Imperial College London

DrAntonioSimoes Monteiro de Marvao

Faculty of MedicineInstitute of Clinical Sciences

Chain Florey Clinical Lecturer
 
 
 
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Contact

 

+44 (0)20 3313 1510antonio.de-marvao

 
 
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Location

 

Robert Steiner MRI UnitHammersmith HospitalHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

108 results found

Meng Q, Bai W, Liu T, Simoes Monteiro de Marvao A, O'Regan D, Rueckert Det al., 2022, MulViMotion: shape-aware 3D myocardial motion tracking from multi-view cardiac MRI, IEEE Transactions on Medical Imaging, Vol: 41, Pages: 1961-1974, ISSN: 0278-0062

Recovering the 3D motion of the heart from cine cardiac magnetic resonance (CMR) imaging enables the assessment of regional myocardial function and is important for understanding and analyzing cardiovascular disease. However, 3D cardiac motion estimation is challenging because the acquired cine CMR images are usually 2D slices which limit the accurate estimation of through-plane motion. To address this problem, we propose a novel multi-view motion estimation network (MulViMotion), which integrates 2D cine CMR images acquired in short-axis and long-axis planes to learn a consistent 3D motion field of the heart. In the proposed method, a hybrid 2D/3D network is built to generate dense 3D motion fields by learning fused representations from multi-view images. To ensure that the motion estimation is consistent in 3D, a shape regularization module is introduced during training, where shape information from multi-view images is exploited to provide weak supervision to 3D motion estimation. We extensively evaluate the proposed method on 2D cine CMR images from 580 subjects of the UK Biobank study for 3D motion tracking of the left ventricular myocardium. Experimental results show that the proposed method quantitatively and qualitatively outperforms competing methods.

Journal article

Cheng HLH, Andreica E-C, Martin A, Teelucksingh S, De Marvao A, McMicking J, Banerjee Aet al., 2022, Improving management pathway for pregnant women with palpitations in a tertiary hospital, Publisher: WILEY, Pages: 164-165, ISSN: 1470-0328

Conference paper

Thanaj M, Mielke J, McGurk K, Bai W, Savioli N, Simoes Monteiro de Marvao A, Meyer H, Zeng L, Sohler F, Lumbers T, Wilkins M, Ware J, Bender C, Rueckert D, MacNamara A, Freitag D, O'Regan Det al., 2022, Genetic and environmental determinants of diastolic heart function, Nature Cardiovascular Research, Vol: 1, Pages: 361-371, ISSN: 2731-0590

Diastole is the sequence of physiological events that occur in the heart during ventricular filling and principally depends onmyocardial relaxation and chamber stiffness. Abnormal diastolic function is related to many cardiovascular disease processesand is predictive of health outcomes, but its genetic architecture is largely unknown. Here, we use machine learning cardiacmotion analysis to measure diastolic functional traits in 39,559 participants of the UK Biobank and perform a genome-wideassociation study. We identified 9 significant, independent loci near genes that are associated with maintaining sarcomericfunction under biomechanical stress and genes implicated in the development of cardiomyopathy. Age, sex and diabetes wereindependent predictors of diastolic function and we found a causal relationship between genetically-determined ventricularstiffness and incident heart failure. Our results provide insights into the genetic and environmental factors influencing diastolicfunction that are relevant for identifying causal relationships and potential tractable targets.

Journal article

Howard LSGE, He J, Watson GMJ, Huang L, Wharton J, Luo Q, Kiely DG, Condliffe R, Pepke-Zaba J, Morrell NW, Sheares KK, Ulrich A, Quan R, Zhao Z, Jing X, An C, Liu Z, Xiong C, Robbins PA, Dawes T, de MA, Rhodes CJ, Richter MJ, Gall H, Ghofrani HA, Zhao L, Huson L, Wilkins MRet al., 2022, Supplementation with Iron in Pulmonary Arterial Hypertension: Two Randomized Crossover Trials (vol 18, pg 981, 2021), ANNALS OF THE AMERICAN THORACIC SOCIETY, Vol: 19, Pages: 703-703, ISSN: 1546-3222

Journal article

McGurk KA, Zheng SL, Henry A, Josephs K, Edwards M, de Marvao A, Whiffin N, Roberts A, Lumbers TR, O'Regan DP, Ware JSet al., 2022, Correspondence on "ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG)" by Miller et al, Genetics in Medicine, Vol: 24, Pages: 744-746, ISSN: 1098-3600

Journal article

Jia X, Thorley A, Chen W, Qiu H, Shen L, Styles IB, Chang HJ, Leonardis A, de Marvao A, O'Regan DP, Rueckert D, Duan Jet al., 2022, Learning a Model-Driven Variational Network for Deformable Image Registration, IEEE TRANSACTIONS ON MEDICAL IMAGING, Vol: 41, Pages: 199-212, ISSN: 0278-0062

Journal article

Osimo E, Sweeney M, De Marvao A, Berry A, Statton B, Perry BI, Pillinger T, Whitehurst T, Cook S, ORegan D, Thomas EL, Howes ODet al., 2021, Adipose tissue dysfunction, inflammation, and insulin resistance: alternative pathways to cardiac remodelling in schizophrenia. A multimodal, case-control study, Translational Psychiatry, Vol: 11, Pages: 1-9, ISSN: 2158-3188

Cardiovascular diseases are the leading cause of death in schizophrenia. Patients with schizophrenia show evidence of concentric cardiac remodelling (CCR), defined as an increase in left-ventricular mass over end-diastolic volumes. CCR is a predictor of cardiac disease, but the molecular pathways leading to this in schizophrenia are unknown. We aimed to explore the relevance of hypertensive and non-hypertensive pathways to CCR and their potential molecular underpinnings in schizophrenia. In this multimodal case–control study, we collected cardiac and whole-body fat magnetic resonance imaging (MRI), clinical measures, and blood levels of several cardiometabolic biomarkers known to potentially cause CCR from individuals with schizophrenia, alongside healthy controls (HCs) matched for age, sex, ethnicity, and body surface area. Of the 50 participants, 34 (68%) were male. Participants with schizophrenia showed increases in cardiac concentricity (d = 0.71, 95% CI: 0.12, 1.30; p = 0.01), indicative of CCR, but showed no differences in overall content or regional distribution of adipose tissue compared to HCs. Despite the cardiac changes, participants with schizophrenia did not demonstrate activation of the hypertensive CCR pathway; however, they showed evidence of adipose dysfunction: adiponectin was reduced (d = −0.69, 95% CI: −1.28, −0.10; p = 0.02), with evidence of activation of downstream pathways, including hypertriglyceridemia, elevated C-reactive protein, fasting glucose, and alkaline phosphatase. In conclusion, people with schizophrenia showed adipose tissue dysfunction compared to body mass-matched HCs. The presence of non-hypertensive CCR and a dysmetabolic phenotype may contribute to excess cardiovascular risk in schizophrenia. If our results are confirmed, acting on this pathway could reduce cardiovascular risk and resultant life-years lost in people with schizophrenia.

Journal article

Lota AS, Hazebroek M, Theotokis P, Wassall R, Salmi S, Halliday B, Tayal U, Verdonschot J, Meena D, de Marvao A, Iacob A, Hammersley D, Jones R, Wage R, Buchan R, Yazdani M, Noseda M, Mittal T, Wong J, Robertus JL, Baksi J, Vassiliou V, Tzoulaki Iet al., 2021, Genetic Overlap of Acute Myocarditis and Inherited Cardiomyopathy, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322

Conference paper

De Marvao A, McGurk K, Zheng S, Thanaj M, Bai W, Duan J, Halliday B, Pantazis A, Prasad S, Rueckert D, Walsh R, Ho C, Cook S, Ware J, O'Regan Det al., 2021, Outcomes and phenotypic expression of rare variants in hypertrophic cardiomyopathy genes in over 200,000 adults, ESC Congress 2021, Publisher: European Society of Cardiology, Pages: 1731-1731, ISSN: 0195-668X

BackgroundHypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population.PurposeTo determine the population prevalence of HCM-associated sarcomeric variants, characterise their phenotypic manifestations, estimate penetrance, and identify associations between sarcomeric variants and clinical outcomes, we performed an observational study of 218,813 adults in the UK Biobank (UKBB), of whom 200,584 have whole exome sequencing (WES).MethodsWe carried out an integrated analysis of WES and cardiac magnetic resonance (CMR) imaging in UK Biobank participants stratified by sarcomere-encoding variant status. Computer vision techniques were used to automatically segment the four chambers of the heart (Figure 1). Cardiac motion analysis was used to derive strain and strain rates. Regional analysis of left ventricular wall thickness was performed using three-dimensional modelling of these segmentations.ResultsMedian age at recruitment was 58 (IQR 50–63 years), and participants were followed up for a median of 10.8 years (IQR 9.9–11.6 years) with a total of 19,507 primary clinical events reported.The prevalence of rare variants (allele frequency <0.ehab724.17314) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n=5,727; 1 in 35), and the prevalence of pathogenic or likely pathogenic variants (SARC-P/LP) was 0.24% (n=474, 1 in 423).SARC-P/LP variants were associated with increased risk of death or major adverse cardiac events (MACE) compared to controls (HR 1.68, 95% CI 1.37–2.06, p<0.001), mainly due to heart failure endpoints (Figure 2: cumulative hazard curves with zoomed plots for lifetime risk of A) death and MACE or B) heart failure, stratified by genotype; genotype negative (SARC-NEG), carriers of indeterminate sarcomeric variants (SARC-IND) or SARC-P/LP; C) Forest plot of comparative lifetime risk of c

Conference paper

Thorley A, Jia X, Chang HJ, Liu B, Bunting K, Stoll V, de Marvao A, O'Regan DP, Gkoutos G, Kotecha D, Duan Jet al., 2021, Nesterov accelerated ADMM for fast diffeomorphic image registration, International Conference on Medical Image Computing and Computer Assisted Intervention (MICCAI), Publisher: SPRINGER INTERNATIONAL PUBLISHING AG, Pages: 150-160, ISSN: 0302-9743

Deterministic approaches using iterative optimisation have been historically successful in diffeomorphic image registration (DiffIR). Although these approaches are highly accurate, they typically carry a significant computational burden. Recent developments in stochastic approaches based on deep learning have achieved sub-second runtimes for DiffIR with competitive registration accuracy, offering a fast alternative to conventional iterative methods. In this paper, we attempt to reduce this difference in speed whilst retaining the performance advantage of iterative approaches in DiffIR. We first propose a simple iterative scheme that functionally composes intermediate non-stationary velocity fields to handle large deformations in images whilst guaranteeing diffeomorphisms in the resultant deformation. We then propose a convex optimisation model that uses a regularisation term of arbitrary order to impose smoothness on these velocity fields and solve this model with a fast algorithm that combines Nesterov gradient descent and the alternating direction method of multipliers (ADMM). Finally, we leverage the computational power of GPU to implement this accelerated ADMM solver on a 3D cardiac MRI dataset, further reducing runtime to less than 2 s. In addition to producing strictly diffeomorphic deformations, our methods outperform both state-of-the-art deep learning-based and iterative DiffIR approaches in terms of dice and Hausdorff scores, with speed approaching the inference time of deep learning-based methods.

Conference paper

Simoes Monteiro de Marvao A, McGurk K, Zheng S, Thanaj M, Bai W, Duan J, Biffi C, Mazzarotto F, Statton B, Dawes T, Savioli N, Halliday B, Xu X, Buchan R, Baksi A, Quinlan M, Tokarczuk P, Tayal U, Francis C, Whiffin N, Theotokis A, Zhang X, Jang M, Berry A, Pantazis A, Barton P, Rueckert D, Prasad S, Walsh R, Ho C, Cook S, Ware J, O'Regan Det al., 2021, Phenotypic expression and outcomes in individuals with rare genetic variants of hypertrophic cardiomyopathy, Journal of the American College of Cardiology, Vol: 78, Pages: 1097-1110, ISSN: 0735-1097

Background: Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomereencoding genes, but little is known about the clinical significance of these variants in thegeneral population.Objectives: To compare lifetime outcomes and cardiovascular phenotypes according to thepresence of rare variants in sarcomere-encoding genes amongst middle-aged adults.Methods: We analysed whole exome sequencing and cardiac magnetic resonance (CMR)imaging in UK Biobank participants stratified by sarcomere-encoding variant status.Results: The prevalence of rare variants (allele frequency <0.00004) in HCM-associatedsarcomere-encoding genes in 200,584 participants was 2.9% (n=5,712; 1 in 35), and theprevalence of variants pathogenic or likely pathogenic for HCM (SARC-HCM-P/LP) was0.25% (n=493, 1 in 407). SARC-HCM-P/LP variants were associated with increased risk ofdeath or major adverse cardiac events compared to controls (HR 1.69, 95% CI 1.38 to 2.07,p<0.001), mainly due to heart failure endpoints (HR 4.23, 95% CI 3.07 to 5.83, p<0.001). In21,322 participants with CMR, SARC-HCM-P/LP were associated with asymmetric increasein left ventricular maximum wall thickness (10.9±2.7 vs 9.4±1.6 mm, p<0.001) buthypertrophy (≥13mm) was only present in 18.4% (n=9/49, 95% CI 9 to 32%). SARC-HCMP/LP were still associated with heart failure after adjustment for wall thickness (HR 6.74,95% CI 2.43 to 18.7, p<0.001).Conclusions: In this population of middle-aged adults, SARC-HCM-P/LP variants have lowaggregate penetrance for overt HCM but are associated with increased risk of adversecardiovascular outcomes and an attenuated cardiomyopathic phenotype. Although absoluteevent rates are low, identification of these variants may enhance risk stratification beyondfamilial disease.

Journal article

Bleakley C, de Marvao A, Athayde A, Kuhn T, Xu T, Weaver C, Singh S, Hill J, Pepper J, Price Set al., 2021, The Impact of Norepinephrine on Myocardial Perfusion in Critical Illness, JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY, Vol: 34, Pages: 1019-1020, ISSN: 0894-7317

Journal article

Halliday BP, de Marvao A, Thilaganathan B, 2021, Peripartum cardiomyopathy and pre-eclampsia: two tips of the same iceberg, EUROPEAN JOURNAL OF HEART FAILURE, Vol: 23, Pages: 2070-2072, ISSN: 1388-9842

Journal article

Bleakley C, de Marvao A, Morosin M, Androulakis E, Russell C, Athayde A, Cannata A, Passariello M, Ledot S, Singh S, Pepper J, Hill J, Cowie M, Price Set al., 2021, Utility of echocardiographic right ventricular subcostal strain in critical care, EUROPEAN HEART JOURNAL-CARDIOVASCULAR IMAGING, Vol: 23, Pages: 820-828, ISSN: 2047-2404

Journal article

Thanaj M, Mielke J, McGurk KA, Bai W, Savioli N, de Marvao A, Meyer HV, Zeng L, Sohler F, Wilkins MR, Ware JS, Bender C, Rueckert D, MacNamara A, Freitag DF, ORegan DPet al., 2021, Genetic and environmental determinants of diastolic heart function, Publisher: Cold Spring Harbor Laboratory

<jats:title>ABSTRACT</jats:title><jats:p>Diastole is the sequence of physiological events that occur in the heart during ventricular filling and principally depends on myocardial relaxation and chamber stiffness. Abnormal diastolic function is related to many cardiovascular disease processes and is predictive of health outcomes, but its genetic architecture is largely unknown. Here, we use machine learning cardiac motion analysis to measure diastolic functional traits in 39,559 participants of UK Biobank and perform a genome-wide association study. We identified 9 significant, independent loci near genes that are associated with maintaining sarcomeric function under biomechanical stress and genes implicated in the development of cardiomyopathy. Age, sex and diabetes were independent predictors of diastolic function and we found a causal relationship between ventricular stiffness and heart failure. Our results provide novel insights into the genetic and environmental factors influencing diastolic function that are relevant for identifying causal relationships and tractable targets in heart failure.</jats:p>

Working paper

Bleakley C, Singh S, de Marvao A, Morosin M, Androulakis E, Cannata A, Price Set al., 2021, Reply to: RV dysfunction in Covid-19 ARDS: Is there a difference in the impact of mechanical ventilation and ECMO?, INTERNATIONAL JOURNAL OF CARDIOLOGY, Vol: 332, Pages: 239-239, ISSN: 0167-5273

Journal article

de Marvao A, Alexander D, Bucciarelli-Ducci C, Price Set al., 2021, Heart disease in women: a narrative review, ANAESTHESIA, Vol: 76, Pages: 118-130, ISSN: 0003-2409

Journal article

Howard LSGE, He J, Watson GMJ, Huang L, Wharton J, Luo Q, Kiely DG, Condliffe R, Pepke-Zaba J, Morrell NW, Sheares KK, Ulrich A, Quan R, Zhao Z, Jing X, An C, Liu Z, Xiong C, Robbins PA, Dawes T, de Marvao A, Rhodes CJ, Richter MJ, Gall H, Ghofrani HA, Zhao L, Huson L, Wilkins MRet al., 2021, Supplementation with iron in pulmonary arterial hypertension: two randomized crossover trials., Annals of the American Thoracic Society, Vol: 18, Pages: 981-988, ISSN: 1546-3222

RATIONALE: Iron deficiency, in the absence of anaemia, is common in patients with idiopathic and heritable pulmonary arterial hypertension (PAH) and is associated with a worse clinical outcome. Oral iron absorption may be impeded by elevated circulating hepcidin levels. The safety and benefit of parenteral iron replacement in this patient population is unclear. OBJECTIVES: To evaluate the safety and efficacy of parenteral iron replacement in pulmonary arterial hypertension. METHODS: In two randomised, double blind, placebo-controlled 12 week crossover studies, 39 patients in Europe received a single infusion of ferric carboxymaltose (Ferinject®) 1000 mg (or 15 mg/kg if weight < 66.7Kg) or saline as placebo and 17 patients in China received iron dextran (Cosmofer®) 20 mg iron/kg body weight or saline placebo. All patients had idiopathic or heritable PAH and iron deficiency at entry as defined by: a serum ferritin < 37 µg/l or iron < 10.3 µmol/l or transferrin saturations < 16.4%. RESULTS: Both iron treatments were well tolerated and improved iron status. Analysed separately and combined, there was no effect on any measure of exercise capacity (using cardiopulmonary exercise testing or 6 minute walk test) or cardio-pulmonary haemodynamics, as assessed by right heart catheterisation, cardiac magnetic resonance or plasma NT-proBNP, at 12 weeks. CONCLUSION: Iron repletion by administration of a slow release iron preparation as a single infusion to PAH patients with iron deficiency without overt anaemia was well tolerated but provided no significant clinical benefit at 12 weeks. Clinical trial registered with ClinicalTrials.gov (NCT01447628).

Journal article

de Marvao A, McGurk KA, Zheng SL, Thanaj M, Bai W, Duan J, Biffi C, Mazzarotto F, Statton B, Dawes TJW, Savioli N, Halliday BP, Xu X, Buchan RJ, Baksi AJ, Quinlan M, Tokarczuk P, Tayal U, Francis C, Whiffin N, Theotokis PI, Zhang X, Jang M, Berry A, Pantazis A, Barton PJR, Rueckert D, Prasad SK, Walsh R, Ho CY, Cook SA, Ware JS, ORegan DPet al., 2021, Outcomes and phenotypic expression of rare variants in hypertrophic cardiomyopathy genes amongst UK Biobank participants, Publisher: Cold Spring Harbor Laboratory

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We compared outcomes and cardiovascular phenotypes in UK Biobank participants with whole exome sequencing stratified by sarcomere-encoding variant status.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The prevalence of rare variants (allele frequency &lt;0.00004) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n=5,727; 1 in 35), of which 0.24% (n=474, 1 in 423) were pathogenic or likely pathogenic variants (SARC-P/LP). SARC-P/LP variants were associated with increased risk of death or major adverse cardiac events compared to controls (HR 1.68, 95% CI 1.37-2.06, p&lt;0.001), mainly due to heart failure (HR 4.40, 95% CI 3.22-6.02, p&lt;0.001) and arrhythmia (HR 1.55, 95% CI 1.18-2.03, p=0.002). In 21,322 participants with cardiac magnetic resonance imaging, SARC-P/LP were associated with increased left ventricular maximum wall thickness (10.9±2.7 vs 9.4±1.6 mm, p&lt;0.001) and concentric remodelling (mass/volume ratio: 0.63±0.12 vs 0.58±0.09 g/mL, p&lt;0.001), but hypertrophy (≥13mm) was only present in 16% (n=7/43, 95% CI 7-31%). Other rare sarcomere-encoding variants had a weak effect on wall thickness (9.5±1.7 vs 9.4±1.6 mm, p=0.002) with no combined excess cardiovascular risk (HR 1.00 95% CI 0.92-1.08, p=0.9).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>In the general population, SARC-P/LP variants have low aggregate penetrance for overt HCM bu

Working paper

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., 2021, Systematic large-scale assessment of the genetic architecture of left ventricular non-compaction reveals diverse aetiologies, Genetics in Medicine, Vol: 23, Pages: 856-864, ISSN: 1098-3600

Purpose: To characterise the genetic architecture of left ventricular non-compaction (LVNC) and investigate the extent to which it may represent a distinct pathology or a secondary phenotype associated with other cardiac diseases.Methods: We performed rare variant association analysis with 840 LVNC cases and 125,748 gnomAD population controls, and compared results to similar analyses on dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Results: We observed substantial genetic overlap indicating that LVNC often represents a phenotypic variation of DCM or HCM. In contrast, truncating variants (TV) in MYH7, ACTN2 and PRDM16 were uniquely associated with LVNC and may reflect a distinct LVNC aetiology. In particular, MYH7 TV, generally considered non-pathogenic for cardiomyopathies, were 20-fold enriched in LVNC cases over controls. MYH7 TV heterozygotes identified in the UK Biobank and healthy volunteer cohorts also displayed significantly greater non-compaction compared to matched controls. RYR2 exon deletions and HCN4 transmembrane variants were also enriched in LVNC, supporting prior reports of association with arrhythmogenic LVNC phenotypes.Conclusions: LVNC is characterised by substantial genetic overlap with DCM/HCM but is also associated with distinct non-compaction and arrhythmia aetiologies. These results will enable enhanced application of LVNC genetic testing and help to distinguish pathological from physiological non-compaction.

Journal article

Ware J, Tadros R, Francis C, Xu X, Matthews P, watkins H, Bezzina Cet al., 2021, Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect, Nature Genetics, Vol: 53, Pages: 128-134, ISSN: 1061-4036

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young otherwise healthy individuals. We conducted genome-wide association studies (GWAS) and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases), and nine left ventricular (LV) traits in 19,260 UK Biobank participants with structurally-normal hearts. We identified 16 loci associated with HCM, 13 with DCM, and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased contractility with HCM risk. A polygenic risk score (PRS) explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that PRS may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.

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., 2021, Disease-specific variant pathogenicity prediction significantly improves variant interpretation in inherited cardiac conditions, Genetics in Medicine, Vol: 23, Pages: 69-79, 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 (&gt;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 (&gt;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

Lu W, Jia X, Chen W, Savioli N, de Marvao A, Shen L, O'Regan D, Duan Jet al., 2021, One-stage Multi-task Detector for 3D Cardiac MR Imaging, 25th International Conference on Pattern Recognition (ICPR), Publisher: IEEE COMPUTER SOC, Pages: 1949-1955, ISSN: 1051-4651

Conference paper

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

Pua CJ, Tham N, Chin CW, Walsh R, Khor CC, Toepfer CN, Repetti GG, Garfinkel AC, Ewoldt JF, Cloonan P, Chen CS, Lim SQ, Cai J, Loo LY, Kong SC, Chiang CWK, Whiffin N, de Marvao A, Lio PM, Hii AA, Yang CX, Le TT, Bylstra Y, Lim WK, Teo JX, Padilha K, Venturini G, Pan B, Govind R, Buchan RJ, Barton PJ, Tan P, Foo R, Yip JWL, Wong RCC, Chan WX, Pereira AC, Tang HC, Jamuar SS, Ware JS, Seidman JG, Seidman CE, Cook SAet al., 2020, Genetic studies of hypertrophic cardiomyopathy in Singaporeans identify variants in TNNI3 and TNNT2 that are common in Chinese patients, Circulation: Genomic and Precision Medicine, Vol: 13, Pages: 424-434, ISSN: 2574-8300

Background - To assess the genetic architecture of hypertrophic cardiomyopathy (HCM) in patients of predominantly Chinese ancestry.Methods - We sequenced HCM disease genes in Singaporean patients (n=224) and Singaporean controls (n=3,634), compared findings with additional populations and Caucasian HCM cohorts (n=6,179) and performed in vitro functional studies.Results - Singaporean HCM patients had significantly fewer confidently interpreted HCM disease variants (Pathogenic (P)/Likely Pathogenic (LP):18%, p<0.0001) but an excess of variants of unknown significance (exVUS: 24%, p<0.0001), as compared to Caucasians (P/LP: 31%, exVUS: 7%). Two missense variants in thin filament encoding genes were commonly seen in Singaporean HCM (TNNI3:p.R79C, disease allele frequency (AF)=0.018; TNNT2:p.R286H, disease AF=0.022) and are enriched in Singaporean HCM when compared with Asian controls (TNNI3:p.R79C, Singaporean controls AF=0.0055, p=0.0057, gnomAD-East Asian (gnomAD-EA) AF=0.0062, p=0.0086; TNNT2:p.R286H, Singaporean controls AF=0.0017, p<0.0001, gnomAD-EA AF=0.0009, p<0.0001). Both these variants have conflicting annotations in ClinVar and are of low penetrance (TNNI3:p.R79C, 0.7%; TNNT2:p.R286H, 2.7%) but are predicted to be deleterious by computational tools. In population controls, TNNI3:p.R79C carriers had significantly thicker left ventricular walls compared to non-carriers while its etiological fraction is limited (0.70, 95% CI: 0.35-0.86) and thus TNNI3:p.R79C is considered a VUS. Mutant TNNT2:p.R286H iPSC-CMs show hypercontractility, increased metabolic requirements and cellular hypertrophy and the etiological fraction (0.93, 95% CI: 0.83-0.97) support the likely pathogenicity of TNNT2:p.R286H.Conclusions - As compared to Caucasians, Chinese HCM patients commonly have low penetrance risk alleles in TNNT2 or TNNI3 but exhibit few clinically actionable HCM variants overall. This highlights the need for greater study of HCM genetics in non-Caucasian pop

Journal article

Pua CJ, Tham N, Chin CW, Walsh R, Khor CC, Toepfer CN, Repetti GG, Garfinkel AC, Ewoldt JF, Cloonan P, Chen CS, Lim SQ, Cai J, Loo LY, Kong SC, Chiang CWK, Whiffin N, de Marvao A, Lio PM, Hii AA, Yang CX, Le TT, Bylstra Y, Lim WK, Teo JX, Padilha K, Venturini G, Pan B, Govind R, Buchan RJ, Barton PJ, Tan P, Foo R, Yip JWL, Wong RCC, Chan WX, Pereira AC, Tang HC, Jamuar SS, Ware JS, Seidman JG, Seidman CE, Cook SAet al., 2020, Genetic Studies of Hypertrophic Cardiomyopathy in Singaporeans Identify Variants in TNNI3 and TNNT2 that Are Common in Chinese Patients., Circ Genom Precis Med

Background - To assess the genetic architecture of hypertrophic cardiomyopathy (HCM) in patients of predominantly Chinese ancestry. Methods - We sequenced HCM disease genes in Singaporean patients (n=224) and Singaporean controls (n=3,634), compared findings with additional populations and Caucasian HCM cohorts (n=6,179) and performed in vitro functional studies. Results - Singaporean HCM patients had significantly fewer confidently interpreted HCM disease variants (Pathogenic (P)/Likely Pathogenic (LP):18%, p<0.0001) but an excess of variants of unknown significance (exVUS: 24%, p<0.0001), as compared to Caucasians (P/LP: 31%, exVUS: 7%). Two missense variants in thin filament encoding genes were commonly seen in Singaporean HCM (TNNI3:p.R79C, disease allele frequency (AF)=0.018; TNNT2:p.R286H, disease AF=0.022) and are enriched in Singaporean HCM when compared with Asian controls (TNNI3:p.R79C, Singaporean controls AF=0.0055, p=0.0057, gnomAD-East Asian (gnomAD-EA) AF=0.0062, p=0.0086; TNNT2:p.R286H, Singaporean controls AF=0.0017, p<0.0001, gnomAD-EA AF=0.0009, p<0.0001). Both these variants have conflicting annotations in ClinVar and are of low penetrance (TNNI3:p.R79C, 0.7%; TNNT2:p.R286H, 2.7%) but are predicted to be deleterious by computational tools. In population controls, TNNI3:p.R79C carriers had significantly thicker left ventricular walls compared to non-carriers while its etiological fraction is limited (0.70, 95% CI: 0.35-0.86) and thus TNNI3:p.R79C is considered a VUS. Mutant TNNT2:p.R286H iPSC-CMs show hypercontractility, increased metabolic requirements and cellular hypertrophy and the etiological fraction (0.93, 95% CI: 0.83-0.97) support the likely pathogenicity of TNNT2:p.R286H. Conclusions - As compared to Caucasians, Chinese HCM patients commonly have low penetrance risk alleles in TNNT2 or TNNI3 but exhibit few clinically actionable HCM variants overall. This highlights the need for greater study of HCM genetics in non-Caucasian

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

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., 2020, Cardiac structure and function in schizophrenia: a cardiac MR 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: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

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

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