scholarly journals Metabolic Therapy in Heart Failure

2015 ◽  
Vol 1 (2) ◽  
pp. 112 ◽  
Author(s):  
Yury Lopatin ◽  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Glucose Oxidation ◽  
Acid Oxidation ◽  
Patients With Heart Failure ◽  
Cardiac Energy Metabolism ◽  
Conventional Medical Therapy ◽  
Cardiac Energy ◽  
Metabolic Impairments

Metabolic impairments play an important role in the development and progression of heart failure. The use of metabolic modulators, the number of which is steadily increasing, may be particularly effective in the treatment of heart failure. Recent evidence suggests that modulating cardiac energy metabolism by reducing fatty acid oxidation and/or increasing glucose oxidation represents a promising approach to the treatment of patients with heart failure. This review focuses on the role of metabolic modulators, in particular trimetazidine, as a potential additional medication to conventional medical therapy in heart failure.

scholarly journals Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart

2016 ◽  
Vol 311 (2) ◽  
pp. H347-H363 ◽  
Author(s):  
Arata Fukushima ◽  
Osama Abo Alrob ◽  
Liyan Zhang ◽  
Cory S. Wagg ◽  
Tariq Altamimi ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Energy Metabolism ◽  
Fatty Acid Oxidation ◽  
Glucose Oxidation ◽  
Acid Oxidation ◽  
Amino Acid Synthesis ◽  
Oxidation Rates ◽  
Cardiac Energy Metabolism ◽  
Cardiac Energy ◽  
The Impact

Dramatic maturational changes in cardiac energy metabolism occur in the newborn period, with a shift from glycolysis to fatty acid oxidation. Acetylation and succinylation of lysyl residues are novel posttranslational modifications involved in the control of cardiac energy metabolism. We investigated the impact of changes in protein acetylation/succinylation on the maturational changes in energy metabolism of 1-, 7-, and 21-day-old rabbit hearts. Cardiac fatty acid β-oxidation rates increased in 21-day vs. 1- and 7-day-old hearts, whereas glycolysis and glucose oxidation rates decreased in 21-day-old hearts. The fatty acid oxidation enzymes, long-chain acyl-CoA dehydrogenase (LCAD) and β-hydroxyacyl-CoA dehydrogenase (β-HAD), were hyperacetylated with maturation, positively correlated with their activities and fatty acid β-oxidation rates. This alteration was associated with increased expression of the mitochondrial acetyltransferase, general control of amino acid synthesis 5 like 1 (GCN5L1), since silencing GCN5L1 mRNA in H9c2 cells significantly reduced acetylation and activity of LCAD and β-HAD. An increase in mitochondrial ATP production rates with maturation was associated with the decreased acetylation of peroxisome proliferator-activated receptor-γ coactivator-1α, a transcriptional regulator for mitochondrial biogenesis. In addition, hypoxia-inducible factor-1α, hexokinase, and phosphoglycerate mutase expression declined postbirth, whereas acetylation of these glycolytic enzymes increased. Phosphorylation rather than acetylation of pyruvate dehydrogenase (PDH) increased in 21-day-old hearts, accounting for the low glucose oxidation postbirth. A maturational increase was also observed in succinylation of PDH and LCAD. Collectively, our data are the first suggesting that acetylation and succinylation of the key metabolic enzymes in newborn hearts play a crucial role in cardiac energy metabolism with maturation. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/acetylation-control-of-energy-metabolism-in-newborn-hearts/ .

Role of CoA and acetyl-CoA in regulating cardiac fatty acid and glucose oxidation

2014 ◽  
Vol 42 (4) ◽  
pp. 1043-1051 ◽  
Author(s):  
Osama Abo Alrob ◽  
Gary D. Lopaschuk
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Oxidative Enzymes ◽  
Acid Oxidation ◽  
Acetyl Coa ◽  
Malonyl Coa ◽  
Mitochondrial Fatty Acid ◽  
Cardiac Energy Metabolism ◽  
Cardiac Energy

CoA (coenzyme A) and its derivatives have a critical role in regulating cardiac energy metabolism. This includes a key role as a substrate and product in the energy metabolic pathways, as well as serving as an allosteric regulator of cardiac energy metabolism. In addition, the CoA ester malonyl-CoA has an important role in regulating fatty acid oxidation, secondary to inhibiting CPT (carnitine palmitoyltransferase) 1, a key enzyme involved in mitochondrial fatty acid uptake. Alterations in malonyl-CoA synthesis by ACC (acetyl-CoA carboxylase) and degradation by MCD (malonyl-CoA decarboxylase) are important contributors to the high cardiac fatty acid oxidation rates seen in ischaemic heart disease, heart failure, obesity and diabetes. Additional control of fatty acid oxidation may also occur at the level of acetyl-CoA involvement in acetylation of mitochondrial fatty acid β-oxidative enzymes. We find that acetylation of the fatty acid β-oxidative enzymes, LCAD (long-chain acyl-CoA dehydrogenase) and β-HAD (β-hydroxyacyl-CoA dehydrogenase) is associated with an increase in activity and fatty acid oxidation in heart from obese mice with heart failure. This is associated with decreased SIRT3 (sirtuin 3) activity, an important mitochondrial deacetylase. In support of this, cardiac SIRT3 deletion increases acetylation of LCAD and β-HAD, and increases cardiac fatty acid oxidation. Acetylation of MCD is also associated with increased activity, decreases malonyl-CoA levels and an increase in fatty acid oxidation. Combined, these data suggest that malonyl-CoA and acetyl-CoA have an important role in mediating the alterations in fatty acid oxidation seen in heart failure.

scholarly journals Cardiac Energy Metabolism in Heart Failure

2021 ◽  
Vol 128 (10) ◽  
pp. 1487-1513
Author(s):  
Gary D. Lopaschuk ◽  
Qutuba G. Karwi ◽  
Rong Tian ◽  
Adam R. Wende ◽  
E. Dale Abel
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Metabolic Pathways ◽  
Energy Deficit ◽  
Acid Oxidation ◽  
Myocardial Fatty Acid ◽  
Atp Production ◽  
Failing Heart ◽  
Cardiac Energy Metabolism ◽  
Cardiac Energy

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/O 2 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.

Abstract 374: EET Agonist Improves Cardiac Energy Metabolism and Heart Function by Regulating Fatty Acid Oxidation and Oxidative Stress in Infarcted Myocardium

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Jian Cao ◽  
Stephen J Peterson ◽  
Gaia Favero ◽  
Rita Rezzani ◽  
Rodella Luigi Fabrizio ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Fatty Acid ◽  
Energy Metabolism ◽  
Cardiac Remodeling ◽  
Capillary Density ◽  
Acid Oxidation ◽  
Infarcted Heart ◽  
Cardiac Energy Metabolism ◽  
Cardiac Energy

Introduction: Myocardial Ischemia (MI), one of the major causes of heart failure, is associated with cardiac remodeling, insufficient angiogenesis and enhanced oxidative stress. Cytochrome P450 epoxygenase metabolites of arachidonic acid, EETs, have multiple cardiovascular effects, including vasodilation, inhibition of inflammatory response and stimulation of epithelial cell growth. In addition, emerging studies indicate a role of these unique lipid mediators in the regulation of metabolic homeostasis. We propose that EET agonists reduce post infarcted cardiac remodeling by improving cardiac dysfunction through increased angiogenesis improved cardiac energy metabolism and a reduction in oxidative stress. Methods: C57B16 mice were divided into 3 groups: sham, mice with myocardial infarction (MI) via LAD ligation and mice with MI treated with an EET-agonist (NUDSA). NUDSA was administered after 5 days of MI (0.5 mg/kg) in C57B16 mice. Myocardial echocardiography was performed 30 days after MI to assess the cardiac function. Capillary density, oxidative stress and cardiac energy metabolism markers were compared among the groups. Results: Echocardiography showed that left ventricle dilatation, measured as end diastolic area (EDA), was reduced in NUDSA treated groups compared to the MI group (C57, EDA: MI: 0.413 ±0.02 cm 2 ; MI+NUDSA: 0.217±0.03 cm 2 ; p<0.05). Cardiac Index, decreased by MI, was restored by NUDSA in C57 mice. Cardiac histological examination revealed an increase in myocardial angiogenesis and capillary density in mice treated with NUDSA (p<0.01 vs. MI). Cardiac tissue showed an increased expression of ETS-1, phosphorylated Acetyl CoA Carboxylase (pACC) and Carnitine Palmitoyl Transferase I (CPT-1) along with a decrease in 3NT and gpphox 91 expression in mice treated with NUDSA as compared to the MI group (p<0.05). Conclusion: This is the first study to demonstrate that EET improves cardiac energy metabolism in infarcted heart by regulating fatty acid oxidation and ameliorating oxidative stress and cardiac remodeling. Thus pharmacological induction of EET may open new avenues in the treatment of patients with post infarcted heart failure.

Abstract 15649: Pharmacological Inhibition of Aldose Reductase by AT001 Prevents Abnormal Cardiac Energy Metabolism and Improves Heart Function in an Animal Model of Diabetic Cardiomyopathy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Keshav Gopal ◽  
Qutuba Karwi ◽  
Seyed Amirhossein Tabatabaei Dakhili ◽  
Riccardo Perfetti ◽  
Ravichandran Ramasamy ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Energy Metabolism ◽  
Fatty Acid Oxidation ◽  
Diabetic Cardiomyopathy ◽  
Acid Oxidation ◽  
Cardiac Energetics ◽  
Cardiac Efficiency ◽  
Oxidation Rates ◽  
Cardiac Energy Metabolism ◽  
Cardiac Energy

Introduction: Diabetic Cardiomyopathy (DCM) is a major cause of death in people with type 2 diabetes (T2D). Alterations in cardiac energy metabolism including increased fatty acid oxidation rates and reduced glucose oxidation rates are key contributing factors to the development of DCM. Studies have shown that Aldose Reductase (AR), an enzyme activated under hyperglycemic conditions, can modulate myocardial glucose and fatty acid oxidation, and promotes cardiac dysfunction. Hypothesis: Pharmacological inhibition of AR using a next-generation inhibitor AT-001, can mitigate DCM in mice by modulating cardiac energy metabolism and improving cardiac efficiency. Methods: Male human AR overexpressing (hAR-Tg) and C57BL/6J (Control) mice were subjected to experimental T2D (high-fat diet [60% kcal from lard] for 10-wk with a single intraperitoneal streptozotocin injection of 75 mg/kg) and treated for the last 3-wk with AT-001 (40mg/kg/day) or vehicle via oral gavage. Cardiac energy metabolism and in vivo cardiac function were assessed via isolated working heart perfusions and ultrasound echocardiography, respectively. Results: AT-001 treatment significantly improved cardiac energetics in a murine model of DCM (hAR-Tg mice with T2D). Particularly, AT-001-treated mice exhibited decreased cardiac fatty acid oxidation rates compared to the vehicle-treated mice (342 ± 53 vs 964 ± 130 nmol/min/g dry wt.). Concurrently, there was a significant decrease in cardiac oxygen consumption in the AT-001-treated compared to the vehicle-treated mice (41 ± 12 vs 60 ± 11 μmol/min/g dry wt.), suggesting increased cardiac efficiency. Furthermore, treatment with AT-001 prevented cardiac structural and functional abnormalities present in DCM, including diastolic dysfunction as reflected by an increase in the tissue Doppler E’/A’ ratio and decrease in E/E’ ratio. Moreover, AT-001 treatment prevented cardiac hypertrophy as reflected by a decrease in LV mass in AT-001-treated mice. Conclusions: AR inhibition with AT-001 prevents cardiac structural and functional abnormalities in a mouse model of DCM, and normalizes cardiac energetics by shifting cardiac metabolism towards a non-diabetic metabolic state.

scholarly journals Modulation of Cardiac Metabolism in Heart Failure

2019 ◽  
Vol 17 ◽  
Author(s):  
Giuseppe Rosano ◽  
Andrew Coats
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Skeletal Muscles ◽  
Cardiac Metabolism ◽  
Acid Oxidation ◽  
Patients With Heart Failure ◽  
Free Fatty Acid Oxidation ◽  
Capacity Modulation

Heart failure is associated with altered cardiac metabolism, in part, due to maladaptive mechanisms, in part secondary to comorbidities such as diabetes and ischaemic heart disease. The metabolic derangements taking place in heart failure are not limited to the cardiac myocytes, but extend to skeletal muscles and the vasculature causing changes that contribute to the worsening of exercise capacity. Modulation of cardiac metabolism with partial inhibition of free fatty acid oxidation has been shown to be beneficial in patients with heart failure. At the present, the bulk of evidence for this class of drugs comes from Trimetazidine. Newer compounds partially inhibiting free fatty acid oxidation or facilitating the electron transport on the mitochondrial cristae are in early phase of their clinical development.

Role of endothelins in congestive heart failure

2003 ◽  
Vol 81 (6) ◽  
pp. 588-597 ◽  
Author(s):  
Gordon W Moe ◽  
Jean L Rouleau ◽  
Quang T Nguyen ◽  
Peter Cernacek ◽  
Duncan J Stewart
Keyword(s):  
Heart Failure ◽  
Large Scale ◽  
Severe Heart Failure ◽  
Endothelin Antagonists ◽  
Short Period ◽  
Patients With Heart Failure ◽  
Conventional Medical Therapy ◽  
Receptor Blockers ◽  
Novel Therapeutic Strategies

Despite major advances in conventional medical therapy, patients with heart failure continue to experience significant morbidity and mortality. Endothelin-1 (ET-1) is a potent vasocontrictor and mitogenic peptide that is activated in heart failure. There is increasing experimental and clinical evidence in support of an important role of ET-1 in the pathophysiology of heart failure. Manipulation of the activity of ET-1, especially using endothelin receptor blockers, has allowed for the further elucidation of the role of this neurohormonal system and development of novel therapeutic strategies in heart failure. Published clinical studies of these agents to date have involved relatively small numbers of patients with severe heart failure, followed for a relatively short period of time, and have mainly examined surrogate endpoints. Large-scale trials that address to hard clinical outcomes are ongoing and their results forthcoming. A key question that remains concerns whether selective ETA or dual ETA–ETB receptor blockade will be more effective.Key words: heart failure, endothelins, endothelin antagonists.

scholarly journals Pathophysiological role of fatty acid‐binding protein 4 in Asian patients with heart failure and preserved ejection fraction

2020 ◽  
Vol 7 (6) ◽  
pp. 4256-4266
Author(s):  
Tomonari Harada ◽  
Hiroaki Sunaga ◽  
Hidemi Sorimachi ◽  
Kuniko Yoshida ◽  
Toshimitsu Kato ◽  
...  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Fatty Acid Binding Protein ◽  
Preserved Ejection Fraction ◽  
Fatty Acid Binding ◽  
Acid Binding Protein ◽  
Asian Patients ◽  
Patients With Heart Failure ◽  
Pathophysiological Role

Cardiac hypertrophy in the newborn delays the maturation of fatty acid β-oxidation and compromises postischemic functional recovery

2012 ◽  
Vol 302 (9) ◽  
pp. H1784-H1794 ◽  
Author(s):  
Tatsujiro Oka ◽  
Victoria H. Lam ◽  
Liyan Zhang ◽  
Wendy Keung ◽  
Virgilio J. J. Cadete ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Cardiac Hypertrophy ◽  
Functional Recovery ◽  
Volume Overload ◽  
Acid Oxidation ◽  
Atp Production ◽  
Oxidation Rates ◽  
Malonyl Coa ◽  
Cardiac Energy Metabolism ◽  
Cardiac Energy

During the neonatal period, cardiac energy metabolism progresses from a fetal glycolytic profile towards one more dependent on mitochondrial oxidative metabolism. In this study, we identified the effects of cardiac hypertrophy on neonatal cardiac metabolic maturation and its impact on neonatal postischemic functional recovery. Seven-day-old rabbits were subjected to either a sham or a surgical procedure to induce a left-to-right shunt via an aortocaval fistula to cause RV volume-overload. At 3 wk of age, hearts were isolated from both groups and perfused as isolated, biventricular preparations to assess cardiac energy metabolism. Volume-overload resulted in cardiac hypertrophy (16% increase in cardiac mass, P < 0.05) without evidence of cardiac dysfunction in vivo or in vitro. Fatty acid oxidation rates were 60% lower ( P < 0.05) in hypertrophied hearts than controls, whereas glycolysis increased 246% ( P < 0.05). In contrast, glucose and lactate oxidation rates were unchanged. Overall ATP production rates were significantly lower in hypertrophied hearts, resulting in increased AMP-to-ATP ratios in both aerobic hearts and ischemia-reperfused hearts. The lowered energy generation of hypertrophied hearts depressed functional recovery from ischemia. Decreased fatty acid oxidation rates were accompanied by increased malonyl-CoA levels due to decreased malonyl-CoA decarboxylase activity/expression. Increased glycolysis in hypertrophied hearts was accompanied by a significant increase in hypoxia-inducible factor-1α expression, a key transcriptional regulator of glycolysis. Cardiac hypertrophy in the neonatal heart results in a reemergence of the fetal metabolic profile, which compromises ATP production in the rapidly maturing heart and impairs recovery of function following ischemia.

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