Publications
424 results found
Chen H, Moreno-Moral A, Pesce F, et al., 2019, WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling, Nature Communications, Vol: 10, Pages: 1-19, ISSN: 2041-1723
Cardiac fibrosis is a final common pathology in inherited and acquired heart diseases that causes cardiac electrical and pump failure. Here, we use systems genetics to identify a pro-fibrotic gene network in the diseased heart and show that this network is regulated by the E3 ubiquitin ligase WWP2, specifically by the WWP2-N terminal isoform. Importantly, the WWP2-regulated pro-fibrotic gene network is conserved across different cardiac diseases characterized by fibrosis: human and murine dilated cardiomyopathy and repaired tetralogy of Fallot. Transgenic mice lacking the N-terminal region of the WWP2 protein show improved cardiac function and reduced myocardial fibrosis in response to pressure overload or myocardial infarction. In primary cardiac fibroblasts, WWP2 positively regulates the expression of pro-fibrotic markers and extracellular matrix genes. TGFβ1 stimulation promotes nuclear translocation of the WWP2 isoforms containing the N-terminal region and their interaction with SMAD2. WWP2 mediates the TGFβ1-induced nucleocytoplasmic shuttling and transcriptional activity of SMAD2.
Ye L, Tao ZT, Loo SJ, et al., 2019, Dexamethasone Inhibits Regeneration and Causes Ventricular Aneurysm in the Neonatal Porcine Heart After Myocardial Infarction, 14th Annual American-Heart-Association's Basic Cardiovascular Sciences (BCVS) Scientific Sessions - Integrative Approaches to Complex Cardiovascular Diseases, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7330
Halliday BP, Baksi AJ, Gulati A, et al., 2019, Outcome in dilated cardiomyopathy related to the extent, location and pattern of late gadolinium enhancement, JACC: Cardiovascular Imaging, Vol: 12, Pages: 1645-1655, ISSN: 1936-878X
ObjectivesThis study sought to investigate the association between the extent, location, and pattern of late gadolinium enhancement (LGE) and outcome in a large dilated cardiomyopathy (DCM) cohort.BackgroundThe relationship between LGE and prognosis in DCM is incompletely understood.MethodsWe examined the association between LGE and all-cause mortality and a sudden cardiac death (SCD) composite based on the extent, location, and pattern of LGE in DCM.ResultsOf 874 patients (588 men, median age 52 years) followed for a median of 4.9 years, 300 (34.3%) had nonischemic LGE. Estimated adjusted hazard ratios for patients with an LGE extent of 0 to 2.55%, 2.55% to 5.10%, and >5.10%, respectively, were 1.59 (95% confidence interval [CI]: 0.99 to 2.55), 1.56 (95% CI: 0.96 to 2.54), and 2.31 (95% CI: 1.50 to 3.55) for all-cause mortality, and 2.79 (95% CI: 1.42 to 5.49), 3.86 (95% CI: 2.09 to 7.13), and 4.87 (95% CI: 2.78 to 8.53) for the SCD end-point. There was a marked nonlinear relationship between LGE extent and outcome such that even small amounts of LGE predicted a substantial increase in risk. The presence of septal LGE was associated with increased mortality, but SCD was most associated with the combined presence of septal and free-wall LGE. Predictive models using LGE presence and location were superior to models based on LGE extent or pattern.ConclusionsIn DCM, the presence of septal LGE is associated with a large increase in the risk of death and SCD events, even when the extent is small. SCD risk is greatest with concomitant septal and free-wall LGE. The incremental value of LGE extent beyond small amounts and LGE pattern is limited.
Biffi C, Cerrolaza JJ, Tarroni G, et 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 ).
Garcia-Pavia P, Kim Y, Restrepo-Cordoba MA, et 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
Thomson KL, Ormondroyd E, Harper AR, et al., 2019, Analysis of 51 proposed hypertrophic cardiomyopathy genes from genome sequencing data in sarcomere negative cases has negligible diagnostic yield, Genetics in Medicine, Vol: 21, Pages: 1576-1584, ISSN: 1098-3600
PURPOSE: Increasing numbers of genes are being implicated in Mendelian disorders and incorporated into clinical test panels. However, lack of evidence supporting the gene-disease relationship can hinder interpretation. We explored the utility of testing 51 additional genes for hypertrophic cardiomyopathy (HCM), one of the most commonly tested Mendelian disorders. METHODS: Using genome sequencing data from 240 sarcomere gene negative HCM cases and 6229 controls, we undertook case-control and individual variant analyses to assess 51 genes that have been proposed for HCM testing. RESULTS: We found no evidence to suggest that rare variants in these genes are prevalent causes of HCM. One variant, in a single case, was categorized as likely to be pathogenic. Over 99% of variants were classified as a variant of uncertain significance (VUS) and 54% of cases had one or more VUS. CONCLUSION: For almost all genes, the gene-disease relationship could not be validated and lack of evidence precluded variant interpretation. Thus, the incremental diagnostic yield of extending testing was negligible, and would, we propose, be outweighed by problems that arise with a high rate of uninterpretable findings. These findings highlight the need for rigorous, evidence-based selection of genes for clinical test panels.
Bylstra YM, Kuan J, Lim W, et al., 2019, Bridging the gaps of uncertainty in genetic counselling with ethnic-specific data, 51st Conference of the European-Society-of-Human-Genetics (ESHG) in conjunction with the European Meeting on Psychosocial Aspects of Genetics (EMPAG), Publisher: NATURE PUBLISHING GROUP, Pages: 697-698, ISSN: 1018-4813
Corden B, Jarman J, Whiffin N, et al., 2019, Association between titin truncating variants and life-threatening cardiac arrhythmias in patients with dilated cardiomyopathy and implantable defibrillator, JAMA Network Open, Vol: 2, Pages: 1-12, ISSN: 2574-3805
Importance There is a need for better arrhythmic risk stratification in nonischemic dilated cardiomyopathy (DCM). Titin-truncating variants (TTNtvs) in the TTN gene are the most common genetic cause of DCM and may be associated with higher risk of arrhythmias in patients with DCM.Objective To determine if TTNtv status is associated with the development of life-threatening ventricular arrhythmia and new persistent atrial fibrillation in patients with DCM and implanted cardioverter defibrillator (ICD) or cardiac resynchronization therapy defibrillator (CRT-D) devices.Design, Setting, and Participants This retrospective, multicenter cohort study recruited 148 patients with or without TTNtvs who had nonischemic DCM and ICD or CRT-D devices from secondary and tertiary cardiology clinics in the United Kingdom from February 1, 2011, to June 30, 2016, with a median (interquartile range) follow-up of 4.2 (2.1-6.5) years. Exclusion criteria were ischemic cardiomyopathy, primary valve disease, congenital heart disease, or a known or likely pathogenic variant in the lamin A/C gene. Analyses were performed February 1, 2017, to May 31, 2017.Main Outcome and Measures The primary outcome was time to first device-treated ventricular tachycardia of more than 200 beats/min or first device-treated ventricular fibrillation. Secondary outcome measures included time to first development of persistent atrial fibrillation.Results Of 148 patients recruited, 117 adult patients with nonischemic DCM and an ICD or CRT-D device (mean [SD] age, 56.9 [12.5] years; 76 [65.0%] men; 106 patients [90.6%] with primary prevention indications) were included. Having a TTNtv was associated with a higher risk of receiving appropriate ICD therapy (shock or antitachycardia pacing) for ventricular tachycardia or fibrillation (hazard ratio [HR], 4.9; 95% CI, 2.2-10.7; P < .001). This association was independent of all covariates, including midwall fibrosis measured by late gadolinium enhanc
van Heesch S, Witte F, Schneider-Lunitz V, et al., 2019, The translational landscape of the human heart, Cell, Vol: 178, Pages: 242-260.e29, ISSN: 0092-8674
Gene expression in human tissue has primarily been studied on the transcriptional level, largely neglecting translational regulation. Here, we analyze the translatomes of 80 human hearts to identify new translation events and quantify the effect of translational regulation. We show extensive translational control of cardiac gene expression, which is orchestrated in a process-specific manner. Translation downstream of predicted disease-causing protein-truncating variants appears to be frequent, suggesting inefficient translation termination. We identify hundreds of previously undetected microproteins, expressed from lncRNAs and circRNAs, for which we validate the protein products in vivo. The translation of microproteins is not restricted to the heart and prominent in the translatomes of human kidney and liver. We associate these microproteins with diverse cellular processes and compartments and find that many locate to the mitochondria. Importantly, dozens of microproteins are translated from lncRNAs with well-characterized noncoding functions, indicating previously unrecognized biology.
Zhou J, Ng B, Ko NSJ, et al., 2019, Titin truncations lead to impaired cardiomyocyte autophagy and mitochondrial function <i>in vivo</i>, HUMAN MOLECULAR GENETICS, Vol: 28, Pages: 1971-1981, ISSN: 0964-6906
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- Citations: 14
Pillinger T, Osimo EF, de Marvao A, et 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.
Bylstra Y, Davila S, Lim WK, et al., 2019, Implementation of genomics in medical practice to deliver precision medicine for an Asian population, npj Genomic Medicine, Vol: 4, ISSN: 2056-7944
Whilst the underlying principles of precision medicine are comparable across the globe, genomic references, health practices, costs and discrimination policies differ in Asian settings compared to the reported initiatives involving European-derived populations. We have addressed these variables by developing an evolving reference base of genomic and phenotypic data and a framework to return medically significant variants to consenting research participants applicable for the Asian context. Targeting 10,000 participants, over 2000 Singaporeans, with no known pre-existing health conditions, have consented to an extensive clinical health screen, family health history collection, genome sequencing and ongoing follow-up. Genomic variants in a subset of genes associated with Mendelian disorders and drug responses are analysed using an in-house bioinformatics pipeline. A multidisciplinary team reviews the classification of variants and a research report is generated. Medically significant variants are returned to consenting participants through a bespoke return-of-result genomics clinic. Variant validation and subsequent clinical referral are advised as appropriate. The design and implementation of this flexible learning framework enables a cohort of detailed phenotyping and genotyping of healthy Singaporeans to be established and the frequency of disease-causing variants in this population to be determined. Our findings will contribute to international precision medicine initiatives, bridging gaps with ethnic-specific data and insights from this understudied population.
Le TT, Bryant JA, Ang BWY, et al., 2019, Discriminating between exercise induced cardiac remodeling and dilated cardiomyopathy using exercise cardiac MRI, Publisher: OXFORD UNIV PRESS, Pages: 160-160, ISSN: 2047-2404
Aw T-C, Huang W-T, Le T-T, et al., 2019, Author correction: high-sensitivity cardiac troponins in cardio-healthy subjects: a cardiovascular magnetic resonance imaging study., Scientific Reports, Vol: 9, Pages: 7686-7686, ISSN: 2045-2322
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Mazzarotto F, Tayal P, Buchan R, et 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
Tarroni G, Oktay O, Bai W, et al., 2019, Learning-based quality control for cardiac MR images, IEEE Transactions on Medical Imaging, Vol: 38, Pages: 1127-1138, ISSN: 0278-0062
The effectiveness of a cardiovascular magnetic resonance (CMR) scan depends on the ability of the operator to correctly tune the acquisition parameters to the subject being scanned and on the potential occurrence of imaging artefacts such as cardiac and respiratory motion. In the clinical practice, a quality control step is performed by visual assessment of the acquired images: however, this procedure is strongly operatordependent, cumbersome and sometimes incompatible with the time constraints in clinical settings and large-scale studies. We propose a fast, fully-automated, learning-based quality control pipeline for CMR images, specifically for short-axis image stacks. Our pipeline performs three important quality checks: 1) heart coverage estimation, 2) inter-slice motion detection, 3) image contrast estimation in the cardiac region. The pipeline uses a hybrid decision forest method - integrating both regression and structured classification models - to extract landmarks as well as probabilistic segmentation maps from both long- and short-axis images as a basis to perform the quality checks. The technique was tested on up to 3000 cases from the UK Biobank as well as on 100 cases from the UK Digital Heart Project, and validated against manual annotations and visual inspections performed by expert interpreters. The results show the capability of the proposed pipeline to correctly detect incomplete or corrupted scans (e.g. on UK Biobank, sensitivity and specificity respectively 88% and 99% for heart coverage estimation, 85% and 95% for motion detection), allowing their exclusion from the analysed dataset or the triggering of a new acquisition.
Lota AS, Halliday BP, Hatipoglu S, et al., 2019, Risk prediction in patients with mild dilated cardiomyopathy by cardiovascular magnetic resonance: integrating assessment of myocardial mechanics with tissue characterisation, Publisher: WILEY, Pages: 406-407, ISSN: 1388-9842
Yap L, Wang J-W, Moreno-Moral A, et al., 2019, <i>In Vivo</i> Generation of Post-infarct Human Cardiac Muscle by Laminin-Promoted Cardiovascular Progenitors, CELL REPORTS, Vol: 26, Pages: 3231-+, ISSN: 2211-1247
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- Citations: 29
Parikh VN, Caleshu C, Reuter C, et al., 2019, Regional Variation in RBM20 Causes a Highly Penetrant Arrhythmogenic Cardiomyopathy, Circulation: Heart Failure, Vol: 12, ISSN: 1941-3289
Background Variants in the cardiomyocyte-specific RNA splicing factor RBM20 have been linked to familial cardiomyopathy, but the causative genetic architecture and clinical consequences of this disease are incompletely defined. Methods and Results To define the genetic architecture of RBM20 cardiomyopathy, we first established a database of RBM20 variants associated with cardiomyopathy and compared these to variants observed in the general population with respect to their location in the RBM20 coding transcript. We identified 2 regions significantly enriched for cardiomyopathy-associated variants in exons 9 and 11. We then assembled a registry of 74 patients with RBM20 variants from 8 institutions across the world (44 index cases and 30 from cascade testing). This RBM20 patient registry revealed highly prevalent family history of sudden cardiac death (51%) and cardiomyopathy (72%) among index cases and a high prevalence of composite arrhythmias (including atrial fibrillation, nonsustained ventricular tachycardia, implantable cardiac defibrillator discharge, and sudden cardiac arrest, 43%). Patients harboring variants in cardiomyopathy-enriched regions identified by our variant database analysis were enriched for these findings. Further, these characteristics were more prevalent in the RBM20 registry than in large cohorts of patients with dilated cardiomyopathy and TTNtv cardiomyopathy and not significantly different from a cohort of patients with LMNA-associated cardiomyopathy. Conclusions Our data establish RBM20 cardiomyopathy as a highly penetrant and arrhythmogenic cardiomyopathy. These findings underline the importance of arrhythmia surveillance and family screening in this disease and represent the first step in defining the genetic architecture of RBM20 disease causality on a population level.
Bello G, Dawes T, Duan J, et al., 2019, Deep learning cardiac motion analysis for human survival prediction, Nature Machine Intelligence, Vol: 1, Pages: 95-104, ISSN: 2522-5839
Motion analysis is used in computer vision to understand the behaviour of moving objects in sequences of images. Optimizing the interpretation of dynamic biological systems requires accurate and precise motion tracking as well as efficient representations of high-dimensional motion trajectories so that these can be used for prediction tasks. Here we use image sequences of the heart, acquired using cardiac magnetic resonance imaging, to create time-resolved three-dimensional segmentations using a fully convolutional network trained on anatomical shape priors. This dense motion model formed the input to a supervised denoising autoencoder (4Dsurvival), which is a hybrid network consisting of an autoencoder that learns a task-specific latent code representation trained on observed outcome data, yielding a latent representation optimized for survival prediction. To handle right-censored survival outcomes, our network used a Cox partial likelihood loss function. In a study of 302 patients, the predictive accuracy (quantified by Harrell’s C-index) was significantly higher (P = 0.0012) for our model C = 0.75 (95% CI: 0.70–0.79) than the human benchmark of C = 0.59 (95% CI: 0.53–0.65). This work demonstrates how a complex computer vision task using high-dimensional medical image data can efficiently predict human survival.
Mazzarotto F, Girolami F, Boschi B, et al., 2019, Defining the diagnostic effectiveness of genes for inclusion in panels: the experience of two decades of genetic testing for hypertrophic cardiomyopathy at a single center, Genetics in Medicine, Vol: 21, Pages: 284-292, ISSN: 1098-3600
PurposeGenetic testing in hypertrophic cardiomyopathy (HCM) has long relied on Sanger sequencing of sarcomeric genes. The advent of next-generation sequencing (NGS) has catalyzed routine testing of additional genes of dubious HCM-causing potential. We used 19 years of genetic testing results to define a reliable set of genes implicated in Mendelian HCM and assess the value of expanded NGS panels.MethodsWe dissected genetic testing results from 1,198 single-center HCM probands and devised a widely applicable score to identify which genes yield effective results in the diagnostic setting.ResultsCompared with early panels targeting only fully validated sarcomeric HCM genes, expanded NGS panels allow the prompt recognition of probands with HCM-mimicking diseases. Scoring by “diagnostic effectiveness” highlighted that PLN should also be routinely screened besides historically validated genes for HCM and its mimics.ConclusionThe additive value of expanded panels in HCM genetic testing lies in the systematic screening of genes associated with HCM mimics, requiring different patient management. Only variants in a limited set of genes are highly actionable and interpretable in the clinic, suggesting that larger panels offer limited additional sensitivity. A score estimating the relative effectiveness of a given gene’s inclusion in diagnostic panels is proposed.
Miles C, Finocchiaro G, Papadakis M, et al., 2019, Sudden death and left ventricular involvement in arrhythmogenic cardiomyopathy, Circulation, Vol: 139, Pages: 1786-1797, ISSN: 0009-7322
BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disorder characterized by myocardial fibro-fatty replacement and an increased risk of sudden cardiac death (SCD). Originally described as a right ventricular (RV) disease, ACM is increasingly recognized as a biventricular entity. We evaluated pathological, genetic, and clinical associations in a large SCD cohort. METHODS: We investigated 5205 consecutive cases of SCD referred to a national cardiac pathology center between 1994 and 2018. Hearts and tissue blocks were examined by expert cardiac pathologists. Following comprehensive histological evaluation, 202 cases (4%) were diagnosed with ACM. Of these, 15 (7%) were diagnosed ante-mortem with dilated cardiomyopathy (DCM)(n=8) or ACM (n=7). Prior symptoms, medical history, circumstances of death, and participation in competitive sport were recorded. Post-mortem genetic testing was undertaken in 24/202 (12%). Rare genetic variants were classified according to American College of Medical Genetics and Genomics (ACMG) criteria. RESULTS: Of 202 ACM decedents (35.4±13.2 years; 82% male), 157 (78%) reported no prior cardiac symptoms. Forty-one decedents (41/202; 20%) were participants in competitive sport. The adjusted odds of dying during physical exertion were higher in males than females (OR 4.58; 95% CI 1.54-13.68; p=0.006) and in competitive athletes compared with non-athletes (OR 16.62; 95% CI 5.39-51.24; p<0.001). None of the decedents with an ante-mortem diagnosis of DCM fulfilled definite 2010 Task Force criteria. Macroscopic appearance of the heart was normal in 40/202 (20%) cases. There was left ventricular (LV) histopathological involvement in 176/202 (87%). Isolated RV disease was seen in 13%, isolated LV disease in 17%, and biventricular involvement in 70%. Among whole hearts, the most common areas of fibro-fatty infiltration were the LV posterobasal (68%) and anterolateral walls (58%). Post-mortem genetic testing yielded pa
Walsh R, Mazzarotto F, Whiffin N, et al., 2019, Quantitative approaches to variant classification increase the yield and precision of genetic testing in Mendelian diseases: The case of hypertrophic cardiomyopathy, Genome Medicine, Vol: 11, ISSN: 1756-994X
BackgroundInternational guidelines for variant interpretation in Mendelian disease set stringent criteria to report a variant as (likely) pathogenic, prioritising control of false-positive rate over test sensitivity and diagnostic yield. Genetic testing is also more likely informative in individuals with well-characterised variants from extensively studied European-ancestry populations. Inherited cardiomyopathies are relatively common Mendelian diseases that allow empirical calibration and assessment of this framework.MethodsWe compared rare variants in large hypertrophic cardiomyopathy (HCM) cohorts (up to 6179 cases) to reference populations to identify variant classes with high prior likelihoods of pathogenicity, as defined by etiological fraction (EF). We analysed the distribution of variants using a bespoke unsupervised clustering algorithm to identify gene regions in which variants are significantly clustered in cases.ResultsAnalysis of variant distribution identified regions in which variants are significantly enriched in cases and variant location was a better discriminator of pathogenicity than generic computational functional prediction algorithms. Non-truncating variant classes with an EF ≥ 0.95 were identified in five established HCM genes. Applying this approach leads to an estimated 14–20% increase in cases with actionable HCM variants, i.e. variants classified as pathogenic/likely pathogenic that might be used for predictive testing in probands’ relatives.ConclusionsWhen found in a patient confirmed to have disease, novel variants in some genes and regions are empirically shown to have a sufficiently high probability of pathogenicity to support a “likely pathogenic” classification, even without additional segregation or functional data. This could increase the yield of high confidence actionable variants, consistent with the framework and recommendations of current guidelines. The techniques outlined offer a consisten
Halliday BP, Wassall R, Lota A, et al., 2019, Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial, The Lancet, Vol: 393, Pages: 61-73, ISSN: 0140-6736
BackgroundPatients with dilated cardiomyopathy whose symptoms and cardiac function have recovered often ask whether their medications can be stopped. The safety of withdrawing treatment in this situation is unknown.MethodsWe did an open-label, pilot, randomised trial to examine the effect of phased withdrawal of heart failure medications in patients with previous dilated cardiomyopathy who were now asymptomatic, whose left ventricular ejection fraction (LVEF) had improved from less than 40% to 50% or greater, whose left ventricular end-diastolic volume (LVEDV) had normalised, and who had an N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) concentration less than 250 ng/L. Patients were recruited from a network of hospitals in the UK, assessed at one centre (Royal Brompton and Harefield NHS Foundation Trust, London, UK), and randomly assigned (1:1) to phased withdrawal or continuation of treatment. After 6 months, patients in the continued treatment group had treatment withdrawn by the same method. The primary endpoint was a relapse of dilated cardiomyopathy within 6 months, defined by a reduction in LVEF of more than 10% and to less than 50%, an increase in LVEDV by more than 10% and to higher than the normal range, a two-fold rise in NT-pro-BNP concentration and to more than 400 ng/L, or clinical evidence of heart failure, at which point treatments were re-established. The primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02859311.FindingsBetween April 21, 2016, and Aug 22, 2017, 51 patients were enrolled. 25 were randomly assigned to the treatment withdrawal group and 26 to continue treatment. Over the first 6 months, 11 (44%) patients randomly assigned to treatment withdrawal met the primary endpoint of relapse compared with none of those assigned to continue treatment (Kaplan-Meier estimate of event rate 45·7% [95% CI 28·5–67·2]; p=0·0001). After 6 months, 25 (96%) of 2
Whiffin N, Roberts AM, Minikel E, et al., 2019, Using high-resolution variant frequencies empowers clinical genome interpretation and enables investigation of genetic architecture, American Journal of Human Genetics, Vol: 104, Pages: 187-190, ISSN: 0002-9297
Horvat C, Johnson R, Lam L, et al., 2019, A gene-centric strategy for identifying disease-causing rare variants in dilated cardiomyopathy, Genetics in Medicine, Vol: 21, Pages: 133-143, ISSN: 1098-3600
PurposeWe evaluated strategies for identifying disease-causing variants in genetic testing for dilated cardiomyopathy (DCM).MethodsCardiomyopathy gene panel testing was performed in 532 DCM patients and 527 healthy control subjects. Rare variants in 41 genes were stratified using variant-level and gene-level characteristics.ResultsA majority of DCM cases and controls carried rare protein-altering cardiomyopathy gene variants. Variant-level characteristics alone had limited discriminative value. Differentiation between groups was substantially improved by addition of gene-level information that incorporated ranking of genes based on literature evidence for disease association. The odds of DCM were increased to nearly 9-fold for truncating variants or high-impact missense variants in the subset of 14 genes that had the strongest biological links to DCM (P <0.0001). For some of these genes, DCM-associated variants appeared to be clustered in key protein functional domains. Multiple rare variants were present in many family probands, however, there was generally only one “driver” pathogenic variant that cosegregated with disease.ConclusionRare variants in cardiomyopathy genes can be effectively stratified by combining variant-level and gene-level information. Prioritization of genes based on their a priori likelihood of disease causation is a key factor in identifying clinically actionable variants in cardiac genetic testing.
Bylstra Y, Kuan JL, Lim WK, et al., 2019, Population genomics in South East Asia captures unexpectedly high carrier frequency for treatable inherited disorders, GENETICS IN MEDICINE, Vol: 21, Pages: 207-212, ISSN: 1098-3600
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Ng B, Dong J, Viswanathan S, et al., 2019, IL-11 Is a Therapeutic Target in Idiopathic Pulmonary Fibrosis, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Lim W-W, Corden B, Sivakumar V, et al., 2018, Therapeutic Targeting of Interleukin-11 with Neutralizing Antibodies Prevents Cardiac Fibrosis, Scientific Sessions of the American-Heart-Association (AHA), Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: E71-E72, ISSN: 0009-7330
Dawes T, Simoes Monteiro de Marvao A, Shi W, et al., 2018, Identifying the optimal regional predictor of right ventricular global function: a high resolution 3D cardiac magnetic resonance study, Anaesthesia, Vol: 74, Pages: 312-320, ISSN: 0003-2409
Right ventricular (RV) function has prognostic value in acute, chronic and peri‐operative disease, although the complex RV contractile pattern makes rapid assessment difficult. Several two‐dimensional (2D) regional measures estimate RV function, however the optimal measure is not known. High‐resolution three‐dimensional (3D) cardiac magnetic resonance cine imaging was acquired in 300 healthy volunteers and a computational model of RV motion created. Points where regional function was significantly associated with global function were identified and a 2D, optimised single‐point marker (SPM‐O) of global function developed. This marker was prospectively compared with tricuspid annular plane systolic excursion (TAPSE), septum‐freewall displacement (SFD) and their fractional change (TAPSE‐F, SFD‐F) in a test cohort of 300 patients in the prediction of RV ejection fraction. RV ejection fraction was significantly associated with systolic function in a contiguous 7.3 cm2 patch of the basal RV freewall combining transverse (38%), longitudinal (35%) and circumferential (27%) contraction and coinciding with the four‐chamber view. In the test cohort, all single‐point surrogates correlated with RV ejection fraction (p < 0.010), but correlation (R) was higher for SPM‐O (R = 0.44, p < 0.001) than TAPSE (R = 0.24, p < 0.001) and SFD (R = 0.22, p < 0.001), and non‐significantly higher than TAPSE‐F (R = 0.40, p < 0.001) and SFD‐F (R = 0.43, p < 0.001). SPM‐O explained more of the observed variance in RV ejection fraction (19%) and predicted it more accurately than any other 2D marker (median error 2.8 ml vs 3.6 ml, p < 0.001). We conclude that systolic motion of the basal RV freewall predicts global function more accurately than other 2D estimators. However, no markers summarise 3D contractile patterns, limiting their predictive accuracy.
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