Imperial College London

ProfessorSanjayPrasad

Faculty of MedicineNational Heart & Lung Institute

Professor of Cardiomyopathy
 
 
 
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Contact

 

+44 (0)20 7352 8121s.prasad

 
 
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Location

 

CMR UnitRoyal BromptonRoyal Brompton Campus

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Summary

 

Publications

Publication Type
Year
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462 results found

Gasperetti A, Carrick R, Protonotarios A, Laredo M, van der Schaaf I, Syrris P, Murray B, Tichnell C, Cappelletto C, Gigli M, Medo K, Crabtree P, Saguner AM, Duru F, Hylind R, Abrams D, Lakdawala NK, Massie C, Cadrin-Tourigny J, Targetti M, Olivotto I, Graziosi M, Cox M, Biagini E, Charron P, Casella M, Tondo C, Yazdani M, Ware J, Prasad S, Calò L, Smith E, Helms A, Hespe S, Ingles J, Tandri H, Ader F, Mestroni L, Wilde A, Merlo M, Gandjbakhch E, Calkins H, SJM te Riele A, van Tintelen JP, Elliot PM, James CAet al., 2024, Long-term arrhythmic follow-up and risk stratification of patients with desmoplakin-associated arrhythmogenic right ventricular cardiomyopathy, JACC: Advances, Vol: 3, ISSN: 2772-963X

Background: Patients with likely pathogenic/pathogenic (LP/P) desmoplakin (DSP) variants are poorly characterized. Some of them meet diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC), but it is unclear how risk stratification strategies for ARVC perform in this setting.Objectives: To characterize arrhythmic outcomes and to test the performance of the recently validatedARVC risk calculator in patients with DSP LP/P variants fulfilling definite 2010 ARVC Task Force Criteria (DSP-TFC+).Methods: DSP-TFC+ patients were enrolled from twenty institutions across three continents. Ventricular arrhythmias (VA), defined as a composite of sustained ventricular tachycardia (VT), appropriate implantable cardioverter defibrillator therapies, and ventricular fibrillation/sudden cardiac death events in follow up, were reported as the primary outcome. We tested performance of the ARVC risk calculator for VA prediction, reporting c-statistics.Results: Among 252 DSP-TFC+ patients (39.6±16.9 y.o., 35.3% male), 94 (37.3%) experienced VA over 44.5 [19.6–78.3] months. Patients with LV involvement (n=194) were at higher VA risk (log-rank p=0.0239). History of non-sustained VT (NSVT) (aHR 2.097; p=0.004) showed the strongest association with VA occurrence during the first 5-yr of follow-up. Neither age (p=0.723) nor male sex (p=0.200) was associated with VAs at follow-up. In 204 patients without VA at diagnosis, incident VA rate was high (32.8%; 7.37%/year). The ARVC Risk Calculator performed poorly overall (c-statistic 0.604 [0.594–0.614]) and very poorly in patients with left ventricular disease (c-statistic 0.558 [0.556–0.560]).Conclusion: DSP-TFC+ patients are at substantial risk for VAs. The ARVC risk calculator performs poorly in DSP-TFC+ patients suggesting need for a gene-specific risk algorithm. Meanwhile, DSP-24 TFC+ patients with NSVT should be considered as high-risk.

Journal article

UK HFpEF Collaborative Group, 2024, Rationale and design of the United Kingdom Heart Failure with Preserved Ejection Fraction Registry., Heart, Vol: 110, Pages: 359-365

OBJECTIVE: Heart failure with preserved ejection fraction (HFpEF) is a common heterogeneous syndrome that remains imprecisely defined and consequently has limited treatment options and poor outcomes. METHODS: The UK Heart Failure with Preserved Ejection Fraction Registry (UK HFpEF) is a prospective data-enabled cohort and platform study. The study will develop a large, highly characterised cohort of patients with HFpEF. A biobank will be established. Deep clinical phenotyping, imaging, multiomics and centrally held national electronic health record data will be integrated at scale, in order to reclassify HFpEF into distinct subgroups, improve understanding of disease mechanisms and identify new biological pathways and molecular targets. Together, these will form the basis for developing diagnostics and targeted therapeutics specific to subgroups. It will be a platform for more effective and efficient trials, focusing on subgroups in whom targeted interventions are expected to be effective, with consent in place to facilitate rapid recruitment, and linkage for follow-up. Patients with a diagnosis of HFpEF made by a heart failure specialist, who have had natriuretic peptide levels measured and a left ventricular ejection fraction >40% are eligible. Patients with an ejection fraction between 40% and 49% will be limited to no more than 25% of the cohort. CONCLUSIONS: UK HFpEF will develop a rich, multimodal data resource to enable the identification of disease endotypes and develop more effective diagnostic strategies, precise risk stratification and targeted therapeutics. TRIAL REGISTRATION NUMBER: NCT05441839.

Journal article

Owen R, Buchan R, Frenneaux M, Jarman JWE, Baruah R, Lota AS, Halliday BP, Roberts AM, Izgi C, Van Spall H, Michos ED, McMurray J, Januzzi JL, Pennell DJ, Cook SA, Ware JS, Barton PJ, Gregson J, Prasad SK, Tayal Uet al., 2024, Sex differences in the clinical presentation and natural history of dilated cardiomyopathy, JACC: Heart Failure, Vol: 12, Pages: 352-363, ISSN: 2213-1787

Background: Biological sex has a diverse impact on the cardiovascular system. Its influence on dilated cardiomyopathy (DCM) remains unresolved.Objective: To investigate sex-specific differences in DCM presentation, natural history, and prognostic factors.Methods We conducted a prospective observational cohort study of DCM patients, assessing baseline characteristics, CMR-imaging, biomarkers and genotype. The composite outcome was cardiovascular mortality or major heart-failure (HF) events. Results: Overall, 206 females and 398 males with DCM were followed for a median of 3.9 years. At baseline female patients had higher left ventricular ejection fraction (LVEF), smaller left ventricular volumes, less prevalent mid-wall myocardial fibrosis (23% vs 42%) and lower high sensitivity cardiac troponin (hs-cTnI) than males (all p<0.05), with no difference in time from diagnosis, age at enrollment, NT-proBNP levels, pathogenic DCM genetic variants, myocardial fibrosis extent or medications used for HF. Despite a more favourable profile, the risk of the primary outcome at 2 years was higher in females than males (8.6% vs 4.4%, adjusted hazard ratio 3.14, 95% CI 1.55 to 6.35, p=0.001). Between 2-5 years, the effect of sex as a prognostic modifier attenuated. Age, mid-wall myocardial fibrosis, LVEF, left atrial volume, NT-proBNP, hs-cTnI, left bundle branch block and NYHA class were not sex specific prognostic factors. Conclusions: We identify a novel paradox in prognosis for females with DCM. Female DCM patients have a paradoxical early increase in major HF events despite less prevalent myocardial fibrosis and a milder phenotype at presentation. Future studies should interrogate the mechanistic basis for these sex differences.

Journal article

Tsampasian V, Merinopoulos I, Ravindrarajah T, Ring L, Heng EL, Prasad S, Vassiliou VSet al., 2024, Prognostic Value of Cardiac Magnetic Resonance Feature Tracking Strain in Aortic Stenosis., J Cardiovasc Dev Dis, Vol: 11

BACKGROUND: Recent data have suggested that global longitudinal strain (GLS) could be useful for risk stratification of patients with severe aortic stenosis (AS). In this study, we aimed to investigate the prognostic role of GLS in patients with AS and also its incremental value in relation to left ventricular ejection fraction (LVEF) and late gadolinium enhancement (LGE). METHODS: We analysed all consecutive patients with AS and LGE-CMR in our institution. Survival data were obtained from office of national statistics, a national body where all deaths in England are registered by law. Death certificates were obtained from the general register office. RESULTS: Some 194 consecutive patients with aortic stenosis were investigated with CMR at baseline and followed up for 7.3 ± 4 years. On multivariate Cox regression analysis, only increasing age remained significant for both all-cause and cardiac mortality, while LGE (any pattern) retained significance for all-cause mortality and had a trend to significance for cardiac mortality. Kaplan-Meier survival analysis demonstrated that patients in the best and middle GLS tertiles had significantly better mortality compared to patients in the worst GLS tertiles. Importantly though, sequential Cox proportional-hazard analysis demonstrated that GLS did not have significant incremental prognostic value for all-cause mortality or cardiac mortality in addition to LVEF and LGE. CONCLUSIONS: Our study has demonstrated that age and LGE but not GLS are significant poor prognostic indicators in patients with moderate and severe AS.

Journal article

Flett A, Cebula A, Nicholas Z, Adam R, Ewings S, Prasad S, Cleland JG, Eminton Z, Curzen Net al., 2023, Rationale and study protocol for the BRITISH randomized trial (Using cardiovascular magnetic resonance identified scar as the benchmark risk indication tool for implantable cardioverter defibrillators in patients with nonischemic cardiomyopathy and severe systolic heart failure)., Am Heart J, Vol: 266, Pages: 149-158

BACKGROUND: For patients with nonischemic cardiomyopathy (NICM), current guidelines recommend implantable cardioverter defibrillators (ICD) when left ventricular ejection fraction (LVEF) is ≤35%, but the DANISH trial failed to confirm that ICDs reduced all-cause mortality for such patients. Circumstantial evidence suggests that scar on CMR is predictive of sudden and arrhythmic death in this population. The presence of myocardial scar identified by cardiac magnetic resonance imaging (CMR) in patients with NICM and an LVEF ≤35% might identify patients at higher risk of sudden arrhythmic death, for whom an ICD is more likely to reduce all-cause mortality. METHODS/DESIGN: The BRITISH trial is a prospective, multicenter, randomized controlled trial aiming to enrol 1,252 patients with NICM and an LVEF ≤35%. Patients with a nonischemic scar on CMR will be randomized to either: (1) ICD, with or without cardiac resynchronization (CRT-D), or (2) implantable loop recorder (ILR) or cardiac resynchronization (CRT-P). Patients who are screened for the trial but are found not to be eligible, predominantly due to an absence of scar or those who decline to be randomized will be enrolled in an observational registry. The primary endpoint is all-cause mortality, which we plan to assess at 3 years after the last participant is randomized. Secondary endpoints include clinical outcomes, appropriate and inappropriate device therapies, symptom severity and well-being, device-related complications, and analysis of the primary endpoint by subgroups with other risk markers. CONCLUSION: The BRITISH trial will assess whether the use of CMR-defined scar to direct ICD implantation in patients with NICM and an LVEF ≤35% is associated with a reduction in mortality.

Journal article

Curran L, Simoes Monteiro de Marvao A, Inglese P, McGurk K, Schiratti P-R, Clement A, Zheng S, Li S, Pua CJ, Shah M, Jafari M, Theotokis P, Buchan R, Jurgens S, Raphael C, Baksi A, Pantazis A, Halliday B, Pennell D, Bai W, Chin C, Tadros R, Bezzina C, Watkins H, Cook S, Prasad S, Ware J, O'Regan Det al., 2023, Genotype-phenotype taxonomy of hypertrophic cardiomyopathy, Circulation: Genomic and Precision Medicine, Vol: 16, Pages: 559-570, ISSN: 2574-8300

Background:Hypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death associated with heterogeneous phenotypes but there is no systematic framework for classifying morphology or assessing associated risks. Here we quantitatively survey genotype-phenotype associations in HCM to derive a data-driven taxonomy of disease expression.Methods:We enrolled 436 HCM patients (median age 60 years; 28.8% women) with clinical, genetic and imaging data. Anindependent cohort of 60 HCM patients from Singapore (median age 59 years; 11% women) and a reference population from UK Biobank (n = 16,691, mean age 55 years; 52.5% women) were also recruited. We used machine learning to analyse the three-dimensional structure of the left ventricle from cardiac magnetic resonance imaging and build a tree-based classification of HCM phenotypes. Genotype and mortality risk distributions were projected on the tree.Results:Carriers of pathogenic or likely pathogenic variants (P/LP) for HCM had lower left ventricular mass, but greater basalseptal hypertrophy, with reduced lifespan (mean follow-up 9.9 years) compared to genotype negative individuals(hazard ratio: 2.66; 95% confidence interval [CI]: 1.42-4.96; P < 0.002). Four main phenotypic branches were identified using unsupervised learning of three-dimensional shape: 1) non-sarcomeric hypertrophy with co-existing hypertension; 2) diffuse and basal asymmetric hypertrophy associated with outflow tract obstruction; 3) isolated basal hypertrophy; 4) milder non-obstructive hypertrophy enriched for familial sarcomeric HCM (odds ratio for P/LP variants: 2.18 [95% CI: 1.93-2.28, P = 0.0001]). Polygenic risk for HCM was also associated with different patterns and degrees of disease expression. The model was generalisable to an independent cohort (trustworthiness M1: 0.86-0.88).Conclusions:We report a data-driven taxonomy of HCM for identifying groups of patients with similar morphology while preserving a continuum of disease severi

Journal article

Hammersley D, Jones R, Owen R, Mach L, Lota A, Khalique Z, de Marvao A, Androulakis E, Hatipoglu S, Gulati A, Reddy R, Yoon WY, Talukder S, Shah R, Baruah R, Guha K, Pantazis A, Baksi J, Gregson J, Cleland J, Tayal U, Pennell D, Ware J, Halliday B, Prasad Set al., 2023, Phenotype, outcomes and natural history of early-stage non-ischaemic cardiomyopathy, European Journal of Heart Failure, Vol: 25, Pages: 2050-2059, ISSN: 1388-9842

AimsTo characterize the phenotype, clinical outcomes and rate of disease progression in patients with early-stage non-ischaemic cardiomyopathy (early-NICM).Methods and resultsWe conducted a prospective observational cohort study of patients with early-NICM assessed by late gadolinium enhancement cardiovascular magnetic resonance (CMR). Cases were classified into the following subgroups: isolated left ventricular dilatation (early-NICM H−/D+), non-dilated left ventricular cardiomyopathy (early-NICM H+/D−), or early dilated cardiomyopathy (early-NICM H+/D+). Clinical follow-up for major adverse cardiovascular events (MACE) included non-fatal life-threatening arrhythmia, unplanned cardiovascular hospitalization or cardiovascular death. A subset of patients (n = 119) underwent a second CMR to assess changes in cardiac structure and function. Of 254 patients with early-NICM (median age 46 years [interquartile range 36–58], 94 [37%] women, median left ventricular ejection fraction [LVEF] 55% [52–59]), myocardial fibrosis was present in 65 (26%). There was no difference in the prevalence of fibrosis between subgroups (p = 0.90), however fibrosis mass was lowest in early-NICM H−/D+, higher in early-NICM H+/D− and highest in early-NICM H+/D+ (p = 0.03). Over a median follow-up of 7.9 (5.5–10.0) years, 28 patients (11%) experienced MACE. Non-sustained ventricular tachycardia (hazard ratio [HR] 5.1, 95% confidence interval [CI] 2.36–11.00, p < 0.001), myocardial fibrosis (HR 3.77, 95% CI 1.73–8.20, p < 0.001) and diabetes mellitus (HR 5.12, 95% CI 1.73–15.18, p = 0.003) were associated with MACE in a multivariable model. Only 8% of patients progressed from early-NICM to dilated cardiomyopathy with LVEF <50% over a median of 16 (11–34) months.ConclusionEarly-NICM is not benign. Fibrosis develops early in the phenot

Journal article

Jones RE, Hammersley DJ, Zheng S, McGurk KA, de Marvao A, Theotokis PI, Owen R, Tayal U, Rea G, Hatipoglu S, Buchan RJ, Mach L, Curran L, Lota AS, Simard F, Reddy RK, Talukder S, Yoon WY, Vazir A, Pennell DJ, O'Regan DP, Baksi AJ, Halliday BP, Ware JS, Prasad SKet al., 2023, Assessing the association between genetic and phenotypic features of dilated cardiomyopathy and outcome in patients with coronary artery disease, European Journal of Heart Failure, ISSN: 1388-9842

AimsTo examine the relevance of genetic and cardiovascular magnetic resonance (CMR) features of dilated cardiomyopathy (DCM) in individuals with coronary artery disease (CAD).Methods and resultsThis study includes two cohorts. First, individuals with CAD recruited into the UK Biobank (UKB) were evaluated. Second, patients with CAD referred to a tertiary centre for evaluation with late gadolinium enhancement (LGE)-CMR were recruited (London cohort); patients underwent genetic sequencing as part of the research protocol and long-term follow-up. From 31 154 individuals with CAD recruited to UKB, rare pathogenic variants in DCM genes were associated with increased risk of death or major adverse cardiac events (hazard ratio 1.57, 95% confidence interval [CI] 1.22–2.01, p < 0.001). Of 1619 individuals with CAD included from the UKB CMR substudy, participants with a rare variant in a DCM-associated gene had lower left ventricular ejection fraction (LVEF) compared to genotype negative individuals (mean 47 ± 10% vs. 57 ± 8%, p < 0.001). Of 453 patients in the London cohort, 63 (14%) had non-infarct pattern LGE (NI-LGE) on CMR. Patients with NI-LGE had lower LVEF (mean 38 ± 18% vs. 48 ± 16%, p < 0.001) compared to patients without NI-LGE, with no significant difference in the burden of rare protein altering variants in DCM-associated genes between groups (9.5% vs. 6.7%, odds ratio 1.5, 95% CI 0.4–4.3, p = 0.4). NI-LGE was not independently associated with adverse clinical outcomes.ConclusionRare pathogenic variants in DCM-associated genes impact left ventricular remodelling and outcomes in stable CAD. NI-LGE is associated with adverse remodelling but is not an independent predictor of outcome and had no rare genetic basis in our study.

Journal article

McGurk K, Zhang X, Theotokis P, Thomson K, Harper A, Buchan R, Mazaika E, Ormondroyd E, Wright W, Macaya D, Chee Jian P, Funke B, MacArthur D, Prasad S, Cook S, Allouba M, Aguib Y, Yacoub M, O'Regan D, Barton P, Watkins H, Bottolo L, Ware Jet al., 2023, The penetrance of rare variants in cardiomyopathy-associated genes: a cross-sectional approach to estimate penetrance for secondary findings, American Journal of Human Genetics, Vol: 110, Pages: 1482-1495, ISSN: 0002-9297

Understanding the penetrance of pathogenic variants identified as secondary findings (SFs) is of paramount importance with the growing availability of genetic testing. We estimated penetrance through large-scale analyses of individuals referred for diagnostic sequencing for hypertrophic cardiomyopathy (HCM; 10,400 affected individuals, 1,332 variants) and dilated cardiomyopathy (DCM; 2,564 affected individuals, 663 variants), using a cross-sectional approach comparing allele frequencies against reference populations (293,226 participants from UK Biobank and gnomAD). We generated updated prevalence estimates for HCM (1:543) and DCM (1:220). In aggregate, the penetrance by late adulthood of rare, pathogenic variants (23% for HCM, 35% for DCM) and likely pathogenic variants (7% for HCM, 10% for DCM) was substantial for dominant cardiomyopathy (CM). Penetrance was significantly higher for variant subgroups annotated as loss of function or ultra-rare and for males compared to females for variants in HCM-associated genes. We estimated variant-specific penetrance for 316 recurrent variants most likely to be identified as SFs (found in 51% of HCM- and 17% of DCM-affected individuals). 49 variants were observed at least ten times (14% of affected individuals) in HCM-associated genes. Median penetrance was 14.6% (±14.4% SD). We explore estimates of penetrance by age, sex, and ancestry and simulate the impact of including future cohorts. This dataset reports penetrance of individual variants at scale and will inform the management of individuals undergoing genetic screening for SFs. While most variants had low penetrance and the costs and harms of screening are unclear, some individuals with highly penetrant variants may benefit from SFs.

Journal article

Jones RE, Gruszczyk AV, Schmidt C, Hammersley DJ, Mach L, Lee M, Wong J, Yang M, Hatipoglu S, Lota AS, Barnett SN, Toscano-Rivalta R, Owen R, Raja S, De Robertis F, Smail H, De-Souza A, Stock U, Kellman P, Griffin J, Dumas M-E, Martin JL, Saeb-Parsy K, Vazir A, Cleland JGF, Pennell DJ, Bhudia SK, Halliday BP, Noseda M, Frezza C, Murphy MP, Prasad SKet al., 2023, Assessment of left ventricular tissue mitochondrial bioenergetics in patients with stable coronary artery disease, Nature Cardiovascular Research, Vol: 2, Pages: 733-745, ISSN: 2731-0590

Recurrent myocardial ischemia can lead to left ventricular (LV) dysfunction in patients with coronary artery disease (CAD). In this observational cohort study, we assessed for chronic metabolomic and transcriptomic adaptations within LV myocardium of patients undergoing coronary artery bypass grafting. During surgery, paired transmural LV biopsies were acquired on the beating heart from regions with and without evidence of inducible ischemia on preoperative stress perfusion cardiovascular magnetic resonance. From 33 patients, 63 biopsies were acquired, compared to analysis of LV samples from 11 donor hearts. The global myocardial adenosine triphosphate (ATP):adenosine diphosphate (ADP) ratio was reduced in patients with CAD as compared to donor LV tissue, with increased expression of oxidative phosphorylation (OXPHOS) genes encoding the electron transport chain complexes across multiple cell types. Paired analyses of biopsies obtained from LV segments with or without inducible ischemia revealed no significant difference in the ATP:ADP ratio, broader metabolic profile or expression of ventricular cardiomyocyte genes implicated in OXPHOS. Differential metabolite analysis suggested dysregulation of several intermediates in patients with reduced LV ejection fraction, including succinate. Overall, our results suggest that viable myocardium in patients with stable CAD has global alterations in bioenergetic and transcriptional profile without large regional differences between areas with or without inducible ischemia.

Journal article

Farrant J, Dodd S, Vaughan C, Reid A, Schmitt M, Garratt C, Akhtar M, Mahmod M, Neubauer S, Cooper RM, Prasad SK, Singh A, Valkovic L, Raman B, Ashkir Z, Clayton D, Baroja O, Duran B, Spowart C, Bedson E, Naish JH, Harrington C, Miller CA, TEMPEST Iet al., 2023, Rationale and design of a randomised trial of trientine in patients with hypertrophic cardiomyopathy, HEART, Vol: 109, Pages: 1175-1182, ISSN: 1355-6037

Journal article

Patel H, Sintou A, Chowdhury RA, Rothery S, Iacob AO, Prasad S, Rainer PP, Martinón-Torres F, Sancho-Shimizu V, Shimizu C, Dummer K, Tremoulet AH, Burns JC, Sattler S, Levin M, DIAMONDS consortiumet al., 2023, Evaluation of autoantibody binding to cardiac tissue in multisystem inflammatory syndrome in children and COVID-19 vaccination-induced myocarditis., JAMA Network Open, Vol: 6, Pages: 1-11, ISSN: 2574-3805

IMPORTANCE: Cardiac dysfunction and myocarditis have emerged as serious complications of multisystem inflammatory syndrome in children (MIS-C) and vaccines against SARS-CoV-2. Understanding the role of autoantibodies in these conditions is essential for guiding MIS-C management and vaccination strategies in children. OBJECTIVE: To investigate the presence of anticardiac autoantibodies in MIS-C or COVID-19 vaccine-induced myocarditis. DESIGN, SETTING, AND PARTICIPANTS: This diagnostic study included children with acute MIS-C or acute vaccine myocarditis, adults with myocarditis or inflammatory cardiomyopathy, healthy children prior to the COVID-19 pandemic, and healthy COVID-19 vaccinated adults. Participants were recruited into research studies in the US, United Kingdom, and Austria starting January 2021. Immunoglobulin G (IgG), IgM, and IgA anticardiac autoantibodies were identified with immunofluorescence staining of left ventricular myocardial tissue from 2 human donors treated with sera from patients and controls. Secondary antibodies were fluorescein isothiocyanate-conjugated antihuman IgG, IgM, and IgA. Images were taken for detection of specific IgG, IgM, and IgA deposits and measurement of fluorescein isothiocyanate fluorescence intensity. Data were analyzed through March 10, 2023. MAIN OUTCOMES AND MEASURES: IgG, IgM and IgA antibody binding to cardiac tissue. RESULTS: By cohort, there were a total of 10 children with MIS-C (median [IQR] age, 10 [13-14] years; 6 male), 10 with vaccine myocarditis (median age, 15 [14-16] years; 10 male), 8 adults with myocarditis or inflammatory cardiomyopathy (median age, 55 [46-63] years; 6 male), 10 healthy pediatric controls (median age, 8 [13-14] years; 5 male), and 10 healthy vaccinated adults (all older than 21 years, 5 male). No antibody binding above background was observed in human cardiac tissue treated with sera from pediatric patients with MIS-C or vaccine myocarditis. One of the 8 adult patients with myocarditi

Journal article

Lu M, Zhu L, Prasad SK, Zhao Set al., 2023, Magnetic resonance imaging mimicking pathology detects myocardial fibrosis: a door to hope for improving the whole course management, SCIENCE BULLETIN, Vol: 68, Pages: 864-867, ISSN: 2095-9273

Journal article

Jones RE, Zaidi HA, Hammersley DJ, Hatipoglu S, Owen R, Balaban G, de Marvao A, Simard F, Lota AS, Mahon C, Almogheer B, Mach L, Musella F, Chen X, Gregson J, Lazzari L, Ravendren A, Leyva F, Zhao S, Vazir A, Lamata P, Halliday BP, Pennell DJ, Bishop MJ, Prasad SKet al., 2023, Comprehensive phenotypic characterization of late gadolinium enhancement predicts sudden cardiac death in coronary artery disease, JACC: Cardiovascular Imaging, Vol: 16, Pages: 628-638, ISSN: 1936-878X

BackgroundLate gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) offers the potential to noninvasively characterize the phenotypic substrate for sudden cardiac death (SCD).ObjectivesThe authors assessed the utility of infarct characterization by CMR, including scar microstructure analysis, to predict SCD in patients with coronary artery disease (CAD).MethodsPatients with stable CAD were prospectively recruited into a CMR registry. LGE quantification of core infarction and the peri-infarct zone (PIZ) was performed alongside computational image analysis to extract morphologic and texture scar microstructure features. The primary outcome was SCD or aborted SCD.ResultsOf 437 patients (mean age: 64 years; mean left ventricular ejection fraction [LVEF]: 47%) followed for a median of 6.3 years, 49 patients (11.2%) experienced the primary outcome. On multivariable analysis, PIZ mass and core infarct mass were independently associated with the primary outcome (per gram: HR: 1.07 [95% CI: 1.02-1.12]; P = 0.002 and HR: 1.03 [95% CI: 1.01-1.05]; P = 0.01, respectively), and the addition of both parameters improved discrimination of the model (Harrell’s C-statistic: 0.64-0.79). PIZ mass, however, did not provide incremental prognostic value over core infarct mass based on Harrell’s C-statistic or risk reclassification analysis. Severely reduced LVEF did not predict the primary endpoint after adjustment for scar mass. On scar microstructure analysis, the number of LGE islands in addition to scar transmurality, radiality, interface area, and entropy were all associated with the primary outcome after adjustment for severely reduced LVEF and New York Heart Association functional class of >1. No scar microstructure feature remained associated with the primary endpoint when PIZ mass and core infarct mass were added to the regression models.ConclusionsComprehensive LGE characterization independently predicted SCD risk beyond conventional predictors used in im

Journal article

Zaidi HA, Jones RE, Hammersley DJ, Hatipoglu S, Balaban G, Mach L, Halliday BP, Lamata P, Prasad SK, Bishop MJet al., 2023, Machine learning analysis of complex late gadolinium enhancement patterns to improve risk prediction of major arrhythmic events, Frontiers in Cardiovascular Medicine, Vol: 10, ISSN: 2297-055X

Background: Machine learning analysis of complex myocardial scar patterns affords the potential to enhance risk prediction of life-threatening arrhythmia in stable coronary artery disease (CAD).Objective: To assess the utility of computational image analysis, alongside a machine learning (ML) approach, to identify scar microstructure features on late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) that predict major arrhythmic events in patients with CAD.Methods: Patients with stable CAD were prospectively recruited into a CMR registry. Shape-based scar microstructure features characterizing heterogeneous (‘peri-infarct’) and homogeneous (‘core’) fibrosis were extracted. An ensemble of machine learning approaches were used for risk stratification, in addition to conventional analysis using Cox modeling.Results: Of 397 patients (mean LVEF 45.4 ± 16.0) followed for a median of 6 years, 55 patients (14%) experienced a major arrhythmic event. When applied within an ML model for binary classification, peri-infarct zone (PIZ) entropy, peri-infarct components and core interface area outperformed a model representative of the current standard of care (LVEF<35% and NYHA>Class I): AUROC (95%CI) 0.81 (0.81–0.82) vs. 0.64 (0.63–0.65), p = 0.002. In multivariate cox regression analysis, these features again remained significant after adjusting for LVEF<35% and NYHA>Class I: PIZ entropy hazard ratio (HR) 1.88, 95% confidence interval (CI) 1.38–2.56, p < 0.001; number of PIZ components HR 1.34, 95% CI 1.08–1.67, p = 0.009; core interface area HR 1.6, 95% CI 1.29–1.99, p = <0.001.Conclusion: Machine learning models using LGE-CMR scar microstructure improved arrhythmic risk stratification as compared to guideline-based clinical parameters; highlighting a potential novel approach to identifying candidates for implantab

Journal article

Tadros R, Zheng SL, Grace C, Jordà P, Francis C, Jurgens SJ, Thomson KL, Harper AR, Ormondroyd E, West DM, Xu X, Theotokis PI, Buchan RJ, McGurk KA, Mazzarotto F, Boschi B, Pelo E, Lee M, Noseda M, Varnava A, Vermeer AM, Walsh R, Amin AS, van Slegtenhorst MA, Roslin N, Strug LJ, Salvi E, Lanzani C, de Marvao A, Hypergenes InterOmics Collaborators, Roberts JD, Tremblay-Gravel M, Giraldeau G, Cadrin-Tourigny J, L'Allier PL, Garceau P, Talajic M, Pinto YM, Rakowski H, Pantazis A, Baksi J, Halliday BP, Prasad SK, Barton PJ, O'Regan DP, Cook SA, de Boer RA, Christiaans I, Michels M, Kramer CM, Ho CY, Neubauer S, HCMR Investigators, Matthews PM, Wilde AA, Tardif J-C, Olivotto I, Adler A, Goel A, Ware JS, Bezzina CR, Watkins Het al., 2023, Large scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy., medRxiv

Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. We here report results from the largest HCM genome-wide association study (GWAS) and multi-trait analysis (MTAG) including 5,900 HCM cases, 68,359 controls, and 36,083 UK Biobank (UKB) participants with cardiac magnetic resonance (CMR) imaging. We identified a total of 70 loci (50 novel) associated with HCM, and 62 loci (32 novel) associated with relevant left ventricular (LV) structural or functional traits. Amongst the common variant HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin, showing that rare truncating SVIL variants cause HCM. Mendelian randomization analyses support a causal role of increased LV contractility in both obstructive and non-obstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, the findings significantly increase our understanding of the genetic basis and molecular mechanisms of HCM, with potential implications for disease management.

Journal article

Artico J, Shiwani H, Moon JC, Gorecka M, McCann GP, Roditi G, Morrow A, Mangion K, Lukaschuk E, Shanmuganathan M, Miller CA, Chiribiri A, Prasad SK, Adam RD, Singh T, Bucciarelli-Ducci C, Dawson D, Knight D, Fontana M, Manisty C, Treibel TA, Levelt E, Arnold R, Macfarlane PW, Young R, McConnachie A, Neubauer S, Piechnik SK, Davies RH, Ferreira VM, Dweck MR, Berry C, Greenwood JPet al., 2023, Myocardial Involvement After Hospitalization for COVID-19 Complicated by Troponin Elevation: A Prospective, Multicenter, Observational Study, CIRCULATION, Vol: 147, Pages: 364-374, ISSN: 0009-7322

Journal article

Hammersley DJ, Jones RE, Mach L, Owen R, Lota AS, Khalique Z, de Marvao A, Gulati A, Baruah R, Guha K, Ware JS, Cleland JG, Pennell DJ, Halliday BP, Tayal U, Prasad SKet al., 2022, Effect of Diabetes Mellitus on Clinical Phenotype and Cardiovascular Mortality in Non-Ischaemic Dilated Cardiomyopathy, Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322

Conference paper

Heidecker B, Dagan N, Balicer R, Eriksson U, Rosano G, Coats A, Tschöpe C, Kelle S, Poland GA, Frustaci A, Klingel K, Martin P, Hare JM, Cooper LT, Pantazis A, Imazio M, Prasad S, Lüscher TFet al., 2022, Myocarditis following COVID-19 vaccine: incidence, presentation, diagnosis, pathophysiology, therapy, and outcomes put into perspective. A clinical consensus document supported by the Heart Failure Association of the European Society of Cardiology (ESC) and the ESC Working Group on Myocardial and Pericardial Diseases., Eur J Heart Fail, Vol: 24, Pages: 2000-2018

Over 10 million doses of COVID-19 vaccines based on RNA technology, viral vectors, recombinant protein, and inactivated virus have been administered worldwide. Although generally very safe, post-vaccine myocarditis can result from adaptive humoral and cellular, cardiac-specific inflammation within days and weeks of vaccination. Rates of vaccine-associated myocarditis vary by age and sex with the highest rates in males between 12 and 39 years. The clinical course is generally mild with rare cases of left ventricular dysfunction, heart failure and arrhythmias. Mild cases are likely underdiagnosed as cardiac magnetic resonance imaging (CMR) is not commonly performed even in suspected cases and not at all in asymptomatic and mildly symptomatic patients. Hospitalization of symptomatic patients with electrocardiographic changes and increased plasma troponin levels is considered necessary in the acute phase to monitor for arrhythmias and potential decline in left ventricular function. In addition to evaluation for symptoms, electrocardiographic changes and elevated troponin levels, CMR is the best non-invasive diagnostic tool with endomyocardial biopsy being restricted to severe cases with heart failure and/or arrhythmias. The management beyond guideline-directed treatment of heart failure and arrhythmias includes non-specific measures to control pain. Anti-inflammatory drugs such as non-steroidal anti-inflammatory drugs, and corticosteroids have been used in more severe cases, with only anecdotal evidence for their effectiveness. In all age groups studied, the overall risks of SARS-CoV-2 infection-related hospitalization and death are hugely greater than the risks from post-vaccine myocarditis. This consensus statement serves as a practical resource for physicians in their clinical practice, to understand, diagnose, and manage affected patients. Furthermore, it is intended to stimulate research in this area.

Journal article

Elming MB, Boas R, Hammer-Hansen S, Voges I, Nyktari E, Svendsen JH, Pehrson S, Dixen U, Philbert BT, Prasad SK, Kober L, Thune JJet al., 2022, Myocardial fibrosis and ventricular ectopy in patients with non-ischemic systolic heart failure: results from the DANISH trial, INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING, Vol: 38, Pages: 2437-2445, ISSN: 1569-5794

Journal article

Hatipoglu S, Mohiaddin RH, Gatehouse P, Alpendurada F, Baksi AJ, Izgi C, Prasad SK, Pennell DJ, Krupickova Set al., 2022, Performance of artificial intelligence for biventricular cardiovascular magnetic resonance volumetric analysis in the clinical setting, INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING, Vol: 38, Pages: 2413-2424, ISSN: 1569-5794

Journal article

Amin R, Morris-Rosendahl D, Edwards M, Tayal U, Buchan R, Hammersley D, Jones R, Gati S, Khalique Z, Almogheer B, Pennell D, Baksi A, Pantazis A, Ware J, Prasad S, Halliday Bet al., 2022, The addition of genetic testing and cardiovascular magnetic resonance to routine clinical data for stratification of aetiology in dilated cardiomyopathy, Frontiers in Cardiovascular Medicine, Vol: 9, ISSN: 2297-055X

Background: Guidelines recommend genetic testing and cardiovascular magnetic resonance (CMR) for the investigation of dilated cardiomyopathy (DCM). However, the incremental value is unclear. We assessed the impact of these investigations in determining etiology.Methods: Sixty consecutive patients referred with DCM and recruited to our hospital biobank were selected. Six independent experts determined the etiology of each phenotype in a step-wise manner based on (1) routine clinical data, (2) clinical and genetic data and (3) clinical, genetic and CMR data. They indicated their confidence (1-3) in the classification and any changes to management at each step.Results: Six physicians adjudicated 60 cases. The addition of genetics and CMR resulted in 57 (15.8%) and 26 (7.2%) changes in the classification of etiology, including an increased number of genetic diagnoses and a reduction in idiopathic diagnoses. Diagnostic confidence improved at each step (p < 0.0005). The number of diagnoses made with low confidence reduced from 105 (29.2%) with routine clinical data to 71 (19.7%) following the addition of genetics and 37 (10.3%) with the addition of CMR. The addition of genetics and CMR led to 101 (28.1%) and 112 (31.1%) proposed changes to management, respectively. Interobserver variability showed moderate agreement with clinical data (κ = 0.44) which improved following the addition of genetics (κ = 0.65) and CMR (κ = 0.68).Conclusion: We demonstrate that genetics and CMR, frequently changed the classification of etiology in DCM, improved confidence and interobserver variability in determining the diagnosis and had an impact on proposed management.

Journal article

Lota A, Hazebroek M, Theotokis P, Wassall R, Salmi S, Halliday B, Tayal U, Verdonschot J, Meena D, Owen R, de Marvao A, Iacob A, Yazdani M, Hammersley D, Jones R, Wage R, Buchan R, Vivian F, Hafouda Y, Noseda M, Gregson J, Mittal T, Wong J, Robertus JL, Baksi AJ, Vassiliou V, Tzoulaki I, Pantazis A, Cleland J, Barton P, Cook S, Pennell D, Cooper L, Garcia-Pavia P, Heymans S, Ware J, Prasad Set al., 2022, Genetic architecture of acute myocarditis and the overlap with inherited cardiomyopathy, Circulation, Vol: 146, Pages: 1123-1134, ISSN: 0009-7322

Background: Acute myocarditis is an inflammatory condition that may herald the onset of dilated (DCM) or arrhythmogenic cardiomyopathy (ACM). We investigated the frequency and clinical consequences of DCM and ACM genetic variants in a population-based cohort of patients with acute myocarditis. Methods: Population-based cohort of 336 consecutive patients with acute myocarditis enrolled in London and Maastricht. All participants underwent targeted DNA-sequencing for well-characterised cardiomyopathy-associated genes with comparison to healthy controls (n=1053) sequenced on the same platform. Case ascertainment in England was assessed against national hospital admission data. The primary outcome was all-cause mortality. Results: Variants that would be considered pathogenic if found in a patient with DCM or ACM were identified in 8% of myocarditis cases compared to <1% of healthy controls (p=0.0097). In the London cohort (n=230; median age 33years; 84% men), patients were representative of national myocarditis admissions (median age 32years; 71% men; 66% case ascertainment), and there was enrichment of rare truncating variants (tv) in ACM-associated genes (3.1% cases vs 0.4% controls; odds ratio 8.2; p=0.001). This was driven predominantly by desmoplakin (DSP)-tv in patients with normal LV ejection fraction and ventricular arrhythmia. In Maastricht (n=106; median age 54years; 61% men), there was enrichment of rare truncating variants in DCM-associated genes, particularly TTN-tv found in 7% (all with LVEF<50%) compared to 1% in controls (OR 3.6; p=0.0116). Across both cohorts over a median of 5.0 years (IQR 3.9-7.8), all-cause mortality was 5.4%. Two thirds of deaths were cardiovascular, due to worsening heart failure (92%) or sudden cardiac death (8%). The 5-year mortality risk was 3.3% in genotype negative patients versus 11.1% for genotype positive patients (Padjusted=0.08). Conclusions: We identified DCM- or ACM-associated genetic variants in 8% of patients wit

Journal article

Balaban G, Halliday BP, Hammersley D, Rinaldi CA, Prasad SK, Bishop MJ, Lamata Pet al., 2022, Left ventricular shape predicts arrhythmic risk in fibrotic dilated cardiomyopathy, EUROPACE, Vol: 24, Pages: 1137-1147, ISSN: 1099-5129

Journal article

Anthony C, Imran M, Pouliopoulos J, Emmanuel S, Iliff J, Liu Z, Moffat K, Qiu MR, McLean CA, Stehning C, Puntmann V, Vassiliou V, Ismail TF, Gulati A, Prasad S, Graham RM, McCrohon J, Holloway C, Kotlyar E, Muthiah K, Keogh AM, Hayward CS, Macdonald PS, Jabbour Aet al., 2022, Cardiovascular Magnetic Resonance for Rejection Surveillance After Cardiac Transplantation, CIRCULATION, Vol: 145, Pages: 1811-1824, ISSN: 0009-7322

Journal article

Tayal U, Verdonschot JAJ, Hazebroek MR, Howard J, Gregson J, Newsome S, Gulati A, Pua CJ, Halliday BP, Lota AS, Buchan RJ, Whiffin N, Kanapeckaite L, Baruah R, Jarman JWE, O'Regan DP, Barton PJR, Ware JS, Pennell DJ, Adriaans BP, Bekkers SCAM, Donovan J, Frenneaux M, Cooper LT, Januzzi JL, Cleland JGF, Cook SA, Deo RC, Heymans SRB, Prasad SKet al., 2022, Precision phenotyping of dilated cardiomyopathy using multidimensional data., Journal of the American College of Cardiology, Vol: 79, Pages: 2219-2232, ISSN: 0735-1097

BACKGROUND: Dilated cardiomyopathy (DCM) is a final common manifestation of heterogenous etiologies. Adverse outcomes highlight the need for disease stratification beyond ejection fraction. OBJECTIVES: The purpose of this study was to identify novel, reproducible subphenotypes of DCM using multiparametric data for improved patient stratification. METHODS: Longitudinal, observational UK-derivation (n = 426; median age 54 years; 67% men) and Dutch-validation (n = 239; median age 56 years; 64% men) cohorts of DCM patients (enrolled 2009-2016) with clinical, genetic, cardiovascular magnetic resonance, and proteomic assessments. Machine learning with profile regression identified novel disease subtypes. Penalized multinomial logistic regression was used for validation. Nested Cox models compared novel groupings to conventional risk measures. Primary composite outcome was cardiovascular death, heart failure, or arrhythmia events (median follow-up 4 years). RESULTS: In total, 3 novel DCM subtypes were identified: profibrotic metabolic, mild nonfibrotic, and biventricular impairment. Prognosis differed between subtypes in both the derivation (P < 0.0001) and validation cohorts. The novel profibrotic metabolic subtype had more diabetes, universal myocardial fibrosis, preserved right ventricular function, and elevated creatinine. For clinical application, 5 variables were sufficient for classification (left and right ventricular end-systolic volumes, left atrial volume, myocardial fibrosis, and creatinine). Adding the novel DCM subtype improved the C-statistic from 0.60 to 0.76. Interleukin-4 receptor-alpha was identified as a novel prognostic biomarker in derivation (HR: 3.6; 95% CI: 1.9-6.5; P = 0.00002) and validation cohorts (HR: 1.94; 95% CI: 1.3-2.8; P = 0.00005). CONCLUSIONS: Three reproducible, mechanistically distinct DCM subtypes were identified using widely available clinical and biological data, adding prognostic value to trad

Journal article

Tayal U, 2022, Exposure to elevated nitrogen dioxide concentrations and cardiac remodelling in patients with dilated cardiomyopathy, Journal of Cardiac Failure, Vol: 28, Pages: 924-934, ISSN: 1071-9164

Rationale: Empirical evidence suggests a strong link between exposure to air pollution and heart failure incidence, hospitalisations and mortality, but the biological basis of this remains unclear. Objective: To determine the relationship between differential air pollution levels and changes in cardiac structure and function in patients with dilated cardiomyopathy. Methods and Results: We undertook a prospective longitudinal observational cohort study of patients in England with dilated cardiomyopathy (enrollment 2009-2015; n=716, 66% male, 85% Caucasian) and conducted cross sectional analysis at the time of study enrollment. Annual average air pollution exposure estimates for nitrogen dioxide (NO2) and particulate matter with diameter ≤ 2.5µm (PM2.5) at enrolment were assigned to each residential postcode (on average 12 households). The relationship between air pollution and cardiac morphology was assessed using linear regression modelling. Greater ambient exposure to NO2 was associated with higher indexed left ventricular mass (4.3 g/m2 increase per interquartile range (IQR) increase in NO2, 95% CI 1.9 to 7.0 g/m2) and lower left ventricular ejection fraction (-1.5% decrease per IQR increase in NO2, 95% CI -2.7 to -0.2%), independent of age, sex, socio-economic status and clinical covariates. The associations were robust to adjustment for smoking status and geographical clustering by postcode area. The effect of air pollution on left ventricular mass was greatest in women. These effects were specific to NO2 exposure. Conclusion: Exposure to air pollution is associated with raised left ventricular mass and lower left ventricular ejection fraction, with the strongest effect in women. Whilst epidemiological associations between air pollution and heart failure have been established and supported by pre-clinical studies, our findings provide novel empirical evidence of cardiac remodelling and exposure to air pollution with important clinical and public health

Journal article

Thornton GD, Musa TA, Rigolli M, Loudon M, Chin C, Pica S, Malley T, Foley JRJ, Vassiliou VS, Davies RH, Captur G, Dobson LE, Moon JC, Dweck MR, Myerson SG, Prasad SK, Greenwood JP, McCann GP, Singh A, Treibel TAet al., 2022, Association of Myocardial Fibrosis and Stroke Volume by Cardiovascular Magnetic Resonance in Patients With Severe Aortic Stenosis With Outcome After Valve Replacement The British Society of Cardiovascular Magnetic Resonance AS700 Study, JAMA CARDIOLOGY, Vol: 7, Pages: 513-520, ISSN: 2380-6583

Journal article

Tsampasian V, Grafton-Clarke C, Ramos AEG, Asimakopoulos G, Garg P, Prasad S, Ring L, McCann GP, Rudd J, Dweck MR, Vassiliou VSet al., 2022, Management of asymptomatic severe aortic stenosis: a systematic review and meta-analysis, OPEN HEART, Vol: 9, ISSN: 2053-3624

Journal article

Tayal U, gregson J, Buchan R, Whiffin N, Halliday B, Lota A, Roberts A, Baksi A, Voges I, Jarman J, Baruah R, Frenneaux M, Cleland J, Barton P, Pennell D, Ware J, Cook S, Prasad Set al., 2022, Moderate excess alcohol consumption and adverse cardiac remodelling in dilated cardiomyopathy, Heart, Vol: 108, Pages: 619-625, ISSN: 1355-6037

Objective The effect of moderate excess alcohol consumption is widely debated and has not been well defined in dilated cardiomyopathy (DCM). There is need for a greater evidence base to help advise patients. We sought to evaluate the effect of moderate excess alcohol consumption on cardiovascular structure, function and outcomes in DCM. Methods Prospective longitudinal observational cohort study. Patients with DCM (n=604) were evaluated for a history of moderate excess alcohol consumption (UK government guidelines; >14 units/week for women, >21 units/week for men) at cohort enrollment, had cardiovascular magnetic resonance and were followed up for the composite endpoint of cardiovascular death, heart failure and arrhythmic events. Patients meeting criteria for alcoholic cardiomyopathy were not recruited. ResultsDCM patients with a history of moderate excess alcohol consumption (n=98, 16%) had lower biventricular function and increased chamber dilatation of the left ventricle, right ventricle and left atrium, as well as increased left ventricular hypertrophy compared to patients without moderate alcohol consumption. They were more likely to be male (alcohol excess group– n =92, 94% vs n =306, 61%, p=<0.001). After adjustment for biological sex, moderate excess alcohol was not associated with adverse cardiac structure. There was no difference in mid-wall myocardial fibrosis between groups. Prior moderate excess alcohol consumption did not affect prognosis (HR 1.29, 0.73 to 2.26, p=0.38) during median follow up of 3.9 years. ConclusionDilated cardiomyopathy patients with moderate excess alcohol consumption have adverse cardiac structure and function at presentation but this is largely due to biological sex. Alcohol may contribute to sex-specific phenotypic differences in DCM. These findings help to inform lifestyle discussions for patients with dilated cardiomyopathy.

Journal article

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