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For more than half a century, metabolic perturbations have been explored in the failing myocardium, highlighting a reversion to a more fetal-like metabolic profile (characterized by depressed fatty acid oxidation and concomitant increased reliance on glucose utilization). More recently, alterations in ketone body and amino acid/protein metabolism have been described during heart failure, as well as mitochondrial dysfunction and perturbed metabolic signaling (e.g., acetylation, O-GlcNAcylation). Although numerous mechanisms are likely involved, the current review provides recent advances regarding the metabolic origins of heart failure, and their potential contribution toward contractile dysfunction of the heart.
In order to meet the exceptionally high metabolic demands of continuous contractility, the heart catabolizes a vast array of substrates. Indeed, the heart has been termed a ‘metabolic omnivore’, capable of consuming fatty acids, glucose, ketone bodies, and amino acids, for the replenishment of ATP. Central to achievement of this goal is metabolic flexibility, wherein the heart shifts reliance from one substrate to another, in response to acute perturbations in workload and/or substrate availability (including feeding-fasting and sleep-wake cycle, which occur on a daily basis). The importance of metabolic flexibility is underscored by appreciation that various substrates are more than just a fuel for the heart, serving also as building blocks for numerous cellular components (e.g., membranes, proteins), cofactors, and signaling molecules. During various disease states, particularly heart failure (HF), cardiac metabolism is perturbed in a chronic manner, resulting in metabolic inflexibility. Thus, HF is characterized by relatively permanent and predictable shifts in metabolism, associated with impaired signaling (e.g., Ca2+, ROS), energy insufficiency, and contractile dysfunction. The purpose of this review is to highlight recent insights regarding the metabolic basis of heart failure; for the contribution of perturbed Ca2+ homeostasis and ROS signaling, the reader is directed to the following reviews (1,2).
Fatty acid oxidation (FAO) represents a significant fuel source for the myocardium, providing an estimated 50%-70% of the ATP consumed during contraction (reviewed in (3)). In comparison to carbohydrate utilization, rates of cardiac FAO are relatively unaffected by acute changes in workload/energetic demand (4,5). Cardiac FAO typically exhibits greater flexibility following changes in substrate availability (6). Such observations could be generalized as an indication of FAO to maintain baseline energetic needs of the heart, while at the same time matching rates of fatty acid uptake with oxidation. If true, then deficits in cardiac FAO could potentially precipitate contractile dysfunction through energetic impairment and/or diverting of excess fatty acids into signaling and/or ‘lipotoxic’ pathways. The purpose of this subsection is to review evidence supporting these concepts.
One of the most consistent metabolic perturbations during HF is decreased fatty acid utilization, being observed in both animal-based and human studies (7-11). In doing so, the failing heart reverts to a fetal-like metabolic program, reflected by a repression of various genes encoding for core FAO pathway proteins (e.g., medium chain acyl-CoA dehydrogenase, beta-hydroxyacyl-CoA dehydrogenase) and their upstream regulators (e.g. PPARα, RXRα, PGC-1α) (12,13). It has been proposed that acutely this metabolic perturbation serves as an adaptation, by promoting increased reliance on more energetically efficient fuels (in terms of ATP per oxygen molecule consumed), which may be particularly important in the setting of ischemic heart disease (14). Consistent with this concept, attenuation of FAO is observed prior to the onset of contractile dysfunction (induced, for example, by pressure overload) (15). However, this metabolic reprogramming causes chronic dyssynchrony between energetic demand (which is increased), substrate availability (circulating fatty acids are typically increased), and utilization (i.e., FAO is decreased) during HF. In other words, a decrease in FAO rates could reduce ATP availability for contraction (if below the capacity of alternative compensating pathways) concomitant with increased diverting of fatty acid species into signaling/lipotoxic pathways, culminating in contractility impairment. Evidence in support of this concept includes reports of modest perturbations in markers of energetic status in the failing myocardium, as well as accumulation of lipotoxic markers (16-18). The latter, when elevated, can contribute to cell death and cardiac remodeling.
Both genetic and pharmacologic approaches have been utilized to address causal relationships between FAO impairment and HF. Genetic studies revealed that inborne errors of FAO, such as inherited deficiencies in acyl-CoA dehydrogenases, can be associated with cardiomyopathy in humans; similar pathologies are often recapitulated through targeted genetic manipulation in mouse models (reviewed in (19)). One example includes very long chain acyl-CoA dehydrogenase (VLCAD); germline deletion results in energetic impairment and a cardiomyopathic phenotype (20). Importantly, cardiac-restricted VLCAD deletion also results in contractile dysfunction, illustrating the importance of normal cardiac FA metabolism (21). Similarly, genetic deletion of lipoprotein lipase (LPL; liberates fatty acids from circulating lipoproteins), long chain acyl-CoA synthetase 1 (ACSL1; activates long chain FAs for metabolism), and adipose triglyceride lipase (ATGL; liberates fatty acids from intracellular triglyceride stores) result in concomitant decreases in cardiac FAO and contractile function (22-24). It is noteworthy, however, that genetic mutations resulting in decreased cardiac FAO do not always result in contractile dysfunction. For example, knockout of CD36 (fatty acid transporter) or PPARα/PGC-1α (transcription factors promoting FAO/mitochondrial metabolism) results in decreased FAO without effects on basal contractility (25-27). Possible explanations for the latter discrepancies include: 1) FAO is only modestly impaired; 2) sufficient compensation from alternative substrate utilization occurs; 3) diverting of fatty acids species into lipotoxic pathways is limited; and/or 4) a secondary stress is required to elicit dysfunction (e.g., pressure overload, high fat diet, etc).
If acquired deficiencies in cardiac FAO were to contribute significantly towards contractile dysfunction of the failing myocardium, then normalization of the fatty acid oxidation deficit would be predicted to improve contractility. Both genetic and dietary strategies have been employed to address this concept. An important example includes the study by Kolwicz et al, wherein selective deletion of acetyl-CoA carboxylase 2, an enzyme that generates malonyl-CoA (a potent inhibitor of β-oxidation), prevents pressure overload-induced depression of fatty acid oxidation, and concomitantly maintains contractile function (28). Interestingly, feeding rodents calorically-dense high fat diets has been shown to preserve/improve contractility in distinct models of heart failure (including pressure overload, myocardial infarction, and hypertension), although not all studies report this benefit (perhaps due to differences in dietary composition, duration of feeding, etc) (29-33). Observations such as these raise the question whether cardiac FAO impairment primarily leads to energetic deficiency, as opposed to lipotoxicity/signaling imbalance. However, strategies designed to cause a mismatch between FA uptake and FAO (e.g., overexpression of FATP1 or ACSL1) invariably result in cardiomyopathy, associated with markers of lipotoxicity (34,35). In addition, the failing heart is considered to be in a pro-lipotoxic environment (36). Furthermore, haploinsufficiency of mCPT1 increases susceptibility to pressure overload-induced cardiac dysfunction through lipotoxic pathways (37). Similarly, germline VLCAD deletion increases cardiac lipotoxicity during high fat feeding (38). Collectively, these studies suggest that impaired cardiac FAO could lead to cardiac dysfunction not only through energetic deficiency, but also through lipotoxicity.
Various mechanisms have been proposed as mediators of cardiac FAO impairment during HF. These include transcriptionally-based mechanisms, post-translational modifications (PTMs), mitochondrial dysfunction, cofactor availability, and substrate competition. With regards to transcriptionally-based mechanisms, particular attention has been given to multiple PPAR isoforms (particularly PPARα); upon complex formation with RXRα, FAs (ligand), and coactivators (e.g., PGC-lα), PPARα induces a number of genes encoding for known FA transporters and core (β-oxidation enzymes (reviewed in (13)). Importantly, during HF, cardiac levels of PPARα, RXRα, and PGC-lα have been shown to decrease to varying degrees, associated with decreased expression of target genes (8,12). Furthermore, PPARα activity may be repressed further through PTMs (39). The enzymes involved in FA metabolism also undergo PTMs during HF, such as acetylation; this PTM potentially promotes FAO in the heart both directly (i.e., acetylation and activation of β-oxidation enzymes) and/or indirectly (i.e., acetylation and inhibition of pyruvate dehydrogenase, and therefore impairment of glucose oxidation) (40,41). It is noteworthy that cardiac FAO capacity is extremely high, such that enzymes involved in β-oxidation must be inhibited markedly in order to impact FAO flux. This is exemplified by VLCAD and CPTlb heterozygous knockout mouse hearts, which exhibit no baseline phenotype despite a 50% loss in enzymatic activity (21,37); homozygous cardiomyocyte-specific knockout of VLCAD also has no significant effects on cardiac FAO rates, likely due to compensation by other acyl-CoA dehydrogenase isoforms (e.g., LCAD) (21). In contrast, cardiac FAO is affected by cofactor availability (e.g., carnitine, CoA) and/or mitochondrial function, which are decreased in the failing myocardium (42-44); decreased carnitine would attenuate mitochondrial fatty acid uptake, decreased CoA would attenuate β-oxidation, while limited mitochondrial electron transfer would attenuate dehydrogenases in the β-oxidation spiral. Furthermore, increased reliance on alternative substrates (e.g., glucose and ketone bodies, as discussed below) during HF would attenuate FAO through established allosteric and cofactor limitation mechanisms. In the failing myocardium, all the above referenced mechanisms likely contribute towards attenuated FAO.
Cardiac glucose utilization (i.e., glycolysis and glucose oxidation; GLOX), is important for the developing (fetal) heart, during which time glucose delivery is high, and oxygen availability is relatively low (45). Soon after birth, glucose utilization decreases concomitant with increased dietary FA and oxygen delivery. However, the healthy adult heart has the capacity to increase reliance on glucose utilization in response to both physiologic (e.g., exercise) and pathologic (e.g., ischemia) stresses. During HF, metabolic flexibility is lost, which may be due in part to cardiac insulin resistance (IR); complex alterations in insulin signaling within cardiomyocytes during HF have been reviewed recently (46). It has been suggested that under some circumstances (e.g., hemodynamic stress) that IR may actually protect the heart, by reducing fuel toxicity (47). However, as HF progresses, an uncoupling between glycolysis and GLOX ensues, potentially contributing towards cellular dysfunction (48). Interestingly, circulating glucose levels tend to be elevated during both acute and chronic HF. For example, elevated serum glucose levels at the time of hospital admission for acute HF syndromes, independent of diabetes status, are associated with higher mortality (49,50). Chronically, HF is also associated with peripheral IR. Whether these perturbations in cardiac and/or whole body glucose homeostasis contribute to the pathogenesis of HF is still under debate (51). The purpose of this subsection (summarized in Figure 1) is to review current knowledge regarding the utilization of glucose during heart failure; we will focus primarily on this independent of diabetes status, as the latter has been reviewed extensively elsewhere (52-54).
Whether perturbations in cardiac glucose utilization are adaptive or maladaptive during HF appears to be dependent on the underlying stress (i.e., ischemic versus non-ischemic), as well as duration (i.e., acute versus chronic). In the context of hypertension induced dilated cardiomyopathy, glucose utilization is increased, with a predominate augmentation of glucose uptake and glycolysis, and a concomitant uncoupling of glycolytic flux from GLOX (48,55). There is mounting evidence that the remodeling of glucose metabolism is one of the initial changes driving the heart to hypertrophy and could act as an early marker of disease progression (56). Acutely enhancing glucose metabolism in the setting of ischemic injury and ventricular fibrillation may be protective (57,58).
Regulation of glucose uptake into the cardiomyocyte is regulated by members of the solute carrier family 2A (SLC2A) that encode the GLUT proteins (55,59). Of the twelve SLC2A genes expressed in human and rodent cardiac tissue, three are predominantly expressed in the myocardium: GLUT1, GLUT4, and GLUT8 (60). Of these GLUT1 and GLUT4 have received extensive attention, in part due to observations that both are decreased in failing human hearts (61). Such observations are consistent with repressed insulin-mediated glucose uptake (primarily through GLUT4) during HF, potentially secondary to chronic activation of GRK2 and IR (62). However, during HF, basal rates of glucose uptake and glycolysis are elevated (and even exceed rates of glucose oxidation) (63). One possible explanation for this apparent disconnect is increased GLUT translocation/activity, in an insulin-independent manner. A number of cardiomyocyte-specific gain- and loss-of-function models have been employed in an attempt to address this question, as well as the importance of glucose utilization during HF.
A number of studies have interrogated the importance of various GLUT isoforms in the maintenance of cardiac function. Lifelong GLUT1 overexpression protects against pressure overload-induced contractile dysfunction (64), while acute GLUT1 augmentation partially rescues disease progression (65), suggesting that enhanced glucose uptake is protective in this setting. However, cardiomyocyte-specific ablation of GLUT1 did not exacerbate pressure-overload induced dysfunction (perhaps due to sufficient glucose uptake by other GLUT isoforms) (66). Conversely, cardiomyocyte specific GLUT4 ablation decreased functional recovery in response to ischemic injury (67). Although loss of GLUT8 has been explored in the context of diet-induced obesity (68), a direct role during HF remains to be explored. Studies of these transporters, as well as those of the other cardiac enriched GLUTs (GLUT3, GLUT10, and GLUT12), will continue to provide crucial insight into the contribution of glucose uptake and metabolism during the progression of HF.
An emerging area has focused on non-GLUT mediated glucose transport via the sodium-glucose cotransporters (SGLT), especially given that empagliflozin (an SGLT2 inhibitor) decreased HF incidence in diabetic patients (69). The mechanism of this protection is likely multifaceted, including both glucose and sodium lowering, as well as influences on glomerular filtration and the cardiorenal axis (70). Interestingly, SGLT1 is induced in the heart during both diabetic and ischemic cardiomyopathy (71), and phlorizin (another SGLT inhibitor) decreased cardiac glucose uptake and directly affects tolerance of the heart to ischemia (72). Future studies will undoubtedly reveal important insights regarding the effects of SGLT inhibitors on cardiac metabolism and protection.
Augmented glucose uptake and glycolytic flux, particularly when in excess of GLOX, enhances diverting of glucose moieties into signaling pathways. This includes the polyol pathway. Although primarily implicated in diabetic complications, overexpression of aldose reductase (AR), the first step in this pathway, results in an age-related decline in heart function and exacerbated ischemic injury (73). Further studies are warranted in order to elucidate fully the importance of the polyol pathway in the pathogenesis of HF.
The PPP is important for NADPH and ribose-5-phosphate generation. In a canine model of congestive HF, post-prandial glycemic levels were sufficient to increase PPP flux. When this was prevented, cardiac GLOX and stroke work were normalized (74). Furthermore, in a genetic mouse model of dilated cardiomyopathy that progresses to HF, non-oxidative glucose pathways such as the PPP and glycogen synthesis were increased (75). The PPP affects ROS balance, not only through NADPH, but via regulation by pyridine nucleotides (76). Interestingly, glucose-6-phosphate dehydrogenase (G6PD; first enzyme of the PPP) deficiency is associated with cardiac disease progression; however, mice with G6PD deletion have shown both protective and deleterious effects on cardiac function (77), suggesting the need for further study.
The HBP requires input from glucose, amino acids, fatty acids, and nucleotides, resulting in the end product, UDP-GlcNAc. This molecule in turn is used to regulate nearly all aspects of cell physiology via the PTM of serine and threonine residues by the addition of an O-linked N-acetylglucosamine (O-GlcNAc) (78).This O-GlcNAc modification is elevated in both hypertrophy and HF (79), and has both adaptive and maladaptive contributions to cardiac function (80,81). Specifically, increased O-GlcNAc is protective following acute ischemic injury, while during HF, elevated O-GlcNAc may contribute to contractile and mitochondrial dysfunction. O-GlcNAc likely impacts a number of cardiac processes, including transcription, epigenetics, metabolism, and Ca2+ handling. In the latter case, O-GlcNAc can regulate SERC2A, CaMKII, and STIM1 (82-85), either increasing or decreasing calcium sensitivity depending on the duration and disease state (e.g., ischemic or non-ischemic).
Compared with fatty acid and glucose metabolism, current knowledge of the role of altered ketone body metabolism during HF is relatively limited. However, a growing body of evidence from pharmacological (86,87), dietary (87-90), and genetic (91) manipulation studies suggest that perturbations of ketone body utilization can play a role in cardiac health and disease. The heart readily utilizes ketone bodies, such that their oxidation is typically increased in proportion to their delivery (92). Acetoacetate (AcAc) and β-hydroxybutyrate (βOHB) are the primary ketone bodies that can be metabolized, which are synthesized by the liver during periods of elevated fatty acid availability, including fasting, prolonged exercise, ketogenic diets, uncontrolled type 1 diabetes, and HF (93). In the latter case, multiple studies have consistently shown that HF patients with no previous history of diabetes present with elevated levels of systemic ketone bodies (94,95). During heart failure, elevated norepinephrine levels secondary to increased sympathetic outflow likely promotes ketogenesis by increasing fatty acid supply via lipolysis in adipose tissue (96). The strength of these associations is such that exhaled acetone (indication of ketoacidosis) is a predictive biomarker for severity of heart failure (97-99). It is noteworthy, however, that a recent study reported reduced circulating ketone body levels in HF patients with reduced ejection fraction (EF) relative to HF patients with preserved ejection fraction and non-HF controls (100). Severity of HF and other co-morbidities associated with the patients recruited in these studies could potentially account for these discrepancies.
Whether altered myocardial ketone body metabolism contributes to the pathogenesis of HF was recently investigated in rodents and humans (101,102). These studies reported increased expression of ketone body metabolism enzymes (D-β-hydroxybutyrate dehydrogenase (BDH1) and succinyl-CoA:3-oxoacid CoA transferase (SCOT), reduced intermediary metabolites of ketone body catabolism, as well as increased ketone body oxidation (stable isotope measurements) in the failing heart. An important question relates to whether increased ketone body utilization during HF is adaptive or maladaptive. In support of an adaptive role, cardiomyocyte-specific deletion of SCOT led to adverse cardiac remodeling following pressure overload (91). However, these studies do not address whether normalization of ketone body utilization, particularly in the setting of heart failure, is beneficial or detrimental (as opposed to ablation during compensated hypertrophy). Interestingly, elevated ketone body availability would be anticipated to repress both FAO and GLOX in the heart through substrate competition, thus resulting in a metabolic signature reminiscent of advanced HF. Furthermore, ketone bodies serve as signaling molecules, acting through both extracellular receptors (e.g., GPR41) and intracellular inhibitors of histone deacetylases (HDACs) (86,103), which in turn could influence cardiac processes (Figure 2). The mechanisms by which ketone body utilization enzymes are induced during HF also remain unanswered. Future studies interrogating these questions are warranted, which will aid in understanding the role ketone body metabolism in the pathogenesis of HF.
When compared to fatty acids and glucose, amino acids quantitatively contribute to a lesser degree towards ATP generation in the heart. However, amino acids play essential roles in myocardial function that extend beyond energetics, such as synthesis of protein, metabolic/signaling intermediates, and cofactors. In the latter case, notable amino acid derivatives include L-carnitine (from lysine and methionine), CoQ10 (from tyrosine and mevalonate), and Taurine (from methionine or cysteine), which play important roles in cardiac processes (e.g., metabolism, redox biology, and calcium homeostasis). Furthermore, it has been estimated that the mammalian heart renews all cellular components within a 30-day period (50), illustrating a significant demand on amino acid availability for protein and cofactor synthesis. Moreover, protein turnover is accelerated in the heart during periods of remodeling, such as hypertrophic growth. Significant efforts have been made to increase our understanding of amino acid metabolism perturbations during HF and have yielded novel insights. This sub-section (summarized in Figure 3) highlights the contribution that amino acid metabolism perturbations potentially play in the etiology of HF.
Both amino acid availability and utilization are influenced by HF. For example, profiling plasma amino acids (and their derivatives) from HF patients using HPLC revealed that the circulating levels of almost half of the species assessed (17 of 41) were altered in HF, the vast majority of which were increased (15 of 17) (104). Furthermore, a subset of these amino acids, including glutamate and monoethanolamine (a serine derivative), negatively correlated with EF in HF patients (with trends for phenylalanine and tyrosine as well), suggesting higher circulating amino acids were indicative of worsening cardiac function. This is likely due to accelerated protein breakdown in skeletal muscle, which serves as an amino acid reservoir during HF (105). Despite increased demand for amino acids in the heart, there is evidence of AA accumulation in the failing myocardium; metabolomic analysis of failing mouse myocardium showed accumulation of amino acids, consistent with the notion that AA catabolism was compromised (106). Transcriptomic analysis in mice shows that genes associated with amino acid catabolism are down regulated during compensated hypertrophy and overt failure (106).
Considerable interest has been placed on branched-chain amino acid (BCAA; leucine, isoleucine, valine) metabolism during HF. Branched chain α keto acids (BCKA; product after initial step of BCAA catabolism) are elevated within the myocardium in human HF patients (107). Furthermore, subunits of the branched chain alpha-keto acid dehydrogenase (BCKD) complex, which is responsible for subsequent catabolism of BCKA's, are transcriptionally repressed. These findings have been replicated in mice during TAC-induced HF, where, pharmacologic activation of BCKD normalized BCAA catabolism, prevented BCKA accumulation and protected against cardiac dysfunction (107). These findings suggest that an imbalance between BCAA availability and utilization during HF may contribute towards contractile dysfunction, and that normalization of this balance may be a novel, efficacious therapeutic strategy.
Consistent with impairment of appropriate amino acid utilization/metabolism by the failing myocardium, various cofactors are often found to be depleted. This includes taurine. The importance of taurine in the heart is supported by studies using taurine deficient mice (induced by genetic ablation of the taurine transporter; TauT) and rats (TauT inhibition with β-alanine), resulting in cardiomyopathy (108). Taurine deficiency is characterized by reduced glucose and fatty acid oxidation in isolated perfused rat hearts (109), reduced mitochondrial complex I and III activity, and increased ROS production in cardiomyocytes (110). Taurine deficiency is also associated with aberrant Ca2+ homeostasis/signaling, involving alterations in phospholamban and SERCA2 (111). Taurine supplementation has been shown to be efficacious during HF, eliciting improvements in LV function (112) and exercise capacity (113).
Various studies suggest that amino acid supplementation increases functional capacity and quality of life in patients with chronic stable HF (reviewed here (114)). For example, mixed amino acid supplementation increased functional exercise capacity (VO2 peak, exercise time during exercise test, 6-minute walk test) in humans with chronic HF (115,116). Similarly, BCAA supplementation preserved cardiac function during high salt-induced heart failure in Dahl salt-sensitive rats (a physiological model of hypertension leading to HF) (117). These somewhat counterintuitive observations (i.e., beneficial effects of amino acid supplementation during HF, when amino acid availability appears to exceed capacity of the myocardium to metabolize them) may be explained by extra-cardiac effects. For instance, BCAA supplementation represses skeletal muscle cachexia (i.e., muscle wasting), and previous studies suggest that the degree of cachexia is a strong independent risk factor for mortality during HF, and significantly reduces survival (118).
Various amino acids (and their derivatives) function as signaling molecules. This is particularly true for BCAAs, which activate the mammalian target of rapamycin (mTOR), a modulator of various anabolic (i.e., protein synthesis) and catabolic (i.e., autophagy, see next sub-section) pathways. Aberrant mTOR signaling has been implicated in the progression of HF (119,120). In mice, mTOR is activated by pressure overload, and pharmacologic inhibition (with rapamycin) improves contractile function of the decompensated myocardium (121). However, ablation of mTOR complex 1 signaling (via genetic deletion of Raptor) prevents compensated hypertrophy following pressure overload (122), resulting in a rapid transition to HF and increased mortality. These findings suggest mTOR activation may be adaptive during the initial compensated phase, but maladaptive during overt failure. It is noteworthy that BCAAs also appear to affect cellular processes in an mTOR-independent manner, potentially through the eukaryotic initiation factor 2 alpha (eIF2α) kinase general control nonderepressible 2 (GCN2). GCN2 is activated by non-charged tRNA during AA starvation (particularly BCAA depletion), which leads to eIF2α phosphorylation and repression of translation. Interestingly, when exposed to pressure overload, GCN2 null mice are protected against contractile dysfunction (123), raising the possibility that BCAA supplementation may afford some protection during HF through GCN2 inhibition.
Turnover of cellular components (such as proteins) is essential for maintenance of function, especially in terminally differentiated cells with limited capacity for renewal, such as cardiomyocytes. Several cellular processes, including autophagy and the ubiquitin proteasome system (UPS), are critical for the turnover/degradation of proteins and organelles, and therefore myocardial quality control. While target-specific forms of autophagy exist, including mitophagy (mitochondria), glycophagy (glycogen) and lipophagy (lipids), this sub-section will focus on macroautophagy (hereafter referred to as autophagy).
Observational evidence (e.g., electron microscopy) in humans with ischemic and dilated cardiomyopathy, as well as congestive heart failure, suggests that autophagy might be induced in the stressed myocardium (124,125). Paired sampling of cardiac tissue during left ventricular assist device (LVAD) implantation/explantation indicates autophagy markers are increased during HF, and are reduced following mechanical unloading (126). However, difficulties with measuring autophagic flux in static samples can hinder interpretation of observational results in clinical human studies, necessitating the use of animal models. Experimental evidence in mice subjected to pressure overload indicated transient activation of autophagy, which is elevated within hours of TAC in mice, returning to sub-basal levels within days (127,128). Interestingly, diminishing myocardial autophagy in cardiomyocyte-specific Beclin-1+/- mice partially rescued myocardial function following pressure overload. Conversely, inducing autophagy in cardiomyocytes (via overexpression of Beclin-1) significantly increases mortality and cardiac remodeling following pressure overload (127), suggesting autophagy is maladaptive during cardiac stress. However, genetic disruption of myocardial autophagy via cardiomyocyte-specific deletion of autophagy related gene 5 (ATG5) exacerbated hypertrophy and remodeling during pressure overload (129). One possible explanation for these seemingly opposing observations is with regards to the manner in which autophagy is disrupted; if inhibited later in the process (as opposed to initiation), autophagosomes will accumulate within the myocardium, thus impairing cellular function. Consistent with this concept, doxorubicin-induced cardiomyopathy is characterized by an imbalance in autophagy initiation versus completion, resulting in autophagasome accumulation and cardiomyocyte dysfunction (130).
The UPS also plays a critical role in protein turnover. Accumulation of ubiquitinated proteins has been consistently observed across studies investigating human HF samples (124,126,131,132). This could result from an imbalance between the activity of ubiquitin ligases, de-ubiquitinating enzymes, and the proteasome. In the latter case, studies assessing proteasome activity have produced inconsistent results. For example, Birks et al reported increased 20S-proteasome chymotrypsin-like activity (132), while Day et al showed chymotrypsin-like and caspase-like proteasome activities were reduced (133). Interestingly, proteasome activity increases in patients after LVAD implantation (131). Additional studies are required to elucidate fully the contribution of perturbed UPS function in the etiology of HF.
Previous sections have outlined macronutrient metabolic perturbations during HF, the potential mechanisms leading to their occurrence, and their potential contribution toward contractile dysfunction of the heart. Here, we propose a unifying hypothesis for the metabolic origins of HF, based on the concept that the failing heart is oversupplied with macronutrients, leading to an imbalance in fuel availability and utilization, and subsequent accumulation of key metabolic intermediates that worsen contractile function of the heart (Figure 4). Rationale for this model will be discussed.
During HF, the myocardium is undoubtedly in a state of dyssynchrony with regards to energy demand and ATP generation. Accordingly, compensatory mechanisms attempt to regain synchrony, through decreasing workload and increasing metabolism. For example, increased ANP/BNP secretion promotes natreurisis, thus reducing workload (134). Elevation of these cardiokines, as well as various cytokines (e.g., TNFα) and sympathetic tone, also serve to signal fuel mobilization during HF, enhancing adipocyte lipolysis (releasing FAs), hepatic gluconeogenesis (releasing glucose), and skeletal muscle proteolysis (releasing amino acids, including BCAAs) (105,135,136). These fuels not only become available to the heart (for ATP generation), but also to extra-cardiac tissues, including the liver; increased FA availability promotes ketogenesis, thereby elevating circulating ketone bodies in HF subjects (96-99). Collectively, the failing myocardium is in an environment rich in fuels (Figure 4A).
The myocardium has a high capacity/preference for ketone body utilization, which attenuates utilization of other substrates; elevated ketone body utilization concomitant with decreased total CoA in the failing myocardium (42), will limit mitochondrial free CoA for FAO, pyruvate oxidation, and BCAA metabolism. One strategy to liberate CoA for continued oxidative metabolism involves exchanging the CoA with carnitine, and subsequent generation of acetyl-carnitine (as observed during HF; (101,102,137)). However, diminished carnitine levels in the failing heart (138) will attenuate FAO capacity further. Impairment of FAO in the face of elevated circulating FAs would promote diversion of FA species into signaling/lipotoxic pathways. Elevated ketone body utilization would also limit the activity status of PDH; in the face of elevated glucose uptake, an uncoupling between glycolysis and glucose oxidation ensues. Similarly, impairment of the BCKD due to co-factor perturbations and/or PTM, coupled with increased circulating BCAAs, will lead to accumulation of BCKA and mitochondrial dysfunction. The latter amplifies metabolic dyssynchrony further, due to activation of mechanisms designed to promote cardiomyocyte substrate uptake in the face of energetic deficit (e.g., AMPK activation promoting GLUT1/4 and CD36 translocation for glucose and FA uptake, respectively). Importantly, during diabetes, dyssynchrony between fuel availability and utilization will be amplified further, due to greater levels of circulating FAs, ketone bodies, glucose, and BCAAs. In other words, the failing myocardium can be considered an engine flooded with fuel.
According to the model described above (Figure 4), strategies designed to regain synchrony between energetic demand, substrate availability, and substrate utilization would be beneficial during HF. Established and emerging HF therapeutics include β-blockers and valsartan/saculcitril. Both treatments focus primarily on reduction of workload, which in turn would help regain synchrony due to attenuation of energetic demand. In addition, β-blockers help regain synchrony further through inhibition of lipolysis, thus decreasing substrate supply (FAs, and likely ketone bodies). In contrast, through promotion of lipolysis, valsartan/saculcitril has the potential to negatively affect metabolic synchrony, augmenting substrate supply further. Although no pharmacological strategy has been taken to specifically attenuate ketogenesis in the setting of HF, some may influence this indirectly. For example, nicotinic acid, an anti-lipolytic agent, has been proposed to be beneficial during ischemic heart disease (139); attenuation of lipolysis would reduce FAs available for ketogenesis and lipotoxicity. Similarly, inhibition of hepatic FAO would attenuate ketogenesis; this may contribute to the benefit of FAO inhibitors, such as trimetazidine, in the setting of HF (140-142). However, some FAO inhibitors, such as etomoxir, appear to have detrimental effects due to hepatic toxicity (143). According to our model, limited availability of specific cofactors (e.g., carnitine and CoA) during HF would exacerbate metabolic dyssynchrony. Interestingly, several studies suggest that carnitine supplementation has benefits during HF (144); whether pantothenoate (precursor for CoA biosynthesis) supplementation has benefit during HF is currently unknown. Promotion of oxidation of individual substrates, such as pyruvate and BCKA, also appears to be beneficial in animal models (107); whether this translates to the clinical setting is currently unknown. However, caution should be taken to promote the use of a single substrate in the presence of excess FA availability, as this in turn could result in further inhibition of FAO, and potentially lipotoxicity.
Because of space constraints, the authors could not include all of the relevant citations on the subject matter, for which they apologize.
Funding: This work was supported by the National Institutes of Health (NIH) HL106199, HL074259, HL123574, and HL122974 to Dr. Young, HL111322 and HL133011 to Dr. Wende, and AHA 16POST270100009 to Dr. McGinnis.
Disclosures: All authors reported that they have no relationships with industry relevant to the contents of this paper to disclose.
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