bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2024‒07‒07
seven papers selected by
Kyle McCommis, Saint Louis University
  1. Human cardiac metabolism.
  2. ATP-dependent citrate lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling of the Heart.
  3. Mitochondrial Structure and Function in Human Heart Failure.
  4. Up-regulation of BRD4 contributes to gestational diabetes mellitus-induced cardiac hypertrophy in offspring by promoting mitochondria dysfunction in sex-independent manner.
  5. Intravenous iron therapy for heart failure and iron deficiency: An updated meta-analysis of randomized clinical trials.
  6. Efficacy of SGLT2 inhibitors for anthracycline-induced cardiotoxicity: a meta-analysis in cancer patients.
  7. Cardiomyocyte PANX1 Controls Glycolysis and Neutrophil Recruitment in Hypertrophy.
  1. Cell Metab. 2024 Jul 02. pii: S1550-4131(24)00228-6. [Epub ahead of print]36(7): 1456-1481
    Human cardiac metabolism.
    Marc R Bornstein, Rong Tian, Zoltan Arany.
      The heart is the most metabolically active organ in the human body, and cardiac metabolism has been studied for decades. However, the bulk of studies have focused on animal models. The objective of this review is to summarize specifically what is known about cardiac metabolism in humans. Techniques available to study human cardiac metabolism are first discussed, followed by a review of human cardiac metabolism in health and in heart failure. Mechanistic insights, where available, are reviewed, and the evidence for the contribution of metabolic insufficiency to heart failure, as well as past and current attempts at metabolism-based therapies, is also discussed.
    Keywords:  11C-palmitate; FDG; PCr/ATP; cardiac; coronary sinus; heart failure; metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2024.06.003
  2. bioRxiv. 2024 Jun 21. pii: 2024.06.21.600099. [Epub ahead of print]
    ATP-dependent citrate lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling of the Heart.
    Shijie Liu, Seth T Gammon, Lin Tan, Yaqi Gao, Kyoungmin Kim, Ian K Williamson, Janet Pham, Angela Davidian, Radhika Khanna, Benjamin D Gould, Rebecca Salazar, Heidi Vitrac, An Dinh, Evan C Lien, Francisca N de L Vitorino, Joanna M Gongora, Sara A Martinez, Czer S C Lawrence, Evan P Kransdorf, David Leffer, Blake Hanson, Benjamin A Garcia, Matthew G Vander Heiden, Philip L Lorenzi, Heinrich Taegtmeyer, David Piwnica-Worms, James F Martin, Anja Karlstaedt.
      Background: Metabolic remodeling is a hallmark of the failing heart. Oncometabolic stress during cancer increases the activity and abundance of the ATP-dependent citrate lyase (ACL, Acly ), which promotes histone acetylation and cardiac adaptation. ACL is critical for the de novo synthesis of lipids, but how these metabolic alterations contribute to cardiac structural and functional changes remains unclear.Methods: We utilized human heart tissue samples from healthy donor hearts and patients with hypertrophic cardiomyopathy. Further, we used CRISPR/Cas9 gene editing to inactivate Acly in cardiomyocytes of MyH6-Cas9 mice. In vivo, positron emission tomography and ex vivo stable isotope tracer labeling were used to quantify metabolic flux changes in response to the loss of ACL. We conducted a multi-omics analysis using RNA-sequencing and mass spectrometry-based metabolomics and proteomics. Experimental data were integrated into computational modeling using the metabolic network CardioNet to identify significantly dysregulated metabolic processes at a systems level.
    Results: Here, we show that in mice, ACL drives metabolic adaptation in the heart to sustain contractile function, histone acetylation, and lipid modulation. Notably, we show that loss of ACL increases glucose oxidation while maintaining fatty acid oxidation. Ex vivo isotope tracing experiments revealed a reduced efflux of glucose-derived citrate from the mitochondria into the cytosol, confirming that citrate is required for reductive metabolism in the heart. We demonstrate that YAP inactivation facilitates ACL deficiency. Computational flux analysis and integrative multi-omics analysis indicate that loss of ACL induces alternative isocitrate dehydrogenase 1 flux to compensate.
    Conclusions: This study mechanistically delineates how cardiac metabolism compensates for suppressed citrate metabolism in response to ACL loss and uncovers metabolic vulnerabilities in the heart.
    DOI:  https://doi.org/10.1101/2024.06.21.600099
  3. Circ Res. 2024 Jul 05. 135(2): 372-396
    Mitochondrial Structure and Function in Human Heart Failure.
    Antentor Hinton, Steven M Claypool, Kit Neikirk, Nanami Senoo, Celestine N Wanjalla, Annet Kirabo, Clintoria R Williams.
      Despite clinical and scientific advancements, heart failure is the major cause of morbidity and mortality worldwide. Both mitochondrial dysfunction and inflammation contribute to the development and progression of heart failure. Although inflammation is crucial to reparative healing following acute cardiomyocyte injury, chronic inflammation damages the heart, impairs function, and decreases cardiac output. Mitochondria, which comprise one third of cardiomyocyte volume, may prove a potential therapeutic target for heart failure. Known primarily for energy production, mitochondria are also involved in other processes including calcium homeostasis and the regulation of cellular apoptosis. Mitochondrial function is closely related to morphology, which alters through mitochondrial dynamics, thus ensuring that the energy needs of the cell are met. However, in heart failure, changes in substrate use lead to mitochondrial dysfunction and impaired myocyte function. This review discusses mitochondrial and cristae dynamics, including the role of the mitochondria contact site and cristae organizing system complex in mitochondrial ultrastructure changes. Additionally, this review covers the role of mitochondria-endoplasmic reticulum contact sites, mitochondrial communication via nanotunnels, and altered metabolite production during heart failure. We highlight these often-neglected factors and promising clinical mitochondrial targets for heart failure.
    Keywords:  cardiovascular diseases; heart failure; hypertension; mitochondria; myocardium
    DOI:  https://doi.org/10.1161/CIRCRESAHA.124.323800
  4. Biochem Pharmacol. 2024 Jun 27. pii: S0006-2952(24)00370-8. [Epub ahead of print]226 116387
    Up-regulation of BRD4 contributes to gestational diabetes mellitus-induced cardiac hypertrophy in offspring by promoting mitochondria dysfunction in sex-independent manner.
    Cailing Huang, Zimo Liu, Mei Chen, Haichuan Zhang, Ruyao Mo, Renshan Chen, Yinghua Liu, Shixiang Wang, Qin Xue.
      Gestational diabetes mellitus (GDM) is associated with cardiovascular disease in postnatal life. The current study tested the hypothesis that GDM caused the cardiac hypertrophy in fetal (ED18.5), postnatal day 7 (PD7), postnatal day 21 (PD21) and postnatal day 90 (PD90) offspring by upregulation of BRD4 and mitochondrial dysfunction. Pregnant mice were divided into control and GDM groups. Hearts were isolated from ED18.5, PD7, PD21 and PD90. GDM increased the body weight (BW) and heart weight (HW) in ED18.5 and PD7, but not PD21 and PD90 offspring. However, HW/BW ratio was increased in all ages of GDM offspring compared to control group. Electron microscopy showed disorganized myofibrils, mitochondrial swelling, vacuolization, and cristae disorder in GDM offspring. GDM resulted in myocardial hypertrophy in offspring, which persisted from fetus to adult in a sex-independent manner. Echocardiography analysis revealed that GDM caused diastolic dysfunction, but had no effect on systolic function. Meanwhile, myocardial BRD4 was significantly upregulated in GDM offspring and BRD4 inhibition by JQ1 alleviated GDM-induced myocardial hypertrophy in offspring. Co-immunoprecipitation showed that BRD4 interacted with DRP1 and there was an increase of BRD4 and DRP1 interaction in GDM offspring. Furthermore, GDM caused the accumulation of damaged mitochondria in hearts from all ages of offspring, including mitochondrial fusion fission imbalance (upregulation of DRP1, and downregulation of MFN1, MFN2 and OPA1) and myocardial mitochondrial ROS accumulation, which was reversed by JQ1. These results suggested that the upregulation of BRD4 is involved in GDM-induced myocardial hypertrophy in the offspring through promoting mitochondrial damage in a gender-independent manner.
    Keywords:  BRD4; Cardiac hypertrophy; Gestational diabetes mellitus; Mitochondria function; Offspring
    DOI:  https://doi.org/10.1016/j.bcp.2024.116387
  5. ESC Heart Fail. 2024 Jul 04.
    Intravenous iron therapy for heart failure and iron deficiency: An updated meta-analysis of randomized clinical trials.
    Mushood Ahmed, Aimen Shafiq, Hira Javaid, Priyansha Singh, Haania Shahbaz, Muhammad Talha Maniya, Hritvik Jain, Najwa Shakir, Huzaifa Ahmad Cheema, Adeel Ahmad, Wajeeh Ur Rehman, Gabriel Yeap, Abdulqadir J Nashwan, Abdul Mannan Khan Minhas, Raheel Ahmed, Marat Fudim, Gregg C Fonarow.
      Heart failure (HF) patients frequently exhibit iron deficiency, which is associated with a poor prognosis. Although various trials have been conducted, it is uncertain if intravenous (IV) iron replenishment improves clinical outcomes in HF patients with iron deficiency. A comprehensive literature search was conducted using PubMed/MEDLINE, Embase, and the Cochrane Library from inception till 15 September 2023 to retrieve randomized controlled trials (RCTs) that compared IV iron therapy with placebo or standard of care in patients with HF and iron deficiency. Clinical outcomes were assessed by generating forest plots using the random-effects model and pooling odds ratios (ORs) or weighted mean differences (WMDs). Fourteen RCTs with 6651 patients were included. IV iron therapy showed a significantly reduced incidence of the composite of first heart failure hospitalization (HHF) or cardiovascular (CV) mortality as compared with the control group (OR = 0.73, 95% CI: 0.58 to 0.92). The IV iron therapy resulted in a trend towards lower CV mortality (OR = 0.88, 95% CI: 0.76 to 1.01), 1-year all-cause mortality (OR = 0.85, 95% CI: 0.71 to 1.02), and first HHF (OR = 0.73, 95% CI: 0.51 to 1.05), and an improved left ventricular ejection fraction (LVEF) (MD = 4.54, 95% CI: -0.13 to 9.21). Meta-regression showed a significant inverse moderating effect of baseline LVEF on the first HHF or CV death. In patients with HF and iron deficiency, IV iron therapy reduced the incidence of composite of first HHF or CV mortality. There was a trend of lower overall CV and 1-year all-cause mortality, first HHF, and improved LVEF with IV iron therapy.
    Keywords:  Ferric carboxymaltose; Heart failure; Intravenous iron; Iron deficiency
    DOI:  https://doi.org/10.1002/ehf2.14905
  6. Future Cardiol. 2024 Jul 04. 1-13
    Efficacy of SGLT2 inhibitors for anthracycline-induced cardiotoxicity: a meta-analysis in cancer patients.
    Sana Mohsin, Misha Hasan, Zubaid Moazzam Sheikh, Fatima Mustafa, Vesna Tegeltija, Sarwan Kumar, Jai Kumar.
      Aim: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) lower anthracycline-induced cardiotoxicity. Methods: PubMed and Google Scholar were searched until September 2023 for studies regarding SGLT2i for treating anthracycline-induced cardiotoxicity. Overall mortality and cardiovascular events were considered. Using a random-effects model, data pooled RR and HR at a 95% confidence interval (CI). Results: 3 cohort studies were identified, analyzing 2817 patients. Results display a significant reduction in overall mortality [RR = 0.52 (0.33-0.82); p = 0.005; I2= 32%], HF hospitalization [RR = 0.20 (0.04-1.02); p = 0.05; I2= 0%] and no significant reduction in HF incidence [RR = 0.50 (0.20-1.16); p = 0.11, I2= 0%]. Conclusion: SGLT2i mitigates mortality and hospitalization due to heart failure, improving cancer patient's chances of survival by undergoing anthracycline treatment.
    Keywords:  SGLT2i; anthracycline; cardiovascular events; overall mortality
    DOI:  https://doi.org/10.1080/14796678.2024.2363673
  7. Circ Res. 2024 Jul 03.
    Cardiomyocyte PANX1 Controls Glycolysis and Neutrophil Recruitment in Hypertrophy.
    Caitlin M Pavelec, Alexander P Young, Hannah L Luviano, Emily E Orrell, Anna Szagdaj, Nabin Poudel, Abigail G Wolpe, Samantha H Thomas, Scott Yeudall, Clint M Upchurch, Mark D Okusa, Brant E Isakson, Matthew J Wolf, Norbert Leitinger.
      BACKGROUND: PANX1 (pannexin 1), a ubiquitously expressed ATP release membrane channel, has been shown to play a role in inflammation, blood pressure regulation, and myocardial infarction. However, the possible role of PANX1 in cardiomyocytes in the progression of heart failure has not yet been investigated.METHOD: We generated a novel mouse line with constitutive deletion of PANX1 in cardiomyocytes (Panx1MyHC6).
    RESULTS: PANX1 deletion in cardiomyocytes had no effect on unstressed heart function but increased the glycolytic metabolism and resulting glycolytic ATP production, with a concurrent decrease in oxidative phosphorylation, both in vivo and in vitro. In vitro, treatment of H9c2 cardiomyocytes with isoproterenol led to PANX1-dependent release of ATP and Yo-Pro-1 uptake, as assessed by pharmacological blockade with spironolactone and siRNA-mediated knockdown of PANX1. To investigate nonischemic heart failure and the preceding cardiac hypertrophy, we administered isoproterenol, and we demonstrated that Panx1MyHC6 mice were protected from systolic and diastolic left ventricle volume increases as a result of cardiomyocyte hypertrophy. Moreover, we found that Panx1MyHC6 mice showed decreased isoproterenol-induced recruitment of immune cells (CD45+), particularly neutrophils (CD11b+, Ly6g+), to the myocardium.
    CONCLUSIONS: Together, these data demonstrate that PANX1 deficiency in cardiomyocytes increases glycolytic metabolism and protects against cardiac hypertrophy in nonischemic heart failure at least in part by reducing immune cell recruitment. Our study implies PANX1 channel inhibition as a therapeutic approach to ameliorate cardiac dysfunction in patients with heart failure.
    Keywords:  heart failure; macrophages; neutrophils; prevalence; stroke volume
    DOI:  https://doi.org/10.1161/CIRCRESAHA.124.324650
This page is being maintained by Thomas Krichel. It was last updated on 2024‒07‒08 at 13:53.