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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, 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
    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
    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
  • 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
    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

  • 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
    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
    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
    Nielles-Vallespin S, Khalique Z, Ferreira PF, de Silva R, Scott AD, Kilner P, McGill L-A, Giannakidis A, Gatehouse PD, Ennis D, otherset al., 2017,

    Assessment of myocardial microstructural dynamics by in vivo diffusion tensor cardiac magnetic resonance

    , Journal of the American College of Cardiology, Vol: 69, Pages: 661-676
  • Journal article
    Ware JS, Seidman JG, Arany Z, 2016,

    Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies REPLY

    , New England Journal of Medicine, Vol: 374, Pages: 2601-2602, ISSN: 1533-4406
  • Journal article
    Patel HC, Rosen SD, Hayward C, Vassiliou V, Smith GC, Wage RR, Bailey J, Rajani R, Lindsay AC, Pennell DJ, Underwood SR, Prasad SK, Mohiaddin R, Gibbs JSR, Lyon AR, Di Mario Cet al., 2016,

    Renal denervation in heart failure with preserved ejection fraction (RDF-PEF): a randomised controlled trial

    , European Journal of Heart Failure, Vol: 18, Pages: 703-712, ISSN: 1879-0844

    AimHeart failure with preserved ejection fraction (HFpEF) is associated with increased sympathetic nervous system (SNS) tone. Attenuating the SNS with renal denervation (RD) might be helpful and there are no data currently in humans with HFpEF.Methods and ResultsIn this single-centre, randomised, open-controlled study we included 25 patients with HFpEF (preserved left ventricular (LV) ejection fraction, left atrial (LA) dilatation or LV hypertrophy and raised B-type natriuretic peptide (BNP) or echocardiographic assessment of filling pressures). Patients were randomised (2:1) to RD with the Symplicity™ catheter or continuing medical therapy. The primary success criterion was not met in that there were no differences between groups at 12 months for Minnesota Living with Heart Failure Questionnaire score, peak oxygen uptake (VO2) on exercise, BNP, E/e’, LA volume index or LV mass index. A greater proportion of patients improved at three months in the RD group with respect to VO2 peak (56% vs 13%, P=0.025) and E/e’ (31% vs 13%, P=0.04). Change in estimated glomerular filtration rate was comparable between groups. Two patients required plain balloon angioplasty during the RD procedure to treat renal artery wall oedema.ConclusionThis study was terminated early due to difficulties in recruitment and was underpowered to detect whether RD improved the endpoints of: quality of life, exercise function, biomarkers and left heart remodelling. The procedure was safe in patients with HFpEF though two patients did require intra-procedure renal artery dilatation.

  • Journal article
    Sharma R, O'Driscoll JM, Saha A, Sritharan M, Sutton R, Rosen SDet al., 2015,

    Differing autonomic responses to dobutamine stress in the presence and absence of myocardial ischaemia

    , JOURNAL OF PHYSIOLOGY-LONDON, Vol: 593, Pages: 2171-2184, ISSN: 0022-3751
  • Journal article
    Roberts AM, Ware JS, Herman DS, Schafer S, Baksi J, Bick AG, Buchan RJ, Walsh R, John S, Wilkinson S, Mazzarotto F, Felkin LE, Gong S, L MacArthur JA, Cunningham F, Flannick J, Gabriel SB, Altshuler DM, Macdonald PS, Heinig M, Keogh AM, Hayward CS, Banner NR, Pennell DJ, O'Regan DP, San TR, de Marvao A, W Dawes TJ, Gulati A, Birks EJ, Yacoub MH, Radke M, Gotthardt M, Wilson JG, O'Donnell CJ, Prasad SK, Barton PJ, Fatkin D, Hubner N, Seidman JG, Seidman CE, Cook SAet al., 2015,

    Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease.

    , Sci Transl Med, Vol: 7

    The recent discovery of heterozygous human mutations that truncate full-length titin (TTN, an abundant structural, sensory, and signaling filament in muscle) as a common cause of end-stage dilated cardiomyopathy (DCM) promises new prospects for improving heart failure management. However, realization of this opportunity has been hindered by the burden of TTN-truncating variants (TTNtv) in the general population and uncertainty about their consequences in health or disease. To elucidate the effects of TTNtv, we coupled TTN gene sequencing with cardiac phenotyping in 5267 individuals across the spectrum of cardiac physiology and integrated these data with RNA and protein analyses of human heart tissues. We report diversity of TTN isoform expression in the heart, define the relative inclusion of TTN exons in different isoforms (using the TTN transcript annotations available at http://cardiodb.org/titin), and demonstrate that these data, coupled with the position of the TTNtv, provide a robust strategy to discriminate pathogenic from benign TTNtv. We show that TTNtv is the most common genetic cause of DCM in ambulant patients in the community, identify clinically important manifestations of TTNtv-positive DCM, and define the penetrance and outcomes of TTNtv in the general population. By integrating genetic, transcriptome, and protein analyses, we provide evidence for a length-dependent mechanism of disease. These data inform diagnostic criteria and management strategies for TTNtv-positive DCM patients and for TTNtv that are identified as incidental findings.

  • Journal article
    Pennell DJ, Porter JB, Piga A, Lai Y, El-Beshlawy A, Belhoul KM, Elalfy M, Yesilipek A, Kilinc Y, Lawniczek T, Habr D, Weisskopf M, Zhang Y, Aydinok Yet al., 2014,

    A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in beta-thalassemia major (CORDELIA)

    , BLOOD, Vol: 123, Pages: 1447-1454, ISSN: 0006-4971

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