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  • Journal article
    Howell S, Yarovova E, Khwanda A, Rosen SDet al., 2019,

    Cardiovascular effects of psychotic illnesses and antipsychotic therapy

    , HEART, Vol: 105, Pages: 1852-1859, ISSN: 1355-6037
  • Journal article
    Khalique Z, Scott AD, Ferreira PF, Nielles-Vallespin S, Firmin DN, Pennell DJet al., 2019,

    Diffusion tensor cardiovascular magnetic resonance in hypertrophic cardiomyopathy: a comparison of motion-compensated spin echo and stimulated echo techniques

    , Magnetic Resonance Materials in Physics, Biology and Medicine, Vol: 33, Pages: 331-342, ISSN: 0968-5243

    ObjectivesDiffusion tensor cardiovascular magnetic resonance (DT-CMR) interrogates myocardial microstructure. Two frequently used in vivo DT-CMR techniques are motion-compensated spin echo (M2-SE) and stimulated echo acquisition mode (STEAM). Whilst M2-SE is strain-insensitive and signal to noise ratio efficient, STEAM has a longer diffusion time and motion compensation is unnecessary. Here we compare STEAM and M2-SE DT-CMR in patients.Materials and methodsBiphasic DT-CMR using STEAM and M2-SE, late gadolinium imaging and pre/post gadolinium T1-mapping were performed in a mid-ventricular short-axis slice, in ten hypertrophic cardiomyopathy (HCM) patients at 3 T.ResultsAdequate quality data were obtained from all STEAM, but only 7/10 (systole) and 4/10 (diastole) M2-SE acquisitions. Compared with STEAM, M2-SE yielded higher systolic mean diffusivity (MD) (p = 0.02) and lower fractional anisotropy (FA) (p = 0.02, systole). Compared with segments with neither hypertrophy nor late gadolinium, segments with both had lower systolic FA using M2-SE (p = 0.02) and trend toward higher MD (p = 0.1). The negative correlation between FA and extracellular volume fraction was stronger with STEAM than M2-SE (r2 = 0.29, p < 0.001 STEAM vs. r2 = 0.10, p = 0.003 M2-SE).DiscussionIn HCM, only STEAM reliably assesses biphasic myocardial microstructure. Higher MD and lower FA from M2-SE reflect the shorter diffusion times. Further work will relate DT-CMR parameters and microstructural changes in disease.

  • Journal article
    Neglia D, Liga R, Caselli C, Carpeggiani C, Lorenzoni V, Sicari R, Lombardi M, Gaemperli O, Kaufmann PA, Scholte AJHA, Underwood SR, Knuuti J, EVINCI Study Investigatorset al., 2019,

    Anatomical and functional coronary imaging to predict long-term outcome in patients with suspected coronary artery disease: the EVINCI-outcome study.

    , Eur Heart J Cardiovasc Imaging

    AIMS: To investigate the prognostic relevance of coronary anatomy, coronary function, and early revascularization in patients with stable coronary artery disease (CAD). METHODS AND RESULTS: From March 2009 to June 2012, 430 patients with suspected CAD (61 ± 9 years, 62% men) underwent coronary anatomical imaging by computed tomography coronary angiography (CTCA) and coronary functional imaging followed by invasive coronary angiography (ICA) if at least one non-invasive test was abnormal. Obstructive CAD was documented by ICA in 119 patients and 90 were revascularized within 90 days of enrolment. Core laboratory analysis showed that 134 patients had obstructive CAD by CTCA (>50% stenosis in major coronary vessels) and 79 significant ischaemia by functional imaging [>10% left ventricular (LV) myocardium]. Over mean follow-up of 4.4 years, major adverse events (AEs) (all-cause death, non-fatal myocardial infarction, or hospital admission for unstable angina or heart failure) or AEs plus late revascularization (LR) occurred in 40 (9.3%) and 58 (13.5%) patients, respectively. Obstructive CAD at CTCA was the only independent imaging predictor of AEs [hazard ratio (HR) 3.2, 95% confidence interval (CI) 1.10-9.30; P = 0.033] and AEs plus LR (HR 4.3, 95% CI 1.56-11.81; P = 0.005). Patients with CAD in whom early revascularization was performed in the presence of ischaemia and deferred in its absence had fewer AEs, similar to patients without CAD (HR 2.0, 95% CI 0.71-5.51; P = 0.195). CONCLUSION: Obstructive CAD imaged by CTCA is an independent predictor of clinical outcome. Early management of CAD targeted to the combined anatomical and functional disease phenotype improves clinical outcome.

  • Journal article
    Vamvakidou A, Jin W, Danylenko O, Chahal N, Khattar R, Senior Ret al., 2019,

    Low transvalvular flow rate predicts mortality in patients with low-gradient aortic stenosis following aortic valve intervention

    , JACC: Cardiovascular Imaging, Vol: 12, Pages: 1715-1724, ISSN: 1936-878X

    OBJECTIVES: This study aimed to assess the value of low transvalvular flow rate (FR) for the prediction of mortality compared with low stroke volume index (SVi) in patients with low-gradient (mean gradient: <40 mm Hg), low aortic valve area (<1 cm2) aortic stenosis (AS) following aortic valve intervention. BACKGROUND: Transaortic FR defined as stroke volume/left ventricular ejection time is also a marker of flow; however, no data exist comparing the relative prognostic value of these 2 transvalvular flow markers in patients with low-gradient AS who had undergone valve intervention. METHODS: We retrospectively followed prospectively assessed consecutive patients with low-gradient, low aortic valve area AS who underwent aortic valve intervention between 2010 and 2014 for all-cause mortality. RESULTS: Of the 218 patients with mean age 75 ± 12 years, 102 (46.8%) had low stroke volume index (SVi) (<35 ml/m2), 95 (43.6%) had low FR (<200 ml/s), and 58 (26.6%) had low left ventricular ejection fraction <50%. The concordance between FR and SVi was 78.8% (p < 0.005). Over a median follow-up of 46.8 ± 21 months, 52 (23.9%) deaths occurred. Patients with low FR had significantly worse outcome compared with those with normal FR (p < 0.005). In patients with low SVi, a low FR conferred a worse outcome than a normal FR (p = 0.005), but FR status did not discriminate outcome in patients with normal SVi. By contrast, SVi did not discriminate survival either in patients with normal or low FR. Low FR was an independent predictor of mortality (p = 0.013) after adjusting for age, clinical prognostic factors, European System for Cardiac Operative Risk Evaluation II, dimensionless velocity index, left ventricular mass index, left ventricular ejection fraction, heart rate, time, type of aortic valve intervention, and SVi (p = 0.59). CONCLUSIONS: In patients with low-gradient, low valve area aortic stenosis undergoi

  • Journal article
    Verdonschot JAJ, Hazebroek MR, Ware JS, Prasad SK, Heymans SRBet al., 2019,

    Role of targeted therapy in dilated cardiomyopathy: the challenging road toward a personalized approach

    , Journal of the American Heart Association, Vol: 8, Pages: e012514-e012514, ISSN: 2047-9980
  • Journal article
    Zhang N, Yang G, Gao Z, Xu C, Zhang Y, Shi R, Keegan J, Xu L, Zhang H, Fan Z, Firmin Det al., 2019,

    Deep learning for diagnosis of chronic myocardial infarction on nonenhanced cardiac cine MRI

    , Radiology, Vol: 294, Pages: 52-60, ISSN: 0033-8419

    BackgroundRenal impairment is common in patients with coronary artery disease and, if severe, late gadolinium enhancement (LGE) imaging for myocardial infarction (MI) evaluation cannot be performed.PurposeTo develop a fully automatic framework for chronic MI delineation via deep learning on non–contrast material–enhanced cardiac cine MRI.Materials and MethodsIn this retrospective single-center study, a deep learning model was developed to extract motion features from the left ventricle and delineate MI regions on nonenhanced cardiac cine MRI collected between October 2015 and March 2017. Patients with chronic MI, as well as healthy control patients, had both nonenhanced cardiac cine (25 phases per cardiac cycle) and LGE MRI examinations. Eighty percent of MRI examinations were used for the training data set and 20% for the independent testing data set. Chronic MI regions on LGE MRI were defined as ground truth. Diagnostic performance was assessed by analysis of the area under the receiver operating characteristic curve (AUC). MI area and MI area percentage from nonenhanced cardiac cine and LGE MRI were compared by using the Pearson correlation, paired t test, and Bland-Altman analysis.ResultsStudy participants included 212 patients with chronic MI (men, 171; age, 57.2 years ± 12.5) and 87 healthy control patients (men, 42; age, 43.3 years ± 15.5). Using the full cardiac cine MRI, the per-segment sensitivity and specificity for detecting chronic MI in the independent test set was 89.8% and 99.1%, respectively, with an AUC of 0.94. There were no differences between nonenhanced cardiac cine and LGE MRI analyses in number of MI segments (114 vs 127, respectively; P = .38), per-patient MI area (6.2 cm2 ± 2.8 vs 5.5 cm2 ± 2.3, respectively; P = .27; correlation coefficient, r = 0.88), and MI area percentage (21.5% ± 17.3 vs 18.5% ± 15.4; P = .17; correlation coefficient, r = 0.89).ConclusionThe proposed deep learning f

  • Journal article
    Sabatino J, Di Salvo G, Krupickova S, Fraisse A, Prota C, Bucciarelli V, Josen M, Paredes J, Sirico D, Voges I, Indolfi C, Prasad S, Daubeney Pet al., 2019,

    Left Ventricular Twist Mechanics to Identify Left Ventricular Noncompaction in Childhood

    , CIRCULATION-CARDIOVASCULAR IMAGING, Vol: 12, ISSN: 1941-9651
  • Journal article
    Keramida K, Farmakis D, Bingcang J, Sulemane S, Sutherland S, Bingcang RA, Ramachandran K, Tzavara C, Charalampopoulos G, Filippiadis D, Kouris N, Nihoyannopoulos Pet al., 2019,

    Longitudinal changes of right ventricular deformation mechanics during trastuzumab therapy in breast cancer patients

    , EUROPEAN JOURNAL OF HEART FAILURE, Vol: 21, Pages: 529-535, ISSN: 1388-9842
  • Journal article
    Diller G-P, Kempny A, Babu-Narayan SV, Henrichs M, Brida M, Uebing A, Lammers AE, Baumgartner H, Li W, Wort SJ, Dimopoulos K, Gatzoulis MAet al., 2019,

    Machine learning algorithms estimating prognosis and guiding therapy in adult congenital heart disease: data from a single tertiary centre including 10 019 patients

    , European Heart Journal, Vol: 40, Pages: 1069-1077, ISSN: 1522-9645

    Aims: To assess the utility of machine learning algorithms on estimating prognosis and guiding therapy in a large cohort of patients with adult congenital heart disease (ACHD) or pulmonary hypertension at a single, tertiary centre. Methods and results: We included 10 019 adult patients (age 36.3 ± 17.3 years) under follow-up at our institution between 2000 and 2018. Clinical and demographic data, ECG parameters, cardiopulmonary exercise testing, and selected laboratory markers where collected and included in deep learning (DL) algorithms. Specific DL-models were built based on raw data to categorize diagnostic group, disease complexity, and New York Heart Association (NYHA) class. In addition, models were developed to estimate need for discussion at multidisciplinary team (MDT) meetings and to gauge prognosis of individual patients. Overall, the DL-algorithms-based on over 44 000 medical records-categorized diagnosis, disease complexity, and NYHA class with an accuracy of 91.1%, 97.0%, and 90.6%, respectively in the test sample. Similarly, patient presentation at MDT-meetings was predicted with a test sample accuracy of 90.2%. During a median follow-up time of 8 years, 785 patients died. The automatically derived disease severity-score derived from clinical information was related to survival on Cox analysis independently of demographic, exercise, laboratory, and ECG parameters. Conclusion: We present herewith the utility of machine learning algorithms trained on large datasets to estimate prognosis and potentially to guide therapy in ACHD. Due to the largely automated process involved, these DL-algorithms can easily be scaled to multi-institutional datasets to further improve accuracy and ultimately serve as online based decision-making tools.

  • Conference paper
    Khalique Z, Ferreira PF, Scott AD, Nielles-Vallespin S, Wage R, Martinez-Naharro A, Fontana M, Hawkins PN, Firmin DN, Pennell DJet al., 2019,

    DIFFUSION TENSOR CARDIOVASCULAR MAGNETIC RESONANCE IN CARDIAC AMYLOIDOSIS

    , Annual Meeting of the British-Society-of-Cardiovascular-Magnetic-Resonance (BSCMR), Publisher: BMJ PUBLISHING GROUP, Pages: A6-A7, ISSN: 1355-6037
  • Journal article
    Vamvakidou A, Jin W, Danylenko O, Pradhan J, Li W, West C, Khattar R, Senior Ret al., 2019,

    Impact of Pre-Intervention Transaortic Flow Rate Versus Stroke Volume Index on Mortality Across the Hemodynamic Spectrum of Severe Aortic Stenosis

    , JACC-CARDIOVASCULAR IMAGING, Vol: 12, Pages: 205-206, ISSN: 1936-878X
  • 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
    Khalique Z, Ferreira P, Scott A, Nielles-Vallespin S, Wage R, Firmin D, Pennell Det al., 2018,

    Diffusion Tensor Cardiovascular Magnetic Resonance of Microstructural Recovery in Dilated Cardiomyopathy

    , JACC: Cardiovascular Imaging, Vol: 11, Pages: 1548-1550, ISSN: 1936-878X
  • Journal article
    Pennell DJ, Khalique Z, Ferreira PF, Scott AD, Nielles-Vallespin S, Kilner PJ, Kutys R, Romero M, Arai AE, Firmin DNet al., 2018,

    Deranged myocyte microstructure in situs inversus totalis demonstrated by diffusion tensor cardiovascular magnetic resonance

    , JACC: Cardiovascular Imaging, Vol: 11, Pages: 1360-1362, ISSN: 1936-878X
  • Journal article
    Shi WY, Moreno-Betancur M, Nugent AW, Cheung M, Colan S, Turner C, Sholler GF, Robertson T, Justo R, Bullock A, King I, Davis AM, Daubeney PEF, Weintraub RG, for the National Australian Childhood Cardiomyopathy Studyet al., 2018,

    Long-term outcomes of childhood left ventricular non-compaction cardiomyopathy: results from a national population-based study

    , Circulation, Vol: 138, Pages: 138-367, ISSN: 0009-7322

    Background -Long-term outcomes for childhood left ventricular non-compaction (LVNC) are uncertain. We examined late outcomes for children with LVNC enrolled in a national population-based study. Methods -The National Australian Childhood Cardiomyopathy Study includes all children in Australia with primary cardiomyopathy diagnosed <10 years of age between 1987 and 1996. Outcomes for LVNC subjects with a dilated phenotype (LVNC-D) were compared to those with dilated cardiomyopathy (DCM). Propensity-score analysis was used for risk factor adjustment. Results -There were 29 subjects with LVNC (9.2% of all cardiomyopathy subjects) with a mean annual incidence of newly diagnosed cases of 0.11 per 100,000 at-risk persons. Congestive heart failure was the initial symptom in 24 (83%) of 29 subjects, and 27 (93%) had a dilated phenotype (LVNC-D). The median age at diagnosis was 0.3 (interquartile interval 0.08 - 1.3) years of age. The median (interquartile interval) duration of follow-up was 6.8 (0.7-14.1) years for all subjects and 24.7 (23.3 - 27.7) years for surviving subjects. Freedom from death or transplantation was 48% (95% CI 30 - 65%) at 10 years after diagnosis and 45% (95% CI 27-63%) at 15 years. By competing risk analysis, 21% of LVNC subjects were alive with normal LV systolic function and 31% were alive with abnormal function at 15 years. Propensity-score matching between LVNC-D and DCM subjects suggested a lower freedom from death/transplantation at 15 years after diagnosis in the LVNC-D subjects (LVNC-D: 46% (95% CI 26-66%) vs. DCM: 70% (95% CI 42-97%), p=0.08). Using propensity-score inverse probability of treatment weighted Cox regression, we found evidence that LVNC-D was associated with a greater risk of death or transplantation (HR 2.3, 95% CI 1.4-3.8, p=0.0012). Conclusions -Symptomatic children with LVNC usu

  • Book
    Manning WJ, Pennell DJ, 2018,

    Cardiovascular Magnetic Resonance A Companion to Braunwald's Heart Disease

    , Publisher: Churchill Livingstone, ISBN: 9780323415613

    Complemented by: Braunwald&#39;s heart disease / edited by Douglas P. Zipes, Peter Libby, Robert O. Bonow, Douglas L. Mann, and Gordon F. Tomaselli. 11th ed. 2018.

  • Journal article
    Ware JS, Amor-Salamanca A, Tayal U, Govind R, Serrano I, Salazar-Mendiguchia J, Garcia-Pinilla JM, Pascual-Figal DA, Nunez J, Guzzo-Merello G, Gonzalez-Vioque E, Bardaji A, Manito N, Lopez-Garrido MA, Padron-Barthe L, Edwards E, Whiffin N, Walsh R, Buchan RJ, Midwinter W, Wilk A, Prasad S, Pantazis A, Baski J, O'Regan DP, Alsonso-Pulpon A, Cook SA, Lara-Pezzi E, Barton PJ, Garcia-Pavia Pet al., 2018,

    A genetic etiology for alcohol-induced cardiac toxicity

    , Journal of the American College of Cardiology, Vol: 71, Pages: 2293-2302, ISSN: 0735-1097

    Background: Alcoholic cardiomyopathy (ACM) is defined by a dilated and impaired left ventricle due to chronic excess alcohol consumption. It is largely unknown what factors determine cardiac toxicity on exposure to alcohol.Objectives: We sought to evaluate the role of variation in cardiomyopathy-associated genes in the pathophysiology of ACM, and to examine the effects of alcohol intake and genotype on DCM severity.Methods: We characterized 141 ACM cases, 716 dilated cardiomyopathy (DCM) cases and 445 healthy volunteers. We compared the prevalence of rare, protein-altering variants in 9 genes associated with inherited DCM. We evaluated the effect of genotype and alcohol-consumption on phenotype in DCM.Results: Variants in well-characterized DCM-causing genes were more prevalent in patients with ACM than controls (13.5% vs 2.9%; P=1.2e-05), but similar between patients with ACM and DCM (19.4%; P=0.12) and with a predominant burden of Titin-truncating variants (TTNtv, 9.9%). Separately, we identified an interaction between TTN genotype and excess alcohol consumption in a cohort of DCM patients not meeting ACM criteria. On multivariate analysis, DCM patients with a TTNtv who consumed excess alcohol had an 8.7% absolute reduction in ejection fraction (95% CI -2.3 to -15.1, P<0.007) compared with those without TTNtv and excess alcohol consumption. The presence of TTNtv did not predict phenotype, outcome or functional recovery on treatment in ACM patients. Conclusions: TTNtv represent a prevalent genetic predisposition for ACM, and are also associated with a worse LVEF in DCM patients who consume alcohol above recommended levels. Familial evaluation and genetic testing should be considered in patients presenting with ACM.

  • Journal article
    Scott AD, Nielles-Vallespin S, Ferreira P, Khalique Z, Gatehouse P, Kilner P, Pennell D, Firmin Det al., 2018,

    An in-vivo comparison of stimulated-echo and motion compensated spin-echo sequences for 3T diffusion tensor cardiovascular magnetic resonance at multiple cardiac phases

    , Journal of Cardiovascular Magnetic Resonance, Vol: 20, ISSN: 1097-6647

    BackgroundStimulated-echo (STEAM) and, more recently, motion-compensated spin-echo (M2-SE) techniques have been used for in-vivo diffusion tensor cardiovascular magnetic resonance (DT-CMR) assessment of cardiac microstructure. The two techniques differ in the length scales of diffusion interrogated, their signal-to-noise ratio efficiency and sensitivity to both motion and strain. Previous comparisons of the techniques have used high performance gradients at 1.5 T in a single cardiac phase. However, recent work using STEAM has demonstrated novel findings of microscopic dysfunction in cardiomyopathy patients, when DT-CMR was performed at multiple cardiac phases. We compare STEAM and M2-SE using a clinical 3 T scanner in three potentially clinically interesting cardiac phases.MethodsBreath hold mid-ventricular short-axis DT-CMR was performed in 15 subjects using M2-SE and STEAM at end-systole, systolic sweet-spot and diastasis. Success was defined by ≥50% of the myocardium demonstrating normal helix angles. From successful acquisitions DT-CMR results relating to tensor orientation, size and shape were compared between sequences and cardiac phases using non-parametric statistics. Strain information was obtained using cine spiral displacement encoding with stimulated echoes for comparison with DT-CMR results.ResultsAcquisitions were successful in 98% of STEAM and 76% of M2-SE cases and visual helix angle (HA) map scores were higher for STEAM at the sweet-spot and diastasis. There were significant differences between sequences (p < 0.05) in mean diffusivity (MD), fractional anisotropy (FA), tensor mode, transmural HA gradient and absolute second eigenvector angle (E2A). Differences in E2A between systole and diastole correlated with peak radial strain for both sequences (p ≤ 0.01).ConclusionM2-SE and STEAM can be performed equally well at peak systole at 3 T using standard gradients, but at the sweet-spot and diastole STEAM is more rel

  • Journal article
    Schafer S, Viswanathan S, Widjaja AA, Lim W-W, Moreno-Moral A, DeLaughter DM, Ng B, Patone G, Chow K, Khin E, Tan J, Chothani SP, Ye L, Rackham OJL, Ko NSJ, Sahib NE, Pua CJ, Zhen NTG, Xie C, Wang M, Maatz H, Lim S, Saar K, Blachut S, Petretto E, Schmidt S, Putoczki T, Guimarães-Camboa N, Wakimoto H, van Heesch S, Sigmundsson K, Lim SL, Soon JL, Chao VTT, Chua YL, Tan TE, Evans SM, Loh YJ, Jamal MH, Ong KK, Chua KC, Ong B-H, Chakaramakkil MJ, Seidman JG, Seidman CE, Hubner N, Sin KYK, Cook SAet al., 2017,

    IL-11 is a crucial determinant of cardiovascular fibrosis

    , Nature, Vol: 552, Pages: 110-115, ISSN: 0028-0836

    Fibrosis is a final common pathology in cardiovascular disease1. In the heart, fibrosis causes mechanical and electrical dysfunction1,2 and in the kidney, it predicts the onset of renal failure3. Transforming growth factor β1 (TGFB1) is the principal pro-fibrotic factor4,5 but its inhibition is associated with side effects due to its pleiotropic roles6,7. We hypothesised that downstream effectors of TGFB1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicities. Using integrated imaging-genomics analyses of primary human fibroblasts, we found that Interleukin 11 (IL11) upregulation is the dominant transcriptional response to TGFB1 exposure and required for its profibrotic effect. IL11 and its receptor (IL11RA) are expressed specifically in fibroblasts where they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il11 injection causes heart and kidney fibrosis and organ failure whereas genetic deletion of Il11ra1 is protective against disease. Thus, inhibition of IL11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These data reveal a central role of IL11 in fibrosis and we propose inhibition of IL11 as a new therapeutic strategy to treat fibrotic diseases.

  • Journal article
    Danad I, Raijmakers PG, Driessen RS, Leipsic J, Raju R, Naoum C, Knuuti J, Mäki M, Underwood RS, Min JK, Elmore K, Stuijfzand WJ, van Royen N, Tulevski II, Somsen AG, Huisman MC, van Lingen AA, Heymans MW, van de Ven PM, van Kuijk C, Lammertsma AA, van Rossum AC, Knaapen Pet al., 2017,

    Comparison of Coronary CT Angiography, SPECT, PET, and Hybrid Imaging for Diagnosis of Ischemic Heart Disease Determined by Fractional Flow Reserve.

    , JAMA Cardiol, Vol: 2, Pages: 1100-1107

    Importance: At present, the choice of noninvasive testing for a diagnosis of significant coronary artery disease (CAD) is ambiguous, but nuclear myocardial perfusion imaging with single-photon emission tomography (SPECT) or positron emission tomography (PET) and coronary computed tomography angiography (CCTA) is predominantly used for this purpose. However, to date, prospective head-to-head studies are lacking regarding the diagnostic accuracy of these imaging modalities. Furthermore, the combination of anatomical and functional assessments configuring a hybrid approach may yield improved accuracy. Objectives: To establish the diagnostic accuracy of CCTA, SPECT, and PET and explore the incremental value of hybrid imaging compared with fractional flow reserve. Design, Setting, and Participants: A prospective clinical study involving 208 patients with suspected CAD who underwent CCTA, technetium 99m/tetrofosmin-labeled SPECT, and [15O]H2O PET with examination of all coronary arteries by fractional flow reserve was performed from January 23, 2012, to October 25, 2014. Scans were interpreted by core laboratories on an intention-to-diagnose basis. Hybrid images were generated in case of abnormal noninvasive anatomical or functional test results. Main Outcomes and Measures: Hemodynamically significant stenosis in at least 1 coronary artery as indicated by a fractional flow reserve of 0.80 or less and relative diagnostic accuracy of SPECT, PET, and CCTA in detecting hemodynamically significant CAD. Results: Of the 208 patients in the study (76 women and 132 men; mean [SD] age, 58 [9] years), 92 (44.2%) had significant CAD (fractional flow reserve ≤0.80). Sensitivity was 90% (95% CI, 82%-95%) for CCTA, 57% (95% CI, 46%-67%) for SPECT, and 87% (95% CI, 78%-93%) for PET, whereas specificity was 60% (95% CI, 51%-69%) for CCTA, 94% (95% CI, 88%-98%) for SPECT, and 84% (95% CI, 75%-89%) for PET. Single-photon emission tomography was found to be noninferior to PET in terms of

  • Journal article
    Bonnet D, Berger F, Jokinen E, Kantor PF, Daubeney PEFet al., 2017,

    Ivabradine in Children With Dilated Cardiomyopathy and Symptomatic Chronic Heart Failure

    , Journal of the American College of Cardiology, Vol: 70, Pages: 1262-1272, ISSN: 0735-1097

    BackgroundHeart rate reduction as a therapeutic target has been investigated in adults with heart failure (HF). Ivabradine has shown promising efficacy, but has not been evaluated in children. Currently, treatment recommendations for chronic pediatric HF are based mainly on chronic HF guidelines for adults.ObjectivesThe authors explored the dose-response relationship of ivabradine in children with dilated cardiomyopathy and symptomatic chronic HF. The primary endpoint was ≥20% reduction in heart rate from baseline without inducing bradycardia or symptoms.MethodsThis was a randomized, double-blind, placebo-controlled, phase II/III study with 12 months of follow-up. Children (n = 116) receiving stable HF therapy were randomized to either ivabradine or placebo. After an initial titration period, the dose was adjusted to attain the primary endpoint. Left ventricular function (echocardiography), clinical status (New York Heart Association functional class or Ross class), N-terminal pro–B-type natriuretic peptide, and quality of life (QOL) were assessed.ResultsThe primary endpoint was reached by 51 of 73 children taking ivabradine (70%) versus 5 of 41 taking placebo (12%) at varying doses (odds ratio: 17.24; p < 0.0001). Between baseline and 12 months, there was a greater increase in left ventricular ejection fraction in patients taking ivabradine than placebo (13.5% vs. 6.9%; p = 0.024). New York Heart Association functional class or Ross class improved more with ivabradine at 12 months than placebo (38% vs. 25%; p = 0.24). There was a trend toward improvement in QOL for ivabradine versus placebo (p = 0.053). N-terminal pro–B-type natriuretic peptide levels decreased similarly in both groups. Adverse events were reported at similar frequencies for ivabradine and placebo.ConclusionsIvabradine safely reduced the resting heart rate of children with chronic HF and dilated cardiomyopathy. Ivabradine’s effect on heart rate was variable, highlighting the

  • Journal article
    Halliday BP, Cleland JGF, Goldberger JJ, Prasad SKet al., 2017,

    Personalizing Risk Stratification for Sudden Death in Dilated Cardiomyopathy:The Past, Present, and Future

    , Circulation, Vol: 136, Pages: 215-231, ISSN: 0009-7322

    Results from the DANISH Study (Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heat Failure on Mortality) suggest that, for many patients with dilated cardiomyopathy (DCM), implantable cardioverter defibrillators (ICD) do not increase longevity. Accurate identification of patients who are more likely to die of an arrhythmia and less likely to die from other causes is required to ensure improvement in outcomes and wise use of resources. Until now, left ventricular ejection fraction (LVEF) has been used as a key criterion for selecting patients with DCM for an ICD for primary prevention purposes. However, registry data suggest that many patients with DCM and an out-of-hospital cardiac arrest do not have a markedly reduced LVEF. Additionally, many patients with reduced LVEF die from non-sudden causes of death. Methods to predict a higher or lower risk of sudden death include the detection of myocardial fibrosis (a substrate for ventricular arrhythmia), microvolt T-wave alternans (MTWA; a marker of electrophysiological vulnerability) and genetic testing. Mid-wall fibrosis is identified by late gadolinium enhancement cardiovascular magnetic resonance imaging in around 30% of patients and provides incremental value in addition to LVEF for the prediction of SCD events. MTWA represents another promising predictor, supported by large meta-analyses that have highlighted the negative predictive value of this test. However, neither of these strategies have been routinely adopted for risk stratification in clinical practice. More convincing data from randomized trials are required to inform the management of patients with these features. Understanding of the genetics of DCM and how specific mutations affect arrhythmic risk is also rapidly increasing. The finding of a mutation in LMNA, the cause of around 6% of idiopathic DCM, commonly underpins more aggressive management due to the malignant nature of the associated phenotype. With the expansi

  • Journal article
    Khan TZ, Hsu LY, Arai AE, Rhodes S, Pottle A, Wage R, Banya W, Gatehouse PD, Giri S, Collins P, Pennell DJ, Barbir Met al., 2017,

    Apheresis as novel treatment for refractory angina with raised lipoprotein(a): a randomised controlled trial

    , European Heart Journal, Vol: 38, Pages: 1561-1569, ISSN: 1522-9645

    AimsTo determine the clinical impact of lipoprotein apheresis in patients with refractory angina and raised lipoprotein(a) > 500 mg/L on the primary end point of quantitative myocardial perfusion, as well as secondary end points including atheroma burden, exercise capacity, symptoms, and quality of life.MethodsWe conducted a single-blinded randomized controlled trial in 20 patients with refractory angina and raised lipoprotein(a) > 500 mg/L, with 3 months of blinded weekly lipoprotein apheresis or sham, followed by crossover. The primary endpoint was change in quantitative myocardial perfusion reserve (MPR) assessed by cardiovascular magnetic resonance. Secondary endpoints included measures of atheroma burden, exercise capacity, symptoms and quality of life.ResultsThe primary endpoint, namely MPR, increased following apheresis (0.47; 95% CI 0.31–0.63) compared with sham (−0.16; 95% CI − 0.33–0.02) yielding a net treatment increase of 0.63 (95% CI 0.37–0.89; P < 0.001 between groups). Improvements with apheresis compared with sham also occurred in atherosclerotic burden as assessed by total carotid wall volume (P < 0.001), exercise capacity by the 6 min walk test (P = 0.001), 4 of 5 domains of the Seattle angina questionnaire (all P < 0.02) and quality of life physical component summary by the short form 36 survey (P = 0.001).ConclusionLipoprotein apheresis may represent an effective novel treatment for patients with refractory angina and raised lipoprotein(a) improving myocardial perfusion, atheroma burden, exercise capacity and symptoms.

  • Journal article
    Ahmadvazir S, Shah BN, Zacharias K, Senior Ret al., 2017,

    Incremental prognostic value of stress echocardiography with carotid ultrasound for suspected CAD.

    , JACC Cardiovasc Imaging, Vol: 11, Pages: 173-180, ISSN: 1936-878X

    OBJECTIVES: This study hypothesized that ischemia and atherosclerosis assessment by ultrasound (US) may provide incremental prognostic information in patients with new-onset chest pain who do not have coronary artery disease (CAD). BACKGROUND: The clinical significance of atherosclerosis assessment by carotid US in patients undergoing stress echocardiography (SE) in such patients is unknown. METHODS: Consecutive patients with suspected angina but no history of CAD underwent simultaneous SE and US prospectively to assess myocardial ischemia and carotid plaque burden (CPB), respectively. Patients were followed up for major adverse events (MAEs)-all-cause mortality, nonfatal myocardial infarction, and unplanned coronary revascularization. RESULTS: Of 591 recruited patients, 580 (men, 46%; mean age 59 ± 11 years) patients were available for follow-up. SE demonstrated myocardial ischemia in 12%, but prevalence of carotid plaques was 59%. During a mean follow-up of 1,117 ± 361 days, 40 first MAEs occurred. In the multivariable regression model, pre-test probability (PTP) of CAD (p = 0.001), abnormal SE (p < 0.0001), and CPB (p < 0.0001) predicted MAEs. MAE rates per year increased from 0.9% versus 1.97% versus 4.3% versus 9.7% in patients with no carotid plaque and normal SE versus patients who had plaque and normal SE versus those with no plaque and abnormal SE versus patients with plaque and abnormal SE, respectively (p < 0.0001). In hierarchical analysis, plaque burden provided incremental prognostic value over PTP of CAD and SE; likewise, SE was incremental to PTP-CAD and CPB (p < 0.0001 for both). CONCLUSIONS: In patients with suspected stable angina without known CAD, simultaneous SE (for ischemia) and US (for atherosclerosis) provided incremental prognostic value.

  • Journal article
    Tayal U, Prasad S, Cook SA, 2017,

    Genetics and genomics of dilated cardiomyopathy and systolic heart failure

    , GENOME MEDICINE, Vol: 9, ISSN: 1756-994X

    Heart failure is a major health burden, affecting 40 million people globally. One of the main causes of systolic heart failure is dilated cardiomyopathy (DCM), the leading global indication for heart transplantation. Our understanding of the genetic basis of both DCM and systolic heart failure has improved in recent years with the application of next-generation sequencing and genome-wide association studies (GWAS). This has enabled rapid sequencing at scale, leading to the discovery of many novel rare variants in DCM and of common variants in both systolic heart failure and DCM. Identifying rare and common genetic variants contributing to systolic heart failure has been challenging given its diverse and multiple etiologies. DCM, however, although rarer, is a reasonably specific and well-defined condition, leading to the identification of many rare genetic variants. Truncating variants in titin represent the single largest genetic cause of DCM. Here, we review the progress and challenges in the detection of rare and common variants in DCM and systolic heart failure, and the particular challenges in accurate and informed variant interpretation, and in understanding the effects of these variants. We also discuss how our increasing genetic knowledge is changing clinical management. Harnessing genetic data and translating it to improve risk stratification and the development of novel therapeutics represents a major challenge and unmet critical need for patients with heart failure and their families.

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