Deranged energy substrate metabolism in the failing heart

Tian, Qi; Barger, Philip M.

doi:10.1007/s11906-006-0024-9

Cited by 12 publications

(6 citation statements)

References 46 publications

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“…Downregulation of FAO gene expression is a well-characterized response in the hypertrophied and failing heart, driven at least in part, by reduced PPARα-mediated transcriptional control of genes involved in fatty acid utilization. 20,52–54 Second, the delivery of ketone bodies is increased in the failing heart (increased plasma concentration). Indeed, previous studies have shown that the mammalian heart is capable of avid ketone body uptake and oxidation.…”

Section: Discussionmentioning

confidence: 99%

The Failing Heart Relies on Ketone Bodies as a Fuel

et al. 2016

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Background Significant evidence indicates that the failing heart is “energy-starved”. During the development of heart failure, the capacity of the heart to utilize fatty acids, the chief fuel, is diminished. Identification of alternate pathways for myocardial fuel oxidation could unveil novel strategies to treat heart failure. Methods and Results Quantitative mitochondrial proteomics was used to identify energy metabolic derangements that occur during the development of cardiac hypertrophy and heart failure in well-defined mouse models. As expected, amounts of proteins involved in fatty acid utilization were downregulated in myocardial samples from the failing heart. Conversely, expression of β-hydroxybutyrate dehydrogenase 1 (BDH1), a key enzyme in the ketone oxidation pathway, was increased in the heart failure samples. Studies of relative oxidation studies in an isolated heart preparation using ex vivo NMR combined with targeted quantitative myocardial metabolomic profiling using mass spectrometry revealed that the hypertrophied and failing heart shifts to oxidizing ketone bodies as a fuel source in the context of reduced capacity to oxidize fatty acids. Distinct myocardial metabolomic signatures of ketone oxidation were identified. Conclusions These results indicate that the hypertrophied and failing heart shifts to ketone bodies as a significant fuel source for oxidative ATP production. Specific metabolite biosignatures of in vivo cardiac ketone utilization were identified. Future studies aimed at determining whether this fuel shift is adaptive or maladaptive could unveil new therapeutic strategies for heart failure.

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Section: Discussionmentioning

confidence: 99%

The Failing Heart Relies on Ketone Bodies as a Fuel

et al. 2016

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“…A study determined human FA levels and found that although the FA oxidation rate increased, percentage of fatty acid oxidation amount was lower due to increased intake (31). Besides, acyl-CoA can accumulate in the cytoplasm if FA overload is imposed (32). Consistently, metabolomics analysis found that compared with non-T2DM patients, oxidation of long chain fatty acids in T2DM patients were incomplete, leading to significance increased plasma levels of C6, C8, C10, C12, and C14 (33).…”

Section: Discussionmentioning

confidence: 99%

The Association Between Acylcarnitine Metabolites and Cardiovascular Disease in Chinese Patients With Type 2 Diabetes Mellitus

Zhao¹,

Feng

Huang

et al. 2020

Front. Endocrinol.

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Objective: The association between acylcarnitine metabolites and cardiovascular disease (CVD) in type 2 diabetes mellitus (T2DM) remains uncertain. This study aimed to investigate associations between acylcarnitines and CVD in Chinese patients with T2DM.Methods: A cross-sectional study was conducted from May 2015 to August 2016. Medical records of 741 patients with T2DM were retrieved from the main electronic database of Liaoning Medical University First Affiliated Hospital. CVD was defined as having either coronary artery disease (CAD) or heart failure (HF) or stroke. Mass Spectrometry was utilized to measure levels of 25 acylcarnitine metabolites in fasting plasma. Factor analysis was used to reduce the dimensions and extracted factors of the 25 acylcarnitine metabolites. Multivariable binary logistic regression was used to obtain odds ratios (OR) of the factors extracted from the 25 acylcarnitine metabolites and their 95% confidence intervals (CI) for CVD.Results: Of the 741 patients with T2DM, 288 had CVD. Five factors were extracted from the 25 acylcarnitines and they accounted for 65.9% of the total variance. Factor 1 consisted of acetylcarnitine, butyrylcarnitine, hydroxylbutyrylcarnitine, glutarylcarnitine, hexanoylcarnitine, octanoylcarnitine, and tetradecanoyldiacylcarnitine. Factor 2 consisted of decanoylcarnitine, lauroylcarnitine, myristoylcarnitine, 3-hydroxyltetradecanoylcarnitine, tetradecenoylcarnitine, and 3-hydroxypalmitoylcarnitine. After adjusting for potential confounders, increased factor 1 and 2 were associated with increased risks of CVD in T2DM (OR of factor 1: 1.45, 95% CI: 1.03-2.03; OR of factor 2: 1.23, 95% CI: 1.02-1.50).Conclusions: Elevated plasma levels of some acylcarnitine metabolites, i.e., those extracted into factor 1 and 2, were associated with CVD risk in T2DM.

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“…Ketone bodies compete with other substrates in the heart, especially FA, to be used as fuel. This is particularly significant in the hypertrophied and failing heart, wherein there is down-regulation of FAO gene expression (Tian & Barger, 2006) and increased blood ketone bodies (Lommi, et al, 1996). The increase in ketone bodies is proportionate to the level of cardiac dysfunction and neurohumoral activation (Lommi, et al, 1996).…”

Section: Shift Of Metabolic Pathways In the Progression Of Heart Failurementioning

confidence: 99%

Myocardial metabolism in heart failure: Purinergic signalling and other metabolic concepts

Birkenfeld

Jordan

Dworak

et al. 2019

Pharmacology & Therapeutics

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Despite significant therapeutic advances in heart failure (HF) therapy, the morbidity and mortality associated with this disease remains unacceptably high. The concept of metabolic dysfunction as an important underlying mechanism in HF is well established. Cardiac function is inextricably linked to metabolism, with dysregulation of cardiac metabolism pathways implicated in a range of cardiac complications, including HF. Modulation of cardiac metabolism has therefore become an attractive clinical target. Cardiac metabolism is based on the integration of adenosine triphosphate (ATP) production and utilization pathways. ATP itself impacts the heart not only by providing energy, but also represents a central element in the purinergic signaling pathway, which has received considerable attention in recent years. Furthermore, novel drugs that have received interest in HF include angiotensin receptor blocker-neprilysin inhibitor (ARNi) and sodium glucose cotransporter 2 (SGLT-2) inhibitors, whose favorable cardiovascular profile has been at least partly attributed to their effects on metabolism. This review, describes the major metabolic pathways and concepts of the healthy heart (including fatty acid oxidation, glycolysis, Krebs cycle, Randle cycle, and purinergic signaling) and their dysregulation in the progression to HF (including ketone and amino acid metabolism). The cardiac implications of HF comorbidities, including metabolic syndrome, diabetes mellitus and cachexia are also discussed. Finally, the impact of current HF and diabetes therapies on cardiac metabolism pathways and the relevance of this knowledge for current clinical practice is discussed. Targeting cardiac metabolism may have utility for the future treatment of patients with HF, complementing current approaches.

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Deranged energy substrate metabolism in the failing heart

Cited by 12 publications

References 46 publications

The Failing Heart Relies on Ketone Bodies as a Fuel

The Failing Heart Relies on Ketone Bodies as a Fuel

The Association Between Acylcarnitine Metabolites and Cardiovascular Disease in Chinese Patients With Type 2 Diabetes Mellitus

Myocardial metabolism in heart failure: Purinergic signalling and other metabolic concepts

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