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(Circulation. 1996;94:2837-2842.)
© 1996 American Heart Association, Inc.
Articles |
Fatty Acid Oxidation Enzyme Gene Expression Is Downregulated in the Failing Heart
the Departments of Medicine (M.N.S., T.A.R., D.P.K.) and Molecular Biology and Pharmacology (D.P.K.), Washington University School of Medicine, St Louis, Mo; the Department of Food Science and Technology, Ohio State University, Columbus (S.P., S.A.M.); and the Universite Paris, INSERM, Paris, France (J.B.).
Correspondence to Daniel P. Kelly, MD, Cardiovascular Division, Box 8086, Washington University School of Medicine, 660 S Euclid Ave, St Louis, MO 63110. E-mail kelly@visar.wustl.edu.
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Abstract |
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Background During the development of heart failure (HF), the chief myocardial energy substrate switches from fatty acids to glucose. This metabolic switch, which recapitulates fetal cardiac energy substrate preferences, is thought to maintain aerobic energetic balance. The regulatory mechanisms involved in this metabolic response are unknown.
Methods and Results To characterize the expression of genes involved in mitochondrial fatty acid ß-oxidation (FAO) in the failing heart, levels of mRNA encoding enzymes that catalyze the first and third steps of the FAO cycle were delineated in the left ventricles (LVs) of human cardiac transplant recipients. FAO enzyme and mRNA levels were coordinately downregulated (>40%) in failing human LVs compared with controls. The temporal pattern of this alteration in FAO enzyme gene expression was characterized in a rat model of progressive LV hypertrophy (LVH) and HF [SHHF/Mcc-facp (SHHF) rat]. FAO enzyme mRNA levels were coordinately downregulated (>70%) during both the LVH and HF stages in the SHHF rats compared with controls. In contrast, the activity and steady-state levels of medium-chain acyl-CoA dehydrogenase, which catalyzes a rate-limiting step in FAO, were not significantly reduced until the HF stage, indicating additional control at the translational or posttranslational levels in the hypertrophied but nonfailing ventricle.
Conclusions These findings identify a gene regulatory pathway involved in the control of cardiac energy production during the development of HF.
Key Words: heart failure • hypertrophy • fatty acids • metabolism
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Introduction |
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During cardiac development, the chief cardiac energy source switches from glycolysis, during the fetal period, to FAO after birth. Previous studies have shown that during the development of HF, the heart reverts to reliance on glycolysis as the primary pathway for energy production: a recapitulation of fetal energy metabolism.1 2 3 4 5 6 7 Little is known about the regulatory mechanisms involved in this cardiac energy substrate switch. Moreover, the role of this metabolic switch as an adaptive versus maladaptive response and its potential contribution to the transition from compensated cardiac hypertrophy to the overtly failing heart is unknown.
Fatty acids are oxidized primarily in the mitochondria via the ß-oxidation cycle.8 The severe clinical manifestations of inborn errors in human FAO enzymes, including cardiomyopathy and sudden death, underscore the importance of this pathway in cardiac energy transduction.9 The objective of this study was to determine whether the expression of nuclear genes encoding mitochondrial FAO enzymes is regulated in parallel with the alteration in myocardial energy substrate utilization in HF. Accordingly, we have characterized the expression of enzymes catalyzing the first (MCAD and LCAD) and third (LCHAD) steps in the FAO cycle during the development of HF. Our results indicate that expression of FAO enzymes is coordinately downregulated at the pretranslational level in the failing human LV. The temporal regulatory pattern of MCAD mRNA and enzyme expression was then delineated in a rat model of pressure overload–induced LVH that progresses to HF (SHHF strain10 11 12 ). We found that although MCAD mRNA levels were downregulated in both hypertrophy and HF stages in the SHHF rats, enzyme activities and protein levels did not decrease significantly until HF ensued. These results indicate that FAO enzyme expression is downregulated during development of HF at pretranslational and posttranslational levels and suggest a mechanism by which energy substrate utilization is altered in the failing heart.
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Methods |
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Human Studies
The HF group was composed of eight heart transplant recipients enrolled in the Heart Transplantation Program at Barnes Hospital. Inclusion criteria for the HF samples included patients who experienced HF symptoms with minimal to no exertion (NYHA functional class III to IV) and an ejection fraction
35% as determined by radionuclide ventricular angiography and confirmed by left ventriculography at the time of cardiac catheterization. Subjects were excluded if HF was the result of an acute insult (eg, cardiogenic shock from an acute myocardial infarction), if the subject had an implanted LV assist device, or if the patient remained on bypass for >30 minutes before explantation of the heart. The control group included five postmortem samples from hearts of individuals who had died of noncardiac causes. The control hearts were rejected as transplant donor organs because of positive cytomegalovirus serology in two subjects, age of patient in one, and for unknown reasons in the final two controls (gross cardiac pathology was excluded by palpation of the coronary arteries, viewing cardiac wall thickness, and a normal ratio of heart weight to body weight at the time of harvest). Additional characteristics of the two groups are provided in Table 1
. LV apical tissue obtained immediately after the heart was removed from the subject's chest was snap-frozen in liquid N2 and stored at -80°C until total RNA was isolated.
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SHHF Rat Studies
The SHHF/Mcc-facp rat developed by S.A. McCune (Ohio State University) is a genetically inbred strain that develops hypertension, LV hypertrophy, and congestive HF.10 11 This strain originated from a cross of the Koletsky rat and the spontaneously hypertensive rat from the NIH colony. Offspring are lean (75%) or obese (25%). All lean male SHHF animals develop hypertension and LVH by 3 to 5 months of age and eventually develop overt congestive HF by 16 to 20 months of age. Only lean, normoglycemic, male SHHF rats were used for this study at different stages in the natural progression to HF. Two-month-old SHHF males that had not yet developed hypertension were used as control rats (C group, n=6). A second group of 9- to 12-month-old animals with established hypertension and concentric LVH without dilatation served as the compensated LVH group (n=5). The third group consisted of animals at 16 to 20 months of age with overt congestive HF (n=6). Previous characterization of the SHHF male lean rats with Doppler and M-mode echocardiographic studies of lean male SHHF rats12 has demonstrated that between 13 and 17 months of age, shortening fraction decreases, LV diastolic and end-systolic diameters increase, and aortic velocity–time integralxheart rate decreases significantly in male lean SHHF rats compared with animals in the LVH group (age, 9 to 12 months). All HF rats used for this study exhibited the external clinical signs of dyspnea, cyanosis, piloerection, lethargy, and cold tails; internally, they had ascites, pulmonary edema, and pleural effusion. The HF hearts were enlarged, with thickened left and right ventricular walls, dilated lumina, and left and right atrial dilatation, and frequently contained left atrial thrombi. At the ages indicated, the rats were weighed, anesthetized with pentobarbital, and euthanatized. The whole heart was removed and weighed, and ventricles were dissected out and snap-frozen. To control for the effect of age on gene expression, LV tissue was obtained from a related rat strain (WF) at 2 and 17 months old. The WF rats do not develop hypertension, LVH, or HF.
Animal experiments were conducted in strict accordance with the NIH guidelines for humane treatment of laboratory animals. All animal experiments were reviewed and approved by the Animal Care Committees of the Institutional Review Boards of Washington University and/or Ohio State University.
RNA Isolation and Northern Blot Analysis
Total RNA isolation and Northern blot analyses were performed as described13 14 with the cDNA probes discussed below. Three nuclear-encoded FAO enzyme–coding region cDNA probes were used to assess mitochondrial FAO enzyme gene expression, including rat MCAD,13 rat LCAD (a gift from Bryan E. Hainline, Indiana University15 ), and human LCHAD: the C-terminal portion of the 
-subunit of mitochondrial trifunctional protein (a gift from Arnold W. Strauss, Washington University16 ). Additional probes included a human GAPDH cDNA17 , rat ANF cDNA (a gift from James E. Greenwald, Washington University), and a rat cardiac troponin I cDNA (a gift from Anne M. Murphy, Johns Hopkins University). A partial cDNA coding and 3' untranslated region sequence (164 bp) of a nuclear-encoded mitochondrial protein, mouse ATP synthase subunit e,18 was obtained by reverse-transcription polymerase chain reaction amplification. The signals were quantified by laser densitometric analysis within the linear range of film sensitivity. The densitometric values shown were normalized to the signal obtained with an 18S ribosomal cDNA probe to control for minor differences in RNA loading or RNA integrity.
Protein Immunoblot Analysis
Total cellular protein was prepared from the human and rat LV for immunoblot analysis. A modification of the protein immunoblot (Western) analysis described previously14 was performed with the enhanced chemiluminescence detection system (Amersham). Primary antibodies used include a polyclonal rabbit antibody to porcine MCAD13 and a polyclonal antibody to the C-terminal actin fragment (universal actin antibody, Sigma Immunochemicals). A horseradish peroxidase–conjugated secondary antibody to rabbit IgG was used on all blots.
Southern Blot Analysis
Genomic DNA was isolated from human LV by a standard protocol.19 The mitochondrial DNA probe was obtained by PCR amplification of a region of the human mitochondrial genome (nucleotides 3108 to 3717) with the following primers: sense, 5'-TTCAAATTCCTCCCTGTACG-3' and antisense, 5'-GGCTACTGCTCGCAGTG-3'. A full-length human GAPDH cDNA probe was also used in these studies to control for loading and for standardization to a nuclear gene signal. Total genomic DNA (15 µg) digested with BamHI restriction enzyme at 37°C overnight was loaded to each lane. Standard Southern blotting protocol was used. The final washing solution concentration was 0.1xSSC/1% SDS for the mitochondrial DNA probe and 1xSSC/1% SDS for the GAPDH probe at a temperature of 65°C.
MCAD Enzyme Activity Assays
MCAD activity was determined by following the decrease in ferricenium ion absorbance at 300 nm, as described.20 21 Activity is shown as micromoles octanoyl-CoA oxidized per minute per gram wet weight.
Statistical Analysis
Differences between values for mRNA, protein levels, and enzyme activity were determined by unpaired Student's t-test analyses (human studies) and one-way ANOVA for the rat studies. A statistically significant difference was defined as a value of P<.05. All values shown represent the mean±SEM.
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Results |
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Characterization of FAO Enzyme Gene Expression in the Failing Human Ventricle
To determine whether the expression of genes encoding FAO cycle enzymes was regulated in the failing human heart, MCAD and LCHAD mRNA levels were analyzed by Northern blot analysis of total RNA isolated from the LV of human cardiac transplant recipients with severe HF (idiopathic cardiomyopathy, n=6; ischemic heart disease, n=2) compared with age-matched normal control hearts (n=5) obtained at postmortem. The clinical characteristics of the two groups are shown in Table 1
. MCAD and LCHAD mRNA levels were significantly reduced in the HF group compared with controls (representative Northern blot autoradiograph, Fig 1A). Compared with controls, mean (±SEM) MCAD and LCHAD mRNA levels were reduced by 56±9% (P=.03) and 64±6% (P=.03), respectively (Fig 1B). LV MCAD and LCHAD mRNA levels in the subgroup of patients with idiopathic cardiomyopathy (n=6) were also significantly reduced compared with controls (data not shown). Levels of mRNA encoding ANF, a known marker for LVH and HF,22 were markedly upregulated in the HF group compared with the controls (Fig 1A). As determined by immunoblot studies, LV steady-state MCAD protein levels paralleled MCAD mRNA levels (decreased by 42±4%; P=.01) in the HF group compared with controls (Fig 1).
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To exclude the possibility that the downregulated expression of MCAD and LCHAD mRNA in the HF samples was due to cardiomyocyte dropout or to a generalized reduction in cardiac gene transcription, several control mRNAs were analyzed. Levels of mRNA encoding the cardiac-specific protein cardiac troponin I or GAPDH were not different in the HF group compared with controls (Fig 1). Similarly, the levels of mRNA encoding ATP synthase subunit e, a nuclear-encoded mitochondrial protein, were unchanged between the two groups.
The coordinate downregulation of FAO enzyme gene expression in human HF could reflect a generalized decrease in expression of all mitochondrial protein genes, such as might occur with reduction of cellular mitochondrial number due to alterations in mitochondrial biogenesis or turnover. As an indicator of mitochondrial number, a semiquantitative analysis of mitochondrial DNA was performed with Southern blot analysis. For these studies, total genomic DNA, isolated from the LV samples, was digested with the restriction endonuclease BamHI, which cleaves the human mitochondrial genome at a single site. Age-matched samples from nonfailing ventricle were used to control for the known accumulation of mitochondrial DNA deletions with aging.23 The blot was sequentially hybridized with a mitochondrial DNA–specific probe and a second probe that hybridizes with the nuclear gene encoding GAPDH. The mitochondrial DNA signal, normalized to the GAPDH signal in three control samples, was not significantly different from that in three age-matched HF samples (Fig 2). These results and the observed lack of regulation of ATP synthase subunit e mRNA expression strongly suggest that the altered expression of FAO enzymes in the failing heart is not due to a decrease in cellular mitochondrial number but rather reflects a pathway-specific regulatory phenomenon.
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Characterization of the Temporal Patterns of FAO Enzyme and mRNA Levels in the Hypertrophied and Failing SHHF Rat LV
The data shown above indicate that expression of genes encoding mitochondrial ß-oxidation enzymes is coordinately downregulated in parallel with the energy substrate switch during the development of HF. To determine whether this alteration in metabolic gene expression occurred in a separate model of HF and to delineate the temporal patterns of FAO enzyme mRNA and protein expression during the development of pressure overload–induced HF, the SHHF rat strain, an established model for progressive LV hypertrophy and HF (see "Methods" and References 10 through 12), was used. Three age groups of SHHF rats were studied: (1) a control group of 2-month-old animals without evidence of significant LVH; (2) a group of animals with compensated LVH between 9 and 12 months old; and (3) a group of rats with overt HF, 16 to 20 months old. Mean absolute heart weights and ratios of heart weight to brain weight were significantly increased in both the LVH and HF groups compared with controls (Table 2). To control for age-related effects, normotensive, nonfailing 2-month-old and 17-month-old WF rats were also studied.
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The levels of mRNA encoding MCAD, LCAD (a second member of the acyl-CoA dehydrogenase family), and LCHAD were all markedly lower in LV samples from the LVH and HF rats compared with controls (Fig 3A). As expected, expression of ANF mRNA was markedly induced in the LVH and HF groups (Fig 3A). Mean steady-state MCAD mRNA levels were reduced in the LVH and HF groups by 79±5% (P<.01) and 89±3% (P<.001), respectively (Fig 3B). Mean LCAD mRNA levels were repressed to a similar degree in the LVH and HF groups (Fig 3B). LCHAD mRNA levels were downregulated by 72±9% in LVH (P<.01) and 85±4% in HF (P<.001) (Fig 3B). Although mean mRNA levels for each enzyme were lower in the HF group than in the LVH group, the difference was not statistically significant. Levels of mRNA encoding the glycolytic enzyme GAPDH were not significantly different among the three groups (Fig 3). No significant difference was found in MCAD and GAPDH mRNA levels in the LV of 2-month-old (n=4) and 17-month-old (n=4) control WF rats, indicating that age-related factors do not account for the reduced FAO enzyme mRNA expression.
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Immunoblot analyses were performed with anti-MCAD antibody to determine whether the downregulated expression of MCAD mRNA in the LVH and HF stages of the SHHF rats was reflected at the protein level. In surprising contrast to MCAD mRNA levels, mean steady-state MCAD protein levels were not significantly different in the LVH samples compared with controls (Fig 4). However, MCAD mRNA and protein levels were coordinately downregulated to a similar degree in the HF group (Fig 4). Compared with controls, steady-state MCAD protein and mRNA levels in the HF rats were reduced by 82±3% and 89±3%, respectively. ß-Actin protein levels were not significantly different among the three groups. As observed with mRNA levels, MCAD protein levels were not significantly different in the 2-month-old and 17-month-old male WF control rats (data not shown). MCAD enzymatic activities paralleled protein levels during the transition from LVH to HF (Fig 4). These findings identify a discordance between MCAD mRNA and protein levels during the LVH stage of this rat model and suggest that translational or posttranslational regulatory mechanisms are involved in the maintenance of MCAD protein levels in compensated LVH.
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Discussion |
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Previous studies have shown that myocardial energy substrate utilization is altered during cardiac hypertrophy and in the failing heart; fatty acid utilization decreases while glycolysis increases.1 2 3 4 5 6 7 24 25 26 27 28 For example, this myocardial energy substrate switch has been observed in the hypertrophied hearts of spontaneously hypertensive rats26 and in a recent dual-tracer study in humans with idiopathic dilated cardiomyopathy.7 Therefore, evidence is emerging that during the development of cardiac failure, the proportion of myocardial energy derived from FAO decreases. In this report, we identify a gene regulatory pathway that probably is involved in this myocardial energy substrate switch.
As with most other genes known to be regulated during the development of cardiac hypertrophy,22 29 30 31 32 33 34 35 36 37 38 the expression of nuclear genes encoding mitochondrial FAO enzymes in the hypertrophied and failing heart mimics the fetal gene regulatory program. Previous studies have demonstrated that expression of FAO enzymes is low during the fetal stages of the developing mammalian heart when glucose serves as the chief energy substrate.8 13 39 During the postnatal period and in the adult heart, expression of genes encoding FAO enzymes increases markedly in parallel with the transition from reliance on glycolysis to ß-oxidation of fatty acids as the major energy source.13 40 The switch from FAO to glycolysis during the development of HF recapitulates the fetal heart energy substrate preference. The cardiac sarcomere also undergoes alterations, including reexpression of fetal isoforms of a variety of contractile22 29 30 31 and calcium-regulatory proteins.32 33 34 35 36 Thus, activation of the "fetal gene" program may comprise an adaptive structural and metabolic response of the overloaded ventricle to maximize chemomechanical energy conversion efficiency and decrease oxygen consumption in the hypertrophied cardiocyte, albeit at a cost of lower performance.
Comparison of the temporal patterns of MCAD mRNA and protein expression during the LVH and HF stages in SHHF rats revealed that regulation occurs at multiple levels. Most notably, MCAD mRNA levels are markedly reduced in LVH compared with controls, whereas MCAD protein levels and enzyme activities are not significantly different until the HF stage. These results suggest that an independent regulatory mechanism increases MCAD translation or stabilizes MCAD protein in compensated LVH. The maintenance of MCAD enzyme levels despite reduced mRNA levels in the hypertrophied but nonfailing ventricle could be due to the known increase in protein synthesis in the hypertrophied cardiocyte or may involve a gene- or metabolic pathway–specific phenomenon.
Our present results do not distinguish between the role of decreased myocardial fatty acid oxidative capacity as a primary event in promoting the transition from compensated LVH to HF versus a secondary phenomenon. Although MCAD protein levels and enzyme activities are reduced in parallel with the transition to HF in SHHF rats, these data do not establish a cause-and-effect relationship. However, our results suggest the intriguing possibility that repression of FAO enzyme expression in the hypertrophied heart becomes maladaptive and therefore contributes to the progression from compensated LVH to overt HF. It is well recognized that genetic defects in almost every enzyme in the FAO pathway, including the acyl-CoA dehydrogenases, cause childhood cardiomyopathy and sudden death.9 One possible cause of HF in the setting of defective FAO is inadequate myocardial energy supply. Alternatively, fatty acid intermediates, which could be injurious to the sarcolemma, may accumulate in the context of diminished myocardial ß-oxidative capacity. In support of this latter hypothesis, long-chain acylcarnitines have been shown to cause ventricular arrhythmias and cardiac dysfunction during myocardial ischemia.41 Furthermore, postmortem studies have revealed lipid droplet accumulation in the myocardium of humans with dilated cardiomyopathy.42 Future studies, including delineation of the temporal pattern of the reduction of ß-oxidative flux during the transition from cardiac hypertrophy to failure, will be useful in determining the role of altered FAO as a causal factor in the development of HF.
In summary, we have shown that expression of genes encoding cardiac FAO enzymes is coordinately repressed in the failing heart: a recapitulation of the fetal energy metabolic gene regulatory program. This alteration in cardiac metabolic gene expression is consistent with previous observations that energy derived from FAO is reduced in the hypertrophied and failing heart. We propose that this regulatory pathway represents a useful target for future experimental studies aimed at the characterization of alterations in cellular lipid metabolism during the transition from cardiac hypertrophy to HF.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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Dr Sack is a Howard Hughes Medical Institute Physician Postdoctoral Fellow, and Dr Kelly is an Established Investigator of the American Heart Association. Drs McCune and Park were supported in part by US Public Health Service grant HL-48835 and in part by state and federal funds appropriated to the Ohio Agricultural Research and Development Center, Ohio State University. We thank Jeffrey Saffitz (Department of Pathology) and the Washington University School of Medicine Cardiac Transplant Group for providing us with human tissues, Harold Sims for the human LCHAD cDNA probe, Arnold Strauss for critical reading of the manuscript, Pilar Herrero for assistance with the statistical analyses, and Kelly Hall for expert secretarial assistance.
Received April 18, 1996; revision received June 25, 1996; accepted July 1, 1996.
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N. Isidoro Tavares, P. Philip-Couderc, A. J. Baertschi, R. Lerch, and C. Montessuit Angiotensin II and tumour necrosis factor {alpha} as mediators of ATP-dependent potassium channel remodelling in post-infarction heart failure Cardiovasc Res, September 1, 2009; 83(4): 726 - 736. [Abstract] [Full Text] [PDF]
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S. SHARMA, J. V. ADROGUE, L. GOLFMAN, I. URAY, J. LEMM, K. YOUKER, G. P. NOON, O. H FRAZIER, and H. TAEGTMEYER Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart FASEB J, November 1, 2004; 18(14): 1692 - 1700. [Abstract] [Full Text] [PDF]
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N. Fujii, T. Nozawa, A. Igawa, B.-i. Kato, N. Igarashi, M. Nonomura, H. Asanoi, S. Tazawa, M. Inoue, and H. Inoue Saturated glucose uptake capacity and impaired fatty acid oxidation in hypertensive hearts before development of heart failure Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H760 - H766. [Abstract] [Full Text] [PDF]
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S. Sharma, H. Taegtmeyer, J. Adrogue, P. Razeghi, S. Sen, K. Ngumbela, and M. F. Essop Dynamic changes of gene expression in hypoxia-induced right ventricular hypertrophy Am J Physiol Heart Circ Physiol, March 1, 2004; 286(3): H1185 - H1192. [Abstract] [Full Text] [PDF]
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H. Irie, I. B. Krukenkamp, J. F. F. Brinkmann, G. R. Gaudette, A. E. Saltman, W. Jou, J. F. C. Glatz, N. A. Abumrad, and A. Ibrahimi Myocardial recovery from ischemia is impaired in CD36-null mice and restored by myocyte CD36 expression or medium-chain fatty acids PNAS, May 27, 2003; 100(11): 6819 - 6824. [Abstract] [Full Text] [PDF]
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M. P. Czubryt, J. McAnally, G. I. Fishman, and E. N. Olson Regulation of peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha ) and mitochondrial function by MEF2 and HDAC5 PNAS, February 18, 2003; 100(4): 1711 - 1716. [Abstract] [Full Text] [PDF]
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 K. Q. Stolen, J. Kemppainen, H. Ukkonen, K. K. Kalliokoski, M. Luotolahti, P. Lehikoinen, H. Hamalainen, T. Salo, K. E. Juhani Airaksinen, P. Nuutila, et al. Exercise training improves biventricular oxidative metabolism and left ventricular efficiency in patients with dilated cardiomyopathy J. Am. Coll. Cardiol., February 5, 2003; 41(3): 460 - 467. [Abstract] [Full Text] [PDF]
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H. Degens, A. J. Gilde, M. Lindhout, P. H. M. Willemsen, G. J. van der Vusse, and M. van Bilsen Functional and metabolic adaptation of the heart to prolonged thyroid hormone treatment Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H108 - H115. [Abstract] [Full Text] [PDF]
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T. Kuznetsova, J. A. Staessen, A. Olszanecka, A. Ryabikov, K. Stolarz, S. Malyutina, R. Fagard, K. Kawecka-Jaszcz, and Y. Nikitin Maternal and Paternal Influences on Left Ventricular Mass of Offspring Hypertension, January 1, 2003; 41(1): 69 - 74. [Abstract] [Full Text] [PDF]
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L. de las Fuentes, P. Herrero, L. R. Peterson, D. P. Kelly, R. J. Gropler, and V. G. Davila-Roman Myocardial Fatty Acid Metabolism: Independent Predictor of Left Ventricular Mass in Hypertensive Heart Disease Hypertension, January 1, 2003; 41(1): 83 - 87. [Abstract] [Full Text] [PDF]
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H. Taegtmeyer Switching Metabolic Genes to Build a Better Heart Circulation, October 15, 2002; 106(16): 2043 - 2045. [Full Text] [PDF]
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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, July 30, 2002; 106(5): 606 - 612. [Abstract] [Full Text] [PDF]
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V.i. G. Davila-Roman, G. Vedala, P. Herrero, L. de las Fuentes, J. G. Rogers, D. P. Kelly, and R. J. Gropler Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy J. Am. Coll. Cardiol., July 17, 2002; 40(2): 271 - 277. [Abstract] [Full Text] [PDF]
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J. Marin-Garcia and M. J. Goldenthal Fatty acid metabolism in cardiac failure: biochemical, genetic and cellular analysis Cardiovasc Res, June 1, 2002; 54(3): 516 - 527. [Full Text] [PDF]
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D. P. Kelly Peroxisome Proliferator-Activated Receptor {alpha} as a Genetic Determinant of Cardiac Hypertrophic Growth: Culprit or Innocent Bystander? Circulation, March 5, 2002; 105(9): 1025 - 1027. [Full Text] [PDF]
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H. Ashrafian, E. Johannsson, O. M. Sejersted, P. K. Lunde, I. Sjaastad, M. J. Thomas, L. Bergersen, T. W. Blackstad, O. P. Ottersen, C. Heddle, et al. Cardiac Energetics in Congestive Heart Failure Response Circulation, February 12, 2002; 105 (6): e44 - e45. [Full Text] [PDF]
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 B.N. FINCK, J.J. LEHMAN, P.M. BARGER, and D.P. KELLY Regulatory Networks Controlling Mitochondrial Energy Production in the Developing, Hypertrophied, and Diabetic Heart Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 371 - 382. [Abstract] [PDF]
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P. Razeghi, M. E. Young, J. L. Alcorn, C. S. Moravec, O.H. Frazier, and H. Taegtmeyer Metabolic Gene Expression in Fetal and Failing Human Heart Circulation, December 11, 2001; 104(24): 2923 - 2931. [Abstract] [Full Text] [PDF]
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L. A. Nikolaidis, T. Hentosz, A. Doverspike, R. Huerbin, C. Stolarski, Y.-T. Shen, and R. P. Shannon Mechanisms whereby rapid RV pacing causes LV dysfunction: perfusion-contraction matching and NO Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2270 - H2281. [Abstract] [Full Text] [PDF]
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N. Rosenblatt-Velin, C. Montessuit, I. Papageorgiou, J. Terrand, and R. Lerch Postinfarction heart failure in rats is associated with upregulation of GLUT-1 and downregulation of genes of fatty acid metabolism Cardiovasc Res, December 1, 2001; 52(3): 407 - 416. [Abstract] [Full Text] [PDF]
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 F.M. Bengel, B. Permanetter, M. Ungerer, S.G. Nekolla, and M. Schwaiger Relationship between altered sympathetic innervation, oxidative metabolism and contractile function in the cardiomyopathic human heart; a non-invasive study using positron emission tomography Eur. Heart J., September 1, 2001; 22(17): 1594 - 1600. [Abstract] [PDF]
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