[Frontiers in Bioscience S4, 556-580, January 1, 2012]
Myocardial substrate metabolism in heart disease
Rhys D. Evans1, Kieran Clarke1
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TABLE OF CONTENTS
1. ABSTRACT
Cardiac disease is commonly associated with changes in energy substrate metabolism. Fatty acid and glucose represent the main fuels used by the heart, and characteristic alterations in substrate preference and utilisation occur early in many cardiac disease processes. Different substrate classes (lipids, carbohydrates) have different metabolic efficiencies, both in terms of energy (ATP) yield and in terms of oxygen requirement; changes in metabolic efficiency may affect, positively and negatively, cardiac function. Furthermore, metabolic diseases alter substrate supply to the heart, which may have an impact on cardiac function. One challenge is to establish whether a primary metabolic abnormality in myocardial fuel utilisation leads to cardiac dysfunction, or whether changes in substrate selection are a consequence of the disease state. The distinction is important as the ability to manipulate cardiac substrate utilisation may offer a therapeutic opportunity for cardiac disease.
2. INTRODUCTION
The heart consumes large amounts of energy. This is required both for myofibre contraction and for maintenance of ionic gradients, and energy transduction involves a rapid turnover of high energy phosphate groups (ADP/ATP and creatine/phosphocreatine). The heart is unique in providing its own energy supply, via the coronary arteries, which is potentially precarious as coronary blood flow occurs principally in diastole. Hence, with limited coronary perfusion pressure and flow, there is a resulting high oxygen extraction. It is also unusual in the quantity of energetic substrate consumed. Also, unlike other tissues, the heart must continue its function uninterrupted. Available energy transduction/yielding pathways include both oxidative and non-oxidative processes; given the large requirement for energy, it is unsurprising that the heart derives most of this energy (> 90%) from oxidative pathways (oxidative phosphorylation), although glycolysis, despite its relatively low ATP yield, may have a vital role in myocardial function by virtue of its intracellular compartmentation (1-8). The energy transduction pathway involves energy production (substrate utilisation and metabolism), energy transfer (oxidative phosphorylation), and energy utilisation (high energy phosphate metabolism)(9). Integrity of all three processes is required for optimal function (10). This review will focus on substrate utilisation and metabolism.
3. ENERGY METABOLISM IN THE HEALTHY HEART
Some organs, such as brain, are specialised to utilise a limited selection of energetic substrates, yet the heart is adapted to use any of the classes of energetic substrate available, possibly an evolutionary requirement to maintain function at all times. Substrates include all the major energetic biomolecular classes - lipids (fatty acids (FA), triacylglycerols (TAG)) and their derivatives (ketone bodies), carbohydrates (glucose, lactate) and amino acids (3, 4, 11-16). Limited intracellular storage is provided by TAG and glycogen (Figure 1). However, although the heart is capable of using any plasma-borne substrate available for energy provision, its substrate preference, and hence substrate selection, is well defined, and varies according to prevailing physiological and pathological state. Furthermore, the substrate that the heart chooses, or is obliged to utilise, may impact on its resulting performance, emphasising the intimate relationship between cardiac metabolism and function (15, 16). It is the relationship between substrate utilisation and mechanical function that makes this area of fundamental importance to cardiac disease.
Glucose is assimilated via glucose transporters, principally insulin-sensitive glucose transporter (GLUT4) (but also through insulin-insensitive GLUT1), and lactate via the monocarboxylate transporter, MCT. Besides being used to synthesise myocardial glycogen, glucose is split in glycolysis yielding limited ATP and pyruvate; following oxidative decarboxylation by pyruvate dehydrogenase complex (PDH) to acetyl-CoA in the mitochondrion, pyruvate may then be oxidized by the tricarboxylic acid (TCA) cycle to produce NADH and FADH2 for the electron transport chain, if sufficient oxygen is present. If not oxidized, pyruvate is converted to lactate (8, 11). Like glucose, lactate can be oxidized only if sufficient oxygen is available to permit TCA cycle activity (17). Lipids are delivered to the heart in plasma as non-esterified fatty acids (NEFA) bound to albumin, and are assimilated through the FA transporters CD36/FAT (fatty acid translocase), FATP (fatty acid transport protein) and FABPpm (plasma membrane fatty acid binding protein)(18-20). Following acylation to coenzyme-A and transport into the mitochondrion via the carnitine shuttle, FAs undergo β-oxidation to acetyl-CoA then oxidation though the TCA cycle and electron transport chain to generate ATP (2, 7, 8). Plasma NEFA is derived primarily from TAG lipolysis in white adipose tissue, which is stimulated by "catabolic" hormones such as catecholamines, and inhibited by insulin. Plasma FAs are also provided esterified in the form of TAG, present within the core of TAG-rich lipoproteins (TGRLP): endogenously-synthesised TAG from the liver within very-low-density lipoproteins (VLDL) and exogenous (dietary) TAG assembled as chylomicrons (CM) by the gut (21-23). TAG in the core of these lipoproteins is hydrolyzed to FA by the endothelial enzyme lipoprotein lipase (LPL) (24-26); LPL activity may liberate substantial amounts of "free" fatty acids into the circulation (27-30). Whole-particle assimilation also occurs through lipoprotein receptor-mediated uptake mechanisms (31, 32). Whether the uptake and subsequent intracellular channelling of NEFA- and TAG-derived FA are identical is currently uncertain (33-35). Some assimilated FA is re-esterified and incorporated into the intracellular lipid pool (10-25% of the assimilated TAG; mostly into TAG and phospholipid) whilst the remainder is oxidized (75-90%); this proportion varies according to the FA source (21, 35). The intracellular TAG pool is extremely labile and has a highly dynamic relationship with FA destined for β-oxidation; although the physiological significance of this pool, and its relationship to cellular lipid toxicity (see below), remains uncertain (36), it is probably an obligatory step in intracellular lipid buffering (> 10% of myocardial energy is derived from endogenous TAG stores in hearts perfused ex vivo, even when FA is present in the perfusate (37)). TAG are a potentially quantitatively important source of FA, given their high plasma concentration (≈ 10 x that of NEFA) and efficient and multiple uptake mechanisms; they may be the major cardiac fuel under physiological conditions (21, 25, 26, 38-40). Ketone bodies derived from the liver in catabolic states associated with TAG mobilisation and ketogenesis (e.g. starvation, diabetes) are also readily oxidized by the heart (8, 41-43). Amino acids (principally the branched chain amino acids) can be oxidized by the heart, although they are quantitatively less important than carbohydrates and lipids and relatively little is known of their metabolic significance and regulation (44-51)(Figure 1 ).
Hence, TAG, NEFA and glucose constitute the principal energy substrates for the healthy heart in vivo and this is partly a function of their availability (prevailing plasma concentrations), but also reflects myocardial preference.
One of the problems in studying cardiac metabolism is that much work has been performed on the isolated perfused heart with typically only one or two substrates (e.g. glucose and FA) present in the perfusate. Although this technique has important advantages, (e.g. workload can be defined and fixed, and the substrates and effectors prescribed), these studies do not address the complex milieu of multiple substrates and hormones/mediators to which the heart is exposed in vivo. Some recent studies have addressed this by examining multiple substrates in the form of stable isotopes using positron emission tomography in vivo (52).
3.1. Fetal cardiac metabolism
The fetal heart exhibits a pattern (program) of gene expression coding both metabolic and contractile proteins that differ from those seen in the adult heart - specific fetal isoforms of many contractile and metabolic enzymes and other proteins exist, reflecting the differing physiological status of the fetal heart. The fetal heart has a relatively low workload and, in addition, fetal plasma lipid levels are low (53), limiting FA availability (54, 55), and the PO2 is also relatively low (56). Probably for this reason, fetal myocardial metabolism relies principally on (anaerobic) glycolysis to provide ATP by substrate-level phosphorylation (56-61). Oxidative mitochondrial metabolism is mostly confined to lactate oxidation (62) with notably low rates of glucose and FA oxidation (61, 63). The fetal heart expresses the fetal form of myosin heavy chain (β-MHC), and the liver form of carnitine palmitoyl transferase-1 (lCPT-1) predominates over the muscle form (mCPT-1) (64, 65), hence malonyl-CoA sensitivity is high, with resulting limited FA β-oxidation (Figure 2).
3.2. Adult cardiac metabolism
Following birth and in the neonatal period, cardiac work increases, as do plasma lipids and arterial oxygen tension. The heart responds with a shift to an adult pattern of isoenzyme expression. A wide variety of metabolic and contractile protein adult isoforms are now expressed (66), including the adult form of myosin heavy chain (a -MHC) and the muscle form of CPT-1 (mCPT-1) together with decreased malonyl-CoA (14). The resulting metabolic profile is decreased glycolysis with increased glucose (pyruvate) oxidation, decreased lactate oxidation, and most notably, increased ketone body and FA oxidation (8, 58, 62, 63, 67, 68). In the adult heart under normal workload, FA oxidation accounts for about 60-70% of ATP synthesis, whilst glucose oxidation accounts for 25-35% of ATP synthesis, with the remainder derived from glycolysis. The relative contribution of NEFA and TAG-FA to myocardial FA utilisation in vivo is still uncertain (20, 21, 33), though LPL is very active in cardiac tissue and recent evidence suggests that TAG is a quantitatively important source of myocardial FA in vivo (26, 38, 39). Of the two forms of plasma TGRLP, CM, being larger, are better substrates for LPL and dietary TAG is likely an important source of myocardial FA (21). Increases in workload result in increased FA oxidation, but a striking finding is the accompanying increase in glycogen metabolism and pyruvate oxidation (69). Amino acid and ketone body utilisation and metabolism are low in the fed state, reflecting their limited plasma concentrations and hence availability.
Substrate selection by the healthy heart changes under varying physiological conditions, a reflection of the varying requirements as well as supply. Hence, when decreased plasma insulin levels lead to increased plasma NEFA concentrations during fasting, cardiac metabolism will shift away from glucose utilisation and towards FA oxidation (70, 71). The inverse relationship between glucose and FA utilisation was originally defined by Randle and co-workers (72) and is now termed the Randle cycle: increased FA utilisation inhibits glucose utilisation via increased acetyl-CoA and citrate levels inhibiting PDH, phosphofructokinase and GLUT - a classical glucose-sparing mechanism. The role of TAG in energy provision in either starvation (when CM are low, but VLDL still provides endogenously synthesised FA) or increased workload is not known. However, in the physiological state of lactation in the rodent, suppression of cardiac LPL redirects VLDL and CM TAG away from heart and towards assimilation by the lactating mammary gland for export as milk lipid (73); cardiac function is maintained despite increased cardiac output in this state, implying increased cardiac work and hence energy demand and altered myocardial substrate selection.
4. ENERGY METABOLISM IN HEART DISEASE
Alterations in cardiac metabolism may be categorised as maintaining or increasing cardiac functional efficiency ("adaptive" changes) or decreasing functional efficiency ("maladaptive" changes) (15, 16). Substrate selection and utilisation changes in the diseased heart in a characteristic way, and a key question is whether the cardiac disease process causes the change in substrate utilisation, or whether a change in cardiac metabolism is a primary etiological event and, if the change decreases cardiac efficiency, whether this leads to cardiac mechanical dysfunction (heart failure). The order of these two events is still unknown; it is likely however that, in some instances, a shift in metabolism is secondary to a primary cardiac disease process, whereas in other instances the change in substrate utilisation is the primary event, impacting on cardiac performance and leading to cardiac dysfunction. In the former case the change may be adaptive, serving to preserve cardiac function; in the latter case, a maladaptive change in substrate selection adversely affects cardiac pump function. Regardless of primacy, the relationship between cardiac metabolism and mechanical function is probably so intimate that the distinction becomes irrelevant.
The basis for the potentially beneficial or detrimental impact of substrate selection on cardiac performance hinges on the concept of metabolic efficiency. Cardiac efficiency may be expressed in several ways, including the ratio of external cardiac power to cardiac energy expenditure (2). As myocardial metabolism is predominantly (> 95%) oxidative, myocardial energy expenditure may be estimated from myocardial oxygen consumption. Because FAs are more reduced than carbohydrates, they yield more ATP per mol when oxidized (palmitate: 104 mol ATP/mol; glucose: 34 mol ATP/mol)(74) but this comes at a greater oxygen cost (P:O ratio; palmitate: 2.80 mol ATP/mol O2; glucose: 3.17 mol ATP/mol O2)(74-76). It is possible that the difference in vivo is even greater than this, partly due to the effect of mitochondrial uncoupling proteins (UCPs)(77). Hence, glucose can be regarded as a more "efficient" oxidative fuel than FA, at least in terms of oxygen consumption, and this may be critical in cardiac metabolism where oxygen supply through the coronary circulation is limited and precarious, and typically decreased in many cardiac diseases. Furthermore, whilst glucose metabolism is undoubtedly more flexible than FA metabolism, providing limited energy even anaerobically by glycolysis, the relationship between glycolysis and glucose oxidation may be critical in cardiac disease. Coupling of glucose (pyruvate) oxidation to glycolysis is thought to be necessary to prevent the generation of intracellular acidosis, although this mechanism has been challenged (78-80). Finally, glucose can be considered a more metabolically efficient fuel than FAs by virtue of its ability to replenish TCA cycle intermediates through anaplerosis (81-85), in contrast to cataplerotic (in the case of even chain carbon number) FAs and ketone bodies (43, 86).
4.1. Cardiac hypertrophy
Hypertrophy of the cardiac ventricle involves a structural remodelling of the cardiomyocyte (87) and may be an adaptive process to physiological stimuli (e.g. exercise), or maladaptive to diverse pathological stimuli, which may be categorised as pressure overload (causing concentric hypertrophy with ventricular wall thickening) and volume overload (causing eccentric hypertrophy and ultimately leading to ventricular dilatation) (88). The natural progression of both these maladaptive processes is towards cardiac failure (inability to maintain an adequate cardiac output). Pressure overloading with ventricular thickening leads principally to diastolic dysfunction, whereas volume overloading with ventricular dilatation leads mainly to systolic dysfunction; primary cardiac muscle disease tends to cause uncompensated wall stretch: idiopathic dilated cardiomyopathy. Adaptive (physiological) and maladaptive (pathological) states have different phenotypes, including the remodelling of metabolic profiles (88-94). Whilst adaptive physiological hypertrophy normalises wall stress and oxygen consumption, the changes in pathological hypertrophy ultimately lead to heart failure and an inability to cope with stress, including ischemia and reperfusion. Attempts have been made to relate observed changes in myocardial metabolism to changes in cardiac function: adaptive metabolic remodelling preserves cardiac function, whilst maladaptive metabolic remodelling compromises cardiac function and may be the trigger for progression to heart failure (95).
In physiological hypertrophy, increased long chain FA oxidation is observed, presumably a reflection of the increased workload (88, 93). However, glycolysis is decreased whilst glucose oxidation is increased, indicating more coupled glucose metabolism (88, 93, 96), an adaptation considered beneficial as glucose uncoupling increases cytosolic acidification (97) and disrupts sodium and calcium handling (see below)(2). Myocardial lactate oxidation is also increased in exercise/physiological hypertrophy: indeed, lactate may be oxidized preferentially to FAs (69, 98-104). The increase in long chain FA oxidation is mediated by increased peroxisome proliferator-activated receptor-α (PPARα) and PPAR-γ coactivator-1α (PGC-1α) activity. By contrast, changes occurring in pathological hypertrophy are variable and time-dependent, according to the conditions leading to the hypertrophy. These changes have been interpreted as initially adaptive, but eventually render the ventricle less able to cope with additional stress (e.g. ischemia-reperfusion) when they become maladaptive, as they may contribute to the disease process itself. The pattern of metabolic phenotype observed in pathological cardiac hypertrophy has been summarized as reverting to the fetal situation (105), with a recapitulation of the fetal metabolic gene expression program (66, 106). The patterns are similar, but not identical. Long chain FA oxidation is decreased (107-109) (though medium chain FA oxidation is unaffected (108, 110) - medium chain FAs do not require carnitine shuttling for transport into mitochondria); there is an early decrease in FA oxidation gene expression, but decreases in proteins of FA oxidation are only seen late in the disease progression, when heart failure supervenes (111). Decreased FA oxidation in hypertrophy can be interpreted as an adaptive mechanism because of the inherent inefficiency of FAs as substrates (see above); however, the (im)balance between glycolysis and glucose oxidation (glucose coupling) is likely to have a significant impact on resulting cardiac efficiency (91). Strikingly, there is increased glucose uptake and glycolysis, but unchanged or even decreased glucose oxidation (88, 91, 93, 107). Hence glucose metabolism is more uncoupled with potentially deleterious consequences (see below). Despite the inherent inefficiency of FA as energetic substrate, it is notable that primary (genetic) defects in FA oxidation result in hypertrophic cardiomyopathy (112-116). The decrease in FA oxidation enzymes in hypertrophy may be mediated by increased FA gene transcription repressors (e.g. the chicken ovalbumin upstream promoter transcription factor (COUP-TF), Sp1, Sp3)(106) together with decreased expression of PPARα and PGC-1α and potentially other transcription factors(66). A potential consequence of decreased FA oxidation is lipid accumulation within the cardiomyocyte, especially if FA supply and uptake is maintained or increased (and it is noteworthy that unlike the low plasma NEFA in the fetus, plasma NEFA concentrations are sometimes increased in cardiac failure) (117-119).
4.2. Cardiac failure
It has proved extremely difficult to categorize changes in myocardial metabolism with cardiac function in the development of heart failure (inability to maintain an adequate cardiac output; for review see (2, 8, 9, 120, 121). This is likely to be due to the variety of the multiple etiologies leading to the final outcome of cardiac failure; indeed, the distinction between hypertrophy and failure may be specious, as hypertrophy ultimately leads to failure, and many causes of failure (e.g. myocardial infarct) are associated with compensatory myocardial hypertrophy. Hence, the diversity of cardiac conditions leading to heart failure may be expected to be associated with diverse metabolic phenotypes and, within the limitations of the number of ways in which the heart is able to respond, this is found to be the case. Hence there are widely varying reports in the literature as to the characteristic changes in metabolism associated with heart failure, and the issue of whether heart failure leads to "metabolic failure" or, conversely, whether primary changes in metabolism are the primary cause of heart failure, remains uncertain.
Heart failure is associated with increased circulating NEFA (117-119), a reflection of the stimulation of the sympatho-adrenal axis in low cardiac output states with resultant increased catecholamine activity and hence increased adipose tissue lipolysis. NEFA availability is increased and, as FA availability regulates the rate of myocardial β-oxidation (122), increased FA utilisation would be anticipated; however, increased (117), decreased (107, 108, 123-128) and unchanged (129, 130) rates of FA uptake and oxidation have all been reported in human patients and animal models of heart failure, and these have largely been associated with reciprocal changes in glucose metabolism (see (2). The observed rates of FA utilisation/oxidation probably reflect prevailing plasma NEFA levels. Plasma ketone body concentrations will also be increased in heart failure if NEFA concentrations are high, and preferential cardiac utilisation of ketones may also influence (decrease) FA and glucose utilisation and metabolism (131). It is likely that, in early heart failure, changes in metabolism are modest, which may argue against altered metabolism as a primary cause of heart failure; however, in advanced disease there is a general decrease in all metabolic enzymes (132), with decreased myocardial capacity for β-oxidation (decreased PPARα activity (133, 134)), together with decreased mitochondrial function and capacity (10, 135-137) (probably as a result of decreased PGC-1α activity (138)) - despite increased plasma NEFA concentrations - leading to suggestions that heart failure causes disruption of the PPARα/RXR/PGC-1α nuclear transcription complex (139, 140). The defects in metabolism in heart failure, including decreased mitochondrial and electron transport chain capacity (i.e. decreased oxidative capacity) result in decreased ATP, increased ADP (decreased energy charge and phosphorylation potential) and decreased creatine phosphate (119, 141). These changes impact on energy-dependent mechanisms of contraction (excitation-contraction coupling through myosin-ATPase) and relaxation (sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a)). The decrease in FA oxidation in severe heart failure has been interpreted as an adaptive mechanism, based on the intrinsic inefficiency of FA as a metabolic fuel, and has led to a variety of strategies to decrease FA oxidation and/or increase glucose oxidation (increase glucose coupling) in the treatment of heart failure (2, 120, 142-148). These interventions include: 1. inhibitors of FA oxidation, including CPT-1 inhibitors (e.g. etomoxir, oxfenicine, perhexiline), partial β-oxidation inhibitors (e.g. trimetazidine, ranolazine), inhibitors of lipolysis and agents to lower plasma lipids (e.g. nicotinic acid, insulin, β-blockers, PPARγ agonists (e.g. thiazolidinediones) and PPARα agonists (e.g. fibrates) to stimulate extracardiac FA oxidation and hence decrease plasma lipids), and 2. direct stimulators of glucose oxidation such as dichloroacetate (DCA), which inhibits PDH kinase (PDK), increasing PDH activity. In general, these strategies have demonstrated that partially decreasing oxidation of energetically inefficient FAs, and stimulating pyruvate oxidation, hence increasing glucose coupling, improves cardiac contractile function, although results to date have been modest and inconsistent, and their role in the clinical management of heart failure in humans is relatively limited (149), with fatty acids remaining a vital energy resource (121).
GLUT1 and GLUT4 expression are both decreased in heart failure (105, 119, 150), implying decreased basal and insulin-stimulated glucose uptake, together with decreased PDH activity (151), but PDK4 is also decreased (105, 150) (a PPARα-dependent enzyme) which may account for the observed increase in glucose metabolism in advanced heart failure (125, 150); it is possible that glucose utilisation increases in response to decreased FA oxidative capacity, rather than as a primary mechanism. Therefore, it seems likely that decreases in enzymes of oxidative metabolism (including FA β-oxidation and electron transport chain complexes (136)) in heart failure result in increased reliance on glucose for energy (notably glycolysis) by the failing heart. One possible explanation for the reversion to a fetal pattern of metabolism in the hypertrophied and failing heart, with decreased oxidative metabolism and increased reliance on glycolysis, is the potentially unifying mechanism of hypoxia: the fetal heart is hypoxic (56) and its gene expression pattern and metabolic phenotype reflect this (58, 61, 105, 152, 153). The pathologically hypertrophied ventricle, with its thickened wall muscle and increased distance from epicardial coronary vascular supply to subendocardial regions increased, together with increased wall tension, may have critically limiting coronary blood flow especially in the subendocardial region, with resulting hypoxia, conditions that could also pertain to the dilated and thinned ventricular wall in the volume overload of late-stage cardiac failure. The resulting hypoxia would trigger reversion to a glycolytic energy economy, resulting in the observed increase in lactate production; such a mechanism may be mediated by induction of the oxygen-sensing transcription factor hypoxia-inducible factor (HIF). Physiological hypertrophy allows adequate neovascular growth, and hence adequate oxygen delivery is maintained to permit increased FA and glucose oxidation. The prevailing difference between fetal and adult hypertrophy/failure phenotypes would be the plasma NEFA concentration - low in the fetus and athletes, high in failure, which may account for some of the differences seen in physiological and pathological states.
4.3. Ischemia-reperfusion injury
Profound changes in substrate metabolism are also seen during ischemia and subsequent reperfusion (154), but again these are variable and highly condition-dependent. An acute fall in cardiac output, secondary to myocardial ischemia, activates the sympathoadrenal axis and hence adipose tissue lipolysis is activated, leading to a rise in plasma NEFA levels and FA availability (155); however, cardiac substrate utilisation will critically depend on coronary flow (156). Total ischemia results in increased glycolysis from endogenous glycogen stores and cessation of oxidative metabolism, with rapid onset of necrosis and cell death. However, partial ischemia, in which some limited coronary blood flow remains, is characterized by increased glycolysis, plus some preservation of pyruvate oxidation (albeit at a decreased rate) and hence uncoupling of glucose metabolism (157, 158) with intracellular lactate and proton production. FA oxidation is decreased at this time due to the relative lack of oxygen availability; this may account for an accumulation of FA intermediates (including fatty acyl-CoA)(159), leading to mitochondrial damage. On restoration of coronary flow (reperfusion), cellular energy-sensing mechanisms (such as 5'AMP-activated protein kinase (AMPK)(160), acting on acetyl-CoA carboxylase and malonyl-CoA decarboxylase to decrease malonyl-CoA levels; Figure 2) stimulate FA oxidation to excessively high rates (161-163), and AMPK inhibition may improve cardiac functional recovery on reperfusion (164). This may be further aggravated by increased LPL activity in reperfusion (165), although LPL activity has been reported to be decreased in ischemia (166). FAs, both as oxidative substrates and tissue lipid substrates, have consistently been found to impair cardiac function in reperfusion (167, 168); cardiac function correlates with phosphorylation potential, which is decreased in ischemia-reperfusion (169). The combination of uncoupled glucose metabolism (glycolysis > pyruvate oxidation) and an oxidative balance favoring FA oxidation over glucose oxidation in reperfusion (170) is energetically inefficient and also leads to intracellular acidification, which is suggested to be central to the abnormalities of Na+, and hence Ca2+, handling which result in intracellular calcium overload in these hearts (171), causing contractile dysfunction ("stone heart"), further mitochondrial damage, and apoptosis (see (2)). Again, the balance between glycolysis, pyruvate oxidation, and FA oxidation, is critical to cardiac function and outcome.
4.4. Unloading
The structural and metabolic changes observed in cardiac hypertrophy, and the ultimate progression of hypertrophy to heart failure, have been termed "ventricular remodelling" and have obvious clinical importance (172, 173). Recently, the phenomenon of "reverse ventricular remodelling" in the unloaded myocardium has attracted considerable interest (174). The prevalence of heart failure has prompted the development of mechanical "ventricular assist" devices in clinical practice that pump blood in parallel with the native heart, resulting in pressure and volume unloading of the failing ventricle (175). This intervention was conceived as a "bridge to transplant" for cardiac failure patients awaiting heart transplant, but it became clear that partial recovery of cardiac function occurred following explantation of devices in some patients (176), a surprising finding given that the structural and functional changes observed in cardiac failure were thought to be irreversible (177). Clinically, this has led to the concept of ventricular assist devices as bridges to recovery, but has also prompted considerable research interest in the structural and metabolic changes that occur in the unloaded myocardium (178).
The changes seen may be categorised as structural (trophic), cellular, metabolic/molecular and, ultimately functional (177, 178). Although the changes may be considered atrophic in nature (179, 180), recovery of function suggests alternative mechanisms. The changes are multifaceted and complex, but a striking feature is a partial reversion to the fetal gene expression program (64, 65, 181-183). In unloading, fetal isoforms of contractile proteins (e.g. MHCa to MHCβ) and metabolic enzymes (e.g. GLUT4 to GLUT1; mCPT-1 to lCPT-1) are re-expressed, together with enhanced expression of characteristically fetal growth factors (e.g. transforming growth factor-β (TGFβ), insulin-like growth factor-1 (IGF-1), fibroblast growth factor-2 (FGF-2) and proto-oncogenes (e.g. c-fos) (64, 65, 184). In addition, calcium handling machinery (SERCA2a, ryanodine receptor (RyR), Na+/Ca2+ exchanger (NCX))(185) and calcium transients (177, 186-188) improve; these changes are associated with improved contractile function. Furthermore, hypertrophy of failing hearts regresses (186). The observation that re-expression of a fetal pattern of components of energy metabolism precedes changes of MHC and trophic factors has led to the concept that the changes may be primarily related to energy provision. This would complement the situation in heart failure, where there is a general decrease in components of energy release, suggesting energy "starvation" itself leads to contractile dysfunction (10, 110, 189). Expression of fetal isoforms of metabolic enzymes, and hence patterns of metabolism (i.e. reversion to a glucose-based energy supply) may indicate that the metabolic strategy in this state is concerned with energy sparing rather than contractile efficiency (64) (though see comments on relative efficiencies of glucose and FA utilisation); furthermore, a particularly striking observation is that a similar recapitulation to the fetal pattern of metabolism seen in unloading also occurs in pressure-overload hypertrophy - the opposite extremes of cardiac workload and trophic response, yet having a similar metabolic transcriptional profile and phenotype, together with similar signalling mechanisms (179). Whilst this may simply reflect the limited ways in which the myocardium can respond to "stress", a teleological explanation would suggest a concerted molecular mechanism to spare energy, rather than optimise contractile efficiency (64). Hence the changes in metabolism seen in both hypertrophy and unloading are adaptive in nature; however, one major difference between the two conditions is that unloading does not progress beyond a limited state (atrophy) whereas hypertrophy will eventually progress to heart failure. In this case, there is down regulation of all metabolic machinery (see, e.g. (2, 8, 120, 173, 183, 189) resulting in inadequate energy supply (energy starvation), culminating in loss of contractile function (132, 190).
Whilst the underlying signalling mechanisms responsible for the rapid change to fetal isoenzyme gene expression are still being investigated, it has become clear that downregulation of PPARα expression mediates at least some of the changes, both in relation to lipid and glucose metabolism (179, 183, 191): there is simultaneously decreased expression of many PPARα-regulated metabolic components, including medium chain acyl-CoA dehydrogenase (MCAD), uncoupling protein-3 (UCP3) and PDK4 (184), a mechanism likely mediated by the transcription factor NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells). Hence, both increased and decreased cardiac work increase glucose and decrease FA utilisation, likely to have been orchestrated by the decreased PPARα occurring in hypertrophy and unloading, with decreased PDK4, MCAD and UCP3 protein expression. The central importance of PPARα in orchestrating these changes, and their adaptive nature, is emphasised by the severe contractile dysfunction which results following reactivation of PPARα in hypertrophy (192).
Not all the changes seen in unloading have been interpreted as beneficial - the issue of atrophy with decreased contractile reserve has been raised (180, 183, 193), together with controversy regarding cellular calcium regulation and increased myocardial collagen and fibrosis (178, 194). However, progression to full fibrosis does not occur, and the changes in protein metabolism reported (increased protein synthesis and simultaneously increased protein degradation, based on mammalian target of rapamycin (mTOR) and ubiquitin proteosome proteolysis (UPP) levels)(195, 196) suggest an active remodelling process, dissimilar in nature to the true atrophy seen in skeletal muscle denervation (decreased mTOR and increased UPP)(196).
Increased caveolin expression occurs in unloading and is associated with increased CD36/FAT expression (197) and, while this latter finding seems unexpected in the context of decreased FA oxidation, it may contribute to improved lipid metabolism; it may also improve cardiomyocyte insulin sensitivity: CD36-/- knockout hearts are insulin-resistant and develop hypertrophic cardiomyopathy (197). This is a particularly striking finding, given the putative relationship between caveolins and integrins (caveolin-1 is involved in integrin signalling). In turn, integrins may form the basis of mechanoreception, sensing contraction through the extracellular matrix. The relationship between cardiac contraction and insulin sensitivity is also suggested by the finding that myocardial glycogen levels are increased in unloading, together with decreased active glycogen synthase (GS-I), slower glycogen synthesis and less activation of GS by infused insulin (198) - contraction is required to maintain insulin responsiveness. Some investigators have reported unchanged levels of cardiac glycogen in unloading (182), but their finding of decreased active GS is consistent, and therefore also argues for the importance of contraction, and myocardial glycogen levels, in cardiac insulin sensitivity (182, 199). The shift from GLUT4 (insulin sensitive; decreased) to GLUT1 (constitutive; increased) expression in unloading also results in a loss of insulin responsiveness in this state.
Besides the observed relationship between FA oxidation rate and contractile function in unloaded (as well as pressure overloaded) hearts ex vivo (182), the importance of lipid metabolism in cardiac function is also demonstrated by the finding of increased cardiolipin levels in unloaded hearts, a finding associated with improved mitochondrial function in these hearts (200); this may also account for the observed decrease in apoptosis in unloaded hearts compared to the increased apoptosis which is considered a central feature of heart failure (178) - although Bugger et al (180) report atrophy and decreased electron transport chain complexes 1 and 2, and decreased state 3 respiration in 8 day unloaded rat hearts. Glucose metabolism is also linked to cell survival (199).
4.5. Diabetes
Diabetes mellitus is the classic metabolic disease and, as such, would be expected to involve changes in substrate metabolism in many tissues, including heart, which has consistently been found to occur in both type 1 (insulin-deficient) and type 2 (insulin-resistant) diabetes. The observation that cardiac contractile function may be decreased in this disease ("diabetic cardiomyopathy") in the absence of associated coronary vascular or hypertensive disease (201-203) has stimulated a large effort to define the underlying mechanism (203-209). Whilst decreased mitochondrial function, impaired calcium signalling and dysfunctional contractile machinery have all been described in the diabetic myocardium (210-212), it is possible that there is a central role for altered metabolism in diabetic cardiac dysfunction, which has led to the suggestion that the etiology may be primarily based on the changes in substrate flux and cardiac utilisation that characteristically occur.
Although plasma insulin levels vary in diabetes (decreased in type 1 diabetes, increased early, but decreased late, in type 2 diabetes), as do blood glucose levels (increased in type 1 diabetes, normal in early, but increased in late type 2 diabetes), changes in plasma lipids are more consistent. Diabetic dyslipidemia is characterised by increased plasma NEFA levels (mainly a result of increased adipose tissue lipolysis secondary to decreased insulin action in this tissue)(213-215) and hypertriglyceridemia (increased plasma VLDL levels)(214, 216-218). Increased VLDL is due to increased hepatic production (219, 220), and also decreased uptake by certain tissues (220), a consequence of tissue-specific changes in LPL activity in diabetes (221), but also a result of the abnormal composition of TGRLP in diabetes (220, 222). The complex pattern of prevailing substrate availability (glucose, NEFA, TAG, ketone bodies) together with changes in hormonal milieu (insulin, leptin) in vivo make studying cardiac substrate utilisation by the diabetic heart, and relating this to cardiac mechanical function, problematic, and caution must be applied when interpreting studies that have examined diabetic cardiac metabolism ex vivo. This is especially true when considering the role of other quantitatively important substrates in diabetes, such as ketone bodies (and amino acids). Furthermore, it has proved difficult to assess the degree of insulin sensitivity/resistance in the heart compared to other tissues (e.g. skeletal muscle)(119, 121, 223-228). However, a consensus pattern of changes in cardiac metabolism in the diabetic heart has emerged.
Diabetic heart may be characterised as having increased reliance on FA as energetic substrate; ex vivo studies have indicated that, when perfused with glucose and FA, FA oxidation accounts for > 90% of ATP generation (see (2, 207, 229-233)). Some dissenting studies have failed to demonstrate this effect (234, 235), but most studies in both insulin-deficient and insulin-resistant diabetes show increased FA oxidation. Furthermore, this increased FA utilisation and oxidation by the diabetic heart is associated with decreased cardiac efficiency (the relationship between contractile power and myocardial oxygen consumption)(231, 236), which may provide a mechanistic basis for diabetic cardiomyopathy. The decreased efficiency is only partly accounted for by the fact that FAs are more reduced than carbohydrates and therefore require more oxygen for complete oxidation; increased FA utilisation also results in increased ATP hydrolysis for non-contractile purposes (237) (including mitochondrial uncoupling of oxidative phosphorylation and increased substrate cycling(2)).The driving force behind this effect is likely the increased plasma NEFA perfusing the heart from increased adipose tissue lipolysis: FA availability determines FA utilisation (including regulation of β-oxidation)(122). However, increased NEFA levels also stimulate cardiac PPARa (238-242), resulting in up-regulation of lipid metabolising pathways (including FA transport proteins, β-oxidation components, and mitochondrial uncoupling proteins). Indeed, it is striking that PPARa -overexpressing mice have a phenotype very similar to diabetes (36, 203, 207, 243, 244). Inhibition of glucose utilisation and pyruvate oxidation by increased FA oxidation, a mechanism based on the Randle cycle, also contributes to dysregulation and decreased efficiency in these hearts in diabetes; the importance of glucose metabolism to metabolic efficiency via anaplerotic reactions has been demonstrated (81, 82, 85, 245, 246).
In addition, it is found that diabetes is accompanied by increased PGC-1a levels (138, 243, 247), a co-activator of PPARa , strongly suggesting upregulation of FA utilising mechanisms and accounting for the (generally) observed increase in cardiac FA utilisation in this state. The reciprocal nature of glucose and FA oxidation in hypertrophy and diabetes is emphasised by the finding that PGC-1a is downregulated in hypertrophy (66, 138), coincidentally with the decreased lipid (and increased glucose) utilisation, compared with the opposite pattern in diabetes, suggesting a role for PGC-1a as a central energy regulator (248-251).
Furthermore, the increased cardiac FA uptake seen in diabetes is also associated with increased accumulation of intracellular lipids (205, 207, 252-256). Since cardiomyocytes are not specialised to store lipid, this finding suggests a deleterious effect, and cellular lipid overloading underlies the concept of "lipotoxicity" as a potential mechanism for impaired cardiac function (36, 257-259). The importance of the cellular lipid (TAG) pool was highlighted by studies by Saddik et al (37, 254, 260), who demonstrated the dynamic nature of this intracellular pool. The disjunction between increased FA uptake and increased cellular lipid deposition, despite increased FA oxidation, has led to controversy regarding the importance of the balance between uptake and disposal (oxidation) in determining cardiac lipid accumulation; for example, PPARa downregulation leading to decreased FA oxidation, and hence decreased intracellular FA disposal, in some rat studies has been proposed as a mechanism leading to cellular lipid accumulation in diabetes (16, 235).
Whilst some FA provision appears essential for normal cardiac function (261), excess FA utilisation clearly has the capacity to be deleterious to cardiac function (256, 262). It is unlikely that TAG itself is cytotoxic, but some other intracellular FA derivative, increased in hyperlipidemic conditions, including (but not limited to) diabetes, may be responsible for the observed impaired cell function. One suggestion is fatty acyl-CoA (205, 263-265), and in this respect it is noteworthy that mitochondrial uncoupling proteins (increased in diabetes (229)) have been suggested as mechanisms to transport FA anions, via activity of mitochondrial thioesterase-1, to replenish intramitochondrial coenzyme-A (266-268). Another suggestion is that sphingolipid derivatives may be involved: excess FA leads to increased ceramide levels (269, 270), causing increased apoptosis with subsequent impairment of cardiac function, an effect observed in the diabetic heart (258, 259, 271). By contrast, FAs may exert protective effects on the diabetic myocardium: although the diabetic myocardium is more susceptible to ischemia-reperfusion injury than healthy hearts (272), FAs are protective during low-flow ischemia (273).
The role of TAG in cardiac energy provision and (dys)function in diabetes has been difficult to define (274, 275), partly because of the conflicting results in animal models and uncertainty regarding the regulation of cardiac LPL activity, and partly because the physiological role of TGRLP in energy provision in the healthy heart is still uncertain (Figure 1)(21, 34). Increased (276-282), unchanged (22, 283-286) and decreased (280, 282, 287-292) myocardial LPL activity have all been reported in response to diabetes or nutritional manipulations that alter insulin; these results reflect the complex nature of LPL biology (27, 29). That TAG is a major cardiac fuel (24, 34) and LPL is essential for heart function are demonstrated by the loss of cardiac function observed in heart-specific LPL knockouts (26, 38, 39) - NEFA cannot replace TAG-derived FA in vivo (despite increased glucose utilisation (39)); its importance is emphasised by the fact that hearts overexpressing LPL accumulate cellular lipid and show mechanical dysfunction (256, 293). Furthermore the importance of cardiac LPL for whole body TAG metabolism (and the quantitative importance of heart LPL as a TAG "sink" (38, 40, 294)) is demonstrated by the finding that heart LPL rescue in LPL-/- knockout mice normalises plasma TAG concentration (38, 294). However, on the balance of published studies, the current consensus view is that fasting and diabetes increase heart LPL activity (i.e. the opposite effect to that seen in white adipose tissue) (28, 29) although this effect is modest. Increased cardiac LPL activity in diabetes would account in part for the lipotoxicity and cardiomyopathy seen in the diabetic heart (22, 29, 229, 295, 296), although this is difficult to reconcile with the hypertriglyceridemia that is characteristic of the diabetic state. It is possible that CM-TAG, but not VLDL-TAG, utilisation is increased in diabetic hearts (22) (since CM are a better substrate for LPL than VLDL) and compositional changes to CM in diabetes may enhance this effect. However, VLDL, and in particular diabetic VLDL, is a relatively poor substrate for cardiac LPL (219) and undergoes significant compositional change in diabetes (220, 222, 274, 297, 298). Recent evidence that AMPK regulates cardiac LPL may provide a clue as to the (dys)regulation of cardiac LPL in diabetes (and other disease states) - it is possible that PPARα provides "chronic" regulation of cardiac LPL activity (and TAG-FA derived from cardiac LPL is known to act as a PPARα ligand (299-301)), whilst AMPK acts to regulate the enzyme acutely (278, 302, 303). However, AMPK inhibition by siRNA does not decrease LPL protein or activity (304). A further mechanism likely to be involved in cardiac TAG metabolism is lipoprotein receptor-mediated uptake. Several lipoprotein receptors have been implicated in cardiac FA uptake, including the apo-E-binding VLDL receptor (VLDL-R)(31) and the apo-B-binding TGRLP receptor (305). These receptors provide the cell with cholesterol, but also account for significant bulk uptake of TAG-FA, both by particle and remnant uptake and by selective core uptake (34, 35), and it is possible that FA assimilated by this route is differentially channelled between tissue deposition and oxidation (35). Indeed, evidence suggests that LPL-derived FAs also enter a different intracellular metabolic pool (and may enter the cell through distinct FA transporters) than NEFA (35), although it is striking that both LPL and CD36/FAT seems to be similarly regulated (including by AMPK, PPARα and insulin). The putative role of muscle contraction in LPL expression, stimulating CD36/FAT (306), remains to be elucidated. Intracellular channelling may direct FA from different sources (NEFA; LPL; lipoprotein receptors) to different metabolic fates, and this may account for some aspects of myocellular lipid accumulation and subsequent lipotoxic cardiomyopathy. Besides hydrolysis of TGRLP, LPL has an important "bridging" function, facilitating TGRLP-lipoprotein receptor binding (307, 308); the effect of diabetes on this process is not known. However, VLDL-R is downregulated in STZ-treated (insulin-deficient) rats (309); VLDL-R is involved in LPL transcytosis from parenchymal cells to the active site on the endothelium (310, 311). LPL is also regulated by angiopoietin-like protein-4 (angPTL-4; an LPL inhibitor)(312) but again the significance of this in diabetes is uncertain. Stress does upregulate cardiac LPL (313), and this may be related to glucocorticoid secretion (314) although catecholamines do not directly alter the activity of cardiac LPL in vivo (315) or in vitro (316).
Whilst the issue of insulin sensitivity/resistance in diabetic cardiomyocytes remains controversial, with rat studies generally suggesting myocardial insulin resistance in type 2 diabetes (227, 228, 317) but human studies demonstrating little or no cardiac insulin resistance in this condition (318), it is apparent that glucose oxidation is decreased in the diabetic myocardium, despite high glucose exposure (319, 320). This may be a reflection of the decreased GLUT4 expression seen in these hearts (321). The issue of insulin sensitivity is central to the resulting cardiac metabolic phenotype. Type 1 (insulin-deficient) diabetic hearts retain insulin sensitivity and hence the ability to switch metabolic substrates ("metabolic flexibility"): the prevailing high lipid (NEFA; TAG) concentrations, together with PPAR-stimulated lipid metabolic pathways (LPL, CD36/FAT, fatty acyl-CoA synthetase (FACS), MCAD, UCP &c.), and downregulated glucose utilising machinery (322), ensure that the resulting metabolism is principally lipid based, with lipotoxicity if FA uptake pathways exceed FA oxidation/uncoupling mechanisms. Metabolic flexibility is however maintained - these hearts are capable of increasing glucose utilisation (228). Type 2 diabetic hearts, however, demonstrate metabolic inflexibility in vivo (227), which may represent insulin resistance in the cardiomyocyte itself. The issue of insulin resistance in the diabetic heart remains controversial however - cardiomyocytes, but not hearts, isolated from db/db diabetic mice are insulin sensitive in vitro. Again, the importance and complexity of the hormone and substrate milieu in vivo demands cautious interpretation of ex vivo data.
5. PERSPECTIVE
Significant advances have been made in characterizing energetic substrate utilisation by the heart in both health and disease, and in defining the regulatory mechanisms controlling substrate selection by the myocardium under varying pathophysiological conditions. The importance of multiple levels of regulation, from substrate supply to the regulation of transcription of substrate transport components and metabolic enzymes is now apparent, together with the fact that they change profoundly in heart disease. However, the fundamental question of whether cardiac pathology causes changes in myocardial metabolism, or whether a primary alteration in substrate utilisation is responsible for cardiac dysfunction, remains uncertain. Regardless of this, the ability to manipulate cardiac metabolism is a promising therapeutic intervention.
6. ACKNOWLEDGEMENTS
We are grateful to the British Heart Foundation for support.
7. REFERENCES
1. G. D. Lopaschuk, D. D. Belke, J. Gamble, T. Itoi and B. O. Schonekess: Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochimica et Biophysica Acta, 1213(3), 263-76 (1994)
PMid:8049240
2. G. D. Lopaschuk, J. R. Ussher, C. D. L. Folmes, J. S. Jaswal and W. C. Stanley: Myocardial fatty acid metabolism in health and disease. Physiological Reviews, 90(1), 207-58 (2010)
doi:10.1152/physrev.00015.2009
PMid:20086077
3. L. H. Opie: Metabolism of the heart in health and disease. I. American Heart Journal, 76(5), 685-98 (1968)
doi:10.1016/0002-8703(68)90168-3
4. L. H. Opie: Metabolism of the heart in health and disease. II. American Heart Journal, 77(1), 100-22 contd (1969)
5. J. R. Neely and H. E. Morgan: Relationship between carbohydrate and lipid metabolism and the energy balance of heart muscle. Annual Review of Physiology, 36, 413-59 (1974)
doi:10.1146/annurev.ph.36.030174.002213
PMid:19400669
6. W. C. Stanley, G. D. Lopaschuk, J. L. Hall and J. G. McCormack: Regulation of myocardial carbohydrate metabolism under normal and ischaemic conditions. Potential for pharmacological interventions. Cardiovascular Research, 33(2), 243-57 (1997)
doi:10.1016/S0008-6363(96)00245-3
7. G. J. van der Vusse, J. F. Glatz, H. C. Stam and R. S. Reneman: Fatty acid homeostasis in the normoxic and ischemic heart. Physiological Reviews, 72(4), 881-940 (1992)
PMid:1438581
8. W. C. Stanley, F. A. Recchia and G. D. Lopaschuk: Myocardial substrate metabolism in the normal and failing heart. Physiological Reviews, 85(3), 1093-129 (2005)
doi:10.1152/physrev.00006.2004
PMid:15987803
9. R. Ventura-Clapier, A. Garnier and V. Veksler: Energy metabolism in heart failure. Journal of Physiology, 555(Pt 1), 1-13 (2004)
PMid:14660709 PMCid:1664831
10. S. Neubauer: The failing heart--an engine out of fuel. New England Journal of Medicine, 356(11), 1140-51 (2007)
doi:10.1056/NEJMra063052
PMid:17360992
11. J. A. Wisneski, E. W. Gertz, R. A. Neese, L. D. Gruenke, D. L. Morris and J. C. Craig: Metabolic fate of extracted glucose in normal human myocardium. Journal of Clinical Investigation, 76(5), 1819-27 (1985)
doi:10.1172/JCI112174
PMid:4056055 PMCid:424216
12. J. A. Wisneski, W. C. Stanley, R. A. Neese and E. W. Gertz: Effects of acute hyperglycemia on myocardial glycolytic activity in humans. Journal of Clinical Investigation, 85(5), 1648-56 (1990)
doi:10.1172/JCI114616
PMid:2185277 PMCid:296617
13. H. Taegtmeyer, M. E. Harinstein and M. Gheorghiade: More than bricks and mortar: comments on protein and amino acid metabolism in the heart. American Journal of Cardiology, 101(11A), 3E-7E (2008)
doi:10.1016/j.amjcard.2008.02.064
PMid:18514624
14. H. Taegtmeyer, C. R. Wilson, P. Razeghi and S. Sharma: Metabolic energetics and genetics in the heart. Annals of the New York Academy of Sciences, 1047, 208-18 (2005)
doi:10.1196/annals.1341.019
PMid:16093498
15. H. Taegtmeyer, P. McNulty and M. E. Young: Adaptation and maladaptation of the heart in diabetes: Part I: general concepts. Circulation, 105(14), 1727-33 (2002)
doi:10.1161/01.CIR.0000012466.50373.E8
PMid:11940554
16. M. E. Young, P. McNulty and H. Taegtmeyer: Adaptation and maladaptation of the heart in diabetes: Part II: potential mechanisms. Circulation, 105(15), 1861-70 (2002)
doi:10.1161/01.CIR.0000012467.61045.87
PMid:11956132
17. B. A. Cason, J. A. Wisneski, R. A. Neese, W. C. Stanley, R. F. Hickey, C. B. Shnier and E. W. Gertz: Effects of high arterial oxygen tension on function, blood flow distribution, and metabolism in ischemic myocardium. Circulation, 85(2), 828-38 (1992)
PMid:1735173
18. G. J. van der Vusse, M. van Bilsen, J. F. Glatz, D. M. Hasselbaink and J. J. Luiken: Critical steps in cellular fatty acid uptake and utilization. Molecular & Cellular Biochemistry, 239(1-2), 9-15 (2002)
doi:10.1023/A:1020538119691
PMid:12479563
19. A. Bonen, A. Chabowski, J. J. Luiken and J. F. Glatz: Is membrane transport of FFA mediated by lipid, protein, or both? Mechanisms and regulation of protein-mediated cellular fatty acid uptake: molecular, biochemical, and physiological evidence.(comment). Physiology, 22, 15-29 (2007)
20. G. J. van der Vusse, M. van Bilsen and J. F. Glatz: Cardiac fatty acid uptake and transport in health and disease. Cardiovascular Research, 45(2), 279-93 (2000)
doi:10.1016/S0008-6363(99)00263-1
21. D. Hauton, M. J. Bennett and R. D. Evans: Utilisation of triacylglycerol and non-esterified fatty acid by the working rat heart: myocardial lipid substrate preference. Biochimica et Biophysica Acta, 1533(2), 99-109 (2001)
PMid:11566447
22. A. S. Neitzel, A. N. Carley and D. L. Severson: Chylomicron and palmitate metabolism by perfused hearts from diabetic mice. American Journal of Physiology - Endocrinology & Metabolism, 284(2), E357-65 (2003)
23. N. Sambandam, M. A. Abrahani, S. Craig, O. Al-Atar, E. Jeon and B. Rodrigues: Metabolism of VLDL is increased in streptozotocin-induced diabetic rat hearts. American Journal of Physiology - Heart & Circulatory Physiology, 278(6), H1874-82 (2000)
24. A. S. Augustus, Y. Kako, H. Yagyu and I. J. Goldberg: Routes of FA delivery to cardiac muscle: modulation of lipoprotein lipolysis alters uptake of TG-derived FA. American Journal of Physiology - Endocrinology & Metabolism, 284(2), E331-9 (2003)
25. H.-L. Noh, H. Yamashita and I. J. Goldberg: Cardiac metabolism and mechanics are altered by genetic loss of lipoprotein triglyceride lipolysis. Cardiovascular Drugs & Therapy, 20(6), 441-4 (2006)
doi:10.1007/s10557-006-0633-1
PMid:17139480
26. J. Lee and I. J. Goldberg: Lipoprotein lipase-derived fatty acids: physiology and dysfunction. Current Hypertension Reports, 9(6), 462-6 (2007)
doi:10.1007/s11906-007-0085-4
PMid:18367009
27. M. Merkel, R. H. Eckel and I. J. Goldberg: Lipoprotein lipase: genetics, lipid uptake, and regulation. Journal of Lipid Research, 43(12), 1997-2006 (2002)
doi:10.1194/jlr.R200015-JLR200
28. H. Wang and R. H. Eckel: Lipoprotein lipase: from gene to obesity. American Journal of Physiology - Endocrinology & Metabolism, 297(2), E271-88 (2009)
doi:10.1152/ajpendo.90920.2008
PMid:19318514
29. T. Pulinilkunnil and B. Rodrigues: Cardiac lipoprotein lipase: metabolic basis for diabetic heart disease. Cardiovascular Research, 69(2), 329-40 (2006)
doi:10.1016/j.cardiores.2005.09.017
PMid:16307734
30. I. J. Goldberg and M. Merkel: Lipoprotein lipase: physiology, biochemistry, and molecular biology. Frontiers in Bioscience, 6, D388-405 (2001)
doi:10.2741/Goldberg
PMid:11229871
31. S. Takahashi, J. Sakai, T. Fujino, H. Hattori, Y. Zenimaru, J. Suzuki, I. Miyamori and T. T. Yamamoto: The very low-density lipoprotein (VLDL) receptor: characterization and functions as a peripheral lipoprotein receptor. Journal of Atherosclerosis & Thrombosis, 11(4), 200-8 (2004)
PMid:15356379
32. S. Takahashi, J. Sakai, T. Fujino, I. Miyamori and T. T. Yamamoto: The very low density lipoprotein (VLDL) receptor--a peripheral lipoprotein receptor for remnant lipoproteins into fatty acid active tissues. Molecular & Cellular Biochemistry, 248(1-2), 121-7 (2003)
doi:10.1023/A:1024184201941
PMid:12870663
33. B. Teusink, P. J. Voshol, V. E. Dahlmans, P. C. Rensen, H. Pijl, J. A. Romijn and L. M. Havekes: Contribution of fatty acids released from lipolysis of plasma triglycerides to total plasma fatty acid flux and tissue-specific fatty acid uptake. Diabetes, 52(3), 614-20 (2003)
doi:10.2337/diabetes.52.3.614
PMid:12606500
34. I. J. Goldberg, R. H. Eckel and N. A. Abumrad: Regulation of fatty acid uptake into tissues: lipoprotein lipase- and CD36-mediated pathways. Journal of Lipid Research, 50 Suppl, S86-90 (2009)
doi:10.1194/jlr.R800085-JLR200
PMid:19033209 PMCid:2674753
35. Y. G. Niu, D. Hauton and R. D. Evans: Utilization of triacylglycerol-rich lipoproteins by the working rat heart: routes of uptake and metabolic fates. Journal of Physiology, 558(Pt 1), 225-37 (2004)
doi:10.1113/jphysiol.2004.061473
PMid:15121801 PMCid:1664916
36. T. S. Park, H. Yamashita, W. S. Blaner and I. J. Goldberg: Lipids in the heart: a source of fuel and a source of toxins. Current Opinion in Lipidology, 18(3), 277-82 (2007)
doi:10.1097/MOL.0b013e32814a57db
PMid:17495601
37. M. Saddik and G. D. Lopaschuk: Myocardial triglyceride turnover and contribution to energy substrate utilization in isolated working rat hearts. Journal of Biological Chemistry, 266(13), 8162-70 (1991)
PMid:1902472
38. H. L. Noh, K. Okajima, J. D. Molkentin, S. Homma and I. J. Goldberg: Acute lipoprotein lipase deletion in adult mice leads to dyslipidemia and cardiac dysfunction. American Journal of Physiology - Endocrinology & Metabolism, 291(4), E755-60 (2006)
doi:10.1152/ajpendo.00111.2006
PMid:16684851
39. A. S. Augustus, J. Buchanan, T. S. Park, K. Hirata, H. L. Noh, J. Sun, S. Homma, J. D'Armiento, E. D. Abel and I. J. Goldberg: Loss of lipoprotein lipase-derived fatty acids leads to increased cardiac glucose metabolism and heart dysfunction. Journal of Biological Chemistry, 281(13), 8716-23 (2006)
doi:10.1074/jbc.M509890200
PMid:16410253
40. A. Augustus, H. Yagyu, G. Haemmerle, A. Bensadoun, R. K. Vikramadithyan, S. Y. Park, J. K. Kim, R. Zechner and I. J. Goldberg: Cardiac-specific knock-out of lipoprotein lipase alters plasma lipoprotein triglyceride metabolism and cardiac gene expression. Journal of Biological Chemistry, 279(24), 25050-7 (2004)
doi:10.1074/jbc.M401028200
PMid:15028738
41. R. G. Forsey, K. Reid and J. T. Brosnan: Competition between fatty acids and carbohydrate or ketone bodies as metabolic fuels for the isolated perfused heart. Canadian Journal of Physiology & Pharmacology, 65(3), 401-6 (1987)
PMid:3107785
42. D. M. Hasselbaink, J. F. Glatz, J. J. Luiken, T. H. Roemen and G. J. Van der Vusse: Ketone bodies disturb fatty acid handling in isolated cardiomyocytes derived from control and diabetic rats. Biochemical Journal, 371(Pt 3), 753-60 (2003)
doi:10.1042/BJ20021617
PMid:12489982 PMCid:1223317
43. H. Taegtmeyer, R. Hems and H. A. Krebs: Utilization of energy-providing substrates in the isolated working rat heart. Biochemical Journal, 186(3), 701-11 (1980)
PMid:6994712 PMCid:1161705
44. M. G. Buse, J. F. Biggers, C. Drier and J. F. Buse: The effect of epinephrine, glucagon, and the nutritional state on the oxidation of branched chain amino acids and pyruvate by isolated hearts and diaphragms of the rat. Journal of Biological Chemistry, 248(2), 697-706 (1973)
PMid:4684697
45. M. L. Brennan and S. L. Hazen: Amino acid and protein oxidation in cardiovascular disease. Amino Acids, 25(3-4), 365-74 (2003)
doi:10.1007/s00726-003-0023-y
PMid:14661097
46. F. L. Shinnick and A. E. Harper: Branched-chain amino acid oxidation by isolated rat tissue preparations. Biochimica et Biophysica Acta, 437(2), 477-86 (1976)
PMid:952929
47. M. E. Tischler and H. Cammisa: Metabolism of protein, amino acids, and glucose and their response to insulin in atria and cardiac myocytes of traumatized rats. Metabolism: Clinical & Experimental, 33(6), 515-20 (1984)
doi:10.1016/0026-0495(84)90005-2
48. J. Letto, J. T. Brosnan and M. E. Brosnan: Oxidation of 2-oxoisocaproate and 2-oxoisovalerate by the perfused rat heart. Interactions with fatty acid oxidation. Biochemistry & Cell Biology, 68(1), 260-5 (1990)
doi:10.1139/o90-036
PMid:2112400
49. C. Carson and G. V. Vahouny: Myocardial metabolism. V. Effect of puromycin on protein synthesis and oxidation of glucose, acetate, and aspartate in perfused rat hearts. Proceedings of the Society for Experimental Biology & Medicine, 132(1), 287-92 (1969)
PMid:5344848
50. I. F. Kodde, J. van der Stok, R. T. Smolenski and J. W. de Jong: Metabolic and genetic regulation of cardiac energy substrate preference. Comparative Biochemistry & Physiology. Part A, Molecular & Integrative Physiology, 146(1), 26-39 (2007)
doi:10.1016/j.cbpa.2006.09.014
51. H. Tapiero, G. Mathe, P. Couvreur and K. D. Tew: I. Arginine. Biomedicine & Pharmacotherapy, 56(9), 439-45 (2002)
doi:10.1016/S0753-3322(02)00284-6
52. S. L. Menard, E. Croteau, O. Sarrhini, R. Gelinas, P. Brassard, R. Ouellet, M. Bentourkia, J. E. van Lier, C. Des Rosiers, R. Lecomte and A. C. Carpentier: Abnormal in vivo myocardial energy substrate uptake in diet-induced type 2 diabetic cardiomyopathy in rats. American Journal of Physiology - Endocrinology & Metabolism, 298(5), E1049-57 (2010)
doi:10.1152/ajpendo.00560.2009
PMid:20159856
53. J. Girard, P. Ferre, J. P. Pegorier and P. H. Duee: Adaptations of glucose and fatty acid metabolism during perinatal period and suckling-weaning transition. Physiological Reviews, 72(2), 507-62 (1992)
PMid:1557431
54. P. Haggarty: Fatty acid supply to the human fetus. Annual Review of Nutrition, 30, 237-55 (2010)
doi:10.1146/annurev.nutr.012809.104742
PMid:20438366
55. E. Herrera: Lipid metabolism in pregnancy and its consequences in the fetus and newborn. Endocrine, 19(1), 43-55 (2002)
doi:10.1385/ENDO:19:1:43
56. D. J. Fisher, M. A. Heymann and A. M. Rudolph: Myocardial oxygen and carbohydrate consumption in fetal lambs in utero and in adult sheep. American Journal of Physiology, 238(3), H399-405 (1980)
57. G. D. Lopaschuk, M. A. Spafford and D. R. Marsh: Glycolysis is predominant source of myocardial ATP production immediately after birth. American Journal of Physiology, 261(6 Pt 2), H1698-705 (1991)
58. G. D. Lopaschuk, R. L. Collins-Nakai and T. Itoi: Developmental changes in energy substrate use by the heart. Cardiovascular Research, 26(12), 1172-80 (1992)
doi:10.1093/cvr/26.12.1172
PMid:1288863
59. T. P. Rolph and C. T. Jones: Glucose metabolism in the perfused heart of the foetal guinea pig. Biochemical Society Transactions, 9(1), 65 (1981)
PMid:7215668
60. T. P. Rolph and C. T. Jones: Regulation of glycolytic flux in the heart of the fetal guinea pig. Journal of Developmental Physiology, 5(1), 31-49 (1983)
PMid:6300215
61. C. T. Jones and T. P. Rolph: Metabolism during fetal life: a functional assessment of metabolic development. Physiological Reviews, 65(2), 357-430 (1985)
PMid:3885272
62. J. C. Werner and R. E. Sicard: Lactate metabolism of isolated, perfused fetal, and newborn pig hearts. Pediatric Research, 22(5), 552-6 (1987)
doi:10.1203/00006450-198711000-00016
PMid:3684382
63. J. C. Werner, R. E. Sicard and H. G. Schuler: Palmitate oxidation by isolated working fetal and newborn pig hearts. American Journal of Physiology, 256(2 Pt 1), E315-21 (1989)
64. C. Depre, P. J. Davies and H. Taegtmeyer: Transcriptional adaptation of the heart to mechanical unloading. American Journal of Cardiology, 83(12A), 58H-63H (1999)
doi:10.1016/S0002-9149(99)00260-X
65. C. Depre, G. L. Shipley, W. Chen, Q. Han, T. Doenst, M. L. Moore, S. Stepkowski, P. J. Davies and H. Taegtmeyer: Unloaded heart in vivo replicates fetal gene expression of cardiac hypertrophy. Nature Medicine, 4(11), 1269-75 (1998)
doi:10.1038/3253
PMid:9809550
66. J. J. Lehman and D. P. Kelly: Transcriptional activation of energy metabolic switches in the developing and hypertrophied heart. Clinical & Experimental Pharmacology & Physiology, 29(4), 339-45 (2002)
doi:10.1046/j.1440-1681.2002.03655.x
PMid:11985547
67. A. Onay-Besikci: Regulation of cardiac energy metabolism in newborn. Molecular & Cellular Biochemistry, 287(1-2), 1-11 (2006)
doi:10.1007/s11010-006-9123-9
PMid:16670818
68. M. A. Yatscoff, J. S. Jaswal, M. R. Grant, R. Greenwood, T. Lukat, D. L. Beker, I. M. Rebeyka and G. D. Lopaschuk: Myocardial hypertrophy and the maturation of fatty acid oxidation in the newborn human heart. Pediatric Research, 64(6), 643-7 (2008)
doi:10.1203/PDR.0b013e318184d281
PMid:18614968
69. G. W. Goodwin, C. S. Taylor and H. Taegtmeyer: Regulation of energy metabolism of the heart during acute increase in heart work. Journal of Biological Chemistry, 273(45), 29530-9 (1998)
doi:10.1074/jbc.273.45.29530
PMid:9792661
70. A. S. Most, N. Brachfeld, R. Gorlin and J. Wahren: Free fatty acid metabolism of the human heart at rest. Journal of Clinical Investigation, 48(7), 1177-88 (1969)
doi:10.1172/JCI106082
PMid:5794244 PMCid:322339
71. C. Montessuit, I. Papageorgiou, I. Tardy and R. Lerch: Effect of nutritional state on substrate metabolism and contractile function in postischemic rat myocardium. American Journal of Physiology, 271(5 Pt 2), H2060-70 (1996)
72. P. J. Randle, P. B. Garland, C. N. Hales and E. A. Newsholme: The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet, 1, 785-9 (1963)
doi:10.1016/S0140-6736(63)91500-9
73. X. Wang, D. G. Hole, T. H. Da Costa and R. D. Evans: Alterations in myocardial lipid metabolism during lactation in the rat. American Journal of Physiology, 275(2 Pt 1), E265-71 (1998)
74. W. C. Stanley and M. P. Chandler: Energy metabolism in the normal and failing heart: potential for therapeutic interventions. Heart Failure Reviews, 7(2), 115-30 (2002)
doi:10.1023/A:1015320423577
PMid:11988636
75. O. D. Mjos: Effect of free fatty acids on myocardial function and oxygen consumption in intact dogs. Journal of Clinical Investigation, 50(7), 1386-9 (1971)
doi:10.1172/JCI106621
PMid:5090055 PMCid:292076
76. O. D. Mjos, J. K. Kjekshus and J. Lekven: Importance of free fatty acids as a determinant of myocardial oxygen consumption and myocardial ischemic injury during norepinephrine infusion in dogs. Journal of Clinical Investigation, 53(5), 1290-9 (1974)
doi:10.1172/JCI107676
PMid:4825226 PMCid:302616
77. D. F. Rolfe, A. J. Hulbert and M. D. Brand: Characteristics of mitochondrial proton leak and control of oxidative phosphorylation in the major oxygen-consuming tissues of the rat. Biochimica et Biophysica Acta, 1188(3), 405-16 (1994)
doi:10.1016/0005-2728(94)90062-0
78. P. Wang, S. G. Lloyd and J. C. Chatham: Impact of high glucose/high insulin and dichloroacetate treatment on carbohydrate oxidation and functional recovery after low-flow ischemia and reperfusion in the isolated perfused rat heart. Circulation, 111(16), 2066-72 (2005)
doi:10.1161/01.CIR.0000162466.06150.D4
PMid:15824201
79. I. Luptak, J. Yan, L. Cui, M. Jain, R. Liao and R. Tian: Long-term effects of increased glucose entry on mouse hearts during normal aging and ischemic stress. Circulation, 116(8), 901-9 (2007)
doi:10.1161/CIRCULATIONAHA.107.691253
PMid:17679614
80. C. J. Zuurbier, J. van Dijk, N. G. Abeling, J. C. M. Meijers, J. H. M. Levels, E. de Jonge, B. A. de Mol and H. B. van Wezel: A perioperative hyperinsulinaemic normoglycaemic clamp causes hypolipidaemia after coronary artery surgery. British Journal of Anaesthesia (2008)
81. B. Comte, G. Vincent, B. Bouchard, M. Jette, S. Cordeau and C. D. Rosiers: A 13C mass isotopomer study of anaplerotic pyruvate carboxylation in perfused rat hearts. Journal of Biological Chemistry, 272(42), 26125-31 (1997)
doi:10.1074/jbc.272.42.26125
PMid:9334177
82. M. J. Gibala, M. E. Young and H. Taegtmeyer: Anaplerosis of the citric acid cycle: role in energy metabolism of heart and skeletal muscle. Acta Physiologica Scandinavica, 168(4), 657-65 (2000)
doi:10.1046/j.1365-201x.2000.00717.x
PMid:10759602
83. N. Sorokina, J. M. O'Donnell, R. D. McKinney, K. M. Pound, G. Woldegiorgis, K. F. LaNoue, K. Ballal, H. Taegtmeyer, P. M. Buttrick and E. D. Lewandowski: Recruitment of compensatory pathways to sustain oxidative flux with reduced carnitine palmitoyltransferase I activity characterizes inefficiency in energy metabolism in hypertrophied hearts. Circulation, 115(15), 2033-41 (2007)
doi:10.1161/CIRCULATIONAHA.106.668665
PMid:17404155
84. J. A. Kline, L. R. Thornton, G. D. Lopaschuk, R. W. Barbee and J. A. Watts: Lactate improves cardiac efficiency after hemorrhagic shock. Shock, 14(2), 215-21 (2000)
doi:10.1097/00024382-200014020-00023
PMid:10947169
85. R. R. Russell, 3rd and H. Taegtmeyer: Changes in citric acid cycle flux and anaplerosis antedate the functional decline in isolated rat hearts utilizing acetoacetate. Journal of Clinical Investigation, 87(2), 384-90 (1991)
doi:10.1172/JCI115008
PMid:1671390 PMCid:295088
86. R. R. Russell, 3rd and H. Taegtmeyer: Pyruvate carboxylation prevents the decline in contractile function of rat hearts oxidizing acetoacetate. American Journal of Physiology, 261(6 Pt 2), H1756-62 (1991)
87. S. Gupta, B. Das and S. Sen: Cardiac hypertrophy: mechanisms and therapeutic opportunities. Antioxidants & Redox Signaling, 9(6), 623-52 (2007)
doi:10.1089/ars.2007.1474
PMid:17511580
88. M. F. Allard: Energy substrate metabolism in cardiac hypertrophy. Current Hypertension Reports, 6(6), 430-5 (2004)
doi:10.1007/s11906-004-0036-2
PMid:15527686
89. J. Zhang: Myocardial energetics in cardiac hypertrophy. Clinical & Experimental Pharmacology & Physiology, 29(4), 351-9 (2002)
doi:10.1046/j.1440-1681.2002.03657.x
PMid:11985549
90. Y. C. Zhu, Y. Z. Zhu, H. Spitznagel, P. Gohlke and T. Unger: Substrate metabolism, hormone interaction, and angiotensin-converting enzyme inhibitors in left ventricular hypertrophy. Diabetes, 45 Suppl 1, S59-65 (1996)
91. H. S. Leong, R. W. Brownsey, J. E. Kulpa and M. F. Allard: Glycolysis and pyruvate oxidation in cardiac hypertrophy--why so unbalanced? Comparative Biochemistry & Physiology. Part A, Molecular & Integrative Physiology, 135(4), 499-513 (2003)
doi:10.1016/S1095-6433(03)00007-2
92. S. Rimbaud, H. Sanchez, A. Garnier, D. Fortin, X. Bigard, V. Veksler and R. Ventura-Clapier: Stimulus specific changes of energy metabolism in hypertrophied heart. Journal of Molecular & Cellular Cardiology, 46(6), 952-9 (2009)
doi:10.1016/j.yjmcc.2009.01.013
PMid:19452634
93. N. Sambandam, G. D. Lopaschuk, R. W. Brownsey and M. F. Allard: Energy metabolism in the hypertrophied heart. Heart Failure Reviews, 7(2), 161-73 (2002)
doi:10.1023/A:1015380609464
94. N. D. Vaziri, K. Liang and C. H. Barton: Effect of increased afterload on cardiac lipoprotein lipase and VLDL receptor expression. Biochimica et Biophysica Acta, 1436(3), 577-84 (1999)
PMid:9989287
95. H. Taegtmeyer: Genetics of energetics: transcriptional responses in cardiac metabolism. Annals of Biomedical Engineering, 28(8), 871-6 (2000)
doi:10.1114/1.1312187
PMid:11144670
96. Y. Burelle, R. B. Wambolt, M. Grist, H. L. Parsons, J. C. Chow, C. Antler, A. Bonen, A. Keller, G. A. Dunaway, K. M. Popov, P. W. Hochachka and M. F. Allard: Regular exercise is associated with a protective metabolic phenotype in the rat heart. American Journal of Physiology - Heart & Circulatory Physiology, 287(3), H1055-63 (2004)
doi:10.1152/ajpheart.00925.2003
PMid:15105170
97. S. C. Dennis, W. Gevers and L. H. Opie: Protons in ischemia: where do they come from; where do they go to? Journal of Molecular & Cellular Cardiology, 23(9), 1077-86 (1991)
doi:10.1016/0022-2828(91)91642-5
98. E. W. Gertz, J. A. Wisneski, W. C. Stanley and R. A. Neese: Myocardial substrate utilization during exercise in humans. Dual carbon-labeled carbohydrate isotope experiments. Journal of Clinical Investigation, 82(6), 2017-25 (1988)
doi:10.1172/JCI113822
PMid:3198763 PMCid:442784
99. B. W. Lassers, L. Kaijser, M. L. Wahlqvist and L. A. Carlson: Relationship in man between plasma free fatty acids and myocardial metabolism of carbohydrate substrates. Lancet, 2(7722), 448-50 (1971)
doi:10.1016/S0140-6736(71)92624-9
100. L. Kaijser, B. W. Lassers, M. L. Wahlqvist and L. A. Carlson: Myocardial lipid and carbohydrate metabolism in fasting men during prolonged exercise. Journal of Applied Physiology, 32(6), 847-58 (1972)
PMid:5034348
101. G. W. Goodwin and H. Taegtmeyer: Improved energy homeostasis of the heart in the metabolic state of exercise. American Journal of Physiology - Heart & Circulatory Physiology, 279(4), H1490-501 (2000)
102. N. Sharma, I. C. Okere, D. Z. Brunengraber, T. A. McElfresh, K. L. King, J. P. Sterk, H. Huang, M. P. Chandler and W. C. Stanley: Regulation of pyruvate dehydrogenase activity and citric acid cycle intermediates during high cardiac power generation. Journal of Physiology, 562(Pt 2), 593-603 (2005)
PMid:15550462 PMCid:1665507
103. L. Zhou, H. Huang, C. L. Yuan, W. Keung, G. D. Lopaschuk and W. C. Stanley: Metabolic response to an acute jump in cardiac workload: effects on malonyl-CoA, mechanical efficiency, and fatty acid oxidation. American Journal of Physiology - Heart & Circulatory Physiology, 294(2), H954-60 (2008)
doi:10.1152/ajpheart.00557.2007
PMid:18083904
104. L. Zhou, M. E. Cabrera, H. Huang, C. L. Yuan, D. K. Monika, N. Sharma, F. Bian and W. C. Stanley: Parallel activation of mitochondrial oxidative metabolism with increased cardiac energy expenditure is not dependent on fatty acid oxidation in pigs. Journal of Physiology, 579(Pt 3), 811-21 (2007)
doi:10.1113/jphysiol.2006.123828
PMid:17185335 PMCid:2151353
105. 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, 104(24), 2923-31 (2001)
doi:10.1161/hc4901.100526
PMid:11739307
106. J. J. Lehman and D. P. Kelly: Gene regulatory mechanisms governing energy metabolism during cardiac hypertrophic growth. Heart Failure Reviews, 7(2), 175-85 (2002)
doi:10.1023/A:1015332726303
107. 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. American Journal of Physiology, 267(2 Pt 2), H742-50 (1994)
108. Z. el Alaoui-Talibi, S. Landormy, A. Loireau and J. Moravec: Fatty acid oxidation and mechanical performance of volume-overloaded rat hearts. American Journal of Physiology, 262(4 Pt 2), H1068-74 (1992)
109. G. Vincent, M. Khairallah, B. Bouchard, C. Des Rosiers, G. Vincent, M. Khairallah, B. Bouchard and C. Des Rosiers: Metabolic phenotyping of the diseased rat heart using 13C-substrates and ex vivo perfusion in the working mode. Molecular & Cellular Biochemistry, 242(1-2), 89-99 (2003)
doi:10.1023/A:1021189728877
PMid:12619870
110. F. Labarthe, R. Gelinas and C. Des Rosiers: Medium-chain fatty acids as metabolic therapy in cardiac disease. Cardiovascular Drugs & Therapy, 22(2), 97-106 (2008)
doi:10.1007/s10557-008-6084-0
PMid:18253821
111. P. M. Barger and D. P. Kelly: Fatty acid utilization in the hypertrophied and failing heart: molecular regulatory mechanisms. American Journal of the Medical Sciences, 318(1), 36-42 (1999)
doi:10.1097/00000441-199907000-00006
PMid:10408759
112. B. Guertl, C. Noehammer and G. Hoefler: Metabolic cardiomyopathies. International Journal of Experimental Pathology, 81(6), 349-72 (2000)
doi:10.1046/j.1365-2613.2000.00186.x
113. C. Amat di San Filippo, M. R. Taylor, L. Mestroni, L. D. Botto and N. Longo: Cardiomyopathy and carnitine deficiency. Molecular Genetics & Metabolism, 94(2), 162-6 (2008)
doi:10.1016/j.ymgme.2008.02.002
PMid:18337137 PMCid:2430214
114. E. Fosslien: Review: Mitochondrial medicine--cardiomyopathy caused by defective oxidative phosphorylation. Annals of Clinical & Laboratory Science, 33(4), 371-95 (2003)
PMid:14584751
115. T. Hajri, A. Ibrahimi, C. T. Coburn, F. F. Knapp, Jr., T. Kurtz, M. Pravenec and N. A. Abumrad: Defective fatty acid uptake in the spontaneously hypertensive rat is a primary determinant of altered glucose metabolism, hyperinsulinemia, and myocardial hypertrophy. Journal of Biological Chemistry, 276(26), 23661-6 (2001)
doi:10.1074/jbc.M100942200
PMid:11323420
116. T. Tanaka, K. Sohmiya and K. Kawamura: Is CD36 deficiency an etiology of hereditary hypertrophic cardiomyopathy? Journal of Molecular & Cellular Cardiology, 29(1), 121-7 (1997)
doi:10.1006/jmcc.1996.0257
PMid:9040027
117. G. Paolisso, A. Gambardella, D. Galzerano, A. D'Amore, P. Rubino, M. Verza, P. Teasuro, M. Varricchio and F. D'Onofrio: Total-body and myocardial substrate oxidation in congestive heart failure. Metabolism: Clinical & Experimental, 43(2), 174-9 (1994)
doi:10.1016/0026-0495(94)90241-0
118. J. Lommi, M. Kupari and H. Yki-Jarvinen: Free fatty acid kinetics and oxidation in congestive heart failure. American Journal of Cardiology, 81(1), 45-50 (1998)
doi:10.1016/S0002-9149(97)00804-7
119. A. J. Murray, C. A. Lygate, M. A. Cole, C. A. Carr, G. K. Radda, S. Neubauer and K. Clarke: Insulin resistance, abnormal energy metabolism and increased ischemic damage in the chronically infarcted rat heart. Cardiovascular Research, 71(1), 149-57 (2006)
doi:10.1016/j.cardiores.2006.02.031
PMid:16616054
120. H. Ashrafian, M. P. Frenneaux and L. H. Opie: Metabolic mechanisms in heart failure. Circulation, 116(4), 434-48 (2007)
doi:10.1161/CIRCULATIONAHA.107.702795
PMid:17646594
121. H. Tuunanen, H. Ukkonen and J. Knuuti: Myocardial fatty acid metabolism and cardiac performance in heart failure. Current Cardiology Reports, 10(2), 142-8 (2008)
doi:10.1007/s11886-008-0024-2
PMid:18417015
122. J. A. Wisneski, E. W. Gertz, R. A. Neese and M. Mayr: Myocardial metabolism of free fatty acids. Studies with 14C-labeled substrates in humans. Journal of Clinical Investigation, 79(2), 359-66 (1987)
doi:10.1172/JCI112820
PMid:3805273 PMCid:424073
123. D. Neglia, A. De Caterina, P. Marraccini, A. Natali, M. Ciardetti, C. Vecoli, A. Gastaldelli, D. Ciociaro, P. Pellegrini, R. Testa, L. Menichetti, A. L'Abbate, W. C. Stanley and F. A. Recchia: Impaired myocardial metabolic reserve and substrate selection flexibility during stress in patients with idiopathic dilated cardiomyopathy. American Journal of Physiology - Heart & Circulatory Physiology, 293(6), H3270-8 (2007)
doi:10.1152/ajpheart.00887.2007
PMid:17921325
124. V. 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. Journal of the American College of Cardiology, 40(2), 271-7 (2002)
doi:10.1016/S0735-1097(02)01967-8
125. 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
126. L. C. Heather, M. A. Cole, C. A. Lygate, R. D. Evans, D. J. Stuckey, A. J. Murray, S. Neubauer and K. Clarke: Fatty acid transporter levels and palmitate oxidation rate correlate with ejection fraction in the infarcted rat heart. Cardiovascular Research, 72(3), 430-7 (2006)
doi:10.1016/j.cardiores.2006.08.020
PMid:17034771
127. B. Christian, Z. El Alaoui-Talibi, M. Moravec and J. Moravec: Palmitate oxidation by the mitochondria from volume-overloaded rat hearts. Molecular & Cellular Biochemistry, 180(1-2), 117-28 (1998)
doi:10.1023/A:1006851325669
PMid:9546638
128. K. Qanud, M. Mamdani, M. Pepe, R. J. Khairallah, J. Gravel, B. Lei, S. A. Gupte, V. G. Sharov, H. N. Sabbah, W. C. Stanley and F. A. Recchia: Reverse changes in cardiac substrate oxidation in dogs recovering from heart failure. American Journal of Physiology - Heart & Circulatory Physiology, 295(5), H2098-105 (2008)
doi:10.1152/ajpheart.00471.2008
PMid:18820029 PMCid:2614573
129. M. P. Chandler, J. Kerner, H. Huang, E. Vazquez, A. Reszko, W. Z. Martini, C. L. Hoppel, M. Imai, S. Rastogi, H. N. Sabbah and W. C. Stanley: Moderate severity heart failure does not involve a downregulation of myocardial fatty acid oxidation. American Journal of Physiology - Heart & Circulatory Physiology, 287(4), H1538-43 (2004)
doi:10.1152/ajpheart.00281.2004
PMid:15191896
130. A. Remondino, N. Rosenblatt-Velin, C. Montessuit, I. Tardy, I. Papageorgiou, P. A. Dorsaz, M. Jorge-Costa and R. Lerch: Altered expression of proteins of metabolic regulation during remodeling of the left ventricle after myocardial infarction. Journal of Molecular & Cellular Cardiology, 32(11), 2025-34 (2000)
doi:10.1006/jmcc.2000.1234
PMid:11040106
131. J. Lommi, P. Koskinen, H. Naveri, M. Harkonen and M. Kupari: Heart failure ketosis. Journal of Internal Medicine, 242(3), 231-8 (1997)
doi:10.1046/j.1365-2796.1997.00187.x
PMid:9350168
132. M. N. Sack, T. A. Rader, S. Park, J. Bastin, S. A. McCune and D. P. Kelly: Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation, 94(11), 2837-42 (1996)
PMid:8941110
133. P. M. Barger and D. P. Kelly: PPAR signaling in the control of cardiac energy metabolism. Trends in Cardiovascular Medicine, 10(6), 238-45 (2000)
doi:10.1016/S1050-1738(00)00077-3
134. J. A. Madrazo and D. P. Kelly: The PPAR trio: regulators of myocardial energy metabolism in health and disease. Journal of Molecular & Cellular Cardiology, 44(6), 968-75 (2008)
doi:10.1016/j.yjmcc.2008.03.021
PMid:18462747
135. M. G. Rosca, E. J. Vazquez, J. Kerner, W. Parland, M. P. Chandler, W. Stanley, H. N. Sabbah and C. L. Hoppel: Cardiac mitochondria in heart failure: decrease in respirasomes and oxidative phosphorylation. Cardiovascular Research, 80(1), 30-9 (2008)
doi:10.1093/cvr/cvn184
PMid:18710878 PMCid:2533423
136. L. C. Heather, C. A. Carr, D. J. Stuckey, S. Pope, K. J. Morten, E. E. Carter, L. M. Edwards and K. Clarke: Critical role of complex III in the early metabolic changes following myocardial infarction. Cardiovascular Research, 85(1), 127-36 (2010)
doi:10.1093/cvr/cvp276
PMid:19666902
137. S. Neubauer, M. Horn, A. Naumann, R. Tian, K. Hu, M. Laser, J. Friedrich, P. Gaudron, K. Schnackerz, J. S. Ingwall and G. Ertl: Impairment of energy metabolism in intact residual myocardium of rat hearts with chronic myocardial infarction. Journal of Clinical Investigation, 95(3), 1092-100 (1995)
doi:10.1172/JCI117756
PMid:7883957 PMCid:441445
138. J. M. Huss and D. P. Kelly: Nuclear receptor signaling and cardiac energetics. Circulation Research, 95(6), 568-78 (2004)
doi:10.1161/01.RES.0000141774.29937.e3
PMid:15375023
139. G. D. Lopaschuk and D. P. Kelly: Signalling in cardiac metabolism. Cardiovascular Research, 79(2), 205-7 (2008)
doi:10.1093/cvr/cvn134
PMid:18515845
140. J. M. Huss and D. P. Kelly: Mitochondrial energy metabolism in heart failure: a question of balance. Journal of Clinical Investigation, 115(3), 547-55 (2005)
PMid:15765136 PMCid:1052011
141. J. S. Ingwall, D. E. Atkinson, K. Clarke and J. K. Fetters: Energetic correlates of cardiac failure: changes in the creatine kinase system in the failing myocardium. European Heart Journal, 11 Suppl B, 108-15 (1990)
142. W. Wang and G. D. Lopaschuk: Metabolic therapy for the treatment of ischemic heart disease: reality and expectations. Expert Review of Cardiovascular Therapy, 5(6), 1123-34 (2007)
doi:10.1586/14779072.5.6.1123
PMid:18035928
143. G. D. Lopaschuk and W. C. Stanley: Malonyl-CoA decarboxylase inhibition as a novel approach to treat ischemic heart disease. Cardiovascular Drugs & Therapy, 20(6), 433-9 (2006)
doi:10.1007/s10557-006-0634-0
PMid:17136490
144. G. D. Lopaschuk: Optimizing cardiac fatty acid and glucose metabolism as an approach to treating heart failure. Seminars in Cardiothoracic & Vascular Anesthesia, 10(3), 228-30 (2006)
doi:10.1177/1089253206291150
PMid:16959756
145. G. D. Lopaschuk: Optimizing cardiac energy metabolism: how can fatty acid and carbohydrate metabolism be manipulated? Coronary Artery Disease, 12 Suppl 1, S8-11 (2001)
146. K. Abozguia, K. Clarke, L. Lee and M. Frenneaux: Modification of myocardial substrate use as a therapy for heart failure. Nature Clinical Practice Cardiovascular Medicine, 3(9), 490-8 (2006)
doi:10.1038/ncpcardio0583
PMid:16932766
147. H. Taegtmeyer, L. M. King and B. E. Jones: Energy substrate metabolism, myocardial ischemia, and targets for pharmacotherapy. American Journal of Cardiology, 82(5A), 54K-60K (1998)
doi:10.1016/S0002-9149(98)00538-4
148. H. N. Sabbah and W. C. Stanley: Metabolic therapy for heart disease: impact of trimetazidine. Heart Failure Reviews, 10(4), 281-8 (2005)
doi:10.1007/s10741-005-7541-5
PMid:16583176
149. L. H. Opie and J. Knuuti: The adrenergic-fatty acid load in heart failure. Journal of the American College of Cardiology, 54(18), 1637-46 (2009)
doi:10.1016/j.jacc.2009.07.024
PMid:19850204
150. B. Lei, V. Lionetti, M. E. Young, M. P. Chandler, C. d'Agostino, E. Kang, M. Altarejos, K. Matsuo, T. H. Hintze, W. C. Stanley and F. A. Recchia: Paradoxical downregulation of the glucose oxidation pathway despite enhanced flux in severe heart failure. Journal of Molecular & Cellular Cardiology, 36(4), 567-76 (2004)
doi:10.1016/j.yjmcc.2004.02.004
PMid:15081316
151. F. Di Lisa, C. Z. Fan, G. Gambassi, B. A. Hogue, I. Kudryashova and R. G. Hansford: Altered pyruvate dehydrogenase control and mitochondrial free Ca2+ in hearts of cardiomyopathic hamsters. American Journal of Physiology, 264(6 Pt 2), H2188-97 (1993)
152. R. J. Ascuitto and N. T. Ross-Ascuitto: Substrate metabolism in the developing heart. Seminars in Perinatology, 20(6), 542-63 (1996)
doi:10.1016/S0146-0005(96)80068-1
153. A. O. Makinde, P. F. Kantor and G. D. Lopaschuk: Maturation of fatty acid and carbohydrate metabolism in the newborn heart. Molecular & Cellular Biochemistry, 188(1-2), 49-56 (1998)
doi:10.1023/A:1006860104840
PMid:9823010
154. G. M. C. Rosano, M. Fini, G. Caminiti and G. Barbaro: Cardiac metabolism in myocardial ischemia. Current Pharmaceutical Design, 14(25), 2551-62 (2008)
doi:10.2174/138161208786071317
PMid:18991672
155. M. F. Oliver: Control of free fatty acids during acute myocardial ischaemia. Heart, 96(23), 1883-4 (2010)
doi:10.1136/hrt.2010.205534
PMid:20962339
156. J. R. Neely, M. J. Rovetto, J. T. Whitmer and H. E. Morgan: Effects of ischemia on function and metabolism of the isolated working rat heart. American Journal of Physiology, 225(3), 651-8 (1973)
PMid:4726499
157. P. H. McNulty, A. J. Sinusas, C. Q. Shi, D. Dione, L. H. Young, G. C. Cline and G. I. Shulman: Glucose metabolism distal to a critical coronary stenosis in a canine model of low-flow myocardial ischemia. Journal of Clinical Investigation, 98(1), 62-9 (1996)
doi:10.1172/JCI118778
PMid:8690805 PMCid:507401
158. S. G. Lloyd, P. Wang, H. Zeng and J. C. Chatham: Impact of low-flow ischemia on substrate oxidation and glycolysis in the isolated perfused rat heart. American Journal of Physiology - Heart & Circulatory Physiology, 287(1), H351-62 (2004)
doi:10.1152/ajpheart.00983.2003
PMid:15001444
159. D. J. Paulson, J. J. Noonan, K. M. Ward, H. Stanley, A. Sherratt and A. L. Shug: Effects of POCA on metabolism and function in the ischemic rat heart. Basic Research in Cardiology, 81(2), 180-7 (1986)
doi:10.1007/BF01907382
PMid:3741356
160. R. Russell, 3rd: Stress signaling in the heart by AMP-activated protein kinase. Current Hypertension Reports, 8(6), 446-50 (2006)
doi:10.1007/s11906-006-0021-z
PMid:17087854
161. E. Aasum, A. D. Hafstad and T. S. Larsen: Changes in substrate metabolism in isolated mouse hearts following ischemia-reperfusion. Molecular & Cellular Biochemistry, 249(1-2), 97-103 (2003)
doi:10.1023/A:1024734605562
PMid:12956404
162. N. Kudo, A. J. Barr, R. L. Barr, S. Desai and G. D. Lopaschuk: High rates of fatty acid oxidation during reperfusion of ischemic hearts are associated with a decrease in malonyl-CoA levels due to an increase in 5'-AMP-activated protein kinase inhibition of acetyl-CoA carboxylase. Journal of Biological Chemistry, 270(29), 17513-20 (1995)
doi:10.1074/jbc.270.29.17513
PMid:7615556
163. N. Kudo, J. G. Gillespie, L. Kung, L. A. Witters, R. Schulz, A. S. Clanachan and G. D. Lopaschuk: Characterization of 5'AMP-activated protein kinase activity in the heart and its role in inhibiting acetyl-CoA carboxylase during reperfusion following ischemia. Biochimica et Biophysica Acta, 1301(1-2), 67-75 (1996)
PMid:8652652
164. C. D. Folmes, C. S. Wagg, M. Shen, A. S. Clanachan, R. Tian and G. D. Lopaschuk: Suppression of 5'-AMP-activated protein kinase activity does not impair recovery of contractile function during reperfusion of ischemic hearts. American Journal of Physiology - Heart & Circulatory Physiology, 297(1), H313-21 (2009)
doi:10.1152/ajpheart.01298.2008
PMid:19429810
165. T. Pulinilkunnil, P. Puthanveetil, M. S. Kim, F. Wang, V. Schmitt and B. Rodrigues: Ischemia-reperfusion alters cardiac lipoprotein lipase. Biochimica et Biophysica Acta, 1801(2), 171-5 (2010)
PMid:19857601
166. H. Vik-Mo, P. Moen and O. D. Mjos: Myocardial lipoproteins lipase activity during acute myocardial ischemia in dogs. Hormone & Metabolic Research, 14(2), 85-8 (1982)
doi:10.1055/s-2007-1018930
PMid:7068101
167. A. J. Liedtke, S. H. Nellis and O. D. Mjos: Effects of reducing fatty acid metabolism on mechanical function in regionally ischemic hearts. American Journal of Physiology, 247(3 Pt 2), H387-94 (1984)
168. J. K. Kjekshus and O. D. Mjos: Effect of free fatty acids on myocardial function and metabolism in the ischemic dog heart. Journal of Clinical Investigation, 51(7), 1767-76 (1972)
doi:10.1172/JCI106978
PMid:5032525 PMCid:292324
169. K. Clarke, A. J. O'Connor and R. J. Willis: Temporal relation between energy metabolism and myocardial function during ischemia and reperfusion. American Journal of Physiology, 253(2 Pt 2), H412-21 (1987)
170. G. D. Lopaschuk, M. A. Spafford, N. J. Davies and S. R. Wall: Glucose and palmitate oxidation in isolated working rat hearts reperfused after a period of transient global ischemia. Circulation Research, 66(2), 546-53 (1990)
PMid:2297817
171. R. H. Benzi and R. Lerch: Dissociation between contractile function and oxidative metabolism in postischemic myocardium. Attenuation by ruthenium red administered during reperfusion. Circulation Research, 71(3), 567-76 (1992)
PMid:1379892
172. J. B. Michel, A. Nicolletti and J. F. Arnal: Left ventricular remodelling following experimental myocardial infarction. European Heart Journal, 16 Suppl I, 49-57 (1995)
PMid:8829957
173. J. S. Ingwall: Energy metabolism in heart failure and remodelling. Cardiovascular Research, 81(3), 412-9 (2009)
doi:10.1093/cvr/cvn301
PMid:18987051 PMCid:2639129
174. P. Razeghi, T. J. Myers, O. H. Frazier and H. Taegtmeyer: Reverse remodeling of the failing human heart with mechanical unloading. Emerging concepts and unanswered questions. Cardiology, 98(4), 167-74 (2002)
doi:10.1159/000067313
PMid:12566644
175. Y. Sezai: Progress and future perspectives in mechanical circulatory support. Artificial Organs, 25(5), 318-22 (2001)
doi:10.1046/j.1525-1594.2001.06804.x
PMid:11403657
176. J. Wang, A. Marui, T. Ikeda and M. Komeda: Partial left ventricular unloading reverses contractile dysfunction and helps recover gene expressions in failing rat hearts. Interactive Cardiovascular & Thoracic Surgery, 7(1), 27-31 (2008)
doi:10.1510/icvts.2007.165563
PMid:18006556
177. D. Burkhoff, J. W. Holmes, J. Madigan, A. Barbone and M. C. Oz: Left ventricular assist device-induced reverse ventricular remodeling. Progress in Cardiovascular Diseases, 43(1), 19-26 (2000)
doi:10.1053/pcad.2000.7190
PMid:10935554
178. G. K. R. Soppa, P. J. R. Barton, C. M. N. Terracciano and M. H. Yacoub: Left ventricular assist device-induced molecular changes in the failing myocardium. Current Opinion in Cardiology, 23(3), 206-18 (2008)
doi:10.1097/HCO.0b013e3282fc7010
PMid:18382208
179. S. Sharma, J. Ying, P. Razeghi, S. Stepkowski and H. Taegtmeyer: Atrophic remodeling of the transplanted rat heart. Cardiology, 105(2), 128-36 (2006)
doi:10.1159/000090550
PMid:16391472
180. H. Bugger, S. Leippert, D. Blum, P. Kahle, B. Barleon, D. Marme and T. Doenst: Subtractive hybridization for differential gene expression in mechanically unloaded rat heart. American Journal of Physiology - Heart & Circulatory Physiology, 291(6), H2714-22 (2006)
doi:10.1152/ajpheart.00445.2005
PMid:16766641
181. T. Doenst, H. Bugger, S. Leippert, B. Barleon, D. Marme and F. Beyersdorf: Differential gene expression in response to ventricular unloading in rat and human myocardium. Thoracic & Cardiovascular Surgeon, 54(6), 381-7 (2006)
doi:10.1055/s-2006-924267
PMid:16967373
182. T. Doenst, G. W. Goodwin, A. M. Cedars, M. Wang, S. Stepkowski and H. Taegtmeyer: Load-induced changes in vivo alter substrate fluxes and insulin responsiveness of rat heart in vitro. Metabolism: Clinical & Experimental, 50(9), 1083-90 (2001)
doi:10.1053/meta.2001.25605
PMid:11555843
183. P. Razeghi, M. E. Young, J. Ying, C. Depre, I. P. Uray, J. Kolesar, G. L. Shipley, C. S. Moravec, P. J. Davies, O. H. Frazier and H. Taegtmeyer: Downregulation of metabolic gene expression in failing human heart before and after mechanical unloading. Cardiology, 97(4), 203-9 (2002)
doi:10.1159/000063122
PMid:12145475
184. H. Taegtmeyer, P. Razeghi and M. E. Young: Mitochondrial proteins in hypertrophy and atrophy: a transcript analysis in rat heart. Clinical & Experimental Pharmacology & Physiology, 29(4), 346-50 (2002)
doi:10.1046/j.1440-1681.2002.03656.x
PMid:11985548
185. A. Rodrigue-Way, D. Burkhoff, B. J. Geesaman, S. Golden, J. Xu, M. J. Pollman, M. Donoghue, R. Jeyaseelan, S. Houser, R. E. Breitbart, A. Marks and S. Acton: Sarcomeric genes involved in reverse remodeling of the heart during left ventricular assist device support. Journal of Heart & Lung Transplantation, 24(1), 73-80 (2005)
doi:10.1016/j.healun.2003.10.016
PMid:15653383
186. D. Burkhoff, S. Klotz and D. M. Mancini: LVAD-induced reverse remodeling: basic and clinical implications for myocardial recovery. Journal of Cardiac Failure, 12(3), 227-39 (2006)
doi:10.1016/j.cardfail.2005.10.012
PMid:16624689
187. T. Takaseya, M. Ishimatsu, E. Tayama, A. Nishi, T. Akasu and S. Aoyagi: Mechanical unloading improves intracellular Ca2+ regulation in rats with doxorubicin-induced cardiomyopathy. Journal of the American College of Cardiology, 44(11), 2239-46 (2004)
doi:10.1016/j.jacc.2004.08.057
PMid:15582323
188. P. M. Heerdt, J. W. Holmes, B. Cai, A. Barbone, J. D. Madigan, S. Reiken, D. L. Lee, M. C. Oz, A. R. Marks and D. Burkhoff: Chronic unloading by left ventricular assist device reverses contractile dysfunction and alters gene expression in end-stage heart failure. Circulation, 102(22), 2713-9 (2000)
PMid:11094037
189. A. M. Katz: Is the failing heart energy depleted? Cardiology Clinics, 16(4), 633-44, viii (1998)
190. M. N. Sack and D. P. Kelly: The energy substrate switch during development of heart failure: gene regulatory mechanisms (Review). International Journal of Molecular Medicine, 1(1), 17-24 (1998)
PMid:9852194
191. 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. Journal of Biological Chemistry, 276(48), 44390-5 (2001)
doi:10.1074/jbc.M103826200
PMid:11574533
192. P. Razeghi, M. E. Wang, K. A. Youker, L. Golfman, S. Stepkowski and H. Taegtmeyer: Lack of NF-kappaB1 (p105/p50) attenuates unloading-induced downregulation of PPARalpha and PPARalpha-regulated gene expression in rodent heart. Cardiovascular Research, 74(1), 133-9 (2007)
doi:10.1016/j.cardiores.2006.12.021
PMid:17276423 PMCid:2034318
193. B. B. Ngimbous, F. Bourgeois, C. Mas, M. Simonneau and J. M. Moalic: Heart transplantation changes the expression of distinct gene families. Physiological Genomics, 7(2), 115-26 (2001)
PMid:11773598
194. W. Oriyanhan, H. Tsuneyoshi, T. Nishina, S. Matsuoka, T. Ikeda and M. Komeda: Determination of optimal duration of mechanical unloading for failing hearts to achieve bridge to recovery in a rat heterotopic heart transplantation model. Journal of Heart & Lung Transplantation, 26(1), 16-23 (2007)
doi:10.1016/j.healun.2006.10.016
PMid:17234512
195. P. Razeghi, M. Buksinska-Lisik, N. Palanichamy, S. Stepkowski, O. H. Frazier and H. Taegtmeyer: Transcriptional regulators of ribosomal biogenesis are increased in the unloaded heart. FASEB Journal, 20(8), 1090-6 (2006)
doi:10.1096/fj.06-5718com
PMid:16770008
196. P. Razeghi, S. Sharma, J. Ying, Y. P. Li, S. Stepkowski, M. B. Reid and H. Taegtmeyer: Atrophic remodeling of the heart in vivo simultaneously activates pathways of protein synthesis and degradation. Circulation, 108(20), 2536-41 (2003)
doi:10.1161/01.CIR.0000096481.45105.13
PMid:14610007
197. I. P. Uray, J. H. Connelly, O. H. Frazier, H. Taegtmeyer and P. J. Davies: Mechanical unloading increases caveolin expression in the failing human heart. Cardiovascular Research, 59(1), 57-66 (2003)
doi:10.1016/S0008-6363(03)00352-3
198. P. H. McNulty, W. X. Liu, M. C. Luba, J. A. Valenti, G. V. Letsou and J. C. Baldwin: Effect of nonworking heterotopic transplantation on rat heart glycogen metabolism. American Journal of Physiology, 268(1 Pt 1), E48-54 (1995)
199. K. Gottlob, N. Majewski, S. Kennedy, E. Kandel, R. B. Robey and N. Hay: Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes & Development, 15(11), 1406-18 (2001)
doi:10.1101/gad.889901
200. S. H. Lee, N. Doliba, M. Osbakken, M. Oz and D. Mancini: Improvement of myocardial mitochondrial function after hemodynamic support with left ventricular assist devices in patients with heart failure. Journal of Thoracic & Cardiovascular Surgery, 116(2), 344-9 (1998)
doi:10.1016/S0022-5223(98)70136-9
201. O. Asghar, A. Al-Sunni, K. Khavandi, A. Khavandi, S. Withers, A. Greenstein, A. M. Heagerty and R. A. Malik: Diabetic cardiomyopathy. Clinical Science, 116(10), 741-60 (2009)
doi:10.1042/CS20080500
PMid:19364331 PMCid:2782307
202. Z. Y. Fang, J. B. Prins and T. H. Marwick: Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications. Endocrine Reviews, 25(4), 543-67 (2004)
doi:10.1210/er.2003-0012
PMid:15294881
203. D. L. Severson: Diabetic cardiomyopathy: recent evidence from mouse models of type 1 and type 2 diabetes. Canadian Journal of Physiology & Pharmacology, 82(10), 813-23 (2004)
doi:10.1139/y04-065
PMid:15573141
204. S. Ghosh and B. Rodrigues: Cardiac cell death in early diabetes and its modulation by dietary fatty acids. Biochimica et Biophysica Acta, 1761(10), 1148-62 (2006)
PMid:16997625
205. I. G. Poornima, P. Parikh and R. P. Shannon: Diabetic cardiomyopathy: the search for a unifying hypothesis. Circulation Research, 98(5), 596-605 (2006)
doi:10.1161/01.RES.0000207406.94146.c2
PMid:16543510
206. R. Harmancey and H. Taegtmeyer: The complexities of diabetic cardiomyopathy: lessons from patients and animal models. Current Diabetes Reports, 8(3), 243-8 (2008)
doi:10.1007/s11892-008-0042-x
PMid:18625124
207. D. An and B. Rodrigues: Role of changes in cardiac metabolism in development of diabetic cardiomyopathy. American Journal of Physiology - Heart & Circulatory Physiology, 291(4), H1489-506 (2006)
doi:10.1152/ajpheart.00278.2006
PMid:16751293
208. D. Feuvray and A. Darmellah: Diabetes-related metabolic perturbations in cardiac myocyte. Diabetes & Metabolism, 34 Suppl 1, S3-9 (2008)
doi:10.1016/S1262-3636(08)70096-X
209. A. Avogaro, S. Vigili de Kreutzenberg, C. Negut, A. Tiengo and R. Scognamiglio: Diabetic cardiomyopathy: a metabolic perspective. American Journal of Cardiology, 93(8A), 13A-16A (2004)
doi:10.1016/j.amjcard.2003.11.003
PMid:15094099
210. X. Han, J. Yang, K. Yang, Z. Zhao, D. R. Abendschein and R. W. Gross: Alterations in myocardial cardiolipin content and composition occur at the very earliest stages of diabetes: a shotgun lipidomics study. Biochemistry, 46(21), 6417-28 (2007)
doi:10.1021/bi7004015
PMid:17487985 PMCid:2139909
211. M. Yoshimura, R. Anzawa and S. Mochizuki: Cardiac metabolism in diabetes mellitus. Current Pharmaceutical Design, 14(25), 2521-6 (2008)
doi:10.2174/138161208786071263
PMid:18991669
212. A. Guha, R. Harmancey and H. Taegtmeyer: Nonischemic heart failure in diabetes mellitus. Current Opinion in Cardiology, 23(3), 241-8 (2008)
doi:10.1097/HCO.0b013e3282fcc2fa
PMid:18382213
213. Y. D. Chen, A. Golay, A. L. Swislocki and G. M. Reaven: Resistance to insulin suppression of plasma free fatty acid concentrations and insulin stimulation of glucose uptake in noninsulin-dependent diabetes mellitus. Journal of Clinical Endocrinology & Metabolism, 64(1), 17-21 (1987)
doi:10.1210/jcem-64-1-17
214. B. Lewis, M. Mancini, M. Mattock, A. Chait and T. R. Fraser: Plasma triglyceride and fatty acid metabolism in diabetes mellitus. European Journal of Clinical Investigation, 2(6), 445-53 (1972)
doi:10.1111/j.1365-2362.1972.tb00676.x
PMid:4655970
215. G. M. Reaven, C. Hollenbeck, C. Y. Jeng, M. S. Wu and Y. D. Chen: Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 h in patients with NIDDM. Diabetes, 37(8), 1020-4 (1988)
doi:10.2337/diabetes.37.8.1020
PMid:3292322
216. E. A. Nikkila: Plasma triglycerides in human diabetes. Proceedings of the Royal Society of Medicine, 67(7), 662-5 (1974)
PMid:4212245 PMCid:1651737
217. B. V. Howard, J. S. Reitman, B. Vasquez and L. Zech: Very-low-density lipoprotein triglyceride metabolism in non-insulin-dependent diabetes mellitus. Relationship to plasma insulin and free fatty acids. Diabetes, 32(3), 271-6 (1983)
doi:10.2337/diabetes.32.3.271
PMid:6337905
218. D. Ballantyne, C. White, E. A. Strevens, T. D. Lawrie, A. R. Lorimer, W. G. Manderson and H. G. Morgan: Lipoprotein concentrations in untreated adult onset diabetes mellitus and the relationship of the fasting plasma triglyceride concentration to insulin secretion. Clinica Chimica Acta, 78(2), 323-9 (1977)
doi:10.1016/0009-8981(77)90323-0
219. B. V. Howard, W. G. Abbott, W. F. Beltz, I. T. Harper, R. M. Fields, S. M. Grundy and M. R. Taskinen: Integrated study of low density lipoprotein metabolism and very low density lipoprotein metabolism in non-insulin-dependent diabetes. Metabolism: Clinical & Experimental, 36(9), 870-7 (1987)
doi:10.1016/0026-0495(87)90096-5
220. B. V. Howard: Lipoprotein metabolism in diabetes. Current Opinion in Lipidology, 5(3), 216-20 (1994)
doi:10.1097/00041433-199405030-00009
PMid:7952916
221. J. E. Braun and D. L. Severson: Regulation of the synthesis, processing and translocation of lipoprotein lipase. Biochemical Journal, 287(Pt 2), 337-47 (1992)
PMid:1445192 PMCid:1133170
222. P. O'Looney, D. Irwin, P. Briscoe and G. V. Vahouny: Lipoprotein composition as a component in the lipoprotein clearance defect in experimental diabetes. Journal of Biological Chemistry, 260(1), 428-32 (1985)
PMid:3965456
223. L. Zhang, W. Keung, V. Samokhvalov, W. Wang and G. D. Lopaschuk: Role of fatty acid uptake and fatty acid beta-oxidation in mediating insulin resistance in heart and skeletal muscle. Biochimica et Biophysica Acta, 1801(1), 1-22 (2010)
PMid:19782765
224. A. Barsotti, A. Giannoni, P. Di Napoli and M. Emdin: Energy metabolism in the normal and in the diabetic heart. Current Pharmaceutical Design, 15(8), 836-40 (2009)
doi:10.2174/138161209787582066
PMid:19275647
225. L. Bertrand, S. Horman, C. Beauloye and J. L. Vanoverschelde: Insulin signalling in the heart. Cardiovascular Research, 79(2), 238-48 (2008)
doi:10.1093/cvr/cvn093
PMid:18390897
226. A. D. Hafstad, G. H. Solevag, D. L. Severson, T. S. Larsen and E. Aasum: Perfused hearts from Type 2 diabetic (db/db) mice show metabolic responsiveness to insulin.(see comment). American Journal of Physiology - Heart & Circulatory Physiology, 290(5), H1763-9 (2006)
doi:10.1152/ajpheart.01063.2005
PMid:16327015
227. N. D. Oakes, P. Thalen, E. Aasum, A. Edgley, T. Larsen, S. M. Furler, B. Ljung and D. Severson: Cardiac metabolism in mice: tracer method developments and in vivo application revealing profound metabolic inflexibility in diabetes. American Journal of Physiology - Endocrinology & Metabolism, 290(5), E870-81 (2006)
doi:10.1152/ajpendo.00233.2005
PMid:16352676
228. T. S. Larsen and E. Aasum: Metabolic (in)flexibility of the diabetic heart. Cardiovascular Drugs & Therapy, 22(2), 91-5 (2008)
doi:10.1007/s10557-008-6083-1
PMid:18247112
229. A. N. Carley and D. L. Severson: Fatty acid metabolism is enhanced in type 2 diabetic hearts. Biochimica et Biophysica Acta, 1734(2), 112-26 (2005)
PMid:15904868
230. E. Aasum, A. D. Hafstad, D. L. Severson and T. S. Larsen: Age-dependent changes in metabolism, contractile function, and ischemic sensitivity in hearts from db/db mice. Diabetes, 52(2), 434-41 (2003)
doi:10.2337/diabetes.52.2.434
231. O. J. How, E. Aasum, D. L. Severson, W. Y. Chan, M. F. Essop and T. S. Larsen: Increased myocardial oxygen consumption reduces cardiac efficiency in diabetic mice. Diabetes, 55(2), 466-73 (2006)
doi:10.2337/diabetes.55.02.06.db05-1164
PMid:16443782
232. P. K. Mazumder, B. T. O'Neill, M. W. Roberts, J. Buchanan, U. J. Yun, R. C. Cooksey, S. Boudina and E. D. Abel: Impaired cardiac efficiency and increased fatty acid oxidation in insulin-resistant ob/ob mouse hearts. Diabetes, 53(9), 2366-74 (2004)
doi:10.2337/diabetes.53.9.2366
PMid:15331547
233. J. Buchanan, P. K. Mazumder, P. Hu, G. Chakrabarti, M. W. Roberts, U. J. Yun, R. C. Cooksey, S. E. Litwin and E. D. Abel: Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity. Endocrinology, 146(12), 5341-9 (2005)
doi:10.1210/en.2005-0938
PMid:16141388
234. 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 Journal, 18(14), 1692-700 (2004)
doi:10.1096/fj.04-2263com
PMid:15522914
235. M. E. Young, P. H. Guthrie, P. Razeghi, B. Leighton, S. Abbasi, S. Patil, K. A. Youker and H. Taegtmeyer: Impaired long-chain fatty acid oxidation and contractile dysfunction in the obese Zucker rat heart. Diabetes, 51(8), 2587-95 (2002)
doi:10.2337/diabetes.51.8.2587
PMid:12145175
236. O. J. How, T. S. Larsen, A. D. Hafstad, A. Khalid, E. S. Myhre, A. J. Murray, N. T. Boardman, M. Cole, K. Clarke, D. L. Severson and E. Aasum: Rosiglitazone treatment improves cardiac efficiency in hearts from diabetic mice. Archives of Physiology & Biochemistry, 113(4-5), 211-20 (2007)
doi:10.1080/13813450701783281
PMid:18158644
237. C. Korvald, O. P. Elvenes and T. Myrmel: Myocardial substrate metabolism influences left ventricular energetics in vivo. American Journal of Physiology - Heart & Circulatory Physiology, 278(4), H1345-51 (2000)
238. A. J. Gilde and M. Van Bilsen: Peroxisome proliferator-activated receptors (PPARS): regulators of gene expression in heart and skeletal muscle. Acta Physiologica Scandinavica, 178(4), 425-34 (2003)
doi:10.1046/j.1365-201X.2003.01161.x
PMid:12864748
239. A. J. Gilde, K. A. van der Lee, P. H. Willemsen, G. Chinetti, F. R. van der Leij, G. J. van der Vusse, B. Staels and M. van Bilsen: Peroxisome proliferator-activated receptor (PPAR) alpha and PPARbeta/delta, but not PPARgamma, modulate the expression of genes involved in cardiac lipid metabolism.(see comment). Circulation Research, 92(5), 518-24 (2003)
doi:10.1161/01.RES.0000060700.55247.7C
PMid:12600885
240. C. H. Lee, P. Olson and R. M. Evans: Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. Endocrinology, 144(6), 2201-7 (2003)
doi:10.1210/en.2003-0288
PMid:12746275
241. G. A. Francis, J. S. Annicotte and J. Auwerx: PPAR-alpha effects on the heart and other vascular tissues. American Journal of Physiology - Heart & Circulatory Physiology, 285(1), H1-9 (2003)
242. G. A. Francis, E. Fayard, F. Picard and J. Auwerx: Nuclear receptors and the control of metabolism. Annual Review of Physiology, 65, 261-311 (2003)
doi:10.1146/annurev.physiol.65.092101.142528
PMid:12518001
243. J. G. Duncan, J. L. Fong, D. M. Medeiros, B. N. Finck and D. P. Kelly: Insulin-resistant heart exhibits a mitochondrial biogenic response driven by the peroxisome proliferator-activated receptor-alpha/PGC-1alpha gene regulatory pathway. Circulation, 115(7), 909-17 (2007)
doi:10.1161/CIRCULATIONAHA.106.662296
PMid:17261654
244. B. N. Finck, J. J. Lehman, T. C. Leone, M. J. Welch, M. J. Bennett, A. Kovacs, X. Han, R. W. Gross, R. Kozak, G. D. Lopaschuk and D. P. Kelly: The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. Journal of Clinical Investigation, 109(1), 121-30 (2002)
PMid:11781357 PMCid:150824
245. C. R. Malloy, A. D. Sherry and F. M. Jeffrey: Evaluation of carbon flux and substrate selection through alternate pathways involving the citric acid cycle of the heart by 13C NMR spectroscopy. Journal of Biological Chemistry, 263(15), 6964-71 (1988)
PMid:3284880
246. G. Vincent, B. Bouchard, M. Khairallah and C. Des Rosiers: Differential modulation of citrate synthesis and release by fatty acids in perfused working rat hearts. American Journal of Physiology - Heart & Circulatory Physiology, 286(1), H257-66 (2004)
doi:10.1152/ajpheart.00717.2003
PMid:12933348
247. S. Soyal, F. Krempler, H. Oberkofler and W. Patsch: PGC-1alpha: a potent transcriptional cofactor involved in the pathogenesis of type 2 diabetes. Diabetologia, 49(7), 1477-88 (2006)
doi:10.1007/s00125-006-0268-6
248. C. Canto and J. Auwerx: PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Current Opinion in Lipidology, 20(2), 98-105 (2009)
doi:10.1097/MOL.0b013e328328d0a4
PMid:19276888
249. H. Liang and W. F. Ward: PGC-1alpha: a key regulator of energy metabolism. Advances in Physiology Education, 30(4), 145-51 (2006)
doi:10.1152/advan.00052.2006
PMid:17108241
250. P. Puigserver and B. M. Spiegelman: Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocrine Reviews, 24(1), 78-90 (2003)
doi:10.1210/er.2002-0012
PMid:12588810
251. E. H. Jeninga, K. Schoonjans and J. Auwerx: Reversible acetylation of PGC-1: connecting energy sensors and effectors to guarantee metabolic flexibility. Oncogene, 29(33), 4617-24 (2010)
doi:10.1038/onc.2010.206
PMid:20531298
252. V. K. Murthy and J. C. Shipp: Accumulation of myocardial triglycerides in ketotic diabetes; evidence for increased biosynthesis. Diabetes, 26(3), 222-9 (1977)
doi:10.2337/diabetes.26.3.222
PMid:402301
253. V. K. Murthy and J. C. Shipp: Heart triglyceride synthesis in diabetes: selective increase in activity of enzymes of phosphatidate synthesis. Journal of Molecular & Cellular Cardiology, 12(3), 299-309 (1980)
doi:10.1016/0022-2828(80)90042-5
254. M. Saddik and G. D. Lopaschuk: Triacylglycerol turnover in isolated working hearts of acutely diabetic rats. Canadian Journal of Physiology & Pharmacology, 72(10), 1110-9 (1994)
PMid:7882174
255. D. J. Paulson and M. F. Crass, 3rd: Endogenous triacylglycerol metabolism in diabetic heart. American Journal of Physiology, 242(6), H1084-94 (1982)
256. H. Yagyu, G. Chen, M. Yokoyama, K. Hirata, A. Augustus, Y. Kako, T. Seo, Y. Hu, E. P. Lutz, M. Merkel, A. Bensadoun, S. Homma and I. J. Goldberg: Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy. Journal of Clinical Investigation, 111(3), 419-26 (2003)
PMid:12569168 PMCid:151861
257. B. N. Finck, X. Han, M. Courtois, F. Aimond, J. M. Nerbonne, A. Kovacs, R. W. Gross and D. P. Kelly: A critical role for PPARalpha-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: modulation by dietary fat content. Proceedings of the National Academy of Sciences of the United States of America, 100(3), 1226-31 (2003)
doi:10.1073/pnas.0336724100
PMid:12552126 PMCid:298755
258. R. H. Unger: Lipotoxic diseases. Annual Review of Medicine, 53, 319-36 (2002)
doi:10.1146/annurev.med.53.082901.104057
PMid:11818477
259. R. H. Unger, G. O. Clark, P. E. Scherer and L. Orci: Lipid homeostasis, lipotoxicity and the metabolic syndrome. Biochimica et Biophysica Acta, 1801(3), 209-14 (2010)
PMid:19948243
260. M. Saddik and G. D. Lopaschuk: Myocardial triglyceride turnover during reperfusion of isolated rat hearts subjected to a transient period of global ischemia. Journal of Biological Chemistry, 267(6), 3825-31 (1992)
PMid:1740430
261. H. Tuunanen, E. Engblom, A. Naum, K. Nagren, B. Hesse, K. E. J. Airaksinen, P. Nuutila, P. Iozzo, H. Ukkonen, L. H. Opie and J. Knuuti: Free fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure. Circulation, 114(20), 2130-7 (2006)
doi:10.1161/CIRCULATIONAHA.106.645184
PMid:17088453
262. M. Yokoyama, H. Yagyu, Y. Hu, T. Seo, K. Hirata, S. Homma and I. J. Goldberg: Apolipoprotein B production reduces lipotoxic cardiomyopathy: studies in heart-specific lipoprotein lipase transgenic mouse. Journal of Biological Chemistry, 279(6), 4204-11 (2004)
doi:10.1074/jbc.M311995200
PMid:14634011
263. G. D. Lopaschuk, C. A. Hansen and J. R. Neely: Fatty acid metabolism in hearts containing elevated levels of CoA. American Journal of Physiology, 250(3 Pt 2), H351-9 (1986)
264. G. D. Lopaschuk and H. Tsang: Metabolism of palmitate in isolated working hearts from spontaneously diabetic "BB" Wistar rats. Circulation Research, 61(6), 853-8 (1987)
PMid:3315291
265. D. K. Reibel, B. W. Wyse, D. A. Berkich and J. R. Neely: Regulation of coenzyme A synthesis in heart muscle: effects of diabetes and fasting. American Journal of Physiology, 240(4), H606-11 (1981)
266. P. Jezek, M. Jaburek and K. D. Garlid: Channel character of uncoupling protein-mediated transport. FEBS Letters, 584(10), 2135-41 (2010)
doi:10.1016/j.febslet.2010.02.068
PMid:20206627
267. K. D. Garlid, M. Jaburek, P. Jezek and M. Varecha: How do uncoupling proteins uncouple? Biochimica et Biophysica Acta, 1459(2-3), 383-9 (2000)
doi:10.1016/S0005-2728(00)00175-4
268. P. Jezek, H. Engstova, M. Zackova, A. E. Vercesi, A. D. Costa, P. Arruda and K. D. Garlid: Fatty acid cycling mechanism and mitochondrial uncoupling proteins. Biochimica et Biophysica Acta, 1365(1-2), 319-27 (1998)
doi:10.1016/S0005-2728(98)00084-X
269. T. S. Park, Y. Hu, H. L. Noh, K. Drosatos, K. Okajima, J. Buchanan, J. Tuinei, S. Homma, X. C. Jiang, E. D. Abel and I. J. Goldberg: Ceramide is a cardiotoxin in lipotoxic cardiomyopathy.(see comment). Journal of Lipid Research, 49(10), 2101-12 (2008)
doi:10.1194/jlr.M800147-JLR200
PMid:18515784 PMCid:2533410
270. Y. T. Zhou, P. Grayburn, A. Karim, M. Shimabukuro, M. Higa, D. Baetens, L. Orci and R. H. Unger: Lipotoxic heart disease in obese rats: implications for human obesity. Proceedings of the National Academy of Sciences of the United States of America, 97(4), 1784-9 (2000)
doi:10.1073/pnas.97.4.1784
271. R. H. Unger and L. Orci: Lipoapoptosis: its mechanism and its diseases. Biochimica et Biophysica Acta, 1585(2-3), 202-12 (2002)
PMid:12531555
272. D. J. Paulson: The diabetic heart is more sensitive to ischemic injury. Cardiovascular Research, 34(1), 104-12 (1997)
doi:10.1016/S0008-6363(97)00018-7
273. L. M. King, R. J. Sidell, J. R. Wilding, G. K. Radda and K. Clarke: Free fatty acids, but not ketone bodies, protect diabetic rat hearts during low-flow ischemia. American Journal of Physiology - Heart & Circulatory Physiology, 280(3), H1173-81 (2001)
274. Y.-G. Niu and R. D. Evans: Metabolism of very-low-density lipoprotein and chylomicrons by streptozotocin-induced diabetic rat heart: effects of diabetes and lipoprotein preference. American Journal of Physiology - Endocrinology & Metabolism, 295(5), E1106-16 (2008)
doi:10.1152/ajpendo.90260.2008
PMid:18780778
275. Y.-G. Niu and R. D. Evans: Myocardial metabolism of triacylglycerol-rich lipoproteins in type 2 diabetes. Journal of Physiology, 587(Pt 13), 3301-15 (2009)
doi:10.1113/jphysiol.2009.173542
PMid:19433573 PMCid:2727038
276. E. J. Blanchette-Mackie, H. Masuno, N. K. Dwyer, T. Olivecrona and R. O. Scow: Lipoprotein lipase in myocytes and capillary endothelium of heart: immunocytochemical study. Am J Physiol, 256, E818-28 (1989)
277. T. Pulinilkunnil, A. Abrahani, J. Varghese, N. Chan, I. Tang, S. Ghosh, J. Kulpa, M. Allard, R. Brownsey and B. Rodrigues: Evidence for rapid "metabolic switching" through lipoprotein lipase occupation of endothelial-binding sites. Journal of Molecular & Cellular Cardiology, 35(9), 1093-103 (2003)
doi:10.1016/S0022-2828(03)00205-0
278. D. An, T. Pulinilkunnil, D. Qi, S. Ghosh, A. Abrahani and B. Rodrigues: The metabolic "switch" AMPK regulates cardiac heparin-releasable lipoprotein lipase. American Journal of Physiology - Endocrinology & Metabolism, 288(1), E246-53 (2005)
doi:10.1152/ajpendo.00211.2004
PMid:15328075
279. R. Rauramaa, P. Kuusela and E. Hietanen: Adipose, muscle and lung tissue lipoprotein lipase activities in young streptozotocin treated rats. Hormone & Metabolic Research, 12(11), 591-5 (1980)
doi:10.1055/s-2007-999207
PMid:6450721
280. A. Cryer and H. M. Jones: The distribution of lipoprotein lipase (clearing factor lipase) activity in the adiposal, muscular and lung tissues of ten animal species. Comparative Biochemistry & Physiology - B: Comparative Biochemistry, 63(4), 501-5 (1979)
doi:10.1016/0305-0491(79)90053-1
281. T. Ruge, M. Svensson, J. W. Eriksson and G. Olivecrona: Tissue-specific regulation of lipoprotein lipase in humans: effects of fasting. European Journal of Clinical Investigation, 35(3), 194-200 (2005)
doi:10.1111/j.1365-2362.2005.01470.x
PMid:15733074
282. B. Rodrigues, M. C. Cam, K. Jian, F. Lim, N. Sambandam and G. Shepherd: Differential effects of streptozotocin-induced diabetes on cardiac lipoprotein lipase activity. Diabetes, 46(8), 1346-53 (1997)
doi:10.2337/diabetes.46.8.1346
PMid:9231661
283. C. Linder, S. S. Chernick, T. R. Fleck and R. O. Scow: Lipoprotein lipase and uptake of chylomicron triglyceride by skeletal muscle of rats. American Journal of Physiology, 231(3), 860-4 (1976)
PMid:970468
284. K. Tavangar, Y. Murata, M. E. Pedersen, J. F. Goers, A. R. Hoffman and F. B. Kraemer: Regulation of lipoprotein lipase in the diabetic rat. Journal of Clinical Investigation, 90(5), 1672-8 (1992)
doi:10.1172/JCI116039
PMid:1430198 PMCid:443223
285. B. Rodrigues and D. L. Severson: Acute diabetes does not reduce heparin-releasable lipoprotein lipase activity in perfused hearts from Wistar-Kyoto rats. Canadian Journal of Physiology & Pharmacology, 71(9), 657-61 (1993)
PMid:8313228
286. K. Kobayashi, T. M. Forte, S. Taniguchi, B. Y. Ishida, K. Oka and L. Chan: The db/db mouse, a model for diabetic dyslipidemia: molecular characterization and effects of Western diet feeding. Metabolism: Clinical & Experimental, 49(1), 22-31 (2000)
doi:10.1016/S0026-0495(00)90588-2
287. Y. Deshaies, A. Geloen, A. Paulin and L. J. Bukowiecki: Restoration of lipoprotein lipase activity in insulin-deficient rats by insulin infusion is tissue-specific. Canadian Journal of Physiology & Pharmacology, 69(6), 746-51 (1991)
PMid:1913321
288. E. Levy and M. Bendayan: Lipoprotein lipase in experimental diabetic rats: beneficial effect of vanadate treatment. Diabete et Metabolisme, 17(1), 44-8 (1991)
PMid:1868959
289. P. O'Looney, M. Vander Maten and G. V. Vahouny: Insulin-mediated modifications of myocardial lipoprotein lipase and lipoprotein metabolism. Journal of Biological Chemistry, 258(21), 12994-3001 (1983)
PMid:6355100
290. L. Liu and D. L. Severson: Endothelial binding sites for lipoprotein lipase are not diminished in perfused hearts from diabetic rats. Canadian Journal of Physiology & Pharmacology, 74(11), 1204-9 (1996)
doi:10.1139/cjpp-74-11-1204
PMid:9028578
291. J. E. Braun and D. L. Severson: Diabetes reduces heparin- and phospholipase C-releasable lipoprotein lipase from cardiomyocytes. American Journal of Physiology, 260(3 Pt 1), E477-85 (1991)
292. A. Boivin and Y. Deshaies: Contribution of hyperinsulinemia to modulation of lipoprotein lipase activity in the obese Zucker rat. Metabolism: Clinical & Experimental, 49(1), 134-40 (2000)
doi:10.1016/S0026-0495(00)91013-8
293. P. Pillutla, Y. C. Hwang, A. Augustus, M. Yokoyama, H. Yagyu, T. P. Johnston, M. Kaneko, R. Ramasamy and I. J. Goldberg: Perfusion of hearts with triglyceride-rich particles reproduces the metabolic abnormalities in lipotoxic cardiomyopathy. American Journal of Physiology - Endocrinology & Metabolism, 288(6), E1229-35 (2005)
doi:10.1152/ajpendo.00273.2004
PMid:15701679
294. S. Levak-Frank, W. Hofmann, P. H. Weinstock, H. Radner, W. Sattler, J. L. Breslow and R. Zechner: Induced mutant mouse lines that express lipoprotein lipase in cardiac muscle, but not in skeletal muscle and adipose tissue, have normal plasma triglyceride and high-density lipoprotein-cholesterol levels. Proceedings of the National Academy of Sciences of the United States of America, 96(6), 3165-70 (1999)
doi:10.1073/pnas.96.6.3165
295. A. N. Carley, L. L. Atkinson, A. Bonen, M.-E. Harper, S. Kunnathu, G. D. Lopaschuk and D. L. Severson: Mechanisms responsible for enhanced fatty acid utilization by perfused hearts from type 2 diabetic db/db mice. Archives of Physiology and Biochemistry, 113(2), 65-75 (2007)
doi:10.1080/13813450701422617
PMid:17558605
296. A. N. Carley and D. L. Severson: What are the biochemical mechanisms responsible for enhanced fatty acid utilization by perfused hearts from type 2 diabetic db/db mice? Cardiovascular Drugs & Therapy, 22(2), 83-9 (2008)
doi:10.1007/s10557-008-6088-9
PMid:18247111
297. G. H. Tomkin and D. Owens: Abnormalities in apo B-containing lipoproteins in diabetes and atherosclerosis. Diabetes/Metabolism Research Reviews, 17(1), 27-43 (2001)
doi:10.1002/dmrr.179
PMid:11241889
298. J. McEneny, M. J. O'Kane, K. W. Moles, C. McMaster, D. McMaster, C. Mercer, E. R. Trimble and I. S. Young: Very low density lipoprotein subfractions in Type II diabetes mellitus: alterations in composition and susceptibility to oxidation. Diabetologia, 43(4), 485-93 (2000)
doi:10.1007/s001250051333
PMid:10819243
299. J. G. Duncan, K. G. Bharadwaj, J. L. Fong, R. Mitra, N. Sambandam, M. R. Courtois, K. J. Lavine, I. J. Goldberg and D. P. Kelly: Rescue of cardiomyopathy in peroxisome proliferator-activated receptor-alpha transgenic mice by deletion of lipoprotein lipase identifies sources of cardiac lipids and peroxisome proliferator-activated receptor-alpha activators. Circulation, 121(3), 426-35 (2010)
doi:10.1161/CIRCULATIONAHA.109.888735
PMid:20065164 PMCid:2825753
300. R. Carroll and D. L. Severson: Peroxisome proliferator-activated receptor-alpha ligands inhibit cardiac lipoprotein lipase activity. American Journal of Physiology - Heart & Circulatory Physiology, 281(2), H888-94 (2001)
301. R. K. Vikramadithyan, K. Hirata, H. Yagyu, Y. Hu, A. Augustus, S. Homma and I. J. Goldberg: Peroxisome proliferator-activated receptor agonists modulate heart function in transgenic mice with lipotoxic cardiomyopathy. Journal of Pharmacology & Experimental Therapeutics, 313(2), 586-93 (2005)
doi:10.1124/jpet.104.080259
PMid:15671204
302. M. S. Kim, G. Kewalramani, P. Puthanveetil, V. Lee, U. Kumar, D. An, A. Abrahani and B. Rodrigues: Acute diabetes moderates trafficking of cardiac lipoprotein lipase through p38 mitogen-activated protein kinase-dependent actin cytoskeleton organization. Diabetes, 57(1), 64-76 (2008)
doi:10.2337/db07-0832
PMid:17942824
303. D. Hauton: Does long-term metformin treatment increase cardiac lipoprotein lipase? Metabolism: Clinical & Experimental, 60(1), 32-42 (2011)
doi:10.1016/j.metabol.2009.12.015
PMid:20153488 PMCid:3004047
304. M. Ohira, Y. Miyashita, T. Murano, F. Watanabe and K. Shirai: Metformin promotes induction of lipoprotein lipase in skeletal muscle through activation of adenosine monophosphate-activated protein kinase. Metabolism: Clinical & Experimental, 58(10), 1408-14 (2009)
doi:10.1016/j.metabol.2009.04.024
PMid:19570550
305. M. L. Brown, M. P. Ramprasad, P. K. Umeda, A. Tanaka, Y. Kobayashi, T. Watanabe, H. Shimoyamada, W. L. Kuo, R. Li, R. Song, W. A. Bradley and S. H. Gianturco: A macrophage receptor for apolipoprotein B48: cloning, expression, and atherosclerosis. Proceedings of the National Academy of Sciences of the United States of America, 97(13), 7488-93 (2000)
doi:10.1073/pnas.120184097
PMid:10852956
306. S. S. Jain, A. Chabowski, L. A. Snook, R. W. Schwenk, J. F. Glatz, J. J. Luiken and A. Bonen: Additive effects of insulin and muscle contraction on fatty acid transport and fatty acid transporters, FAT/CD36, FABPpm, FATP1, 4 and 6. FEBS Letters, 583(13), 2294-300 (2009)
doi:10.1016/j.febslet.2009.06.020
PMid:19527715
307. R. Zechner: The tissue-specific expression of lipoprotein lipase: implications for energy and lipoprotein metabolism. Current Opinion in Lipidology, 8(2), 77-88 (1997)
doi:10.1097/00041433-199704000-00005
PMid:9183545
308. M. Merkel, Y. Kako, H. Radner, I. S. Cho, R. Ramasamy, J. D. Brunzell, I. J. Goldberg and J. L. Breslow: Catalytically inactive lipoprotein lipase expression in muscle of transgenic mice increases very low density lipoprotein uptake: direct evidence that lipoprotein lipase bridging occurs in vivo. Proceedings of the National Academy of Sciences of the United States of America, 95(23), 13841-6 (1998)
doi:10.1073/pnas.95.23.13841
309. T. Iwasaki, S. Takahashi, M. Takahashi, Y. Zenimaru, T. Kujiraoka, M. Ishihara, M. Nagano, J. Suzuki, I. Miyamori, H. Naiki, J. Sakai, T. Fujino, N. E. Miller, T. T. Yamamoto and H. Hattori: Deficiency of the very low-density lipoprotein (VLDL) receptors in streptozotocin-induced diabetic rats: insulin dependency of the VLDL receptor. Endocrinology, 146(8), 3286-94 (2005)
doi:10.1210/en.2005-0043
PMid:15878964
310. H. Yagyu, E. P. Lutz, Y. Kako, S. Marks, Y. Hu, S. Y. Choi, A. Bensadoun and I. J. Goldberg: Very low density lipoprotein (VLDL) receptor-deficient mice have reduced lipoprotein lipase activity. Possible causes of hypertriglyceridemia and reduced body mass with VLDL receptor deficiency. Journal of Biological Chemistry, 277(12), 10037-43 (2002)
doi:10.1074/jbc.M109966200
PMid:11790777
311. J. C. Obunike, E. P. Lutz, Z. Li, L. Paka, T. Katopodis, D. K. Strickland, K. F. Kozarsky, S. Pillarisetti and I. J. Goldberg: Transcytosis of lipoprotein lipase across cultured endothelial cells requires both heparan sulfate proteoglycans and the very low density lipoprotein receptor. Journal of Biological Chemistry, 276(12), 8934-41 (2001)
doi:10.1074/jbc.M008813200
PMid:11121409
312. X. Yu, S. C. Burgess, H. Ge, K. K. Wong, R. H. Nassem, D. J. Garry, A. D. Sherry, C. R. Malloy, J. P. Berger and C. Li: Inhibition of cardiac lipoprotein utilization by transgenic overexpression of Angptl4 in the heart. Proceedings of the National Academy of Sciences of the United States of America, 102(5), 1767-72 (2005)
doi:10.1073/pnas.0409564102
PMid:15659544 PMCid:547881
313. D. Ricart-Jane, P. Cejudo-Martin, J. Peinado-Onsurbe, M. D. Lopez-Tejero and M. Llobera: Changes in lipoprotein lipase modulate tissue energy supply during stress. Journal of Applied Physiology, 99(4), 1343-51 (2005)
doi:10.1152/japplphysiol.00971.2004
PMid:15947029
314. G. Kewalramani, P. Puthanveetil, M. S. Kim, F. Wang, V. Lee, N. Hau, E. Beheshti, N. Ng, A. Abrahani and B. Rodrigues: Acute dexamethasone-induced increase in cardiac lipoprotein lipase requires activation of both Akt and stress kinases. American Journal of Physiology - Endocrinology & Metabolism, 295(1), E137-47 (2008)
doi:10.1152/ajpendo.00004.2008
PMid:18460599
315. Y. Deshaies, A. Geloen, A. Paulin, A. Marette and L. J. Bukowiecki: Tissue-specific alterations in lipoprotein lipase activity in the rat after chronic infusion of isoproterenol. Hormone & Metabolic Research, 25(1), 13-6 (1993)
doi:10.1055/s-2007-1002036
PMid:8428704
316. D. L. Severson, R. Carroll, A. Kryski, Jr. and I. Ramirez: Short-term incubation of cardiac myocytes with isoprenaline has no effect on heparin-releasable or cellular lipoprotein lipase activity. Biochemical Journal, 248(1), 289-92 (1987)
PMid:2829825 PMCid:1148534
317. R. Carroll, A. N. Carley, J. R. Dyck and D. L. Severson: Metabolic effects of insulin on cardiomyocytes from control and diabetic db/db mouse hearts. American Journal of Physiology - Endocrinology & Metabolism, 288(5), E900-6 (2005)
doi:10.1152/ajpendo.00491.2004
PMid:15632103
318. T. Utriainen, T. Takala, M. Luotolahti, T. Ronnemaa, H. Laine, U. Ruotsalainen, M. Haaparanta, P. Nuutila and H. Yki-Jarvinen: Insulin resistance characterizes glucose uptake in skeletal muscle but not in the heart in NIDDM. Diabetologia, 41(5), 555-9 (1998)
doi:10.1007/s001250050946
PMid:9628273
319. J. C. Chatham and A. M. Seymour: Cardiac carbohydrate metabolism in Zucker diabetic fatty rats. Cardiovascular Research, 55(1), 104-12 (2002)
doi:10.1016/S0008-6363(02)00399-1
320. D. D. Belke, T. S. Larsen, E. M. Gibbs and D. L. Severson: Altered metabolism causes cardiac dysfunction in perfused hearts from diabetic (db/db) mice. American Journal of Physiology - Endocrinology & Metabolism, 279(5), E1104-13 (2000)
321. M. Panagia, J. E. Schneider, B. Brown, M. A. Cole and K. Clarke: Abnormal function and glucose metabolism in the type-2 diabetic db/db mouse heart. Canadian Journal of Physiology & Pharmacology, 85(3-4), 289-94 (2007)
doi:10.1139/Y07-028
PMid:17612636
322. M. Panagia, G. F. Gibbons, G. K. Radda and K. Clarke: PPAR-alpha activation required for decreased glucose uptake and increased susceptibility to injury during ischemia. American Journal of Physiology - Heart & Circulatory Physiology, 288(6), H2677-83 (2005)
doi:10.1152/ajpheart.00200.2004
PMid:15665064
Key Words: Heart, Metabolism; Disease, Review
Send correspondence to: Rhys D. Evans, Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, South Parks Road, Oxford OX1 3PT, U.K., Tel: 4401865 272445, Fax: 4401865 282272, E-mail:rhys.evans@dpag.ox.ac.uk