elevated wall stress (β = 0.28–0.34) including increased levels of tRNA-specific modified nucleosides and fatty acid acylcarnitines, and decreased levels (β = −0.40) of sulfated androgen.ConclusionUsing computational image phenotyping, we identify metabolic profiles, reporting on energy metabolism and cellular stress-response, which are associated with adaptive RV mechanisms to PH.

Journal article

Mazzarotto F, Tayal P, Buchan R, Midwinter W, Wilk A, Whiffin N, Govind R, Mazaika E, De Marvao A, Felkin L, Dawes T, Ahmad M, Edwards E, Ing A, Thomson K, Chan L, Sim D, Baksi J, Pantazis A, Roberts A, Watkins H, Funke B, O'Regan D, Olivotto I, Barton P, Prasad S, Cook S, Ware J, Walsh Ret al., 2019, RE-EVALUATING THE GENETIC CONTRIBUTION OF MONOGENIC DILATED CARDIOMYOPATHY, Annual Conference of the British-Cardiovascular-Society (BCS) - Digital Health Revolution, Publisher: BMJ PUBLISHING GROUP, Pages: A100-A100, ISSN: 1355-6037

Conference paper

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