bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2024–09–08
eight papers selected by
Kyle McCommis, Saint Louis University
  1. Semaglutide versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: a pooled analysis of the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM randomised trials.
  2. Mechanistic Insights of SGLT2 Inhibition in Heart Failure Through Proteomics: Appreciating the Cardiovascular-Kidney Connection.
  3. Metabolomic profiling identifies novel metabolites associated with cardiac dysfunction.
  4. Effect of Semaglutide on Cardiac Structure and Function in Patients With Obesity-Related Heart Failure.
  5. Post-translational modifications of pyruvate dehydrogenase complex in cardiovascular disease.
  6. GLP-1 Receptor Agonists Among Patients With Overweight or Obesity, Diabetes, and HFpEF on SGLT2 Inhibitors.
  7. Metabolome analysis in patients with heart failure and implantable cardioverter defibrillators.
  8. Lactate regulates pathological cardiac hypertrophy via histone lactylation modification.
  1. Lancet. 2024 Aug 29. pii: S0140-6736(24)01643-X. [Epub ahead of print]
    Semaglutide versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: a pooled analysis of the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM randomised trials.
    SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM Trial Committees and Investigators
       BACKGROUND: Heart failure with mildly reduced or preserved ejection fraction (hereafter referred to as HFpEF) is the most common type of heart failure and is associated with a high risk of hospitalisation and death, especially in patients with overweight, obesity, or type 2 diabetes. In the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide improved heart failure-related symptoms and physical limitations in participants with HFpEF. Whether semaglutide also reduces clinical heart failure events in this group remains to be established.
    METHODS: We conducted a post-hoc pooled, participant-level analysis of four randomised, placebo-controlled trials (SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM) to examine the effects of once-weekly subcutaneous semaglutide (2·4 mg in SELECT, STEP-HFpEF, and STEP-HFpEF DM; 1·0 mg in FLOW) on heart failure events. The STEP-HFpEF and STEP-HFpF DM trials enrolled participants with obesity-related HFpEF, the SELECT trial enrolled participants with atherosclerotic cardiovascular disease and overweight or obesity, and the FLOW trial enrolled participants with type 2 diabetes and chronic kidney disease. Hence, for this analysis, we include all participants from the STEP-HFpEF trials and those with an investigator-reported history of HFpEF from SELECT and FLOW. The main outcomes for this analysis were the composite endpoint of time to cardiovascular death or first worsening heart failure event (defined as hospitalisation or urgent visit due to heart failure), time to first worsening heart failure event, and time to cardiovascular death. Efficacy and safety endpoints were analysed with the full analysis set (ie, all participants randomly assigned to treatment, according to the intention-to-treat principle). The SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM trials are registered at ClinicalTrials.gov, NCT03574597, NCT03819153, NCT04788511, and NCT04916470, respectively, and all are complete.
    FINDINGS: Across the four trials, 3743 (16·8%) of 22 282 participants had a history of HFpEF (1914 assigned to semaglutide and 1829 assigned to placebo). In this group of participants with HFpEF, semaglutide reduced the risk of the combined endpoint of cardiovascular death or heart failure events (103 [5·4%] of 1914 in the semaglutide group had events vs 138 [7·5%] of 1829 in the placebo group; hazard ratio [HR] 0·69 [95% CI 0·53-0·89]; p=0·0045). Semaglutide also reduced the risk of worsening heart failure events (54 [2·8%] vs 86 [4·7%]; HR 0·59 [0·41-0·82]; p=0·0019). No significant effect on cardiovascular death alone was seen (59 [3·1%] vs 67 [3·7%]; HR 0·82 [0·57-1·16]; p=0·25). A lower proportion of patients treated with semaglutide had serious adverse events than did those who were treated with placebo (572 [29·9%] vs 708 [38·7%]).
    INTERPRETATION: In patients with HFpEF, semaglutide reduced the risk of the combined endpoint of cardiovascular death or worsening heart failure events, and worsening heart failure events alone, whereas its effect on cardiovascular death alone was not significant. These data support the use of semaglutide as an efficacious therapy to reduce the risk of clinical heart failure events in patients with HFpEF, for whom few treatment options are currently available.
    FUNDING: Novo Nordisk.
    DOI:  https://doi.org/10.1016/S0140-6736(24)01643-X
  2. J Am Coll Cardiol. 2024 Aug 12. pii: S0735-1097(24)08016-1. [Epub ahead of print]
    Mechanistic Insights of SGLT2 Inhibition in Heart Failure Through Proteomics: Appreciating the Cardiovascular-Kidney Connection.
    Ravi B Patel.
      
    Keywords:  SGLT2 inhibitors; autophagy; empagliflozin; heart failure; iron; mitochondria; proteomics
    DOI:  https://doi.org/10.1016/j.jacc.2024.07.030
  3. Sci Rep. 2024 Sep 05. 14(1): 20694
    Metabolomic profiling identifies novel metabolites associated with cardiac dysfunction.
    Kasen L Culler, Arjun Sinha, Mallory Filipp, Pedro Giro, Norrina B Allen, Kent D Taylor, Xiuqing Guo, Ed Thorp, Benjamin H Freed, Philip Greenland, Wendy S Post, Alain Bertoni, David Herrington, Chen Gao, Yibin Wang, Sanjiv J Shah, Ravi B Patel.
      Metabolic comorbidities, such as obesity and diabetes, are associated with subclinical alterations in both cardiac structure/function and natriuretic peptides prior to the onset of heart failure (HF). Despite this, the exact metabolic pathways of cardiac dysfunction which precede HF are not well-defined. Among older individuals without HF in the Multi-Ethnic Study of Atherosclerosis (MESA), we evaluated the associations of 47 circulating metabolites measured by 1H-NMR with echocardiographic measures of cardiac structure and function. We then evaluated associations of significant metabolites with circulating N-terminal pro-B-type natriuretic peptide (NT-proBNP). In a separate cohort, we evaluated differences between top metabolites in patients with HF with preserved ejection fraction (HFpEF) and comorbidity-matched controls. Genetic variants associated with top metabolites (mQTLs) were then related to echocardiographic measures and NT-proBNP. Among 3440 individuals with metabolic and echocardiographic data in MESA (62 ± 10 years, 52% female, 38% White), 10 metabolites broadly reflective of glucose and amino acid metabolism were associated with at least 1 measure of cardiac structure or function. Of these 10 metabolites, 4 (myo-inositol, glucose, dimethylsulfone, carnitine) were associated with higher NT-proBNP and 2 (d-mannose, acetone) were associated with lower NT-proBNP. In a separate cohort, patients with HFpEF had higher circulating myo-inositol levels compared with comorbidity-matched controls. Genetic analyses revealed that 1 of 6 known myo-inositol mQTLs conferred risk of higher NT-proBNP. In conclusion, metabolomic profiling identifies several novel metabolites associated with cardiac dysfunction in a cohort at high risk for HF, revealing pathways potentially relevant to future HF risk.
    Keywords:  Cardiac structure; Echocardiography; Genetics; Heart failure; Metabolomics; Myo-inositol; Natriuretic peptide
    DOI:  https://doi.org/10.1038/s41598-024-71329-y
  4. J Am Coll Cardiol. 2024 Aug 29. pii: S0735-1097(24)08192-0. [Epub ahead of print]
    Effect of Semaglutide on Cardiac Structure and Function in Patients With Obesity-Related Heart Failure.
    STEP-HFpEF Trial Committees and Investigators
       BACKGROUND: Obesity is associated with adverse cardiac remodeling and is a key driver for the development and progression of heart failure (HF). Once-weekly semaglutide (2.4 mg) has been shown to improve HF-related symptoms and physical limitations, body weight, and exercise function in patients with obesity-related heart failure with preserved ejection fraction (HFpEF), but the effects of semaglutide on cardiac structure and function in this population remain unknown.
    OBJECTIVES: In this echocardiography substudy of the STEP-HFpEF Program, we evaluated treatment effects of once-weekly semaglutide (2.4 mg) vs placebo on cardiac structure and function.
    METHODS: Echocardiography at randomization and 52 weeks was performed in 491 of 1,145 participants (43%) in the STEP-HFpEF Program (pooled STEP-HFpEF [Semaglutide Treatment Effect in People with Obesity and HFpEF] and STEP-HFpEF DM [Semaglutide Treatment Effect in People with Obesity, HFpEF, and Type 2 Diabetes] trials). The prespecified primary outcome was change in left atrial (LA) volume, with changes in other echocardiography parameters evaluated as secondary outcomes. Treatment effects of semaglutide vs placebo were assessed using analysis of covariance stratified by trial and body mass index, with adjustment for baseline parameter values.
    RESULTS: Overall, baseline clinical and echocardiographic characteristics were balanced among those receiving semaglutide (n = 253) and placebo (n = 238). Between baseline and 52 weeks, semaglutide attenuated progression of LA remodeling (estimated mean difference [EMD] in LA volume, -6.13 mL; 95% CI: -9.85 to -2.41 mL; P = 0.0013) and right ventricular (RV) enlargement (EMD in RV end-diastolic area: -1.99 cm2; 95% CI: -3.60 to -0.38 cm2; P = 0.016; EMD in RV end-systolic area: -1.41 cm2; 95% CI: -2.42 to -0.40] cm2; P = 0.0064) compared with placebo. Semaglutide additionally improved E-wave velocity (EMD: -5.63 cm/s; 95% CI: -9.42 to -1.84 cm/s; P = 0.0037), E/A (early/late mitral inflow velocity) ratio (EMD: -0.14; 95% CI: -0.24 to -0.04; P = 0.0075), and E/e' (early mitral inflow velocity/early diastolic mitral annular velocity) average (EMD: -0.79; 95% CI: -1.60 to 0.01; P = 0.05). These associations were not modified by diabetes or atrial fibrillation status. Semaglutide did not significantly affect left ventricular dimensions, mass, or systolic function. Greater weight loss with semaglutide was associated with greater reduction in LA volume (Pinteraction = 0.033) but not with changes in E-wave velocity, E/e' average, or RV end-diastolic area.
    CONCLUSIONS: In the STEP-HFpEF Program echocardiography substudy, semaglutide appeared to improve adverse cardiac remodeling compared with placebo, further suggesting that treatment with semaglutide may be disease modifying among patients with obesity-related HFpEF. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF]; NCT04788511; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP-HFpEF DM]; NCT04916470).
    Keywords:  cardiac remodeling; echocardiography; glucagon-like peptide-1 receptor agonists; heart failure; heart failure with preserved ejection fraction; obesity
    DOI:  https://doi.org/10.1016/j.jacc.2024.08.021
  5. iScience. 2024 Sep 20. 27(9): 110633
    Post-translational modifications of pyruvate dehydrogenase complex in cardiovascular disease.
    Bo Guo, Fujiao Zhang, Yue Yin, Xingmin Ning, Zihui Zhang, Qinglei Meng, Ziqi Yang, Wenhua Jiang, Manling Liu, Yishi Wang, Lijuan Sun, Lu Yu, Nan Mu.
      Pyruvate dehydrogenase complex (PDC) is a crucial enzyme that connects glycolysis and the tricarboxylic acid (TCA) cycle pathway. It plays an essential role in regulating glucose metabolism for energy production by catalyzing the oxidative decarboxylation of pyruvate to acetyl coenzyme A. Importantly, the activity of PDC is regulated through post-translational modifications (PTMs), phosphorylation, acetylation, and O-GlcNAcylation. These PTMs have significant effects on PDC activity under both physiological and pathophysiological conditions, making them potential targets for metabolism-related diseases. This review specifically focuses on the PTMs of PDC in cardiovascular diseases (CVDs) such as myocardial ischemia/reperfusion injury, diabetic cardiomyopathy, obesity-related cardiomyopathy, heart failure (HF), and vascular diseases. The findings from this review offer theoretical references for the diagnosis, treatment, and prognosis of CVD.
    Keywords:  Biochemistry; Cardiovascular medicine; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2024.110633
  6. JACC Heart Fail. 2024 Aug 16. pii: S2213-1779(24)00561-4. [Epub ahead of print]
    GLP-1 Receptor Agonists Among Patients With Overweight or Obesity, Diabetes, and HFpEF on SGLT2 Inhibitors.
    Rushin Patel, Mark Wadid, Bhargav Makwana, Ashish Kumar, Sumanth Khadke, Ammar Bhatti, Ahan Banker, Zaid Husami, Sherif Labib, David Venesy, Gregg Fonarow, Mikhail Kosiborod, Sadeer Al-Kindi, Deepak L Bhatt, Sourbha Dani, Anju Nohria, Javed Butler, Sarju Ganatra.
       BACKGROUND: Although the use of glucagon-like peptide-1 receptor agonist (GLP-1 RA) in patients with obesity and heart failure with preserved ejection fraction (HFpEF) has demonstrated improvement in cardiovascular outcomes, the incremental benefits of GLP-1 RA for patients already on sodium-glucose cotransporter 2 inhibitors (SGLT2is) remain underexplored.
    OBJECTIVES: This study aimed to assess the incremental benefits of GLP-1 RA in patients with type 2 diabetes mellitus, overweight/obesity, and HFpEF receiving SGLT2i therapy.
    METHODS: The authors conducted a retrospective cohort study using the TriNetX research database including patients ≥18 years with type 2 diabetes mellitus, body mass index ≥27 kg/m2, and HFpEF on SGLT2i. Two cohorts were created based on GLP-1 RA prescription. The outcomes were heart failure exacerbation, all-cause emergency department visits/hospitalizations among others over a 12-month period.
    RESULTS: A total of 7,044 patients remained in each cohort after propensity score matching. There was a significantly lower risk of heart failure exacerbations, all-cause emergency department visits/hospitalizations, new-onset atrial arrhythmias, new-onset acute kidney injury, and pulmonary hypertension in the GLP-1 RA plus SGLT2i cohort compared with the SGLT2i-only cohort. The associated benefits persisted across different body mass indexes and ejection fractions as well as in patients with elevated natriuretic peptide. The risk of diabetic retinopathy was higher in the combination therapy group than with SGLT2i-only use.
    CONCLUSIONS: GLP-1 RA, in addition to SGLT2i, was associated with a significantly lower risk of heart failure hospitalizations in this patient population, suggesting a potential incremental benefit. This highlights the need for prospective studies to confirm the clinical benefits.
    Keywords:  GLP-1 receptor agonists; SGLT2is; heart failure with preserved ejection fraction; obesity; overweight
    DOI:  https://doi.org/10.1016/j.jchf.2024.07.006
  7. Heart Vessels. 2024 Aug 31.
    Metabolome analysis in patients with heart failure and implantable cardioverter defibrillators.
    Atsushi Suzuki, Tsuyoshi Shiga, Kayoko Sato, Morio Shoda, Junichi Yamaguchi.
      Heart failure (HF) is a complex, heterogeneous syndrome with several comorbidities, often life-threatening and requires urgent therapy. In HF, metabolic alterations that can be assessed using comprehensive plasma, and tissue profiling will help establish new biomarkers and therapeutic targets. Metabolomic analysis of sudden death in HF cases remains unresolved. We prospectively evaluated 19 patients who underwent implantable cardioverter defibrillator (ICD) placement for the primary prevention of sudden cardiac death (SCD). Metabolomic analysis was performed using plasma samples before ICD implantation. Ventricular arrhythmia (VA)/SCD was defined as VA with an appropriate ICD therapy or SCD. During a median follow-up of 29 months (range, 13-35 months), four patients developed VA and one patient developed SCD. Using metabolomic analysis, arginine, lysine, and valine were significantly reduced in patients with VA/SCD (n = 5) compared with those without VA/SCD (n = 14). The molecules involved in energy metabolism might be associated with VA/SCD, thus requiring further investigation as a predictive value of metabolomic analysis of VA/SCD.
    Keywords:  Cardiac arrhythmia; Heart failure; Implantable defibrillators; Primary prevention; Sudden cardiac death
    DOI:  https://doi.org/10.1007/s00380-024-02452-z
  8. J Cell Mol Med. 2024 Aug;28(16): e70022
    Lactate regulates pathological cardiac hypertrophy via histone lactylation modification.
    Shuai-Shuai Zhao, Jinlong Liu, Qi-Cai Wu, Xue-Liang Zhou.
      Under the long-term pressure overload stimulation, the heart experiences embryonic gene activation, leading to myocardial hypertrophy and ventricular remodelling, which can ultimately result in the development of heart failure. Identifying effective therapeutic targets is crucial for the prevention and treatment of myocardial hypertrophy. Histone lysine lactylation (HKla) is a novel post-translational modification that connects cellular metabolism with epigenetic regulation. However, the specific role of HKla in pathological cardiac hypertrophy remains unclear. Our study aims to investigate whether HKla modification plays a pathogenic role in the development of cardiac hypertrophy. The results demonstrate significant expression of HKla in cardiomyocytes derived from an animal model of cardiac hypertrophy induced by transverse aortic constriction surgery, and in neonatal mouse cardiomyocytes stimulated by Ang II. Furthermore, research indicates that HKla is influenced by glucose metabolism and lactate generation, exhibiting significant phenotypic variability in response to various environmental stimuli. In vitro experiments reveal that exogenous lactate and glucose can upregulate the expression of HKla and promote cardiac hypertrophy. Conversely, inhibition of lactate production using glycolysis inhibitor (2-DG), LDH inhibitor (oxamate) and LDHA inhibitor (GNE-140) reduces HKla levels and inhibits the development of cardiac hypertrophy. Collectively, these findings establish a pivotal role for H3K18la in pathological cardiac hypertrophy, offering a novel target for the treatment of this condition.
    Keywords:  H3K18la; HKla; cardiac hypertrophy; histone lysine lactylation; post‐translational modification
    DOI:  https://doi.org/10.1111/jcmm.70022
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