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
to

393 results found

Papageorgiou V, Jones K, Halliday BP, Mindham R, Bruton J, Wassall R, Cleland JGF, Prasad SK, Ward Het al., 2021, A qualitative exploration of participant and investigator perspectives from the TRED-HF trial, ESC HEART FAILURE, ISSN: 2055-5822

Journal article

Bermejo IA, Bautista-Rodriguez C, Fraisse A, Voges I, Gatehouse P, Kang H, Piccinelli E, Rowlinson G, Lane M, Semple T, Moscatelli S, Dwornik M, Lota A, Di Salvo G, Wage R, Prasad SK, Mohiaddin R, Pennell DJ, Thavendiranathan P, Krupickova Set al., 2021, Short-Term sequelae of Multisystem Inflammatory Syndrome in Children Assessed by CMR, JACC-CARDIOVASCULAR IMAGING, Vol: 14, Pages: 1666-1667, ISSN: 1936-878X

Journal article

Hatipoglu S, Almogheer B, Mahon C, Houshmand G, Uygur B, Giblin GT, Krupickova S, Baksi AJ, Alpendurada F, Prasad SK, Babu-Narayan SV, Gatzoulis MA, Mohiaddin RH, Pennell DJ, Izgi Cet al., 2021, Clinical Significance of Partial Anomalous Pulmonary Venous Connections (Isolated and Atrial Septal Defect Associated) Determined by Cardiovascular Magnetic Resonance, CIRCULATION-CARDIOVASCULAR IMAGING, Vol: 14, ISSN: 1941-9651

Journal article

Krupickova S, Hatipoglu S, DiSalvo G, Voges I, Redfearn D, Foldvari S, Eichhorn C, Chivers S, Puricelli F, Delle-Donne G, Barth C, Pennell DJ, Prasad SK, Daubeney PEFet al., 2021, Left ventricular noncompaction in pediatric population: could cardiovascular magnetic resonance derived fractal analysis aid diagnosis?, JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE, Vol: 23, ISSN: 1097-6647

Journal article

Simoes Monteiro de Marvao A, McGurk K, Zheng S, Thanaj M, Bai W, Duan J, Biffi C, Mazzarotto F, Statton B, Dawes T, Savioli N, Halliday B, Xu X, Buchan R, Baksi A, Quinlan M, Tokarczuk P, Tayal U, Francis C, Whiffin N, Theotokis A, Zhang X, Jang M, Berry A, Pantazis A, Barton P, Rueckert D, Prasad S, Walsh R, Ho C, Cook S, Ware J, O'Regan Det al., 2021, Phenotypic expression and outcomes in individuals with rare genetic variants of hypertrophic cardiomyopathy, Journal of the American College of Cardiology, ISSN: 0735-1097

Background: Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomereencoding genes, but little is known about the clinical significance of these variants in thegeneral population.Objectives: To compare lifetime outcomes and cardiovascular phenotypes according to thepresence of rare variants in sarcomere-encoding genes amongst middle-aged adults.Methods: We analysed whole exome sequencing and cardiac magnetic resonance (CMR)imaging in UK Biobank participants stratified by sarcomere-encoding variant status.Results: The prevalence of rare variants (allele frequency <0.00004) in HCM-associatedsarcomere-encoding genes in 200,584 participants was 2.9% (n=5,712; 1 in 35), and theprevalence of variants pathogenic or likely pathogenic for HCM (SARC-HCM-P/LP) was0.25% (n=493, 1 in 407). SARC-HCM-P/LP variants were associated with increased risk ofdeath or major adverse cardiac events compared to controls (HR 1.69, 95% CI 1.38 to 2.07,p<0.001), mainly due to heart failure endpoints (HR 4.23, 95% CI 3.07 to 5.83, p<0.001). In21,322 participants with CMR, SARC-HCM-P/LP were associated with asymmetric increasein left ventricular maximum wall thickness (10.9±2.7 vs 9.4±1.6 mm, p<0.001) buthypertrophy (≥13mm) was only present in 18.4% (n=9/49, 95% CI 9 to 32%). SARC-HCMP/LP were still associated with heart failure after adjustment for wall thickness (HR 6.74,95% CI 2.43 to 18.7, p<0.001).Conclusions: In this population of middle-aged adults, SARC-HCM-P/LP variants have lowaggregate penetrance for overt HCM but are associated with increased risk of adversecardiovascular outcomes and an attenuated cardiomyopathic phenotype. Although absoluteevent rates are low, identification of these variants may enhance risk stratification beyondfamilial disease.

Journal article

Halliday B, Vazir A, Owen R, Gregson J, Wassall R, Lota A, Khalique Z, Tayal U, Jones R, Hammersley D, Pantazis A, Baksi A, Rosen S, Pennell D, Cowie M, Cleland J, Prasad Set al., 2021, Heart rate as a marker of relapse during withdrawal of therapy in recovered dilated cardiomyopathy, JACC: Heart Failure, Vol: 9, Pages: 509-517, ISSN: 2213-1779

Objective: To determine the relationship between heart rate and relapse amongst patients in the TRED-HF trial. Background: Understanding markers and mechanisms of relapse amongst patients with recovered dilated cardiomyopathy (DCM) might enable personalised management.Methods: The relationship between serial heart rate measurements and relapse was examined amongst patients TRED-HF, a randomised trial which examined the safety and feasibility of withdrawing heart failure therapy amongst 51 patients with recovered DCM over 6 months. In total, 25 patients were randomised to therapy withdrawal and 26 to continue therapy, of whom 25 subsequently began therapy withdrawal in a single arm crossover phase.Results: The mean heart rate (standard deviation) for those who had therapy withdrawn and did not relapse was 64.6bpm (10.7) at baseline and 74.7bpm (10.4) at follow-up compared to 68.3bpm (11.3) and 86.1bpm (11.8) for those who relapsed. After adjusting for baseline heart rate, patients who had therapy withdrawn and relapsed had a 10.4bpm (95% confidence intervals [CIs] 4.0-16.8) greater rise in heart rate compared to patients who had therapy withdrawn and did not relapse (p=0.002). After adjusting for age, log NT-pro-BNP and LVEF, heart rate (per 10bpm - hazard ratio: 1.65, 95%CI 1.10-2.57, p=0.01) and change in heart rate from baseline (per 10bpm - hazard ratio: 1.70, 95%CI 1.12-2.57, p=0.01) were associated with relapse. The results remained qualitatively the same after adjusting for beta-blocker dose.Conclusion: For patients with DCM and improved LVEF, the rise in heart rate after withdrawing treatment identifies patients who are more likely to relapse. Whether the increase in heart rate is a marker or mediator of relapse requires investigation.

Journal article

Tayal U, Ware JS, Lakdawala NK, Heymans S, Prasad SKet al., 2021, Understanding the genetics of adult-onset dilated cardiomyopathy: what a clinician needs to know., European Heart Journal, Vol: 42, Pages: 2384-2396, ISSN: 0195-668X

There is increasing understanding of the genetic basis to dilated cardiomyopathy and in this review, we offer a practical primer for the practising clinician. We aim to help all clinicians involved in the care of patients with dilated cardiomyopathy to understand the clinical relevance of the genetic basis of dilated cardiomyopathy, introduce key genetic concepts, explain which patients and families may benefit from genetic testing, which genetic tests are commonly performed, how to interpret genetic results, and the clinical applications of results. We conclude by reviewing areas for future research in this dynamic field.

Journal article

Gorecka M, McCann GP, Berry C, Ferreira VM, Moon JC, Miller CA, Chiribiri A, Prasad S, Dweck MR, Bucciarelli-Ducci C, Dawson D, Fontana M, Macfarlane PW, McConnachie A, Neubauer S, Greenwood JPet al., 2021, Demographic, multi-morbidity and genetic impact on myocardial involvement and its recovery from COVID-19: protocol design of COVID-HEART-a UK, multicentre, observational study, JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE, Vol: 23, ISSN: 1097-6647

Journal article

Garnier S, Harakalova M, Weiss S, Mokry M, Regitz-Zagrosek V, Hengstenberg C, Cappola TP, Isnard R, Arbustini E, Cook SA, van Setten J, Calis JJA, Hakonarson H, Morley MP, Stark K, Prasad SK, Li J, O'Regan DP, Grasso M, Mueller-Nurasyid M, Meitinger T, Empana J-P, Strauch K, Waldenberger M, Marguiles KB, Seidman CE, Kararigas G, Meder B, Haas J, Boutouyrie P, Lacolley P, Jouven X, Erdmann J, Blankenberg S, Wichter T, Ruppert V, Tavazzi L, Dubourg O, Roizes G, Dorent R, de Groote P, Fauchier L, Trochu J-N, Aupetit J-F, Bilinska ZT, Germain M, Voelker U, Hemerich D, Raji I, Bacq-Daian D, Proust C, Remior P, Gomez-Bueno M, Lehnert K, Maas R, Olaso R, Saripella GV, Felix SB, McGinn S, Duboscq-Bidot L, van Mil A, Besse C, Fontaine V, Blanche H, Ader F, Keating B, Curjol A, Boland A, Komajda M, Cambien F, Deleuze J-F, Doerr M, Asselbergs FW, Villard E, Tregoueet D-A, Charron Pet 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

Journal article

Zhang Q, Werys K, Popescu IA, Biasiolli L, Ntusi NAB, Desai M, Zimmerman SL, Shah DJ, Autry K, Kim B, Kim HW, Jenista ER, Huber S, White JA, McCann GP, Mohiddin SA, Boubertakh R, Chiribiri A, Newby D, Prasad S, Radjenovic A, Dawson D, Schulz-Menger J, Mahrholdt H, Carbone I, Rimoldi O, Colagrande S, Calistri L, Michels M, Hofman MBM, Anderson L, Broberg C, Andrew F, Sanz J, Bucciarelli-Ducci C, Chow K, Higgins D, Broadbent DA, Semple S, Hafyane T, Wormleighton J, Salerno M, He T, Plein S, Kwong RY, Jerosch-Herold M, Kramer CM, Neubauer S, Ferreira VM, Piechnik SKet al., 2021, Quality assurance of quantitative cardiac T1-mapping in multicenter clinical trials - A T1 phantom program from the hypertrophic cardiomyopathy registry (HCMR) study, INTERNATIONAL JOURNAL OF CARDIOLOGY, Vol: 330, Pages: 251-258, ISSN: 0167-5273

Journal article

Halliday B, Owen R, Gregson J, Vassiliou V, Chen X, Wage R, Lota A, Khalique Z, Tayal U, Hammersley D, Jones R, Baksi A, Cowie M, Cleland J, Pennell D, Prasad Set al., 2021, Myocardial remodelling after withdrawing therapy for heart failure in patients with recovered dilated cardiomyopathy: insights from TRED-HF, European Journal of Heart Failure, Vol: 23, Pages: 293-301, ISSN: 1388-9842

Aims: To characterize adverse ventricular remodelling after withdrawing therapy in recovered dilated cardiomyopathy (DCM). Methods and results: TRED-HF was a randomized controlled trial with a follow-on single-arm cross-over phase that examined the safety and feasibility of therapy withdrawal in patients with recovered DCM over 6 months. The primary endpoint was relapse of heart failure defined by (i) a reduction in left ventricular (LV) ejection fraction >10% and to <50%, (ii) >10% increase in LV end-diastolic volume and to above the normal range, (iii) a twofold rise in N-terminal pro-B-type natriuretic peptide and to >400 ng/L, or (iv) evidence of heart failure. LV mass, LV and right ventricular (RV) global longitudinal strain (GLS) and extracellular volume were measured using cardiovascular magnetic resonance at baseline and follow-up (6 months or relapse) for 48 patients. LV cell and extracellular matrix masses were derived. The effect of withdrawing therapy, stratified by relapse and genotype, was investigated in the randomized and follow-on phases. In the randomized comparison, withdrawing therapy led to an increase in mean LV mass [5.4 g/m2; 95% confidence interval (CI) 1.3–9.5] and cell mass (4.2 g/m2; 95% CI 0.5–8.0) and a reduction in LV (3.5; 95% CI 1.6–5.5) and RV (2.4; 95% CI 0.1–4.7) GLS. In a non-randomized comparison of all patients (n = 47) who had therapy withdrawn in either phase, there was an increase in LV mass (6.2 g/m2; 95% CI 3.6–8.9; P = 0.0001), cell mass (4.0 g/m2; 95% CI 1.8–6.2; P = 0.0007) and matrix mass (1.7 g/m2; 95% CI 0.7–2.6; P = 0.001) and a reduction in LV GLS (2.7; 95% CI 1.5–4.0; P = 0.0001). Amongst those who had therapy withdrawn and did not relapse, similar changes were observed (n = 28; LV mass: 5.1 g/m2, 95% CI 1.5–8.8, P = 0.007; cell mass: 3.7 g/m2, 95% CI 0.3–7.0, P = 0.03; matrix mass: 1.7 g/m2, 95% CI 0.4–3.0, P = 0.02; LV GLS: 1.7, 95% CI

Journal article

Prasad S, Halliday B, 2021, Myocardial fibrosis in dilated cardiomyopathy – moving from stratifying risk to improving outcomes, JACC: Cardiovascular Imaging, ISSN: 1876-7591

Journal article

Raphael C, Mitchell F, Kanaganayagam G, liew A, Di Pietro E, Vieira M, Kanapeckaite L, Newsome S, Gregson J, Owen R, Hsu L-Y, Vassiliou V, Cooper R, Ali A, Ismail T, Wong B, Sun K, Gatehouse P, Firmin D, Cook S, Frenneaux M, Arai A, O'Hanlon R, Pennell D, Prasad Set 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

Journal article

Jenner WJ, Kanji R, Mirsadraee S, Gue YX, Price S, Prasad S, Gorog DAet al., 2021, Thrombotic complications in 2928 patients with COVID-19 treated in intensive care: a systematic review, Journal of Thrombosis and Thrombolysis, Vol: 51, Pages: 595-607, ISSN: 0929-5305

A prothrombotic state is reported with severe COVID-19 infection, which can manifest in venous and arterial thrombotic events. Coagulopathy is reflective of more severe disease and anticoagulant thromboprophylaxis is recommended in hospitalized patients. However, the prevalence of thrombosis on the intensive care unit (ICU) remains unclear, including whether this is sufficiently addressed by conventional anticoagulant thromboprophylaxis. We aimed to identify the rate of thrombotic complications in ICU-treated patients with COVID-19, to inform recommendations for diagnosis and management. A systematic review was conducted to assess the incidence of thrombotic complications in ICU-treated patients with COVID-19. Observational studies and registries reporting thrombotic complications in ICU-treated patients were included. Information extracted included patient demographics, use of thromboprophylaxis or anticoagulation, method of identifying thrombotic complications, and reported patient outcomes. In 28 studies including 2928 patients, thrombotic complications occurred in 34% of ICU-managed patients, with deep venous thrombosis reported in 16.1% and pulmonary embolism in 12.6% of patients, despite anticoagulant thromboprophylaxis, and were associated with high mortality. Studies adopting systematic screening for venous thrombosis with Duplex ultrasound reported a significantly higher incidence of venous thrombosis compared to those relying on clinical suspicion (56.3% vs. 11.0%, p < 0.001). Despite thromboprophylaxis, there is a very high incidence of thrombotic complications in patients with COVID-19 on the ICU. Systematic screening identifies many thrombotic complications that would be missed by relying on clinical suspicion and should be employed, with consideration given to increased dose anticoagulant thromboprophylaxis, whilst awaiting results of prospective trials of anticoagulation in this cohort.

Journal article

Bhalodiya JM, Palit A, Giblin G, Tiwari MK, Prasad SK, Bhudia SK, Arvanitis TN, Williams MAet al., 2021, Identifying Myocardial Infarction Using Hierarchical Template Matching-Based Myocardial Strain: Algorithm Development and Usability Study, JMIR MEDICAL INFORMATICS, Vol: 9

Journal article

Balaban G, Halliday B, Bradley P, Bai W, Nygaard S, Owen R, Hatipoglu S, Ferreira ND, Izgi C, Tayal U, Corden B, Ware J, Pennell D, Rueckert D, Plank G, Rinaldi CA, Prasad SK, Bishop Met al., 2021, Late-gadolinium enhancement interface area and electrophysiological simulations predict arrhythmic events in non-ischemic dilated cardiomyopathy patients, JACC: Clinical Electrophysiology, Vol: 7, Pages: 238-249, ISSN: 2405-5018

BACKGROUND: The presence of late-gadolinium enhancement (LGE) predicts life threatening ventricular arrhythmias in non-ischemic dilated cardiomyopathy (NIDCM); however, risk stratification remains imprecise. LGE shape and simulations of electrical activity may be able to provide additional prognostic information.OBJECTIVE: This study sought to investigate whether shape-based LGE metrics and simulations of reentrant electrical activity are associated with arrhythmic events in NIDCM patients.METHODS: CMR-LGE shape metrics were computed for a cohort of 156 NIDCM patients with visible LGE and tested retrospectively for an association with an arrhythmic composite end-point of sudden cardiac death and ventricular tachycardia. Computational models were created from images and used in conjunction with simulated stimulation protocols to assess the potential for reentry induction in each patient’s scar morphology. A mechanistic analysis of the simulations was carried out to explain the associations. RESULTS: During a median follow-up of 1611 [IQR 881-2341] days, 16 patients (10.3%) met the primary endpoint. In an inverse probability weighted Cox regression, the LGE-myocardial interface area (HR:1.75; 95% CI:1.24-2.47; p=0.001), number of simulated reentries (HR: 1.4; 95% CI: 1.23-1.59; p<0.01) and LGE volume (HR:1.44; 95% CI:1.07-1.94; p=0.02) were associated with arrhythmic events. Computational modeling revealed repolarisation heterogeneity and rate-dependent block of electrical wavefronts at the LGE-myocardial interface as putative arrhythmogenic mechanisms directly related to LGE interface area.CONCLUSION: The area of interface between scar and surviving myocardium, as well as simulated reentrant activity, are associated with an elevated risk of major arrhythmic events in NIDCM patients with LGE and represent novel risk predictors.

Journal article

Mazzarotto F, Hawley MH, Beltrami M, Beekman L, De Marvao A, McGurk K, Statton B, Boschi B, Girolami F, Roberts AM, Lodder EM, Allouba M, Romeih S, Aguib Y, Baksi J, Pantazis A, Prasad SK, Cerbai E, Yacoub M, O'Regan D, Cook S, Ware J, Funke B, Olivotto I, Bezzina C, Barton P, Walsh Ret 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.

Journal article

Harper AR, Goel A, Grace C, Thomson KL, Petersen SE, Xu X, Waring A, Ormondroyd E, Kramer CM, Ho CY, Neubauer S, Tadros R, Ware JS, Bezzina CR, Farrall M, Watkins Het al., 2021, Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity, Nature Genetics, Vol: 53, Pages: 135-142, ISSN: 1061-4036

Hypertrophic cardiomyopathy (HCM) is a common, serious, genetic heart disorder. Rare pathogenic variants in sarcomere genes cause HCM, but with unexplained phenotypic heterogeneity. Moreover, most patients do not carry such variants. We report a genome-wide association study of 2,780 cases and 47,486 controls that identified 12 genome-wide-significant susceptibility loci for HCM. Single-nucleotide polymorphism heritability indicated a strong polygenic influence, especially for sarcomere-negative HCM (64% of cases; h2g = 0.34 ± 0.02). A genetic risk score showed substantial influence on the odds of HCM in a validation study, halving the odds in the lowest quintile and doubling them in the highest quintile, and also influenced phenotypic severity in sarcomere variant carriers. Mendelian randomization identified diastolic blood pressure (DBP) as a key modifiable risk factor for sarcomere-negative HCM, with a one standard deviation increase in DBP increasing the HCM risk fourfold. Common variants and modifiable risk factors have important roles in HCM that we suggest will be clinically actionable.

Journal article

Ware J, Tadros R, Francis C, Xu X, Matthews P, watkins H, Bezzina Cet 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.

Journal article

Hammersley DJ, Jones RE, Mach L, Halliday BP, Prasad SKet al., 2021, Cardiovascular Magnetic Resonance in Heritable Cardiomyopathies, HEART FAILURE CLINICS, Vol: 17, Pages: 25-39, ISSN: 1551-7136

Journal article

Castiello T, Georgiopoulos G, Finocchiaro G, Claudia M, Gianatti A, Delialis D, Aimo A, Prasad Set al., 2021, COVID-19 and myocarditis: a systematic review and overview of current challenges, Heart Failure Reviews, ISSN: 1382-4147

Myocardial inflammation in COVID-19 has been documented. Its pathogenesis is not fully elucidated, but the two main theories foresee a direct role of ACE2 receptor and a hyperimmune response, which may also lead to isolated presentation of COVID-19-mediated myocarditis. The frequency and prognostic impact of COVID-19-mediated myocarditis is unknown. This review aims to summarise current evidence on this topic. We performed a systematic review of MEDLINE and Cochrane Library (1/12/19–30/09/20). We also searched clinicaltrials.gov for unpublished studies testing therapies with potential implication for COVID-19-mediated cardiovascular complication. Eligible studies had laboratory confirmed COVID-19 and a clinical and/or histological diagnosis of myocarditis by ESC or WHO/ISFC criteria. Reports of 38 cases were included (26 male patients, 24 aged < 50 years). The first histologically proven case was a virus-negative lymphocytic myocarditis; however, biopsy evidence of myocarditis secondary to SARS-CoV-2 cardiotropism has been recently demonstrated. Histological data was found in 12 cases (8 EMB and 4 autopsies) and CMR was the main imaging modality to confirm a diagnosis of myocarditis (25 patients). There was a substantial variability in biventricular systolic function during the acute episode and in therapeutic regimen used. Five patients died in hospital. Cause-effect relationship between SARS-CoV-2 infection and myocarditis is difficult to demonstrate. However, current evidence demonstrates myocardial inflammation with or without direct cardiomyocyte damage, suggesting different pathophysiology mechanisms responsible of COVID-mediated myocarditis. Established clinical approaches should be pursued until future evidence support different actions. Large multicentre registries are advisable to elucidate further.

Journal article

Raphael CE, Liew AC, Mitchell F, Kanaganayagam GS, Di Pietro E, Newsome S, Owen R, Gregson J, Cooper R, Amin FR, Gatehouse P, Vassiliou V, Ernst S, O'Hanlon R, Frenneaux M, Pennell DJ, Prasad SKet al., 2020, Predictors and Mechanisms of Atrial Fibrillation in Patients With Hypertrophic Cardiomyopathy, AMERICAN JOURNAL OF CARDIOLOGY, Vol: 136, Pages: 140-148, ISSN: 0002-9149

Journal article

Balaban G, Costa CM, Porter B, Halliday B, Rinaldi CA, Prasad S, Plank G, Ismail TF, Bishop MJet al., 2020, 3D Electrophysiological Modeling of Interstitial Fibrosis Networks and Their Role in Ventricular Arrhythmias in Non-Ischemic Cardiomyopathy, IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, Vol: 67, Pages: 3125-3133, ISSN: 0018-9294

Journal article

Zemrak F, Raisi-Estabragh Z, Khanji MY, Mohiddin SA, Bruder O, Wagner A, Lombardi M, Schwitter J, van Rossum AC, Pilz G, Nothnagel D, Steen H, Nagel E, Prasad SK, Deluigi CC, Dill T, Frank H, Schneider S, Mahrholdt H, Petersen SEet al., 2020, Left Ventricular Hypertrabeculation Is Not Associated With Cardiovascular Morbity or Mortality: Insights From the Eurocmr Registry, FRONTIERS IN CARDIOVASCULAR MEDICINE, Vol: 7, ISSN: 2297-055X

Journal article

Celutkiene J, Pudil R, Lopez-Fernandez T, Grapsa J, Nihoyannopoulos P, Bergler-Klein J, Cohen-Solal A, Farmakis D, Tocchetti CG, von Haehling S, Barberis V, Flachskampf FA, Ceponiene I, Haegler-Laube E, Suter T, Lapinskas T, Prasad S, de Boer RA, Wechalekar K, Anker MS, Iakobishvili Z, Bucciarelli-Ducci C, Schulz-Menger J, Cosyns B, Gaemperli O, Belenkov Y, Hulot J-S, Galderisi M, Lancellotti P, Bax J, Marwick TH, Chioncel O, Jaarsma T, Mullens W, Piepoli M, Thum T, Heymans S, Mueller C, Moura B, Ruschitzka F, Zamorano JL, Rosano G, Coats AJS, Asteggiano R, Seferovic P, Edvardsen T, Lyon ARet al., 2020, Role of cardiovascular imaging in cancer patients receiving cardiotoxic therapies: a position statement on behalf of the Heart Failure Association (HFA), the European Association of Cardiovascular Imaging (EACVI) and the Cardio-Oncology Council of the European Society of Cardiology (ESC), EUROPEAN JOURNAL OF HEART FAILURE, Vol: 22, Pages: 1504-1524, ISSN: 1388-9842

Journal article

Meyer H, Dawes T, Serrani M, Bai W, Tokarczuk P, Cai J, Simoes Monteiro de Marvao A, Henry A, Lumbers T, Gierten J, Thumberger T, Wittbrodt J, Ware J, Rueckert D, Matthews P, Prasad S, Costantino M, Cook S, Birney E, O'Regan Det 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

Journal article

Sintou A, Mansfield C, Iacob A-O, Chowdhury RA, Narodden S, Rothery SM, Podoveo R, Sanchez Alonso JL, Ferraro E, Swiatlowska P, Harding S, Prasad S, Rosenthal N, Gorelik J, Sattler Set al., 2020, Mediastinal lymphadenopathy, class-switched auto-antibodies and myocardial immune-complexes during heart failure in rodents and humans, Frontiers in Cell and Developmental Biology, Vol: 8, Pages: 1-12, ISSN: 2296-634X

Mediastinal lymphadenopathy and auto-antibodies are clinical phenomena during ischemicheart failure pointing to an autoimmune response against the heart. T and B cell have beenconvincingly demonstrated to be activated after myocardial infarction, a prerequisite for thegeneration of mature auto-antibodies. Yet, little is known about the immunoglobulin isotyperepertoire thus pathological potential of anti-heart auto-antibodies during heart failure.We obtained human myocardial tissue from ischemic heart failure patients and inducedexperimental MI in rats. We found that anti-heart autoimmunity persists during heart failure.Rat mediastinal lymph nodes are enlarged and contain active secondary follicles with matureisotype-switched IgG2a B cells. Mature IgG2a auto-antibodies specific for cardiac antigens arepresent in rat heart failure serum, and IgG and complement C3 deposits are evident in heartfailure tissue of both rats and human patients.Previously established myocardial inflammation, and the herein provided proof of B cellmaturation in lymph nodes and myocardial deposition of mature auto-antibodies, provide allthe hallmark signs of an established autoimmune response in chronic heart failure.

Journal article

Yakupoglu HY, De Robertis F, Prasad S, Khattar RS, Cavarretta E, Van De Sande D, Rodríguez-Zanella Het al., 2020, Detection of multiple exercise-induced pathophysiological processes in concomitant coronary artery disease and hypertrophic cardiomyopathy by stress echocardiography, European Heart Journal - Case Reports, Vol: 4

Journal article

Thaventhiran JED, Lango Allen H, Burren OS, Rae W, Greene D, Staples E, Zhang Z, Farmery JHR, Simeoni I, Rivers E, Maimaris J, Penkett CJ, Stephens J, Deevi SVV, Sanchis-Juan A, Gleadall NS, Thomas MJ, Sargur RB, Gordins P, Baxendale HE, Brown M, Tuijnenburg P, Worth A, Hanson S, Linger RJ, Buckland MS, Rayner-Matthews PJ, Gilmour KC, Samarghitean C, Seneviratne SL, Sansom DM, Lynch AG, Megy K, Ellinghaus E, Ellinghaus D, Jorgensen SF, Karlsen TH, Stirrups KE, Cutler AJ, Kumararatne DS, Chandra A, Edgar JDM, Herwadkar A, Cooper N, Grigoriadou S, Huissoon AP, Goddard S, Jolles S, Schuetz C, Boschann Fet 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

Journal article

Thaventhiran JED, Lango Allen H, Burren OS, Rae W, Greene D, Staples E, Zhang Z, Farmery JHR, Simeoni I, Rivers E, Maimaris J, Penkett CJ, Stephens J, Deevi SVV, Sanchis-Juan A, Gleadall NS, Thomas MJ, Sargur RB, Gordins P, Baxendale HE, Brown M, Tuijnenburg P, Worth A, Hanson S, Linger RJ, Buckland MS, Rayner-Matthews PJ, Gilmour KC, Samarghitean C, Seneviratne SL, Sansom DM, Lynch AG, Megy K, Ellinghaus E, Ellinghaus D, Jorgensen SF, Karlsen TH, Stirrups KE, Cutler AJ, Kumararatne DS, Chandra A, Edgar JDM, Herwadkar A, Cooper N, Grigoriadou S, Huissoon AP, Goddard S, Jolles S, Schuetz C, Boschann F, Primary Immunodeficiency Consortium for the NIHR Bioresource, Lyons PA, Hurles ME, Savic S, Burns SO, Kuijpers TW, Turro E, Ouwehand WH, Thrasher AJ, Smith KGCet 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.

Journal article

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