bims-hafaim 2023-10-01 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2023–10–01
eight papers selected by
Kyle McCommis, Saint Louis University

Sustained Increases in Cardiomyocyte Protein O-Linked β-N-Acetylglucosamine Levels Lead to Cardiac Hypertrophy and Reduced Mitochondrial Function Without Systolic Contractile Impairment.
Metabolic adaptations in pressure overload hypertrophic heart.
Pharmacological Effects of Botanical Drugs on Myocardial Metabolism in Chronic Heart Failure.
Multi-omics analysis reveals attenuation of cellular stress by empagliflozin in high glucose-treated human cardiomyocytes.
SGLT2 inhibitors among patients with heart failure with preserved ejection fraction: A meta-analysis of randomised controlled trials.
The Impact of Ketone Body Metabolism on Mitochondrial Function and Cardiovascular Diseases.
Inhibition of fatty acid oxidation enables heart regeneration in adult mice.
PGC-1α Agonist Rescues Doxorubicin-Induced Cardiomyopathy by Mitigating the Oxidative Stress and Necroptosis.

J Am Heart Assoc. 2023 Sep 26. e029898

Sustained Increases in Cardiomyocyte Protein O-Linked β-N-Acetylglucosamine Levels Lead to Cardiac Hypertrophy and Reduced Mitochondrial Function Without Systolic Contractile Impairment.

Chae-Myeong Ha, Sayan Bakshi, Manoja K Brahma, Luke A Potter, Samuel F Chang, Zhihuan Sun, Gloria A Benavides, Lihao He, Prachi Umbarkar, Luyun Zou, Samuel Curfman, Sini Sunny, Andrew J Paterson, Namakkal-Soorappan Rajasekaran, Jarrod W Barnes, Jianhua Zhang, Hind Lal, Min Xie, Victor M Darley-Usmar, John C Chatham, Adam R Wende.

  Background Lifestyle and metabolic diseases influence the severity and pathogenesis of cardiovascular disease through numerous mechanisms, including regulation via posttranslational modifications. A specific posttranslational modification, the addition of O-linked β-N acetylglucosamine (O-GlcNAcylation), has been implicated in molecular mechanisms of both physiological and pathologic adaptations. The current study aimed to test the hypothesis that in cardiomyocytes, sustained protein O-GlcNAcylation contributes to cardiac adaptations, and its progression to pathophysiology. Methods and Results Using a naturally occurring dominant-negative O-GlcNAcase (dnOGA) inducible cardiomyocyte-specific overexpression transgenic mouse model, we induced dnOGA in 8- to 10-week-old mouse hearts. We examined the effects of 2-week and 24-week dnOGA overexpression, which progressed to a 1.8-fold increase in protein O-GlcNAcylation. Two-week increases in protein O-GlcNAc levels did not alter heart weight or function; however, 24-week increases in protein O-GlcNAcylation led to cardiac hypertrophy, mitochondrial dysfunction, fibrosis, and diastolic dysfunction. Interestingly, systolic function was maintained in 24-week dnOGA overexpression, despite several changes in gene expression associated with cardiovascular disease. Specifically, mRNA-sequencing analysis revealed several gene signatures, including reduction of mitochondrial oxidative phosphorylation, fatty acid, and glucose metabolism pathways, and antioxidant response pathways after 24-week dnOGA overexpression. Conclusions This study indicates that moderate increases in cardiomyocyte protein O-GlcNAcylation leads to a differential response with an initial reduction of metabolic pathways (2-week), which leads to cardiac remodeling (24-week). Moreover, the mouse model showed evidence of diastolic dysfunction consistent with a heart failure with preserved ejection fraction. These findings provide insight into the adaptive versus maladaptive responses to increased O-GlcNAcylation in heart.

Keywords:  cardiac remodeling; diabetic cardiomyopathy; metabolism; mitochondria; protein O‐GlcNAcylation

DOI:  https://doi.org/10.1161/JAHA.123.029898
Heart Fail Rev. 2023 Sep 28.

Metabolic adaptations in pressure overload hypertrophic heart.

Jinfeng Wei, Xuefei Duan, Jiaying Chen, Dengwen Zhang, Jindong Xu, Jian Zhuang, Sheng Wang.

  This review article offers a detailed examination of metabolic adaptations in pressure overload hypertrophic hearts, a condition that plays a pivotal role in the progression of heart failure with preserved ejection fraction (HFpEF) to heart failure with reduced ejection fraction (HFrEF). The paper delves into the complex interplay between various metabolic pathways, including glucose metabolism, fatty acid metabolism, branched-chain amino acid metabolism, and ketone body metabolism. In-depth insights into the shifts in substrate utilization, the role of different transporter proteins, and the potential impact of hypoxia-induced injuries are discussed. Furthermore, potential therapeutic targets and strategies that could minimize myocardial injury and promote cardiac recovery in the context of pressure overload hypertrophy (POH) are examined. This work aims to contribute to a better understanding of metabolic adaptations in POH, highlighting the need for further research on potential therapeutic applications.

Keywords:  Cardiac hypertrophy; Energy metabolism; Heart failure

DOI:  https://doi.org/10.1007/s10741-023-10353-y
Chin J Integr Med. 2023 Sep 26.

Pharmacological Effects of Botanical Drugs on Myocardial Metabolism in Chronic Heart Failure.

Yu-Xuan Hu, Sheng-Lei Qiu, Ju-Ju Shang, Zi Wang, Xiao-Lei Lai.

  Although there have been significant advances in the treatment of heart failure in recent years, chronic heart failure remains a leading cause of cardiovascular disease-related death. Many studies have found that targeted cardiac metabolic remodeling has good potential for the treatment of heart failure. However, most of the drugs that increase cardiac energy are still in the theoretical or testing stage. Some research has found that botanical drugs not only increase myocardial energy metabolism through multiple targets but also have the potential to restore the balance of myocardial substrate metabolism. In this review, we summarized the mechanisms by which botanical drugs (the active ingredients/formulas/Chinese patent medicines) improve substrate utilization and promote myocardial energy metabolism by activating AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptors (PPARs) and other related targets. At the same time, some potential protective effects of botanical drugs on myocardium, such as alleviating oxidative stress and dysbiosis signaling, caused by metabolic disorders, were briefly discussed.

Keywords:  botanical drugs; chronic heart failure; myocardial metabolism; pharmacological effects; review

DOI:  https://doi.org/10.1007/s11655-023-3649-5
J Transl Med. 2023 09 23. 21(1): 662

Multi-omics analysis reveals attenuation of cellular stress by empagliflozin in high glucose-treated human cardiomyocytes.

Lucia Scisciola, Ugo Chianese, Vicky Caponigro, Manuela Giovanna Basilicata, Emanuela Salviati, Lucia Altucci, Pietro Campiglia, Giuseppe Paolisso, Michelangela Barbieri, Rosaria Benedetti, Eduardo Sommella.

   BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors constitute the gold standard treatment for type 2 diabetes mellitus (T2DM). Among them, empagliflozin (EMPA) has shown beneficial effects against heart failure. Because cardiovascular diseases (mainly diabetic cardiomyopathy) are the leading cause of death in diabetic patients, the use of EMPA could be, simultaneously, cardioprotective and antidiabetic, reducing the risk of death from cardiovascular causes and decreasing the risk of hospitalization for heart failure in T2DM patients. Interestingly, recent studies have shown that EMPA has positive benefits for people with and without diabetes. This finding broadens the scope of EMPA function beyond glucose regulation alone to include a more intricate metabolic process that is, in part, still unknown. Similarly, this significantly increases the number of people with heart diseases who may be eligible for EMPA treatment.
METHODS: This study aimed to clarify the metabolic effect of EMPA on the human myocardial cell model by using orthogonal metabolomics, lipidomics, and proteomics approaches. The untargeted and multivariate analysis mimicked the fasting blood sugar level of T2DM patients (hyperglycemia: HG) and in the average blood sugar range (normal glucose: NG), with and without the addition of EMPA.
RESULTS: Results highlighted that EMPA was able to modulate and partially restore the levels of multiple metabolites associated with cellular stress, which were dysregulated in the HG conditions, such as nicotinamide mononucleotide, glucose-6-phosphate, lactic acid, FA 22:6 as well as nucleotide sugars and purine/pyrimidines. Additionally, EMPA regulated the levels of several lipid sub-classes, in particular dihydroceramide and triacylglycerols, which tend to accumulate in HG conditions resulting in lipotoxicity. Finally, EMPA counteracted the dysregulation of endoplasmic reticulum-derived proteins involved in cellular stress management.
CONCLUSIONS: These results could suggest an effect of EMPA on different metabolic routes, tending to rescue cardiomyocyte metabolic status towards a healthy phenotype.

Keywords:  High glucose; Human cardiomyocytes; Metabolomics; SGLT2i; Type-2-diabetes mellitus

DOI:  https://doi.org/10.1186/s12967-023-04537-1
Medicine (Baltimore). 2023 Sep 29. 102(39): e34693

SGLT2 inhibitors among patients with heart failure with preserved ejection fraction: A meta-analysis of randomised controlled trials.

Akash Jaiswal, Vikash Jaiswal, Song Peng Ang, Muhammad Hanif, Ananya Vadhera, Vibhor Agrawal, Tushar Kumar, Anagha M Nair, VamsikalyanReddy Borra, Vamsi Garimella, Angela Ishak, Zarghoona Wajid, David Song, Abdelrahman M Attia, Helen Huang, Victor Hugo Aguilera Alvarez, Abhigan Babu Shrestha, Monodeep Biswas.

BACKGROUND: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been recommended in the practice guidelines for the treatment of patients with heart failure with reduced ejection fraction; however, their effects among patients with preserved ejection fraction have been debatable.
OBJECTIVE: We aim to evaluate the SGLT2 inhibitor effect among patients with heart failure with reduced ejection fraction, including DELIVER and EMPEROR-Preserved trials.
METHODS: We performed a systematic literature search using the PubMed, Embase, Scopus, and Cochrane libraries for relevant articles from inception until August 30th, 2022. Statistical analysis was performed by calculating hazard ratio (HR) using the random effect model with a 95% confidence interval (CI) and probability value (P). Statistical significance was met if 95% CI does not cross numeric "1" and P < .05.
RESULTS: Six studies with a total of 15,989 total patients were included in the final analysis. The mean age of patients enrolled in SGLT2 inhibitors and placebo was 69.13 and 69.37 years, respectively. The median follow-up duration was 2.24 years. SGLT2 inhibitors reduced composite cardiovascular mortality or first hospitalization for heart failure (HR, 0.80 [95% CI: 0.74-0.87], P < .001, I2 = 0%), heart failure hospitalization (HR, 0.74 [95% CI: 0.67-0.82], P < .001, I2 = 0%) compared with placebo. However, all-cause mortality (HR, 0.97 [95% CI: 0.89-1.06], P = .54, I2 = 0%) and cardiovascular mortality (HR, 0.96 [95% CI: 0.82-1.13), P = .66, I2 = 35.09%] were comparable between both groups.
CONCLUSION: Our study finding shows that SGLT2 inhibitors significantly reduced the risk of first HF hospitalization or cardiovascular death and HF hospitalization; however, all-cause mortality was comparable between the groups.

DOI: https://doi.org/10.1097/MD.0000000000034693
J Atheroscler Thromb. 2023 Sep 28.

The Impact of Ketone Body Metabolism on Mitochondrial Function and Cardiovascular Diseases.

Yuichiro Arima.

  Ketone bodies, consisting of beta-hydroxybutyrate, acetoacetate, and acetone, are metabolic byproducts known as energy substrates during fasting. Recent advancements have shed light on the multifaceted effects of ketone body metabolism, which led to increased interest in therapeutic interventions aimed at elevating ketone body levels. However, excessive elevation of ketone body concentration can lead to ketoacidosis, which may have fatal consequences. Therefore, in this review, we aimed to focus on the latest insights on ketone body metabolism, particularly emphasizing its association with mitochondria as the primary site of interaction. Given the distinct separation between ketone body synthesis and breakdown pathways, we provide an overview of each metabolic pathway. Additionally, we discuss the relevance of ketone bodies to conditions such as nonalcoholic fatty liver disease or nonalcoholic steatohepatitis and cardiovascular diseases. Moreover, we explore the utilization of ketone body metabolism, including dietary interventions, in the context of aging, where mitochondrial dysfunction plays a crucial role. Through this review, we aim to present a comprehensive understanding of ketone body metabolism and its intricate relationship with mitochondrial function, spanning the potential implications in various health conditions and the aging process.

Keywords:  Aging; Cardiovascular diseases; Ketone body metabolism; Mitochondria

DOI:  https://doi.org/10.5551/jat.RV22011
Nature. 2023 Sep 27.

Inhibition of fatty acid oxidation enables heart regeneration in adult mice.

Xiang Li, Fan Wu, Stefan Günther, Mario Looso, Carsten Kuenne, Ting Zhang, Marion Wiesnet, Stephan Klatt, Sven Zukunft, Ingrid Fleming, Gernot Poschet, Astrid Wietelmann, Ann Atzberger, Michael Potente, Xuejun Yuan, Thomas Braun.

Postnatal maturation of cardiomyocytes is characterized by a metabolic switch from glycolysis to fatty acid oxidation, chromatin reconfiguration and exit from the cell cycle, instating a barrier for adult heart regeneration1,2. Here, to explore whether metabolic reprogramming can overcome this barrier and enable heart regeneration, we abrogate fatty acid oxidation in cardiomyocytes by inactivation of Cpt1b. We find that disablement of fatty acid oxidation in cardiomyocytes improves resistance to hypoxia and stimulates cardiomyocyte proliferation, allowing heart regeneration after ischaemia-reperfusion injury. Metabolic studies reveal profound changes in energy metabolism and accumulation of α-ketoglutarate in Cpt1b-mutant cardiomyocytes, leading to activation of the α-ketoglutarate-dependent lysine demethylase KDM5 (ref. 3). Activated KDM5 demethylates broad H3K4me3 domains in genes that drive cardiomyocyte maturation, lowering their transcription levels and shifting cardiomyocytes into a less mature state, thereby promoting proliferation. We conclude that metabolic maturation shapes the epigenetic landscape of cardiomyocytes, creating a roadblock for further cell divisions. Reversal of this process allows repair of damaged hearts.

DOI: https://doi.org/10.1038/s41586-023-06585-5
Antioxidants (Basel). 2023 Sep 05. pii: 1720. [Epub ahead of print]12(9):

PGC-1α Agonist Rescues Doxorubicin-Induced Cardiomyopathy by Mitigating the Oxidative Stress and Necroptosis.

Shipra, Manoj Kumar Tembhre, Milind Padmakar Hote, Neetu Bhari, Ramakrishnan Lakshmy, S Senthil Kumaran.

  Cardiomyopathy (particularly dilated cardiomyopathy (DCM)) significantly contributes to development and progression of heart failure (HF), and inflammatory factors further deteriorate the symptoms. Morphological and functional defects of the heart in doxorubicin (DOX)-induced cardiomyopathy (cardiotoxicity) are similar to those of DCM. We used anagonist of PGC-1α (PPAR (peroxisome proliferator-activated receptor-gamma)-γ coactivator-1α) that is considered as the 'master regulator' of mitochondrial biogenesis with an aim to rescue the DOX-induced deleterious effects on the heart. Forty male C57BL/6J mice (8 weeks old) were divided in four groups, Control, DOX, ZLN005, and ZLN005 + DOX (n = 10 each group). The DOX-induced (10 mg/kg, single dose) cardiomyopathy mimics a DCM-like phenotype with marked morphologic alteration in cardiac tissue and functional derangements. Significant increased staining was observed for Masson Trichrome/Picrosirius red and α-Smooth Muscle Actinin (α-SMA) that indicated enhanced fibrosis in the DOX group compared to the control that was attenuated by (peroxisome proliferator-activated receptor-gamma (PPAR-γ) coactivator) (PGC)-1α (alpha) agonist (four doses of 2.5 mg/kg/dose; cumulative dose = 10 mg/kg). Similarly, elevated expression of necroptosis markers along with enhanced oxidative stress in the DOX group were alleviated by PGC-1α agonist. These data collectively suggested the potent therapeutic efficacy of PGC-1α agonist in mitigating the deleterious effects of DOX-induced cardiomyopathy, and it may be targeted in developing the future therapeutics for the management of DCM/HF.

Keywords:  DCM; PGC-1α; cardiomyopathy; fibrosis; necroptosis; oxidative stress

DOI:  https://doi.org/10.3390/antiox12091720