Metabolic flexibility and Atrial Fibrillation: Comparison
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Atrial fibrillation (AF), the most commonly encountered arrhythmia in clinical practice, is characterized by irregular contractions of atrial cardiomyocytes. AF causes substantial disability and morbidity with a high risk of heart failure (HF) and ischemic stroke, and has exerted a tremendous burden on society, the health care system, and the economy. Metabolic flexibility is a novel concept that aptly describes switches in substrate metabolism depending on availability and requirements, thus coping with the dramatic fluctuations in energy supply and demand under physiological and pathological stimuli. Metabolic flexibility is critical for normal heart function, as it provides sufficient energy when the rapid and irregular contraction of atrial cardiomyocytes occurs during AF. 

  • atrial fibrillation
  • metabolic flexibility
  • insulin resistance

1. Metabolic Flexibility in the Normal Heart

The concept of metabolic flexibility was first proposed by Kelley et al., who found that the skeletal muscle of lean individuals showed a rapid fuel switch in response to fasting and insulin infusion compared with that of obese individuals [1]. The concept of metabolic flexibility was initially linked to the fuel selection in response to nutritional changes such as fasting/feeding transition, or insulin stimulation. Now, this concept has been expanded to the fuel selection of any given system (whole-body, organ, cell or organelle) in response to any energy stress (exercise, caloric restriction, caloric overload, hibernation, or cold exposure) [2].
The heart needs metabolic flexibility, which allows the utilization of different substrates (FAs, carbohydrates, amino acid and ketones) to maintain the contractile function in response to energy stress. Within the heart, metabolic flexibility is governed by (1) substrate availability, and (2) a complex regulatory metabolic mechanism.

1.1. Substrate Availability

The heart is a muscular pump with high efficiency and rhythmicity that incessantly provides arterial blood to meet the nutritional requirements of all cells of the whole body [3]. The heart can form approximately 15–20-fold of adenosine triphosphate (ATP) of its own weight every day to meet the immense amount of energy required, the majority of which fuels contraction/relaxation (60–70% of total energy demand) while the remaining fuels ion pumps (30–40% of total energy demand) [3][4]. Regarding the high energy demands of the heart, continuous and rapid energy replenishment is a prerequisite for normal cardiac function [5].
The maintenance of substrate metabolic homeostasis is the determinant of cardiac metabolic flexibility, and the underlying mechanism has been partly investigated in recent years (for details see reviews [5][6]). Briefly, the heart is metabolically versatile and can utilize all classes of energy substrates for ATP production including FAs, carbohydrates (glucose and lactate), amino acids, and ketones. Cardiomyocytes can intake these energy substrates directly from the bloodstream or mobilize fuels from endogenous pools (triacylglycerol and glycogen). Next, substrate catabolism converges on acetyl coenzyme A (acetyl CoA) formation to fuel mitochondria through the tricarboxylic acid (TCA) cycle and subsequent oxidative phosphorylation, which operates as the major source of cardiac ATP (>95%) under non-ischemic conditions. Glycolysis (GL) in the cytoplasm and GTP generated by the TCA cycle provide the remaining energy consumed by the heart [7].
Cardiac fuel selection is largely determined by the type and amount of available fuel. In a healthy adult heart, FAs are the predominant substrate accounting for ~60–90% of the ATP supply [8]; glucose (glycolysis and glucose oxidation) accounts for 10–40%, and ketones contribute up to 5%. However, under pathological conditions, an apparent metabolic switch in substrate usage occurs. For example, glycolysis only provides 5–10% of the overall ATP production, whereas it increases by as much as 10- to 20-fold under hypoxic conditions such as hypoxia, anoxia or ischemia [6]. In addition, ketones are of low concentration in plasma under physiological conditions [9]; however, after overnight fasting, ketones provide 10–20% of the overall energy supply, providing a compensatory source of energy in nutritionally deficient states such as HF, ketosis, and fasting/starvation [10][11].

1.2. Metabolic Regulatory Network

Oxygen/substrate, total phosphates (ATP, ADP, and AMP) and phosphocreatine, inorganic phosphate, calcium, metabolites related to redox state and phospho-transfer systems have all been identified as key endogenous signaling molecules and can dynamically change in response to mechanical load and the metabolic environment of the heart. These signaling molecules were highly regulated by multiple metabolic sensors, such as AMP-activated protein kinase (AMPK) [12], peroxisome proliferator-activated receptor (PPAR) [13][14], protein kinase B (Akt) [15], hypoxia-inducible factor-α (HIF-1α) [16][17], and peroxisome proliferator-activated receptor γ coactivators 1α (PGC-1α). These stressors can orchestrate the cellular response to such signals and perform opposing, complementary or interlinked functions in the cardiac metabolism and multiple biological actions at transcriptional, post-transcriptional, and allosteric levels.

2. Metabolic Inflexibility as the Basis of Pathogenesis among AF Stressors

Metabolic inflexibility is common in pathological conditions. It has been reported that metabolic abnormalities in adults, including obesity, insulin resistance and/or T2DM, induce a state of impaired metabolic flexibility [18]. Stull et al. showed that insulin resistance is a major contributor to metabolic flexibility in humans, and metabolic flexibility is negatively associated with aging [19]. In addition, metabolic inflexibility is also evident in the failing heart [20]. Therefore, a negative relationship between AF risk and metabolic flexibility was proposed, as shown in Figure 1. Under physiological conditions, the heart is highly metabolically flexible, which is associated with lower AF risk, whereas under pathological conditions metabolic flexibility is impaired and causes the energy substrate preference to switch either towards FAs or glucose, resulting in increased AF risk. The underlying mechanisms of the switch in energy substrate preference contributing to metabolic inflexibility will be discussed in the following section.
Figure 1. A negative correlation between the AF risk and cardiac metabolic flexibility.

3. The Substrate-Metabolism Mechanism Underlying Metabolic Inflexibility

3.1. Substrate Metabolic Flexibility

Metabolic inflexibility has been implicated in decreased FAO capacity in FAs’ metabolism and insulin resistance and/or impaired insulin signaling in glucose metabolism. In the following, how the alterations in each substrate metabolism (glucose, FAs, amino acids and ketones) and their regulatory signaling affect metabolic flexibility will be discussed.

3.1.1. Glucose Metabolic Inflexibility Underlying AF

  • Glucose metabolic abnormalities and pathogenesis
There is increasing evidence suggesting that abnormal glucose metabolism is crucial for AF pathogenesis. Diabetes was shown to be correlated with a 34% greater risk of developing AF in a meta-analysis [21], and to increase by 3% for each additional year of treatment [22]. Epidemic studies have shown that hyperglycemia is also associated with an increased risk of AF [22][23]. In addition, glucose fluctuations have been reported to play a key role in AF pathogenesis, as evidenced in diabetic rats [24] and human subjects with diabetes [25]. Chao et al. demonstrated an increase in the activation time of both atria and a decrease in bipolar voltage in patients with abnormal glucose metabolism, compared with those without [26].
  • Insulin resistance and AF pathogenesis
Insulin resistance, a key component of metabolic inflexibility, has been suggested as an independent risk factor for incident AF even before diabetes develops. However, some controversies regarding the role of insulin resistance in the epidemiology of AF still remain. Increasing numbers of studies have shown that metabolic syndrome, of which insulin resistance is a key component, is highly associated with AF risk. Lee reported that high values of insulin resistance assessed by homeostasis model (HOMA-IR), an insulin resistance index, were significantly associated with an increased risk of AF independent of other known risk factors in nondiabetic subjects [27]. Conversely, several studies showed neutral or even opposite results. A cohort study proposed a negative relationship between fasting plasma insulin levels and AF risk [28]. Several large cohort studies reported no independent association between insulin resistance and AF development [29][30]. However, emerging animal studies have identified the positive relationship between IR and AF risk. Chan et al. showed an increase in AF susceptibility in insulin-resistant rats fed high-fat and high-fructose/cholesterol diets for 15 weeks [31]. In addition, the loss of insulin signaling contributed to increased AF risk in Type 1 diabetic mice, and insulin treatment reduced AF susceptibility [32][33].
  • Mechanisms of glucose metabolic inflexibility underlying AF
Glucose metabolic flexibility relies on the configuration of metabolic pathways that manage glucose availability, uptake, glycolysis and glucose oxidation. The pro-glycolysis effect in pathological conditions is always correlated to impaired insulin sensitivity. Insulin resistance is connected with abnormalities in switching between lipid and glucose utilization, thus acting as a key component of metabolic inflexibility. The potential mechanism underlying insulin-resistance-induced AF is associated with the decreased expression of NaV1.5 and sodium current (INa) [32], the abnormal up-regulation of calcium-homeostasis-related proteins (CaMKII) [31], and the decreased expression and membrane translocation of glucose transporter type 4 (GLUT4) and GLUT8 [34] in an insulin-resistant state. It was reported that glucose uptake and glycolysis are markedly increased in the failing heart, whereas glucose oxidation and mitochondrial function are decreased, indicating the uncoupling of glycolysis and glucose oxidation [20]. This phenomenon is much like the “Warburg effect” commonly observed in rapidly growing tumor cells. Liu et al. reviewed and confirmed the existence of the Warburg effect in AF [35]. The signaling pathway involved in the Warburg effect during AF includes the anti-Warburg-effect AMPK and pro-Warburg-effect pyruvate dehydrogenase kinase (PDK) and HIF-1α. Unlike AMPK, the negative regulator of the Warburg effect, which is widely accepted to promote metabolic flexibility and decrease AF risk, pro-Warburg PDK and HIF-1α, is underestimated in their role in AF pathogenesis. PDK is a key regulator of glycolysis–GO coupling by phosphorylating and inactivating the pyruvate dehydrogenase (PDH), leading to increased glycolysis and FAs’ metabolism. The heart needs to oxidize enough carbohydrate to meet energy needs, and previous reports showed that PDK overexpression can cause a loss of metabolic flexibility and exacerbate cardiomyopathy [36]. In concert, the genetic inactivation of PDK4 improves hyperglycemia and insulin resistance [37]. AF is associated with stimulated PDK expression. The specific inhibition of PDK4 via Dichloroacetic acid (DCA) can attenuate metabolic stress, myocardial fibrosis remodeling, and atrial intracardiac waveform activity in a paroxysmal canine model of AF [38]. HIF-1α is a transcription factor driving the transcription of a variety of glycolysis-related genes, including PDK, GLUT1, hexokinase II (HKII), and lactate dehydrogenase A (LDHA), thus serving as a key regulator of glycolysis. It has been reported that the ratio between glycolytic and oxidative enzyme activities is correlated negatively with insulin sensitivity [39], indicating the pivotal role of glycolysis in metabolic flexibility. However, the role of the Warburg effect in AF pathogenesis has been under-estimated.

3.1.2. FAs Metabolic Inflexibility Underlying AF Pathogenesis

  • FAO and AF pathogenesis
FAs are the preferred substrate of the heart, especially the atria. Excessive FA availability is highly relevant to AF. An increased circulating level of FAs is found in multiple metabolic AF etiologies, including obesity, T2DM [40], HF [41], and aging [42]. In a prospective cohort study, plasma phospholipid 16:0, the most abundant saturated FA in diet and circulation, was positively associated with incident AF [43]. In another observational study, high levels of circulating ceramides and sphingomyelins with palmitic acid (C16:0) appeared to increase the risk of incident AF [44]. A recent metagenomic sequencing and metabolomics study demonstrated higher levels of plasma palmitic acid and oleic acid (C18:0) in AF patients relative to healthy individuals [40].
  • Mechanisms of FAs’ metabolic inflexibility underlying AF
FAs’ metabolic flexibility relies on the configuration of the metabolic pathways that manage FA availability, uptake, transportation and oxidation. Accumulating studies have attested that disrupted FA metabolism induces atrial metabolic inflexibility in the complex pathophysiology of AF. Atrial FAs’ metabolic inflexibility was further explained as the permanent augment of CD36 to the sarcolemma that leads to chronic FA overloading, as occurs in a variety of AF etiologies, such as IR, obesity [45], rapid atrial pacing [46], and aging [47]. Besides FA uptake, decreased FA transport and oxidation also contribute to FA overload. In concert, post-operation AF patients showed a repressed atrial expression of fatty acid binding protein 3 (FABP3), indicating the impairment of cytosol FA transportation [48]. In the atria of permanent AF patients, the gene [49] and protein [50] levels of FAO-related enzymes were reduced. In addition, the results demonstrate that restoring FAO, targeting carnitine palmitoyltransferase-1B (CPT-1B) via L-carnitine (its endogenous cofactor), could attenuate obesity-induced AF [51]. Physiologically, FAO capacity is coupled with FA uptake. However, under pathological conditions, the coupling between FAs uptake and FAO is disrupted, thereby inducing lipid accumulation and subsequent atrial lipo-toxicity [52]. Lipo-toxicity is commonly associated with risk factors for AF, including IR, obesity, aging, and myocardial ischemia–reperfusion, caused by toxic lipid intermediates, including long-chain acyl-CoAs, lipid peroxides, ceramides, diacylglycerols and acyl-carnitines. Atrial lipo-toxicity elicits mitochondrial and endoplasmic reticulum dysfunctions, activates apoptotic cell death signaling, and interferes with insulin-stimulated glycogen uptake, which together engage mechanisms underlying alterations in the atrial anatomy (hypertrophy and fibrosis [52]) and electrophysiology (connexin 43 lateralization, conduction propagation impairment [53]), culminating in AF. The FAs metabolic disorders, characterized by the uncoupling of FAs uptake and utilization, are divided into two classes: lipid accumulation and resultant lipo-toxicity, or over-activated mitochondrial β-oxidation. Of note, these two pathological conditions are both associated with impaired glucose metabolism and/or insulin signaling, as postulated by the “Randle cycle”. Lipid accumulation and lipo-toxicity aggravates insulin sensitivity and inhibits glycolysis via lipid intermediates such as ceramides and diacylglycerols [54]. Over-activated mitochondrial β-oxidation inhibits glucose oxidation via increased acetyl-CoA and NADH/NAD+ ratio, and inhibited glycolysis, targeting PK and PFK, via increasing citrate [55]. The role of diverse FAs metabolism-related enzymes and regulators in metabolic inflexibility-induced AF are still under debate, especially these involved in triglyceride turnover (diacylglycerol transferase/DAGT, acetyl-CoA carboxylase/ACC, and adipose triglyceride lipase/ATGL), FAO (malonyl-CoA decarboxylase/MCD and carnitine acetyltransferase/CrAT) and FAs delivery (FABP). In addition, little is known about the actual degree to which lipid handling is disrupted under physiological and pathological stimulations in the atrium with AF and AF risk factors.

3.1.3. Amino Acids’ Metabolic Flexibility

  • BCAA and AF pathogenesis
Branched-chain amino acids (BCAA), including leucine, isoleucine and valine, are the only amino acids that can be utilized as a source of energy generation in the TCA. BCAA have been acknowledged as bio-energetic fuel for protein synthesis and cell growth, and as bio-active molecules regulating nutrient-sensitive pathways involved in multiple metabolic processes. A dysregulated BCAA metabolism confers a high degree of risk for cardiovascular diseases [56] and was recently revealed to have clinical and experimental relevance to AF. The circulating BCAA level is increased in metabolic AF stressors including IR, obesity, and HF individuals [57]. In an ongoing study (unpublished), it was found that an 8-week BCAA supplement (0.75%) can significantly enhance AF invincibility and increase left atrial volume in mice. Likewise, atrial BCAA catabolic deficiency can promote angiotensin II (Ang II)-induced AF and atrial fibrosis [58], and underlie myocardial fibrosis and hypertrophy via the PI3K-AKT-mTOR pathway [59]. These results can be explained by the elevated accumulation of toxic BCAA or their derivatives (such as branched-chain α-keto acids), which induces mitochondrial oxidative stress by enhancing superoxide production, inhibiting mitochondrial complex I, and reducing superoxide dismutase (SOD) activity [60].
  • Mechanisms of BCAA metabolic inflexibility underlying AF
Although the specific role of BCAA catabolism in cardiac substrate metabolism is underexplored, recent studies on extra-cardiac tissues (pancreas, adipose, and skeletal muscle) have indicated that the quantity and proportion of circulating BCAA can modulate glucose, lipid, and protein handling [57]. It has been reported that elevated circulating levels of BCAA are positively associated with metabolic disorder and insulin resistance [61]. Mechanistically, (1) the BCAA-induced activation of mammalian target of rapamycin complex 1 (mTORC1) and the resultant negative feedback regulation of insulin signaling, and (2) the accumulation of toxic BCAA metabolites and the resultant mitochondrial dysfunction could be two plausible explanations linking BCAA and insulin resistance [62]. Restoring BCAA metabolic flexibility is an under-appreciated anti-AF metabolic strategy, and the underlying mechanism and the independent impacts of different AA components await further validation.

3.1.4. Ketones and Metabolic Flexibility

  • Ketones and AF pathogenesis
Ketones, namely β-hydroxybutyrate (β-OHB), acetoacetate (AcAc) and acetone, are initially synthesized in liver mitochondria through “ketogenesis” and can circulate to extrahepatic tissues for terminal oxidation. Serum β-OHB, the predominate (70%) circulating form of ketones, can be transported into cardiomyocytes via mono-carboxylate transporters (MCT1 and MCT2) or simple diffusion, then converted to acetyl-CoA via β-OHB dehydrogenase (BDH1) and succinyl-CoA:3-oxoacid-CoA-transferase (SCOT) in the mitochondrial matrix, and finally enter into the TCA cycle to generate ATP [63]. The heart utilizes ketones in proportion to their delivery determined by circulating content, thus generally make a minor contribution to cardiac energy supply under basal conditions (<3%) [64]. Hence, cardiac ketone metabolism is augmented in parallel to stimulated hepatic ketogenesis, as occurs in the nutrient deprivation or diminished carbohydrate availability that accompanies encompassing starvation/fasting, exercise, and ketogenic diets [65]. Interestingly, most of the AF risk factors, such as diabetes/IR [65], congestive HF [66][67], and dilated and hypertrophic cardiomyopathies [68], can stimulate hepatic ketogenesis, which is presumably associated with cardiac dysfunction, hemodynamic abnormalities and increased neuro-hormonal stress-related lipolysis. In a metabolomics profiling analysis of atria in AF patients, the concentrations of β-OHB, tyrosine, leucine (ketogenic AA) and fumarate (a metabolic intermediate in the TCA cycle) were reported to be elevated, indicating that ketone metabolism might be up-regulated in AF [69].
  • Mechanisms of ketone metabolic inflexibility underlying AF
Ketones are an alternative energy source in the energetically compromised heart; and are thus capable of promoting metabolic flexibility. Supportively, ketones can improve energy efficiency in the failing heart [68], and decrease the infarct size and myocardial cell death following ischemic injury [70]. These findings are further explained by ketones’ oxygen-efficient nature, which improves cardiac cell excitation–contraction coupling during hypoxia, as evidenced by its higher P/O ratio (2.50) relative to FAs (2.33), and the ability to inhibit FAO and accelerate the mitochondrial energy transduction of GO in working rat hearts [71]. However, the role of ketones in regulating glucose metabolism and insulin sensitivity is equivocal, and was reviewed in [72]. Generally, a short-term ketone diet improved glucose metabolism and insulin sensitivity, whereas a long-term ketone diet showed neutral or negative results [73][74]. More importantly, the metabolic modification targeting ketone metabolism is complicated in AF patients, since a long-term up-regulated ketone metabolism can impose potential arrhythmogenic risks. Supportively, β-OHB can prolong the action potential by blocking the Ito in murine ventricular cardiomyocytes, and suppress sympathetic nervous system (SNS) activity to reduce the heart rate and cardiac energy expenditure by antagonization via G protein-coupled receptor 41 (GPR41) [75]. In addition, a recent rodent study demonstrated that long-term exogenous β-OHB administration (16 weeks) can induce cardiac fibrosis and cellar apoptosis by inhibiting mitochondrial biogenesis [76]. Ketones and intermediate metabolites (such as acetyl-CoAs) are also understudied metabolic signals that regulate the provision of fuel and mitochondrial energetics [77][78]; thus, the alteration of ketone-derived signal components possibly influences the metabolic status to confer a metabolic risk of AF. Given recent evidence, up-regulated ketone metabolism might be an emergency anti-AF strategy by remedying metabolic flexibility, but is not applicable for long-term AF management. A deeper understanding of ketone metabolism in AF with different etiologies is urgent in the field of AF.

3.2. Metabolism Regulatory Signaling and Metabolic Flexibility

The inactivation of AMPK is highly relevant to AF, as evidenced by the increase in AF vulnerability in various pre-clinical AF models and in genetically modified strains (Cardiac LKB1 KO mice) [79]. The pharmacological activation of AMPK and its downstream regulator, PGC-1α, can retard/reverse the pathological processes underlying AF in human [80][81] and pre-clinical AF models induced by rapid atrial pacing [82][83][84] and obesity [51], in addition to genetic modified rodents [85]. Besides AMPK, a number of signaling pathways, including PGC-1α, sirtuins, and FOXO, HIF-1α, PPAR, and Akt, are also implicated in the regulation of metabolic flexibility. Their roles in metabolic flexibility and the pharmaceutical approaches to improving metabolic flexibility are beyond the scope of this entreviewy; please refer to [2][86].

3.3. The Substrate-Metabolism Mechanism Underlying Metabolic Inflexibility and AF Pathogenesis

Under different forms of pathogenesis, the energy substrate preference shifts either towards (e.g., obesity and diabetes) or away from (e.g., aging, heart failure, and hypertension) FAO in the atria. As previously mentioned, the atria need metabolic flexibility to enable them to switch from fat to carbohydrate oxidation in response to AF and AF-induced ischemia. The overall (glucose–FAs utilization) and internal balance (glycolysis–glucose oxidation or FA uptake–FAO) of energy substrate metabolism is crucial for normal heart function (Figure 2).
Figure 2. The substrate-metabolism mechanism underlying metabolic inflexibility. GL, Glycolysis; GO, Glucose oxidation; FAO, Fatty acid oxidation; FAU, Fatty acid uptake.
The uncoupling of glycolysis and oxidative phosphorylation is called “the Warburg effect”, and is mainly mediated via the up-regulation of PDK4 and the resultant inactivation of PDH activity. In hypoxic conditions such as aging, hypertension and HF, the metabolic balance shifts from oxidative phosphorylation to glycolysis to increase the efficiency of ATP produced in relation to oxygen consumed. It has been reported that the glycolysis rate is negatively associated with mitochondrial function and insulin sensitivity; thus, this metabolic switch to aerobic glycolysis leads to metabolic inflexibility. However, the relevant mechanism of glycolysis in insulin resistance and metabolic inflexibility warrants further investigation.

4. Anti-AF Strategies Targeting Metabolic Inflexibility

An AF strategy targeting metabolic inflexibility must consider the unique metabolic profile of certain AF etiologies, thus the recommendation of prevention and treatment for AF patients must be prudent and personal. To further elaborate the individualization of AF management, AF populations are divided into two categories based on their metabolic characteristics: (1) energy-rich pro-FAO condition (e.g., obesity and diabetes), and (2) energy-demanding pro-GL condition (e.g., aging, hypertension, myocardial ischemia, and HF). When atrial cardiomyocytes are in an energy-rich pro-FAO condition such as obesity or T2DM, the atrium is characterized by over-whelming FAs intake and insufficient FAO in the atrium. The uncoupling of FAs uptake and FAO leads to lipid accumulation and lipo-toxicity, thereby inducing insulin resistance and metabolic inflexibility via toxic lipid intermediates. When atrial cardiomyocytes are in an energy-starved/demanding pro-GL state such as aging, hypertension and HF, mitochondrial dysfunction occurs, and the TCA intermediate citrate can (1) inhibit the PDH activity and GO rate, and (2) block FAO by inhibiting CPT-1B through its derivation malonyl-CoA [87]. Thus, the atrium usually enhances the metabolism of glucose or other alternative substrates (KBs) at the expense of diminished FAO to compensate for energy deficiency. Previous animal and human studies have shown that the altered preference for atrial fuel, namely metabolic remodeling, is responsible for inducing reversible electrical reconfiguration and the irreversible structural reconfiguration that predispose patients to AF occurrence and maintenance [88]. Therefore, when treating this type of AF, moderate exercise, a heart-healthy diet, and pharmaceutical approaches to improve metabolic flexibility are of higher clinical relevance. For more details on the pharmaceutical approaches to improving metabolic flexibility, please refer to [2][86].

References

  1. Kelley, D.E.; He, J.; Menshikova, E.V.; Ritov, V.B. Dysfunction of Mitochondria in Human Skeletal Muscle in Type 2 Diabetes. Diabetes 2002, 51, 2944–2950.
  2. Smith, R.L.; Soeters, M.R.; Wust, R.; Houtkooper, R.H. Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease. Endocr. Rev. 2018, 39, 489–517.
  3. Abe, J.; Abriel, H.; Accili, E.A.; Acosta, D.; Allen, L.F.; Allen, T.J.; Antzelevitch, C.; Aoki, H.; Ardell, J.L.; Arita, M.; et al. Contributors. In Heart Physiology and Pathophysiology, 4th ed.; Sperelakis, N., Kurachi, Y., Terzic, A., Cohen, M.V., Eds.; Academic Press: San Diego, CA, USA, 2001; pp. xiii–xvii. ISBN 978-0-12-656975-9.
  4. Suga, H. Ventricular Energetics. Physiol. Rev. 1990, 70, 247–277.
  5. Kolwicz, S.J.; Purohit, S.; Tian, R. Cardiac Metabolism and Its Interactions with Contraction, Growth, and Survival of Cardiomyocytes. Circ. Res. 2013, 113, 603–616.
  6. Neely, J.R.; Morgan, H.E. Relationship between Carbohydrate and Lipid Metabolism and the Energy Balance of Heart Muscle. Annu. Rev. Physiol. 1974, 36, 413–459.
  7. Lopaschuk, G.D.; Jaswal, J.S. Energy Metabolic Phenotype of the Cardiomyocyte during Development, Differentiation, and Postnatal Maturation. J. Cardiovasc. Pharmacol. 2010, 56, 130–140.
  8. Stanley, W.C.; Recchia, F.A.; Lopaschuk, G.D. Myocardial Substrate Metabolism in the Normal and Failing Heart. Physiol. Rev. 2005, 85, 1093–1129.
  9. Wentz, A.E.; D’Avignon, D.A.; Weber, M.L.; Cotter, D.G.; Doherty, J.M.; Kerns, R.; Nagarajan, R.; Reddy, N.; Sambandam, N.; Crawford, P.A. Adaptation of Myocardial Substrate Metabolism to a Ketogenic Nutrient Environment. J. Biol. Chem. 2010, 285, 24447–24456.
  10. Kolb, H.; Kempf, K.; Röhling, M.; Lenzen-Schulte, M.; Schloot, N.C.; Martin, S. Ketone Bodies: From Enemy to Friend and Guardian Angel. BMC Med. 2021, 19, 313.
  11. McGarry, J.D.; Foster, D.W. Regulation of Hepatic Fatty Acid Oxidation and Ketone Body Production. Annu. Rev. Biochem. 1980, 49, 395–420.
  12. Zaha, V.G.; Young, L.H. AMP-Activated Protein Kinase Regulation and Biological Actions in the Heart. Circ. Res. 2012, 111, 800–814.
  13. Lehman, J.J.; Barger, P.M.; Kovacs, A.; Saffitz, J.E.; Medeiros, D.M.; Kelly, D.P. Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Promotes Cardiac Mitochondrial Biogenesis. J. Clin. Invest. 2000, 106, 847–856.
  14. Francis, G.A.; Annicotte, J.S.; Auwerx, J. PPAR-Alpha Effects on the Heart and Other Vascular Tissues. Am. J. Physiol. Heart Circ. Physiol. 2003, 285, H1–H9.
  15. Miyamoto, S.; Murphy, A.N.; Brown, J.H. Akt Mediated Mitochondrial Protection in the Heart: Metabolic and Survival Pathways to the Rescue. J. Bioenerg. Biomembr. 2009, 41, 169–180.
  16. Cerychova, R.; Pavlinkova, G. HIF-1, Metabolism, and Diabetes in the Embryonic and Adult Heart. Front. Endocrinol. 2018, 9, 460.
  17. Semenza, G.L. Hypoxia-Inducible Factor 1: Regulator of Mitochondrial Metabolism and Mediator of Ischemic Preconditioning. Biochim. Biophys. Acta 2011, 1813, 1263–1268.
  18. Aucouturier, J.; Duché, P.; Timmons, B.W. Metabolic Flexibility and Obesity in Children and Youth: Metabolic Flexibility in Youth. Obes. Rev. 2011, 12, e44–e53.
  19. Stull, A.J.; Galgani, J.E.; Johnson, W.D.; Cefalu, W.T. The Contribution of Race and Diabetes Status to Metabolic Flexibility in Humans. Metabolism 2010, 59, 1358–1364.
  20. Karwi, Q.G.; Uddin, G.M.; Ho, K.L.; Lopaschuk, G.D. Loss of Metabolic Flexibility in the Failing Heart. Front. Cardiovasc. Med. 2018, 5, 68.
  21. Huxley, R.R.; Filion, K.B.; Konety, S.; Alonso, A. Meta-Analysis of Cohort and Case-Control Studies of Type 2 Diabetes Mellitus and Risk of Atrial Fibrillation. Am. J. Cardiol. 2011, 108, 56–62.
  22. Dublin, S.; Glazer, N.L.; Smith, N.L.; Psaty, B.M.; Lumley, T.; Wiggins, K.L.; Page, R.L.; Heckbert, S.R. Diabetes Mellitus, Glycemic Control, and Risk of Atrial Fibrillation. J. Gen. Intern. Med. 2010, 25, 853–858.
  23. Qi, W.; Zhang, N.; Korantzopoulos, P.; Letsas, K.P.; Cheng, M.; Di, F.; Tse, G.; Liu, T.; Li, G. Serum Glycated Hemoglobin Level as a Predictor of Atrial Fibrillation: A Systematic Review with Meta-Analysis and Meta-Regression. PLoS ONE 2017, 12, e0170955.
  24. Saito, S.; Teshima, Y.; Fukui, A.; Kondo, H.; Nishio, S.; Nakagawa, M.; Saikawa, T.; Takahashi, N. Glucose Fluctuations Increase the Incidence of Atrial Fibrillation in Diabetic Rats. Cardiovasc. Res. 2014, 104, 5–14.
  25. Gu, J. Impact of Long-Term Glycemic Variability on Development of Atrial Fibrillation in Type 2 Diabetic Patients. Anatol. J. Cardiol. 2017, 18, 410–416.
  26. Chao, T.-F.; Suenari, K.; Chang, S.-L.; Lin, Y.-J.; Lo, L.-W.; Hu, Y.-F.; Tuan, T.-C.; Tai, C.-T.; Tsao, H.-M.; Li, C.-H.; et al. Atrial Substrate Properties and Outcome of Catheter Ablation in Patients With Paroxysmal Atrial Fibrillation Associated With Diabetes Mellitus or Impaired Fasting Glucose. Am. J. Cardiol. 2010, 106, 1615–1620.
  27. Lee, Y.; Cha, S.J.; Park, J.H.; Shin, J.H.; Lim, Y.H.; Park, H.C.; Shin, J.; Kim, C.K.; Park, J.K. Association between Insulin Resistance and Risk of Atrial Fibrillation in Non-Diabetics. Eur. J. Prev. Cardiol. 2020, 27, 1934–1941.
  28. Johnson, L.S.; Juhlin, T.; Engström, G.; Nilsson, P.M. Low Fasting Plasma Insulin Is Associated with Atrial Fibrillation in Men from a Cohort Study—The Malmö Preventive Project. BMC Cardiovasc. Disord. 2014, 14, 107.
  29. Fontes, J.D.; Lyass, A.; Massaro, J.M.; Rienstra, M.; Dallmeier, D.; Schnabel, R.B.; Wang, T.J.; Vasan, R.S.; Lubitz, S.A.; Magnani, J.W.; et al. Insulin Resistance and Atrial Fibrillation (from the Framingham Heart Study). Am. J. Cardiol. 2012, 109, 87–90.
  30. Garg, P.K.; Biggs, M.L.; Kaplan, R.; Kizer, J.R.; Heckbert, S.R.; Mukamal, K.J. Fasting and Post-Glucose Load Measures of Insulin Resistance and Risk of Incident Atrial Fibrillation: The Cardiovascular Health Study. Nutr. Metab. Cardiovasc. 2018, 28, 716–721.
  31. Chan, Y.-H.; Chang, G.-J.; Lai, Y.-J.; Chen, W.-J.; Chang, S.-H.; Hung, L.-M.; Kuo, C.-T.; Yeh, Y.-H. Atrial Fibrillation and Its Arrhythmogenesis Associated with Insulin Resistance. Cardiovasc. Diabetol. 2019, 18, 125.
  32. Polina, I.; Jansen, H.J.; Li, T.; Moghtadaei, M.; Bohne, L.J.; Liu, Y.; Krishnaswamy, P.; Egom, E.E.; Belke, D.D.; Rafferty, S.A.; et al. Loss of Insulin Signaling May Contribute to Atrial Fibrillation and Atrial Electrical Remodeling in Type 1 Diabetes. Proc. Natl. Acad. Sci. USA 2020, 117, 7990–8000.
  33. Maria, Z.; Campolo, A.R.; Scherlag, B.J.; Ritchey, J.W.; Lacombe, V.A. Insulin Treatment Reduces Susceptibility to Atrial Fibrillation in Type 1 Diabetic Mice. Front. Cardiovasc. Med. 2020, 7, 134.
  34. Maria, Z.; Campolo, A.R.; Scherlag, B.J.; Ritchey, J.W.; Lacombe, V.A. Dysregulation of Insulin-Sensitive Glucose Transporters During Insulin Resistance-Induced Atrial Fibrillation. BBA Mol. Basis Dis. 2018, 1864, 987–996.
  35. Liu, Y.; Bai, F.; Liu, N.; Ouyang, F.; Liu, Q. The Warburg Effect: A New Insight into Atrial Fibrillation. Clin. Chim. Acta 2019, 499, 4–12.
  36. Zhang, S.; Hulver, M.W.; McMillan, R.P.; Cline, M.A.; Gilbert, E.R. The Pivotal Role of Pyruvate Dehydrogenase Kinases in Metabolic Flexibility. Nutr. Metab. 2014, 11, 10.
  37. Tao, R.; Xiong, X.; Harris, R.A.; White, M.F.; Dong, X.C. Genetic Inactivation of Pyruvate Dehydrogenase Kinases Improves Hepatic Insulin Resistance Induced Diabetes. PLoS ONE 2013, 8, e71997.
  38. Hu, H.J.; Zhang, C.; Tang, Z.H.; Qu, S.L.; Jiang, Z.S. Regulating the Warburg Effect on Metabolic Stress and Myocardial Fibrosis Remodeling and Atrial Intracardiac Waveform Activity Induced by Atrial Fibrillation. Biochem. Biophys. Res. Commun. 2019, 516, 653–660.
  39. Simoneau, J.-A.; Kelley, D.E. Altered Glycolytic and Oxidative Capacities of Skeletal Muscle Contribute to Insulin Resistance in NIDDM. J. Appl. Physiol. 1997, 83, 166–171.
  40. Forouhi, N.G.; Koulman, A.; Sharp, S.J.; Imamura, F.; Kroger, J.; Schulze, M.B.; Crowe, F.L.; Huerta, J.M.; Guevara, M.; Beulens, J.W.; et al. Differences in the Prospective Association between Individual Plasma Phospholipid Saturated Fatty Acids and Incident Type 2 Diabetes: The EPIC-InterAct Case-Cohort Study. Lancet Diabetes Endocrinol. 2014, 2, 810–818.
  41. Zhao, G.; Cheng, D.; Wang, Y.; Cao, Y.; Xiang, S.; Yu, Q. A Metabolomic Study for Chronic Heart Failure Patients Based on a Dried Blood Spot Mass Spectrometry Approach. RSC Adv. 2020, 10, 19621–19628.
  42. Pararasa, C.; Ikwuobe, J.; Shigdar, S.; Boukouvalas, A.; Nabney, I.T.; Brown, J.E.; Devitt, A.; Bailey, C.J.; Bennett, S.J.; Griffiths, H.R. Age-Associated Changes in Long-Chain Fatty Acid Profile during Healthy Aging Promote pro-Inflammatory Monocyte Polarization via PPARgamma. Aging Cell 2016, 15, 128–139.
  43. Fretts, A.M.; Mozaffarian, D.; Siscovick, D.S.; Djousse, L.; Heckbert, S.R.; King, I.B.; McKnight, B.; Sitlani, C.; Sacks, F.M.; Song, X.; et al. Plasma Phospholipid Saturated Fatty Acids and Incident Atrial Fibrillation: The Cardiovascular Health Study. J. Am. Heart Assoc. 2014, 3, e000889.
  44. Jensen, P.N.; Fretts, A.M.; Hoofnagle, A.N.; Sitlani, C.M.; McKnight, B.; King, I.B.; Siscovick, D.S.; Psaty, B.M.; Heckbert, S.R.; Mozaffarian, D.; et al. Plasma Ceramides and Sphingomyelins in Relation to Atrial Fibrillation Risk: The Cardiovascular Health Study. J. Am. Heart Assoc. 2020, 9, e012853.
  45. Steinbusch, L.K.; Schwenk, R.W.; Ouwens, D.M.; Diamant, M.; Glatz, J.F.; Luiken, J.J. Subcellular Trafficking of the Substrate Transporters GLUT4 and CD36 in Cardiomyocytes. Cell Mol. Life Sci. 2011, 68, 2525–2538.
  46. Lenski, M.; Schleider, G.; Kohlhaas, M.; Adrian, L.; Adam, O.; Tian, Q.; Kaestner, L.; Lipp, P.; Lehrke, M.; Maack, C.; et al. Arrhythmia Causes Lipid Accumulation and Reduced Glucose Uptake. Basic Res. Cardiol. 2015, 110, 40.
  47. Koonen, D.P.; Febbraio, M.; Bonnet, S.; Nagendran, J.; Young, M.E.; Michelakis, E.D.; Dyck, J.R. CD36 Expression Contributes to Age-Induced Cardiomyopathy in Mice. Circulation 2007, 116, 2139–2147.
  48. Shingu, Y.; Yokota, T.; Takada, S.; Niwano, H.; Ooka, T.; Katoh, H.; Tachibana, T.; Kubota, S.; Matsui, Y. Decreased Gene Expression of Fatty Acid Binding Protein 3 in the Atrium of Patients with New Onset of Atrial Fibrillation in Cardiac Perioperative Phase. J. Cardiol. 2018, 71, 65–70.
  49. Barth, A.S.; Merk, S.; Arnoldi, E.; Zwermann, L.; Kloos, P.; Gebauer, M.; Steinmeyer, K.; Bleich, M.; Kääb, S.; Hinterseer, M.; et al. Reprogramming of the Human Atrial Transcriptome in Permanent Atrial Fibrillation: Expression of a Ventricular-like Genomic Signature. Circ. Res. 2005, 96, 1022–1029.
  50. Tu, T.; Zhou, S.; Liu, Z.; Li, X.; Liu, Q. Quantitative Proteomics of Changes in Energy Metabolism-Related Proteins in Atrial Tissue from Valvular Disease Patients with Permanent Atrial Fibrillation. Circ. J. 2014, 78, 993–1001.
  51. Zhang, Y.; Fu, Y.; Jiang, T.; Liu, B.; Sun, H.; Zhang, Y.; Fan, B.; Li, X.; Qin, X.; Zheng, Q. Enhancing Fatty Acids Oxidation via L-Carnitine Attenuates Obesity-Related Atrial Fibrillation and Structural Remodeling by Activating AMPK Signaling and Alleviating Cardiac Lipotoxicity. Front. Pharmacol. 2021, 12, 771940.
  52. D’Souza, K.; Nzirorera, C.; Kienesberger, P.C. Lipid Metabolism and Signaling in Cardiac Lipotoxicity. Biochim. Biophys. Acta 2016, 1861, 1513–1524.
  53. Sato, S.; Suzuki, J.; Hirose, M.; Yamada, M.; Zenimaru, Y.; Nakaya, T.; Ichikawa, M.; Imagawa, M.; Takahashi, S.; Ikuyama, S.; et al. Cardiac Overexpression of Perilipin 2 Induces Atrial Steatosis, Connexin 43 Remodeling, and Atrial Fibrillation in Aged Mice. Am. J. Physiol. Endocrinol. Metab. 2019, 317, E1193–E1204.
  54. Kwak, H.-B. Exercise and Obesity-Induced Insulin Resistance in Skeletal Muscle. Integr. Med. Res. 2013, 2, 131–138.
  55. Zhelev, Z.; Aoki, I.; Lazarova, D.; Vlaykova, T.; Higashi, T.; Bakalova, R. A “Weird” Mitochondrial Fatty Acid Oxidation as a Metabolic “Secret” of Cancer. Oxid. Med. Cell Longev. 2022, 2022, 1–38.
  56. Taegtmeyer, H.; Harinstein, M.E.; Gheorghiade, M. More than Bricks and Mortar: Comments on Protein and Amino Acid Metabolism in the Heart. Am. J. Cardiol. 2008, 101, 3E–7E.
  57. Nie, C.; He, T.; Zhang, W.; Zhang, G.; Ma, X. Branched Chain Amino Acids: Beyond Nutrition Metabolism. Int. J. Mol. Sci. 2018, 19, 954.
  58. Yu, L.-M.; Dong, X.; Zhao, J.-K.; Xu, Y.-L.; Xu, D.-Y.; Xue, X.-D.; Zhou, Z.-J.; Huang, Y.-T.; Zhao, Q.-S.; Luo, L.-Y.; et al. Activation of PKG-CREB-KLF15 by Melatonin Attenuates Angiotensin II-Induced Vulnerability to Atrial Fibrillation via Enhancing Branched-Chain Amino Acids Catabolism. Free Radical Biol. Med. 2022, 178, 202–214.
  59. Wang, W.; Zhang, F.; Xia, Y.; Zhao, S.; Yan, W.; Wang, H.; Lee, Y.; Li, C.; Zhang, L.; Lian, K.; et al. Defective Branched Chain Amino Acid Catabolism Contributes to Cardiac Dysfunction and Remodeling Following Myocardial Infarction. Am. J. Physiol. Heart C 2016, 311, H1160–H1169.
  60. Sun, H.; Olson, K.C.; Gao, C.; Prosdocimo, D.A.; Zhou, M.; Wang, Z.; Jeyaraj, D.; Youn, J.-Y.; Ren, S.; Liu, Y.; et al. Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure. Circulation 2016, 133, 2038–2049.
  61. Yoon, M.-S. The Emerging Role of Branched-Chain Amino Acids in Insulin Resistance and Metabolism. Nutrients 2016, 8, 405.
  62. Lynch, C.J.; Adams, S.H. Branched-Chain Amino Acids in Metabolic Signalling and Insulin Resistance. Nat. Rev. Endocrinol. 2014, 10, 723–736.
  63. Bing, R.J. The Metabolism of the Heart. Harvey Lect. 1954, 50, 27–70.
  64. Rudolph, W.; Maas, D.; Richter, J.; Hasinger, F.; Hofmann, H.; Dohrn, P. On the Significance of Acetoacetate and Beta-Hydroxybutyrate in Human Myocardial Metabolism. Klin. Wochenschr. 1965, 43, 445–451.
  65. Harvey, K.L.; Holcomb, L.E.; Kolwicz, S.J. Ketogenic Diets and Exercise Performance. Nutrients 2019, 11, 2296.
  66. Lommi, J.; Koskinen, P.; Naveri, H.; Harkonen, M.; Kupari, M. Heart Failure Ketosis. J. Intern. Med. 1997, 242, 231–238.
  67. Lommi, J.; Kupari, M.; Koskinen, P.; Naveri, H.; Leinonen, H.; Pulkki, K.; Harkonen, M. Blood Ketone Bodies in Congestive Heart Failure. J. Am. Coll. Cardiol. 1996, 28, 665–672.
  68. Rudolph, W.; Schinz, A. Studies on Myocardial Blood Flow, Oxygen Consumption, and Myocardial Metabolism in Patients with Cardiomyopathy. Recent Adv. Stud. Cardiac. Struct. Metab. 1973, 2, 739–749.
  69. Mayr, M.; Yusuf, S.; Weir, G.; Chung, Y.L.; Mayr, U.; Yin, X.; Ladroue, C.; Madhu, B.; Roberts, N.; De Souza, A.; et al. Combined Metabolomic and Proteomic Analysis of Human Atrial Fibrillation. J. Am. Coll. Cardiol. 2008, 51, 585–594.
  70. Zou, Z.; Sasaguri, S.; Rajesh, K.G.; Suzuki, R. Dl-3-Hydroxybutyrate Administration Prevents Myocardial Damage after Coronary Occlusion in Rat Hearts. Am. J. Physiol. Heart Circ. Physiol. 2002, 283, H1968–H1974.
  71. Sato, K.; Kashiwaya, Y.; Keon, C.A.; Tsuchiya, N.; King, M.T.; Radda, G.K.; Chance, B.; Clarke, K.; Veech, R.L. Insulin, Ketone Bodies, and Mitochondrial Energy Transduction. FASEB J. 1995, 9, 651–658.
  72. Watt, M.J.; Miotto, P.M.; De Nardo, W.; Montgomery, M.K. The Liver as an Endocrine Organ—Linking NAFLD and Insulin Resistance. Endocr. Rev. 2019, 40, 1367–1393.
  73. Goday, A.; Bellido, D.; Sajoux, I.; Crujeiras, A.B.; Burguera, B.; García-Luna, P.P.; Oleaga, A.; Moreno, B.; Casanueva, F.F. Short-Term Safety, Tolerability and Efficacy of a Very Low-Calorie-Ketogenic Diet Interventional Weight Loss Program versus Hypocaloric Diet in Patients with Type 2 Diabetes Mellitus. Nutr. Diabetes 2016, 6, e230.
  74. Ellenbroek, J.H.; van Dijck, L.; Töns, H.A.; Rabelink, T.J.; Carlotti, F.; Ballieux, B.E.P.B.; de Koning, E.J.P. Long-Term Ketogenic Diet Causes Glucose Intolerance and Reduced β- and α-Cell Mass but No Weight Loss in Mice. Am. J. Physiol. Endocr. Metab. 2014, 306, E552–E558.
  75. Kimura, I.; Inoue, D.; Maeda, T.; Hara, T.; Ichimura, A.; Miyauchi, S.; Kobayashi, M.; Hirasawa, A.; Tsujimoto, G. Short-Chain Fatty Acids and Ketones Directly Regulate Sympathetic Nervous System via G Protein-Coupled Receptor 41 (GPR41). Proc. Natl. Acad. Sci. USA 2011, 108, 8030–8035.
  76. Xu, S.; Tao, H.; Cao, W.; Cao, L.; Lin, Y.; Zhao, S.M.; Xu, W.; Cao, J.; Zhao, J.Y. Ketogenic Diets Inhibit Mitochondrial Biogenesis and Induce Cardiac Fibrosis. Signal Transduct. Target Ther. 2021, 6, 54.
  77. Hasselbaink, D.M.; Glatz, J.F.; Luiken, J.J.; Roemen, T.H.; Van der Vusse, G.J. Ketone Bodies Disturb Fatty Acid Handling in Isolated Cardiomyocytes Derived from Control and Diabetic Rats. Biochem. J. 2003, 371, 753–760.
  78. Vanoverschelde, J.L.; Wijns, W.; Kolanowski, J.; Bol, A.; Decoster, P.M.; Michel, C.; Cogneau, M.; Heyndrickx, G.R.; Essamri, B.; Melin, J.A. Competition between Palmitate and Ketone Bodies as Fuels for the Heart: Study with Positron Emission Tomography. Am. J. Physiol. 1993, 264, H701–H707.
  79. Ozcan, C.; Battaglia, E.; Young, R.; Suzuki, G. LKB1 Knockout Mouse Develops Spontaneous Atrial Fibrillation and Provides Mechanistic Insights Into Human Disease Process. JAHA 2015, 4, e001733.
  80. Deshmukh, A.; Ghannam, M.; Liang, J.; Saeed, M.; Cunnane, R.; Ghanbari, H.; Latchamsetty, R.; Crawford, T.; Batul, S.A.; Chung, E.; et al. Effect of Metformin on Outcomes of Catheter Ablation for Atrial Fibrillation. J. Cardiovasc. Electrophysiol. 2021, 32, 1232–1239.
  81. Ostropolets, A.; Elias, P.A.; Reyes, M.V.; Wan, E.Y.; Pajvani, U.B.; Hripcsak, G.; Morrow, J.P. Metformin Is Associated With a Lower Risk of Atrial Fibrillation and Ventricular Arrhythmias Compared With Sulfonylureas: An Observational Study. Circ. Arrhythm. Electrophysiol. 2021, 14, e009115.
  82. Liu, G.Z.; Hou, T.T.; Yuan, Y.; Hang, P.Z.; Zhao, J.J.; Sun, L.; Zhao, G.Q.; Zhao, J.; Dong, J.M.; Wang, X.B.; et al. Fenofibrate Inhibits Atrial Metabolic Remodelling in Atrial Fibrillation through PPAR-Alpha/Sirtuin 1/PGC-1alpha Pathway. Br. J. Pharmacol. 2016, 173, 1095–1109.
  83. Yu, J.; Li, W.; Li, Y.; Zhao, J.; Wang, L.; Dong, D.; Pan, Z.; Yang, B. Activation of Beta(3)-Adrenoceptor Promotes Rapid Pacing-Induced Atrial Electrical Remodeling in Rabbits. Cell Physiol. Biochem. 2011, 28, 87–96.
  84. Bai, F.; Liu, Y.; Tu, T.; Li, B.; Xiao, Y.; Ma, Y.; Qin, F.; Xie, J.; Zhou, S.; Liu, Q. Metformin Regulates Lipid Metabolism in a Canine Model of Atrial Fibrillation through AMPK/PPAR-Alpha/VLCAD Pathway. Lipids Health Dis. 2019, 18, 109.
  85. Ozcan, C.; Dixit, G.; Li, Z. Activation of AMP-Activated Protein Kinases Prevents Atrial Fibrillation. J. Cardiovasc. Trans. Res. 2021, 14, 492–502.
  86. Goodpaster, B.H.; Sparks, L.M. Metabolic Flexibility in Health and Disease. Cell Metab. 2017, 25, 1027–1036.
  87. Williams, N.C.; O’Neill, L.A.J. A Role for the Krebs Cycle Intermediate Citrate in Metabolic Reprogramming in Innate Immunity and Inflammation. Front. Immunol. 2018, 9, 141.
  88. Wijesurendra, R.S.; Casadei, B. Mechanisms of Atrial Fibrillation. Heart 2019, 105, 1860–1867.
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