Metabolic Heart Failure Research Articles

Integrated Control of Fatty Acid Metabolism in Heart Failure.

Disrupted fatty acid metabolism is one of the most important metabolic features in heart failure. The heart obtains energy from fatty acids via oxidation. However, heart failure results in markedly decreased fatty acid oxidation and is accompanied by the accumulation of excess lipid moieties that lead to cardiac lipotoxicity. Herein, we summarized and discussed the current understanding of the integrated regulation of fatty acid metabolism (including fatty acid uptake, lipogenesis, lipolysis, and fatty acid oxidation) in the pathogenesis of heart failure. The functions of many enzymes and regulatory factors in fatty acid homeostasis were characterized. We reviewed their contributions to the development of heart failure and highlighted potential targets that may serve as promising new therapeutic strategies.

Cardiac Metabolism in Heart Failure and Implications for Uremic Cardiomyopathy

Chronic kidney disease is associated with an increased risk for the development and progression of cardiovascular disorders including hypertension, dyslipidemia, and coronary artery disease. Chronic kidney disease may also affect the myocardium through complex systemic changes, resulting in structural remodeling such as hypertrophy and fibrosis, as well as impairments in both diastolic and systolic function. These cardiac changes in the setting of chronic kidney disease define a specific cardiomyopathic phenotype known as uremic cardiomyopathy. Cardiac function is tightly linked to its metabolism, and research over the past 3 decades has revealed significant metabolic remodeling in the myocardium during the development of heart failure. Because the concept of uremic cardiomyopathy has only been recognized in recent years, there are limited data on metabolism in the uremic heart. Nonetheless, recent findings suggest overlapping mechanisms with heart failure. This work reviews key features of metabolic remodeling in the failing heart in the general population and extends this to patients with chronic kidney disease. The knowledge of similarities and differences in cardiac metabolism between heart failure and uremic cardiomyopathy may help identify new targets for mechanistic and therapeutic research on uremic cardiomyopathy.

Increased Risk of Cardiovascular Complications in Chronic Kidney Disease: Introduction to a Compendium.

Increased Risk of Cardiovascular Complications in Chronic Kidney Disease: Introduction to a Compendium.

Ketones and the Heart: Metabolic Principles and Therapeutic Implications.

The ketone bodies beta-hydroxybutyrate and acetoacetate are hepatically produced metabolites catabolized in extrahepatic organs. Ketone bodies are a critical cardiac fuel and have diverse roles in the regulation of cellular processes such as metabolism, inflammation, and cellular crosstalk in multiple organs that mediate disease. This review focuses on the role of cardiac ketone metabolism in health and disease with an emphasis on the therapeutic potential of ketosis as a treatment for heart failure (HF). Cardiac metabolic reprogramming, characterized by diminished mitochondrial oxidative metabolism, contributes to cardiac dysfunction and pathologic remodeling during the development of HF. Growing evidence supports an adaptive role for ketone metabolism in HF to promote normal cardiac function and attenuate disease progression. Enhanced cardiac ketone utilization during HF is mediated by increased availability due to systemic ketosis and a cardiac autonomous upregulation of ketolytic enzymes. Therapeutic strategies designed to restore high-capacity fuel metabolism in the heart show promise to address fuel metabolic deficits that underpin the progression of HF. However, the mechanisms involved in the beneficial effects of ketone bodies in HF have yet to be defined and represent important future lines of inquiry. In addition to use as an energy substrate for cardiac mitochondrial oxidation, ketone bodies modulate myocardial utilization of glucose and fatty acids, two vital energy substrates that regulate cardiac function and hypertrophy. The salutary effects of ketone bodies during HF may also include extra-cardiac roles in modulating immune responses, reducing fibrosis, and promoting angiogenesis and vasodilation. Additional pleotropic signaling properties of beta-hydroxybutyrate and AcAc are discussed including epigenetic regulation and protection against oxidative stress. Evidence for the benefit and feasibility of therapeutic ketosis is examined in preclinical and clinical studies. Finally, ongoing clinical trials are reviewed for perspective on translation of ketone therapeutics for the treatment of HF.

Contribution of skeletal muscle-specific microRNA-133b to insulin resistance in heart failure.

Insulin resistance (IR) is one of the hallmarks of heart failure (HF). Abnormalities in skeletal muscle (SM) metabolism have been identified in patients with HF. However, the underlying mechanisms of IR development in SM in HF are poorly understood. Herein, we hypothesize that HF upregulates miR-133b in SM and in turn alters glucose metabolism and the propensity toward IR. Mitochondria isolated from SM of mice with HF induced by transverse aortic constriction (TAC) showed lower respiration and downregulation of muscle-specific components of the tricarboxylic acid (TCA) cycle, AMP deaminase 1 (AMPD1), and fumarate compared with those from control animals. RNA-Seq and subsequent qPCR validation confirmed upregulation of SM-specific microRNA (miRNA), miR-133b, in TAC versus sham animals. miR-133b overexpression alone resulted in significantly lower mitochondrial respiration, cellular glucose uptake, and glycolysis along with lower ATP production and cellular energy reserve compared with the scramble (Scr) in C2C12 cells. miR-133b binds to the 3'-untranslated region (UTR) of KLF15, the transcription factor for the insulin-sensitive glucose transporter, GLUT4. Overexpression of miR-133b lowers GLUT4 and lowers pAkt in presence of insulin in C2C12 cells. Finally, lowering miR-133b in primary skeletal myocytes isolated from TAC mice using antagomir-133b reversed the changes in KLF15, GLUT4, and AMPD1 compared with the scramble-transfected myocytes. Taken together, these data demonstrate a role for SM miR-133b in altered glucose metabolism in HF and suggest the therapeutic potential in HF to improve glucose uptake and glycolysis by restoring GLUT4 abundance. The data uncover a novel mechanism for IR and ultimately SM metabolic abnormalities in patients with HF.NEW & NOTEWORTHY Heart failure is associated with systemic insulin resistance and abnormalities in glucose metabolism but the underlying mechanisms are poorly understood. In the skeletal muscle, the major peripheral site of glucose utilization, we observe an increase in miR-133b in heart failure mice, which reduces the insulin-sensitive glucose transporter (GLUT4), glucose uptake, and metabolism in C2C12 and in myocytes. The antagomir for miR-133b restores GLUT4 protein and markers of metabolism in skeletal myocytes from heart failure mice demonstrating that miR-133b is an exciting target for systemic insulin resistance in heart failure and an important player in the cross talk between the heart and the periphery in the heart failure syndrome.

Glucose loading for heart failure protects the myocardium and improves physical function.

[Purpose] The purpose of this study was to investigate the effects of glucose intake on physical function in a heart failure rat model. [Materials and Methods] Five-week-old male Wistar rats were used for this study. Monocrotalin (40 mg/kg) was administered intraperitoneally to rats to induce heart failure. The rats were divided into two groups, control and MCT; the MCT group was further classified according to glucose concentration (0%, 10%, and 50%). [Results] Glucose intake during heart failure prevented the loss of body weight, skeletal muscle, and fat mass. Myocardial metabolism in heart failure was enhanced by hypoxia, which in turn, enhanced the glycolytic system. [Conclusion] Glucose loading suppressed cardiac hypertrophy and improved physical function in the heart failure rat model.

Abstract 12618: Human And Mouse Demonstration Of The Reticulum-Mitochondria Ca 2+ Coupling As A New Therapeutic Target In Metabolic HFpEF

Context: Metabolic heart failure with preserved ejection fraction (HFpEF) is a frequent and disabling disease with yet no therapy and limited knowledge on the cardiac underlying molecular mechanisms. Ca 2+ transfer at mitochondria-associated reticular membranes (MAM) is crucial in the cardiomyocyte to tightly regulate mitochondrial Ca 2+ content and assure the excitation-energetics coupling. We aimed to specify the role of the MAM Ca 2+ coupling in both human and mouse hearts with metabolic HFpEF. Results: Mass spectrometry analysis of cardiac MAM showed an upregulation of cellular response to stress and lipid metabolism processes in two obesogenic T2D mouse models (16 weeks of high-fat high-sucrose diet, HFHSD vs standard diet, SD; 12-week old leptin-deficient ob/ob vs WT), while Ca 2+ transport was downregulated only in the HFHSD MAM. MAM Ca 2+ coupling assessment by adenoviral infection of a FRET-based mitochondrial Ca 2+ sensor, revealed a MAM Ca 2+ uncoupling in the HFHSD cardiomyocyte, leading to reduced mitochondrial Ca 2+ content and bioenergetics, while no change was measured in the ob/ob cell. HFHSD mice exhibited cardiac hypertrophy, diastolic dysfunction and mild strain rate reduction with preserved EF. Ob/ob mice only displayed strain rate reduction and concentric hypertrophy. Principal component analysis (PCA) demonstrated a divergence between the HFHSD group and the three others, as displayed by their scattering along the first PC (61% of variance) contributed mainly by strain rate, wall thickness, body weight and Ca 2+ peak amplitude. Proximity ligation assay revealed a decreased proximity between the reticular IP3-receptor and the mitochondrial porin VDAC in human left ventricle biopsies from T2D versus non-diabetic patients, obtained during valve replacement surgery: this suggests a reduced formation of the IP3R-driven Ca 2+ channeling complex. Conclusion: The ob/ob model does not recapitulate the main hallmarks of metabolic HFpEF and does not display any change in MAM Ca 2+ coupling. On the contrary, a MAM Ca 2+ uncoupling was detected both in the human T2D heart and in the heart of the HFHSD-induced metabolic HFpEF mouse, suggesting the reticulum-mitochondria Ca 2+ coupling as a critical therapeutic target in metabolic HFpEF.

Effect of iron deficiency on skeletal muscle metabolism in heart failure with preserved ejection fraction

Abstract Background Iron deficiency (ID) is suggested to be one of the key comorbidities contributing to heart failure with preserved ejection fraction (HFpEF) and concomitant exercise intolerance, possibly by inducing systemic inflammation and microvascular dysfunction (MVD). ID is associated with poorer prognosis in HFpEF, but its exact impact on exercise capacity in HFpEF patients remains to be further investigated. Purpose To evaluate the effect of ID on exercise capacity in HFpEF patients by assessing skeletal muscle metabolism. Additionally, to assess the association between ID and MVD in HFpEF patients. Methods This prospective study included patients diagnosed with HFpEF according to the ESC Heart Failure 2016 guidelines between January 2018 and May 2021. Patients were excluded if they were of childbearing potential, had any iron supplementation 6 months or chemotherapy 1 year prior to inclusion, were known with significant peripheral artery disease, or had any contraindication for phosphorus-magnetic resonance spectroscopy (31P-MRS). Iron status was defined as absolute ID (serum ferritin <100μg/L), relative ID (serum ferritin 100–299μg/L and transferrin saturation <20%), and no ID. Skeletal muscle oxidative capacity of the upper leg was evaluated by determining phosphocreatine (PCr) recovery kinetics with 31P-MRS in the vastus lateralis muscle after isometric knee extension exercise. Microvascular function was assessed as heat-induced skin hyperemia using laser-Doppler flowmetry. Clinical data up to 6 months prior to or after inclusion was used. Results Twenty-four HFpEF patients without ID and 18 with ID were included, including 14 patients with absolute ID. Clinical characteristics of patients without ID and with ID were comparable: median age 74 [69–79] vs. 77 [69–81] years, 13 (54%) vs. 14 (78%) were females, and 20 (83%) vs. 16 (89%) had a history of hypertension (Table 1). Both groups showed similar halftime of PCr recovery after exercise (29.2 [22.8–33.2] vs. 27.0 [21.1–31.4] seconds, p=0.416), and similar skin hyperaemic flow increase (1142 [576–2247] vs. 1023 [574–1511] %, p=0.554). These measures of skeletal muscle metabolism and microvascular function were not correlated. In a subset of patients (11 without ID and 13 with ID), elevated high-sensitive C-reactive protein (hsCRP) was correlated with PCr recovery halftime in those with ID (R2 0.565, p=0.003). This correlation was not found in patients without ID (R2 0.119, p=0.300) in the original data (Figure 1), but was found after removal of a prominent outlier (R2 0.654, p=0.005). Conclusion HFpEF patients without ID showed comparable skeletal muscle oxidative capacity and microvascular skin hyperaemia compared to HFpEF patients with ID. Post-hoc analysis suggests that inflammation affects skeletal muscle metabolism in HFpEF patients, possibly regardless of ID. Future studies on the effects of ID and inflammation on cellular metabolism could suggest therapeutic targets in HFpEF. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This study was funded by Vifor Pharma. The funder had no influence on the study results.

Magnetic resonance imaging of cardiac metabolism in heart failure: how far have we come?

As one of the highest energy consumer organs in the body, the heart requires tremendous amount of adenosine triphosphate (ATP) to maintain its continuous mechanical work. Fatty acids, glucose, and ketone bodies are the primary fuel source of the heart to generate ATP with perturbations in ATP generation possibly leading to contractile dysfunction. Cardiac metabolic imaging with magnetic resonance imaging (MRI) plays a crucial role in understanding the dynamic metabolic changes occurring in the failing heart, where the cardiac metabolism is deranged. Also, targeting and quantifying metabolic changes in vivo noninvasively is a promising approach to facilitate diagnosis, determine prognosis, and evaluate therapeutic response. Here, we summarize novel MRI techniques used for detailed investigation of cardiac metabolism in heart failure including magnetic resonance spectroscopy (MRS), hyperpolarized MRS, and chemical exchange saturation transfer based on evidence from preclinical and clinical studies and to discuss the potential clinical application in heart failure.

GCN5 contributes to intracellular lipid accumulation in human primary cardiac stromal cells from patients affected by Arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is a genetic disease associated with sudden cardiac death and cardiac fibro‐fatty replacement. Over the last years, several works have demonstrated that different epigenetic enzymes can affect not only gene expression changes in cardiac diseases but also cellular metabolism. Specifically, the histone acetyltransferase GCN5 is known to facilitate adipogenesis and modulate cardiac metabolism in heart failure. Our group previously demonstrated that human primary cardiac stromal cells (CStCs) contribute to adipogenesis in the ACM pathology. Thus, this study aims to evaluate the role of GCN5 in ACM intracellular lipid accumulation. To do so, CStCs were obtained from right ventricle biopsies of ACM patients and from samples of healthy cadaveric donors (CTR). GCN5 expression was increased both in ex vivo and in vitro ACM samples compared to CTR. When GCN5 expression was silenced or pharmacologically inhibited by the administration of MB‐3, we observed a reduction in lipid accumulation and a mitigation of reactive oxygen species (ROS) production in ACM CStCs. In agreement, transcriptome analysis revealed that the presence of MB‐3 modified the expression of pathways related to cellular redox balance. Altogether, our findings suggest that GCN5 inhibition reduces fat accumulation in ACM CStCs, partially by modulating intracellular redox balance pathways.

Targeting Myocardial Substrate Metabolism in the Failing Heart: Ready for Prime Time?

We review the clinical benefits of altering myocardial substrate metabolism in heart failure. Modulation of cardiac substrates (fatty acid, glucose, or ketone metabolism) offers a wide range of therapeutic possibilities which may be applicable to heart failure. Augmenting ketone oxidation seems to offer great promise as a new therapeutic modality in heart failure. The heart has long been recognized as metabolic omnivore, meaning it can utilize a variety of energy substrates to maintain adequate ATP production. The adult heart uses fatty acid as a major fuel source, but it can also derive energy from other substrates including glucose and ketone, and to some extent pyruvate, lactate, and amino acids. However, cardiomyocytes of the failing heart endure remarkable metabolic remodeling including a shift in substrate utilization and reduced ATP production, which account for cardiac remodeling and dysfunction. Research to understand the implication of myocardial metabolic perturbation in heart failure has grown in recent years, and this has raised interest in targeting myocardial substrate metabolism for heart failure therapy. Due to the interdependency between different pathways, the main therapeutic metabolic approaches include inhibiting fatty acid uptake/fatty acid oxidation, reducing circulating fatty acid levels, increasing glucose oxidation, and augmenting ketone oxidation.

Design and rationale for a comparison study of Olmesartan and Valsartan On myocardial metabolism In patients with Dilated cardiomyopathy (OVOID) trial: study protocol for a randomized controlled trial

BackgroundDilated cardiomyopathy (DCMP) is characterized by ventricular chamber enlargement and systolic dysfunction which may cause heart failure. Patients with DCMP have overactivation of the renin-angiotensin-aldosterone systems, which can also adversely affect myocardial metabolism in heart failure. The impairment of myocardial metabolism can contribute to the progression of left ventricular remodeling and contractile dysfunction in heart failure. Although angiotensin II receptor blockers (ARBs) have been used to treat patients with DCMP, there has been no direct comparison of the efficacy of these agents. The objective of this study is to compare the effects of olmesartan and valsartan on myocardial metabolism in patients with DCMP.Methods/designThe OVOID study (a comparison study of Olmesartan and Valsartan On myocardial metabolism In patients with Dilated cardiomyopathy) is designed as a non-blinded, open-label, parallel-group, prospective, randomized, controlled, multicenter clinical trial. A total of 40 DCMP patients aged between 20 and 85 years will be randomly allocated into the olmesartan or the valsartan group. 18F-fluoro-2-deoxyglucose (FDG) cardiac positron emission tomography (PET) will be performed at baseline and six months after receiving the study agent. The primary endpoint is myocardial glucose consumption per square meter, measured using 18F-FDG PET 6 months after receiving the study agent.DiscussionThe purpose of this trial is to compare the efficacy between olmesartan and valsartan in improving myocardial metabolism in DCMP patients. This will be the first randomized comparative study investigating the differential effects of ARBs on heart failure.Trial registrationClinicalTrials.govNCT04174456. Registered on 18 November 2019

SGLT2 Inhibitors and Ketone Metabolism in Heart Failure.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have emerged as powerful drugs that can be used to treat heart failure (HF) patients, both with preserved and reduced ejection fraction and in the presence or absence of type 2 diabetes. While the mechanisms underlying the salutary effects of SGLT2 inhibitors have not been fully elucidated, there is clear evidence for a beneficial metabolic effect of these drugs. In this review, we discuss the effects of SGLT2 inhibitors on cardiac energy provision secondary to ketone bodies, pathological ventricular remodeling, and inflammation in patients with HF. While the specific contribution of ketone bodies to the pleiotropic cardiovascular benefits of SGLT2 inhibitors requires further clarification, ketone bodies themselves may also be used as a therapy for HF.

Treatments for skeletal muscle abnormalities in heart failure: sodium-glucose transporter 2 and ketone bodies.

Various skeletal muscle abnormalities are known to occur in heart failure (HF) and are closely associated with exercise intolerance. Particularly, abnormal energy metabolism caused by mitochondrial dysfunction in skeletal muscle is a cause of decreased endurance exercise capacity. However, to date, no specific drug treatment has been established for the skeletal muscle abnormalities and exercise intolerance occurring in patients with HF. Sodium-glucose transporter 2 (SGLT2) inhibitors promote glucose excretion by suppressing glucose reabsorption in the renal tubules, which has a hypoglycemic effect independent of insulin secretion. Recently, large clinical trials have demonstrated that treatment with SGLT2 inhibitors suppresses cardiovascular events in patients who have HF with systolic dysfunction. Mechanisms of the therapeutic effects of SGLT2 inhibitors for HF have been suggested to be diuretic, suppression of neurohumoral factor activation, renal protection, and improvement of myocardial metabolism, but this has not been clarified to date. SGLT2 inhibitors are known to increase blood ketone bodies. This suggests that they may improve the abnormal skeletal muscle metabolism in HF, that is, improve fatty acid metabolism, suppress glycolysis, and use ketone bodies in mitochondrial energy production. Ultimately, they may improve aerobic metabolism in skeletal muscle, suppress anaerobic metabolism, and improve aerobic exercise capacity at the level of the anaerobic threshold. The potential actions of such SGLT2 inhibitors explain their effectiveness in HF and may be candidates for new drug treatments aimed at improving exercise intolerance. In this review, we outlined the effects of SGLT2 inhibitors on skeletal muscle metabolism, with a particular focus on ketone metabolism.

Modulating gut microbial metabolism in heart failure: Opportunities and challenges.

Alterations in gut microbial composition and metabolism have been mechanistically linked to the development of heart failure (HF) [1]. However, the promise of targeting the gut microbiome to prevent or even reverse disease progression remains somewhat unfulfilled despite the exponential growth of technological advances that have allowed us to gain insights and deliver therapeutic interventions to modulate gut microbial metabolism [2]. In a recent issue of EBioMedicine, an esteemed group of clinical investigators from Norway and Brazil reported their primary findings of the GutHeart trial, a prospective multicenter study that demonstrated that short-term treatment of either rifaximin or Saccharomyces boulardii did not improve cardiac function in patients with HF with reduced ejection fraction [3].

The Role of Metabolism in Heart Failure and Regeneration.

Heart failure is the leading cause of death worldwide. The inability of the adult mammalian heart to regenerate following injury results in the development of systolic heart failure. Thus, identifying novel approaches toward regenerating the adult heart has enormous therapeutic potential for adult heart failure. Mitochondrial metabolism is an essential homeostatic process for maintaining growth and survival. The emerging role of mitochondrial metabolism in controlling cell fate and function is beginning to be appreciated. Recent evidence suggests that metabolism controls biological processes including cell proliferation and differentiation, which has profound implications during development and regeneration. The regenerative potential of the mammalian heart is lost by the first week of postnatal development when cardiomyocytes exit the cell cycle and become terminally differentiated. This inability to regenerate following injury is correlated with the metabolic shift from glycolysis to fatty acid oxidation that occurs during heart maturation in the postnatal heart. Thus, understanding the mechanisms that regulate cardiac metabolism is key to unlocking metabolic interventions during development, disease, and regeneration. In this review, we will focus on the emerging role of metabolism in cardiac development and regeneration and discuss the potential of targeting metabolism for treatment of heart failure.

Metagenomic analysis of gut microbiota reveals its role in trimethylamine metabolism in heart failure

BackgroundWe had previously reported an increase in trimethylamine N-oxide (TMAO) levels in patients with both compensated and decompensated heart failure (HF) and alteration in gut microbiota composition using 16S rRNA gene amplicon analysis. Although a metagenome-wide analysis showed that choline-TMA lyase levels increased in HF patients, which TMA generation pathway from choline, carnitine, or betaine contributes to the increase in TMAO levels in HF needs to be elucidated. MethodsWe conducted a metagenome-wide shotgun sequencing analysis of gut microbiota and measured the TMAO levels in plasma of 22 HF patients during the compensated phase and 11 age-, sex-, and comorbidity-matched control subjects, whose gut microbiota compositions were reported in a previous 16S rRNA-based analysis. ResultsThe abundance of cntA/B was positively correlated with TMAO, especially in HF patients, whereas that of cutC/D or betaine reductase was not correlated either in controls or HF patients. The abundance of cntA/B was mainly derived from the genera Escherichia and Klebsiella either in controls or HF patients. ConclusionTMAO levels in plasma depend on the abundance of cntA/B in HF. Although it is difficult to exclude the involvement of confounding factors, microbial dysbiosis connecting the abundance of cntA/B in the gut and the increase of TMAO in plasma can be a therapeutic target for HF.

Potential role for pyruvate kinase M2 in the regulation of murine cardiac glycolytic flux during in vivo chronic hypoxia.

Carbohydrate metabolism in heart failure shares similarities to that following hypoxic exposure, and is thought to maintain energy homoeostasis in the face of reduced O2 availability. As part of these in vivo adaptations during sustained hypoxia, the heart up-regulates and maintains a high glycolytic flux, but the underlying mechanism is still elusive. We followed the cardiac glycolytic responses to a chronic hypoxic (CH) intervention using [5-3H]-glucose labelling in combination with detailed and extensive enzymatic and metabolomic approaches to provide evidence of the underlying mechanism that allows heart survivability. Following 3 weeks of in vivo hypoxia (11% oxygen), murine hearts were isolated and perfused in a retrograde mode with function measured via an intraventricular balloon and glycolytic flux quantified using [5-3H]-glucose labelling. At the end of perfusion, hearts were flash-frozen and central carbon intermediates determined via liquid chromatography tandem mass spectrometry (LC-MS/MS). The maximal activity of glycolytic enzymes considered rate-limiting was assessed enzymatically, and protein abundance was determined using Western blotting. Relative to normoxic hearts, CH increased ex vivo cardiac glycolytic flux 1.7-fold with no effect on cardiac function. CH up-regulated cardiac pyruvate kinase (PK) flux 3.1-fold and cardiac pyruvate kinase muscle isoenzyme M2 (PKM2) protein content 1.4-fold compared with normoxic hearts. CH also augmented cardiac pentose phosphate pathway (PPP) flux, reflected by higher ribose-5-phosphate (R5P) content. These findings support an increase in the covalent (protein expression) and allosteric (flux) control of PKM2 as being central to the sustained up-regulation of the glycolytic flux in the chronically hypoxic heart.

Cardiac Energy Metabolism in Heart Failure.

Alterations in cardiac energy metabolism contribute to the severity of heart failure. However, the energy metabolic changes that occur in heart failure are complex and are dependent not only on the severity and type of heart failure present but also on the co-existence of common comorbidities such as obesity and type 2 diabetes. The failing heart faces an energy deficit, primarily because of a decrease in mitochondrial oxidative capacity. This is partly compensated for by an increase in ATP production from glycolysis. The relative contribution of the different fuels for mitochondrial ATP production also changes, including a decrease in glucose and amino acid oxidation, and an increase in ketone oxidation. The oxidation of fatty acids by the heart increases or decreases, depending on the type of heart failure. For instance, in heart failure associated with diabetes and obesity, myocardial fatty acid oxidation increases, while in heart failure associated with hypertension or ischemia, myocardial fatty acid oxidation decreases. Combined, these energy metabolic changes result in the failing heart becoming less efficient (ie, a decrease in cardiac work/O2 consumed). The alterations in both glycolysis and mitochondrial oxidative metabolism in the failing heart are due to both transcriptional changes in key enzymes involved in these metabolic pathways, as well as alterations in NAD redox state (NAD+ and nicotinamide adenine dinucleotide levels) and metabolite signaling that contribute to posttranslational epigenetic changes in the control of expression of genes encoding energy metabolic enzymes. Alterations in the fate of glucose, beyond flux through glycolysis or glucose oxidation, also contribute to the pathology of heart failure. Of importance, pharmacological targeting of the energy metabolic pathways has emerged as a novel therapeutic approach to improving cardiac efficiency, decreasing the energy deficit and improving cardiac function in the failing heart.

CircSnx12 Is Involved in Ferroptosis During Heart Failure by Targeting miR-224-5p.

Circular RNA (circRNA) is a subclass of non-coding RNAs that enables the circular transcripts resistant to the exonuclease digestion. Iron homeostasis is essential for the body to maintain normal physiological functions. At present, the relationship among circRNA, iron metabolism and heart failure remains largely unknown. This study aimed to explore the regulatory mechanism of circRNA and iron metabolism in heart failure. We obtained circRNA, miRNA and mRNA data from public databases and built a ceRNA network. The prediction results were verified in the myocardial tissues of pressure overload-induced heart failure mice through the use of histopathological staining methods, iron and malondialdehyde (MDA) measurement tests, quantitative real-time PCR (qRT-PCR), Western blot analysis and luciferase reporter assay. A total of 4 genes related to iron metabolism and oxidative stress were identified, and a ceRNA network involving 7 circRNAs, 7 miRNAs, and 4 mRNAs was constructed using bioinformatics tools. The results of qRT-PCR and Western blot analyses indicated that the expression level of FTH1 was similar with that predicted by bioinformatics analysis. Echocardiographic measurement showed that heart failure mice have lower fractional shortening and ejection fraction. Moreover, the myocardium of heart failure mice displayed obvious fibrosis as well as increased levels of iron and MDA compared to control mice. Besides, circSnx12 could act as an endogenous sponge to bind with miR-224-5p, and the 3'UTR region of FTH1 also had miRNA binding sites. A circRNA-miRNA-mRNA regulatory network was successfully constructed by identifying differentially expressed genes related to iron metabolism. This new approach reveals potential circRNA targets for the treatment of heart failure.