bims-hafaim 2024-06-09 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2024‒06‒09
ten papers selected by
Kyle McCommis, Saint Louis University

Semaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization through the Creb5/NR4a1 axis.
MARK4 aggravates cardiac dysfunction in mice with STZ-induced diabetic cardiomyopathy by regulating ACSL4-mediated myocardial lipid metabolism.
Effects of different sodium-glucose cotransporter 2 inhibitors in heart failure with reduced or preserved ejection fraction: a network meta-analysis.
Empagliflozin Improves Diastolic Function in HFpEF by Restabilizing the Mitochondrial Respiratory Chain.
Proving SGLT2 Inhibitor-Mediated Improvement in Cardiomyocyte Energetics: Beyond a Reasonable Doubt?
Sodium-glucose cotransporter-2 inhibitors improve cardiovascular outcomes post-acute coronary syndrome complicated by acute heart failure.
Inherent Metabolic Adaptations in Adult Spiny Mouse ( Acomys ) Cardiomyocytes Facilitate Enhanced Cardiac Recovery Following Myocardial Infarction.
Mitochondrial glycerol 3-phosphate dehydrogenase deficiency exacerbates lipotoxic cardiomyopathy.
Epidemiology of Heart Failure and the Discovery of the Cardioprotective Effects of SGLT2 Inhibitors.
Inhibition of autophagy prevents cardiac dysfunction at early stages of cardiomyopathy in Bag3-deficient hearts.

Nat Commun. 2024 Jun 04. 15(1): 4757

Semaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization through the Creb5/NR4a1 axis.

Yu-Lan Ma, Chun-Yan Kong, Zhen Guo, Ming-Yu Wang, Pan Wang, Fang-Yuan Liu, Dan Yang, Zheng Yang, Qi-Zhu Tang.

Semaglutide, a glucagon-like peptide-1 receptor agonist, is clinically used as a glucose-lowering and weight loss medication due to its effects on energy metabolism. In heart failure, energy production is impaired due to altered mitochondrial function and increased glycolysis. However, the impact of semaglutide on cardiomyocyte metabolism under pressure overload remains unclear. Here we demonstrate that semaglutide improves cardiac function and reduces hypertrophy and fibrosis in a mouse model of pressure overload-induced heart failure. Semaglutide preserves mitochondrial structure and function under chronic stress. Metabolomics reveals that semaglutide reduces mitochondrial damage, lipid accumulation, and ATP deficiency by promoting pyruvate entry into the tricarboxylic acid cycle and increasing fatty acid oxidation. Transcriptional analysis shows that semaglutide regulates myocardial energy metabolism through the Creb5/NR4a1 axis in the PI3K/AKT pathway, reducing NR4a1 expression and its translocation to mitochondria. NR4a1 knockdown ameliorates mitochondrial dysfunction and abnormal glucose and lipid metabolism in the heart. These findings suggest that semaglutide may be a therapeutic agent for improving cardiac remodeling by modulating energy metabolism.

DOI: https://doi.org/10.1038/s41467-024-48970-2
Sci Rep. 2024 06 05. 14(1): 12978

MARK4 aggravates cardiac dysfunction in mice with STZ-induced diabetic cardiomyopathy by regulating ACSL4-mediated myocardial lipid metabolism.

Yi Wu, Jingqi Zhang, Weiyi Wang, Dongdong Wu, Yang Kang, Lu Fu.

Diabetic cardiomyopathy is a specific type of cardiomyopathy. In DCM, glucose uptake and utilization are impaired due to insulin deficiency or resistance, and the heart relies more heavily on fatty acid oxidation for energy, resulting in myocardial lipid toxicity-related injury. MARK4 is a member of the AMPK-related kinase family, and improves ischaemic heart failure through microtubule detyrosination. However, the role of MARK4 in cardiac regulation of metabolism is unclear. In this study, after successful establishment of a diabetic cardiomyopathy model induced by streptozotocin and a high-fat diet, MARK4 expression was found to be significantly increased in STZ-induced DCM mice. After AAV9-shMARK4 was administered through the tail vein, decreased expression of MARK4 alleviated diabetic myocardial damage, reduced oxidative stress and apoptosis, and facilitated cardiomyocyte mitochondrial fusion, and promoted myocardial lipid oxidation metabolism. In addition, through the RNA-seq analysis of differentially expressed genes, we found that MARK4 deficiency promoted lipid decomposition and oxidative metabolism by downregulating the expression of ACSL4, thus reducing myocardial lipid accumulation in the STZ-induced DCM model.

DOI: https://doi.org/10.1038/s41598-024-64006-7
Front Cardiovasc Med. 2024 ;11 1379765

Effects of different sodium-glucose cotransporter 2 inhibitors in heart failure with reduced or preserved ejection fraction: a network meta-analysis.

Xiaohua Lan, Huijing Zhu, Yanjie Cao, Yue Hu, Xingman Fan, Kaijie Zhang, Mengdi Wu.

  Background: This systematic review and meta-analysis aimed to explore the effects of different sodium-glucose cotransporter-2 inhibitors (SGLT2i) on prognosis and cardiac structural remodeling in patients with heart failure (HF).Methods: Relevant studies published up to 20 March 2024 were retrieved from PubMed, EMBASE, Web of Science, and Cochrane Library CNKI, China Biomedical Literature Service, VIP, and WanFang databases. We included randomized controlled trials of different SGLT2i and pooled the prognosis data of patients with HF. We compared the efficacy of different SGLT2i in patients with HF and conducted a sub-analysis based on left ventricular ejection fraction (LVEF).
Results: We identified 77 randomized controlled trials involving 43,561 patients. The results showed that SGLT2i significantly enhanced outcomes in HF, including a composite of hospitalizations for HF and cardiovascular death, individual hospitalizations for HF, Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, left atrial volume index (LAVi), and LVEF among all HF patients (P < 0.05) compared to a placebo. Sotagliflozin was superior to empagliflozin [RR = 0.88, CI (0.79-0.97)] and dapagliflozin [RR = 0.86, CI (0.77-0.96)] in reducing hospitalizations for HF and CV death. Dapagliflozin significantly reduced hospitalizations [RR = 0.51, CI (0.33-0.80)], CV death [RR = 0.73, CI (0.54-0.97)], and all-cause mortality [RR = 0.69, CI (0.48-0.99)] in patients with HF with reduced ejection fraction (HFrEF). SGLT2i also plays a significant role in improving cardiac remodeling and quality of life (LVMi, LVEDV, KCQQ) (P < 0.05). Among patients with HF with preserved ejection fraction (HFpEF), SGLT2i significantly improved cardiac function in HFpEF patients (P < 0.05). In addition, canagliflozin [RR = 0.09, CI (0.01-0.86)] demonstrated greater safety compared to sotagliflozin in a composite of urinary and reproductive infections of HFpEF patients.
Conclusion: Our systematic review showed that SGLT2i generally enhances the prognosis of patients with HF. Sotagliflozin demonstrated superiority over empagliflozin and dapagliflozin in a composite of hospitalization for HF and CV death in the overall HF patients. Canagliflozin exhibited greater safety compared to sotagliflozin in a composite of urinary and reproductive infections of HFpEF. Overall, the efficacy of SGLT2i was greater in HFrEF patients than in HFpEF patients.

Keywords:  cardiac structural remodeling; heart failure; heart failure with preserved ejection fraction; heart failure with reduced ejection fraction; sodium–glucose cotransporter 2 inhibitors

DOI:  https://doi.org/10.3389/fcvm.2024.1379765
Circ Heart Fail. 2024 Jun 07. e011107

Empagliflozin Improves Diastolic Function in HFpEF by Restabilizing the Mitochondrial Respiratory Chain.

Antje Schauer, Volker Adams, Susanne Kämmerer, Erik Langner, Antje Augstein, Peggy Barthel, Anita Männel, Gunar Fabig, Paula Ketilly Nascimento Alves, Mario Günscht, Ali El-Armouche, Thomas Müller-Reichert, Axel Linke, Ephraim B Winzer.

  BACKGROUND: Clinical studies demonstrated beneficial effects of sodium-glucose-transporter 2 inhibitors on the risk of cardiovascular death in patients with heart failure with preserved ejection fraction (HFpEF). However, underlying processes for cardioprotection remain unclear. The present study focused on the impact of empagliflozin (Empa) on myocardial function in a rat model with established HFpEF and analyzed underlying molecular mechanisms.METHODS: Obese ZSF1 (Zucker fatty and spontaneously hypertensive) rats were randomized to standard care (HFpEF, n=18) or Empa (HFpEF/Empa, n=18). ZSF1 lean rats (con, n=18) served as healthy controls. Echocardiography was performed at baseline and after 4 and 8 weeks, respectively. After 8 weeks of treatment, hemodynamics were measured invasively, mitochondrial function was assessed and myocardial tissue was collected for either molecular and histological analyses or transmission electron microscopy.
RESULTS: In HFpEF Empa significantly improved diastolic function (E/é: con: 17.5±2.8; HFpEF: 24.4±4.6; P<0.001 versus con; HFpEF/Empa: 19.4±3.2; P<0.001 versus HFpEF). This was accompanied by improved hemodynamics and calcium handling and by reduced inflammation, hypertrophy, and fibrosis. Proteomic analysis demonstrated major changes in proteins involved in mitochondrial oxidative phosphorylation. Cardiac mitochondrial respiration was significantly impaired in HFpEF but restored by Empa (Vmax complex IV: con: 0.18±0.07 mmol O2/s/mg; HFpEF: 0.13±0.05 mmol O2/s/mg; P<0.041 versus con; HFpEF/Empa: 0.21±0.05 mmol O2/s/mg; P=0.012 versus HFpEF) without alterations of mitochondrial content. The expression of cardiolipin, an essential stability/functionality-mediating phospholipid of the respiratory chain, was significantly decreased in HFpEF but reverted by Empa (con: 15.9±1.7 nmol/mg protein; HFpEF: 12.5±1.8 nmol/mg protein; P=0.002 versus con; HFpEF/Empa: 14.5±1.8 nmol/mg protein; P=0.03 versus HFpEF). Transmission electron microscopy revealed a reduced size of mitochondria in HFpEF, which was restored by Empa.
CONCLUSIONS: The study demonstrates beneficial effects of Empa on diastolic function, hemodynamics, inflammation, and cardiac remodeling in a rat model of HFpEF. These effects were mediated by improved mitochondrial respiratory capacity due to modulated cardiolipin and improved calcium handling.

Keywords:  cardiolipins; empagliflozin; heart failure; hypertension; inflammation

DOI:  https://doi.org/10.1161/CIRCHEARTFAILURE.123.011107
Circ Heart Fail. 2024 Jun 07. e011646

Proving SGLT2 Inhibitor-Mediated Improvement in Cardiomyocyte Energetics: Beyond a Reasonable Doubt?

Mallory Filipp, Sanjiv J Shah.



Keywords:  Editorials; heart failure; metabolic disease; molecular mechanisms of pharmacological action; sodium-glucose transporter 2

DOI:  https://doi.org/10.1161/CIRCHEARTFAILURE.124.011646
Front Cardiovasc Med. 2024 ;11 1383669

Sodium-glucose cotransporter-2 inhibitors improve cardiovascular outcomes post-acute coronary syndrome complicated by acute heart failure.

Alaa Rahhal, Tahseen Hamamyh, Ammar Chapra, Khaled J Zaza, Mostafa Najim, Mohammad Hemadneh, Hazem Faraj, Wael Kanjo, Ahmed Yasin, Haneen Toba, Wafa Mohammed, Mohammad Khair Hamad, Nawras Al-Tikrety, Mhd Baraa Habib, Ahmed Awaisu, Ahmed Mahfouz, Sumaya Alyafei, Abdul Rahman Arabi, Ashfaq Patel, Mohammed Al-Hijji.

  Background: Acute coronary syndrome (ACS) remains a risk factor for heart failure (HF). Therefore, we aimed to assess the cardioprotective role of sodium-glucose cotransporter-2 (SGLT2) inhibitors post-ACS in patients with acute HF (AHF) and diabetes.Methods: We conducted a retrospective observational cohort study employing propensity score matching. This study involved patients with diabetes admitted with ACS complicated by AHF, defined as either new clinical HF requiring diuretics during the index admission or having an ejection fraction (EF) of <40%. The study population was divided into two groups; (1) SGLT2 inhibitor users and (2) SGLT2 inhibitor non-users. The Cox proportional hazard regression analysis was used to evaluate the outcomes.
Results: A total of 465 patients (93% male; mean age, 55 ± 10 years) were included in this study. Using a 1 : 1 propensity score matching, 78 patients were included per arm with an absolute standardized difference of <0.1 for all baseline characteristics. The use of SGLT2 inhibitors resulted in lower composite outcomes of ACS, HF hospitalization, and all-cause mortality at 1 month and 12 months [1 month: 2.6% vs. 11.5%, HR = 0.20 (0.04-0.94), p = 0.041; 12 months: 14.1% vs. 23.1%, HR = 0.46 (0.22-0.99), p = 0.046].
Conclusion: The findings suggest that SGLT2 inhibitors may confer cardioprotective effects in ACS-induced AHF, thereby widening the spectrum for indications of SGLT2 inhibitors.

Keywords:  HF hospitalization; acute coronary syndrome; cardioprotection; heart failure; sodium–glucose cotransporter-2 (SGLT-2) inhibitors

DOI:  https://doi.org/10.3389/fcvm.2024.1383669
bioRxiv. 2024 May 26. pii: 2024.05.22.595229. [Epub ahead of print]

Inherent Metabolic Adaptations in Adult Spiny Mouse ( Acomys ) Cardiomyocytes Facilitate Enhanced Cardiac Recovery Following Myocardial Infarction.

Annapurna Kuppa, Afnan Alzamrooni, Rachel Lopez, Tahra Suhan, Rajesh Chaudhary, Nicole Collins, Fran Van den Bergh, Riham Abouleisa, Harrison Wang, Tamer Mohamed, Jonathan Satin, Costas Lyssiotis, Daniel A Beard, Ahmed Abdel-Latif.

The adult mammalian heart has limited regenerative capacity following injury, leading to progressive heart failure and mortality. Recent studies have identified the spiny mouse ( Acomys ) as a unique model for mammalian cardiac isch3emic resilience, exhibiting enhanced recovery after myocardial infarction (MI) compared to commonly used laboratory mouse strains. However, the underlying cellular and molecular mechanisms behind this unique response remain poorly understood. In this study, we comprehensively characterized the metabolic characteristics of cardiomyocytes in Acomys compared to the non-regenerative Mus musculus . We utilized single-nucleus RNA sequencing (snRNA-seq) in sham-operated animals and 1, 3, and 7 days post-myocardial infarction to investigate cardiomyocytes' transcriptomic and metabolomic profiles in response to myocardial infarction. Complementary targeted metabolomics, stable isotope-resolved metabolomics, and functional mitochondrial assays were performed on heart tissues from both species to validate the transcriptomic findings and elucidate the metabolic adaptations in cardiomyocytes following ischemic injury. Transcriptomic analysis revealed that Acomys cardiomyocytes inherently upregulate genes associated with glycolysis, the pentose phosphate pathway, and glutathione metabolism while downregulating genes involved in oxidative phosphorylation (OXPHOS). These metabolic characteristics are linked to decreased reactive oxygen species (ROS) production and increased antioxidant capacity. Our targeted metabolomic studies in heart tissue corroborated these findings, showing a shift from fatty acid oxidation to glycolysis and ancillary biosynthetic pathways in Acomys at baseline with adaptive changes post-MI. Functional mitochondrial studies indicated a higher reliance on glycolysis in Acomys compared to Mus , underscoring the unique metabolic phenotype of Acomys hearts. Stable isotope tracing experiments confirmed a shift in glucose utilization from oxidative phosphorylation in Acomys . In conclusion, our study identifies unique metabolic characteristics of Acomys cardiomyocytes that contribute to their enhanced ischemic resilience following myocardial infarction. These findings provide novel insights into the role of metabolism in regulating cardiac repair in adult mammals. Our work highlights the importance of inherent and adaptive metabolic flexibility in determining cardiomyocyte ischemic responses and establishes Acomys as a valuable model for studying cardiac ischemic resilience in adult mammals.Graphical abstract:

DOI: https://doi.org/10.1101/2024.05.22.595229
iScience. 2024 Jun 21. 27(6): 109796

Mitochondrial glycerol 3-phosphate dehydrogenase deficiency exacerbates lipotoxic cardiomyopathy.

Hua Qu, Xiufei Liu, Jiaran Zhu, Niexia He, Qingshan He, Linlin Zhang, Yuren Wang, Xiaoli Gong, Xin Xiong, Jinbo Liu, Chuan Wang, Gangyi Yang, Qingwu Yang, Gang Luo, Zhiming Zhu, Yi Zheng, Hongting Zheng.

  Metabolic diseases such as obesity and diabetes induce lipotoxic cardiomyopathy, which is characterized by myocardial lipid accumulation, dysfunction, hypertrophy, fibrosis and mitochondrial dysfunction. Here, we identify that mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH) is a pivotal regulator of cardiac fatty acid metabolism and function in the setting of lipotoxic cardiomyopathy. Cardiomyocyte-specific deletion of mGPDH promotes high-fat diet induced cardiac dysfunction, pathological hypertrophy, myocardial fibrosis, and lipid accumulation. Mechanically, mGPDH deficiency inhibits the expression of desuccinylase SIRT5, and in turn, the hypersuccinylates majority of enzymes in the fatty acid oxidation (FAO) cycle and promotes the degradation of these enzymes. Moreover, manipulating SIRT5 abolishes the effects of mGPDH ablation or overexpression on cardiac function. Finally, restoration of mGPDH improves lipid accumulation and cardiomyopathy in both diet-induced and genetic obese mouse models. Thus, our study indicates that targeting mGPDH could be a promising strategy for lipotoxic cardiomyopathy in the context of obesity and diabetes.

Keywords:  biological sciences; cell biology; cellular physiology; diabetology; endocrinology; natural sciences; pathophysiology; physiology

DOI:  https://doi.org/10.1016/j.isci.2024.109796
JACC Heart Fail. 2024 Jun;pii: S2213-1779(24)00262-2. [Epub ahead of print]12(6S): S1-S3

Epidemiology of Heart Failure and the Discovery of the Cardioprotective Effects of SGLT2 Inhibitors.

Javed Butler, Jonathan Rich.

  In this video, Javed Butler, MD, introduces the series on the use of SGLT2 inhibitors in heart failure. He discusses the epidemiology of heart failure and the effects of SGLT2 inhibitors on heart failure outcomes. Jonathan Rich, MD, joins to summarize the effects of SGLT2 inhibitors from dedicated trials in patients with heart failure.

Keywords:  SGLT2 inhibitors; cardiovascular outcomes; heart failure

DOI:  https://doi.org/10.1016/j.jchf.2024.01.025
J Mol Cell Cardiol. 2024 Jun 03. pii: S0022-2828(24)00090-7. [Epub ahead of print]

Inhibition of autophagy prevents cardiac dysfunction at early stages of cardiomyopathy in Bag3-deficient hearts.

Giovanni Maroli, Anne Schänzer, Stefan Günther, Claudia Garcia-Gonzalez, Stefan Rupp, Hannah Schlierbach, Yanpu Chen, Johannes Graumann, Astrid Wietelmann, Johnny Kim, Thomas Braun.

  The HSP70 co-chaperone BAG3 targets unfolded proteins to degradation via chaperone assisted selective autophagy (CASA), thereby playing pivotal roles in the proteostasis of adult cardiomyocytes (CMs). However, the complex functions of BAG3 for regulating autophagy in cardiac disease are not completely understood. Here, we demonstrate that conditional inactivation of Bag3 in murine CMs leads to age-dependent dysregulation of autophagy, associated with progressive cardiomyopathy. Surprisingly, Bag3-deficient CMs show increased canonical and non-canonical autophagic flux in the juvenile period when first signs of cardiac dysfunction appear, but reduced autophagy during later stages of the disease. Juvenile Bag3-deficient CMs are characterized by decreased levels of soluble proteins involved in synchronous contraction of the heart, including the gap junction protein Connexin 43 (CX43). Reiterative administration of chloroquine (CQ), an inhibitor of canonical and non-canonical autophagy, but not inactivation of Atg5, restores normal concentrations of soluble cardiac proteins in juvenile Bag3-deficient CMs without an increase of detergent-insoluble proteins, leading to complete recovery of early-stage cardiac dysfunction in Bag3-deficient mice. We conclude that loss of Bag3 in CMs leads to age-dependent differences in autophagy and cardiac dysfunction. Increased non-canonical autophagic flux in the juvenile period removes soluble proteins involved in cardiac contraction, leading to early-stage cardiomyopathy, which is prevented by reiterative CQ treatment.

Keywords:  Autophagy; Bag3; Cardiomyopathy; Chloroquine; Cx43; Heart failure; Hypertrophic cardiomyopathy; Pediatric

DOI:  https://doi.org/10.1016/j.yjmcc.2024.06.001