bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2024–01–28
six papers selected by
Kyle McCommis, Saint Louis University
  1. Metabolic Flexibility of the Heart: The Role of Fatty Acid Metabolism in Health, Heart Failure, and Cardiometabolic Diseases.
  2. Metabolic remodeling in cardiac hypertrophy and heart failure with reduced ejection fraction occurs independent of transcription factor EB in mice.
  3. A ketogenic diet lowers myocardial fatty acid oxidation but does not affect oxygen consumption: a study in overweight humans.
  4. α-Ketoglutarate improves cardiac insufficiency through NAD+-SIRT1 signaling-mediated mitophagy and ferroptosis in pressure overload-induced mice.
  5. CTRP3 alleviates mitochondrial dysfunction and oxidative stress injury in pathological cardiac hypertrophy by activating UPRmt via the SIRT1/ATF5 axis.
  6. CHRONIC KIDNEY DISEASE AND LEFT VENTRICULAR DIASTOLIC DYSFUNCTION (CKD-LVDD) ALTER CARDIAC EXPRESSION OF MITOCHONDRIA-RELATED GENES IN SWINE.
  1. Int J Mol Sci. 2024 Jan 19. pii: 1211. [Epub ahead of print]25(2):
    Metabolic Flexibility of the Heart: The Role of Fatty Acid Metabolism in Health, Heart Failure, and Cardiometabolic Diseases.
    Virginia Actis Dato, Stephan Lange, Yoshitake Cho.
      This comprehensive review explores the critical role of fatty acid (FA) metabolism in cardiac diseases, particularly heart failure (HF), and the implications for therapeutic strategies. The heart's reliance on ATP, primarily sourced from mitochondrial oxidative metabolism, underscores the significance of metabolic flexibility, with fatty acid oxidation (FAO) being a dominant source. In HF, metabolic shifts occur with an altered FA uptake and FAO, impacting mitochondrial function and contributing to disease progression. Conditions like obesity and diabetes also lead to metabolic disturbances, resulting in cardiomyopathy marked by an over-reliance on FAO, mitochondrial dysfunction, and lipotoxicity. Therapeutic approaches targeting FA metabolism in cardiac diseases have evolved, focusing on inhibiting or stimulating FAO to optimize cardiac energetics. Strategies include using CPT1A inhibitors, using PPARα agonists, and enhancing mitochondrial biogenesis and function. However, the effectiveness varies, reflecting the complexity of metabolic remodeling in HF. Hence, treatment strategies should be individualized, considering that cardiac energy metabolism is intricate and tightly regulated. The therapeutic aim is to optimize overall metabolic function, recognizing the pivotal role of FAs and the need for further research to develop effective therapies, with promising new approaches targeting mitochondrial oxidative metabolism and FAO that improve cardiac function.
    Keywords:  cardiometabolic diseases; fatty acid metabolism; heart failure; metabolic flexibility; mitochondrial oxidative metabolism
    DOI:  https://doi.org/10.3390/ijms25021211
  2. Front Cardiovasc Med. 2023 ;10 1323760
    Metabolic remodeling in cardiac hypertrophy and heart failure with reduced ejection fraction occurs independent of transcription factor EB in mice.
    Niklas Dörmann, Elke Hammer, Karlotta Struckmann, Julia Rüdebusch, Kirsten Bartels, Kristin Wenzel, Julia Schulz, Stefan Gross, Stefan Schwanz, Elisa Martin, Britta Fielitz, Cristina Pablo Tortola, Alexander Hahn, Alexander Benkner, Uwe Völker, Stephan B Felix, Jens Fielitz.
       Background: A metabolic shift from fatty acid (FAO) to glucose oxidation (GO) occurs during cardiac hypertrophy (LVH) and heart failure with reduced ejection fraction (HFrEF), which is mediated by PGC-1α and PPARα. While the transcription factor EB (TFEB) regulates the expression of both PPARGC1A/PGC-1α and PPARA/PPARα, its contribution to metabolic remodeling is uncertain.
    Methods: Luciferase assays were performed to verify that TFEB regulates PPARGC1A expression. Cardiomyocyte-specific Tfeb knockout (cKO) and wildtype (WT) male mice were subjected to 27G transverse aortic constriction or sham surgery for 21 and 56 days, respectively, to induce LVH and HFrEF. Echocardiographic, morphological, and histological analyses were performed. Changes in markers of cardiac stress and remodeling, metabolic shift and oxidative phosphorylation were investigated by Western blot analyses, mass spectrometry, qRT-PCR, and citrate synthase and complex II activity measurements.
    Results: Luciferase assays revealed that TFEB increases PPARGC1A/PGC-1α expression, which was inhibited by class IIa histone deacetylases and derepressed by protein kinase D. At baseline, cKO mice exhibited a reduced cardiac function, elevated stress markers and a decrease in FAO and GO gene expression compared to WT mice. LVH resulted in increased cardiac remodeling and a decreased expression of FAO and GO genes, but a comparable decline in cardiac function in cKO compared to WT mice. In HFrEF, cKO mice showed an improved cardiac function, lower heart weights, smaller myocytes and a reduction in cardiac remodeling compared to WT mice. Proteomic analysis revealed a comparable decrease in FAO- and increase in GO-related proteins in both genotypes. A significant reduction in mitochondrial quality control genes and a decreased citrate synthase and complex II activities was observed in hearts of WT but not cKO HFrEF mice.
    Conclusions: TFEB affects the baseline expression of metabolic and mitochondrial quality control genes in the heart, but has only minor effects on the metabolic shift in LVH and HFrEF in mice. Deletion of TFEB plays a protective role in HFrEF but does not affect the course of LVH. Further studies are needed to elucidate if TFEB affects the metabolic flux in stressed cardiomyocytes.
    Keywords:  TFEB; fatty acid oxidation; heart failure with reduced ejection fraction; left ventricular hypertrophy; metabolic remodeling; transverse aortic constriction
    DOI:  https://doi.org/10.3389/fcvm.2023.1323760
  3. Obesity (Silver Spring). 2024 Jan 23.
    A ketogenic diet lowers myocardial fatty acid oxidation but does not affect oxygen consumption: a study in overweight humans.
    Thien Vinh Luong, Mette Glavind Bülow Pedersen, Caroline Bruun Abild, Stephen C Cunnane, Etienne Croteau, Katrine Meyer Lauritsen, Mette Louise Gram Kjaerulff, Lars Poulsen Tolbod, Niels Møller, Esben Søndergaard, Lars Christian Gormsen.
       OBJECTIVE: A ketogenic diet (KD) characterized by very low carbohydrate intake and high fat consumption may simultaneously induce weight loss and be cardioprotective. The "thrifty substrate hypothesis" posits that ketone bodies are more energy efficient compared with other cardiac oxidative substrates such as fatty acids. This work aimed to study whether a KD with presumed increased myocardial ketone body utilization reduces cardiac fatty acid uptake and oxidation, resulting in decreased myocardial oxygen consumption (MVO2 ).
    METHODS: This randomized controlled crossover trial examined 11 individuals with overweight or obesity on two occasions: (1) after a KD and (2) after a standard diet. Myocardial free fatty acid (FFA) oxidation, uptake, and esterification rate were measured using dynamic [11 C]palmitate positron emission tomography (PET)/computed tomography, whereas MVO2 and myocardial external efficiency (MEE) were measured using dynamic [11 C]acetate PET.
    RESULTS: The KD increased plasma β-hydroxybutyrate, reduced myocardial FFA oxidation (p < 0.01) and uptake (p = 0.03), and increased FFA esterification (p = 0.03). No changes were observed in MVO2 (p = 0.2) or MEE (p = 0.87).
    CONCLUSIONS: A KD significantly reduced myocardial FFA uptake and oxidation, presumably by increasing ketone body oxidation. However, this change in cardiac substrate utilization did not improve MVO2 , speaking against the thrifty substrate hypothesis.
    DOI:  https://doi.org/10.1002/oby.23967
  4. Mol Med. 2024 Jan 22. 30(1): 15
    α-Ketoglutarate improves cardiac insufficiency through NAD+-SIRT1 signaling-mediated mitophagy and ferroptosis in pressure overload-induced mice.
    Hao Yu, Daojing Gan, Zhen Luo, Qilin Yang, Dongqi An, Hao Zhang, Yingchun Hu, Zhuang Ma, Qingchun Zeng, Dingli Xu, Hao Ren.
       BACKGROUND: In heart failure (HF), mitochondrial dysfunction and metabolic remodeling lead to a reduction in energy productivity and aggravate cardiomyocyte injury. Supplementation with α-ketoglutarate (AKG) alleviated myocardial hypertrophy and fibrosis in mice with HF and improved cardiac insufficiency. However, the myocardial protective mechanism of AKG remains unclear. We verified the hypothesis that AKG improves mitochondrial function by upregulating NAD+ levels and activating silent information regulator 2 homolog 1 (SIRT1) in cardiomyocytes.
    METHODS: In vivo, 2% AKG was added to the drinking water of mice undergoing transverse aortic constriction (TAC) surgery. Echocardiography and biopsy were performed to evaluate cardiac function and pathological changes. Myocardial metabolomics was analyzed by liquid chromatography‒mass spectrometry (LC‒MS/MS) at 8 weeks after surgery. In vitro, the expression of SIRT1 or PINK1 proteins was inhibited by selective inhibitors and siRNA in cardiomyocytes stimulated with angiotensin II (AngII) and AKG. NAD+ levels were detected using an NAD test kit. Mitophagy and ferroptosis levels were evaluated by Western blotting, qPCR, JC-1 staining and lipid peroxidation analysis.
    RESULTS: AKG supplementation after TAC surgery could alleviate myocardial hypertrophy and fibrosis and improve cardiac function in mice. Metabolites of the malate-aspartate shuttle (MAS) were increased, but the TCA cycle and fatty acid metabolism pathway could be inhibited in the myocardium of TAC mice after AKG supplementation. Decreased NAD+ levels and SIRT1 protein expression were observed in heart of mice and AngII-treated cardiomyocytes. After AKG treatment, these changes were reversed, and increased mitophagy, inhibited ferroptosis, and alleviated damage in cardiomyocytes were observed. When the expression of SIRT1 was inhibited by a selective inhibitor and siRNA, the protective effect of AKG was suppressed.
    CONCLUSION: Supplementation with AKG can improve myocardial hypertrophy, fibrosis and chronic cardiac insufficiency caused by pressure overload. By increasing the level of NAD+, the SIRT-PINK1 and SIRT1-GPX4 signaling pathways are activated to promote mitophagy and inhibit ferroptosis in cardiomyocytes, which ultimately alleviates cardiomyocyte damage.
    Keywords:  Angiotensin II; Cardiac insufficiency; Ferroptosis; Mitophagy; NAD; SIRT1; Transverse aortic constriction; α-Ketoglutarate
    DOI:  https://doi.org/10.1186/s10020-024-00783-1
  5. Cell Death Discov. 2024 Jan 26. 10(1): 53
    CTRP3 alleviates mitochondrial dysfunction and oxidative stress injury in pathological cardiac hypertrophy by activating UPRmt via the SIRT1/ATF5 axis.
    Lei Shi, Yanzhen Tan, Wenying Zheng, Guojie Cao, Haitao Zhou, Panpan Li, Jun Cui, Yujie Song, Lele Feng, Hong Li, Wenju Shan, Bing Zhang, Wei Yi.
      Pathological cardiac hypertrophy is an independent risk factor for heart failure. Disruption of mitochondrial protein homeostasis plays a key role in pathological cardiac hypertrophy; however, the mechanism of maintaining mitochondrial homeostasis in pathological cardiac hypertrophy remains unclear. In this study, we investigated the regulatory mechanisms of mitochondrial protein homeostasis in pathological cardiac hypertrophy. Wildtype (WT) mice, knockout mice, and mice transfected with lentivirus overexpressing mouse C1q-tumor necrosis factor-related protein-3 (CTRP3) underwent transverse aortic constriction or sham surgery. After 4 weeks, cardiac function, mitochondrial function, and oxidative stress injury were examined. For mechanistic studies, neonatal rat cardiomyocytes were treated with small interfering RNA or overexpression plasmids for the relevant genes. CTRP3 overexpression attenuated transverse aortic constriction (TAC) induced pathological cardiac hypertrophy, mitochondrial dysfunction, and oxidative stress injury compared to that in WT mice. TAC or Ang II resulted in compensatory activation of UPRmt, but this was not sufficient to counteract pathologic cardiac hypertrophy. CTRP3 overexpression further induced activation of UPRmt during pathologic cardiac hypertrophy and thereby alleviated pathologic cardiac hypertrophy, whereas CTRP3 knockout or knockdown inhibited UPRmt. ATF5 was a key regulatory molecule of UPRmt, as ATF5 knockout prevented the cardioprotective effect of CTRP3 in TAC mice. In vitro, SIRT1 was identified as a possible downstream CTRP3 effector molecule, and SIRT1 knockout blocked the cardioprotective effects of CTRP3. Our results also suggest that ATF5 may be regulated by SIRT1. Our study demonstrates that CTRP3 activates UPRmt via the SIRT1/ATF5 axis under pathological myocardial hypertrophy, thus attenuating mitochondrial dysfunction and oxidative stress injury.
    DOI:  https://doi.org/10.1038/s41420-024-01813-x
  6. Transl Res. 2024 Jan 21. pii: S1931-5244(23)00205-0. [Epub ahead of print]
    CHRONIC KIDNEY DISEASE AND LEFT VENTRICULAR DIASTOLIC DYSFUNCTION (CKD-LVDD) ALTER CARDIAC EXPRESSION OF MITOCHONDRIA-RELATED GENES IN SWINE.
    Alejandro R Chade, Rhys Sitz, Taylor J Kelty, Elizabeth McCarthy, Darla L Tharp, R Scott Rector, Alfonso Eirin.
      Cardiovascular disease and heart failure doubles in patients with chronic kidney disease (CKD), but the underlying mechanisms remain obscure. Mitochondria are central to maintaining cellular respiration and modulating cardiomyocyte function. We took advantage of our novel swine model of CKD and left ventricular diastolic dysfunction (CKD-LVDD) to investigate the expression of mitochondria-related genes and potential mechanisms regulating their expression. CKD-LVDD and normal control pigs (n=6/group, 3 males/3 females) were studied for 14 weeks. Renal and cardiac hemodynamics were quantified by multidetector-CT, echocardiography, and pressure-volume loop studies, respectively. Mitochondrial morphology (electron microscopy) and function (Oroboros) were assessed ex vivo. In randomly selected pigs (n=3/group), cardiac mRNA-, MeDIP-, and miRNA-sequencing (seq) were performed to identify mitochondria-related genes and study their pre- and post -transcriptional regulation. CKD-LVDD exhibited cardiac mitochondrial structural abnormalities and elevated mitochondrial H2O2 emission but preserved mitochondrial function. Cardiac mRNA-seq identified 862 mitochondria-related genes, of which 69 were upregulated and 33 downregulated (fold-change ≥2, false discovery rate≤0.05). Functional analysis showed that upregulated genes were primarily implicated in processes associated with oxidative stress, whereas those downregulated mainly participated in respiration and ATP synthesis. Integrated mRNA/miRNA/MeDIP-seq analysis showed that upregulated genes were modulated predominantly by miRNAs, whereas those downregulated were by miRNA and epigenetic mechanisms. CKD-LVDD alters cardiac expression of mitochondria-related genes, associated with mitochondrial structural damage but preserved respiratory function, possibly reflecting intrinsic compensatory mechanisms. Our findings may guide the development of early interventions at stages of cardiac dysfunction in which mitochondrial injury could be prevented, and the development of LVDD ameliorated.
    Keywords:  chronic renal disease; heart failure; mitochondria; pathophysiology; transcriptomic
    DOI:  https://doi.org/10.1016/j.trsl.2023.12.004
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