Publications
424 results found
Le TT, Tan RS, De Deyn M, et al., 2016, Cardiovascular magnetic resonance reference ranges for the heart and aorta in Chinese at 3T., Journal of Cardiovascular Magnetic Resonance, Vol: 18, Pages: 21-21, ISSN: 1532-429X
BACKGROUND: Cardiovascular magnetic resonance (CMR) reference ranges have not been well established in Chinese. Here we determined normal cardiac and aortic reference ranges in healthy Singaporean Chinese and investigated how these data might affect clinical interpretation of CMR scans. METHODS: In 180 healthy Singaporean Chinese (20 to 69 years old; males, n = 91), comprehensive cardiac assessment was performed using the steady state free precision technique (3T Ingenia, Philips) and images were analysed by two independent observers (CMR42, Circle Cardiovascular Imaging). Measurements were internally validated using standardized approaches: left ventricular mass (LVM) was measured in diastole and systole (with and without papillary muscles) and stroke volumes were compared in both ventricles. All reference ranges were stratified by sex and age; and "indeterminate/borderline" regions were defined statistically at the limits of the normal reference ranges. Results were compared with clinical measurements reported in the same individuals. RESULTS: LVM was equivalent in both phases (mean difference 3.0 ± 2.5 g; P = 0.22) and stroke volumes were not significantly different in the left and right ventricles (P = 0.91). Compared to females, males had larger left and right ventricular volumes (P < 0.001 for all). Indexed LVM was significantly higher in males compared to females (50 ± 7 versus 38 ± 5 g/m(2), respectively; P < 0.001). Overall, papillary muscles accounted for only ~2 % of the total LVM. Indexed atrial sizes and aortic root dimensions were similar between males and females (P > 0.05 for all measures). In both sexes, age correlated negatively with left and right ventricular volumes; and positively with aortic sinus and sinotubular junction diameters (P < 0.0001 f
Ye L, Tan S-H, Su L-P, et al., 2016, THREE-DIMENSIONAL SCAFFOLDS FOR EFFICIENT ARTERIAL ENDOTHELIAL CELL DIFFERENTIATION FROM HUMAN INDUCED PLURIPOTENT STEM CELLS, 65th Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC), Publisher: ELSEVIER SCIENCE INC, Pages: 2291-2291, ISSN: 0735-1097
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- Citations: 1
Rea G, Ware JS, Homfray T, et al., 2016, HISTIOCYTOID CARDIOMYOPATHY AND MICROPHTHALMIA WITH LINEAR SKIN DEFECTS SYNDROME: PHENOTYPES LINKED BY TRUNCATING VARIANTS IN <i>NDUFB11</i>, Annual Meeting of the British-Congenital-Cardiac-Association, Publisher: BMJ PUBLISHING GROUP, Pages: A18-A18, ISSN: 1355-6037
Durighel G, Tokarczuk PF, Karsa A, et al., 2016, Acute myocardial infarction: susceptibility-weighted cardiac MRI for the detection of reperfusion haemorrhage at 1.5 T, CLINICAL RADIOLOGY, Vol: 71, Pages: E150-E156, ISSN: 0009-9260
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- Citations: 2
Dawes T, de Marvao A, Shi W, et al., 2016, Use of artificial intelligence to predict survival in pulmonary hypertension, Spring Meeting on Clinician Scientists in Training, Publisher: ELSEVIER SCIENCE INC, Pages: 35-35, ISSN: 0140-6736
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- Citations: 1
de Marvao A, Meyer H, Dawes T, et al., 2016, Development of integrated high-resolution three-dimensional MRI and computational modelling techniques to identify novel genetic and anthropometric determinants of cardiac form and function, Spring Meeting on Clinician Scientists in Training, Publisher: ELSEVIER SCIENCE INC, Pages: 36-36, ISSN: 0140-6736
Walsh R, Thomson K, Ware J, et al., 2016, Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples, Publisher: bioRxiv
The accurate interpretation of variation in Mendelian disease genes has lagged behind data generation as sequencing has become increasingly accessible. Ongoing large sequencing efforts present huge interpretive challenges, but also provide an invaluable opportunity to characterize the spectrum and importance of rare variation. Here we analyze sequence data from 7,855 clinical cardiomyopathy cases and 60,706 ExAC reference samples to better understand genetic variation in a representative autosomal dominant disorder. We show that in some genes previously reported as important causes of a given cardiomyopathy, rare variation is not clinically informative and there is a high likelihood of false positive interpretation. By contrast, in other genes, we find that diagnostic laboratories may be overly conservative when assessing variant pathogenicity. We outline improved interpretation approaches for specific genes and variant classes and propose that these will increase the clinical utility of testing across a range of Mendelian diseases.
Dawes TJW, Gandhi A, de Marvao A, et al., 2016, Pulmonary artery stiffness is independently associated with right ventricular mass and function: a cardiac magnetic resonance study., Radiology, Vol: 280, ISSN: 1527-1315
PurposeTo determine the relationship between pulmonary artery (PA) stiffness and both right ventricular (RV) mass and function with cardiac magnetic resonance (MR) imaging.Materials and MethodsThe study was approved by the local research ethics committee, and all participants gave written informed consent. Cardiac MR imaging was performed at 1.5 T in 156 healthy volunteers (63% women; age range, 19–61 years; mean age, 36.1 years). High-temporal-resolution phase-contrast imaging was performed in the main and right PAs. Pulmonary pulse wave velocity (PWV) was determined by the interval between arterial systolic upslopes. RV function was assessed with feature tracking to derive peak systolic strain and strain rate, as well as peak early-diastolic strain rate. RV volumes, ejection fraction (RVEF), and mass were measured from the cine images. The association of pulmonary PWV with RV function and mass was quantified with univariate linear regression. Interstudy repeatability was assessed with intraclass correlation.ResultsThe repeatability coefficient for pulmonary PWV was 0.96. Increases in pulmonary PWV and RVEF were associated with increases in age (r = 0.32, P < .001 and r = 0.18, P = .025, respectively). After adjusting for age (P = .090), body surface area (P = .073), and sex (P = .005), pulmonary PWV demonstrated an independent positive association with RVEF (r = 0.34, P = .026). Significant associations were also seen with RV mass (r = 0.41, P = .004), RV radial strain (r = 0.38, P = .022), and strain rate (r = 0.35, P = .002), and independent negative associations were seen with radial (r = 0.27, P = .003), longitudinal (r = 0.40, P = .007), and circumferential (r = 0.31, P = .005) peak early-diastolic strain rate with the same covariates.ConclusionPulmonary PWV is reliably assessed with cardiac MR imaging. In subjects with no known cardiovascular disease, increasing PA stiffness is associated with increasing age and is also moderately associated with bo
Pua CJ, Bhalshankar J, Miao K, et al., 2016, Development of a Comprehensive Sequencing Assay for Inherited Cardiac Condition Genes, Journal of Cardiovascular Translational Research, Vol: 9, Pages: 3-11, ISSN: 1937-5395
Inherited cardiac conditions (ICCs) are characterisedby marked genetic and allelic heterogeneity and require extensivesequencing for genetic characterisation. We iterativelyoptimised a targeted gene capture panel for ICCs that includesdisease-causing, putatively pathogenic, research and phenocopygenes (n = 174 genes). We achieved high coverage ofthe target region on both MiSeq (>99.8 % at ≥20× read depth,n= 12) and NextSeq (>99.9 % at ≥20×, n= 48) platforms with100 % sensitivity and precision for single nucleotide variantsand indels across the protein-coding target on the MiSeq. In thefinal assay, 40 out of 43 established ICC genes informative inclinical practice achieved complete coverage (100 % at ≥20×).By comparison, whole exome sequencing (WES; ∼80×),deep WES (∼500×) and whole genome sequencing(WGS; ∼70×) had poorer performance (88.1, 99.2 and99.3 % respectively at ≥20×) across the ICC target. Theassay described here delivers highly accurate and affordablesequencing of ICC genes, complemented by accessiblecloud-based computation and informatics.
Creemers EE, Bawazeer A, Ugalde AP, et al., 2016, Genome-Wide Polyadenylation Maps Reveal Dynamic mRNA 3′-End Formation in the Failing Human Heart, CIRCULATION RESEARCH, Vol: 118, Pages: 433-438, ISSN: 0009-7330
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- Citations: 31
Van Aelst L, Voss S, Carai P, et al., 2016, Osteoglycin prevents cardiac dilatation and dysfunction after myocardial infarction through infarct collagen strengthening, Publisher: ACTA CARDIOLOGICA, Pages: 93-93, ISSN: 0001-5385
Marvao AD, Meyer HV, Dawes TJ, et al., 2016, Genome wide association analysis of the heart using high-resolution 3D cardiac MRI identifies new genetic loci underlying cardiac structure and function., Journal of Cardiovascular Magnetic Resonance, Vol: 18, ISSN: 1097-6647
Ware JS, Li J, Mazaika E, et al., 2016, Shared genetic etiology of peripartum and dilated cardiomyopathies, New England Journal of Medicine, Vol: 374, Pages: 233-241, ISSN: 1533-4406
Background: Peripartum cardiomyopathy (PPCM) shares some clinical features with idiopathic dilated cardiomyopathy, a disorder caused by mutations in over 40 genes, including TTN, which encodes the sarcomere protein titin.Methods: We sequenced 43 genes, with variants that have been associated with dilated cardiomyopathy, in 172 women with peripartum cardiomyopathy. We compared the prevalence of different types of variant (nonsense, frameshift, and splicing) in these women with the prevalence of these variants in persons with dilated cardiomyopathy and population controls.Results: We identified 26 distinct rare truncating variants in eight genes in women with PPCM. The prevalence of truncating variants (26 in 172 [15%]) was significantly higher than in a reference population of 60,706 individuals (4.7%, P=1.3x10-7), but was similar to a cohort of 332 dilated cardiomyopathy cases (55 in 332 [17%], P=0.81). Two thirds of identified truncating variants were in TTN ([10%], P=2.7x10-10 versus 1.4% in reference population), almost all located in the titin A-band. Seven of the TTN truncating variants were previously reported in cases of idiopathic dilated cardiomyopathy. In a clinically well-characterized cohort of women with PPCM (n=83), the presence of TTN truncating variants correlated with lower ejection fraction at one-year follow-up (P=0.005). Conclusions: The distribution of truncating variants in a large series of women with PPCM is remarkably similar to that found in idiopathic dilated cardiomyopathy. TTN truncating variants are the most prevalent genetic predisposition of each disorder.
Fatkin D, Lam L, Herman DS, et al., 2016, Titin truncating mutations: a rare cause of dilated cardiomyopathy in the young, Progress in Pediatric Cardiology, Vol: 40, Pages: 41-45, ISSN: 1058-9813
Truncating mutations in the TTN gene are the most common genetic cause of dilated cardiomyopathy in adults but their role in young patients is unknown. We studied 82 young dilated cardiomyopathy subjects and found that the prevalence of truncating TTN mutations in adolescents was similar to adults, but surprisingly few truncating TTN mutations were identified in affected children, including one confirmed de novo variant. In several cases, truncating TTN mutations in children with dilated cardiomyopathy had evidence of additional clinical or genetic risk factors. These findings have implications for genetic testing and suggest that single truncating TTN mutations are insufficient alone to cause pediatric-onset dilated cardiomyopathy.
Bai W, Peressutti D, Parisot S, et al., 2016, Beyond the AHA 17-segment model: Motion-driven parcellation of the left ventricle, 6th International Workshop, STACOM 2015, Held in Conjunction with MICCAI 2015, Munich, Germany, October 9, 2015, Publisher: Springer, Pages: 13-20, ISSN: 0302-9743
A major challenge for cardiac motion analysis is the highdimensionality of the motion data. Conventionally, the AHA model is used for dimensionality reduction, which divides the left ventricle into 17 segments using criteria based on anatomical structures. In this paper, a novel method is proposed to divide the left ventricle into homogeneous parcels in terms of motion trajectories. We demonstrate that the motion-driven parcellation has good reproducibility and use it for data reduction and motion description on a dataset of 1093 subjects. The resulting motion descriptor achieves high performance on two exemplar applications, namely gender and age predictions. The proposed method has the potential to be applied to groupwise motion analysis.
Hinson JT, Chopra A, Swist S, et al., 2015, Titin Mutations in IPS Cells Define Sarcomere Insufficiency as a Cause of Dilated Cardiomyopathy (<i>Best of Basic Science Abstract</i>), Scientific Sessions and Resuscitation Science Symposium of the American-Heart-Association (AHA), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Dawes T, Gandhi A, de Marvao AS, et al., 2015, Pulmonary Artery Stiffness is an Independent Predictor of Right Ventricular Mass and Function, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Dawes T, de Marvao A, Shi W, et al., 2015, Systolic Motion of the Basal Right Ventricular Freewall is the Strongest Predictor of Global Function: A High Resolution 3D Cardiac Magnetic Resonance Study, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
de Marvao A, Dawes TJW, Shi W, et al., 2015, Precursors of the hypertensive heart phenotype develop in normotensive adults: a high resolution 3D MRI study, JACC: Cardiovascular Imaging, Vol: 8, Pages: 1260-1269, ISSN: 1936-878X
ObjectivesThis 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.BackgroundLV hypertrophy and remodeling occur in response to hemodynamic stress but little is known about how these phenotypic changes are initiated in the general population.MethodsIn 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.ResultsThere 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).ConclusionsThese 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 hyper
Schafer S, Miao K, Benson CC, et al., 2015, Alternative Splicing Signatures in RNA-seq Data: Percent Spliced in (PSI)., Curr Protoc Hum Genet, Vol: 87, Pages: 11.16.1-11.16.14
Thousands of alternative exons are spliced out of messenger RNA to increase protein diversity. High-throughput sequencing of short cDNA fragments (RNA-seq) generates a genome-wide snapshot of these post-transcriptional processes. RNA-seq reads yield insights into the regulation of alternative splicing by revealing the usage of known or unknown splice sites as well as the expression level of exons. Constitutive exons are never covered by split alignments, whereas alternative exonic parts are located within highly expressed splicing junctions. The ratio between reads including or excluding exons, also known as percent spliced in index (PSI), indicates how efficiently sequences of interest are spliced into transcripts. This protocol describes a method to calculate the PSI without prior knowledge of splicing patterns. It provides a quantitative, global assessment of exon usage that can be integrated with other tools that identify differential isoform processing. Novel, complex splicing events along a genetic locus can be visualized in an exon-centric manner and compared across conditions.
Bai W, Shi W, de Marvao A, et al., 2015, A bi-ventricular cardiac atlas built from 1000+ high resolution MR images of healthy subjects and an analysis of shape and motion, Medical Image Analysis, Vol: 26, Pages: 133-145, ISSN: 1361-8423
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.
Hinson JT, Chopra A, Nafissi N, et al., 2015, Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy, Science, Vol: 349, Pages: 982-986, ISSN: 1095-9203
Human mutations that truncate the massive sarcomere protein titin [TTN-truncating variants (TTNtvs)] are the most common genetic cause for dilated cardiomyopathy (DCM), a major cause of heart failure and premature death. Here we show that cardiac microtissues engineered from human induced pluripotent stem (iPS) cells are a powerful system for evaluating the pathogenicity of titin gene variants. We found that certain missense mutations, like TTNtvs, diminish contractile performance and are pathogenic. By combining functional analyses with RNA sequencing, we explain why truncations in the A-band domain of TTN cause DCM, whereas truncations in the I band are better tolerated. Finally, we demonstrate that mutant titin protein in iPS cell-derived cardiomyocytes results in sarcomere insufficiency, impaired responses to mechanical and β-adrenergic stress, and attenuated growth factor and cell signaling activation. Our findings indicate that titin mutations cause DCM by disrupting critical linkages between sarcomerogenesis and adaptive remodeling.
Dawes T, De Marvao A, Shi W, et al., 2015, Prognostic value of right heart adaptation to pulmonary arterial hypertension: a prospective cohort study, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 708-709, ISSN: 0195-668X
Mazzarotto F, Walsh R, Buchan RJ, et al., 2015, Comprehensive sequencing of dilated cardiomyopathy genes reveals additive effects of multiple genes on disease risk and severity, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 523-523, ISSN: 0195-668X
Wang M, Sips P, Khin E, et al., 2015, Wars2 regulates cardiac angiogenesis, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 255-255, ISSN: 0195-668X
Pua CJ, Miao K, Bhalshankar J, et al., 2015, Targeted versus whole exome re-sequencing for clinical diagnostic application in inherited cardiac conditions, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 531-531, ISSN: 0195-668X
Schafer S, Adami E, Heinig M, et al., 2015, Translational regulation shapes the molecular landscape of complex disease phenotypes, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 605-606, ISSN: 0195-668X
Tayal U, Mazzarotto F, Buchan R, et al., 2015, Comprehensive Assessment of Rare Genetic Variation in Dilated Cardiomyopathy Genes in Patients and Controls (vol 101, pg A41, 2015), HEART, Vol: 101, ISSN: 1355-6037
Corden B, De Marvao ASM, Dawes TJW, et al., 2015, Left ventricular remodelling with increasing body fat: a 3D cardiac phenotyping study, Congress of the European-Society-of-Cardiology (ESC), Publisher: Oxford University Press (OUP), Pages: 118-118, ISSN: 1522-9645
Francis C, de Marvao A, O'Regan DP, et al., 2015, AORTOPATHY-CAUSING MUTATIONS INCREASE AORTIC STIFFNESS IN HEALTHY INDIVIDUALS, British-Cardiac-Society (BCS) Annual Conference on Hearts and Genes, Publisher: BMJ PUBLISHING GROUP, Pages: A99-A99, ISSN: 1355-6037
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