Publications
424 results found
Ware JS, 2018, Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: Recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel, Genetics in Medicine, Vol: 20, Pages: 351-359, ISSN: 1098-3600
PurposeIntegrating genomic sequencing in clinical care requires standardization of variant interpretation practices. The Clinical Genome Resource has established expert panels to adapt the American College of Medical Genetics and Genomics/Association for Molecular Pathology classification framework for specific genes and diseases. The Cardiomyopathy Expert Panel selected MYH7, a key contributor to inherited cardiomyopathies, as a pilot gene to develop a broadly applicable approach.MethodsExpert revisions were tested with 60 variants using a structured double review by pairs of clinical and diagnostic laboratory experts. Final consensus rules were established via iterative discussions.ResultsAdjustments represented disease-/gene-informed specifications (12) or strength adjustments of existing rules (5). Nine rules were deemed not applicable. Key specifications included quantitative frameworks for minor allele frequency thresholds, the use of segregation data, and a semiquantitative approach to counting multiple independent variant occurrences where fully controlled case-control studies are lacking. Initial inter-expert classification concordance was 93%. Internal data from participating diagnostic laboratories changed the classification of 20% of the variants (n = 12), highlighting the critical importance of data sharing.ConclusionThese adapted rules provide increased specificity for use in MYH7-associated disorders in combination with expert review and clinical judgment and serve as a stepping stone for genes and disorders with similar genetic and clinical characteristics.
Cai J, Bryant JA, Thu-Thao L, et al., 2017, Fractal analysis of left ventricular trabeculations is associated with impaired myocardial deformation in healthy Chinese, Journal of Cardiovascular Magnetic Resonance, Vol: 19, ISSN: 1097-6647
Background:Left ventricular (LV) non-compaction (LVNC) is defined by extreme LV trabeculation, but is measured variably. Here we examined the relationship between quantitative measurement in LV trabeculation and myocardial deformation in health and disease and determined the clinical utility of semi-automated assessment of LV trabeculations.Methods:Cardiovascular magnetic resonance (CMR) was performed in 180 healthy Singaporean Chinese (age 20–69 years; males, n = 91), using balanced steady state free precession cine imaging at 3T. The degree of LV trabeculation was assessed by fractal dimension (FD) as a robust measure of trabeculation complexity using a semi-automated technique. FD measures were determined in healthy men and women to derive normal reference ranges. Myocardial deformation was evaluated using feature tracking. We tested the utility of this algorithm and the normal ranges in 10 individuals with confirmed LVNC (non-compacted/compacted; NC/C ratio > 2.3 and ≥1 risk factor for LVNC) and 13 individuals with suspected disease (NC/C ratio > 2.3).Results:Fractal analysis is a reproducible means of assessing LV trabeculation extent (intra-class correlation coefficient: intra-observer, 0.924, 95% CI [0.761–0.973]; inter-observer, 0.925, 95% CI [0.821–0.970]). The overall extent of LV trabeculation (global FD: 1.205 ± 0.031) was independently associated with increased indexed LV end-diastolic volume and mass (sβ = 0.35; p < 0.001 and sβ = 0.13; p < 0.01, respectively) after adjusting for age, sex and body mass index. Increased LV trabeculation was independently associated with reduced global circumferential strain (sβ = 0.17, p = 0.013) and global diastolic circumferential and radial strain rates (sβ = 0.25, p < 0.001 and sβ = −0.15, p
Ware JS, Cook SA, 2017, Role of titin in cardiomyopathy: from DNA variants to patient stratification, Nature Reviews Cardiology, Vol: 15, Pages: 241-252, ISSN: 1759-5002
Dilated cardiomyopathy (DCM) affects approximately 1 in 250 individuals and is the leading indication for heart transplantation. DCM is often familial, and the most common genetic predisposition is a truncating variation in the giant sarcomeric protein, titin, which occurs in up to 15% of ambulant patients with DCM and 25% of end-stage or familial cases. In this article, we review the evidence for the role of titin truncation in the pathogenesis of DCM and our understanding of the molecular mechanisms and pathophysiological consequences of variation in the gene encoding titin (TTN). Such variation is common in the general population (up to 1% of individuals), and we consider key features that discriminate variants with disease-causing potential from those that are benign. We summarize strategies for clinical interpretation of genetic variants for use in the diagnosis of patients and the evaluation of their relatives. Finally, we consider the contemporary and potential future role for genetic stratification in cardiomyopathy and in the general population, evaluating titin variation as a predictor of outcome and treatment response for precision medicine.
Walsh R, Buchan R, Wilk A, et al., 2017, Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes, European Heart Journal, Vol: 38, Pages: 3461-3468, ISSN: 1522-9645
Aim: Hypertrophic cardiomyopathy (HCM)exhibits genetic heterogeneity that is dominated by variation in eight sarcomericgenes.Genetic variation in a large number of non-sarcomeric genes has also been implicated in HCM but not formally assessed. Here we used very large case and control cohorts to determine the extent to which variation in non-sarcomeric genes contributes to HCM.Methods and results: We sequenced known and putative HCM genes ina new large prospective HCM cohort (n=804) and analysed data alongside the largest published series of clinically genotyped HCM patients (n=6179), previously published HCM cohorts and reference population samples from the Exome Aggregation Consortium (ExAC, n=60,706) to assess variation in 31 genes implicated in HCM. We foundno significant excess of rare (minor allele frequency < 1:10,000 in ExAC)protein-alteringvariants over controls for most genes tested and conclude that novel variantsin these genes are rarely interpretable, even for genes with previous evidence of co-segregation (e.g. ACTN2). To provide an aid for variant interpretation, weintegratedHCM gene sequencedata with aggregatedpedigreeand functional data and suggest ameans of assessing genepathogenicity in HCMusing this evidence. Conclusions: We show that genetic variation in the majority of non-sarcomeric genes implicated in HCM is not associated with the condition, reinforce the fact that the sarcomeric gene variation is the primary cause of HCM known to date and underscore that the aetiology of HCM is unknown in the majority ofpatients.
Corden B, Jarman J, Whiffin N, et al., 2017, Titin Truncating Variants Predict Life-threatening Arrhythmias in Patients With Dilated Cardiomyopathy, Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Schafer S, Viswanathan S, Widjaja AA, et al., 2017, IL-11 is a crucial determinant of cardiovascular fibrosis, Nature, Vol: 552, Pages: 110-115, ISSN: 0028-0836
Fibrosis is a final common pathology in cardiovascular disease1. In the heart, fibrosis causes mechanical and electrical dysfunction1,2 and in the kidney, it predicts the onset of renal failure3. Transforming growth factor β1 (TGFB1) is the principal pro-fibrotic factor4,5 but its inhibition is associated with side effects due to its pleiotropic roles6,7. We hypothesised that downstream effectors of TGFB1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicities. Using integrated imaging-genomics analyses of primary human fibroblasts, we found that Interleukin 11 (IL11) upregulation is the dominant transcriptional response to TGFB1 exposure and required for its profibrotic effect. IL11 and its receptor (IL11RA) are expressed specifically in fibroblasts where they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il11 injection causes heart and kidney fibrosis and organ failure whereas genetic deletion of Il11ra1 is protective against disease. Thus, inhibition of IL11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These data reveal a central role of IL11 in fibrosis and we propose inhibition of IL11 as a new therapeutic strategy to treat fibrotic diseases.
Corden B, Jarman J, Whiffin N, et al., 2017, Titin Truncating Variants Predict Life-threatening Arrhythmias in Patients With Dilated Cardiomyopathy, Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: American Heart Association, Pages: E96-E96, ISSN: 0009-7322
Introduction: There is an urgent need for better arrhythmic risk stratification in non-ischaemic dilated cardiomyopathy (DCM), where the benefit of ICD implantation is unclear. Titin truncating variants (TTNtv) are the commonest genetic cause of DCM and are associated with early onset non-sustained ventricular tachycardia (NSVT) and atrial fibrillation (AF) in these patients.Hypothesis: We hypothesize that TTNtv status can predict potentially life threatening ventricular tachycardia (VT) or fibrillation (VF) and development of new persistent AF in DCM patients with CRT-D or ICD devices.Methods: We studied 117 DCM patients with an ICD or CRT-D and documented device-recorded arrhythmia over a median period of 4.2 years. Patients were stratified by TTN genotype (28 positive for a TTNtv, 89 negative). The primary outcome was time to first device-treated VT >200bpm or VF. Secondary outcome measures included time to first development of persistent AF.Results: TTNtv predicted the risk of receiving an appropriate ICD therapy for VT/VF (hazard ratio [HR] = 4.9, 95% confidence interval [CI]=2.3-10.7, P<0.0001). This association was independent of all covariates, including replacement fibrosis measured by late-gadolinium enhancement (LGE), (adjusted HR = 8.2, 95% CI 1.9-36.5, P=0.005). Individuals with both a TTNtv and fibrosis had a markedly greater risk for appropriate device therapy than those with neither (HR = 16.6, CI 3.5-79.3, P<0.0001). TTNtv were also a risk factor for developing new persistent AF (HR = 4.4, 95% CI = 1.45-13.1, P=0.006).Conclusion: TTNtv status is an important risk factor for clinically significant arrhythmia in patients with DCM and CRT-D or ICD devices. TTNtv status alone, or more powerfully in combination with fibrosis imaging by MRI, may provide an effective approach for risk stratifying the need for ICD therapy in DCM patients.
Tayal U, Newsome S, Buchan R, et al., 2017, Phenotype and clinical outcomes of titin cardiomyopathy, Journal of the American College of Cardiology, Vol: 70, Pages: 2264-2274, ISSN: 0735-1097
Background Improved understanding of dilated cardiomyopathy (DCM) due to titin truncation (TTNtv) may help guide patient stratification.Objectives The purpose of this study was to establish relationships among TTNtv genotype, cardiac phenotype, and outcomes in DCM.Methods In this prospective, observational cohort study, DCM patients underwent clinical evaluation, late gadolinium enhancement cardiovascular magnetic resonance, TTN sequencing, and adjudicated follow-up blinded to genotype for the primary composite endpoint of cardiovascular death, and major arrhythmic and major heart failure events.Results Of 716 subjects recruited (mean age 53.5 ± 14.3 years; 469 men [65.5%]; 577 [80.6%] New York Heart Association function class I/II), 83 (11.6%) had TTNtv. Patients with TTNtv were younger at enrollment (49.0 years vs. 54.1 years; p = 0.002) and had lower indexed left ventricular mass (5.1 g/m2 reduction; padjusted = 0.03) compared with patients without TTNtv. There was no difference in biventricular ejection fraction between TTNtv+/− groups. Overall, 78 of 604 patients (12.9%) met the primary endpoint (median follow-up 3.9 years; interquartile range: 2.0 to 5.8 years), including 9 of 71 patients with TTNtv (12.7%) and 69 of 533 (12.9%) without. There was no difference in the composite primary outcome of cardiovascular death, heart failure, or arrhythmic events, for patients with or without TTNtv (hazard ratio adjusted for primary endpoint: 0.92 [95% confidence interval: 0.45 to 1.87]; p = 0.82).Conclusions In this large, prospective, genotype-phenotype study of ambulatory DCM patients, we show that prognostic factors for all-cause DCM also predict outcome in TTNtv DCM, and that TTNtv DCM does not appear to be associated with worse medium-term prognosis.
Kassem HS, Walsh R, Barton PJ, et al., 2017, A comparative study of mutation screening of sarcomeric genes ( MYBPC3 , MYH7 , TNNT2 ) using single gene approach versus targeted gene panel next generation sequencing in a cohort of HCM patients in Egypt, Egyptian Journal of Medical Human Genetics, Vol: 18, Pages: 381-387, ISSN: 1110-8630
BackgroundNGS enables simultaneous sequencing of large numbers of associated genes in genetic heterogeneous disorders, in a more rapid and cost-effective manner than traditional technologies. However there have been limited direct comparisons between NGS and more established technologies to assess the sensitivity and false negative rates of this new approach. The scope of the present manuscript is to compare variants detected in MYBPC3, MYH7 and TNNT2 genes using the stepwise dHPLC/Sanger versus targeted NGS.MethodsIn this study, we have analysed a group of 150 samples of patients from the Bibliotheca Alexandrina-Aswan Heart Centre National HCM program. The genetic testing was simultaneously undertaken by high throughput denaturing high-performance liquid chromatography (dHPLC) followed by Sanger based sequencing and targeted next generation deep sequencing using panel of inherited cardiac genes (ICC). The panel included over 100 genes including the 3 sarcomeric genes. Analysis of the sequencing data of the 3 genes was undertaken in a double blinded strategy.ResultsNGS analysis detected all pathogenic and likely pathogenic variants identified by dHPLC (50 in total, some samples had double hits). There was a 0% false negative rate for NGS based analysis. Nineteen variants were missed by dHPLC and detected by NGS, thus increasing the diagnostic yield in this co- analysed cohort from 22.0% (33/150) to 31.3% (47/150).Of interest to note that the mutation spectrum in this Egyptian HCM population revealed a high rate of homozygosity in MYBPC3 and MYH7 genes in comparison to other population studies (6/150, 4%). None of the homozygous samples were detected by dHPLC analysis.ConclusionNGS provides a useful and rapid tool to allow panoramic screening of several genes simultaneously with a high sensitivity rate amongst genes of known etiologic role allowing high throughput analysis of HCM patients and relevant control series in a less characterised population.
Heinig M, Adriaens ME, Schafer S, et al., 2017, Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy, Genome Biology, Vol: 18, ISSN: 1474-7596
Background: Genetic variation is an important determinant of RNA transcription and splicing, which in turncontributes to variation in human traits, including cardiovascular diseases.Results: Here we report the first in-depth survey of heart transcriptome variation using RNA-sequencing in 97patients with dilated cardiomyopathy and 108 non-diseased controls. We reveal extensive differences of geneexpression and splicing between dilated cardiomyopathy patients and controls, affecting known as well as noveldilated cardiomyopathy genes. Moreover, we show a widespread effect of genetic variation on the regulation oftranscription, isoform usage, and allele-specific expression. Systematic annotation of genome-wide association SNPsidentifies 60 functional candidate genes for heart phenotypes, representing 20% of all published heart genome-wideassociation loci. Focusing on the dilated cardiomyopathy phenotype we found that eQTL variants are also enriched fordilated cardiomyopathy genome-wide association signals in two independent cohorts.Conclusions: RNA transcription, splicing, and allele-specific expression are each important determinants of the dilatedcardiomyopathy phenotype and are controlled by genetic factors. Our results represent a powerful resource for thefield of cardiovascular genetics.
Biffi C, Simoes Monteiro de Marvao A, Attard M, et al., 2017, Three-dimensional Cardiovascular Imaging-Genetics: A Mass Univariate Framework, Bioinformatics, ISSN: 1367-4803
Motivation: Left ventricular (LV) hypertrophy is a strong predictor of cardiovascular outcomes, but its genetic regulation remains largely unexplained. Conventional phenotyping relies on manual calculation of LV mass and wall thickness, but advanced cardiac image analysis presents an opportunity for highthroughput mapping of genotype-phenotype associations in three dimensions (3D).Results: High-resolution cardiac magnetic resonance images were automatically segmented in 1,124 healthy volunteers to create a 3D shape model of the heart. Mass univariate regression was used to plot a 3D effect-size map for the association between wall thickness and a set of predictors at each vertex in the mesh. The vertices where a significant effect exists were determined by applying threshold-free cluster enhancement to boost areas of signal with spatial contiguity. Experiments on simulated phenotypic signals and SNP replication show that this approach offers a substantial gain in statistical power for cardiac genotype-phenotype associations while providing good control of the false discovery rate. This framework models the effects of genetic variation throughout the heart and can be automatically applied to large population cohorts.Availability: The proposed approach has been coded in an R package freely available at https://doi.org/10.5281/zenodo.834610 together with the clinical data used in this work.
Ware JS, Wain LV, Channavajjhala SK, et al., 2017, Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia., Journal of Clinical Investigation, Vol: 127, Pages: 3367-3374, ISSN: 0021-9738
Thiazide diuretics are among the most widely used treatments for hypertension, but thiazide-induced hyponatremia (TIH), a clinically significant adverse effect, is poorly understood. Here, we have studied the phenotypic and genetic characteristics of patients hospitalized with TIH. In a cohort of 109 TIH patients, those with severe TIH displayed an extended phenotype of intravascular volume expansion, increased free water reabsorption, urinary prostaglandin E2 excretion, and reduced excretion of serum chloride, magnesium, zinc, and antidiuretic hormone. GWAS in a separate cohort of 48 TIH patients and 2,922 controls from the 1958 British birth cohort identified an additional 14 regions associated with TIH. We identified a suggestive association with a variant in SLCO2A1, which encodes a prostaglandin transporter in the distal nephron. Resequencing of SLCO2A1 revealed a nonsynonymous variant, rs34550074 (p.A396T), and association with this SNP was replicated in a second cohort of TIH cases. TIH patients with the p.A396T variant demonstrated increased urinary excretion of prostaglandin E2 and metabolites. Moreover, the SLCO2A1 phospho-mimic p.A396E showed loss of transporter function in vitro. These findings indicate that the phenotype of TIH involves a more extensive metabolic derangement than previously recognized. We propose one mechanism underlying TIH development in a subgroup of patients in which SLCO2A1 regulation is altered.
Goh VJ, Le T-T, Bryant J, et al., 2017, Novel index of maladaptive myocardial remodeling in hypertension, Circulation: Cardiovascular Imaging, Vol: 10, ISSN: 1941-9651
BACKGROUND: Hypertensive left ventricular hypertrophy (HTN-LVH) is a leading cause of heart failure. Conventional patterns of cardiac geometry do not adequately risk-stratify patients with HTN-LVH. Using cardiovascular magnetic resonance, we developed a novel Remodeling Index (RI) that was designed to detect an exaggerated hypertrophic response to hypertension and tested its potential to risk-stratify hypertensive patients. METHODS AND RESULTS: The RI was derived using LaPlace's Law (), and normal RI ranges were established in 180 healthy volunteers. The utility of the RI was examined in 256 asymptomatic hypertensive patients and 10 patients with heart failure with preserved ejection fraction. Hypertensive patients underwent multimodal cardiac assessment: contrast-enhanced cardiovascular magnetic resonance, echocardiograms, 24-hour blood pressure monitoring, and cardiac biomarkers (high-sensitivity cardiac troponins, NT-proBNP [N-terminal pro-B-type natriuretic peptide], and galectin-3). Blood pressure accounted for only 20% of the variance observed in LV mass. Although there was no association between blood pressure and myocardial fibrosis, LV mass was independently associated with fibrosis. Compared with hypertensive patients without LVH (n=191; 74.6%) and those with HTN-LVH and normal RI (n=50; 19.5%), patients with HTN-LVH and low RI (HTN-LVH/low RI; n=15, 5.9%) had an amplified myocardial response: elevated indexed LV masses (83±24 g/m2), more fibrosis (73%), and higher biomarkers of myocardial injury and dysfunction (P<0.05 for all). RI was similar in HTN-LVH/low RI and heart failure with preserved ejection fraction (4.1 [3.4-4.5] versus 3.7 [3.4-4.0], respectively; P=0.15). CONCLUSIONS: We suggest that RI provides an approach for stratifying hypertensive patients and is suitable for testing in other disease cohorts to assess its clinical utility. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT02670031.
Whiffin N, Walsh R, Govind R, et al., 2017, CardioClassifier – demonstrating the power of disease- and gene-specific computational decision support for clinical genome interpretation
<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Purpose</jats:title><jats:p>Internationally-adopted variant interpretation guidelines from the American College of Medical Genetics and Genomics (ACMG) are generic and require disease-specific refinement. Here we developed CardioClassifier (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.cardioclassifier.org">www.cardioclassifier.org</jats:ext-link>), a semi-automated decision-support tool for inherited cardiac conditions (ICCs).</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>CardioClassifier integrates data retrieved from multiple sources with user-input case-specific information, through an interactive interface, to support varian interpretation. Combining disease- and gene-specific knowledge with variant observations in large cohorts of cases and controls, we refined 14 computational ACMG criteria and created three ICC-specific rules.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We benchmarked CardioClassifier on 57 expertly-curated variants and show full retrieval of all computational data, concordantly activating 87.3% of rules. A generic annotation tool identified fewer than half as many clinically-actionable variants (64/219 vs 156/219, Fisher’s <jats:bold>P</jats:bold>=1.1x10-18), with important false positives; illustrating the critical importance of disease and gene-specific annotations. CardioClassifier identified putatively disease-causing variants in 33.7% of 327 cardiomyopathy cases, comparable with leading ICC laboratories. Through addition of manually-curated data, variants found in over 40% of cardiomyopathy cases are fully annotated, without requiring additional user-input data.</jats:p></jats:sec><jats:sec><jat
Tayal U, Newsome S, Walsh R, et al., 2017, Defining the genetic architecture of dilated cardiomyopathy- insights from population genetic variation and the role of titin, Publisher: OXFORD UNIV PRESS, Pages: 821-822, ISSN: 0195-668X
Schaefer S, Viswanathan S, Widjaja A, et al., 2017, Integrated target discovery screens identify a novel therapeutic target for cardiovascular fibrosis, Publisher: OXFORD UNIV PRESS, Pages: 1412-1412, ISSN: 0195-668X
Goh VJ, Le TT, Bryant J, et al., 2017, A novel marker of advanced ventricular remodeling in hypertension, Publisher: OXFORD UNIV PRESS, Pages: 618-618, ISSN: 0195-668X
Vassiliou VS, Flynn PD, Raphael CE, et al., 2017, Lipoprotein(a) in patients with aortic stenosis: insights from cardiovascular magnetic resonance, PLOS One, Vol: 12, ISSN: 1932-6203
BackgroundAortic stenosis is the most common age-related valvular pathology. Patients with aortic stenosis and myocardial fibrosis have worse outcome but the underlying mechanism is unclear. Lipoprotein(a) is associated with adverse cardiovascular risk and is elevated in patients with aortic stenosis. Although mechanistic pathways could link Lipoprotein(a) with myocardial fibrosis, whether the two are related has not been previously explored. In this study, we investigated whether elevated Lipoprotein(a) was associated with the presence of myocardial replacement fibrosis.MethodsA total of 110 patients with mild, moderate and severe aortic stenosis were assessed by late gadolinium enhancement (LGE) cardiovascular magnetic resonance to identify fibrosis. Mann Whitney U tests were used to assess for evidence of an association between Lp(a) and the presence or absence of myocardial fibrosis and aortic stenosis severity and compared to controls. Univariable and multivariable linear regression analysis were undertaken to identify possible predictors of Lp(a).ResultsThirty-six patients (32.7%) had no LGE enhancement, 38 (34.6%) had midwall enhancement suggestive of midwall fibrosis and 36 (32.7%) patients had subendocardial myocardial fibrosis, typical of infarction. The aortic stenosis patients had higher Lp(a) values than controls, however, there was no significant difference between the Lp(a) level in mild, moderate or severe aortic stenosis. No association was observed between midwall or infarction pattern fibrosis and Lipoprotein(a), in the mild/moderate stenosis (p = 0.91) or severe stenosis patients (p = 0.42).ConclusionThere is no evidence to suggest that higher Lipoprotein(a) leads to increased myocardial midwall or infarction pattern fibrosis in patients with aortic stenosis.
Tayal U, Buchan R, Whiffin N, et al., 2017, EVALUATION OF TITIN CARDIOMYOPATHY IN PATIENTS WITH DILATED CARDIOMYOPATHY REVEALS A BLUNTED HYPERTROPHIC RESPONSE, AN EARLY ARRHYTHMIC RISK AND A SIGNIFICANT INTERACTION WITH ALCOHOL, Annual Conference of the British-Cardiovascular-Society (BCS), Publisher: BMJ PUBLISHING GROUP, Pages: A95-A95, ISSN: 1355-6037
Lota A, Mouy F, Wassall R, et al., 2017, RELATIONSHIP BETWEEN PLASMA CONCENTRATIONS OF B-TYPE NATRIURETIC PEPTIDE AND EXERCISE CAPACITY IN HYPERTROPHIC CARDIOMYOPATHY, Annual Conference of the British-Cardiovascular-Society (BCS), Publisher: BMJ PUBLISHING GROUP, Pages: A96-A97, ISSN: 1355-6037
Tsao A, Lota A, Wassall R, et al., 2017, INCREMENTAL DIAGNOSTIC VALUE OF CARDIOVASCULAR MAGNETIC RESONANCE IN YOUNG ADULT SURVIVORS OF SUDDEN CARDIAC ARREST, Annual Conference of the British-Cardiovascular-Society (BCS), Publisher: BMJ PUBLISHING GROUP, Pages: A39-A40, ISSN: 1355-6037
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Halliday BP, Gulati A, Ali A, et al., 2017, Association between mid-wall late gadolinium enhancement and sudden cardiac death in patients with dilated cardiomyopathy and mild and moderate left ventricular systolic dysfunction, Circulation, Vol: 135, Pages: 2106-2115, ISSN: 0009-7322
Background—Current guidelines only recommend the use of an implantable cardioverter defibrillator (ICD) in patients with dilated cardiomyopathy (DCM) for the primary prevention of sudden cardiac death (SCD) in those with a left ventricular ejection fraction (LVEF)<35%. However, registries of out-of-hospital cardiac arrests demonstrate that 70-80% of such patients have a LVEF>35%. Patients with a LVEF>35% also have low competing risks of death from non-sudden causes. Therefore, those at high-risk of SCD may gain longevity from successful ICD therapy. We investigated whether late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) identified patients with DCM without severe LV systolic dysfunction at high-risk of SCD.Methods—We prospectively investigated the association between mid-wall late gadolinium enhancement (LGE) and the pre-specified primary composite outcome of SCD or aborted SCD amongst consecutive referrals with DCM and a LVEF≥40% to our center between January 2000 and December 2011, who did not have a pre-existing indication for ICD implantation.Results—Of 399 patients (145 women, median age 50 years, median LVEF 50%, 25.3% with LGE) followed for a median of 4.6 years, 18 of 101 (17.8%) patients with LGE reached the pre-specified end-point, compared to 7 of 298 (2.3%) without (HR 9.2; 95% CI 3.9-21.8; p<0.0001). Nine patients (8.9%) with LGE compared to 6 (2.0%) without (HR 4.9; 95% CI 1.8-13.5; p=0.002) died suddenly, whilst 10 patients (9.9%) with LGE compared to 1 patient (0.3%) without (HR 34.8; 95% CI 4.6-266.6; p<0.001) had aborted SCD. Following adjustment, LGE predicted the composite end-point (HR 9.3; 95% CI 3.9-22.3; p<0.0001), SCD (HR 4.8; 95% CI 1.7-13.8; p=0.003) and aborted SCD (HR 35.9; 95% CI 4.8-271.4; p<0.001). Estimated hazard ratios for the primary end-point for patients with a LGE extent of 0-2.5%, 2.5-5% and >5% compared to those without LGE were 10.6 (95%CI 3.9-29.4), 4.9 (9
Tarroni G, Oktay O, Bai W, et al., 2017, Learning-based heart coverage estimation for short-axis cine cardiac MR images, Functional Imaging and Modelling of the Heart (FIMH), Publisher: Springer, Pages: 73-82
The correct acquisition of short axis (SA) cine cardiac MRimage stacks requires the imaging of the full cardiac anatomy betweenthe apex and the mitral valve plane via multiple 2D slices. While in theclinical practice the SA stacks are usually checked qualitatively to en-sure full heart coverage, visual inspection can become infeasible for largeamounts of imaging data that is routinely acquired, e.g. in populationstudies such as the UK Biobank (UKBB). Accordingly, we propose alearning-based technique for the fully-automated estimation of the heartcoverage for SA image stacks. The technique relies on the identificationof cardiac landmarks (i.e. the apex and the mitral valve sides) on twochamber view long axis images and on the comparison of the landmarks’positions to the volume covered by the SA stack. Landmark detection isperformed using a hybrid random forest approach integrating both re-gression and structured classification models. The technique was appliedon 3000 cases from the UKBB and compared to visual assessment. Theobtained results (error rate = 2.3%, sens. = 73%, spec. = 90%) indicatethat the proposed technique is able to correctly detect the vast majorityof the cases with insufficient coverage, suggesting that it could be usedas a fully-automated quality control step for CMR SA image stacks.
Whiffin N, Minikel E, Walsh R, et al., 2017, Using high-resolution variant frequencies to empower clinical genome interpretation, Genetics in Medicine, Vol: 19, Pages: 1151-1158, ISSN: 1530-0366
Purpose: Whole exome and genome sequencing have transformed the discovery of genetic variants that cause human Mendelian disease, but discriminating pathogenic from benign variants remains a daunting challenge. Rarity is recognised as a necessary, although not sufficient, criterion for pathogenicity, but frequency cutoffs used in Mendelian analysis are often arbitrary and overly lenient. Recent very large reference datasets, such as the Exome Aggregation Consortium (ExAC), provide an unprecedented opportunity to obtain robust frequency estimates even for very rare variants.Methods: We present a statistical framework for the frequency-based filtering of candidate disease-causing variants, accounting for disease prevalence, genetic and allelic heterogeneity, inheritance mode, penetrance, and sampling variance in reference datasets.Results: Using the example of cardiomyopathy, we show that our approach reduces by two-thirds the number of candidate variants under consideration in the average exome, without removing true pathogenic variants (false positive rate<0.001).Conclusion: We outline a statistically robust framework for assessing whether a variant is 'too common' to be causative for a Mendelian disorder of interest. We present precomputed allele frequency cutoffs for all variants in the ExAC dataset.
Tayal U, Newsome S, Buchan R, et al., 2017, Truncating variants in titin independently predict early arrhythmias in patients with dilated cardiomyopathy, Journal of the American College of Cardiology, Vol: 69, Pages: 2466-2468, ISSN: 1558-3597
Lota A, Wassall R, Scott A, et al., 2017, T2 mapping by cardiovasular magnetic resonance in acute and recovered myocarditis: potential role in clinical surveillance, European Journal of Heart Failure, Supplement, Vol: 19, Pages: 258-258, ISSN: 1567-4215
Dawes T, Simoes monteiro de marvao A, Shi W, et al., 2017, Machine learning of three-dimensional right ventricular motion enables outcome prediction in pulmonary hypertension: a cardiac MR imaging study, Radiology, Vol: 283, Pages: 381-390, ISSN: 1527-1315
Purpose: To determine if patient survival and mechanisms of right ventricular (RV) failure in pulmonary hypertension (PH) could be predicted using supervised machine learning of three dimensional patterns of systolic cardiac motion. Materials and methods: The study was approved by a research ethics committee and participants gave written informed consent. 256 patients (143 females, mean age 63 ± 17) with newly diagnosed PH underwent cardiac MR imaging, right heart catheterization (RHC) and six minute walk testing (6MWT) with a median follow up of 4.0 years. Semi automated segmentation of short axis cine images was used to create a three dimensional model of right ventricular motion. Supervised principal components analysis identified patterns of systolic motion which were most strongly predictive of survival. Survival prediction was assessed by the difference in median survival time and the area under the curve (AUC) using time dependent receiver operator characteristic for one year survival. Results: At the end of follow up 33% (93/256) died and one underwent lung transplantation. Poor outcome was predicted by a loss of effective contraction in the septum and freewall coupled with reduced basal longitudinal motion. When added to conventional imaging, hemodynamic, functional and clinical markers, three dimensional cardiac motion improved survival prediction (area under the curve 0.73 vs 0.60, p<0.001) and provided greater differentiation by difference in median survival time between high and low risk groups (13.8 vs 10.7 years, p<0.001). Conclusion:Three dimensional motion modeling with machine learning approaches reveal the adaptations in function that occur early in right heart failure and independently predict outcomes in newly diagnosed PH patients.
Lahrouchi N, Raju H, Lodder EM, et al., 2017, Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome, Journal of the American College of Cardiology, Vol: 69, Pages: 2134-2145, ISSN: 1558-3597
BackgroundSudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology.ObjectivesThis study investigated the clinical utility and combined yield of post-mortem genetic testing (molecular autopsy) in cases of SADS and comprehensive clinical evaluation of surviving relatives.MethodsWe evaluated 302 expertly validated SADS cases with suitable DNA (median age: 24 years; 65% males) who underwent next-generation sequencing using an extended panel of 77 primary electrical disorder and cardiomyopathy genes. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. The yield of combined molecular autopsy and clinical evaluation in 82 surviving families was evaluated. A gene-level rare variant association analysis was conducted in SADS cases versus controls.ResultsA clinically actionable pathogenic or likely pathogenic variant was identified in 40 of 302 cases (13%). The main etiologies established were catecholaminergic polymorphic ventricular tachycardia and long QT syndrome (17 [6%] and 11 [4%], respectively). Gene-based rare variants association analysis showed enrichment of rare predicted deleterious variants in RYR2 (p = 5 × 10-5). Combining molecular autopsy with clinical evaluation in surviving families increased diagnostic yield from 26% to 39%.ConclusionsMolecular autopsy for electrical disorder and cardiomyopathy genes, using ACMG guidelines for variant classification, identified a modest but realistic yield in SADS. Our data highlighted the predominant role of catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, especially the RYR2 gene, as well as the minimal yield from other genes. Furthermore, we showed the enhanced utility of combined clinical and genetic evaluation.
Tayal U, Newsome S, Voges I, et al., 2017, MULTIMODALITY ASSESSMENT OF RISK IN DILATED CARDIOMYOPATHY-THE IMPORTANCE OF CMR, 12th Annual Meeting of the British-Society-of-Cardiovascular-Magnetic-Resonance (BSCMR), Publisher: BMJ PUBLISHING GROUP, Pages: A4-A4, ISSN: 1355-6037
Lota AS, Wassall R, Scott AD, et al., 2017, T2 MAPPING IN ACUTE AND RECOVERED MYOCARDITIS: POTENTIAL ROLE IN CLINICAL SURVEILLANCE, 12th Annual Meeting of the British-Society-of-Cardiovascular-Magnetic-Resonance (BSCMR), Publisher: BMJ PUBLISHING GROUP, Pages: A22-A24, ISSN: 1355-6037
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