Imperial College London

Dr John Baksi

Faculty of MedicineNational Heart & Lung Institute

Honorary Clinical Senior Lecturer
 
 
 
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Contact

 

+44 (0)20 7352 8121j.baksi

 
 
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Location

 

Cardiovascular MR UnitRoyal Brompton Campus

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Summary

 

Publications

Publication Type
Year
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73 results found

Bhuva AN, Moralee R, Brunker T, Lascelles K, Cash L, Patel KP, Lowe M, Sekhri N, Alpendurada F, Pennell DJ, Schilling R, Lambiase PD, Chow A, Moon JC, Litt H, Baksi AJ, Manisty CHet al., 2021, Evidence to support magnetic resonance conditional labelling of all pacemaker and defibrillator leads in patients with cardiac implantable electronic devices., Eur Heart J

AIMS: Many cardiac pacemakers and defibrillators are not approved by regulators for magnetic resonance imaging (MRI). Even following generator exchange to an approved magnetic resonance (MR)-conditional model, many systems remain classified 'non-MR conditional' due to the leads. This classification makes patient access to MRI challenging, but there is no evidence of increased clinical risk. We compared the effect of MRI on non-MR conditional and MR-conditional pacemaker and defibrillator leads. METHODS AND RESULTS: Patients undergoing clinical 1.5T MRI with pacemakers and defibrillators in three centres over 5 years were included. Magnetic resonance imaging protocols were similar for MR-conditional and non-MR conditional systems. Devices were interrogated pre- and immediately post-scan, and at follow-up, and adverse clinical events recorded. Lead parameter changes peri-scan were stratified by MR-conditional labelling. A total of 1148 MRI examinations were performed in 970 patients (54% non-MR conditional systems, 39% defibrillators, 15% pacing-dependent) with 2268 leads. There were no lead-related adverse clinical events, and no clinically significant immediate or late lead parameter changes following MRI in either MR-conditional or non-MR conditional leads. Small reductions in atrial and right ventricular sensed amplitudes and impedances were similar between groups, with no difference in the proportion of leads with parameter changes greater than pre-defined thresholds (7.1%, 95% confidence interval: 6.1-8.3). CONCLUSIONS: There was no increased risk of MRI in patients with non-MR conditional pacemaker or defibrillator leads when following recommended protocols. Standardizing MR conditions for all leads would significantly improve access to MRI by enabling patients to be scanned in non-specialist centres, with no discernible incremental risk.

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., 2021, Moderate excess alcohol consumption and adverse cardiac remodelling in dilated cardiomyopathy, Heart, 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

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

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

Thavendiranathan P, Zhang L, Zafar A, Drobni ZD, Mahmood SS, Cabral M, Awadalla M, Nohria A, Zlotoff DA, Thuny F, Heinzerling LM, Barac A, Sullivan RJ, Chen CL, Gupta D, Kirchberger MC, Hartmann SE, Weinsaft JW, Gilman HK, Rizvi MA, Kovacina B, Michel C, Sahni G, Gonzalez-Mansilla A, Calles A, Fernandez-Aviles F, Mahmoudi M, Reynolds KL, Ganatra S, Jose Gavira J, Salterain Gonzalez N, de Yebenes Castro MG, Kwong RY, Jerosch-Herold M, Coelho-Filho OR, Afilalo J, Zatarain-Nicolas E, Baksi AJ, Wintersperger BJ, Calvillo-Arguelles O, Ederhy S, Yang EH, Lyon AR, Fradley MG, Neilan TGet al., 2021, Myocardial T1 and T2 Mapping by Magnetic Resonance in Patients With Immune Checkpoint Inhibitor-Associated Myocarditis, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, Vol: 77, Pages: 1503-1516, ISSN: 0735-1097

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

de Marvao A, McGurk KA, Zheng SL, Thanaj M, Bai W, Duan J, Biffi C, Mazzarotto F, Statton B, Dawes TJW, Savioli N, Halliday BP, Xu X, Buchan RJ, Baksi AJ, Quinlan M, Tokarczuk P, Tayal U, Francis C, Whiffin N, Theotokis PI, Zhang X, Jang M, Berry A, Pantazis A, Barton PJR, Rueckert D, Prasad SK, Walsh R, Ho CY, Cook SA, Ware JS, ORegan DPet al., 2021, Outcomes and phenotypic expression of rare variants in hypertrophic cardiomyopathy genes amongst UK Biobank participants, Publisher: Cold Spring Harbor Laboratory

<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 &lt;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&lt;0.001), mainly due to heart failure (HR 4.40, 95% CI 3.22-6.02, p&lt;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&lt;0.001) and concentric remodelling (mass/volume ratio: 0.63±0.12 vs 0.58±0.09 g/mL, p&lt;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

Working paper

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

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

Yakupoglu HY, Wechalekar K, Baksi AJ, Lyon AR, Khattar RSet al., 2020, Exercise-Induced Reversible Apical Ballooning in a Patient With Previous Takotsubo Syndrome and Ongoing Symptoms, CIRCULATION-CARDIOVASCULAR IMAGING, Vol: 13, ISSN: 1941-9651

Journal article

Zhang L, Awadalla M, Mahmood SS, Nohria A, Hassan MZO, Thuny F, Zlotoff DA, Murphy SP, Stone JR, Golden DLA, Alvi RM, Rokicki A, Jones-O'Connor M, Cohen J, Heinzerling LM, Mulligan C, Armanious M, Barac A, Forrestal BJ, Sullivan RJ, Kwong RY, Yang EH, Damrongwatanasuk R, Chen CL, Gupta D, Kirchberger MC, Moslehi JJ, Coelho-Filho OR, Ganatra S, Rizvi MA, Sahni G, Tocchetti CG, Mercurio V, Mahmoudi M, Lawrence DP, Reynolds KL, Weinsaft JW, Baksi AJ, Ederhy S, Groarke JD, Lyon AR, Fradley MG, Thavendiranathan P, Neilan TGet al., 2020, Cardiovascular megnetic resonance in immune checkpoint Inhibitor-associated myocarditis, EUROPEAN HEART JOURNAL, Vol: 41, Pages: 1733-+, ISSN: 0195-668X

Journal article

Bhuva AN, Baksi AJ, Charles-Edwards G, Roditi G, Manisty Cet al., 2020, Re: Performing MRI on patients with MRI-conditional and non-conditional cardiac implantable electronic devices: an update for radiologists, CLINICAL RADIOLOGY, Vol: 75, Pages: 391-393, ISSN: 0009-9260

Journal article

Khattar A, Kouranos V, Wechalekar K, Baksi AJ, Sharma Ret al., 2020, An unusual cause of ventricular tachycardia in a 50 years old man, INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING, Vol: 36, Pages: 563-564, ISSN: 1569-5794

Journal article

Martinez-Naharro A, Baksi AJ, Hawkins PN, Fontana Met al., 2020, Diagnostic imaging of cardiac amyloidosis, NATURE REVIEWS CARDIOLOGY, Vol: 17, Pages: 413-426, ISSN: 1759-5002

Journal article

Mazzarotto F, Tayal U, Buchan RJ, Midwinter W, Wilk A, Whiffin N, Govind R, Mazaika E, de Marvao A, Dawes T, Felkin LE, Ahmad M, Theotokis PI, Edwards E, Ing AI, Thomson KL, Chan LLH, Sim D, Baksi AJ, Pantazis A, Roberts AM, Watkins H, Funke B, O'Regan D, Olivotto I, Barton PJR, Prasad SK, Cook SA, Ware JS, Walsh Ret al., 2020, Re-evaluating the genetic contribution of monogenic dilated cardiomyopathy, Circulation, Vol: 141, Pages: 387-398, ISSN: 0009-7322

Background: Dilated cardiomyopathy (DCM) is genetically heterogeneous, with >100 purported disease genes tested in clinical laboratories. However, many genes were originally identified based on candidate-gene studies that did not adequately account for background population variation. Here we define the frequency of rare variation in 2538 DCM patients across protein-coding regions of 56 commonly tested genes and compare this to both 912 confirmed healthy controls and a reference population of 60,706 individuals in order to identify clinically interpretable genes robustly associated with dominant monogenic DCM.Methods: We used the TruSight Cardio sequencing panel to evaluate the burden of rare variants in 56 putative DCM genes in 1040 DCM patients and 912 healthy volunteers processed with identical sequencing and bioinformatics pipelines. We further aggregated data from 1498 DCM patients sequenced in diagnostic laboratories and the ExAC database for replication and meta-analysis.Results: Truncating variants in TTN and DSP were associated with DCM in all comparisons. Variants in MYH7, LMNA, BAG3, TNNT2, TNNC1, PLN, ACTC1, NEXN, TPM1 and VCL were significantly enriched in specific patient subsets, with the last 2 genes potentially contributing primarily to early-onset forms of DCM. Overall, rare variants in these 12 genes potentially explained 17% of cases in the outpatient clinic cohort representing a broad range of adult DCM patients and 26% of cases in the diagnostic referral cohort enriched in familial and early-onset DCM. Whilst the absence of a significant excess in other genes cannot preclude a limited role in disease, such genes have limited diagnostic value since novel variants will be uninterpretable and their diagnostic yield is minimal.Conclusion: In the largest sequenced DCM cohort yet described, we observe robust disease association with 12 genes, highlighting their importance in DCM and translating into high interpretability in diagnostic testing. The

Journal article

Mazzarotto F, Hawley M, Beltrami M, Beekman L, Boschi B, Girolami F, Roberts A, Lodder E, Cerbai E, Cook S, Ware J, Funke B, Olivotto I, Bezzina C, Barton PJR, Walsh Ret 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, Publisher: bioRxiv

Rationale: Left ventricular non-compaction (LVNC) is a condition characterised by trabeculations in the myocardial wall and is the subject of considerable conjecture as to whether it represents a distinct pathology or a secondary phenotype associated with other cardiac diseases, particularly cardiomyopathies. Objective: To investigate the genetic architecture of LVNC by identifying genes and variant classes robustly associated with disease and comparing these to other genetically characterised cardiomyopathies. Methods and Results: We performed rare variant association analysis using six different LVNC cohorts comprising 840 cases together with 125,748 gnomAD population controls and compared results to similar analyses with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) cases. We observed substantial overlap in genes and variant classes enriched in LVNC and DCM/HCM, indicating that in many cases LVNC belongs to a spectrum of more established cardiomyopathies, with non-compaction representing a phenotypic variation in patients with DCM- or HCM-causing variants. In contrast, five variant classes were uniquely enriched in LVNC cases, of which truncating variants in MYH7, ACTN2 and PRDM16 may represent a distinct LVNC aetiology. MYH7 truncating variants are generally considered as non-pathogenic but were detected in 2% of LVNC cases compared to 0.1% of controls, including a cluster of variants around a single splice region. Additionally, structural variants (exon deletions) in RYR2 and missense variants in the transmembrane region of HCN4 were enriched in LVNC cases, confirming prior reports regarding the association of these variant classes with combined LVNC and arrhythmia phenotypes. Conclusions: We demonstrated that genetic association analysis can clarify the relationship between LVNC and established cardiomyopathies, highlighted substantial overlap with DCM/HCM but also identified variant classes associated with distinct LVNC and with joint LVN

Working paper

Yakupoglu HY, Saeed S, Manivarmane R, Senior R, Lyon AR, Khattar RSet al., 2019, Reversible exercise-induced left ventricular dysfunction in symptomatic patients with previous Takotsubo syndrome - Insights from exercise echocardiography, Congress of the European-Society-of-Cardiology (ESC) / World Congress of Cardiology, Publisher: OXFORD UNIV PRESS, Pages: 804-804, ISSN: 0195-668X

Conference paper

Halliday BP, Baksi AJ, Gulati A, Ali A, Newsome S, Izgi C, Arzanauskaite M, Lota A, Tayal U, Vassiliou V, Gregson J, Alpendurada F, Frenneaux M, Cook S, Cleland J, Pennell D, Prasad Set al., 2019, Outcome in dilated cardiomyopathy related to the extent, location and pattern of late gadolinium enhancement, JACC: Cardiovascular Imaging, Vol: 12, Pages: 1645-1655, ISSN: 1936-878X

ObjectivesThis study sought to investigate the association between the extent, location, and pattern of late gadolinium enhancement (LGE) and outcome in a large dilated cardiomyopathy (DCM) cohort.BackgroundThe relationship between LGE and prognosis in DCM is incompletely understood.MethodsWe examined the association between LGE and all-cause mortality and a sudden cardiac death (SCD) composite based on the extent, location, and pattern of LGE in DCM.ResultsOf 874 patients (588 men, median age 52 years) followed for a median of 4.9 years, 300 (34.3%) had nonischemic LGE. Estimated adjusted hazard ratios for patients with an LGE extent of 0 to 2.55%, 2.55% to 5.10%, and >5.10%, respectively, were 1.59 (95% confidence interval [CI]: 0.99 to 2.55), 1.56 (95% CI: 0.96 to 2.54), and 2.31 (95% CI: 1.50 to 3.55) for all-cause mortality, and 2.79 (95% CI: 1.42 to 5.49), 3.86 (95% CI: 2.09 to 7.13), and 4.87 (95% CI: 2.78 to 8.53) for the SCD end-point. There was a marked nonlinear relationship between LGE extent and outcome such that even small amounts of LGE predicted a substantial increase in risk. The presence of septal LGE was associated with increased mortality, but SCD was most associated with the combined presence of septal and free-wall LGE. Predictive models using LGE presence and location were superior to models based on LGE extent or pattern.ConclusionsIn DCM, the presence of septal LGE is associated with a large increase in the risk of death and SCD events, even when the extent is small. SCD risk is greatest with concomitant septal and free-wall LGE. The incremental value of LGE extent beyond small amounts and LGE pattern is limited.

Journal article

Holdsworth DA, Parsons IT, Chamley R, Britton J, Pavitt C, Baksi AJ, Neubauer S, d'Arcy J, Nicol EDet al., 2019, Cardiac MRI improves cardiovascular risk stratification in hazardous occupations, JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE, Vol: 21, ISSN: 1097-6647

Journal article

Garcia-Pavia P, Kim Y, Restrepo-Cordoba MA, Lunde IG, Wakimoto H, Smith AM, Toepfer CN, Getz K, Gorham J, Patel P, Ito K, Willcox JA, Arany Z, Li J, Owens AT, Govind R, Nuñez B, Mazaika E, Bayes-Genis A, Walsh R, Finkelman B, Lupon J, Whiffin N, Serrano I, Midwinter W, Wilk A, Bardaji A, Ingold N, Buchan R, Tayal U, Pascual-Figal DA, de Marvao A, Ahmad M, Garcia-Pinilla JM, Pantazis A, Dominguez F, John Baksi A, O'Regan DP, Rosen SD, Prasad SK, Lara-Pezzi E, Provencio M, Lyon AR, Alonso-Pulpon L, Cook SA, DePalma SR, Barton PJR, Aplenc R, Seidman JG, Ky B, Ware JS, Seidman CEet al., 2019, Genetic variants associated with cancer therapy-induced cardiomyopathy, Circulation, Vol: 140, Pages: 31-41, ISSN: 0009-7322

BackgroundCancer therapy-induced cardiomyopathy (CCM) is associated with cumulative drug exposures and pre-existing cardiovascular disorders. These parametersincompletely account for substantial inter-individual susceptibility to CCM. We hypothesized that rare variants in cardiomyopathy genes contribute to CCM.MethodsWe studied 213 CCM patients from three cohorts: retrospectively recruited adults with diverse cancers (n=99), prospectively phenotyped breast cancer adults (n=73) and prospectively phenotyped children with acute myeloid leukemia (n=41). Cardiomyopathy genes, including nine pre-specified genes were sequenced. The prevalence of rare variants was compared between CCM cohorts and The Cancer Genome Atlas (TCGA) participants(n=2053), healthy volunteers(n=445), and ancestry-matchedreference population. Clinical characteristics and outcomes were assessed, stratified by genotypes. A prevalent CCM genotype was modeled in anthracycline-treated mice.ResultsCCM was diagnosed 0.4-9 years after chemotherapy; 90% of these patients received anthracyclines. Adult CCM patients had cardiovascular risk factors similar to the U.S. population. Among nine prioritized genes CCM patients had more rare protein-altering variants than comparative cohorts (p≤1.98e-04). Titin-truncating variants (TTNtv) predominated, occurring in 7.5% CCM patients versus 1.1% TCGA participants (p=7.36e-08), 0.7% healthy volunteers (p=3.42e-06), and 0.6% reference population (p=5.87e-14). Adult CCM patients with TTNtv experienced more heart failure and atrial fibrillation (p=0.003)and impaired myocardial recovery (p=0.03) than those without.Consistent with human data, anthracycline-treated TTNtv mice and isolated TTNtv cardiomyocytes showed sustained contractile dysfunction unlike wildtype (p=0.0004 and p<0.002, respectively).ConclusionsUnrecognized rare variants in cardiomyopathy-associated genes, particularly TTNtv, increased the risk for CCM in children and adults, and adverse cardiac events

Journal article

Naharro MA, Kotecha T, Gonzalez-Lopez E, Corovic A, Anderson S, Chacko L, Brown J, Knight DS, Baksi AJ, Moon JC, Kellman P, Garcia-Pavia P, Gillmore J, Hawkins P, Fontana Met al., 2019, High prevalence of intracardiac thrombi in cardiac amyloidosis, Publisher: OXFORD UNIV PRESS, Pages: 428-428, ISSN: 2047-2404

Conference paper

Martinez-Naharro A, Gonzalez-Lopez E, Corovic A, Mirelis JG, Baksi AJ, Moon JC, Garcia-Pavia P, Gillmore JD, Hawkins PN, Fontana Met al., 2019, High Prevalence of Intracardiac Thrombi in Cardiac Amyloidosis, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, Vol: 73, Pages: 1733-1734, ISSN: 0735-1097

Journal article

Kotecha T, Gonzalez-Lopez E, Corovic A, Anderson S, Chacko L, Brown J, Knight DS, Baksi AJ, Moon JC, Kellman P, Garcia-Pavia P, Gillmore JD, Hawkins PN, Fontana Met al., 2019, INTRACARDIAC THROMBI IN CARDIAC AMYLOIDOSIS, A COMMON FINDING, Annual Meeting of the British-Society-of-Cardiovascular-Magnetic-Resonance (BSCMR), Publisher: BMJ PUBLISHING GROUP, Pages: A18-A18, ISSN: 1355-6037

Conference paper

Halliday BP, Wassall R, Lota A, Khalique Z, Gregson J, Newsome S, Jackson R, Rahneva T, Wage R, Smith G, Venneri L, Tayal U, Auger D, Midwinter W, Whiffin N, Rajani R, Dungu J, Cook S, Ware J, Baksi J, Pennell D, Rosen S, Cowie M, Cleland J, Prasad Set al., 2019, Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial, The Lancet, Vol: 393, Pages: 61-73, ISSN: 0140-6736

BackgroundPatients with dilated cardiomyopathy whose symptoms and cardiac function have recovered often ask whether their medications can be stopped. The safety of withdrawing treatment in this situation is unknown.MethodsWe did an open-label, pilot, randomised trial to examine the effect of phased withdrawal of heart failure medications in patients with previous dilated cardiomyopathy who were now asymptomatic, whose left ventricular ejection fraction (LVEF) had improved from less than 40% to 50% or greater, whose left ventricular end-diastolic volume (LVEDV) had normalised, and who had an N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) concentration less than 250 ng/L. Patients were recruited from a network of hospitals in the UK, assessed at one centre (Royal Brompton and Harefield NHS Foundation Trust, London, UK), and randomly assigned (1:1) to phased withdrawal or continuation of treatment. After 6 months, patients in the continued treatment group had treatment withdrawn by the same method. The primary endpoint was a relapse of dilated cardiomyopathy within 6 months, defined by a reduction in LVEF of more than 10% and to less than 50%, an increase in LVEDV by more than 10% and to higher than the normal range, a two-fold rise in NT-pro-BNP concentration and to more than 400 ng/L, or clinical evidence of heart failure, at which point treatments were re-established. The primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02859311.FindingsBetween April 21, 2016, and Aug 22, 2017, 51 patients were enrolled. 25 were randomly assigned to the treatment withdrawal group and 26 to continue treatment. Over the first 6 months, 11 (44%) patients randomly assigned to treatment withdrawal met the primary endpoint of relapse compared with none of those assigned to continue treatment (Kaplan-Meier estimate of event rate 45·7% [95% CI 28·5–67·2]; p=0·0001). After 6 months, 25 (96%) of 2

Journal article

Halliday BP, Wassail R, Lota AS, Khalique Z, Gregson J, Newsome S, Jackson R, Tayal T, Wage R, Smith G, Venneri L, Tayal U, Auger D, Midwinter W, Whiffin N, Rajani R, Dungu JN, Pantazis A, Cook SA, Ware JS, Baksi AJ, Pennell DJ, Rosen SD, Cowie MR, Cleland JGF, Prasad SKet al., 2019, Brief Comment Video to the Recommended Article of the Month, REVISTA PORTUGUESA DE CARDIOLOGIA, Vol: 38, Pages: 71-71, ISSN: 0870-2551

Journal article

Pareek N, Cevallos J, Moliner P, Shah M, Tan LL, Chambers V, Baksi AJ, Khattar RS, Sharma R, Rosen SD, Lyon ARet al., 2018, Activity and outcomes of a cardio-oncology service in the United Kingdom - a five-year experience, European Journal of Heart Failure, Vol: 20, Pages: 1721-1731, ISSN: 1388-9842

AIMS: Cardio-oncology clinics optimise the cardiovascular status of cancer patients but there is a limited description of their structure, case mix, activity and results. The purpose of this paper is to describe the activity and outcomes of a cardio-oncology service, particularly with respect to supporting optimal cancer treatment and survival. METHODS AND RESULTS: We prospectively studied patients referred to our service from February 2011 to February 2016. New York Heart Association (NYHA) class and parameters of cardiac function were measured at baseline and after optimisation by our service. Up-titration of cardiac treatment, continuation of cancer therapy and mortality were used as outcome measures. Of the 535 patients (55.8% females) referred, rates of cardiotoxicity for anthracyclines, anti-HER2 agents and tyrosine kinase inhibitors were 75.8%, 69.8% and 62.1%, respectively. Patients with left ventricular systolic dysfunction (LVSD) (n =128) were younger, had higher rates of hypertension and previous exposure to chemotherapy/radiotherapy (P < 0.001). At a median follow-up of 360 days, 93.8% of the patients with LVSD showed improvement in left ventricular ejection fraction (45% pre vs. 53% post; P < 0.001) and NYHA class (NYHA III-IV in 22% pre vs. 10% post; P = 0.01). All patients with normal left ventricular ejection fraction and biochemical or functional myocardial toxicity and 88% of patients with LVSD were deemed fit for continuation of cancer therapy after cardiovascular optimisation. CONCLUSIONS: Through the establishment of a cardio-oncology service, it is feasible to achieve high rates of cardiac optimisation and cancer treatment continuation.

Journal article

Ferreira-Martins J, Tan L, Venneri L, Cevallos J, Pareek N, Ciburiene E, Moliner-Borja P, Chambers V, Khattar RS, Baksi AJ, Rosen SD, Lyon ARet al., 2018, Cardiovascular risk profiles in cardio-oncology - time matters, Heart Failure Association of ESC, Publisher: WILEY, Pages: 38-39, ISSN: 1388-9842

Conference paper

Halliday BP, Baksi AJ, Izgi C, Arzanauskaite M, Newsome S, Gulati A, Lota AS, Cook SA, Cleland JGF, Pennell DJ, Prasad SKet al., 2018, Improving risk stratification for sudden cardiac death in dilated cardiomyopathy using late gadolinium enhancement cardiovascular magnetic resonance, Heart Failure 2018, Publisher: WILEY, Pages: 184-184, ISSN: 1388-9842

Conference paper

Tayal U, Newsome S, Buchan R, Whiffin N, Halliday B, Lota A, Roberts A, Baksi AJ, Voges I, Midwinter W, Wilk A, Govind R, Walsh R, Daubeney P, Jarman JWE, Baruah R, Frenneaux M, Barton PJ, Pennell D, Ware JS, Prasad SK, Cook SAet al., 2017, Phenotype and clinical outcomes of titin cardiomyopathy, Journal of the American College of Cardiology, Vol: 70, Pages: 2264-2274, ISSN: 0735-1097

Background Improved understanding of dilated cardiomyopathy (DCM) due to titin truncation (TTNtv) may help guide patient stratification.Objectives The purpose of this study was to establish relationships among TTNtv genotype, cardiac phenotype, and outcomes in DCM.Methods In this prospective, observational cohort study, DCM patients underwent clinical evaluation, late gadolinium enhancement cardiovascular magnetic resonance, TTN sequencing, and adjudicated follow-up blinded to genotype for the primary composite endpoint of cardiovascular death, and major arrhythmic and major heart failure events.Results Of 716 subjects recruited (mean age 53.5 ± 14.3 years; 469 men [65.5%]; 577 [80.6%] New York Heart Association function class I/II), 83 (11.6%) had TTNtv. Patients with TTNtv were younger at enrollment (49.0 years vs. 54.1 years; p = 0.002) and had lower indexed left ventricular mass (5.1 g/m2 reduction; padjusted = 0.03) compared with patients without TTNtv. There was no difference in biventricular ejection fraction between TTNtv+/− groups. Overall, 78 of 604 patients (12.9%) met the primary endpoint (median follow-up 3.9 years; interquartile range: 2.0 to 5.8 years), including 9 of 71 patients with TTNtv (12.7%) and 69 of 533 (12.9%) without. There was no difference in the composite primary outcome of cardiovascular death, heart failure, or arrhythmic events, for patients with or without TTNtv (hazard ratio adjusted for primary endpoint: 0.92 [95% confidence interval: 0.45 to 1.87]; p = 0.82).Conclusions In this large, prospective, genotype-phenotype study of ambulatory DCM patients, we show that prognostic factors for all-cause DCM also predict outcome in TTNtv DCM, and that TTNtv DCM does not appear to be associated with worse medium-term prognosis.

Journal article

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