bims-hafaim 2024-10-20 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2024‒10‒20
nine papers selected by
Kyle McCommis, Saint Louis University

Metabolic Effects of the SGLT2 Inhibitor Dapagliflozin in Heart Failure Across the Spectrum of Ejection Fraction.
SGLT2 Inhibitors and Their Effect on Metabolism in Patients With Heart Failure.
Direct mitochondrial import of lactate supports resilient carbohydrate oxidation.
PFKP inhibition protects against pathological cardiac hypertrophy by regulating protein synthesis.
Mitochondrial transfer in the progression and treatment of cardiac disease.
MICUs protect the heart by regulating mitochondrial calcium.
Empagliflozin and other SGLT2 inhibitors in patients with heart failure and preserved ejection fraction: a systematic review and meta-analysis.
Inhibiting glycosphingolipids alleviates cardiac hypertrophy by reducing reactive oxygen species and restoring autophagic homeostasis.
Longitudinal lipidomic profiles of left ventricular mass and hypertrophy in American Indians.

Circ Heart Fail. 2024 Oct 18. e011980

Metabolic Effects of the SGLT2 Inhibitor Dapagliflozin in Heart Failure Across the Spectrum of Ejection Fraction.

Senthil Selvaraj, Shachi Patel, Andrew J Sauer, Robert W McGarrah, Philip Jones, Lydia Coulter Kwee, Sheryl L Windsor, Olga Ilkayeva, Michael J Muehlbauer, Christopher B Newgard, Barry A Borlaug, Dalane W Kitzman, Sanjiv J Shah, Kenneth B Margulies, Mansoor Husain, Silvio E Inzucchi, Darren K McGuire, David E Lanfear, Ali Javaheri, Guillermo Umpierrez, Robert J Mentz, Kavita Sharma, Mikhail N Kosiborod, Svati H Shah.

  BACKGROUND: Mechanisms of benefit with SGLT2is (sodium-glucose cotransporter-2 inhibitors) in heart failure (HF) remain incompletely characterized. Dapagliflozin alters ketone and fatty acid metabolism in HF with reduced ejection fraction though similar effects have not been observed in HF with preserved ejection fraction. We explore whether metabolic effects of SGLT2is vary across the left ventricular ejection fraction spectrum and their relationship with cardiometabolic end points in 2 randomized trials of dapagliflozin in HF.METHODS: Metabolomic profiling of 61 metabolites was performed in 527 participants from DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients With HF With Reduced Ejection Fraction) and PRESERVED-HF (Dapagliflozin in PRESERVED Ejection Fraction HF; 12-week, placebo-controlled trials of dapagliflozin in HF with reduced ejection fraction and HF with preserved ejection fraction, respectively). Linear regression was used to assess changes in principal components analysis-defined metabolite factors with treatment from baseline to 12 weeks, as well as the relationship between changes in metabolite clusters and HF-related end points.
RESULTS: The mean age was 66±11 years, 43% were female, and 33% were self-identified as Black. Two principal components analysis-derived metabolite factors (which were comprised of ketone and short-/medium-chain acylcarnitines) increased with dapagliflozin compared with placebo. Ketosis (defined as 3-hydroxybutyrate >500 μM) was achieved in 4.5% with dapagliflozin versus 1.2% with placebo (P=0.03). There were no appreciable treatment effects on amino acids, including branched-chain amino acids. Increases in several acylcarnitines were consistent across LVEF (Pinteraction>0.10), whereas the ketogenic effect diminished at higher LVEF (Pinteraction=0.01 for 3-hydroxybutyrate). Increases in metabolites reflecting mitochondrial dysfunction (particularly long-chain acylcarnitines) and aromatic amino acids and decreases in branched-chain amino acids were associated with worse HF-related outcomes in the overall cohort, with consistency across treatment and LVEF.
CONCLUSIONS: SGLT2is demonstrate common (fatty acid) and distinct (ketogenic) metabolic signatures across the LVEF spectrum. Changes in key pathways related to fatty acid and amino acid metabolism are associated with HF-related end points and may serve as therapeutic targets across HF subtypes.
REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifiers: NCT03030235 and NCT02653482.

Keywords:  fatty acid; heart failure; ketone bodies; metabolomics; quality of life

DOI:  https://doi.org/10.1161/CIRCHEARTFAILURE.124.011980
Circ Heart Fail. 2024 Oct 18. e012373

SGLT2 Inhibitors and Their Effect on Metabolism in Patients With Heart Failure.

Henrik Wiggers.



Keywords:  Editorials; arterial pressure; blood glucose; heart failure; metabolism

DOI:  https://doi.org/10.1161/CIRCHEARTFAILURE.124.012373
bioRxiv. 2024 Oct 08. pii: 2024.10.07.617073. [Epub ahead of print]

Direct mitochondrial import of lactate supports resilient carbohydrate oxidation.

Ahmad A Cluntun, Joseph R Visker, Jesse N Velasco-Silva, Marisa J Lang, Luis Cedeño-Rosario, Thirupura S Shankar, Rana Hamouche, Jing Ling, Ji Eon Kim, Ashish G Toshniwal, Hayden K Low, Corey N Cunningham, James Carrington, Jonathan Leon Catrow, Quentinn Pearce, Mi-Young Jeong, Alex J Bott, Álvaro J Narbona-Pérez, Claire E Stanley, Qing Li, David R Eberhardt, Jeffrey T Morgan, Tarun Yadav, Chloe E Wells, Dinesh K A Ramadurai, Wojciech I Swiatek, Dipayan Chaudhuri, Jeffery D Rothstein, Deborah M Muoio, Joao A Paulo, Steven P Gygi, Steven A Baker, Sutip Navankasattusas, James E Cox, Katsuhiko Funai, Stavros G Drakos, Jared Rutter, Gregory S Ducker.

Lactate is the highest turnover circulating metabolite in mammals. While traditionally viewed as a waste product, lactate is an important energy source for many organs, but first must be oxidized to pyruvate for entry into the tricarboxylic acid cycle (TCA cycle). This reaction is thought to occur in the cytosol, with pyruvate subsequently transported into mitochondria via the mitochondrial pyruvate carrier (MPC). Using 13 C stable isotope tracing, we demonstrated that lactate is oxidized in the myocardial tissue of mice even when the MPC is genetically deleted. This MPC-independent lactate import and mitochondrial oxidation is dependent upon the monocarboxylate transporter 1 (MCT1/ Slc16a1 ). Mitochondria isolated from the myocardium without MCT1 exhibit a specific defect in mitochondrial lactate, but not pyruvate, metabolism. The import and subsequent mitochondrial oxidation of lactate by mitochondrial lactate dehydrogenase (LDH) acts as an electron shuttle, generating sufficient NADH to support respiration even when the TCA cycle is disrupted. In response to diverse cardiac insults, animals with hearts lacking MCT1 undergo rapid progression to heart failure with reduced ejection fraction. Thus, the mitochondrial import and oxidation of lactate enables carbohydrate entry into the TCA cycle to sustain cardiac energetics and maintain myocardial structure and function under stress conditions.

DOI: https://doi.org/10.1101/2024.10.07.617073
Biochim Biophys Acta Mol Basis Dis. 2024 Oct 15. pii: S0925-4439(24)00536-2. [Epub ahead of print]1871(1): 167542

PFKP inhibition protects against pathological cardiac hypertrophy by regulating protein synthesis.

Xiao-Yu Wu, Shi Peng, Xin-Tao Li, Song-Wen Chen, Yong Wei, Yu-Tong Ye, Chang-Zuan Zhou, Zi-Kan Zhong, Long-Zhe Gao, Chen-Yang Jin, De-Ping Kong, Shao-Wen Liu, Gen-Qing Zhou.

  Metabolic reprogramming precedes most alterations during pathological cardiac hypertrophy and heart failure (HF). Recent studies have revealed that Phosphofructokinase, platelet (PFKP) has a wealth of metabolic and non-metabolic functions. In this study, we explored the role of PFKP in cardiac hypertrophic growth and HF. The expression level of PFKP was elevated both in pathological cardiac remodeling mouse model challenged by transverse aortic constriction (TAC) surgery and in the neonatal rat cardiomyocytes (NRCMs) stimulated by phenylephrine (PE). In global PFKP knockout (PFKP-KO) mice, cardiac hypertrophy was ameliorated under TAC surgery, while overexpression of PFKP by intravenous injection of adeno-associated virus 9 (AAV9) under the cardiac troponin T (cTnT) promoter worsened myocardial hypertrophy and fibrosis. In NRCMs, small interfering RNA (SiRNA) knockdown or adenovirus (Adv) overexpression of PFKP was employed and the intervention of PFKP showed a similar phenotype. Mechanistically, immunoprecipitation combined with liquid chromatography-tandem mass spectrometry (IP-MS/MS) analysis was used to identify the interacting proteins of PFKP. Eukaryotic translation initiation factor 2 subunit beta (EIF2S2) was identified as the downstream target of PFKP. In the PE-stimulated NRCM hypertrophy model and mouse TAC model, knocking down EIF2S2 after PFKP overexpression reduced the synthesis of new proteins and alleviated the hypertrophy phenotype. Our findings illuminate that PFKP participates in pathological cardiac hypertrophy partly by regulating protein synthesis through EIF2S2, which provides a new clue for the involvement of metabolic intermediates in signal transduction.

Keywords:  EIF2S2; Hypertrophy; Myocyte, cardiac; PFKP; Protein synthesis

DOI:  https://doi.org/10.1016/j.bbadis.2024.167542
Life Sci. 2024 Oct 10. pii: S0024-3205(24)00709-4. [Epub ahead of print]358 123119

Mitochondrial transfer in the progression and treatment of cardiac disease.

Yaqing Huang, Wanling Li, Hongyu Sun, Xin Guo, Yue Zhou, Jun Liu, Feila Liu, Yonghong Fan.

  Mitochondria are the primary site for energy production and play a crucial role in supporting normal physiological functions of the human body. In cardiomyocytes (CMs), mitochondria can occupy up to 30 % of the cell volume, providing sufficient energy for CMs contraction and relaxation. However, some pathological conditions such as ischemia, hypoxia, infection, and the side effect of drugs, can cause mitochondrial dysfunction in CMs, leading to various myocardial injury-related diseases including myocardial infarction (MI), myocardial hypertrophy, and heart failure. Self-control of mitochondria quality and conversion of metabolism pathway in energy production can serve as the self-rescue measure to avoid autologous mitochondrial damage. Particularly, mitochondrial transfer from the neighboring or extraneous cells enables to mitigate mitochondrial dysfunction and restore their biological functions in CMs. Here, we described the homeostatic control strategies and related mechanisms of mitochondria in injured CMs, including autologous mitochondrial quality control, mitochondrial energy conversion, and especially the exogenetic mitochondrial donation. Additionally, this review emphasizes on the therapeutic effects and potential application of utilizing mitochondrial transfer in reducing myocardial injury. We hope that this review can provide theoretical clues for the developing of advanced therapeutics to treat cardiac diseases.

Keywords:  Cardiac diseases; Cardiomyocyte; Mitochondrial quality control; Mitochondrial therapy; Mitochondrial transfer

DOI:  https://doi.org/10.1016/j.lfs.2024.123119
Trends Pharmacol Sci. 2024 Oct 14. pii: S0165-6147(24)00209-8. [Epub ahead of print]

MICUs protect the heart by regulating mitochondrial calcium.

Ulas Ozkurede, Shanmugasundaram Pakkiriswami, Julia C Liu.

  Regulation of mitochondrial calcium uptake by the mitochondrial calcium uniporter (mtCU) complex is crucial for heart function. In a recent study, Hasan et al. demonstrated that mitochondrial calcium uptake (MICU)1 and MICU2, regulatory subunits of the complex, help maintain calcium homeostasis in cardiac mitochondria, providing potential targets for therapies aimed at improving mitochondrial function in heart disease.

Keywords:  EMRE; MCU; MICU1; MICU2; calcium; heart; mitochondria

DOI:  https://doi.org/10.1016/j.tips.2024.09.010
Ther Adv Cardiovasc Dis. 2024 Jan-Dec;18:18 17539447241289067

Empagliflozin and other SGLT2 inhibitors in patients with heart failure and preserved ejection fraction: a systematic review and meta-analysis.

Abdulrahman Khaldoon Hamid, AbdulJaber A'Ed Tayem, Sandra Thair Al-Aish, Ahmed Sermed Al Sakini, Dalia Dhia Hadi, Rami Thair Al-Aish.

  BACKGROUND: Heart failure (HF) is a highly prevalent disease, among the primary factors contributing to morbidity and death. One of its types is heart failure with preserved ejection fraction (HFpEF) comprising 40%-50% of newly diagnosed HF cases. Despite the high prevalence of HFpEF, there is still a lack of knowledge regarding the best drugs and treatment approaches to be used. However, the sodium-glucose co-transporter 2 (SGLT2) inhibitors could be a promising treatment.OBJECTIVES: To examine SGLT2 inhibitors' effect on hospitalization, cardiovascular death, and estimated glomerular filtration rate (eGFR) in HFpEF patients.
SEARCH METHODS: We conducted searches for randomized controlled trials (RCTs) in PubMed, Embase, Scopus, and Web of Science up to July 2024.
SELECTION CRITERIA: We chose RCTs that examined the effects of SGLT2 inhibitors and placebo in individuals with higher than 40% ejection fraction (HFpEF).
DATA COLLECTION AND ANALYSIS: The methodology for the systematic review and meta-analysis was in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis.
MAIN RESULTS: We included 8 studies with 16,509 participants. Drugs examined in our paper included empagliflozin, dapagliflozin, sotogliflozin, and ertugliflozin. Various outcomes were analyzed in different papers. However, different SGLT2 inhibitors lead to a decreased risk of cardiovascular hospitalization and kidney injury. Our meta-analysis showed a decreased risk of cardiovascular hospitalization but not death due to cardiovascular causes or other causes. These results were regardless of baseline status of eGFR, systolic blood pressure, atrial fibrillation or flutter, diabetes mellitus, sex, body mass index, and nt-proBNP. The included studies were of moderate to high quality.
CONCLUSION: For individuals with HFpEF, SGLT2 inhibitors have been proven to be a safe and effective medication. However, more studies are needed for longer durations, reporting adverse events, effects on exercise tolerance, and other secondary outcomes.

Keywords:  SGLT2 inhibitors; cardiovascular death; dapagliflozin; empagliflozin; ertugliflozin; estimated glomerular filtration rate (eGFR); heart failure with preserved ejection fraction (HFpEF); hospitalization; quality of life; sotagliflozin

DOI:  https://doi.org/10.1177/17539447241289067
Front Pharmacol. 2024 ;15 1409625

Inhibiting glycosphingolipids alleviates cardiac hypertrophy by reducing reactive oxygen species and restoring autophagic homeostasis.

Chunxin Jiang, Menglei Tan, Lunmeng Lai, Yanping Wang, Zijun Chen, Qing Xie, Yunsen Li.

  Introduction: Cardiac hypertrophy is a compensatory stress response produced by a variety of factors, and pathologic hypertrophy can lead to irreversible, severe cardiac disease. Glycosphingolipids (GSLs) are vital constituents of cells, and changes in their content and composition are important factors causing mitochondrial dysfunction in diabetic cardiomyopathy; however, the relationship between GSLs expression and cardiac hypertrophy and specific mechanisms associated with it are not clear.Methods: Here, using male C57BL/6 mice, we performed aortic arch reduction surgery to establish an animal model of pressure overload cardiac hypertrophy. In addition, phenylephrine was used in vitro to induce H9c2 cells and neonatal rat left ventricular myocytes (NRVMs) to establish a cellular hypertrophy model.
Results: Mass spectrometry revealed that the composition of GSLs was altered in pressure overload-induced hypertrophied mouse hearts and in stimulated hypertrophied cardiomyocyte cell lines. Specifically, in both cases, the proportion of endogenous lactosylceramide (LacCer) was significantly higher than in controls. Inhibition of GSL synthesis with Genz-123346 in NRVMs reduced cell hypertrophy, as well as fibrosis and apoptosis. By Western blotting, we detected decreased intracellular expression of Sirt3 and elevated phosphorylation of JNK after phenylephrine stimulation, but this was reversed in cells pretreated with Genz-123346. Additionally, increased protein expression of FoxO3a and Parkin, along with a decreased LC3-II/I protein ratio in phenylephrine-stimulated cells (compared with unstimulated cells), indicated that the mitochondrial autophagy process was disrupted; again, pretreatment with Genz-123346 reversed that.
Discussion: Our results revealed that changes in GSLs in cardiomyocytes, especially an increase of LacCer, may be a factor causing cellular hypertrophy, which can be alleviated by inhibition of GSLs synthesis. A possible mechanism is that GSLs inhibition increases the expression of Sirt3 protein, scavenges intracellular reactive oxygen species, and restores mitochondrial autophagy homeostasis, thereby lessening cardiomyocyte hypertrophy. In all, these results provide a new perspective for developing drugs for cardiac hypertrophy.

Keywords:  cardiac hypertrophy; glycosphingolipid; lactosylceramide; mitochondrial autophagy; reactive oxygen species

DOI:  https://doi.org/10.3389/fphar.2024.1409625
JCI Insight. 2024 Oct 15. pii: e181172. [Epub ahead of print]

Longitudinal lipidomic profiles of left ventricular mass and hypertrophy in American Indians.

Mingjing Chen, Zhijie Huang, Guanhong Miao, Jin Ren, Jinling Liu, Mary J Roman, Richard B Devereux, Richard R Fabsitz, Ying Zhang, Jason G Umans, Shelley A Cole, Tanika N Kelly, Oliver Fiehn, Jinying Zhao.

  Left ventricular hypertrophy (LVH) and dyslipidemia are strong, independent predictors for cardiovascular disease, but their relationship is less well-studied. A longitudinal lipidomic profiling of left ventricular mass (LVM) and LVH is still lacking. Using LC-MS, we repeatedly measured 1,542 lipids from 1,755 unique American Indians attending two exams (mean~5-year apart). Cross-sectional associations of individual lipid species with LVM index (LVMI) were examined by generalized estimating equation (GEE), followed by replication in an independent bi-racial cohort (65% white, 35% black). Baseline plasma lipids associated with LVH risk beyond traditional risk factors were identified by Cox frailty model in American Indians. Longitudinal associations between changes in lipids and changes in LVMI were examined by GEE, adjusting for baseline lipids, baseline LVMI, and covariates. Multiple lipid species (e.g., glycerophospholipids, sphingomyelins, acylcarnitines) were significantly associated with LVMI or the risk of LVH in American Indians. Some lipids were confirmed in black and white individuals. Moreover, some LVH-related lipids were inversely associated with risk of coronary heart disease (CHD). Longitudinal changes in several lipid species (e.g., glycerophospholipids, sphingomyelins, cholesterol esters) were significantly associated with changes in LVMI. These findings provide insights into the role of lipid metabolism in LV remodeling and the risk of LVH or CHD.

Keywords:  Cardiology; Cardiovascular disease; Lipoproteins; Metabolism

DOI:  https://doi.org/10.1172/jci.insight.181172