bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2024–01–21
nine papers selected by
Kyle McCommis, Saint Louis University



  1. Eur J Heart Fail. 2024 Jan 18.
       AIMS: The therapeutic mechanism of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on left cardiac remodelling in patients with heart failure with reduced ejection fraction (HFrEF) is not well-established. This study meta-analysed the impact of SGLT2i on left cardiac structure and function in patients with HFrEF.
    METHODS AND RESULTS: Online databases were queried up to April 2023 for trials reporting indicators of left cardiac structure and function in patients with HFrEF treated with SGLT2i. Data from studies were pooled using a random-effects model to derive weighted mean differences (WMDs) and 95% confidence intervals (CIs). Six trials were included (n = 555). Compared with control, SGLT2i significantly improved left ventricular end-diastolic volume (LVEDV; WMD: -17.07 ml [-23.84, -10.31]; p < 0.001), LVEDV index (WMD: -5.62 ml/m2 [-10.28, -0.97]; p = 0.02), left ventricular end-systolic volume (LVESV; WMD: -15.63 ml [-26.15, -5.12]; p = 0.004), LVESV index (WMD: -6.90 ml/m2 [-10.68, -3.11]; p = 0.001), left ventricular ejection fraction (WMD: 2.71% [0.70, 4.72]; p = 0.008), and left atrial volume index (WMD: -2.19 ml/m2 [-4.26, -0.11]; p = 0.04) in patients with HFrEF. SGLT2i use was associated with a non-significant trend towards a reduction in left ventricular mass index (WMD: -6.25 g/m2 [-12.79, 0.28]; p = 0.06). No significant impact on left ventricular global longitudinal strain was noted (WMD: 0.21% [-0.25, 0.67]; p = 0.38).
    CONCLUSIONS: Sodium-glucose cotransporter 2 inhibitors improve cardiac structure and function in patients with HFrEF.
    Keywords:  Heart failure with reduced ejection fraction; Left cardiac remodelling; Sodium-glucose cotransporter 2 inhibitors
    DOI:  https://doi.org/10.1002/ejhf.3129
  2. World J Nephrol. 2023 Dec 25. 12(5): 182-200
       BACKGROUND: Gliflozins or Sodium glucose cotransporter 2 inhibitors (SGLT2i) are relatively novel antidiabetic medications that have recently been shown to represent favorable effects on patients' cardiorenal outcomes. However, there is shortage of data on potential disparities in this therapeutic effect across different patient subpopulations.
    AIM: To investigate differential effects of SGLT2i on the cardiorenal outcomes of heart failure patients across left ventricular ejection fraction (LVEF) levels.
    METHODS: Literature was searched systematically for the large randomized double-blind controlled trials with long enough follow up periods reporting cardiovascular and renal outcomes in their patients regarding heart failure status and LVEF levels. Data were then meta-analyzed after stratification of the pooled data across the LVEF strata and New York Heart Associations (NYHA) classifications for heart failure using Stata software version 17.0.
    RESULTS: The literature search returned 13 Large clinical trials and 13 post hoc analysis reports. Meta-analysis of the effects of gliflozins on the primary composite outcome showed no significant difference in efficacy across the heart failure subtypes, but higher efficacy were detected in patient groups at lower NYHA classifications (I2 = 46%, P = 0.02). Meta-analyses across the LVEF stratums revealed that a baseline LVEF lower than 30% was associated with enhanced improvement in the primary composite outcome compared to patients with higher LVEF levels at the borderline statistical significance (HR: 0.70, 95%CI: 0.60 to 0.79 vs 0.81, 95%CI: 0.75 to 0.87; respectively, P = 0.06). Composite renal outcome was improved significantly higher in patients with no heart failure than in heart failure patients with preserved ejection fraction (HFpEF) (HR: 0.60, 95%CI: 0.49 to 0.72 vs 0.94, 95%CI: 0.74 to 1.13; P = 0.04). Acute renal injury occurred significantly less frequently in heart failure patients with reduced ejection fraction who received gliflozins than in HFpEF (HR: 0.67, 95%CI: 51 to 0.82 vs 0.94, 95%CI: 0.82 to 1.06; P = 0.01). Volume depletion was consistently increased in response to SGLT2i in all the subgroups.
    CONCLUSION: Heart failure patients with lower LVEF and lower NYHA sub-classifications were found to be generally more likely to benefit from therapy with gliflozins. Further research are required to identify patient subgroups representing the highest benefits or adverse events in response to SGLT2i.
    Keywords:  Cardiovascular; Heart failure with preserved ejection fraction; Heart failure with reduced ejection fraction; Renal outcome; Sodium glucose cotransporter 2 inhibitors; efficacy
    DOI:  https://doi.org/10.5527/wjn.v12.i5.182
  3. World J Diabetes. 2023 Dec 15. 14(12): 1862-1876
       BACKGROUND: Diabetic cardiomyopathy (DCM) increases the risk of hospitalization for heart failure (HF) and mortality in patients with diabetes mellitus. However, no specific therapy to delay the progression of DCM has been identified. Mitochondrial dysfunction, oxidative stress, inflammation, and calcium handling imbalance play a crucial role in the pathological processes of DCM, ultimately leading to cardiomyocyte apoptosis and cardiac dysfunctions. Empagliflozin, a novel glucose-lowering agent, has been confirmed to reduce the risk of hospitalization for HF in diabetic patients. Nevertheless, the molecular mechanisms by which this agent provides cardioprotection remain unclear.
    AIM: To investigate the effects of empagliflozin on high glucose (HG)-induced oxidative stress and cardiomyocyte apoptosis and the underlying molecular mechanism.
    METHODS: Twelve-week-old db/db mice and primary cardiomyocytes from neonatal rats stimulated with HG (30 mmol/L) were separately employed as in vivo and in vitro models. Echocardiography was used to evaluate cardiac function. Flow cytometry and TdT-mediated dUTP-biotin nick end labeling staining were used to assess apoptosis in myocardial cells. Mitochondrial function was assessed by cellular ATP levels and changes in mitochondrial membrane potential. Furthermore, intracellular reactive oxygen species production and superoxide dismutase activity were analyzed. Real-time quantitative PCR was used to analyze Bax and Bcl-2 mRNA expression. Western blot analysis was used to measure the phosphorylation of AMP-activated protein kinase (AMPK) and myosin phosphatase target subunit 1 (MYPT1), as well as the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and active caspase-3 protein levels.
    RESULTS: In the in vivo experiment, db/db mice developed DCM. However, the treatment of db/db mice with empagliflozin (10 mg/kg/d) for 8 wk substantially enhanced cardiac function and significantly reduced myocardial apoptosis, accompanied by an increase in the phosphorylation of AMPK and PGC-1α protein levels, as well as a decrease in the phosphorylation of MYPT1 in the heart. In the in vitro experiment, the findings indicate that treatment of cardiomyocytes with empagliflozin (10 μM) or fasudil (FA) (a ROCK inhibitor, 100 μM) or overexpression of PGC-1α significantly attenuated HG-induced mitochondrial injury, oxidative stress, and cardiomyocyte apoptosis. However, the above effects were partly reversed by the addition of compound C (CC). In cells exposed to HG, empagliflozin treatment increased the protein levels of p-AMPK and PGC-1α protein while decreasing phosphorylated MYPT1 levels, and these changes were mitigated by the addition of CC. Adding FA and overexpressing PGC-1α in cells exposed to HG substantially increased PGC-1α protein levels. In addition, no sodium-glucose cotransporter (SGLT)2 protein expression was detected in cardiomyocytes.
    CONCLUSION: Empagliflozin partially achieves anti-oxidative stress and anti-apoptotic effects on cardiomyocytes under HG conditions by activating AMPK/PGC-1α and suppressing of the RhoA/ROCK pathway independent of SGLT2.
    Keywords:  AMPK; Apoptosis; Diabetic cardiomyopathy; Empagliflozin; Oxidative stress; ROCK
    DOI:  https://doi.org/10.4239/wjd.v14.i12.1862
  4. Sci Rep. 2024 01 14. 14(1): 1290
      During myocardial injury, inflammatory mediators and oxidative stress significantly increase to impair cardiac mitochondria. Emerging evidence has highlighted interplays between circadian protein-period 2 (Per2) and mitochondrial metabolism. However, besides circadian rhythm regulation, the direct role of Per2 in mitochondrial performance particularly following acute stress, remains unknown. In this study, we aim to determine the importance of Per2 protein's regulatory role in mitochondrial function following exposure to inflammatory cytokine TNFα and oxidative stressor H2O2 in human cardiomyocytes. Global warm ischemia (37 °C) significantly impaired complex I activity with concurrently reduced mitochondrial Per2 in adult mouse hearts. TNFα or H2O2 decreased Per2 protein levels and damaged mitochondrial respiratory function in adult mouse cardiomyocytes. Next, mitochondrial membrane potential ([Formula: see text] M) using JC-1 fluorescence probe and mitochondrial respiration capacity via Seahorse Cell Mito Stress Test were then detected in Per2 or control siRNA transfected AC16 Human Cardiomyocytes (HCM) that were subjected to 2 h-treatment of TNFα (100 ng/ml) or H2O2 (100 μM). After 4 h-treatment, cell death was also measured using Annexin V and propidium iodide apoptosis kit through flow cytometry. We found that knockdown of Per2 enhanced TNFα-induced cell death and TNFα- or H2O2-disrupted [Formula: see text]M, as well as TNFα- or H2O2-impaired mitochondrial respiration function. In conclusion, Per2 knockdown increases likelihood of cell death and mitochondrial dysfunction in human cardiomyocytes exposed to either TNFα or H2O2, supporting the protective role of Per2 in HCM during stress with a focus on mitochondrial function.
    DOI:  https://doi.org/10.1038/s41598-024-51799-w
  5. J Pharm Anal. 2023 Dec;13(12): 1496-1509
      Diabetic cardiomyopathy (DCM) is a metabolic disease and a leading cause of heart failure among people with diabetes. Mass spectrometry imaging (MSI) is a versatile technique capable of combining the molecular specificity of mass spectrometry (MS) with the spatial information of imaging. In this study, we used MSI to visualize metabolites in the rat heart with high spatial resolution and sensitivity. We optimized the air flow-assisted desorption electrospray ionization (AFADESI)-MSI platform to detect a wide range of metabolites, and then used matrix-assisted laser desorption ionization (MALDI)-MSI for increasing metabolic coverage and improving localization resolution. AFADESI-MSI detected 214 and 149 metabolites in positive and negative analyses of rat heart sections, respectively, while MALDI-MSI detected 61 metabolites in negative analysis. Our study revealed the heterogenous metabolic profile of the heart in a DCM model, with over 105 region-specific changes in the levels of a wide range of metabolite classes, including carbohydrates, amino acids, nucleotides, and their derivatives, fatty acids, glycerol phospholipids, carnitines, and metal ions. The repeated oral administration of ferulic acid during 20 weeks significantly improved most of the metabolic disorders in the DCM model. Our findings provide novel insights into the molecular mechanisms underlying DCM and the potential of ferulic acid as a therapeutic agent for treating this condition.
    Keywords:  Diabetic cardiomyopathy; Ferulic acid; Mass spectrometry imaging; Metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.jpha.2023.08.011
  6. Cardiovasc Drugs Ther. 2024 Jan 18.
      Metabolic disorders of cardiomyocytes play an important role in the progression of various cardiovascular diseases. Metabolic reprogramming can provide ATP to cardiomyocytes and protect them during diseases, but this transformation also leads to adverse consequences such as oxidative stress, mitochondrial dysfunction, and eventually aggravates myocardial injury. Moreover, abnormal accumulation of metabolites induced by metabolic reprogramming of cardiomyocytes alters the cardiac microenvironment and affects the metabolism of immune cells. Immunometabolism, as a research hotspot, is involved in regulating the phenotype and function of immune cells. After myocardial injury, both cardiac resident immune cells and heart-infiltrating immune cells significantly contribute to the inflammation, repair and remodeling of the heart. In addition, metabolites generated by the metabolic reprogramming of immune cells can further affect the microenvironment, thereby affecting the function of cardiomyocytes and other immune cells. Therefore, metabolic reprogramming and abnormal metabolite levels may serve as a bridge between cardiomyocytes and immune cells, leading to the development of cardiovascular diseases. Herein, we summarize the metabolic relationship between cardiomyocytes and immune cells in cardiovascular diseases, and the effect on cardiac injury, which could be therapeutic strategy for cardiovascular diseases, especially in drug research.
    Keywords:  Cardiomyocytes; Cardiovascular diseases; Immune cells; Metabolism
    DOI:  https://doi.org/10.1007/s10557-024-07545-5
  7. Cardiovasc Res. 2024 Jan 18. pii: cvae004. [Epub ahead of print]
       AIMS: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy, often caused by pathogenic sarcomere mutations. Early characteristics of HCM are diastolic dysfunction and hypercontractility. Treatment to prevent mutation-induced cardiac dysfunction is lacking. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a group of antidiabetic drugs that recently showed beneficial cardiovascular outcomes in patients with acquired forms of heart failure. We here studied if SGLT2i represent a potential therapy to correct cardiomyocyte dysfunction induced by a HCM sarcomere mutation.
    METHODS AND RESULTS: Contractility was measured of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) harbouring a HCM mutation cultured in 2D and in 3D engineered heart tissue (EHT). Mutations in the gene encoding β-myosin heavy chain (MYH7-R403Q) or cardiac troponin T (TNNT2-R92Q) were investigated. In 2D, intracellular [Ca2+], action potential and ion currents were determined. HCM mutations in hiPSC-CMs impaired relaxation or increased force, mimicking early features observed in human HCM. SGLT2i enhance relaxation of hiPSC-CMs, to a larger extent in HCM compared to control hiPSC-CMs. Moreover, SGLT2i-effects on relaxation in R403Q EHT increased with culture duration, i.e. hiPSC-CMs maturation. Canagliflozin effects on relaxation were more pronounced than empagliflozin and dapagliflozin. SGLT2i acutely altered Ca2+ handling in HCM hiPSC-CMs. Analyses of SGLT2i-mediated mechanisms that may underlie enhanced relaxation in mutant hiPSC-CMs excluded SGLT2, Na+/H+ exchanger, peak and late Nav1.5 currents, and L-type Ca2+ current, but indicate an important role for the Na+/Ca2+ exchanger. Indeed electrophysiological measurements in mutant hiPSC-CM indicate that SGLT2i altered Na+/Ca2+ exchange current.
    CONCLUSIONS: SGLT2i (canagliflozin>dapagliflozin> empagliflozin) acutely enhance relaxation in human EHT, especially in HCM and upon prolonged culture. SGLT2i may represent a potential therapy to correct early cardiac dysfunction in HCM.
    TRANSLATIONAL PERSPECTIVE: HCM is the most common inherited cardiomyopathy and treatment to prevent mutation-induced cardiac dysfunction is lacking. Early HCM characteristics are diastolic dysfunction and hypercontractility. We show in hiPSC-CM models that SGLT2i represent a potential therapy to correct cardiomyocyte dysfunction induced by HCM sarcomere mutations. SGLT2i acutely enhanced relaxation and altered Ca2+ handling in HCM hiPSC-CMs, targeting important early HCM disease hallmarks.
    Keywords:  Ca2+ handling; Hypertrophic cardiomyopathy; Sodium-glucose cotransporter 2 inhibitors; contractility; engineered heart tissue; human induced pluripotent stem cell-derived cardiomyocytes
    DOI:  https://doi.org/10.1093/cvr/cvae004
  8. ESC Heart Fail. 2024 Jan 19.
       AIMS: Heart failure with preserved ejection fraction (HFpEF) is a multifactorial, multisystemic syndrome that involves alterations in lipid metabolism. This study aimed to test whether distinct plasma lipid profiles or lipid entities or both are associated with clinical and functional echocardiographic parameters in HFpEF.
    METHODS AND RESULTS: We examined the human plasma lipidome in HFpEF patients (n = 18) with left ventricular ejection fraction ≥50% and N-terminal pro-brain natriuretic peptide (NT-proBNP) >125 pg/mL and control subjects (n = 12) using mass spectrometry-based shotgun lipidomics. The cohort included 8 women and 22 men with average age of 67.8 ± 8.6 SD. The control and disease groups were not significantly different with respect to age, body mass index, systolic and diastolic blood pressure, and waist-to-hip ratio. The disease group experienced more fatigue (P < 0.001), had more often coronary artery disease (P = 0.04), and received more medications (beta-blockers, P < 0.001). The disease group had significantly different levels of HFpEF-relevant parameters, including NT-proBNP (P < 0.001), left ventricular mass index (P = 0.005), left atrial volume index (P = 0.001), and left ventricular filling index (P < 0.001), and lower left ventricular end-diastolic diameter (P = 0.014), with no difference in left ventricular ejection fraction. Significant differences in lipid profiles between HFpEF patients and controls could not be detected, including no significant differences in abundance of circulating lipids binned by carbon chain length or by double bonds, nor at the level of individual lipid species. However, there was a striking correlation between selected lipids with smoking status that was independent of disease status, as well as between specific lipids and hyperlipidaemia [with corresponding significance of either false discovery rate (FDR) <0.1 or FDR < 0.01]. In an exploratory network analysis of correlations, we observed significantly stronger correlations within the HFpEF group between individual lipids from the cholesterol ester and phosphatidylcholine (PC) classes and clinical/echocardiographic parameters such as left atrial volume index, left ventricular end-diastolic diameters, and heart rate (FDR < 0.1). In contrast, the control group showed significantly stronger negative correlations (FDR < 0.1) between individual species from the PC and sphingomyelin classes and left ventricular mass index or systolic blood pressure.
    CONCLUSIONS: We did not find significant direct associations between plasma lipidomic parameters and HFpEF and therefore could not conclude that any specific lipids are biomarkers of HFpEF. The validation in larger cohort is needed to confidently conclude the absence of first-order associations.
    Keywords:  HFpEF; Heart failure; Lipid metabolism; Lipidomics; Plasma lipids
    DOI:  https://doi.org/10.1002/ehf2.14654
  9. Free Radic Biol Med. 2024 Jan 12. pii: S0891-5849(24)00015-7. [Epub ahead of print]
      Overloaded glucose levels in several metabolic diseases such as type 2 diabetes (T2D) can lead to mitochondrial dysfunction and enhanced production of reactive oxygen species (ROS). Oxidative stress and altered mitochondrial homeostasis, particularly in the cardiovascular system, contribute to the development of chronic comorbidities of diabetes. Diabetes-associated hyperglycemia and dyslipidemia can directly damage vascular vessels and lead to coronary artery disease or stroke, and indirectly damage other organs and lead to kidney dysfunction, known as diabetic nephropathy. The new diabetes treatments include Na+-glucose cotransporter 2 inhibitors (iSGLT2) and glucagon-like 1 peptide receptor agonists (GLP-1RA), among others. The iSGLT2 are oral anti-diabetic drugs, whereas GLP-1RA are preferably administered through subcutaneous injection, even though GLP-1RA oral formulations have recently become available. Both therapies are known to improve both carbohydrate and lipid metabolism, as well as to improve cardiovascular and cardiorenal outcomes in diabetic patients. In this review, we present an overview of current knowledge on the relationship between oxidative stress, mitochondrial dysfunction, and cardiovascular therapeutic benefits of iSGLT2 and GLP-1RA. We explore the benefits, limits and common features of the treatments and remark how both are an interesting target in the prevention of obesity, T2D and cardiovascular diseases, and emphasize the lack of a complete understanding of the underlying mechanism of action.
    Keywords:  Diabetes; GLP-1 receptor agonists; Heart disease; Inflammation; Mitochondria; Obesity; Oxidative stress; ROS; SGLT2 inhibitors
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.01.015