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  • 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, Aliotta E, Al-Khalil M, Kellman P, Mazilu D, Balaban RS, Firmin DN, Arai AE, Pennell DJet 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, ISSN: 0735-1097

    BackgroundCardiomyocytes are organized in microstructures termed sheetlets that reorientate during left ventricular thickening. Diffusion tensor cardiac magnetic resonance (DT-CMR) may enable noninvasive interrogation of in vivo cardiac microstructural dynamics. Dilated cardiomyopathy (DCM) is a condition of abnormal myocardium with unknown sheetlet function.ObjectivesThis study sought to validate in vivo DT-CMR measures of cardiac microstructure against histology, characterize microstructural dynamics during left ventricular wall thickening, and apply the technique in hypertrophic cardiomyopathy (HCM) and DCM.MethodsIn vivo DT-CMR was acquired throughout the cardiac cycle in healthy swine, followed by in situ and ex vivo DT-CMR, then validated against histology. In vivo DT-CMR was performed in 19 control subjects, 19 DCM, and 13 HCM patients.ResultsIn swine, a DT-CMR index of sheetlet reorientation (E2A) changed substantially (E2A mobility ∼46°). E2A changes correlated with wall thickness changes (in vivo r2 = 0.75; in situ r2 = 0.89), were consistently observed under all experimental conditions, and accorded closely with histological analyses in both relaxed and contracted states. The potential contribution of cyclical strain effects to in vivo E2A was ∼17%. In healthy human control subjects, E2A increased from diastole (18°) to systole (65°; p < 0.001; E2A mobility = 45°). HCM patients showed significantly greater E2A in diastole than control subjects did (48°; p < 0.001) with impaired E2A mobility (23°; p < 0.001). In DCM, E2A was similar to control subjects in diastole, but systolic values were markedly lower (40°; p < 0.001) with impaired E2A mobility (20°; p < 0.001).ConclusionsMyocardial microstructure dynamics can be characterized by in vivo DT-CMR. Sheetlet function was abnormal in DCM with altered systolic conformation and reduced mobility, contrasting with HCM, which showed reduced mobility with alte

  • 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
    Grapsa J, Nunes MCP, Tan TC, Cabrita IZ, Coulter T, Smith BCF, Dawson D, Gibbs JSR, Nihoyannopoulos Pet al., 2015,

    Echocardiographic and Hemodynamic Predictors of Survival in Precapillary Pulmonary Hypertension Seven-Year Follow-Up

    , CIRCULATION-CARDIOVASCULAR IMAGING, Vol: 8, ISSN: 1941-9651
  • 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.

    , Science Translational Medicine, Vol: 7, Pages: 270ra6-270ra6, ISSN: 1946-6234

    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

    Randomized comparison data on the efficacy and safety of deferasirox for myocardial iron removal in transfusion dependent patients are lacking. CORDELIA was a prospective, randomized comparison of deferasirox (target dose 40 mg/kg per day) vs subcutaneous deferoxamine (50-60 mg/kg per day for 5-7 days/week) for myocardial iron removal in 197 β-thalassemia major patients with myocardial siderosis (T2* 6-20 milliseconds) and no signs of cardiac dysfunction (mean age, 19.8 years). Primary objective was to demonstrate noninferiority of deferasirox for myocardial iron removal, assessed by changes in myocardial T2* after 1 year using a per-protocol analysis. Geometric mean (Gmean) myocardial T2* improved with deferasirox from 11.2 milliseconds at baseline to 12.6 milliseconds at 1 year (Gmeans ratio, 1.12) and with deferoxamine (11.6 milliseconds to 12.3 milliseconds; Gmeans ratio, 1.07). The between-arm Gmeans ratio was 1.056 (95% confidence interval [CI], 0.998, 1.133). The lower 95% CI boundary was greater than the prespecified margin of 0.9, establishing noninferiority of deferasirox vs deferoxamine (P = .057 for superiority of deferasirox). Left ventricular ejection fraction remained stable in both arms. Frequency of drug-related adverse events was comparable between deferasirox (35.4%) and deferoxamine (30.8%). CORDELIA demonstrated the noninferiority of deferasirox compared with deferoxamine for myocardial iron removal. This trial is registered at www.clinicaltrials.gov as #NCT00600938.

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