Anne-Marie L Seymour

Hull and East Yorkshire Hospitals NHS Trust, Kingston upon Hull, England, United Kingdom

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Publications (24)73.92 Total impact

  • Anne-Marie Seymour, Veena Reddy, Sunil Bhandari
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    ABSTRACT: Cardiovascular complications are the leading cause of death in patients with chronic kidney disease. The uraemic heart undergoes remodelling and changes in metabolic function. Experimental uraemia produces a reduction in the myocardial energy reserve phosphocreatine in parallel with left ventricular hypertrophy and depletion of serum carnitine. This study investigated the effects of chronic L-carnitine supplementation on myocardial substrate metabolism and function in the experimental uraemia. Experimental uraemia was induced surgically in male Sprague-Dawley rats via a subtotal nephrectomy. Carnitine was administered continuously via subcutaneous mini-osmotic pumps. Cardiac function and substrate oxidation were assessed in vitro by means of isovolumic perfusion using 13C NMR, at 3 and 6 weeks. Uraemic animals exhibited anaemia, kidney dysfunction and systemic carnitine deficiency but no myocardial tissue carnitine deficiency. Myocardial hypertrophy was abolished following carnitine supplementation. This was associated with a reduction in glucose utilisation. In summary carnitine supplementation prevents cardiac hypertrophy, and this effect is amplified with the duration of treatment. This is associated with a reduction in myocardial glucose utilisation but no significant modulation of myocardial function.
    Frontiers in bioscience (Elite edition) 01/2013; E5:834-44.
  • David J Semple, Sunil Bhandari, Anne-Marie L Seymour
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    ABSTRACT: Chronic kidney disease is associated with a unique cardiomyopathy, characterised by a combination of structural and cellular remodelling, and an enhanced susceptibility to ischaemia-reperfusion injury. This may represent dysfunction of the reperfusion injury salvage kinase pathway, due to insulin resistance. Aims: The susceptibility of the uraemic heart to ischaemia-reperfusion injury and the cardioprotective effects of insulin and rosiglitazone were investigated. Methods and Results: Uraemia was induced in Sprague-Dawley rats by subtotal nephrectomy. Functional recovery from ischaemia was investigated in vitro in control and uraemic hearts ±insulin ±rosiglitazone. The response of myocardial oxidative metabolism to insulin was determined by 13C NMR spectroscopy. Activation of reperfusion injury salvage kinase pathway intermediates (Akt and GSK3β) were assessed by SDS-PAGE and immuno-precipitation. Insulin improved post-ischaemic rate pressure product in control but not uraemic hearts, (recovered rate pressure product (%), control 59.6±10.7 vs 88.9±8.5, p<0.05; uraemic 19.3±4.6 vs 28.5±10.4, p=ns). Rosiglitazone resensitised uraemic hearts to insulin-mediated cardio-protection (recovered rate pressure product (%) 12.7±7.0 vs. 61.8±15.9, p<0.05). Myocardial carbohydrate metabolism remained responsive to insulin in uraemic hearts. Uraemia was associated with increased phosphorylation of Akt (1.00±0.08 vs. 1.31±0.11, p<0.05) in normoxia, but no change in post-ischaemic phosphorylation of Akt or GSK3β. Akt2 isoform expression was decreased post-ischaemia in uraemic hearts (p<0.05). Conclusion: Uraemia is associated with enhanced susceptibility to ischaemia-reperfusion injury and a loss of insulin-mediated cardio-protection, which can be restored by administration of rosiglitazone. Altered Akt2 expression in uraemic hearts post ischaemia-reperfusion and impaired activation of reperfusion injury salvage kinase pathway may underlie these findings.
    AJP Renal Physiology 08/2012; · 4.42 Impact Factor
  • David Semple, Katie Smith, Sunil Bhandari, Anne-Marie L Seymour
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    ABSTRACT: Uremic cardiomyopathy is a classic complication of chronic renal failure whose cause is unclear and treatment remains disappointing. Insulin resistance is an independent predictor of cardiovascular mortality in chronic renal failure. Underlying insulin resistance are defects in insulin signaling through the protein kinase, Akt. Akt acts as a nodal point in the control of both the metabolic and pleiotropic effects of insulin. Imbalance among these effects leads to cardiac hypertrophy, fibrosis, and apoptosis; less angiogenesis; metabolic remodeling; and altered calcium cycling, all key features of uremic cardiomyopathy. Here we consider the role of Akt in the development of uremic cardiomyopathy, drawing parallels from models of hypertrophic cardiac disease.
    Journal of the American Society of Nephrology 02/2011; 22(2):207-15. · 8.99 Impact Factor
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    ABSTRACT: Recent evidence has shown that prolonged exposure to exogenous tissue factor (TF) can alter the cellular functions of cardiomyocytes resulting in cardiac dysfunction. The effect of TF may arise from local inflammation within or in the vicinity of the heart. The aim of this study was to investigate the effect of TF on cardiomyocyte proliferation and growth. H9c2 rat cardiomyocytes were exposed to a range of concentrations of recombinant TF (rTF) (1.3-52 ng/ml) for up to 10 days and the outcome on cell proliferation and induction of apoptosis measured. At lower concentrations examined (1.3 ng/ml), rTF had a proliferative influence on the H9c2 cells. In contrast, elevated concentrations of rTF (52 ng/ml) induced cellular apoptosis as indicated by increased caspase-3 activity and nuclear localisation of p53. Moreover, incubation with intermediate concentrations of rTF (13 ng/ml) resulted in an initial increase in proliferation but subsequently, led to cellular apoptosis by day 7 of the incubation. In order to determine if these effects induced hypertrophic cell growth, expression of mechano-growth factor (MGF) was analysed. Incubation of cells with rTF resulted in enhanced expression of MGF particularly at the intermediate concentrations of rTF (13 ng/ml) as well as mean cellular transverse diameter. In addition, there was a rapid increase in the expression of atrial natriuretic factor (ANF) in the cells, on incubation with rTF but diminished rapidly when exposed to higher concentrations of rTF. These data indicate that exposure to increasing concentrations of rTF can accelerate the rate of cardiomyocyte turnover which may ultimately lead to depletion of viable cells within the heart. Moreover, at lower concentrations of rTF, the induction of cell proliferation together with hypertrophic markers indicates that rTF may contribute to the induction and progression of cardiac hypertrophy.
    Molecular and Cellular Biochemistry 12/2010; 345(1-2):119-30. · 2.33 Impact Factor
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    ABSTRACT: Chronic kidney disease is associated with a cardiomyopathy characterised by hypertrophy, hypertension, myocardial fibrosis, reduced cardiac output and increased arrhythmias. We have previously shown that myocytes isolated from uremic (5/6ths nephrectomized rats) show changes in EC coupling consistent with Na and Ca overload. We have therefore investigated the effects of uremia on Na/K ATPase, SERCA2a and their accessory proteins phospholemman (PLM) and phospholamban (PLB). Control rats underwent bilateral renal decapsulation, without removal of renal tissue while uremic animals were subjected to 5/6ths nephrectomy. Uremic animals showed progressive LV hypertrophy (increased heart dry wt to tibia length: 0.45±0.01 vs 0.38±0.01 g/cm, n=26; p<0.05 vs sham), elevated systolic (163±1 vs 147±2 mmHg, n=26; p<0.01 vs sham) and diastolic blood pressure (106±1 vs 95±1 mmHg, n=26; p<0.01 vs sham), as well as elevated serum urea concentration (15.5±0.4 vs 6.4±0.4mM, n=26; p<0.01 vs sham). There was an increased expression of both {alpha}1 (49±6%, n=8; p<0.05) and {alpha}2 (37±7%, n=8; p<0.05) Na/K ATPase subunits in uremic hearts cf sham. There was no change in total SERCA2a, PLM or PLB expression. However, there was a significant increase in phosphorylation of PLM Ser 68 and Thr 69 and PLB Ser 16 and Thr 17 residues in uremic animals, cf sham (n=8; p<0.05). Surprisingly, despite increased expression of Na/K ATPase catalytic subunit, and elevated PLM phosphorylation, Na/K ATPase activity in crude ventricular homogenates was decreased in uremic hearts (37±20 vs 66±13µmol/g/5min, n=8; p<0.05 vs sham). However, when sarcolemmal membranes were purified away from the soluble homogenate, Na/K ATPase activity in uremic hearts was stimulated compared to sham-operated animals (75±21 vs 29±8µmol/g/5min, n=8; p<0.05). This suggests the presence of an unidentified Na/K ATPase inhibitor in the crude ventricular homogenate that does not co-purify with sarcolemmal membranes. The changes in PLM phosphorylation and Na/K ATPase {alpha} subunit expression may reflect an adaptive change to the reduced pump function mediated by the presence of this inhibitor. These results are consistent with Na and Ca overload contributing to the contractile dysfunction observed in uremic cardiomyopathy.
    Circulation 11/2010; 122(21):A16016. · 15.20 Impact Factor
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    ABSTRACT: A microfluidic device has been developed to maintain viable heart tissue samples in a biomimetic microenvironment. This device allows rat or human heart tissue to be studied under pseudo in vivo conditions. Effluent levels of lactate dehydrogenase and hydrogen peroxide were used as markers of damaged tissue in combination with in situ electrochemical measurement of the release of reactive oxygen species (ROS). The parameters for perfusion were optimized to maintain biopsies of rat right ventricular or human right atrial tissue viable for up to 5 and 3.5 hours, respectively. Electrochemical assessment of the oxidation current of total ROS, employing cyclic voltammetry, gave results in real-time that were in good agreement to biochemical assessment using conventional, off-chip, commercial assays. This proof-of-principle, integrated microfluidic device, may be exploited in providing a platform technology for future cardiac research, offering an alternative approach for investigating heart pathophysiology and facilitating the development of new therapeutic strategies.
    Lab on a Chip 10/2010; 10(20):2720-6. · 5.70 Impact Factor
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    ABSTRACT: Cardiovascular complications are the leading cause of death in patients with chronic kidney disease (CKD). The uraemic heart undergoes substantial remodelling, including left ventricular hypertrophy (LVH), an important determinant of heart failure. LVH results in a shift in myocardial substrate oxidation from fatty acids towards carbohydrates however, whether this metabolic adaptation occurs in the uraemic heart is unknown. The aim of this study was to investigate the progression of kidney dysfunction in parallel with cardiac remodelling in experimental uraemia. Experimental uraemia was induced surgically via a subtotal nephrectomy. At 3, 6 and 12 weeks post-surgery, renal function, LVH, in vitro cardiac function and metabolic remodelling using 13C-NMR were assessed. Uraemic animals exhibited anaemia and kidney dysfunction at 3 weeks, with further deterioration as uraemia progressed. By 12 weeks, uraemic hearts showed marked LVH, preserved cardiac function and markedly reduced fatty acid oxidation. This change in substrate preference may contribute to the deterioration of cardiac function in the uraemic heart and ultimately failure.
    Frontiers in bioscience (Elite edition) 01/2010; 2:1492-501.
  • Cardiovascular Research. 01/2010; 87(supplement 1):S65-S65.
  • Katie Smith, David Semple, Sunil Bhandari, Anne-Marie L Seymour
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    ABSTRACT: The use of erythropoietin (EPO) has revolutionized the treatment of anaemia associated with many conditions including chronic kidney disease (CKD). However, little is known of the cellular impact of EPO on the uraemic heart. The discovery that the EPO receptor (EPOR) is also expressed on non-haematopoietic cells including cardiomyocytes highlights a role of EPO beyond haematopoiesis. Animal models of heart failure have shown EPO can potentially reverse cardiac remodelling and improve myocardial function. Damage to the kidney, during uraemia, results in a decreased EPO production, which may render the uraemic heart more susceptible to damage and heart failure. Here we review current data on the cellular actions of EPO in models of left ventricular hypertrophy and heart failure and highlight parallels with the uraemic heart.
    European Journal of Heart Failure 09/2009; 11(8):732-8. · 5.25 Impact Factor
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    Dunja Aksentijević, Sunil Bhandari, Anne-Marie L Seymour
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    ABSTRACT: Progressive ventricular hypertrophy can lead to the development of insulin resistance, a feature of both chronic kidney disease and heart failure. Here we induced uremia in adult male Sprague-Dawley rats using a remnant kidney model and studied the expression of glucose transporters. As expected, the reduction of nephron mass resulted in impaired renal function, cardiac hypertrophy, glucose intolerance, hyperinsulinemia, anemia, and hypertension. Insulin sensitivity was significantly reduced in the uremic animals as determined by oral glucose tolerance tests. After six weeks of uremia, at a point when cardiac hypertrophy had been established, left ventricle tissue had a marked increase in the expression of GLUT4 (insulin-dependent glucose transporter 4), consistent with hypertrophic remodeling, but not GLUT1 (insulin-independent glucose transporter 1). However, although uremic animals had systemic insulin resistance and glucose intolerance, there was no evidence of impaired GLUT4 translocation in the heart at 6 weeks of uremia, suggesting that other mechanisms may underpin insulin resistance in the uremic heart.
    Kidney International 02/2009; 75(7):711-8. · 8.52 Impact Factor
  • Ashwin Akki, Anne-Marie L Seymour
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    ABSTRACT: Metabolic remodelling in cardiac hypertrophy is underscored by a reduction in fatty acid (FA) oxidation. We tested whether this decline in FA oxidation in the presence of enhanced FA supply may predispose the hypertrophied myocardium to lipid accumulation, functional deterioration, and eventually heart failure. and results Left ventricular hypertrophy was induced surgically in Sprague-Dawley rats by inter-renal aortic constriction. Rats were fed a Western diet (WD, 45% kcal from lipids) or standard diet (SD, 12% kcal from fat) for 9 weeks post-surgery. Hearts were perfused in the isovolumic mode with a physiological mixture of substrates including 5 mM 1-(13)C glucose, 1 mM 3-(13)C lactate, and 0.3 mM U-(13)C palmitate, and cardiac function was monitored. Real-time PCR was used to determine transcript levels of peroxisome proliferator-activated receptor-alpha (PPARalpha) and PPARalpha-regulated metabolic enzymes. Palmitate oxidation and PPARalpha-regulated gene expression were markedly reduced in the hypertrophied myocardium of rats fed SD. However, 9 weeks of WD normalized both palmitate oxidation and PPARalpha-regulated gene expression but significantly increased glucose and lactate oxidation in the hypertrophied hearts. This was accompanied by cardiac triglyceride accumulation and a decline in ventricular function despite an increase in oxygen consumption. These results highlight that WD-induced dysregulation of FA metabolism has deleterious functional consequences in cardiac hypertrophy.
    Cardiovascular research 12/2008; 81(3):610-7. · 5.80 Impact Factor
  • Ashwin Akki, Katie Smith, Anne-Marie L Seymour
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    ABSTRACT: Cardiac hypertrophy is an independent risk factor in the development of heart failure. However, the cellular mechanisms underlying the transition from compensated hypertrophy to heart failure are incompletely understood. The aim of this study was to investigate changes in myocardial substrate utilisation and function in pressure-overload hypertrophy (using 13C NMR spectroscopy) in parallel with alterations in the expression pattern of genes involved in cardiac fatty acid and glucose uptake and oxidation. Left ventricular hypertrophy was induced surgically in Sprague-Dawley rats by inter-renal aortic constriction. Nine weeks later, hearts were perfused in the isovolumic mode with a physiological mixture of substrates including 5 mM 1-13C glucose, 1 mM 3-13C lactate, 0.1 mM U-13C pyruvate and 0.3 mM U-13C palmitate and cardiac function monitored simultaneously. Real-time PCR was used to determine mRNA levels of PPARalpha and PPARalpha-regulated metabolic enzymes. Results showed that at the stage of compensated hypertrophy, fatty acid oxidation (FAO) and expression of genes involved in FAO were markedly reduced, whilst pyruvate oxidation was enhanced, highlighting the fact that metabolic remodelling is an early event in the development of cardiac hypertrophy.
    Molecular and Cellular Biochemistry 05/2008; 311(1-2):215-24. · 2.33 Impact Factor
  • Ashwin Akki, Anne-Marie L. Seymour
    Journal of Molecular and Cellular Cardiology - J MOL CELL CARDIOL. 01/2007; 42(6).
  • Dunja Aksentijević, Sunil Bhandari, Anne-Marie L. Seymour
    Journal of Molecular and Cellular Cardiology - J MOL CELL CARDIOL. 01/2007; 42(6).
  • Journal of Molecular and Cellular Cardiology - J MOL CELL CARDIOL. 01/2007; 42(6).
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    Veena Reddy, Sunil Bhandari, Anne-Marie L Seymour
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    ABSTRACT: Cardiac complications are the leading cause of mortality in patients with chronic renal failure. Secondary carnitine deficiency, which is frequently observed in hemodialysis patients, has been associated with cardiac hypertrophy and heart failure and may impair myocardial fatty acid oxidation. In chronic kidney disease, impaired carnitine homeostasis also may affect myocardial metabolism. In this study, myocardial function and substrate oxidation in conjunction with carnitine deficiency were investigated in experimental renal failure. Uremia was induced in male Sprague-Dawley rats via a two-stage five-sixths nephrectomy. Cardiac function and substrate oxidation were assessed in vitro by means of isovolumic perfusion using 13C nuclear magnetic resonance at 3 and 6 wk of uremia. Renal impairment as assessed by serum creatinine was more severe initially and was associated with a significant deficiency in serum free carnitine (43%; P < 0.001) and elevated acyl carnitine/free carnitine ratio. Myocardial tissue carnitine concentrations, however, were unaffected. A moderate degree of cardiac hypertrophy (10 to 14%; P < 0.05) was observed in uremia without evidence of dysfunction or changes in myocardial substrate utilization. It is concluded that renal dysfunction is associated with cardiac hypertrophy in the presence of normal myocardial carnitine levels, despite a significant depletion in serum carnitine. This may be a factor in maintaining normal cardiac function and metabolism.
    Journal of the American Society of Nephrology 01/2007; 18(1):84-92. · 8.99 Impact Factor
  • Dunja Aksentijevic, Sunil Bhandari, Anne-Marie L. Seymour
    Journal of Molecular and Cellular Cardiology - J MOL CELL CARDIOL. 01/2007; 42(6).
  • Jessica Sample, John G F Cleland, Anne-Marie L Seymour
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    ABSTRACT: The aim of this study was to investigate the effects of aging on the profile of myocardial substrate utilization and cardiac function using a physiological profile of substrates. Hearts from 6-, 15- and 24-month male Wistar rats were perfused in the isovolumic Langendorff mode, with physiological concentrations of 13C labeled palmitate, and either 13C labeled lactate or 13C glucose. 13C-NMR glutamate isotopomer analysis was performed to determine the contribution of the different substrates to oxidative metabolism. Palmitate oxidation was significantly increased and lactate oxidation depressed in the 24-month old, senescent hearts compared to the mature 6-month hearts. This metabolic remodeling was paralleled with a marked decline in cardiac function and efficiency. These results highlight that adaptations in substrate utilization occur during senescence and may contribute to the age-related increase in the incidence of heart failure.
    Journal of Molecular and Cellular Cardiology 02/2006; 40(1):56-63. · 5.15 Impact Factor
  • Dunja Aksentijević, Sunil Bhandari, Anne-Marie L. Seymour
    Journal of Molecular and Cellular Cardiology - J MOL CELL CARDIOL. 01/2006; 40(6):932-932.
  • Jessica Sample, John G. F. Cleland, Anne-Marie L. Seymour
    Journal of Molecular and Cellular Cardiology - J MOL CELL CARDIOL. 01/2006; 40(6):975-975.