Publications
424 results found
Raphael C, Mitchell F, Kanaganayagam G, et al., 2021, Cardiovascular magnetic resonance predictors of heart failure in hypertrophic cardiomyopathy: the role of myocardial replacement fibrosis and the microcirculation, Journal of Cardiovascular Magnetic Resonance, Vol: 26, ISSN: 1097-6647
IntroductionHeart failure (HF) in hypertrophic cardiomyopathy (HCM) is associated with high morbidity and mortality. Predictors of HF, in particular the role of myocardial fibrosis and microvascular ischemia remain unclear. We assessed the predictive value of cardiovascular magnetic resonance (CMR) for development of HF in HCM in an observational cohort study.MethodsSerial patients with HCM underwent CMR, including adenosine first-pass perfusion, left atrial (LA) and left ventricular (LV) volumes indexed to body surface area (i) and late gadolinium enhancement (%LGE- as a % of total myocardial mass). We used a composite endpoint of HF death, cardiac transplantation, and progression to NYHA class III/IV.ResultsA total of 543 patients with HCM underwent CMR, of whom 94 met the composite endpoint at baseline. The remaining 449 patients were followed for a median of 5.6 years. Thirty nine patients (8.7%) reached the composite endpoint of HF death (n = 7), cardiac transplantation (n = 2) and progression to NYHA class III/IV (n = 20). The annual incidence of HF was 2.0 per 100 person-years, 95% CI (1.6–2.6). Age, previous non-sustained ventricular tachycardia, LV end-systolic volume indexed to body surface area (LVESVI), LA volume index ; LV ejection fraction, %LGE and presence of mitral regurgitation were significant univariable predictors of HF, with LVESVI (Hazard ratio (HR) 1.44, 95% confidence interval (95% CI) 1.16–1.78, p = 0.001), %LGE per 10% (HR 1.44, 95%CI 1.14–1.82, p = 0.002) age (HR 1.37, 95% CI 1.06–1.77, p = 0.02) and mitral regurgitation (HR 2.6, p = 0.02) remaining independently predictive on multivariable analysis. The presence or extent of inducible perfusion defect assessed using a visual score did not predict outcome (p = 0.16, p = 0.27 respectively).DiscussionThe annual incidence of HF in a contemporary ambulatory HCM population undergoing CMR
Le T-T, Ang BWY, Bryant JA, et al., 2021, Multiparametric exercise stress cardiovascular magnetic resonance in the diagnosis of coronary artery disease: the EMPIRE trial, Journal of Cardiovascular Magnetic Resonance, Vol: 23, Pages: 1-11, ISSN: 1097-6647
BackgroundStress cardiovascular magnetic resonance (CMR) offers assessment of ventricular function, myocardial perfusion and viability in a single examination to detect coronary artery disease (CAD).We developed an in-scanner exercise stress CMR (ExCMR) protocol using supine cycle ergometer and aimed to examine the diagnostic value of a multiparametric approach in patients with suspected CAD, compared with invasive fractional flow reserve (FFR) as the reference gold standard.MethodsIn this single-centre prospective study, patients who had symptoms of angina and at least one cardiovascular disease risk factor underwent both ExCMR and invasive angiography with FFR. Rest-based left ventricular function (ejection fraction, regional wall motion abnormalities), tissue characteristics and exercise stress-derived (perfusion defects, inducible regional wall motion abnormalities and peak exercise cardiac index percentile-rank) CMR parameters were evaluated in the study.ResultsIn the 60 recruited patients with intermediate CAD risk, 50% had haemodynamically significant CAD based on FFR. Of all the CMR parameters assessed, the late gadolinium enhancement, stress-inducible regional wall motion abnormalities, perfusion defects and peak exercise cardiac index percentile-rank were independently associated with FFR-positive CAD. Indeed, this multiparametric approach offered the highest incremental diagnostic value compared to a clinical risk model (χ2 for the diagnosis of FFR-positive increased from 7.6 to 55.9; P < 0.001) and excellent performance [c-statistic area under the curve 0.97 (95% CI: 0.94–1.00)] in discriminating between FFR-normal and FFR-positive patients.ConclusionThe study demonstrates the clinical potential of using in-scanner multiparametric ExCMR to accurately diagnose CAD.Trial registration: ClinicalTrials.gov, NCT03217227, Registered 11 July 2017–Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03217227?id=NCT03
Garnier S, Harakalova M, Weiss S, et al., 2021, Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23, European Heart Journal, Vol: 42, Pages: 2000-2011, ISSN: 0195-668X
Aims Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure.Methods and results We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10−11 and 7.7 × 10−4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10−8 and 1.4 × 10−3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene.Conclusion This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.
Whiffin N, Karczewski KJ, Zhang X, et al., 2021, Characterising the loss-of-function impact of 5 ' untranslated region variants in 15,708 individuals (vol 11, 2523, 2020), Nature Communications, Vol: 12, Pages: 1-1, ISSN: 2041-1723
de Marvao A, McGurk KA, Zheng SL, et al., 2021, Outcomes and phenotypic expression of rare variants in hypertrophic cardiomyopathy genes amongst UK Biobank participants
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We compared outcomes and cardiovascular phenotypes in UK Biobank participants with whole exome sequencing stratified by sarcomere-encoding variant status.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The prevalence of rare variants (allele frequency <0.00004) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n=5,727; 1 in 35), of which 0.24% (n=474, 1 in 423) were pathogenic or likely pathogenic variants (SARC-P/LP). SARC-P/LP variants were associated with increased risk of death or major adverse cardiac events compared to controls (HR 1.68, 95% CI 1.37-2.06, p<0.001), mainly due to heart failure (HR 4.40, 95% CI 3.22-6.02, p<0.001) and arrhythmia (HR 1.55, 95% CI 1.18-2.03, p=0.002). In 21,322 participants with cardiac magnetic resonance imaging, SARC-P/LP were associated with increased left ventricular maximum wall thickness (10.9±2.7 vs 9.4±1.6 mm, p<0.001) and concentric remodelling (mass/volume ratio: 0.63±0.12 vs 0.58±0.09 g/mL, p<0.001), but hypertrophy (≥13mm) was only present in 16% (n=7/43, 95% CI 7-31%). Other rare sarcomere-encoding variants had a weak effect on wall thickness (9.5±1.7 vs 9.4±1.6 mm, p=0.002) with no combined excess cardiovascular risk (HR 1.00 95% CI 0.92-1.08, p=0.9).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>In the general population, SARC-P/LP variants have low aggregate penetrance for overt HCM bu
Mazzarotto F, Hawley MH, Beltrami M, et al., 2021, Systematic large-scale assessment of the genetic architecture of left ventricular non-compaction reveals diverse aetiologies, Genetics in Medicine, Vol: 23, Pages: 856-864, ISSN: 1098-3600
Purpose: To characterise the genetic architecture of left ventricular non-compaction (LVNC) and investigate the extent to which it may represent a distinct pathology or a secondary phenotype associated with other cardiac diseases.Methods: We performed rare variant association analysis with 840 LVNC cases and 125,748 gnomAD population controls, and compared results to similar analyses on dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Results: We observed substantial genetic overlap indicating that LVNC often represents a phenotypic variation of DCM or HCM. In contrast, truncating variants (TV) in MYH7, ACTN2 and PRDM16 were uniquely associated with LVNC and may reflect a distinct LVNC aetiology. In particular, MYH7 TV, generally considered non-pathogenic for cardiomyopathies, were 20-fold enriched in LVNC cases over controls. MYH7 TV heterozygotes identified in the UK Biobank and healthy volunteer cohorts also displayed significantly greater non-compaction compared to matched controls. RYR2 exon deletions and HCN4 transmembrane variants were also enriched in LVNC, supporting prior reports of association with arrhythmogenic LVNC phenotypes.Conclusions: LVNC is characterised by substantial genetic overlap with DCM/HCM but is also associated with distinct non-compaction and arrhythmia aetiologies. These results will enable enhanced application of LVNC genetic testing and help to distinguish pathological from physiological non-compaction.
Ware J, Tadros R, Francis C, et al., 2021, Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect, Nature Genetics, Vol: 53, Pages: 128-134, ISSN: 1061-4036
The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young otherwise healthy individuals. We conducted genome-wide association studies (GWAS) and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases), and nine left ventricular (LV) traits in 19,260 UK Biobank participants with structurally-normal hearts. We identified 16 loci associated with HCM, 13 with DCM, and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased contractility with HCM risk. A polygenic risk score (PRS) explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that PRS may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.
Bylstra Y, Lim WK, Kam S, et al., 2021, Family history assessment significantly enhances delivery of precision medicine in the genomics era, Genome Medicine: medicine in the post-genomic era, Vol: 13, ISSN: 1756-994X
BACKGROUND: Family history has traditionally been an essential part of clinical care to assess health risks. However, declining sequencing costs have precipitated a shift towards genomics-first approaches in population screening programs rendering the value of family history unknown. We evaluated the utility of incorporating family history information for genomic sequencing selection. METHODS: To ascertain the relationship between family histories on such population-level initiatives, we analysed whole genome sequences of 1750 research participants with no known pre-existing conditions, of which half received comprehensive family history assessment of up to four generations, focusing on 95 cancer genes. RESULTS: Amongst the 1750 participants, 866 (49.5%) had high-quality standardised family history available. Within this group, 73 (8.4%) participants had an increased family history risk of cancer (increased FH risk cohort) and 1 in 7 participants (n = 10/73) carried a clinically actionable variant inferring a sixfold increase compared with 1 in 47 participants (n = 17/793) assessed at average family history cancer risk (average FH risk cohort) (p = 0.00001) and a sevenfold increase compared to 1 in 52 participants (n = 17/884) where family history was not available (FH not available cohort) (p = 0.00001). The enrichment was further pronounced (up to 18-fold) when assessing only the 25 cancer genes in the American College of Medical Genetics (ACMG) Secondary Findings (SF) genes. Furthermore, 63 (7.3%) participants had an increased family history cancer risk in the absence of an apparent clinically actionable variant. CONCLUSIONS: These findings demonstrate that the collection and analysis of comprehensive family history and genomic data are complementary and in combination can prioritise individuals for genomic analysis. Thus, family history remains a critical component of health risk assessment, p
Dong J, Viswanathan S, Adami E, et al., 2021, Hepatocyte-specific IL11 cis-signaling drives lipotoxicity and underlies the transition from NAFLD to NASH, Nature Communications, Vol: 12, Pages: 1-15, ISSN: 2041-1723
IL11 is important for fibrosis in non-alcoholic steatohepatitis (NASH) but its role beyond the stroma in liver disease is unclear. Here, we investigate the role of IL11 in hepatocyte lipotoxicity. Hepatocytes highly express IL11RA and secrete IL11 in response to lipid loading. Autocrine IL11 activity causes hepatocyte death through NOX4-derived ROS, activation of ERK, JNK and caspase-3, impaired mitochondrial function and reduced fatty acid oxidation. Paracrine IL11 activity stimulates hepatic stellate cells and causes fibrosis. In mouse models of NASH, hepatocyte-specific deletion of Il11ra1 protects against liver steatosis, fibrosis and inflammation while reducing serum glucose, cholesterol and triglyceride levels and limiting obesity. In mice deleted for Il11ra1, restoration of IL11 cis-signaling in hepatocytes reconstitutes steatosis and inflammation but not fibrosis. We found no evidence for the existence of IL6 or IL11 trans-signaling in hepatocytes or NASH. These data show that IL11 modulates hepatocyte metabolism and suggests a mechanism for NAFLD to NASH transition.
Zhang X, Walsh R, Whiffin N, et al., 2021, Disease-specific variant pathogenicity prediction significantly improves variant interpretation in inherited cardiac conditions, Genetics in Medicine, Vol: 23, Pages: 69-79, ISSN: 1098-3600
Background: Accurate discrimination of benign and pathogenic rare variation remains a priority for clinical genome interpretation. State-of-the-art machine learning tools are useful for genome-wide variant prioritisation but remain imprecise. Since the relationship between molecular consequence and likelihood of pathogenicity varies between genes with distinct molecular mechanisms, we hypothesised that a disease-specific classifier may outperform existing genome-wide tools. Methods: We present a novel disease-specific variant classification tool, CardioBoost, that estimates the probability of pathogenicity for rare missense variants in inherited cardiomyopathies and arrhythmias, trained with variants of known clinical effect. To benchmark against state-of-the-art genome-wide pathogenicity classification tools, we assessed classification of hold-out test variants using both overall performance metrics, and metrics of high-confidence (>90%) classifications relevant to variant interpretation. We further evaluated the prioritisation of variants associated with disease and patient clinical outcomes, providing validations that are robust to potential mis-classification in gold-standard reference datasets.Results: CardioBoost has higher discriminating power than published genome-wide variant classification tools in distinguishing between pathogenic and benign variants based on overall classification performance measures with the highest area under the Precision-Recall Curve as 91% for cardiomyopathies and as 96% for inherited arrhythmias. When assessed at high-confidence (>90%) classification thresholds, prediction accuracy is improved by at least 120% over existing tools for both cardiomyopathies and arrhythmias, with significantly improved sensitivity and specificity. Finally, CardioBoost improves prioritisation of variants significantly associated with disease, and stratifies survival of patients with cardiomyopathies, confirming biologically relevant vari
Ng B, Cook SA, Schafer S, 2020, Interleukin-11 signaling underlies fibrosis, parenchymal dysfunction, and chronic inflammation of the airway, Experimental and Molecular Medicine, Vol: 52, Pages: 1871-1878, ISSN: 0378-8512
Interleukin (IL)-11 evolved as part of the innate immune response. In the human lung, IL-11 upregulation has been associated with viral infections and a range of fibroinflammatory diseases, including idiopathic pulmonary fibrosis. Transforming growth factor-beta (TGFβ) and other disease factors can initiate an autocrine loop of IL-11 signaling in pulmonary fibroblasts, which, in a largely ERK-dependent manner, triggers the translation of profibrotic proteins. Lung epithelial cells also express the IL-11 receptor and transition into a mesenchymal-like state in response to IL-11 exposure. In mice, therapeutic targeting of IL-11 with antibodies can arrest and reverse bleomycin-induced pulmonary fibrosis and inflammation. Intriguingly, fibroblast-specific blockade of IL-11 signaling has anti-inflammatory effects, which suggests that lung inflammation is sustained, in part, through IL-11 activity in the stroma. Proinflammatory fibroblasts and their interaction with the damaged epithelium may represent an important but overlooked driver of lung disease. Initially thought of as a protective cytokine, IL-11 is now increasingly recognized as an important determinant of lung fibrosis, inflammation, and epithelial dysfunction.
Rajewsky N, Almouzni G, Gorski SA, et al., 2020, LifeTime and improving European healthcare through cell-based interceptive medicine, Nature, Vol: 587, Pages: 377-386
Here we describe the LifeTime Initiative, which aims to track, understand and target human cells during the onset and progression of complex diseases, and to analyse their response to therapy at single-cell resolution. This mission will be implemented through the development, integration and application of single-cell multi-omics and imaging, artificial intelligence and patient-derived experimental disease models during the progression from health to disease. The analysis of large molecular and clinical datasets will identify molecular mechanisms, create predictive computational models of disease progression, and reveal new drug targets and therapies. The timely detection and interception of disease embedded in an ethical and patient-centred vision will be achieved through interactions across academia, hospitals, patient associations, health data management systems and industry. The application of this strategy to key medical challenges in cancer, neurological and neuropsychiatric disorders, and infectious, chronic inflammatory and cardiovascular diseases at the single-cell level will usher in cell-based interceptive medicine in Europe over the next decade.
Walsh R, Mazzarotto F, Hawley M, et al., 2020, The genetic architecture of left ventricular non-compaction reveals both substantial overlap with other cardiomyopathies and a distinct aetiology in a subset of cases, European-Society-of-Cardiology (ESC) Congress, Publisher: OXFORD UNIV PRESS, Pages: 3715-3715, ISSN: 0195-668X
Aguib Y, Allouba M, Afify A, et al., 2020, The Egyptian collaborative cardiac genomics (ECCO-GEN) Project: defining a healthy volunteer cohort, npj Genomic Medicine, Vol: 5, Pages: 1-8, ISSN: 2056-7944
The integration of comprehensive genomic and phenotypic data from diverse ethnic populations offers unprecedented opportunities towards advancements in precision medicine and novel diagnostic technologies. Current reference genomic databases are not representative of the global human population, making variant interpretation challenging, especially in underrepresented populations such as the North African population. To address this, the Egyptian Collaborative Cardiac Genomics (ECCO-GEN) Project launched a study comprising 1,000 individuals free of cardiovascular disease (CVD). Here, we present the first 391 Egyptian healthy volunteers (EHVols) recruited to establish a pilot phenotyped control cohort. All individuals underwent detailed clinical investigation, including cardiac MRI, and were sequenced using a targeted panel of 174 genes with reported roles in inherited cardiac conditions (ICC). We identified 1,262 variants in 27 cardiomyopathy genes of which 15.1% were not captured in current global and regional genetic reference databases (here: gnomAD and Great Middle Eastern (GME) Variome). The ECCO-GEN project aims at defining the genetic landscape of an understudied population and providing individual-level genetic and phenotypic data to support future studies in CVD and population genetics.
Lim W-W, Corden B, Ng B, et al., 2020, Interleukin-11 is important for vascular smooth muscle phenotypic switching and aortic inflammation, fibrosis and remodeling in mouse models, Scientific Reports, Vol: 10, Pages: 1-18, ISSN: 2045-2322
Transforming growth factor beta-1 (TGFβ1) is a major driver of vascular smooth muscle cell (VSMC) phenotypic switching, an important pathobiology in arterial disease. We performed RNA-sequencing of TGFβ1-stimulated human aortic or arterial VSMCs which revealed large and consistent upregulation of Interleukin 11 (IL11). IL11 has an unknown function in VSMCs, which highly express the IL11 receptor alpha, suggestive of an autocrine loop. In vitro, IL11 activated ERK signaling, but inhibited STAT3 activity, and caused VSMC phenotypic switching to a similar extent as TGFβ1 or angiotensin II (ANGII) stimulation. Genetic or therapeutic inhibition of IL11 signaling reduced TGFβ1- or ANGII-induced VSMC phenotypic switching, placing IL11 activity downstream of these factors. Aortas of mice with Myh11-driven IL11 expression were remodeled and had reduced contractile but increased matrix and inflammatory genes expression. In two models of arterial pressure loading, IL11 was upregulated in the aorta and neutralizing IL11 antibodies reduced remodeling along with matrix and pro-inflammatory gene expression. These data show that IL11 plays an important role in VSMC phenotype switching, vascular inflammation and aortic pathobiology.
Sweeney M, Corden B, Cook SA, 2020, Targeting cardiac fibrosis in heart failure with preserved ejection fraction: mirage or miracle?, EMBO Molecular Medicine, Vol: 12, Pages: 1-26, ISSN: 1757-4676
Cardiac fibrosis is central to the pathology of heart failure, particularly heart failure with preserved ejection fraction (HFpEF). Irrespective of the underlying profibrotic condition (e.g. ageing, diabetes, hypertension), maladaptive cardiac fibrosis is defined by the transformation of resident fibroblasts to matrix-secreting myofibroblasts. Numerous profibrotic factors have been identified at the molecular level (e.g. TGFβ, IL11, AngII), which activate gene expression programs for myofibroblast activation. A number of existing HF therapies indirectly target fibrotic pathways; however, despite multiple clinical trials in HFpEF, a specific clinically effective antifibrotic therapy remains elusive. Therapeutic inhibition of TGFβ, the master-regulator of fibrosis, has unfortunately proven toxic and ineffective in clinical trials to date, and new approaches are needed. In this review, we discuss the pathophysiology and clinical implications of interstitial fibrosis in HFpEF. We provide an overview of trials targeting fibrosis in HFpEF to date and discuss the promise of potential new therapeutic approaches and targets in the context of underlying molecular mechanisms.
Ruan XX, Cook S, Sim D, et al., 2020, Clinical characteristics of patients with dilated cardiomyopathy in an asian population, Publisher: WILEY, Pages: 198-198, ISSN: 1388-9842
Ng B, Dong J, Viswanathan S, et al., 2020, Fibroblast-specific IL11 signaling drives chronic inflammation in murine fibrotic lung disease, FASEB JOURNAL, Vol: 34, Pages: 11802-11815, ISSN: 0892-6638
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Meyer H, Dawes T, Serrani M, et al., 2020, Genetic and functional insights into the fractal structure of the heart, Nature, Vol: 584, Pages: 589-594, ISSN: 0028-0836
The inner surfaces of the human heart are covered by a complex network of muscular strands that is thought to be a vestigeof embryonic development.1,2 The function of these trabeculae in adults and their genetic architecture are unknown. Toinvestigate this we performed a genome-wide association study using fractal analysis of trabecular morphology as animage-derived phenotype in 18,096 UK Biobank participants. We identified 16 significant loci containing genes associatedwith haemodynamic phenotypes and regulation of cytoskeletal arborisation.3,4 Using biomechanical simulations and humanobservational data, we demonstrate that trabecular morphology is an important determinant of cardiac performance. Throughgenetic association studies with cardiac disease phenotypes and Mendelian randomisation, we find a causal relationshipbetween trabecular morphology and cardiovascular disease risk. These findings suggest an unexpected role for myocardialtrabeculae in the function of the adult heart, identify conserved pathways that regulate structural complexity, and reveal theirinfluence on susceptibility to disease
Pua CJ, Tham N, Chin CW, et al., 2020, Genetic studies of hypertrophic cardiomyopathy in Singaporeans identify variants in TNNI3 and TNNT2 that are common in Chinese patients, Circulation: Genomic and Precision Medicine, Vol: 13, Pages: 424-434, ISSN: 2574-8300
Background - To assess the genetic architecture of hypertrophic cardiomyopathy (HCM) in patients of predominantly Chinese ancestry.Methods - We sequenced HCM disease genes in Singaporean patients (n=224) and Singaporean controls (n=3,634), compared findings with additional populations and Caucasian HCM cohorts (n=6,179) and performed in vitro functional studies.Results - Singaporean HCM patients had significantly fewer confidently interpreted HCM disease variants (Pathogenic (P)/Likely Pathogenic (LP):18%, p<0.0001) but an excess of variants of unknown significance (exVUS: 24%, p<0.0001), as compared to Caucasians (P/LP: 31%, exVUS: 7%). Two missense variants in thin filament encoding genes were commonly seen in Singaporean HCM (TNNI3:p.R79C, disease allele frequency (AF)=0.018; TNNT2:p.R286H, disease AF=0.022) and are enriched in Singaporean HCM when compared with Asian controls (TNNI3:p.R79C, Singaporean controls AF=0.0055, p=0.0057, gnomAD-East Asian (gnomAD-EA) AF=0.0062, p=0.0086; TNNT2:p.R286H, Singaporean controls AF=0.0017, p<0.0001, gnomAD-EA AF=0.0009, p<0.0001). Both these variants have conflicting annotations in ClinVar and are of low penetrance (TNNI3:p.R79C, 0.7%; TNNT2:p.R286H, 2.7%) but are predicted to be deleterious by computational tools. In population controls, TNNI3:p.R79C carriers had significantly thicker left ventricular walls compared to non-carriers while its etiological fraction is limited (0.70, 95% CI: 0.35-0.86) and thus TNNI3:p.R79C is considered a VUS. Mutant TNNT2:p.R286H iPSC-CMs show hypercontractility, increased metabolic requirements and cellular hypertrophy and the etiological fraction (0.93, 95% CI: 0.83-0.97) support the likely pathogenicity of TNNT2:p.R286H.Conclusions - As compared to Caucasians, Chinese HCM patients commonly have low penetrance risk alleles in TNNT2 or TNNI3 but exhibit few clinically actionable HCM variants overall. This highlights the need for greater study of HCM genetics in non-Caucasian pop
Osimo EF, Brugger SP, de Marvao A, et al., 2020, Cardiac structure and function in schizophrenia: cardiac magnetic resonance imaging study, British Journal of Psychiatry, Vol: 217, Pages: 450-457, ISSN: 0007-1250
BACKGROUND: Heart disease is the leading cause of death in schizophrenia. However, there has been little research directly examining cardiac function in schizophrenia. AIMS: To investigate cardiac structure and function in individuals with schizophrenia using cardiac magnetic resonance imaging (CMR) after excluding medical and metabolic comorbidity. METHOD: In total, 80 participants underwent CMR to determine biventricular volumes and function and measures of blood pressure, physical activity and glycated haemoglobin levels. Individuals with schizophrenia ('patients') and controls were matched for age, gender, ethnicity and body surface area. RESULTS: Patients had significantly smaller indexed left ventricular (LV) end-diastolic volume (effect size d = -0.82, P = 0.001), LV end-systolic volume (d = -0.58, P = 0.02), LV stroke volume (d = -0.85, P = 0.001), right ventricular (RV) end-diastolic volume (d = -0.79, P = 0.002), RV end-systolic volume (d = -0.58, P = 0.02), and RV stroke volume (d = -0.87, P = 0.001) but unaltered ejection fractions relative to controls. LV concentricity (d = 0.73, P = 0.003) and septal thickness (d = 1.13, P < 0.001) were significantly larger in the patients. Mean concentricity in patients was above the reference range. The findings were largely unchanged after adjusting for smoking and/or exercise levels and were independent of medication dose and duration. CONCLUSIONS: Individuals with schizophrenia show evidence of concentric cardiac remodelling compared with healthy controls of a similar age, gender, ethnicity, body surface area and blood pressure, and independent of smoking and activity levels. This could be contributing to the excess cardiovascular mortality observed in schizophrenia. Future studies should investigate the contribution of antipsychotic medication to these changes.
Osimo E, Brugger S, De Marvao A, et al., 2020, Cardiac structure and function in schizophrenia: a cardiac MR imaging study, British Journal of Psychiatry, Vol: 217, Pages: 450-457, ISSN: 0007-1250
Background: Heart disease is the leading cause of death in schizophrenia. However, there has been little research directly examining cardiac function in schizophrenia.Aims:We investigated cardiac structure and function in patients with schizophrenia using cardiac magnetic resonance imaging (CMR) after excluding medical and metabolic comorbidity. Methods:80 participants underwent CMR to determine biventricular volumes and function and measures of blood pressure, physical activity, and glycated haemoglobin levels. Patients and controls were matched for age, sex, ethnicity, and body surface area. Results:Patients with schizophrenia had significantly smaller indexed left ventricular (LV) end-diastolic volume (effect size, d=-0.82, p=0.001), LV end-systolic volume (d=-0.58, p=0.02), LV stroke volume (d=-0.85, p=0.001), right ventricular (RV) end-diastolic volume (d=-0.79, p=0.002), RV end-systolic volume (d=-0.58, p=0.02), and RV stroke volume (d=-0.87, p=0.001) but unaltered ejection fractions relative to controls. LV concentricity (d=0.73, p=0.003) and septal thickness (d=1.13, p<0.001) were significantly larger in schizophrenia. Mean concentricity in patients was above the reference range. The findings were largely unchanged after adjusting for smoking and/or exercise levels and were independent of medication dose and duration. Conclusions:Patients with schizophrenia show evidence of concentric cardiac remodelling compared to healthy controls of a similar age, sex, ethnicity, body surface area and blood pressure, and independent of smoking and activity levels. This could be contributing to the excess cardiovascular mortality observed in patients. Future studies should investigate the contribution of antipsychotic medication to these changes.
Thaventhiran JED, Lango Allen H, Burren OS, et al., 2020, Whole-genome sequencing of a sporadic primary immunodeficiency cohort (vol 583, pg 90, 2020), Nature, Vol: 584, Pages: E2-E2, ISSN: 0028-0836
Lopez-Sainz A, Dominguez F, Rocha Lopes L, et al., 2020, Clinical features and natural history of PRKAG2 variant cardiac glycogenosis, Journal of the American College of Cardiology, Vol: 76, Pages: 186-197, ISSN: 0735-1097
BackgroundPRKAG2 gene variants cause a syndrome characterized by cardiomyopathy, conduction disease, and ventricular pre-excitation. Only a small number of cases have been reported to date, and the natural history of the disease is poorly understood.ObjectivesThe aim of this study was to describe phenotype and natural history of PRKAG2 variants in a large multicenter European cohort.MethodsClinical, electrocardiographic, and echocardiographic data from 90 subjects with PRKAG2 variants (53% men; median age 33 years; interquartile range [IQR]: 15 to 50 years) recruited from 27 centers were retrospectively studied.ResultsAt first evaluation, 93% of patients were in New York Heart Association functional class I or II. Maximum left ventricular wall thickness was 18 ± 8 mm, and left ventricular ejection fraction was 61 ± 12%. Left ventricular hypertrophy (LVH) was present in 60 subjects (67%) at baseline. Thirty patients (33%) had ventricular pre-excitation or had undergone accessory pathway ablation; 17 (19%) had pacemakers (median age at implantation 36 years; IQR: 27 to 46 years), and 16 (18%) had atrial fibrillation (median age 43 years; IQR: 31 to 54 years). After a median follow-up period of 6 years (IQR: 2.3 to 13.9 years), 71% of subjects had LVH, 29% had AF, 21% required de novo pacemakers (median age at implantation 37 years; IQR: 29 to 48 years), 14% required admission for heart failure, 8% experienced sudden cardiac death or equivalent, 4% required heart transplantation, and 13% died.ConclusionsPRKAG2 syndrome is a progressive cardiomyopathy characterized by high rates of atrial fibrillation, conduction disease, advanced heart failure, and life-threatening arrhythmias. Classical features of pre-excitation and severe LVH are not uniformly present, and diagnosis should be considered in patients with LVH who develop atrial fibrillation or require permanent pacemakers at a young age.
Turro E, Astle WJ, Megy K, et al., 2020, Whole-genome sequencing of patients with rare diseases in a national health system, Nature, Vol: 583, Pages: 96-102, ISSN: 0028-0836
Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.
Thaventhiran JED, Lango Allen H, Burren OS, et al., 2020, Whole-genome sequencing of a sporadic primary immunodeficiency cohort, Nature, Vol: 583, Pages: 90-95, ISSN: 0028-0836
Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies1-3. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed4) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of-and interplay between-novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.
Tayal U, Wage R, Newsome S, et al., 2020, Predictors of left ventricular remodelling in patients with dilated cardiomyopathy - a cardiovascular magnetic resonance study, European Journal of Heart Failure, Vol: 22, Pages: 1160-1170, ISSN: 1388-9842
AimsThere is an important need for better biomarkers to predict left ventricular (LV) remodelling in dilated cardiomyopathy (DCM). We undertook a comprehensive assessment of cardiac structure and myocardial composition to determine predictors of remodelling.Methods and resultsProspective study of patients with recent‐onset DCM with cardiovascular magnetic resonance (CMR) assessment of ventricular structure and function, extracellular volume (T1 mapping), myocardial strain, myocardial scar (late gadolinium enhancement) and contractile reserve (dobutamine stress). Regression analyses were used to evaluate predictors of change in LV ejection fraction (LVEF) over 12 months. We evaluated 56 participants (34 DCM patients, median LVEF 43%; 22 controls). Absolute LV contractile reserve predicted change in LVEF (1% increase associated with 0.4% increase in LVEF at 12 months, P = 0.02). Baseline myocardial strain (P = 0.39 global longitudinal strain), interstitial myocardial fibrosis (P = 0.41), replacement myocardial fibrosis (P = 0.25), and right ventricular contractile reserve (P = 0.17) were not associated with LV reverse remodelling. There was a poor correlation between contractile reserve and either LV extracellular volume fraction (r = −0.22, P = 0.23) or baseline LVEF (r = 0.07, P = 0.62). Men were more likely to experience adverse LV remodelling (P = 0.01) but age (P = 0.88) and disease‐modifying heart failure medication (beta‐blocker, P = 0.28; angiotensin‐converting enzyme inhibitor, P = 0.92) did not predict follow‐up LVEF.ConclusionsSubstantial recovery of LV function occurs within 12 months in most patients with recent‐onset DCM. Women had the greatest improvement in LVEF. A low LV contractile reserve measured by dobutamine stress CMR appears to identify patients whose LVEF is less likely to recover.
Tayal U, Fecht D, Chadeau M, et al., 2020, RESIDENTIAL EXPOSURE TO FINE PARTICULATE MATTER AIR POLLUTION IS ASSOCIATED WITH IMPAIRED CARDIAC PHENOTYPES IN DILATED CARDIOMYOPATHY, Publisher: BMJ PUBLISHING GROUP, Pages: A2-A3, ISSN: 1355-6037
Biffi C, Cerrolaza Martinez JJ, Tarroni G, et al., 2020, Explainable anatomical shape analysis through deep hierarchical generative models, IEEE Transactions on Medical Imaging, Vol: 39, Pages: 2088-2099, ISSN: 0278-0062
Quantification of anatomical shape changes currently relies on scalar global indexes which are largely insensitive to regional or asymmetric modifications. Accurate assessment of pathology-driven anatomical remodeling is a crucial step for the diagnosis and treatment of many conditions. Deep learning approaches have recently achieved wide success in the analysis of medical images, but they lack interpretability in the feature extraction and decision processes. In this work, we propose a new interpretable deep learning model for shape analysis. In particular, we exploit deep generative networks to model a population of anatomical segmentations through a hierarchy of conditional latent variables. At the highest level of this hierarchy, a two-dimensional latent space is simultaneously optimised to discriminate distinct clinical conditions, enabling the direct visualisation of the classification space. Moreover, the anatomical variability encoded by this discriminative latent space can be visualised in the segmentation space thanks to the generative properties of the model, making the classification task transparent. This approach yielded high accuracy in the categorisation of healthy and remodelled left ventricles when tested on unseen segmentations from our own multi-centre dataset as well as in an external validation set, and on hippocampi from healthy controls and patients with Alzheimer’s disease when tested on ADNI data. More importantly, it enabled the visualisation in three-dimensions of both global and regional anatomical features which better discriminate between the conditions under exam. The proposed approach scales effectively to large populations, facilitating highthroughput analysis of normal anatomy and pathology in largescale studies of volumetric imaging.
Wu RR, Sultana R, Bylstra Y, et al., 2020, Evaluation of family health history collection methods impact on data and risk assessment outcomes, Preventive Medicine Reports, Vol: 18, ISSN: 2211-3355
Information technology applications for patient-collection of family health history (FHH) increase identification of elevated-risk individuals compared to usual care. It is unknown if the method of collection impacts data collected or if simply going directly to the patient is what makes the difference. The objective of this study was to examine differences in data detail and risk identification rates between FHH collection directly from individuals using paper-based forms and an interactive web-based platform. This is a non-randomized epidemiologic study in Singaporean population from 2016 to 2018. Intervention was paper-based versus web-based interactive platform for FHH collection. Participant demographics, FHH detail, and risk assessment results were analyzed. 882 participants enrolled in the study, 481 in the paper-based group and 401 in the web-based group with mean (SD) age of 45.4 (12.98) years and 47.5% male. Web-based FHH collection participants had an increased number of conditions per relative (p-value <0.001), greater frequency of reporting age of onset (p-value <0.001), and greater odds of receiving ≥1 risk recommendation both overall (OR: 3.99 (2.41, 6.59)) and within subcategories of genetic counselling for hereditary cancer syndromes (p-value = 0.041) and screening and prevention for breast (p-value = 0.002) and colon cancer (p-value = 0.005). This has significant implications for clinical care and research efforts where FHH is being assessed. Using interactive information technology platforms to collect FHH can improve the completeness of the data collected and result in increased rates of risk identification. Methods of data collection to maximize benefit should be taken into account in future studies and clinical care.
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