Evidence of Glycolysis Upregulation and Pyruvate Mitochondrial Oxidation Mismatch During Mechanical Unloading of the Failing Human Heart: Implications for Cardiac Reloading and Conditioning

Διάκος, Νικόλαος; Navankasattusas, Sutip; Rutter, Jared; Stehlik, Josef; DeBerardinis, Ralph J.; McKellar, Stephen H.; McCreath, Lauren; Ferrin, Peter; Miller, Dylan V.; Park, Song; Richardson, Russell S.; Kfoury, Abdallah G.; Selzman, Craig H.; Li, Dean; Fang, James C.; Drakos, Stavros

doi:10.1016/s0735-1097(16)31275-x

Cited by 16 publications

(26 citation statements)

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“…3, G-I, and 4). Thus, the present model of MI-induced HF did not have upregulated ketone oxidation in the myocardium in contrast to HF models in earlier studies (Schugar et al, 2014;Aubert et al, 2016;Bedi et al, 2016;Diakos et al, 2016;Uchihashi et al, 2017), possibly because the duration of cardiac overload (12 hours vs. 4-8 weeks), severity of HF (post-MI vs. aortic banding model), and/or presence of DM were different. Nevertheless, treatment with empagliflozin increased blood and myocardial bOHB levels by approximately 2-and 10-fold, respectively, and the increased tissue level of bOHB was accompanied by preservation of ATP level after MI.…”

Section: Discussioncontrasting

confidence: 83%

“…It has been shown that a failing heart switches the main energy sources from fatty acid to glucose metabolism, which is more efficient fuel (Lopaschuk et al, 2010;Lopaschuk, 2017). However, when HF reduces glucose oxidation by reduction of pyruvate dehydrogenase activity, it leads to a mismatch between glycolysis and glucose oxidation (Diakos et al, 2016). On the other hand, ketone oxidation increases to compensate for the decrease in acetyl CoA production in the failing heart (Aubert et al, 2016;Bedi et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

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Empagliflozin, an SGLT2 Inhibitor, Reduced the Mortality Rate after Acute Myocardial Infarction with Modification of Cardiac Metabolomes and Antioxidants in Diabetic Rats

Oshima¹,

Miki²,

Kuno³

et al. 2018

J Pharmacol Exp Ther

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The mechanism by which SGLT2 inhibitors reduce cardiac events in diabetic patients remains unclear. Here, we examined the effects of an SGLT2 inhibitor on the acute survival rate after myocardial infarction (MI) in an animal model of type 2 diabetes mellitus (DM) and the possible involvement of modification of cardiac metabolomes and antioxidative proteins. MI was induced in DM Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Long-Evans Tokushima Otsuka (LETO) control rats. Treatment with empagliflozin (10 mg/kg per day, 14 days) before MI reduced blood glucose and increased blood and myocardial b-hydroxybutyrate (bOHB) levels in OLETF. Survival rate at 48 hours after MI was significantly lower in OLETF rats than in LETO rats (40% vs. 84%), and empagliflozin significantly improved the survival rate in OLETF rats to 70%, although the sizes of MI were comparable. Patterns of metabolomes and gene expression in the noninfarcted myocardium of OLETF rats were consistent with increased fatty acid oxidation and decreased glucose oxidation. The patterns were modified by empagliflozin, suggesting both increased glucose oxidation and ketone utilization in OLETF rats. Empagliflozin prevented reduction of ATP level in the noninfarcted myocardium after MI and significantly increased myocardial levels of Sirt3 and superoxide dismutase 2 in OLETF rats. Administration of bOHB partially mimicked the effects of empagliflozin in OLETF rats. The results suggest that empagliflozin prevents DM-induced increase in post-MI mortality, possibly by protective modification of cardiac energy metabolism and antioxidant proteins.

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Section: Discussioncontrasting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Empagliflozin, an SGLT2 Inhibitor, Reduced the Mortality Rate after Acute Myocardial Infarction with Modification of Cardiac Metabolomes and Antioxidants in Diabetic Rats

Oshima¹,

Miki²,

Kuno³

et al. 2018

J Pharmacol Exp Ther

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“…55 Moreover, patients with severe HF have reduced LV levels of methionine, phenylalanine, tyrosine, histidine, threonine, homoserine, glutamine, and alanine. 46, 47 Although the role of amino acid metabolism in HF is yet to be defined, studies have indicated that maintenance of amino acid homeostasis is crucial to suppressing the pathological progression of HF.…”

Section: Metabolites Of Glycolysis and The Tca Cyclementioning

confidence: 99%

Metabolomic Analysis in Heart Failure

Ikegami

Shimizu

Yoshida

et al. 2018

Circ J

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10 s, resulting in the cycling of approximately 6 kg of ATP daily, and the heart displays metabolic flexibility to meet this extremely high demand for energy. 8 Under normal conditions, more than 95% of the ATP consumed in the heart is generated by oxidative phosphorylation, while glycolysis is responsible for approximately 5% and the tricarboxylic acid (TCA) cycle for the remainder. Metabolism of fatty acids generates 70-90% of the ATP required by the heart, with the rest being produced by oxidation of glucose, lactate, ketone bodies, and amino acids. 9 It is well known that utilization of fatty acids is reduced in the failing heart and there is a metabolic shift to generation of ATP from glucose. Such metabolic remodeling is considered to be reasonable because HF is associated with hypoxia and ATP generation per oxygen atom is more efficient when glucose is consumed, compared with fatty acids. 9 In patients with advanced HF, the heart is unable to utilize either metabolite and thus "runs out of fuel". 10 It is reported that the ATP level is approximately 30% lower in failing human hearts compared with non-failing hearts. 11 In addition to this classical premise about the metabolic profile of the failing heart, recent advances in the field of metabolomics have indicated that several metabolites and/or metabolic pathways have a role in HF, as described next. LipidsUnder physiological conditions, the heart mainly generates ATP from fatty acids, but this process declines with progression of HF. Under left ventricular (LV) pressure overload, excessive lipolysis occurs in visceral fat because of increased adrenergic signaling, and this leads to high circulating levels of free fatty acids (FFAs). 12 The serum I t is thought that at least 6,500 low-molecular-weight metabolites exist in humans, and these metabolites have various important roles in biological systems in addition to proteins and genes. 1 Comprehensive assessment of endogenous metabolites is called metabolomics, and recent advances in this field have enabled us to understand the critical role of previously unknown metabolites or metabolic pathways in the maintenance of homeostasis under both physiological and stress conditions. Techniques of metabolomic analysis have been elegantly reported and reviewed elsewhere, 2-4 so the details will not be repeated here. Instead, we will describe the metabolites/metabolic pathways that have been characterized using these techniques and analyzed to improve understanding of various physiological and pathological processes in the field of cardiology. In particular, we will focus on heart failure (HF) and how metabolomic analysis has contributed for improving our understanding of the pathogenesis of this critical condition. Cardiac MetabolismThe number of patients with HF continues to increase and this condition has become a major healthcare issue in many countries. Because the prognosis of severe HF is poor, there are many unmet medical needs for these patients, 5, 6 The pathogenesis of HF is complex and a simple approa...

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“…Examination of tissue from patients with various degrees of MCS-induced myocardial functional recovery (i.e., ”responders”) and from MCS patients without functional myocardial improvement (i.e., “nonresponders”) is critical. Thus, combined functional and biological studies represent a sound approach to begin distinguishing between these 2 scenarios: true mechanistic insights versus epiphenomena (22–29). Future, in-depth, investigational steps incorporating a rigorous basic science scientific approach could assign causality and lead to the discovery of novel therapeutic targets.…”

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confidence: 99%

Advancing the Science of Myocardial Recovery with Mechanical Circulatory Support: A Working Group of the National, Heart, Lung, and Blood Institute

Drakos¹,

Pagani

Lundberg

et al. 2017

ASAIO Journal

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The medical burden of heart failure (HF) has spurred interest in clinicians and scientists to develop therapies to restore the function of a failing heart. To advance this agenda, the National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group of experts from June 2 to 3, 2016, in Bethesda, Maryland, to develop NHLBI recommendations aimed at advancing the science of cardiac recovery in the setting of mechanical circulatory support (MCS). MCS devices effectively reduce volume and pressure overload that drives the cycle of progressive myocardial dysfunction, thereby triggering structural and functional reverse remodeling. Research in this field could be innovative in many ways, and the Working Group specifically discussed opportunities associated with genome-phenome systems biology approaches; genetic epidemiology; bioinformatics and precision medicine at the population level; advanced imaging modalities, including molecular and metabolic imaging; and the development of minimally invasive surgical and percutaneous bioengineering approaches. These new avenues of investigations could lead to new treatments that target phylogenetically conserved pathways involved in cardiac reparative mechanisms. A central point that emerged from the NHLBI Working Group meeting was that the lessons learned from the MCS investigational setting can be extrapolated to the broader HF population. With the precedents set by the significant effect of studies of other well-controlled and tractable subsets on larger populations, such as the genetic work in both cancer and cardiovascular disease, the work to improve our understanding of cardiac recovery and resilience in MCS patients could be transformational for the greater HF population.

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Evidence of Glycolysis Upregulation and Pyruvate Mitochondrial Oxidation Mismatch During Mechanical Unloading of the Failing Human Heart: Implications for Cardiac Reloading and Conditioning

Cited by 16 publications

References 0 publications

Empagliflozin, an SGLT2 Inhibitor, Reduced the Mortality Rate after Acute Myocardial Infarction with Modification of Cardiac Metabolomes and Antioxidants in Diabetic Rats

Empagliflozin, an SGLT2 Inhibitor, Reduced the Mortality Rate after Acute Myocardial Infarction with Modification of Cardiac Metabolomes and Antioxidants in Diabetic Rats

Metabolomic Analysis in Heart Failure

Advancing the Science of Myocardial Recovery with Mechanical Circulatory Support: A Working Group of the National, Heart, Lung, and Blood Institute

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