bims-hafaim 2021-05-16 papers

bims-hafaim

Biomed News

on Heart Failure Metabolism

Issue of 2021‒05‒16
fifteen papers selected by
Kyle McCommis
Saint Louis University

Cardiac Energy Metabolism in Heart Failure.
Increasing fatty acid oxidation elicits a sex-dependent response in failing mouse hearts.
Distinct Phenotypes Induced by Different Degrees of Transverse Aortic Constriction in C57BL/6N Mice.
Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations.
Mechanisms and Models in Heart Failure: A Translational Approach.
The Protective Effect of 1,25(OH)2D3 on Myocardial Function is Mediated via Sirtuin 3-Regulated Fatty Acid Metabolism.
Potential Role For Pyruvate Kinase M2 In The Regulation Of Murine Cardiac Glycolytic Flux During In Vivo Chronic Hypoxia.
Small molecule QF84139 ameliorates cardiac hypertrophy via activating the AMPK signaling pathway.
Hypertrophic Preconditioning Attenuates Myocardial Ischaemia-Reperfusion Injury by Modulating SIRT3-SOD2-mROS-Dependent Autophagy.
TNAP is a novel regulator of cardiac fibrosis after myocardial infarction by mediating TGF-β/Smads and ERK1/2 signaling pathways.
Resistin-Like Molecule α Dysregulates Cardiac Bioenergetics in Neonatal Rat Cardiomyocytes.
Pharmacological Inhibition of GLUT1 As a New Immunotherapeutic Approach After Myocardial Infarction.
Role of the Heart in Lactate Shuttling.
The effect of SGLT-2 inhibitors on mortality and heart failure in randomized trials versus observational studies.
Multimodality assessment of heart failure with preserved ejection fraction skeletal muscle reveals differences in the machinery of energy fuel metabolism.

Circ Res. 2021 May 14. 128(10): 1487-1513

Cardiac Energy Metabolism in Heart Failure.

Gary D Lopaschuk, Qutuba G Karwi, Rong Tian, Adam R Wende, E Dale Abel.

  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.

Keywords:  acetylation; diabetic cardiomyopathies; insulin resistance; ketones; mitochondria

DOI:  https://doi.org/10.1161/CIRCRESAHA.121.318241
J Mol Cell Cardiol. 2021 May 11. pii: S0022-2828(21)00098-5. [Epub ahead of print]

Increasing fatty acid oxidation elicits a sex-dependent response in failing mouse hearts.

Julia Ritterhoff, Timothy S McMillen, Outi Villet, Sara Young, Stephen C Kolwicz, Taurence Senn, Arianne Caudal, Rong Tian.

  BACKGROUND: Reduced fatty acid oxidation (FAO) is a hallmark of metabolic remodeling in heart failure. Enhancing mitochondrial long-chain fatty acid uptake by Acetyl-CoA carboxylase 2 (ACC2) deletion increases FAO and prevents cardiac dysfunction during chronic stresses, but therapeutic efficacy of this approach has not been determined.METHODS: Male and female ACC2f/f-MCM (ACC2KO) and their respective littermate controls were subjected to chronic pressure overload by TAC surgery. Tamoxifen injection 3 weeks after TAC induced ACC2 deletion and increased FAO in ACC2KO mice with pathological hypertrophy.
RESULTS: ACC2 deletion in mice with pre-existing cardiac pathology promoted FAO in female and male hearts, but improved cardiac function only in female mice. In males, pressure overload caused a downregulation in the mitochondrial oxidative function. Stimulating FAO by ACC2 deletion caused unproductive acyl-carnitine accumulation, which failed to improve cardiac energetics. In contrast, mitochondrial oxidative capacity was sustained in female pressure overloaded hearts and ACC2 deletion improved myocardial energetics. Mechanistically, we revealed a sex-dependent regulation of PPARα signaling pathway in heart failure, which accounted for the differential response to ACC2 deletion.
CONCLUSION: Metabolic remodeling in the failing heart is sex-dependent which could determine the response to metabolic intervention. The findings suggest that both mitochondrial oxidative capacity and substrate preference should be considered for metabolic therapy of heart failure.

Keywords:  Energy metabolism; Fatty acid oxidation; Heart failure

DOI:  https://doi.org/10.1016/j.yjmcc.2021.05.004
Front Cardiovasc Med. 2021 ;8 641272

Distinct Phenotypes Induced by Different Degrees of Transverse Aortic Constriction in C57BL/6N Mice.

Haiyan Deng, Lei-Lei Ma, Fei-Juan Kong, Zengyong Qiao.

  The transverse aortic constriction (TAC) model surgery is a widely used disease model to study pressure overload-induced cardiac hypertrophy and heart failure in mice. The severity of adverse cardiac remodeling of the TAC model is largely dependent on the degree of constriction around the aorta, and the phenotypes of TAC are also different in different mouse strains. Few studies focus on directly comparing phenotypes of the TAC model with different degrees of constriction around the aorta, and no study compares the difference in C57BL/6N mice. In the present study, C57BL/6N mice aged 10 weeks were subjected to sham, 25G TAC, 26G TAC, and 27G TAC surgery for 4 weeks. We then analyzed the different phenotypes induced by 25G TAC, 26G TAC, and 27G TAC in c57BL/6N mice in terms of pressure gradient, cardiac hypertrophy, cardiac function, heart failure situation, survival condition, and cardiac fibrosis. All C57BL/6N mice subjected to TAC surgery developed significantly hypertrophy. Mice subjected to 27G TAC had severe cardiac dysfunction, severe cardiac fibrosis, and exhibited characteristics of heart failure at 4 weeks post-TAC. Compared with 27G TAC mice, 26G TAC mice showed a much milder response in cardiac dysfunction and cardiac fibrosis compared to 27G TAC, and a very small fraction of the 26G TAC group exhibited characteristics of heart failure. There was no obvious cardiac dysfunction, cardiac fibrosis, and characteristics of heart failure observed in 25G TAC mice. Based on our results, we conclude that the 25G TAC, 26G TAC, and 27G TAC induced distinct phenotypes in C57BL/6N mice.

Keywords:  C57BL/6N mice; cardiac fibrosis; cardiac hypertrophy; heart failure; transverse aortic constriction

DOI:  https://doi.org/10.3389/fcvm.2021.641272
JCI Insight. 2021 May 10. pii: 134340. [Epub ahead of print]6(9):

Myocardial Lipin 1 knockout in mice approximates cardiac effects of human LPIN1 mutations.

Kari T Chambers, Michael A Cooper, Alison R Swearingen, Rita T Brookheart, George G Schweitzer, Carla J Weinheimer, Attila Kovacs, Timothy R Koves, Deborah M Muoio, Kyle S McCommis, Brian N Finck.

  Lipin 1 is a bifunctional protein that is a transcriptional regulator and has phosphatidic acid (PA) phosphohydrolase activity, which dephosphorylates PA to generate diacylglycerol. Human lipin 1 mutations lead to episodic rhabdomyolysis, and some affected patients exhibit cardiac abnormalities, including exercise-induced cardiac dysfunction and cardiac triglyceride accumulation. Furthermore, lipin 1 expression is deactivated in failing heart, but the effects of lipin 1 deactivation in myocardium are incompletely understood. We generated mice with cardiac-specific lipin 1 KO (cs-Lpin1-/-) to examine the intrinsic effects of lipin 1 in the myocardium. Cs-Lpin1-/- mice had normal systolic cardiac function but mild cardiac hypertrophy. Compared with littermate control mice, PA content was higher in cs-Lpin1-/- hearts, which also had an unexpected increase in diacylglycerol and triglyceride content. Cs-Lpin1-/- mice exhibited diminished cardiac cardiolipin content and impaired mitochondrial respiration rates when provided with pyruvate or succinate as metabolic substrates. After transverse aortic constriction-induced pressure overload, loss of lipin 1 did not exacerbate cardiac hypertrophy or dysfunction. However, loss of lipin 1 dampened the cardiac ionotropic response to dobutamine and exercise endurance in association with reduced protein kinase A signaling. These data suggest that loss of lipin 1 impairs cardiac functional reserve, likely due to effects on glycerolipid homeostasis, mitochondrial function, and protein kinase A signaling.

Keywords:  Cardiology; Cardiovascular disease; Intermediary metabolism; Metabolism; Mitochondria

DOI:  https://doi.org/10.1172/jci.insight.134340
Circ Res. 2021 May 14. 128(10): 1435-1450

Mechanisms and Models in Heart Failure: A Translational Approach.

Douglas L Mann, G Michael Felker.

  Despite multiple attempts to develop a unifying hypothesis that explains the pathophysiology of heart failure with a reduced ejection fraction (HFrEF), no single conceptual model has withstood the test of time. In the present review, we discuss how the results of recent successful phase III clinical development programs in HFrEF are built upon existing conceptual models for drug development. We will also discuss where recent successes in clinical trials do not fit existing models to identify areas where further refinement of current paradigms may be needed. To provide the necessary structure for this review, we will begin with a brief overview of the pathophysiology of HFrEF, followed by an overview of the current conceptual models for HFrEF, and end with an analysis of the scientific rationale and clinical development programs for 4 new therapeutic classes of drugs that have improved clinical outcomes in HFrEF. The 4 new therapeutic classes discussed are ARNIs, SGLT2 (sodium-glucose cotransporter 2) inhibitors, soluble guanylate cyclase stimulators, and myosin activators. With the exception of SGLT2 inhibitors, each of these therapeutic advances was informed by the insights provided by existing conceptual models of heart failure. Although the quest to determine the mechanism of action of SGLT2 inhibitors is ongoing, this therapeutic class of drugs may represent the most important advance in cardiovascular therapeutics of recent decades and may lead to rethinking or expanding our current conceptual models for HFrEF.

Keywords:  angiotensin; clinical trial; drug therapy; heart failure; neprilysin; soluble guanylate cyclase

DOI:  https://doi.org/10.1161/CIRCRESAHA.121.318158
Front Cell Dev Biol. 2021 ;9 627135

The Protective Effect of 1,25(OH)2D3 on Myocardial Function is Mediated via Sirtuin 3-Regulated Fatty Acid Metabolism.

Jingxin Yang, Yalin Zhang, Yiming Pan, Can Sun, Zuwang Liu, Ning Liu, Yu Fu, Xiaofeng Li, Ye Li, Juan Kong.

  Energy substrate imbalance is a major cause of cardiac dysfunction. Vitamin D/vitamin D receptor (VD/VDR) deficiency is involved in the pathogenesis of various cardiac diseases; however, the exact underlying mechanism remains unclear. The aim of this study was to investigate whether vitamin D modulates mitochondrial fatty acid oxidase via sirtuin 3 signaling to protect the myocardium. 1-Alpha-hydroxylase-defficient mice exhibited a high metabolic rate and lower myocardial contractility than wild-type mice. Sirtuin 3 upregulation was detected in high-fat diet-fed mice receiving vitamin D3 compared with that in high-fat diet-fed mice. Both sirtuin 3 blockade and knockout inhibited the VD/VDR-induced downregulation of fatty acid oxidase in myocardial mitochondria. VD/VDR suppressed fatty acid metabolism by upregulating sirtuin 3 and lowering mitochondrial fat uptake, thereby improving myocardial function and balancing energy substrates, rather than by altering fat endocytosis and exocytosis.

Keywords:  Sirtuin 3; Vitamin D; cardiac function; fatty acid metabolism; mitochondria

DOI:  https://doi.org/10.3389/fcell.2021.627135
Biosci Rep. 2021 May 11. pii: BSR20203170. [Epub ahead of print]

Potential Role For Pyruvate Kinase M2 In The Regulation Of Murine Cardiac Glycolytic Flux During In Vivo Chronic Hypoxia.

Michal K Handzlik, David Tooth, Dumitru Constantin-Teodosiu, Paul L Greenhaff, Mark Cole.

  Carbohydrate metabolism in heart failure shares similarities to that following hypoxic exposure, and is thought to maintain energy homeostasis in the face of reduced O2 availability. As part of these in vivo adaptations during sustained hypoxia, the heart upregulates and maintains a high glycolytic flux, but the underlying mechanism it 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 three 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 upregulated cardiac pyruvate kinase (PK) flux 3.1-fold and cardiac pyruvate kinase M2 (PKM2) protein content 1.4-fold compared to normoxic hearts. CH also augmented cardiac pentose phosphate pathway flux, reflected by higher ribose-5-phosphate content. These findings support an increase in the covalent (protein expression) and allosteric (flux) control of PKM2 as being central to the sustained upregulation of the glycolytic flux in the chronically hypoxic heart.

Keywords:  hypoxia; myocardium; pyruvate kinase M2

DOI:  https://doi.org/10.1042/BSR20203170
Acta Pharmacol Sin. 2021 May 09.

Small molecule QF84139 ameliorates cardiac hypertrophy via activating the AMPK signaling pathway.

Xu-Xia Li, Peng Zhang, Yang Yang, Jing-Jing Wang, Yan-Jun Zheng, Ji-Liang Tan, Shen-Yan Liu, Yong-Ming Yan, You-Yi Zhang, Yong-Xian Cheng, Huang-Tian Yang.

  Cardiac hypertrophy is a common adaptive response to a variety of stimuli, but prolonged hypertrophy leads to heart failure. Hence, discovery of agents treating cardiac hypertrophy is urgently needed. In the present study, we investigated the effects of QF84139, a newly synthesized pyrazine derivative, on cardiac hypertrophy and the underlying mechanisms. In neonatal rat cardiomyocytes (NRCMs), pretreatment with QF84139 (1-10 μM) concentration-dependently inhibited phenylephrine-induced hypertrophic responses characterized by fetal genes reactivation, increased ANP protein level and enlarged cardiomyocytes. In adult male mice, administration of QF84139 (5-90 mg·kg-1·d-1, i.p., for 2 weeks) dose-dependently reversed transverse aortic constriction (TAC)-induced cardiac hypertrophy displayed by cardiomyocyte size, left ventricular mass, heart weights, and reactivation of fetal genes. We further revealed that QF84139 selectively activated the AMPK signaling pathway without affecting the phosphorylation of CaMKIIδ, ERK1/2, AKT, PKCε, and P38 kinases in phenylephrine-treated NRCMs and in the hearts of TAC-treated mice. In NRCMs, QF84139 did not show additive effects with metformin on the AMPK activation, whereas the anti-hypertrophic effect of QF84139 was abolished by an AMPK inhibitor Compound C or knockdown of AMPKα2. In AMPKα2-deficient mice, the anti-hypertrophic effect of QF84139 was also vanished. These results demonstrate that QF84139 attenuates the PE- and TAC-induced cardiac hypertrophy via activating the AMPK signaling. This structurally novel compound would be a promising lead compound for developing effective agents for the treatment of cardiac hypertrophy.

Keywords:  AMPK signaling pathway; QF84139; cardiac hypertrophy; phenylephrine; pyrazine derivative; transverse aortic constriction

DOI:  https://doi.org/10.1038/s41401-021-00678-5
Cell Prolif. 2021 May 11. e13051

Hypertrophic Preconditioning Attenuates Myocardial Ischaemia-Reperfusion Injury by Modulating SIRT3-SOD2-mROS-Dependent Autophagy.

Lei-Lei Ma, Fei-Juan Kong, Zheng Dong, Kai-Yue Xin, Xing-Xu Wang, Ai-Jun Sun, Yun-Zeng Zou, Jun-Bo Ge.

  BACKGROUND: Ischaemic preconditioning elicited by brief periods of coronary occlusion and reperfusion protects the heart from a subsequent prolonged ischaemic insult. Here, we test the hypothesis that short-term non-ischaemic stimulation of hypertrophy renders the heart resistant to subsequent ischaemic injury.METHODS AND RESULTS: Transient transverse aortic constriction (TAC) was performed for 3 days in mice and then withdrawn for 4 days by aortic debanding, followed by subsequent exposure to myocardial ischaemia-reperfusion (I/R) injury. Following I/R injury, myocardial infarct size and apoptosis were significantly decreased, and cardiac dysfunction was markedly improved in the TAC preconditioning group compared with the control group. Mechanistically, TAC preconditioning markedly suppressed I/R-induced autophagy and preserved autophagic flux by deacetylating SOD2 via a SIRT3-dependent mechanism. Moreover, treatment with an adenovirus encoding SIRT3 partially mimicked the effects of hypertrophic preconditioning, whereas genetic ablation of SIRT3 in mice blocked the cardioprotective effects of hypertrophic preconditioning. Furthermore, in vivo lentiviral-mediated knockdown of Beclin 1 in the myocardium ameliorated the I/R-induced impairment of autophagic flux and was associated with a reduction in cell death, whereas treatment with a lentivirus encoding Beclin 1 abolished the cardioprotective effect of TAC preconditioning.
CONCLUSIONS: The present study identifies TAC preconditioning as a novel strategy for induction of an endogenous self-defensive and cardioprotective mechanism against cardiac injury. Specifically, TAC preconditioning reduced myocardial autophagic cell death in a SIRT3/SOD2 pathway-dependent manner.

Keywords:  SIRT3; autophagy; hypertrophic preconditioning; ischaemia-reperfusion injury

DOI:  https://doi.org/10.1111/cpr.13051
EBioMedicine. 2021 May 06. pii: S2352-3964(21)00163-8. [Epub ahead of print]67 103370

TNAP is a novel regulator of cardiac fibrosis after myocardial infarction by mediating TGF-β/Smads and ERK1/2 signaling pathways.

Xiaocheng Cheng, Liyou Wang, Xuesong Wen, Lei Gao, Guoxing Li, Guanglei Chang, Shu Qin, Dongying Zhang.

  BACKGROUND: Cardiac fibrosis is the most important pathogenesis leading to cardiac remodeling and heart failure after myocardial infarction (MI). Tissue nonspecific alkaline phosphatase (TNAP) has recently been recognized as a potential prognostic factor for MI. Nevertheless, the role of TNAP in cardiac fibrosis after MI has not been explicitly delineated.METHODS: A systematic review and meta-analysis was conducted to assess the effect of serum TNAP levels on mortality in patients with ischemic heart disease (IHD). A correlation analysis was performed to investigate the relationship between serum levels of TNAP and biomarkers of fibrosis. Heart biopsies from patients with MI and a mouse model of MI were used to detect the expression and distribution of TNAP. Furthermore, we established adenovirus-mediated knockdown and overexpression of TNAP, using a combination of in vivo and in vitro studies in mice, to determine the role and mechanism of TNAP in cardiac fibrosis after MI. In the in vitro studies, cardiac fibroblasts were cultured on soft plates.
FINDINGS: After searching the main databases and performing a detailed assessment of the full-text articles, eight studies with 14,816 individuals were included in the quantitative analysis. We found that a high serum TNAP level was associated with an increased risk of mortality in patients with IHD and MI. The correlation analysis revealed a positive correlation between serum TNAP levels and the concentration of fibrosis biomarkers (PICP/PIIINP). The expression of TNAP was upregulated in the myocardium of patients with MI and in a mouse model of MI, accompanied by fibroblast activation and the deposition of collagen fibers. In the in vivo study, TNAP knockdown ameliorated cardiac fibrosis and improved cardiac function in mice. TNAP overexpression aggravated cardiac fibrosis and worsened cardiac function. In the in vitro study, TNAP promoted cardiac fibroblast differentiation, migration and proliferation. Mechanistically, the pro-fibrotic effect of TNAP on cardiac fibroblasts was at least partially achieved by activating the TGF-β1/Smads and ERK1/2 signaling pathways.
INTERPRETATION: Based on these findings, TNAP plays an important pro-fibrotic role in cardiac fibrosis after MI by activating TGF-β/Smads and ERK1/2 signaling, indicating that it functions as a potential regulator of and therapeutic target in cardiac fibrosis.
FUNDING: This work was supported by the National Natural Science Foundation of China.

Keywords:  Cardiac fibrosis; ERK1/2; Myocardial infarction; TGF-β1/Smads; TNAP

DOI:  https://doi.org/10.1016/j.ebiom.2021.103370
Front Cardiovasc Med. 2021 ;8 574708

Resistin-Like Molecule α Dysregulates Cardiac Bioenergetics in Neonatal Rat Cardiomyocytes.

Bingdong Tao, Santosh Kumar, Jose Gomez-Arroyo, Chunling Fan, Ailan Zhang, John Skinner, Elizabeth Hunter, Kazuyo Yamaji-Kegan, Idris Samad, Alexander T Hillel, Qing Lin, Wenqian Zhai, Wei Dong Gao, Roger A Johns.

  Heart (right) failure is the most frequent cause of death in patients with pulmonary arterial hypertension. Although historically, increased right ventricular afterload has been considered the main contributor to right heart failure in such patients, recent evidence has suggested a potential role of load-independent factors. Here, we tested the hypothesis that resistin-like molecule α (RELMα), which has been implicated in the pathogenesis of vascular remodeling in pulmonary artery hypertension, also contributes to cardiac metabolic remodeling, leading to heart failure. Recombinant RELMα (rRELMα) was generated via a Tet-On expression system in the T-REx 293 cell line. Cultured neonatal rat cardiomyocytes were treated with purified rRELMα for 24 h at a dose of 50 nM. Treated cardiomyocytes exhibited decreased mRNA and protein expression of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) and transcription factors PPARα and ERRα, which regulate mitochondrial fatty acid metabolism, whereas genes that encode for glycolysis-related proteins were significantly upregulated. Cardiomyocytes treated with rRELMα also exhibited a decreased basal respiration, maximal respiration, spare respiratory capacity, ATP-linked OCR, and increased glycolysis, as assessed with a microplate-based cellular respirometry apparatus. Transmission electron microscopy revealed abnormal mitochondrial ultrastructure in cardiomyocytes treated with rRELMα. Our data indicate that RELMα affects cardiac energy metabolism and mitochondrial structure, biogenesis, and function by downregulating the expression of the PGC-1α/PPARα/ERRα axis.

Keywords:  RELMα; fatty acid oxidation; heart failiure; mitochondria; oxygen consumption rate

DOI:  https://doi.org/10.3389/fcvm.2021.574708
Biochem Pharmacol. 2021 May 06. pii: S0006-2952(21)00203-3. [Epub ahead of print] 114597

Pharmacological Inhibition of GLUT1 As a New Immunotherapeutic Approach After Myocardial Infarction.

Ziyi Chen, Jan Dudek, Christoph Maack, Ulrich Hofmann.

Myocardial infarction (MI) is one of the major contributors to cardiovascular morbidity and mortality. Excess inflammation significantly contributes to cardiac remodeling and heart failure after MI. Accumulating evidence has shown the central role of cellular metabolism in regulating the differentiation and function of cells. Metabolic rewiring is particularly relevant for proinflammatory responses induced by ischemia. Hypoxia reduces mitochondrial oxidative phosphorylation(OXPHOS) and induces increased reliance on glycolysis. Moreover, activation of a proinflammatory transcriptional program is associated with preferential glucose metabolism in leukocytes. An improved understanding of the mechanisms that regulate metabolic adaptations holds the potential to identify new metabolic targets and strategies to reduce ischemic cardiac damage, attenuate excess local inflammation and ultimately prevent the development of heart failure. Among possible drug targets, glucose transporter 1 (GLUT1) gained considerable interest considering its pivotal role in regulating glucose availability in activated leukocytes and the availability of small molecules that selectively inhibit it. Therefore, we summarize current evidence on the role of GLUT1 in leukocytes (focusing on macrophages and T cells) and non-leukocytes, including cardiomyocytes, endothelial cells and fibroblasts regarding ischemic heart disease. Beyond myocardial infarction, we can foresee the role of GLUT1 blockers as a possible pharmacological approach to limit pathogenic inflammation in other conditions driven by excess sterile inflammation.

DOI: https://doi.org/10.1016/j.bcp.2021.114597
Front Nutr. 2021 ;8 663560

Role of the Heart in Lactate Shuttling.

George A Brooks.

  After almost a century of misunderstanding, it is time to appreciate that lactate shuttling is an important feature of energy flux and metabolic regulation that involves a complex series of metabolic, neuroendocrine, cardiovascular, and cardiac events in vivo. Cell-cell and intracellular lactate shuttles in the heart and between the heart and other tissues fulfill essential purposes of energy substrate production and distribution as well as cell signaling under fully aerobic conditions. Recognition of lactate shuttling came first in studies of physical exercise where the roles of driver (producer) and recipient (consumer) cells and tissues were obvious. One powerful example of cell-cell lactate shuttling was the exchange of carbohydrate energy in the form of lactate between working limb skeletal muscle and the heart. The exchange of mass represented a conservation of mass that required the integration of neuroendocrine, autoregulatory, and cardiovascular systems. Now, with greater scrutiny and recognition of the effect of the cardiac cycle on myocardial blood flow, there brings an appreciation that metabolic fluxes must accommodate to pressure-flow realities within an organ in which they occur. Therefore, the presence of an intra-cardiac lactate shuttle is posited to explain how cardiac mechanics and metabolism are synchronized. Specifically, interruption of blood flow during the isotonic phase of systole is supported by glycolysis and subsequent return of blood flow during diastole allows for recovery sustained by oxidative metabolism.

Keywords:  exercise; fatty acids; glucose; heart; ketones; lactate; metabolism; muscle

DOI:  https://doi.org/10.3389/fnut.2021.663560
Diabet Med. 2021 May 15. e14600

The effect of SGLT-2 inhibitors on mortality and heart failure in randomized trials versus observational studies.

Jesper Krogh, Carsten Hjorthøj, Søren Lund Kristensen, Christian Selmer, Steen Bendix Haugaard.

  AIM: Randomized clinical trials (RCTs) allocating type 2 diabetes patients to treatment with sodium-glucose transport protein 2 (SGLT-2) inhibitors or placebo have found significant effects on the risk of heart failure and modest effects on mortality. In the wake of the first trials a number of observational studies have been conducted, some of these reporting a mortality reduction of 50% compared to active comparators. In this review we systematically assess and compare the results on all-cause mortality, cardiovascular mortality and heart failure hospitalization observed in randomized clinical trials with the results obtained in observational studies.METHOD: We performed a systematic bibliographical search including cardiovascular outcome trials and observational studies assessing the effect of SGLT-2 inhibitors on mortality and heart failure.
RESULTS: Seven randomized clinical trials and 23 observational studies were included in the current review. The observed heterogeneity between study results for all-cause mortality (p-interaction <0.001) and cardiovascular mortality (p-interaction < 0.001) was explained by study type, whereas this was not the case for heart failure (p-interaction = 0.18).
CONCLUSION: Methodological considerations such as the omission of important confounders, immortal-time bias and residual confounding such as unmeasured social economic inequality may be the cause of the inflated results observed in observational studies and that calls for caution when observational studies are used to guide treatment of patients with type 2 diabetes.

Keywords:  SGLT-2 inhibitors; diabetes; heart failure; mortality; propensity score; real-world studies

DOI:  https://doi.org/10.1111/dme.14600
ESC Heart Fail. 2021 May 15.

Multimodality assessment of heart failure with preserved ejection fraction skeletal muscle reveals differences in the machinery of energy fuel metabolism.

Payman Zamani, Elizabeth A Proto, Neil Wilson, Hossein Fazelinia, Hua Ding, Lynn A Spruce, Antonio Davila, Thomas C Hanff, Jeremy A Mazurek, Stuart B Prenner, Benoit Desjardins, Kenneth B Margulies, Daniel P Kelly, Zoltan Arany, Paschalis-Thomas Doulias, John W Elrod, Mitchell E Allen, Shana E McCormack, Gayatri Maria Schur, Kevin D'Aquilla, Dushyant Kumar, Deepa Thakuri, Karthik Prabhakaran, Michael C Langham, David C Poole, Steven H Seeholzer, Ravinder Reddy, Harry Ischiropoulos, Julio A Chirinos.

  AIMS: Skeletal muscle (SkM) abnormalities may impact exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF). We sought to quantify differences in SkM oxidative phosphorylation capacity (OxPhos), fibre composition, and the SkM proteome between HFpEF, hypertensive (HTN), and healthy participants.METHODS AND RESULTS: Fifty-nine subjects (20 healthy, 19 HTN, and 20 HFpEF) performed a maximal-effort cardiopulmonary exercise test to define peak oxygen consumption (VO2, peak ), ventilatory threshold (VT), and VO2 efficiency (ratio of total work performed to O2 consumed). SkM OxPhos was assessed using Creatine Chemical-Exchange Saturation Transfer (CrCEST, n = 51), which quantifies unphosphorylated Cr, before and after plantar flexion exercise. The half-time of Cr recovery (t1/2, Cr ) was taken as a metric of in vivo SkM OxPhos. In a subset of subjects (healthy = 13, HTN = 9, and HFpEF = 12), percutaneous biopsy of the vastus lateralis was performed for myofibre typing, mitochondrial morphology, and proteomic and phosphoproteomic analysis. HFpEF subjects demonstrated lower VO2,peak , VT, and VO2 efficiency than either control group (all P < 0.05). The t1/2, Cr was significantly longer in HFpEF (P = 0.005), indicative of impaired SkM OxPhos, and correlated with cycle ergometry exercise parameters. HFpEF SkM contained fewer Type I myofibres (P = 0.003). Proteomic analyses demonstrated (a) reduced levels of proteins related to OxPhos that correlated with exercise capacity and (b) reduced ERK signalling in HFpEF.
CONCLUSIONS: Heart failure with preserved ejection fraction patients demonstrate impaired functional capacity and SkM OxPhos. Reductions in the proportions of Type I myofibres, proteins required for OxPhos, and altered phosphorylation signalling in the SkM may contribute to exercise intolerance in HFpEF.

Keywords:  Exercise; HFpEF; Skeletal muscle

DOI:  https://doi.org/10.1002/ehf2.13329