From Beats to Metabolism: the Heart at the Core of Interorgan Metabolic Cross Talk.

The heart, once considered a mere blood pump, is now recognized as a multifunctional metabolic and endocrine organ. Its function is tightly regulated by various metabolic processes, at the same time it serves as an endocrine organ, secreting bioactive molecules that impact systemic metabolism. In recent years, research has shed light on the intricate interplay between the heart and other metabolic organs, such as adipose tissue, liver, and skeletal muscle. The metabolic flexibility of the heart and its ability to switch between different energy substrates play a crucial role in maintaining cardiac function and overall metabolic homeostasis. Gaining a comprehensive understanding of how metabolic disorders disrupt cardiac metabolism is crucial, as it plays a pivotal role in the development and progression of cardiac diseases. The emerging understanding of the heart as a metabolic and endocrine organ highlights its essential contribution to whole body metabolic regulation and offers new insights into the pathogenesis of metabolic diseases, such as obesity, diabetes, and cardiovascular disorders. In this review, we provide an in-depth exploration of the heart's metabolic and endocrine functions, emphasizing its role in systemic metabolism and the interplay between the heart and other metabolic organs. Furthermore, emerging evidence suggests a correlation between heart disease and other conditions such as aging and cancer, indicating that the metabolic dysfunction observed in these conditions may share common underlying mechanisms. By unraveling the complex mechanisms underlying cardiac metabolism, we aim to contribute to the development of novel therapeutic strategies for metabolic diseases and improve overall cardiovascular health.

Metabolic profiling of aortic stenosis and hypertrophic cardiomyopathy identifies mechanistic contrasts in substrate utilization.

Aortic stenosis (AS) and hypertrophic cardiomyopathy (HCM) are distinct disorders leading to left ventricular hypertrophy (LVH), but whether cardiac metabolism substantially differs between these in humans remains to be elucidated. We undertook an invasive (aortic root, coronary sinus) metabolic profiling in patients with severe AS and HCM in comparison with non-LVH controls to investigate cardiac fuel selection and metabolic remodeling. These patients were assessed under different physiological states (at rest, during stress induced by pacing). The identified changes in the metabolome were further validated by metabolomic and orthogonal transcriptomic analysis, in separately recruited patient cohorts. We identified a highly discriminant metabolomic signature in severe AS in all samples, regardless of sampling site, characterized by striking accumulation of long-chain acylcarnitines, intermediates of fatty acid transport across the inner mitochondrial membrane, and validated this in a separate cohort. Mechanistically, we identify a downregulation in the PPAR-α transcriptional network, including expression of genes regulating fatty acid oxidation (FAO). In silico modeling of ß-oxidation demonstrated that flux could be inhibited by both the accumulation of fatty acids as a substrate for mitochondria and the accumulation of medium-chain carnitines which induce competitive inhibition of the acyl-CoA dehydrogenases. We present a comprehensive analysis of changes in the metabolic pathways (transcriptome to metabolome) in severe AS, and its comparison to HCM. Our results demonstrate a progressive impairment of ß-oxidation from HCM to AS, particularly for FAO of long-chain fatty acids, and that the PPAR-α signaling network may be a specific metabolic therapeutic target in AS.

Myocardial glycophagy flux dysregulation and glycogen accumulation characterize diabetic cardiomyopathy.

Diabetic heart disease morbidity and mortality is escalating. No specific therapeutics exist and mechanistic understanding of diabetic cardiomyopathy etiology is lacking. While lipid accumulation is a recognized cardiomyocyte phenotype of diabetes, less is known about glycolytic fuel handling and storage. Based on in vitro studies, we postulated the operation of an autophagy pathway in the myocardium specific for glycogen homeostasis - glycophagy. Here we visualize occurrence of cardiac glycophagy and show that the diabetic myocardium is characterized by marked glycogen elevation and altered cardiomyocyte glycogen localization. We establish that cardiac glycophagy flux is disturbed in diabetes. Glycophagy may represent a potential therapeutic target for alleviating the myocardial impacts of metabolic disruption in diabetic heart disease.

Metabolic cycles: A unifying concept for energy transfer in the heart.

It is still debated whether changes in metabolic flux are cause or consequence of contractile dysfunction in non-ischemic heart disease. We have previously proposed a model of cardiac metabolism grounded in a series of six moiety-conserved, interconnected cycles. In view of a recent interest to augment oxygen availability in heart failure through iron supplementation, we integrated this intervention in terms of moiety conservation. Examining published work from both human and murine models, we argue this strategy restores a mitochondrial cycle of energy transfer by enhancing mitochondrial pyruvate carrier (MPC) expression and providing pyruvate as a substrate for carboxylation and anaplerosis. Metabolomic data from failing heart muscle reveal elevated pyruvate levels with a concomitant decrease in the levels of Krebs cycle intermediates. Additionally, MPC is downregulated in the same failing hearts, as well as under hypoxic conditions. MPC expression increases upon mechanical unloading in the failing human heart, as does contractile function. We note that MPC deficiency also alters expression of enzymes involved in pyruvate carboxylation and decarboxylation, increases intermediates of biosynthetic pathways, and eventually leads to cardiac hypertrophy and dilated cardiomyopathy. Collectively, we propose that an unbroken chain of moiety-conserved cycles facilitates energy transfer in the heart. We refer to the transport and subsequent carboxylation of pyruvate in the mitochondrial matrix as an example and a proposed target for metabolic support to reverse impaired contractile function.

Maternal high fat-high energy diet alters metabolic factors in the non-human primate fetal heart.

The consumption of high fat-high energy diets (HF-HEDs) continues to rise worldwide and parallels the rise in maternal obesity (MO) that predisposes offspring to cardiometabolic disorders. Although the underlying mechanisms are unclear, thyroid hormones (TH) modulate cardiac maturation in utero. Therefore, we aimed to determine the impact of a high fat-high energy diet (HF-HED) on the hormonal, metabolic and contractility profile of the non-human primate (NHP) fetal heart. At ∼9 months preconception, female baboons (Papio hamadryas) were randomly assigned to either a control diet or HF-HED. At 165 days gestational age (term = 184 days), fetuses were delivered by Caesarean section under anaesthesia, humanely killed, and left ventricular cardiac tissue (Control (n = 6 female, 6 male); HF-HED (n = 6 F, 6 M)) was collected. Maternal HF-HED decreased the concentration of active cardiac TH (i.e. triiodothyronine (T3)), and type 1 iodothyronine deiodinase (DIO1) mRNA expression. Maternal HF-HED decreased the abundance of cardiac markers of insulin-mediated glucose uptake phosphorylated insulin receptor substrate 1 (Ser789) and glucose transporter 4, and increased protein abundance of key oxidative phosphorylation complexes (I, III, IV) and mitochondrial abundance in both sexes. Maternal HF-HED alters cardiac TH status, which may induce early signs of cardiac insulin resistance. This may increase the risk of cardiometabolic disorders in later life in offspring born to these pregnancies. KEY POINTS: Babies born to mothers who consume a high fat-high energy diet (HF-HED) prior to and during pregnancy are predisposed to an increased risk of cardiometabolic disorders across the life course. Maternal HF-HED prior to and during pregnancy decreased thyroid hormone triiodothyronine (T3) concentrations and type 1 iodothyronine deiodinase DIO1 mRNA expression in the non-human primate fetal heart. Maternal HF-HED decreased markers of insulin-dependent glucose uptake, phosphorylated insulin receptor substrate 1 and glucose transporter 4 in the fetal heart. Maternal HF-HED increased mitochondrial abundance and mitochondrial OXPHOS complex I, III and IV in the fetal heart. Fetuses from HF-HED pregnancies are predisposed to cardiometabolic disorders that may be mediated by changes in T3, placing them on a poor lifetime cardiovascular health trajectory.

Hyperpolarized [1-13C]pyruvate Magnetic Resonance Imaging Identifies Metabolic Phenotypes in Patients with Heart Failure.

BACKGROUND: Hyperpolarized [1-13C]pyruvate magnetic resonance imaging (HP MRI) visualizes key steps in myocardial metabolism. The present study aimed to examine patients with heart (HF) using HP MRI. METHODS: A cross-sectional study of patients with HF and healthy controls using HP MRI. Metabolic imaging was obtained using a cardiac-gated spectral-spatial excitation with spiral read-out acquisition. The metabolite signal was analyzed for lactate, bicarbonate, and the alanine signal. Metabolite signal was normalized to the total carbon signal (TC). At the one-year follow-up, echocardiography was performed in all patients and HP MRI in two patients. RESULTS: We included six patients with ischemic heart disease (IHD), six with dilated cardiomyopathy and six healthy controls. In patients, left ventricular ejection fraction (LVEF) correlated with lactate/bicarbonate (r = -0.6, p = 0.03) and lactate/TC (r = -0.7, p = 0.01). In patients with LVEF < 30%, lactate/TC was increased (p = 0.01) and bicarbonate/TC reduced (p = 0.03). Circumferential strain correlated with metabolite ratios: lactate/bicarbonate, r = 0.87 (p = 0.0002); lactate/TC, r = 0.85 (p = 0.0005); bicarbonate/TC, r = -0.82 (p = 0.001). In patients with IHD, a strong correlation was found between baseline metabolite ratios and the change in LVEF at follow-up: lactate/bicarbonate (p = 0.001); lactate/TC (p = 0.011); and bicarbonate/TC (p = 0.012). CONCLUSIONS: This study highlighted the ability of HP MRI to detect changes in metabolism in HF. HP MRI has potential for metabolic phenotyping of patients with HF and for predicting treatment response. TRIAL REGISTRATION: EUDRACT, 2018-003533-15. Registered 4 December 2018, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2018-003533-15.

Cardiac Metabolism.

The heart is composed of a heterogeneous mixture of cellular components perfectly intermingled and able to integrate common environmental signals to ensure proper cardiac function and performance. Metabolism defines a cell context-dependent signature that plays a critical role in survival, proliferation, or differentiation, being a recognized master piece of organ biology, modulating homeostasis, disease progression, and adaptation to tissue damage. The heart is a highly demanding organ, and adult cardiomyocytes require large amount of energy to fulfill adequate contractility. However, functioning under oxidative mitochondrial metabolism is accompanied with a concomitant elevation of harmful reactive oxygen species that indeed contributes to the progression of several cardiovascular pathologies and hampers the regenerative capacity of the mammalian heart. Cardiac metabolism is dynamic along embryonic development and substantially changes as cardiomyocytes mature and differentiate within the first days after birth. During early stages of cardiogenesis, anaerobic glycolysis is the main energetic program, while a progressive switch toward oxidative phosphorylation is a hallmark of myocardium differentiation. In response to cardiac injury, different signaling pathways participate in a metabolic rewiring to reactivate embryonic bioenergetic programs or the utilization of alternative substrates, reflecting the flexibility of heart metabolism and its central role in organ adaptation to external factors. Despite the well-established metabolic pattern of fetal, neonatal, and adult cardiomyocytes, our knowledge about the bioenergetics of other cardiac populations like endothelial cells, cardiac fibroblasts, or immune cells is limited. Considering the close intercellular communication and the influence of nonautonomous cues during heart development and after cardiac damage, it will be fundamental to better understand the metabolic programs in different cardiac cells in order to develop novel interventional opportunities based on metabolic rewiring to prevent heart failure and improve the limited regenerative capacity of the mammalian heart.

Advancing Human iPSC-Derived Cardiomyocyte Hypoxia Resistance for Cardiac Regenerative Therapies through a Systematic Assessment of In Vitro Conditioning.

Acute myocardial infarction (MI) is a sudden, severe cardiac ischemic event that results in the death of up to one billion cardiomyocytes (CMs) and subsequent decrease in cardiac function. Engineered cardiac tissues (ECTs) are a promising approach to deliver the necessary mass of CMs to remuscularize the heart. However, the hypoxic environment of the heart post-MI presents a critical challenge for CM engraftment. Here, we present a high-throughput, systematic study targeting several physiological features of human induced pluripotent stem cell-derived CMs (hiPSC-CMs), including metabolism, Wnt signaling, substrate, heat shock, apoptosis, and mitochondrial stabilization, to assess their efficacy in promoting ischemia resistance in hiPSC-CMs. The results of 2D experiments identify hypoxia preconditioning (HPC) and metabolic conditioning as having a significant influence on hiPSC-CM function in normoxia and hypoxia. Within 3D engineered cardiac tissues (ECTs), metabolic conditioning with maturation media (MM), featuring high fatty acid and calcium concentration, results in a 1.5-fold increase in active stress generation as compared to RPMI/B27 control ECTs in normoxic conditions. Yet, this functional improvement is lost after hypoxia treatment. Interestingly, HPC can partially rescue the function of MM-treated ECTs after hypoxia. Our systematic and iterative approach provides a strong foundation for assessing and leveraging in vitro culture conditions to enhance the hypoxia resistance, and thus the successful clinical translation, of hiPSC-CMs in cardiac regenerative therapies.

Cardiomyocyte tetrahydrobiopterin synthesis regulates fatty acid metabolism and susceptibility to ischaemia-reperfusion injury.

NEW FINDINGS: What is the central question of this study? What are the physiological roles of cardiomyocyte-derived tetrahydrobiopterin (BH4) in cardiac metabolism and stress response? What is the main finding and its importance? Cardiomyocyte BH4 has a physiological role in cardiac metabolism. There was a shift of substrate preference from fatty acid to glucose in hearts with targeted deletion of BH4 synthesis. The changes in fatty-acid metabolic profile were associated with a protective effect in response to ischaemia-reperfusion (IR) injury, and reduced infarct size. Manipulating fatty acid metabolism via BH4 availability could play a therapeutic role in limiting IR injury. ABSTRACT: Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide (NO) synthases in which its production of NO is crucial for cardiac function. However, non-canonical roles of BH4 have been discovered recently and the cell-specific role of cardiomyocyte BH4 in cardiac function and metabolism remains to be elucidated. Therefore, we developed a novel mouse model of cardiomyocyte BH4 deficiency, by cardiomyocyte-specific deletion of Gch1, which encodes guanosine triphosphate cyclohydrolase I, a required enzyme for de novo BH4 synthesis. Cardiomyocyte (cm)Gch1 mRNA expression and BH4 levels from cmGch1 KO mice were significantly reduced compared to Gch1flox/flox (WT) littermates. Transcriptomic analyses and protein assays revealed downregulation of genes involved in fatty acid oxidation in cmGch1 KO hearts compared with WT, accompanied by increased triacylglycerol concentration within the myocardium. Deletion of cardiomyocyte BH4 did not alter basal cardiac function. However, the recovery of left ventricle function was improved in cmGch1 KO hearts when subjected to ex vivo ischaemia-reperfusion (IR) injury, with reduced infarct size compared to WT hearts. Metabolomic analyses of cardiac tissue after IR revealed that long-chain fatty acids were increased in cmGch1 KO hearts compared to WT, whereas at 5 min reperfusion (post-35 min ischaemia) fatty acid metabolite levels were higher in WT compared to cmGch1 KO hearts. These results indicate a new role for BH4 in cardiomyocyte fatty acid metabolism, such that reduction of cardiomyocyte BH4 confers a protective effect in response to cardiac IR injury. Manipulating cardiac metabolism via BH4 could play a therapeutic role in limiting IR injury.

Functional and Metabolic Imaging in Heart Failure with Preserved Ejection Fraction: Promises, Challenges, and Clinical Utility.

Heart failure with preserved ejection fraction (HFpEF) is recognised as an increasingly prevalent, morbid and burdensome condition with a poor outlook. Recent advances in both the understanding of HFpEF and the technological ability to image cardiac function and metabolism in humans have simultaneously shone a light on the molecular basis of this complex condition of diastolic dysfunction, and the inflammatory and metabolic changes that are associated with it, typically in the context of a complex patient. This review both makes the case for an integrated assessment of the condition, and highlights that metabolic alteration may be a measurable outcome for novel targeted forms of medical therapy. It furthermore highlights how recent technological advancements and advanced medical imaging techniques have enabled the characterisation of the metabolism and function of HFpEF within patients, at rest and during exercise.

Parkinson's Disease and the Heart: Studying Cardiac Metabolism in the 6-Hydroxydopamine Model.

Parkinson's-disease (PD) is an incurable, age-related neurodegenerative disease, and its global prevalence of disability and death has increased exponentially. Although motor symptoms are the characteristic manifestations of PD, the clinical spectrum also contains a wide variety of non-motor symptoms, which are the main cause of disability and determinants of the decrease in a patient's quality of life. Noteworthy in this regard is the stress on the cardiac system that is often observed in the course of PD; however, its effects have not yet been adequately researched. Here, an untargeted metabolomics approach was used to assess changes in cardiac metabolism in the 6-hydroxydopamine model of PD. Beta-sitosterol, campesterol, cholesterol, monoacylglycerol, α-tocopherol, stearic acid, beta-glycerophosphoric acid, o-phosphoethanolamine, myo-inositol-1-phosphate, alanine, valine and allothreonine are the metabolites that significantly discriminate parkinsonian rats from sham counterparts. Upon analysis of the metabolic pathways with the aim of uncovering the main biological pathways involved in concentration patterns of cardiac metabolites, the biosynthesis of both phosphatidylethanolamine and phosphatidylcholine, the glucose-alanine cycle, glutathione metabolism and plasmalogen synthesis most adequately differentiated sham and parkinsonian rats. Our results reveal that both lipid and energy metabolism are particularly involved in changes in cardiac metabolism in PD. These results provide insight into cardiac metabolic signatures in PD and indicate potential targets for further investigation.

Ketone Bodies and Cardiovascular Disease: An Alternate Fuel Source to the Rescue.

The increased metabolic activity of the heart as a pump involves a high demand of mitochondrial adenosine triphosphate (ATP) production for its mechanical and electrical activities accomplished mainly via oxidative phosphorylation, supplying up to 95% of the necessary ATP production, with the rest attained by substrate-level phosphorylation in glycolysis. In the normal human heart, fatty acids provide the principal fuel (40-70%) for ATP generation, followed mainly by glucose (20-30%), and to a lesser degree (<5%) by other substrates (lactate, ketones, pyruvate and amino acids). Although ketones contribute 4-15% under normal situations, the rate of glucose use is drastically diminished in the hypertrophied and failing heart which switches to ketone bodies as an alternate fuel which are oxidized in lieu of glucose, and if adequately abundant, they reduce myocardial fat delivery and usage. Increasing cardiac ketone body oxidation appears beneficial in the context of heart failure (HF) and other pathological cardiovascular (CV) conditions. Also, an enhanced expression of genes crucial for ketone break down facilitates fat or ketone usage which averts or slows down HF, potentially by avoiding the use of glucose-derived carbon needed for anabolic processes. These issues of ketone body utilization in HF and other CV diseases are herein reviewed and pictorially illustrated.

Unravelling the Interplay between Cardiac Metabolism and Heart Regeneration.

Ischemic heart disease (IHD) is the leading cause of heart failure (HF) and is a significant cause of morbidity and mortality globally. An ischemic event induces cardiomyocyte death, and the ability for the adult heart to repair itself is challenged by the limited proliferative capacity of resident cardiomyocytes. Intriguingly, changes in metabolic substrate utilisation at birth coincide with the terminal differentiation and reduced proliferation of cardiomyocytes, which argues for a role of cardiac metabolism in heart regeneration. As such, strategies aimed at modulating this metabolism-proliferation axis could, in theory, promote heart regeneration in the setting of IHD. However, the lack of mechanistic understanding of these cellular processes has made it challenging to develop therapeutic modalities that can effectively promote regeneration. Here, we review the role of metabolic substrates and mitochondria in heart regeneration, and discuss potential targets aimed at promoting cardiomyocyte cell cycle re-entry. While advances in cardiovascular therapies have reduced IHD-related deaths, this has resulted in a substantial increase in HF cases. A comprehensive understanding of the interplay between cardiac metabolism and heart regeneration could facilitate the discovery of novel therapeutic targets to repair the damaged heart and reduce risk of HF in patients with IHD.

Metabolic, structural and biochemical changes in diabetes and the development of heart failure.

Diabetes contributes to the development of heart failure through various metabolic, structural and biochemical changes. The presence of diabetes increases the risk for the development of cardiovascular disease (CVD), and since the introduction of cardiovascular outcome trials to test diabetic drugs, the importance of improving our understanding of the mechanisms by which diabetes increases the risk for heart failure has come under the spotlight. In addition to the coronary vasculature changes that predispose individuals with diabetes to coronary artery disease, diabetes can also lead to cardiac dysfunction independent of ischaemic heart disease. The hyperlipidaemic, hyperglycaemic and insulin resistant state of diabetes contributes to a perturbed energy metabolic milieu, whereby the heart increases its reliance on fatty acids and decreases glucose oxidative rates. In addition to changes in cardiac energy metabolism, extracellular matrix remodelling contributes to the development of cardiac fibrosis, and impairments in calcium handling result in cardiac contractile dysfunction. Lipotoxicity and glucotoxicity also contribute to impairments in vascular function, cardiac contractility, calcium signalling, oxidative stress, cardiac efficiency and lipoapoptosis. Lastly, changes in protein acetylation, protein methylation and DNA methylation contribute to a myriad of gene expression and protein activity changes. Altogether, these changes lead to decreased cardiac efficiency, increased vulnerability to an ischaemic insult and increased risk for the development of heart failure. This review explores the above mechanisms and the way in which they contribute to cardiac dysfunction in diabetes.

Transcriptomic analysis provides insights into molecular mechanisms of thermal physiology.

Physiological trait variation underlies health, responses to global climate change, and ecological performance. Yet, most physiological traits are complex, and we have little understanding of the genes and genomic architectures that define their variation. To provide insight into the genetic architecture of physiological processes, we related physiological traits to heart and brain mRNA expression using a weighted gene co-expression network analysis. mRNA expression was used to explain variation in six physiological traits (whole animal metabolism (WAM), critical thermal maximum (CTmax), and four substrate specific cardiac metabolic rates (CaM)) under 12 °C and 28 °C acclimation conditions. Notably, the physiological trait variations among the three geographically close (within 15 km) and genetically similar F. heteroclitus populations are similar to those found among 77 aquatic species spanning 15-20° of latitude (~ 2,000 km). These large physiological trait variations among genetically similar individuals provide a powerful approach to determine the relationship between mRNA expression and heritable fitness related traits unconfounded by interspecific differences. Expression patterns explained up to 82% of metabolic trait variation and were enriched for multiple signaling pathways known to impact metabolic and thermal tolerance (e.g., AMPK, PPAR, mTOR, FoxO, and MAPK) but also contained several unexpected pathways (e.g., apoptosis, cellular senescence), suggesting that physiological trait variation is affected by many diverse genes.

α-Tubulin acetylation on lysine 40 controls cardiac glucose uptake.

Our group previously demonstrated that an excess of nutrients, as observed in diabetes, provokes an increase in cardiac protein acetylation responsible for a reduced insulin-stimulated translocation of the glucose transporter GLUT4 to the plasma membrane. The acetylated proteins involved in this event have yet not been identified. α-Tubulin is a promising candidate as a major cytoskeleton component involved, among other things, in the translocation of GLUT4-containing vesicles from their intracellular pools toward the plasma membrane. Moreover, α-tubulin is known to be acetylated, Lys40 (K40) being its best characterized acetylated residue. The present work sought to evaluate the impact of α-tubulin K40 acetylation on cardiac glucose entry, with a particular interest in GLUT4 translocation. First, we observed that a mouse model of high-fat diet-induced obesity presented an increase in cardiac α-tubulin K40 acetylation level. We next showed that treatment of insulin-sensitive primary cultured adult rat cardiomyocytes with tubacin, a specific tubulin acetylation inducer, reduced insulin-stimulated glucose uptake and GLUT4 translocation. Conversely, decreasing α-tubulin K40 acetylation by expressing a nonacetylable dominant form of α-tubulin (mCherry α-tubulin K40A mutant) remarkably intensified insulin-induced glucose transport. Finally, mCherry α-tubulin K40A expression similarly improved glucose transport in insulin-resistant cardiomyocytes or after AMP-activated protein kinase activation. Taken together, our study demonstrates that modulation of α-tubulin K40 acetylation level affects glucose transport in cardiomyocytes, offering new putative therapeutic insights regarding modulation of glucose metabolism in insulin-resistant and diabetic hearts.NEW & NOTEWORTHY Acetylation level of α-tubulin on K40 is increased in the heart of a diet-induced mouse model of type 2 diabetes. Pharmacological stimulation of α-tubulin K40 acetylation lowers insulin-mediated GLUT4 vesicles translocation to the plasma membrane, reducing glucose transport. Expressing a nonacetylable dominant form of α-tubulin boosts glucose uptake in both insulin-sensitive and insulin-resistant cardiomyocytes.

Sympathetic nerve innervation and metabolism in ischemic myocardium in response to remote ischemic perconditioning.

Sympathetic nerve denervation after myocardial infarction (MI) predicts risk of sudden cardiac death. Therefore, therapeutic approaches limit infarct size, improving adverse remodeling and restores sympathetic innervation have a great clinical potential. Remote ischemic perconditioning (RIPerc) could markedly attenuate MI-reperfusion (MIR) injury. In this study, we aimed to assess its effects on cardiac sympathetic innervation and metabolism. Transient myocardial ischemia is induced by ligature of the left anterior descending coronary artery (LAD) in male Sprague-Dawley rats, and in vivo cardiac 2-[18F]FDG and [11C]mHED PET scans were performed at 14-15 days after ischemia. RIPerc was induced by three cycles of 5-min-long unilateral hind limb ischemia and intermittent 5 min of reperfusion during LAD occlusion period. The PET quantitative parameters were quantified in parametric polar maps. This standardized format facilitates the regional radioactive quantification in deficit regions to remote areas. The ex vivo radionuclide distribution was additionally identified using autoradiography. Myocardial neuron density (tyrosine hydroxylase positive staining) and chondroitin sulfate proteoglycans (CSPG, inhibiting neuron regeneration) expression were assessed by immunohistochemistry. There was no significant difference in the mean hypometabolism 2-[18F]FDG uptake ratio (44.6 ± 4.8% vs. 45.4 ± 4.4%) between MIR rats and MIR + RIPerc rats (P > 0.05). However, the mean [11C]mHED nervous activity of denervated myocardium was significantly elevated in MIR + RIPerc rats compared to the MIR rats (35.9 ± 7.1% vs. 28.9 ± 2.3%, P < 0.05), coupled with reduced denervated myocardium area (19.5 ± 5.3% vs. 27.8 ± 6.6%, P < 0.05), which were associated with preserved left-ventricular systolic function, a less reduction in neuron density, and a significant reduction in CSPG and CD68 expression in the myocardium. RIPerc presented a positive effect on cardiac sympathetic-nerve innervation following ischemia, but showed no significant effect on myocardial metabolism.

Cardiomyocyte-specific miR-100 overexpression preserves heart function under pressure overload in mice and diminishes fatty acid uptake as well as ROS production by direct suppression of Nox4 and CD36.

MicroRNAs are key regulators of the cardiac response to injury. MiR-100 has recently been suggested to be involved in different forms of heart failure, but functional studies are lacking. In the present study, we examined the impact of transgenic miR-100 overexpression on cardiac structure and function during physiological aging and pathological pressure-overload-induced heart failure in mice after transverse aortic constriction surgery. MiR-100 was moderately upregulated after induction of pressure overload in mice. While in our transgenic model the cardiomyocyte-specific overexpression of miR-100 did not result in an obvious cardiac phenotype in unchallenged mice, the transgenic mouse strain exhibited less left ventricular dilatation and a higher ejection fraction than wildtype animals, demonstrating an attenuation of maladaptive cardiac remodeling by miR-100. Cardiac transcriptome analysis identified a repression of several regulatory genes related to cardiac metabolism, lipid peroxidation, and production of reactive oxygen species (ROS) by miR-100 overexpression, possibly mediating the observed functional effects. While the modulation of ROS-production seemed to be indirectly affected by miR-100 via Alox5-and Nox4-downregulation, we demonstrated that miR-100 induced a direct repression of the scavenger protein CD36 in murine hearts resulting in a decreased uptake of long-chain fatty acids and an alteration of mitochondrial respiratory function with an enhanced glycolytic state. In summary, we identified miR-100 as a modulator of cardiac metabolism and ROS production without an apparent cardiac phenotype at baseline but a protective effect under conditions of pressure-overload-induced cardiac stress, providing new insight into the mechanisms of heart failure.

Glucose 6-Phosphate Accumulates via Phosphoglucose Isomerase Inhibition in Heart Muscle.

RATIONALE: Metabolic and structural remodeling is a hallmark of heart failure. This remodeling involves activation of the mTOR (mammalian target of rapamycin) signaling pathway, but little is known on how intermediary metabolites are integrated as metabolic signals. OBJECTIVE: We investigated the metabolic control of cardiac glycolysis and explored the potential of glucose 6-phosphate (G6P) to regulate glycolytic flux and mTOR activation. METHODS AND RESULTS: We developed a kinetic model of cardiomyocyte carbohydrate metabolism, CardioGlyco, to study the metabolic control of myocardial glycolysis and G6P levels. Metabolic control analysis revealed that G6P concentration is dependent on phosphoglucose isomerase (PGI) activity. Next, we integrated ex vivo tracer studies with mathematical simulations to test how changes in glucose supply and glycolytic flux affect mTOR activation. Nutrient deprivation promoted a tight coupling between glucose uptake and oxidation, G6P reduction, and increased protein-protein interaction between hexokinase II and mTOR. We validated the in silico modeling in cultured adult mouse ventricular cardiomyocytes by modulating PGI activity using erythrose 4-phosphate. Inhibition of glycolytic flux at the level of PGI caused G6P accumulation, which correlated with increased mTOR activation. Using click chemistry, we labeled newly synthesized proteins and confirmed that inhibition of PGI increases protein synthesis. CONCLUSIONS: The reduction of PGI activity directly affects myocyte growth by regulating mTOR activation.

Detection of increased pyruvate dehydrogenase flux in the human heart during adenosine stress test using hyperpolarized [1-13C]pyruvate cardiovascular magnetic resonance imaging.

BACKGROUND: Hyperpolarized (HP) [1-13C]pyruvate cardiovascular magnetic resonance (CMR) imaging can visualize the uptake and intracellular conversion of [1-13C]pyruvate to either [1-13C]lactate or 13C-bicarbonate depending on the prevailing metabolic state. The aim of the present study was to combine an adenosine stress test with HP [1-13C]pyruvate CMR to detect cardiac metabolism in the healthy human heart at rest and during moderate stress. METHODS: A prospective descriptive study was performed between October 2019 and August 2020. Healthy human subjects underwent cine CMR and HP [1-13C]pyruvate CMR at rest and during adenosine stress. HP [1-13C]pyruvate CMR images were acquired at the mid-left-ventricle (LV) level. Semi-quantitative assessment of first-pass myocardial [1-13C]pyruvate perfusion and metabolism were assessed. Paired t-tests were used to compare mean values at rest and during stress. RESULTS: Six healthy subjects (two female), age 29 ± 7 years were studied and no adverse reactions occurred. Myocardial [1-13C]pyruvate perfusion was significantly increased during stress with a reduction in time-to-peak from 6.2 ± 2.8 to 2.7 ± 1.3 s, p = 0.02. This higher perfusion was accompanied by an overall increased myocardial uptake and metabolism. The conversion rate constant (kPL) for lactate increased from 11 ± 9 *10-3 to 20 ± 10 * 10-3 s-1, p = 0.04. The pyruvate oxidation rate (kPB) increased from 4 ± 4 *10-3 to 12 ± 7 *10-3 s-1, p = 0.008. This increase in carbohydrate metabolism was positively correlated with heart rate (R2 = 0.44, p = 0.02). CONCLUSIONS: Adenosine stress testing combined with HP [1-13C]pyruvate CMR is feasible and well-tolerated in healthy subjects. We observed an increased pyruvate oxidation during cardiac stress. The present study is an important step in the translation of HP [1-13C]pyruvate CMR into clinical cardiac imaging. Trial registration EUDRACT, 2018-003533-15. Registered 4th of December 2018, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2018-003533-15.