[Frontiers in Bioscience E2, 1492-1501, June 1, 2010]
Functional and metabolic adaptation in uraemic cardiomyopathy
Katie Smith1, David Semple1, Dunja Aksentijevic2, Sunil Bhandari3, Anne-Marie L. Seymour1
1
TABLE OF CONTENTS
1. 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.
2. INTRODUCTION
Cardiovascular complications remain the leading cause of mortality in patients with chronic kidney disease (CKD), accounting for approximately 50% of all deaths (1). Cardiac risk is increased 10-20 times in uraemic patients when compared to the aged matched general population (2-3). Interestingly, the relative importance of arteriosclerotic disease is diminished and those of left ventricular hypertrophy (LVH), heart failure and sudden cardiac death increased in patients with CKD (4). Uraemia is characterised by anaemia and hypertension which contribute to phenotypic cardiac alterations including a reduction in capillary density, fibrosis and LVH (5).
LVH is the most frequently observed cardiac alteration, present in up to 75% of CKD patients (6). Although initially beneficial in terms of reducing wall tension and preserving systolic function, the hypertrophied heart is accompanied by a plethora of cellular alterations, which can ultimately produce a pathophysiological phenotype leading to heart failure (7). Experimental models of volume-overload (8) and pressure-overload (9-10) cardiac hypertrophy have shown a switch in substrate usage from fatty acids, towards glucose utilisation, known as metabolic remodelling (11-13). The change in substrate preference is consistent with a re-expression of the foetal phenotype and may represent a beneficial adaptation in LVH to reduce oxygen consumption and sustain function (11). However, in the longer-term, this remodelling may result in complications including lipid accumulation and energy depletion (14). Specifically, the build up of fatty acyl components, due to the reduced oxidation of lipids, can lead to sequestration of CoA and consequently a reduction in the CoA to acetyl-CoA ratio (15). This would subsequently lead to an inhibition of the key enzyme involved in glucose oxidation, pyruvate dehydrogenase (PDH), thus limiting oxidative capacity and depleting the heart of energy, initiating the transition to heart failure (15).
Little research has been undertaken to determine the profile of myocardial substrate utilisation in uraemia. However, given that LVH is frequently observed in both experimental models of CKD and in the clinical scenario, it is feasible that the metabolic remodelling characteristic of LVH also occurs in the uraemic heart and may contribute to cardiac failure. Furthermore, experimental models of CKD have observed a decrease in the myocardial phosphocreatine/ATP ratio, suggesting that the heart is depleted of energy reserves, potentially reflecting altered myocardial energy metabolism (16).
To understand the complex relationship between the heart and kidney, and to reduce the high impact of cardiac complications on the mortality associated with CKD, a robust and reliable experimental animal model is required. Several models have been developed employing different strategies of renal mass reduction or renal ischaemia to produce phenotypic alterations with a clinical similarity to those observed in CKD patients (17). The aim of this study was to characterise the progression of kidney dysfunction longitudinally (using the 5/6th nephrectomy model) and sequence of events relating to the development of LVH, cardiac dysfunction and altered energy metabolism.
3. MATERIALS AND METHODS
3.1. Experimental model of uraemia
All animal experiments conformed to the UK Animals (Scientific Procedures) Act 1986. Uraemia was induced in male Sprague-Dawley rats (approximately 250 g) (Charles River, Sussex, UK), via a one-stage 5/6th nephrectomy as described previously (16, 18-19). Briefly, animals were anaesthetised using a mixture of halothane in oxygen (2.5% in 1L), a laparotomy was performed, the left kidney exposed, and approximately two-thirds removed. Subsequently, the right kidney was removed. Care was taken to ensure no damage was done to the adrenal glands. For control animals, a sham operation was performed whereby both kidneys were decapsulated and replaced intact.
Animals were maintained for 3, 6 or 12 weeks post induction of uraemia, housed individually and pair-fed with control animals. Water was available ad libitum. Blood pressure was monitored at 3 and 6 weeks in conscious animals using tail plethysmography (19). Cardiac hypertrophy was assessed at the time of sacrifice by determining wet heart weight/body weight (HW/BW) and HW/tibia length.
3.2. Isolated heart perfusion
Following anaesthesia with sodium thiopentone (100 mg/Kg body weight), hearts were rapidly excised and cannulated via the aorta. Hearts were perfused in an isovolumic Langendorff mode, as described previously (20), using Krebs-Henseleit buffer containing 3% BSA and the following components (mmol/L) NaCl (118.5), NaHCO3 (25), KCl (4.8), KH2PO4 (1.2), MgSO4 (1.2), CaCl2 (2.5), glucose (5), sodium pyruvate (0.1), sodium lactate (1), sodium palmitate (0.3), glutamine (0.5) and 0.1 mU/ml insulin. The buffer was gassed with 95% O2, 5% CO2 and maintained at 37�C.
Cardiac function was recorded continuously via a fluid filled balloon (inserted into the left ventricle) and a physiological pressure transducer (SensoNor, Norway) connected to a bridge amplifier and Powerlab 4/30 (20). Data were recorded using Chart 5.5 software (AD Instruments, Hastings UK). The end diastolic pressure (EDP) was set to 5-7 mmHg by adjusting the balloon volume and hearts were paced at 300 bpm. Effluent samples were taken every 15 minutes and oxygen content measured using a blood gas analyser (ABL77 Radiometer, Copenhagen, Denmark). Oxygen consumption (MVO2) was calculated as the product of arterio-venous oxygen content difference and coronary flow rate (ml/min) normalised to wet heart weight (21). Heart rate (HR), left ventricular developed pressure (LVDP) and +/- dP/dt were recorded. As a measure of cardiac work, rate pressure product (RPP) was calculated from LVDP � HR and the ratio RPP/MVO2 used as an indicator of myocardial efficiency.
After a 20-minute equilibration period, the perfusion medium was switched to an identical buffer replacing unlabelled substrates with 1-13C labelled glucose and U-13C palmitate for 45 minutes. Hearts were then freeze-clamped using Wollenberger tongs and extracted using 6% perchloric acid for 13C NMR analysis (22).
3.3. 13C- NMR spectroscopy
High-resolution 1H decoupled 13C NMR spectra were collected at 500 MHz using an 11.7 Tesla ultra-shielded superconducting vertical wide bore Bruker magnet and 5mm broadband probe interfaced with a Bruker spectrophotometer. Free induction decays (FIDs) were acquired over 32000 scans with a 90� pulse (9.95 us pulse duration and 1 s inter-pulse delay) and fourier transformed for analysis using Bruker Topspin (1.3) software. The relative contributions of glucose and palmitate to oxidative metabolism were determined using the TCAcalc program provided by Dr Mark Jeffrey (University of Texas, Southwestern Medical centre, TX) (10).
3.4. Haematocrit and serum metabolite analysis
Immediately after excision of the heart, blood samples were collected from the chest cavity into heparinised syringes for determination of haematocrit using the blood gas analyser or centrifuged at 3000 g for 10 minutes at 4�C. Serum was removed and stored at -20�C for metabolite analysis. Serum urea and creatinine were analysed at the clinical biochemistry department, Hull Royal Infirmary, Hull and East Yorkshire Hospitals NHS trust.
3.5. Protein expression
Expression of peroxisome proliferator-activated receptor alpha (PPAR-alpha) and CD36 proteins in 12 week uraemic and control hearts were determined by western blotting as described previously (23). Briefly, samples containing 50μg protein were separated using 10% SDS PAGE and transferred onto nitrocellulose membranes. Membranes were incubated with the primary antibodies (PPAR-alpha 1:1000 dilution rabbit polyclonal, Santa Cruz Biotechnology Inc, USA, CD36 1:6000 dilution rabbit polyclonal, Abcam, Cambridge, UK and actin 1:1000 dilution rabbit monoclonal, New England Biolabs) followed by secondary antibodies, PPAR-alpha (1:4000 dilution donkey anti-rabbit Santa Cruz Biotechnology Inc, USA), CD36 (1:8000 dilution goat anti-rabbit Santa Cruz Biotechnology Inc, USA) and actin (1:2000 dilution anti-rabbit Santa Cruz Biotechnology Inc, USA). Protein bands were visualised using enhanced chemiluminescence (ECL) (Amersham, Uppsala, Sweden) and quantified using scanning densitometry and ImageJ software.
3.6. Statistical analysis
Results are expressed as mean +/- SEM. Statistical significance was determined using an unpaired t test (for single mean comparisons) or two-way ANOVA where appropriate (using the Scheffe post-hoc test). Pearsons analysis was used to determine the significance of bi-variate correlations. Statistical analysis was performed using SPSS software (16.0) and level of significance was set at p less than 0.05.
4. RESULTS
4.1. Characterisation of the experimental model
Characteristics of the experimental model are given in Table 1. Serum creatinine was significantly elevated in uraemic animals compared to controls at 3 weeks, and progressively increased throughout uraemia, indicating worsening kidney function with time. By 12 weeks, the serum creatinine concentration was approximately 282% higher (Figure 1) and the serum urea concentration 448% higher (data not shown) in uraemic animals than in respective control animals.
Uraemic animals exhibited a reduced haematocrit when compared to controls, highlighting development of anaemia. The degree of anaemia did not alter during the progression of kidney dysfunction. Hypertension was also observed from 3 weeks uraemia (18-19).
At 3 and 6 weeks, the percentage water content of the lungs was comparable between control and uraemic animals. 12-week uraemic animals had an increased water content of the lungs relative to controls.
At 3 weeks uraemia, there was no evidence of LVH (Table 2). By 6 weeks, uraemic animals showed a significant increase in HW/BW (p less than 0.05) and at 12 weeks, wet heart weight, HW/BW and HW/tibia length were significantly increased in uraemic animals compared to controls (Table 2). In addition, a positive correlation was observed between serum creatinine concentration and HW/tibia length (r=0.74 p less than 0.05) (Figure 2) and between haematocrit and HW/tibia length (r=0.60 p less than 0.05) (Figure 3) at 12 weeks.
4.2. In vitro cardiac function
At 3, 6 and 12 weeks, myocardial LVDP, RPP and contractility (+dP/dt) were comparable between the two groups (Figure 4 a-c). Furthermore, at 3 and 6 weeks uraemia, MVO2 and cardiac efficiency were similar to controls (Figure 5). Interestingly, 12-week uraemic hearts exhibited a relative reduction in MVO2 (0.83 +/-0.03 vs. 0.94 +/-0.03 umol/ g wet heart weight/ min p less than 0.05) resulting in an apparent improvement in cardiac efficiency compared to control hearts (Figure 5).
4.3. Myocardial metabolism
The relative contributions of substrates to myocardial oxidative metabolism over the duration of uraemia are given in Figure 6 (a-c). At 3 weeks, no change in substrate utilisation was observed. By 6 weeks, there was a decrease in the contribution of palmitate in uraemic hearts (27.5 +/-1.9 vs. 20.0 +/-1.5% p less than 0.05). Palmitate utilisation remained depressed by 12-weeks in uraemic compared to control hearts (26.7 +/-1.9 vs. 19.2 +/-1.0% p less than 0.05) however this was compensated for by a significant rise in glucose (12.7 +/-0.6 vs. 15.5 +/-0.8% p less than 0.05) and unlabelled substrate utilisation (60.6 +/-1.6 vs. 65.2 +/-0.9% p less than 0.05).
4.4. Protein expression
At 12 weeks, cardiac PPAR-alpha expression was similar in control and uraemic animals (1.00 +/-0.11 vs. 1.00 +/-0.17), whereas CD36 expression decreased significantly in uraemic hearts compared to controls (1.00 +/-0.08 vs. 0.78 +/-0.04 p less than 0.05) (Figure 7).
5. DISCUSSION
5.1. Experimental model of CKD
Surgical induction of uraemia using the 5/6th nephrectomy model induced kidney dysfunction as evidenced by the increased serum creatinine and development of anaemia. This is in keeping with previous observations from our group (18-19), and others (24-25).
Uraemic animals had a reduced haematocrit by 3 weeks, which remained depressed when the duration of uraemia was extended to 12 weeks. The anaemia observed may be due to decreased erythropoietin (EPO) production from the damaged kidney, which parallels observations from uraemic patients (26). Indeed, anaemia is present in 60-80% of patients with end stage renal disease (ESRD) and low EPO levels correlate with a reduction in haematocrit (27-28). EPO resistance also occurs in CKD patients as a consequence of high circulating levels of inflammatory cytokines including TNF-alpha and IL-6, potentially contributing to worsening anaemia (29-30). Low haematocrit levels are associated with an increased risk of hospitalisation in CKD patients and improving haematocrit decreases risk (31-32).
Cardiac hypertrophy was observed from 6 weeks post-surgery, increasing after 12 weeks of uraemia. The development of LVH during CKD is complex and incompletely understood. However, the association and persistence of haemodynamic factors, including increased afterload (hypertension and aortic stiffening) and increased preload (anaemia and hypervolaemia) in addition to metabolic and endocrine abnormalities will undoubtedly play a role (33).
Hypertension, in this model, is observed at 3 weeks post induction of uraemia (systolic blood pressure 138 +/-4 vs. 164 +/-5 mmHg p less than 0.05) (18), however the mechanisms underlying this remain incompletely understood. Activation of the renin-angiotensin-aldosterone system (RAAS) is considered a key contributor. Indeed, a major impact on the mortality associated with CKD patients has been achieved through treatment with angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) (34). The release of angiotensin II acts directly on vascular smooth muscles cells as a potent vasoconstrictor and also regulates renal sodium and water absorption via release of aldosterone. Furthermore, angiotensin II affects cardiac contractility and heart rate through activation of the sympathetic nervous system. Locally generated angiotensin II is also involved in paracrine signalling and has a mitogenic effect, acting as a growth factor in the development of LVH (35). Interestingly, several large multicentre trials have proposed renoprotective effects of ACEi independent of their anti-hypertensive actions (36-37).
Clinical and experimental studies have shown that administration of antihypertensive agents during CKD leads to a decrease in blood pressure correlating with regression of LVH (38-39). Conversely, experimental studies have shown that LVH persists despite normalisation of blood pressure (40). Furthermore, LVH was observed in a mouse model of CKD without a corresponding increase in blood pressure, suggesting that development of hypertrophy during uraemia can be partly dissociated from hypertension (41).
Anaemia can also contribute to the development of LVH, independent of blood pressure changes. A combination of decreased blood viscosity and increased flow due to low tissue oxygenation cause an increase in demand and cardiac output (42). Both experimental (43) and clinical studies (44-45) have shown that EPO treatment is associated with an improvement in haematocrit and reduction in LVH. However, controversy exists over the degree of anaemia correction, with some studies finding that partial, rather than full correction of haematocrit is associated with LVH regression (46-47)
5.2. In vitro cardiac function
At 3 and 6 weeks uraemia, little change in myocardial function or efficiency was observed in uraemia in keeping with previous results (18). In contrast, experimental studies using the working heart preparation have shown cardiac dysfunction at early stages of uraemia (16) and clinical studies suggest that cardiac dysfunction occurs early in the progression of renal failure (48-49). However, it is difficult to extrapolate results from experimental studies to the clinical setting due to the existence of co-morbidities, such as diabetes, which are frequently present in CKD patients.
At 12 weeks, no differences were observed in myocardial function, however there was a reduction in MVO2 resulting in an increased cardiac efficiency in uraemic compared to control hearts consistent with a compensatory phase of LVH. This is in contrast to previous studies showing impaired contractility by 4 weeks uraemia (16). McMahon et al. (2002) demonstrated impaired relaxation (evidenced by prolonged calcium transients) in isolated cardiomyocytes from uraemic hearts compared to controls in the presence of 4 mM (Ca2+) (50). Thus, a combination of uraemia with additional stresses such as elevated (Ca2+) or increased pacing may unmask dysfunction in uraemic hearts.
5.3. Myocardial metabolism
In this study, by 6 weeks, palmitate utilisation decreased in uraemic hearts and when the duration was extended to 12 weeks, palmitate oxidation was reduced with a corresponding rise in glucose and unlabelled substrate utilisation compared to control hearts. The decrease in palmitate utilisation may account for the reduction in MVO2 in uraemic hearts as glucose utilisation is more oxygen-efficient than fatty acid oxidation.
Few studies have investigated the metabolic profile in the uraemic heart. Reddy et al. (2007) showed no alterations in substrate utilisation at 3 or 6 weeks uraemia when hearts were perfused using 1.25mM calcium (18). However, increasing buffer calcium concentration could highlight changes in metabolism due to the increased contractile demand. In support of these alterations, Raine et al. (1993) found a decreased phosphocreatine/ATP ratio highlighting diminished energy stores in experimental uraemia, possibly reflecting a change in cardiac energy metabolism (16).
At 6 and 12 weeks, uraemic animals demonstrated marked LVH compared to controls, and the altered profile of substrate use observed consistent with findings from models of both pressure (9-10, 13) and volume overload hypertrophy (8). Here, consistent with the observed decrease in fatty acid oxidation (FAO) is the down-regulation in CD36 protein expression in uraemic hearts. This parallels observations in patients with hypertrophic cardiomyopathy exhibiting CD36 deficiency (51). Moreover, in an experimental model of angiotensin II- induced hypertension, cardiac CD36 mRNA expression was significantly decreased compared to controls (52). In contrast, models of pressure-overload hypertrophy have shown CD36 expression remains unaltered despite reduced FAO (10, 53). Given that metabolic remodelling is a feature of LVH, which persists despite normalisation of hypertension in uraemic cardiomyopathy (40-41), the alteration in substrate use may occur independently of changes in blood pressure.
Experimental studies of LVH have shown the metabolic remodelling to reflect a re-expression of the foetal gene programme. The foetus relies primarily on glucose for ATP production (54). After birth, the upregulation of FAO parallels mitochondrial development and an increased expression of the regulatory transcription factor PPAR-alpha (11). PPAR-alpha interacts with the heterodimeric receptor RXR (retinoid X receptor), which together bind to the consensus DNA sequence known as the peroxisome proliferator response element (PPRE). Gene transcription is initiated upon activation of the complex by the co-factor PGC-1 (peroxisome proliferator receptor co-activator-1) (55).
During hypertrophy, expression of myocardial PPAR-alpha is reduced, causing a reduction in the expression of FAO enzymes including carnitine palmitoyl transferase 1 (CPT1) and medium chain acyl CoA dehydrogenase (MCAD) (56). In this study however, PPAR-alpha expression was unchanged in uraemic hearts at 12 weeks despite the decrease in palmitate utilisation. It is the combination of all three elements PPAR-alpha, PGC-1 and RXR that are required to modify transcription, therefore reduced PGC-1 may account for the reduced impact of PPAR-alpha in this model. In support of this, Garnier et al (2003) showed a down-regulation of PGC-1 in an experimental model of chronic heart failure (57). Furthermore, PGC-1 mRNA is decreased when Akt is overexpressed (58). Given that uraemia is associated with high levels of Angiotensin II, which activate the Akt pathway, this may reduce PGC-1 and therefore account for the decreased FAO in this model (59). In support of this, angiotensin II directly reduced palmitate oxidation in cultured adult cardiomyocytes (60). Interestingly, Barger et al. showed the activity of PPAR-alpha can also be regulated by post-transcriptional modification involving the extracellular signal- regulated kinase (ERK) and mitogen activated protein kinase (MAPK) pathways, which may also account for the reduced impact of PPAR-alpha without the change in protein expression (56).
The shift towards glucose utilisation may be initially beneficial in terms of oxygen efficiency. Indeed, stimulating glucose utilisation with drugs such as ranolazine, is associated with improved cardiac function in the ischaemic rat heart (61-62). However, the change in metabolic profile may in the longer-term potentially result in complications including accumulation of lipids and energy depletion. The build up of fatty acyl components can lead to sequestration of CoA and consequently decrease the CoA to acetyl-CoA ratio, inhibiting PDH and resulting in a limited capacity to utilise both fatty acids and glucose leading to energy starvation (15). A number of experimental studies have shown that increasing PPAR-alpha activity and thus FAO, leads to improved cardiac function and slows the progression towards heart failure (63-64). However, Young et al. (2001) demonstrated that inappropriate reactivation of PPAR-alpha during cardiac hypertrophy exacerbates dysfunction (65). This suggests that down-regulation of PPAR-alpha and reduced FAO may be essential for sustaining cardiac function during hypertrophy.
6. CONCLUSIONS
In this model, kidney dysfunction was evident from 3 weeks uraemia, without cardiac hypertrophy. When the duration of uraemia was prolonged to 6 and 12 weeks, animals showed marked LVH, evidence of metabolic remodelling but no change in function highlighting a compensatory phase of hypertrophy. To our knowledge, this is the first study to show a decrease in palmitate utilisation in the hypertrophied uraemic heart. This remodelling may be a factor in the transition from compensatory LVH into dysfunction and heart failure in uraemia.
7. ACKNOWLEDGEMENTS
This work was supported by the British Heart Foundation (grant FS/06/047) (K.S.). We are grateful to Jenny Foster and Kathleen Bulmer for invaluable technical support and Dr. Ian Hanning of Hull Royal Infirmary for analyses of serum urea and electrolytes.
8. REFERENCES
1. Causes of death. United States Renal Data System. Am J Kidney Dis, 32(2 Suppl 1), S81-8 (1998)
doi:10.1053/ajkd.1998.v32.pm9713410
PMid:9713410
2. A. E. Raine, R. Margreiter, F. P. Brunner, J. H. Ehrich, W. Geerlings, P. Landais, C. Loirat, N. P. Mallick, N. H. Selwood, G. Tufveson: Report on management of renal failure in Europe, XXII, 1991. Nephrol Dial Transplant, 7 Suppl 2, 7-35 (1992)
PMid:1338121
3. R. N. Foley, P. S. Parfrey and M. J. Sarnak: Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis, 32(5 Suppl 3), S112-9 (1998)
doi:10.1053/ajkd.1998.v32.pm9820470
PMid:9820470
4. R. N. Foley, C. A. Herzog and A. J. Collins: Smoking and cardiovascular outcomes in dialysis patients: the United States Renal Data System Wave 2 study. Kidney Int, 63(4), 1462-7 (2003)
doi:10.1046/j.1523-1755.2003.00860.x
PMid:12631362
5. K. Smith, D. Semple, S. Bhandari and A. M. Seymour: Cellular basis of uraemic cardiomyopathy: a role for erythropoietin? Eur J Heart Fail, 11(8), 732-8 (2009)
doi:10.1093/eurjhf/hfp093
PMid:19633100
6. R. N. Foley, P. S. Parfrey, J. D. Harnett, G. M. Kent, C. J. Martin, D. C. Murray and P. E. Barre: Clinical and echocardiographic disease in patients starting end-stage renal disease therapy. Kidney Int, 47(1), 186-92 (1995)
doi:10.1038/ki.1995.22
PMid:7731145
7. D. Levy, R. J. Garrison, D. D. Savage, W. B. Kannel and W. P. Castelli: Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med, 322(22), 1561-6 (1990)
PMid:2139921
8. Z. el Alaoui-Talibi, S. Landormy, A. Loireau and J. Moravec: Fatty acid oxidation and mechanical performance of volume-overloaded rat hearts. Am J Physiol, 262(4 Pt 2), H1068-74 (1992)
9. M. F. Allard, B. O. Schonekess, S. L. Henning, D. R. English and G. D. Lopaschuk: Contribution of oxidative metabolism and glycolysis to ATP production in hypertrophied hearts. Am J Physiol, 267(2 Pt 2), H742-50 (1994)
10. A. Akki, K. Smith and A. M. Seymour: Compensated cardiac hypertrophy is characterised by a decline in palmitate oxidation. Mol Cell Biochem, 311(1-2), 215-24 (2008)
doi:10.1007/s11010-008-9711-y
PMid:18278440
11. P. M. Barger and D. P. Kelly: Fatty acid utilization in the hypertrophied and failing heart: molecular regulatory mechanisms. Am J Med Sci, 318(1), 36-42 (1999)
doi:10.1097/00000441-199907000-00006
PMid:10408759
12. J. C. Osorio, W. C. Stanley, A. Linke, M. Castellari, Q. N. Diep, A. R. Panchal, T. H. Hintze, G. D. Lopaschuk and F. A. Recchia: Impaired myocardial fatty acid oxidation and reduced protein expression of retinoid X receptor-alpha in pacing-induced heart failure. Circulation, 106(5), 606-12 (2002)
doi:10.1161/01.CIR.0000023531.22727.C1
PMid:12147544
13. N. Sambandam, G. D. Lopaschuk, R. W. Brownsey and M. F. Allard: Energy metabolism in the hypertrophied heart. Heart Fail Rev, 7(2), 161-73 (2002)
doi:10.1023/A:1015380609464
14. T. C. Leone, C. J. Weinheimer and D. P. Kelly: A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders. Proc Natl Acad Sci U S A, 96(13), 7473-8 (1999)
doi:10.1073/pnas.96.13.7473
15. A. S. J. Chatham: The effects of hypertrophy and diabetes on cardiac pyruvate dehydrogenase activity. Journal of Molecular and Cellular cardiology, 29, 2771-2778 (1997)
doi:10.1006/jmcc.1997.0512
PMid:9344771
16. A. E. Raine, A. M. Seymour, A. F. Roberts, G. K. Radda and J. G. Ledingham: Impairment of cardiac function and energetics in experimental renal failure. J Clin Invest, 92(6), 2934-40 (1993)
doi:10.1172/JCI116916
PMid:8254048 PMCid:288497
17. T. D. Hewitson, T. Ono and G. J. Becker: Small animal models of kidney disease: a review. Methods Mol Biol, 466, 41-57 (2009)
PMid:19148602
18. V. Reddy, S. Bhandari and A. M. Seymour: Myocardial function, energy provision, and carnitine deficiency in experimental uremia. J Am Soc Nephrol, 18(1), 84-92 (2007)
doi:10.1681/ASN.2005080876
PMid:17182887
19. D. Aksentijevic, S. Bhandari and A. M. Seymour: Insulin resistance and altered glucose transporter 4 expression in experimental uremia. Kidney Int, 75(7), 711-8 (2009)
doi:10.1038/ki.2008.691
PMid:19177156
20. J. Sample, J. G. Cleland and A. M. Seymour: Metabolic remodeling in the aging heart. J Mol Cell Cardiol, 40(1), 56-63 (2006)
doi:10.1016/j.yjmcc.2005.09.018
PMid:16324710
21. J. R. Neely, H. Liebermeister, E. J. Battersby and H. E. Morgan: Effect of pressure development on oxygen consumption by isolated rat heart. Am J Physiol, 212(4), 804-14 (1967)
PMid:6024443
22. A. M. Seymour, H. Eldar and G. K. Radda: Hyperthyroidism results in increased glycolytic capacity in the rat heart. A 31P-NMR study. Biochim Biophys Acta, 1055(2), 107-16 (1990)
doi:10.1016/0167-4889(90)90110-Y
23. A. Akki and A. M. Seymour: Western diet impairs metabolic remodelling and contractile efficiency in cardiac hypertrophy. Cardiovasc Res, 81(3), 610-7 (2009)
doi:10.1093/cvr/cvn316
PMid:19028723
24. R. Dikow, L. P. Kihm, M. Zeier, J. Kapitza, J. Tornig, K. Amann, C. Tiefenbacher and E. Ritz: Increased infarct size in uremic rats: reduced ischemia tolerance? J Am Soc Nephrol, 15(6), 1530-6 (2004)
doi:10.1097/01.ASN.0000130154.42061.C6
PMid:15153563
25. P. Kalk, B. Eggert, K. Relle, M. Godes, S. Heiden, Y. Sharkovska, Y. Fischer, D. Ziegler, G. W. Bielenberg and B. Hocher: The adenosine A1 receptor antagonist SLV320 reduces myocardial fibrosis in rats with 5/6 nephrectomy without affecting blood pressure. Br J Pharmacol, 151(7), 1025-32 (2007)
doi:10.1038/sj.bjp.0707319
PMid:17558436 PMCid:2042943
26. J. Caro, S. Brown, O. Miller, T. Murray and A. J. Erslev: Erythropoietin levels in uremic nephric and anephric patients. J Lab Clin Med, 93(3), 449-58 (1979)
PMid:570997
27. C. Y. Hsu: Epidemiology of anemia associated with chronic renal insufficiency. Curr Opin Nephrol Hypertens, 11(3), 337-41 (2002)
doi:10.1097/00041552-200205000-00011
28. G. T. Obrador, T. Roberts, W. L. St Peter, E. Frazier, B. J. Pereira and A. J. Collins: Trends in anemia at initiation of dialysis in the United States. Kidney Int, 60(5), 1875-84 (2001)
doi:10.1046/j.1523-1755.2001.00002.x
PMid:11703606
29. M. Goicoechea, J. Martin, P. de Sequera, J. A. Quiroga, A. Ortiz, V. Carreno and C. Caramelo: Role of cytokines in the response to erythropoietin in hemodialysis patients. Kidney Int, 54(4), 1337-43 (1998)
doi:10.1046/j.1523-1755.1998.00084.x
PMid:9767553
30. E. Costa, S. Rocha, P. Rocha-Pereira, H. Nascimento, E. Castro, V. Miranda, S. Faria Mdo, A. Loureiro, A. Quintanilha, L. Belo and A. Santos-Silva: Neutrophil activation and resistance to recombinant human erythropoietin therapy in hemodialysis patients. Am J Nephrol, 28(6), 935-40 (2008)
doi:10.1159/000142147
PMid:18587235
31. H. Xia, J. Ebben, J. Z. Ma and A. J. Collins: Hematocrit levels and hospitalization risks in hemodialysis patients. J Am Soc Nephrol, 10(6), 1309-16 (1999)
PMid:10361870
32. I. S. Anand, M. A. Kuskowski, T. S. Rector, V. G. Florea, R. D. Glazer, A. Hester, Y. T. Chiang, N. Aknay, A. P. Maggioni, C. Opasich, R. Latini and J. N. Cohn: Anemia and change in hemoglobin over time related to mortality and morbidity in patients with chronic heart failure: results from Val-HeFT. Circulation, 112(8), 1121-7 (2005)
doi:10.1161/CIRCULATIONAHA.104.512988
PMid:16103233
33. G. M. London: Left ventricular hypertrophy: why does it happen? Nephrol Dial Transplant, 18 Suppl 8, viii2-6 (2003)
34. G. Maschio, D. Alberti, G. Janin, F. Locatelli, J. F. Mann, M. Motolese, C. Ponticelli, E. Ritz and P. Zucchelli: Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med, 334(15), 939-45 (1996)
doi:10.1056/NEJM199604113341502
PMid:8596594
35. S. Rosenkranz: TGF-beta1 and angiotensin networking in cardiac remodeling. Cardiovasc Res, 63(3), 423-32 (2004)
doi:10.1016/j.cardiores.2004.04.030
PMid:15276467
36. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet, 355(9200), 253-9 (2000)
doi:10.1016/S0140-6736(99)12323-7
37. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet, 358(9287), 1033-41 (2001)
doi:10.1016/S0140-6736(01)06178-5
38. C. Zoccali, F. A. Benedetto, G. Tripepi and F. Mallamaci: Cardiac consequences of hypertension in hemodialysis patients. Semin Dial, 17(4), 299-303 (2004)
doi:10.1111/j.0894-0959.2004.17331.x
PMid:15250922
39. J. D. Harnett and P. S. Parfrey: Blood pressure control and regression of LV hypertrophy in dialysis patients. Contrib Nephrol, 106, 110-3 (1994)
PMid:8174353
40. M. Rambausek, K. Amann, G. Mall and E. Ritz: Structural causes of cardiac dysfunction in uremia. Ren Fail, 15(3), 421-8 (1993)
doi:10.3109/08860229309054955
PMid:8516501
41. A. M. Siedlecki, X. Jin and A. J. Muslin: Uremic cardiac hypertrophy is reversed by rapamycin but not by lowering of blood pressure. Kidney Int, 75(8), 800-8 (2009)
doi:10.1038/ki.2008.690
PMid:19165175 PMCid:2764402
42. G. M. London and P. S. Parfrey: Cardiac disease in chronic uremia: pathogenesis. Adv Ren Replace Ther, 4(3), 194-211 (1997)
PMid:9239425
43. K. Amann, M. Buzello, A. Simonaviciene, G. Miltenberger-Miltenyi, A. Koch, A. Nabokov, M. L. Gross, B. Gless, G. Mall and E. Ritz: Capillary/myocyte mismatch in the heart in renal failure--a role for erythropoietin? Nephrol Dial Transplant, 15(7), 964-9 (2000)
doi:10.1093/ndt/15.7.964
44. J. Silberberg, N. Racine, P. Barre and A. D. Sniderman: Regression of left ventricular hypertrophy in dialysis patients following correction of anemia with recombinant human erythropoietin. Can J Cardiol, 6(1), 1-4 (1990)
PMid:2138048
45. T. Hayashi, A. Suzuki, T. Shoji, M. Togawa, N. Okada, Y. Tsubakihara, E. Imai and M. Hori: Cardiovascular effect of normalizing the hematocrit level during erythropoietin therapy in predialysis patients with chronic renal failure. Am J Kidney Dis, 35(2), 250-6 (2000)
doi:10.1016/S0272-6386(00)70334-9
46. J. Pascual, J. L. Teruel, J. L. Moya, F. Liano, M. Jimenez-Mena and J. Ortuno: Regression of left ventricular hypertrophy after partial correction of anemia with erythropoietin in patients on hemodialysis: a prospective study. Clin Nephrol, 35(6), 280-7 (1991)
PMid:1831414
47. C. Massimetti, D. Pontillo, S. Feriozzi, S. Costantini, A. Capezzuto and E. Ancarani: Impact of recombinant human erythropoietin treatment on left ventricular hypertrophy and cardiac function in dialysis patients. Blood Purif, 16(6), 317-24 (1998)
doi:10.1159/000014351
PMid:10343078
48. P. S. Parfrey, R. N. Foley, J. D. Harnett, G. M. Kent, D. Murray and P. E. Barre: Outcome and risk factors of ischemic heart disease in chronic uremia. Kidney Int, 49(5), 1428-34 (1996)
doi:10.1038/ki.1996.201
PMid:8731110
49. S. K. Pehrsson, R. Jonasson and L. E. Lins: Cardiac performance in various stages of renal failure. Br Heart J, 52(6), 667-73 (1984)
doi:10.1136/hrt.52.6.667
50. A. C. McMahon, S. E. Greenwald, S. M. Dodd, M. J. Hurst and A. E. Raine: Prolonged calcium transients and myocardial remodelling in early experimental uraemia. Nephrol Dial Transplant, 17(5), 759-64 (2002)
doi:10.1093/ndt/17.5.759
51. T. Tanaka, K. Sohmiya and K. Kawamura: Is CD36 deficiency an etiology of hereditary hypertrophic cardiomyopathy? J Mol Cell Cardiol, 29(1), 121-7 (1997)
doi:10.1006/jmcc.1996.0257
PMid:9040027
52. H. Yamashita, K. G. Bharadwaj, S. Ikeda, T. S. Park and I. J. Goldberg: Cardiac metabolic compensation to hypertension requires lipoprotein lipase. Am J Physiol Endocrinol Metab, 295(3), E705-13 (2008)
doi:10.1152/ajpendo.90338.2008
PMid:18647880 PMCid:2536729
53. C. C. Strom, M. Aplin, T. Ploug, T. E. Christoffersen, J. Langfort, M. Viese, H. Galbo, S. Haunso and S. P. Sheikh: Expression profiling reveals differences in metabolic gene expression between exercise-induced cardiac effects and maladaptive cardiac hypertrophy. Febs J, 272(11), 2684-95 (2005)
doi:10.1111/j.1742-4658.2005.04684.x
PMid:15943803
54. B. Wittels and R. Bressler: Lipid metabolism in the newborn heart. J Clin Invest, 44(10), 1639-46 (1965)
doi:10.1172/JCI105270
PMid:5840533 PMCid:292648
55. B. N. Finck and D. P. Kelly: PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J Clin Invest, 116(3), 615-22 (2006)
doi:10.1172/JCI27794
PMid:16511594 PMCid:1386111
56. P. M. Barger, J. M. Brandt, T. C. Leone, C. J. Weinheimer and D. P. Kelly: Deactivation of peroxisome proliferator-activated receptor-alpha during cardiac hypertrophic growth. J Clin Invest, 105(12), 1723-30 (2000)
doi:10.1172/JCI9056
PMid:10862787 PMCid:378509
57. A. Garnier, D. Fortin, C. Delomenie, I. Momken, V. Veksler and R. Ventura-Clapier: Depressed mitochondrial transcription factors and oxidative capacity in rat failing cardiac and skeletal muscles. J Physiol, 551(Pt 2), 491-501 (2003)
doi:10.1113/jphysiol.2003.045104
PMid:12824444 PMCid:2343221
58. S. A. Cook, T. Matsui, L. Li and A. Rosenzweig: Transcriptional effects of chronic Akt activation in the heart. J Biol Chem, 277(25), 22528-33 (2002)
doi:10.1074/jbc.M201462200
PMid:11956204
59. A. Perlman, L. M. Lawsin, P. Kolachana, M. Saji, J. Moore, Jr. and M. D. Ringel: Angiotensin II regulation of TGF-beta in murine mesangial cells involves both PI3 kinase and MAP kinase. Ann Clin Lab Sci, 34(3), 277-86 (2004)
PMid:15487702
60. C. Pellieux, C. Montessuit, I. Papageorgiou and R. Lerch: Angiotensin II downregulates the fatty acid oxidation pathway in adult rat cardiomyocytes via release of tumour necrosis factor-alpha. Cardiovasc Res, 82(2), 341-50 (2009)
doi:10.1093/cvr/cvp004
PMid:19131364
61. J. G. McCormack, R. L. Barr, A. A. Wolff and G. D. Lopaschuk: Ranolazine stimulates glucose oxidation in normoxic, ischemic, and reperfused ischemic rat hearts. Circulation, 93(1), 135-42 (1996)
PMid:8616920
62. W. C. Stanley and M. P. Chandler: Energy metabolism in the normal and failing heart: potential for therapeutic interventions. Heart Fail Rev, 7(2), 115-30 (2002)
doi:10.1023/A:1015320423577
PMid:11988636
63. F. Brigadeau, P. Gele, M. Wibaux, C. Marquie, F. Martin-Nizard, G. Torpier, J. C. Fruchart, B. Staels, P. Duriez and D. Lacroix: The PPARalpha activator fenofibrate slows down the progression of the left ventricular dysfunction in porcine tachycardia-induced cardiomyopathy. J Cardiovasc Pharmacol, 49(6), 408-15 (2007)
doi:10.1097/FJC.0b013e3180544540
PMid:17577106
64. V. Labinskyy, M. Bellomo, M. P. Chandler, M. E. Young, V. Lionetti, K. Qanud, F. Bigazzi, T. Sampietro, W. C. Stanley and F. A. Recchia: Chronic Activation of PPAR{alpha} With Fenofibrate Prevents Alterations in Cardiac Metabolic Phenotype Without Changing The Onset Of Decompensation in Pacing-Induced Heart Failure. J Pharmacol Exp Ther (2007)
65. M. E. Young, F. A. Laws, G. W. Goodwin and H. Taegtmeyer: Reactivation of peroxisome proliferator-activated receptor alpha is associated with contractile dysfunction in hypertrophied rat heart. J Biol Chem, 276(48), 44390-5 (2001)
doi:10.1074/jbc.M103826200
PMid:11574533
Key Words: Chronic kidney disease, uraemic cardiomyopathy, left ventricular hypertrophy, metabolic remodelling, 13C NMR
Send correspondence to: Anne-Marie. L. Seymour, Department of Biological Sciences & Hull York Medical School, University of Hull, Cottingham, Kingston-upon-Hull, United Kingdom, Tel: 44-14824-65517, Fax: 44-14824-65458, E-mail:a.m.seymour@hull.ac.uk