bims-hafaim 2023-11-12 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2023‒11‒12
nine papers selected by
Kyle McCommis, Saint Louis University

SGLT2i‑treated heart failure patients with a reduced ejection fraction: A meta‑analysis.
Mitophagy-dependent Cardioprotection of Resistance Training on Heart Failure.
Activation of the integrated stress response rewires cardiac metabolism in Barth syndrome.
Musashi-2 causes cardiac hypertrophy and heart failure by inducing mitochondrial dysfunction through destabilizing Cluh and Smyd1 mRNA.
Sodium-glucose co-transporter 2 inhibitor canagliflozin modulates myocardial metabolism and inflammation in a swine model for chronic myocardial ischemia.
Drug treatment with empagliflozin was beneficial in people with heart failure with preserved ejection fraction: plain language summary of the EMPEROR-Preserved study.
Regenerating the heart by metabolically reprogramming the cardiomyocyte epigenome.
Multiomics Analysis Provides Novel Pathways Related to Progression of Heart Failure.
The role of glycolytic metabolic pathways in cardiovascular disease and potential therapeutic approaches.

Exp Ther Med. 2023 Dec;26(6): 548

SGLT2i‑treated heart failure patients with a reduced ejection fraction: A meta‑analysis.

Qiang Ye, Kelan Zha.

  The aim of this study was to investigate the effects of SGLT2 inhibitors (SGLT2i) on patients with heart failure (HF) and reduced ejection fraction, with or without diabetes. A systematic review of randomized controlled trials (RCTs) was conducted, comparing SGLT2i to a placebo for HF patients. Relevant studies from PubMed, Web of Science, and EMBASE were searched from inception to July 2021, without any language restrictions. The pooled effect was estimated using the odds ratio (OR) and 95% confidence interval (CI). Depending on the heterogeneity test results, either random effects or fixed effects models were selected to estimate the pooled effects. Sensitivity analysis was conducted by gradually removing each study to evaluate the results' stability. A total of 5 RCT studies were included in the analysis. The fixed-effects model demonstrated that the patients in the SGLT2i group had a lower risk of hospitalization for HF/cardiovascular death (OR=0.72; 95% CI, 0.67-0.78), P<0.0001; I2=0.0%, P=0.966), cardiovascular death (OR=0.84, 95% CI (0.77, 0.93), P<0.0001; I2=0.0%, P=0.633), hospitalization for HF (OR=0.69, 95% CI (0.63, 0.75), P<0.0001; I2=0.0%, P=0.933), and all-cause mortality (OR=0.79, 95% CI (0.71, 0.89), P<0.0001; I2=3.3%, P=0.376) compared to the placebo group. Sensitivity analysis showed that the pooled effect value remained stable within the corresponding range, even after each study was gradually removed. In conclusion, SGLT2i can reduce the risk of HF hospitalization, cardiovascular death, and all-cause mortality in patients with HF and a reduced ejection fraction, regardless of the presence or absence of diabetes.

Keywords:  diabetes; heart failure; randomized clinical trials; reduced ejection fraction; sodium-glucose cotransoporter-2 inhibitors

DOI:  https://doi.org/10.3892/etm.2023.12248
J Appl Physiol (1985). 2023 Nov 09.

Mitophagy-dependent Cardioprotection of Resistance Training on Heart Failure.

Chen Guo, Rui-Yun Wu, Jia-Hao Dou, Shou-Fang Song, Xue-Lu Sun, Yi-Wei Hu, Fan-Shun Guo, Jia Wei, Lin Lin, Jin Wei.

  Resistance exercise is an indispensable mode of exercise rehabilitation for heart failure. Here we elucidate the cardiac effects of resistance training alone or combined with different aerobic trainings on heart failure and explore the critical regulation of mitophagy. The chronic heart failure model was constructed by transverse aortic constriction surgery, followed by 8 weeks of resistance training (RT), moderate-intensity continuous training combined with resistance training (MRT), and high-intensity interval training combined with resistance training (HRT), and subsequently analyzed the changes of maximum load, cardiac structure and function, and myocardial mitophagic activity. The role and signaling of mitophagy in exercise protection of heart failure were investigated by knockdown of Hif1α and Parkin genes in primary neonatal cardiomyocytes. RT and especially MRT improved maximum load (P < 0.0001), myocardial morphology and fibrosis (P < 0.0001), reduced left ventricular diameter and enhanced left ventricular systolic function (P < 0.01), and enhanced myocardial mitophagic activity and HIF1α expression (P < 0.05) in heart failure mice. But HRT had no obvious protective effect on ventricular diameter and function or mitophagy. The abilities of exercise stimulation to regulate reactive oxygen species, adenosine triphosphate, and brain natriuretic peptide were impaired after knockdown of Hif1α and Parkin genes inhibited mitophagy in failing cardiomyocytes (P < 0.05). Different exercise modalities provide discrepant cardiovascular effects on heart failure, and MRT exhibits optimal protection. The HIF1α-Parkin-mitophagy pathway is involved in the protection and regulation of exercise on heart failure.

Keywords:  Resistance training; heart failure; mitophagy

DOI:  https://doi.org/10.1152/japplphysiol.00674.2023
Basic Res Cardiol. 2023 Nov 06. 118(1): 47

Activation of the integrated stress response rewires cardiac metabolism in Barth syndrome.

Ilona Kutschka, Edoardo Bertero, Christina Wasmus, Ke Xiao, Lifeng Yang, Xinyu Chen, Yasuhiro Oshima, Marcus Fischer, Manuela Erk, Berkan Arslan, Lin Alhasan, Daria Grosser, Katharina J Ermer, Alexander Nickel, Michael Kohlhaas, Hanna Eberl, Sabine Rebs, Katrin Streckfuss-Bömeke, Werner Schmitz, Peter Rehling, Thomas Thum, Takahiro Higuchi, Joshua Rabinowitz, Christoph Maack, Jan Dudek.

  Barth Syndrome (BTHS) is an inherited cardiomyopathy caused by defects in the mitochondrial transacylase TAFAZZIN (Taz), required for the synthesis of the phospholipid cardiolipin. BTHS is characterized by heart failure, increased propensity for arrhythmias and a blunted inotropic reserve. Defects in Ca2+-induced Krebs cycle activation contribute to these functional defects, but despite oxidation of pyridine nucleotides, no oxidative stress developed in the heart. Here, we investigated how retrograde signaling pathways orchestrate metabolic rewiring to compensate for mitochondrial defects. In mice with an inducible knockdown (KD) of TAFAZZIN, and in induced pluripotent stem cell-derived cardiac myocytes, mitochondrial uptake and oxidation of fatty acids was strongly decreased, while glucose uptake was increased. Unbiased transcriptomic analyses revealed that the activation of the eIF2α/ATF4 axis of the integrated stress response upregulates one-carbon metabolism, which diverts glycolytic intermediates towards the biosynthesis of serine and fuels the biosynthesis of glutathione. In addition, strong upregulation of the glutamate/cystine antiporter xCT increases cardiac cystine import required for glutathione synthesis. Increased glutamate uptake facilitates anaplerotic replenishment of the Krebs cycle, sustaining energy production and antioxidative pathways. These data indicate that ATF4-driven rewiring of metabolism compensates for defects in mitochondrial uptake of fatty acids to sustain energy production and antioxidation.

Keywords:  Amino acid; Barth syndrome; Fatty acid oxidation; Metabolism; Mitochondria; Oxidative stress

DOI:  https://doi.org/10.1007/s00395-023-01017-x
Basic Res Cardiol. 2023 Nov 03. 118(1): 46

Musashi-2 causes cardiac hypertrophy and heart failure by inducing mitochondrial dysfunction through destabilizing Cluh and Smyd1 mRNA.

Sandhya Singh, Aakash Gaur, Rakesh Kumar Sharma, Renu Kumari, Shakti Prakash, Sunaina Kumari, Ayushi Devendrasingh Chaudhary, Pankaj Prasun, Priyanka Pant, Hannah Hunkler, Thomas Thum, Kumaravelu Jagavelu, Pragya Bharati, Kashif Hanif, Pragya Chitkara, Shailesh Kumar, Kalyan Mitra, Shashi Kumar Gupta.

  Regulation of RNA stability and translation by RNA-binding proteins (RBPs) is a crucial process altering gene expression. Musashi family of RBPs comprising Msi1 and Msi2 is known to control RNA stability and translation. However, despite the presence of MSI2 in the heart, its function remains largely unknown. Here, we aim to explore the cardiac functions of MSI2. We confirmed the presence of MSI2 in the adult mouse, rat heart, and neonatal rat cardiomyocytes. Furthermore, Msi2 was significantly enriched in the heart cardiomyocyte fraction. Next, using RNA-seq data and isoform-specific PCR primers, we identified Msi2 isoforms 1, 4, and 5, and two novel putative isoforms labeled as Msi2 6 and 7 to be expressed in the heart. Overexpression of Msi2 isoforms led to cardiac hypertrophy in cultured cardiomyocytes. Additionally, Msi2 exhibited a significant increase in a pressure-overload model of cardiac hypertrophy. We selected isoforms 4 and 7 to validate the hypertrophic effects due to their unique alternative splicing patterns. AAV9-mediated overexpression of Msi2 isoforms 4 and 7 in murine hearts led to cardiac hypertrophy, dilation, heart failure, and eventually early death, confirming a pathological function for Msi2. Using global proteomics, gene ontology, transmission electron microscopy, seahorse, and transmembrane potential measurement assays, increased MSI2 was found to cause mitochondrial dysfunction in the heart. Mechanistically, we identified Cluh and Smyd1 as direct downstream targets of Msi2. Overexpression of Cluh and Smyd1 inhibited Msi2-induced cardiac malfunction and mitochondrial dysfunction. Collectively, we show that Msi2 induces hypertrophy, mitochondrial dysfunction, and heart failure.

Keywords:  Cardiac hypertrophy; Heart failure; MSI2; Mitochondrial dysfunction; RNA-binding protein

DOI:  https://doi.org/10.1007/s00395-023-01016-y
Surgery. 2023 Nov 06. pii: S0039-6060(23)00713-4. [Epub ahead of print]

Sodium-glucose co-transporter 2 inhibitor canagliflozin modulates myocardial metabolism and inflammation in a swine model for chronic myocardial ischemia.

Dwight D Harris, Sharif A Sabe, Cynthia M Xu, Mohamed Sabra, Mark Broadwin, Akshay Malhotra, Janelle W Li, M Ruhul Abid, Frank W Sellke.

BACKGROUND: Inflammation and disruption of cardiac metabolism are prevalent in the setting of myocardial ischemia. Canagliflozin, a sodium-glucose costransporter-2 inhibitor, has beneficial effects on the heart, though the precise mechanisms are unknown. This study investigated the effects of canagliflozin therapy on metabolic pathways and inflammation in ischemic myocardial tissue using a swine model of chronic myocardial ischemia.METHODS: Sixteen Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic ischemia. Two weeks later, pigs received either no drug (n = 8) or 300 mg canagliflozin (n = 8) daily. Five weeks later, pigs underwent terminal harvest and tissue collection.
RESULTS: Canagliflozin treatment was associated with a trend toward decreased expression of fatty acid oxidation inhibitor acetyl-CoA carboxylase and decreased phosphorylated/inactivated acetyl-CoA carboxylase, a promotor of fatty acid oxidation, compared with control ischemic myocardium (P = .08, P = .03). There was also a significant modulation in insulin resistance markers p-IRS1, p-PKCα, and phosphoinositide 3-kinase in ischemic myocardium of the canagliflozin group compared with the control group (all P < .05). Canagliflozin treatment was associated with a significant increase in inflammatory markers interleukin 6, interleukin 17, interferon-gamma, and inducible nitric oxide synthase (all P < .05). There was a trend toward decreased expression of the anti-inflammatory cytokines interleukin 10 (P = .16) and interleukin 4 (P = .31) with canagliflozin treatment.
CONCLUSION: The beneficial effects of canagliflozin therapy appear to be associated with inhibition of fatty acid oxidation and enhancement of insulin signaling in ischemic myocardium. Interestingly, canagliflozin appears to increase the levels of several inflammatory markers, but further studies are required to better understand how canagliflozin modulates inflammatory signaling pathways.

DOI: https://doi.org/10.1016/j.surg.2023.09.043
Future Cardiol. 2023 Nov 09.

Drug treatment with empagliflozin was beneficial in people with heart failure with preserved ejection fraction: plain language summary of the EMPEROR-Preserved study.

Faiez Zannad, Steven Macari.

  WHAT IS THIS SUMMARY ABOUT?: This summary describes a study of a new pill for treating chronic heart failure called empagliflozin (brand name Jardiance®). The study is called EMPEROR-Preserved and was published in the New England Journal of Medicine. Chronic heart failure is a condition where the heart does not pump blood around the body properly. Heart failure causes symptoms such as shortness of breath, tiredness and build-up of too much water in the body (fluid retention). These symptoms often need hospital treatment and increase the risk of early death.WHAT WAS THE EMPEROR-PRESERVED STUDY?: The EMPEROR-Preserved study looked at how empagliflozin works in people living with a type of heart failure called heart failure with preserved ejection fraction. In this type of heart failure, the lower left chamber (ventricle) of the heart is too stiff to fill with enough blood during each heartbeat.
WHAT HAPPENED DURING THE STUDY?: Almost 6000 people living with preserved ejection fraction heart failure were asked to take either a pill containing empagliflozin or a placebo, an identical pill lacking empagliflozin, daily. The choice of pill for each participant was randomly assigned. The study was double-blinded, meaning that neither the participants nor their doctors knew which pill the participants were taking.
WHAT WERE THE RESULTS?: After an average of 26 months of treatment, empagliflozin reduced the risk of participants needing hospital treatment for complications of heart failure by about 30%. Side effects were generally similar in participants who took empagliflozin and in those who took the placebo, except for genital infections like thrush, which happened in more people who took empagliflozin (2.2%) than in those who took the placebo (0.7%).
WHAT DO THE RESULTS MEAN?: A previous study called EMPEROR-Reduced found that empagliflozin had similar benefits in participants with heart failure with reduced ejection fraction. Therefore, the overall evidence shows that empagliflozin can help people with heart failure whether it is caused by reduced ejection fraction or preserved ejection fraction. Clinical Trial Registration: NCT03057951 (EMPEROR-Preserved study) (ClinicalTrials.gov).

Keywords:  Heart failure; empagliflozin; lay summary; plain language summary; sodium-glucose transporter 2 inhibitors

DOI:  https://doi.org/10.2217/fca-2023-0091
Cell Metab. 2023 Nov 07. pii: S1550-4131(23)00376-5. [Epub ahead of print]35(11): 1849-1851

Regenerating the heart by metabolically reprogramming the cardiomyocyte epigenome.

Xiaoqiang Tang.

In mammal adolescence, cardiomyocytes rapidly exit the cell cycle, and heart regeneration in adults is limited after cardiac injury. Recent work by Li et al. in Nature revealed that inhibition of fatty acid oxidation can rewire cell metabolism and lead to epigenetic reprogramming of cardiomyocytes to an immature state that facilitates cardiomyocyte cell-cycle reentry and heart regeneration in adult animals.

DOI: https://doi.org/10.1016/j.cmet.2023.10.007
J Am Coll Cardiol. 2023 Nov 14. pii: S0735-1097(23)07560-5. [Epub ahead of print]82(20): 1921-1931

Multiomics Analysis Provides Novel Pathways Related to Progression of Heart Failure.

Wouter Ouwerkerk, Joao P Belo Pereira, Troy Maasland, Johanna E Emmens, Sylwia M Figarska, Jasper Tromp, Andrea L Koekemoer, Christopher P Nelson, Mintu Nath, Simon P R Romaine, John G F Cleland, Faiez Zannad, Dirk J van Veldhuisen, Chim C Lang, Piotr Ponikowski, Gerasimos Filippatos, Stefan Anker, Marco Metra, Kenneth Dickstein, Leong L Ng, Rudolf A de Boer, Natal van Riel, Max Nieuwdorp, Albert K Groen, Erik Stroes, Aeilko H Zwinderman, Nilesh J Samani, Carolyn S P Lam, Evgeni Levin, Adriaan A Voors.

  BACKGROUND: Despite major advances in pharmacological treatment for patients with heart failure, residual mortality remains high. This suggests that important pathways are not yet targeted by current heart failure therapies.OBJECTIVES: We sought integration of genetic, transcriptomic, and proteomic data in a large cohort of patients with heart failure to detect major pathways related to progression of heart failure leading to death.
METHODS: We used machine learning methodology based on stacked generalization framework and gradient boosting algorithms, using 54 clinical phenotypes, 403 circulating plasma proteins, 36,046 transcript expression levels in whole blood, and 6 million genomic markers to model all-cause mortality in 2,516 patients with heart failure from the BIOSTAT-CHF (Systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure) study. Results were validated in an independent cohort of 1,738 patients.
RESULTS: The mean age of the patients was 70 years (Q1-Q3: 61-78 years), 27% were female, median N-terminal pro-B-type natriuretic peptide was 4,275 ng/L (Q1-Q3: 2,360-8,486 ng/L), and 7% had heart failure with preserved ejection fraction. During a median follow-up of 21 months, 657 (26%) of patients died. The 4 major pathways with a significant association to all-cause mortality were: 1) the PI3K/Akt pathway; 2) the MAPK pathway; 3) the Ras signaling pathway; and 4) epidermal growth factor receptor tyrosine kinase inhibitor resistance. Results were validated in an independent cohort of 1,738 patients.
CONCLUSIONS: A systems biology approach integrating genomic, transcriptomic, and proteomic data identified 4 major pathways related to mortality. These pathways are related to decreased activation of the cardioprotective ERBB2 receptor, which can be modified by neuregulin.

Keywords:  heart failure; machine learning; omics; systems biology

DOI:  https://doi.org/10.1016/j.jacc.2023.08.053
Basic Res Cardiol. 2023 Nov 08. 118(1): 48

The role of glycolytic metabolic pathways in cardiovascular disease and potential therapeutic approaches.

Shuxian Chen, Yuanming Zou, Chunyu Song, Kexin Cao, Kexin Cai, Yanjiao Wu, Zhaobo Zhang, Danxi Geng, Wei Sun, Nanxiang Ouyang, Naijin Zhang, Zhao Li, Guozhe Sun, Yixiao Zhang, Yingxian Sun, Ying Zhang.

  Cardiovascular disease (CVD) is a major threat to human health, accounting for 46% of non-communicable disease deaths. Glycolysis is a conserved and rigorous biological process that breaks down glucose into pyruvate, and its primary function is to provide the body with the energy and intermediate products needed for life activities. The non-glycolytic actions of enzymes associated with the glycolytic pathway have long been found to be associated with the development of CVD, typically exemplified by metabolic remodeling in heart failure, which is a condition in which the heart exhibits a rapid adaptive response to hypoxic and hypoxic conditions, occurring early in the course of heart failure. It is mainly characterized by a decrease in oxidative phosphorylation and a rise in the glycolytic pathway, and the rise in glycolysis is considered a hallmark of metabolic remodeling. In addition to this, the glycolytic metabolic pathway is the main source of energy for cardiomyocytes during ischemia-reperfusion. Not only that, the auxiliary pathways of glycolysis, such as the polyol pathway, hexosamine pathway, and pentose phosphate pathway, are also closely related to CVD. Therefore, targeting glycolysis is very attractive for therapeutic intervention in CVD. However, the relationship between glycolytic pathway and CVD is very complex, and some preclinical studies have confirmed that targeting glycolysis does have a certain degree of efficacy, but its specific role in the development of CVD has yet to be explored. This article aims to summarize the current knowledge regarding the glycolytic pathway and its key enzymes (including hexokinase (HK), phosphoglucose isomerase (PGI), phosphofructokinase-1 (PFK1), aldolase (Aldolase), phosphoglycerate metatase (PGAM), enolase (ENO) pyruvate kinase (PKM) lactate dehydrogenase (LDH)) for their role in cardiovascular diseases (e.g., heart failure, myocardial infarction, atherosclerosis) and possible emerging therapeutic targets.

Keywords:  Cardiovascular disease; Glycolysis; Heart failure; Ischemia–reperfusion; Metabolism

DOI:  https://doi.org/10.1007/s00395-023-01018-w