bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2022‒08‒28
six papers selected by
Kyle McCommis
Saint Louis University
  1. Empagliflozin improves cardiac mitochondrial function and survival through energy regulation in a murine model of heart failure.
  2. Glutamine uptake and catabolism is required for myofibroblast formation and persistence.
  3. PERM1 regulates genes involved in fatty acid metabolism in the heart by interacting with PPARα and PGC-1α.
  4. META-ANALYSIS EVALUATING THE EFFICACY OF SODIUM-GLUCOSE CO-TRANSPORTER-2 INHIBITORS IN SUBJECTS WITH HEART FAILURE WITH PRESERVED LEFT VENTRICULAR EJECTION FRACTION.
  5. ASSOCIATION OF NDUFC2 POLYMORPHIC VARIANTS WITH LEFT VENTRICULAR HYPERTROPHY IN HUMAN HYPERTENSION.
  6. Effect of Empagliflozin on Circulating Proteomics in Heart Failure: Mechanistic Insights from the EMPEROR Program.
  1. Eur J Pharmacol. 2022 Aug 17. pii: S0014-2999(22)00455-1. [Epub ahead of print]931 175194
    Empagliflozin improves cardiac mitochondrial function and survival through energy regulation in a murine model of heart failure.
    Aya Shiraki, Jun-Ichi Oyama, Takahiko Shimizu, Takayuki Nakajima, Takashi Yokota, Koichi Node.
      BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been demonstrated to have beneficial effects on HF in large clinical trials; however, the mechanisms remain to be elucidated. The aim of this study was to clarify the mechanisms by which empagliflozin, one of SGLT2 inhibitors, affects heart failure.METHOD AND RESULTS: Eight-week-old male mice deficient for heart and skeletal muscle-specific manganese superoxide dismutase (MnSOD-cKO mice), a murine model of dilated cardiomyopathy, were given food mixed with or without 10 mg/kg empagliflozin for 7 weeks and evaluated. Both the survival rate and cardiac fibrosis were significantly improved in the empagliflozin group. The capacity for oxidative phosphorylation in cardiac mitochondria was significantly upregulated as measured with Oxygraph-2k respirometer, and blood lactate levels produced by anaerobic metabolism were significantly lower in the empagliflozin group. Energy expenditure was significantly improved in the empagliflozin group, measured by respiratory gas analysis, with a concomitant reduction in serum leptin concentration and increase in food intake. A moderate amount of glucose was excreted in urine in the empagliflozin group; however, the available energy substrate in the body nonetheless expanded because of the much higher caloric intake.
    CONCLUSIONS: We conclude that empagliflozin improved cardiac mitochondrial function and upregulated energy metabolism even in HF in mice. These findings provide novel mechanisms for the beneficial effects of SGLT2 inhibitors on HF.
    Keywords:  Empagliflozin; Energy metabolism; Heart failure; Mitochondria; SGLT2 inhibitor
    DOI:  https://doi.org/10.1016/j.ejphar.2022.175194
  2. J Mol Cell Cardiol. 2022 Aug 18. pii: S0022-2828(22)00158-4. [Epub ahead of print]172 78-89
    Glutamine uptake and catabolism is required for myofibroblast formation and persistence.
    Andrew A Gibb, Anh T Huynh, Ryan B Gaspar, Tori L Ploesch, Alyssa A Lombardi, Pawel K Lorkiewicz, Michael P Lazaropoulos, Ken Bedi, Zolt Arany, Kenneth B Margulies, Bradford G Hill, John W Elrod.
      BACKGROUND: Fibrosis and extracellular matrix remodeling are mediated by resident cardiac fibroblasts (CFs). In response to injury, fibroblasts activate, differentiating into specialized synthetic and contractile myofibroblasts producing copious extracellular matrix proteins (e.g., collagens). Myofibroblast persistence in chronic diseases, such as HF, leads to progressive cardiac dysfunction and maladaptive remodeling. We recently reported that an increase in αKG (alpha-ketoglutarate) bioavailability, which contributes to enhanced αKG-dependent lysine demethylase activity and chromatin remodeling, is required for myofibroblast formation. Therefore, we aimed to determine the substrates and metabolic pathways contributing to αKG biosynthesis and their requirement for myofibroblast formation.METHODS: Stable isotope metabolomics identified glutaminolysis as a key metabolic pathway required for αKG biosynthesis and myofibroblast formation, therefore we tested the effects of pharmacologic inhibition (CB-839) or genetic deletion of glutaminase (Gls1-/-) on myofibroblast formation in both murine and human cardiac fibroblasts. We employed immunofluorescence staining, functional gel contraction, western blotting, and bioenergetic assays to determine the myofibroblast phenotype.
    RESULTS: Carbon tracing indicated enhanced glutaminolysis mediating increased αKG abundance. Pharmacological and genetic inhibition of glutaminolysis prevented myofibroblast formation indicated by a reduction in αSMA+ cells, collagen gel contraction, collagen abundance, and the bioenergetic response. Inhibition of glutaminolysis also prevented TGFβ-mediated histone demethylation and supplementation with cell-permeable αKG rescued the myofibroblast phenotype. Importantly, inhibition of glutaminolysis was sufficient to prevent myofibroblast formation in CFs isolated from the human failing heart.
    CONCLUSIONS: These results define glutaminolysis as necessary for myofibroblast formation and persistence, providing substantial rationale to evaluate several new therapeutic targets to treat cardiac fibrosis.
    Keywords:  Epigenetics; Fibrosis; Glutamine; Heart failure; Metabolism; Myofibroblast
    DOI:  https://doi.org/10.1016/j.yjmcc.2022.08.002
  3. Sci Rep. 2022 Aug 26. 12(1): 14576
    PERM1 regulates genes involved in fatty acid metabolism in the heart by interacting with PPARα and PGC-1α.
    Chun-Yang Huang, Shin-Ichi Oka, Xiaoyong Xu, Chian-Feng Chen, Chien-Yi Tung, Ya-Yuan Chang, Youssef Mourad, Omair Vehra, Andreas Ivessa, Ghassan Yehia, Peter Romanienko, Chiao-Po Hsu, Junichi Sadoshima.
      PERM1 (PGC-1/ERR-induced regulator in muscle 1) is a muscle-specific protein induced by PGC-1 and ERRs. Previous studies have shown that PERM1 promotes mitochondrial biogenesis and metabolism in cardiomyocytes in vitro. However, the role of endogenous PERM1 in the heart remains to be investigated with loss-of-function studies in vivo. We report the generation and characterization of systemic Perm1 knockout (KO) mice. The baseline cardiac phenotype of the homozygous Perm1 KO mice appeared normal. However, RNA-sequencing and unbiased pathway analyses showed that homozygous downregulation of PERM1 leads to downregulation of genes involved in fatty acid and carbohydrate metabolism in the heart. Transcription factor binding site analyses suggested that PPARα and PGC-1α are involved in changes in the gene expression profile. Chromatin immunoprecipitation assays showed that PERM1 interacts with the proximal regions of PPAR response elements (PPREs) in endogenous promoters of genes involved in fatty acid oxidation. Co-immunoprecipitation and reporter gene assays showed that PERM1 promoted transcription via the PPRE, partly in a PPARα and PGC-1α dependent manner. These results suggest that endogenous PERM1 is involved in the transcription of genes involved in fatty acid oxidation through physical interaction with PPARα and PGC-1α in the heart in vivo.
    DOI:  https://doi.org/10.1038/s41598-022-18885-3
  4. J Hypertens. 2022 Jun 01. 40(Suppl 1): e69-e70
    META-ANALYSIS EVALUATING THE EFFICACY OF SODIUM-GLUCOSE CO-TRANSPORTER-2 INHIBITORS IN SUBJECTS WITH HEART FAILURE WITH PRESERVED LEFT VENTRICULAR EJECTION FRACTION.
    Dimitrios Patoulias, Alexandra Katsimardou, Maria Toumpourleka, Ioanna Zografou, Konstantinos Petidis, Konstantinos Imprialos, George Kassimis, Aristi Boulmpou, Christodoulos Papadopoulos, Michael Doumas.
      OBJECTIVE: Heart failure (HF) is a chronic, disabling and deadly disease. Subjects with HF feature an increased risk for death and recurrent ospitalisation for HF decompensation. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are a novel class of drugs primarily developed for patients with diabetes mellitus. SGLT-2 inhibitors have proven cardiovascular efficacy in HFrEF; however, their efficacy in subjects with HFpEF has not be elucidated. Therefore, we sought to determine the effect of SGLT-2 inhibitors on surrogate cardiovascular outcomes in HFpEF, utilizing both data from ospitalis controlled trials and real-world studies.DESIGN AND METHOD: We searched PubMed and the Cochrane Library for RCTs and observational studies enrolling adult subjects with HFpEF regardless of concomitant type 2 diabetes mellitus (T2DM), assigned to a SGLT-2 inhibitor versus placebo or active comparator. We set as primary efficacy outcome the composite of cardiovascular death or ospitalisation for HF decompensation. We set as secondary efficacy outcome that of all-cause death.
    RESULTS: We pooled data from four RCTs and one observational study for a total of 7,920 subjects with HFpEF. We demonstrated that treatment with SGLT-2 inhibitors versus placebo or active comparator produced a significant decrease in the risk for the primary composite outcome by 30% (RR = 0.70, 95% CI; 0.52 - 0.93, I2 = 48%, p = 0.01). As far as all-cause death is concerned, we showed that SGLT-2 inhibitors compared to control did not produce a significant effect on the corresponding risk (RR = 0.65, 95% CI; 0.34 - 1.26, I2 = 67%, p = 0.21). Overall risk of bias was evaluated as low across the selected studies.
    CONCLUSIONS: Current evidence suggests that SGLT-2 inhibitors are also efficacious in HFpEF. Although total mortality was not significantly reduced, the trend towards beneficial effects along with the demonstrated morbidity benefits point towards the use of SGLT-2 inhibitors in this patient population.
    DOI:  https://doi.org/10.1097/01.hjh.0000835860.07190.e8
  5. J Hypertens. 2022 Jun 01. 40(Suppl 1): e227
    ASSOCIATION OF NDUFC2 POLYMORPHIC VARIANTS WITH LEFT VENTRICULAR HYPERTROPHY IN HUMAN HYPERTENSION.
    Giovanna Gallo, Maurizio Forte, Giuliano Tocci, Maria Cotugno, Simona Marchitti, Rosita Stanzione, Franca Bianchi, Silvia Palmerio, Sebastiano Sciarretta, Massimo Volpe, Speranza Rubattu.
      OBJECTIVE: Previous experimental studies showed that a dysfunction of the NADH dehydrogenase (ubiquinone), the mitochondrial Complex I (CI), is associated with the development of left ventricular hypertrophy (LVH). A deficiency of Ndufc2 (a subunit of CI) impairs CI activity and causes severe mitochondrial dysfunction. The NDUFC2/rs11237379 polymorphic variant is associated with reduced gene expression and impaired mitochondrial function, contributing to increased susceptibility to vascular diseases.We examined the association of NDUFC2/rs11237379 and another NDUFC2 polymorphic variant (rs641836) with the development of LVH in hypertensive patients.DESIGN AND METHOD: Two-hundred-fourty-six hypertensive subjects (147 male, 59.7%) with a mean age of 59 ± 15 years were studied. Seventy-nine individuals (32%) presented LVH.
    RESULTS: The association analysis for both SNPs showed that hypertensive patients carrying the TT genotype at the NDUFC2/rs11237379 had a significant increase of echocardiographically assessed septal thickness (p = 0.001), posterior wall thickness (p = 0.003), relative wall thickness (RWT) (p = 0.01), LV mass/ body surface area (BSA) (p = 0.012) and LV mass/height2.(p = 0.0033) compared to subjects carrying either CC or CT genotypes. To better dissect the genetic effect, a covariate ANOVA was performed for each cardiac variable, considering age, gender, body mass index (BMI), office blood pressure (BP), antihypertensive treatment with a combination of 2 or more drugs and the number of BP-lowering agents as covariates. The adjustment for covariates revealed significant differences for septal thickness (p = 0.07), posterior wall thickness (p = 0.008), RWT (p = 0.021), LV mass/BSA (p = 0.03). With regard to NDUFC2/rs641836, hypertensive subjects carrying the mutant A allele had a significant increase of septal thickness (p = 0.001), posterior wall thickness (p = 0.001), RWT (p = 0.005), LV mass (p = 0.001), LV mass/BSA(p = 0.001), LV mass/height2.7(p = 0.002) compared to wild-type homozygotes. After adjustment for covariates, the results were significant for septal thickness (p = 0.017), posterior wall thickness (p = 0.011), LV mass (p = 0.003), LV mass/BSA (p = 0.002) and LV mass/height2.7(p = 0.010).
    CONCLUSIONS: Our results demonstrate for the first time a significant association of NDUFC2 variants with LVH in hypertensives and highlight a novel role of CI dependent mitochondrial dysfunction on increased susceptibility to cardiac damage in human hypertension. This study paves the way of a new pathophysiological mechanism of LVH which may lead to new clinical strategies.
    DOI:  https://doi.org/10.1097/01.hjh.0000837796.87372.91
  6. Eur Heart J. 2022 Aug 26. pii: ehac495. [Epub ahead of print]
    Effect of Empagliflozin on Circulating Proteomics in Heart Failure: Mechanistic Insights from the EMPEROR Program.
    Faiez Zannad, João Pedro Ferreira, Javed Butler, Gerasimos Filippatos, James L Januzzi, Mikhail Sumin, Matthias Zwick, Maral Saadati, Stuart J Pocock, Naveed Sattar, Stefan D Anker, Milton Packer.
      BACKGROUND: Sodium glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in diverse patient populations, but their mechanism of action requires further study.AIMS: To explore the effect of empagliflozin on circulating levels of intracellular proteins in patients with heart failure, using large-scale proteomics.
    METHODS: Over 1250 circulating proteins were measured at baseline, week 12 and week 52 in 1134 patients from EMPEROR-Reduced and EMPEROR-Preserved, using the Olink® Explore 1536 platform. Statistical and bioinformatical analyses identified differentially expressed proteins (empagliflozin vs placebo), which were then linked to demonstrated biological actions in the heart and kidneys.
    RESULTS: At week 12, 32 of 1283 proteins fulfilled our threshold for being differentially expressed, i.e., their levels were changed by ≥10% with a false discovery rate < 1% (empagliflozin vs placebo). Among these, nine proteins demonstrated the largest treatment effect of empagliflozin: insulin-like growth factor-binding protein 1, transferrin receptor protein 1, carbonic anhydrase 2, erythropoietin, protein-glutamine gamma-glutamyltransferase 2, thymosin beta-10, U-type mitochondrial creatine kinase, insulin-like growth factor-binding protein 4, and adipocyte fatty acid-binding protein 4. The changes of the proteins from baseline to week 52 were generally concordant with the changes from baseline to week 12, except empagliflozin reduced levels of kidney injury molecule-1 by ≥10% at week 52, but not at week 12. The most common biological action of differentially-expressed proteins appeared to be the promotion of autophagic flux in the heart, kidney or endothelium, a feature of 6 proteins. Other effects of differentially-expressed proteins on the heart included the reduction of oxidative stress, inhibition of inflammation and fibrosis, and the enhancement of mitochondrial health and energy, repair and regenerative capacity. The actions of differentially expressed proteins in the kidney involved promotion of autophagy, integrity and regeneration, suppression of renal inflammation and fibrosis, and modulation of renal tubular sodium reabsorption.
    CONCLUSIONS: Changes in circulating protein levels in patients with heart failure are consistent with the findings of experimental studies that have shown that the effects of SGLT2 inhibitors are likely related to actions on the heart and kidney to promote autophagic flux, nutrient deprivation signaling and transmembrane sodium transport.
    Keywords:  SGLT2 inhibitors; differentially expressed proteins; heart failure; proteomics
    DOI:  https://doi.org/10.1093/eurheartj/ehac495
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