Trends in Pharmacological Sciences, Год журнала: 2025, Номер unknown
Опубликована: Март 1, 2025
Язык: Английский
Circulation Research, Год журнала: 2023, Номер 132(7), С. 882 - 898
Опубликована: Март 30, 2023
The ketone bodies beta-hydroxybutyrate and acetoacetate are hepatically produced metabolites catabolized in extrahepatic organs. Ketone a critical cardiac fuel have diverse roles the regulation of cellular processes such as metabolism, inflammation, crosstalk multiple organs that mediate disease. This review focuses on role metabolism health disease with an emphasis therapeutic potential ketosis treatment for heart failure (HF). Cardiac metabolic reprogramming, characterized by diminished mitochondrial oxidative contributes to dysfunction pathologic remodeling during development HF. Growing evidence supports adaptive HF promote normal function attenuate progression. Enhanced utilization is mediated increased availability due systemic autonomous upregulation ketolytic enzymes. Therapeutic strategies designed restore high-capacity show promise address deficits underpin progression However, mechanisms involved beneficial effects yet be defined represent important future lines inquiry. In addition use energy substrate oxidation, modulate myocardial glucose fatty acids, two vital substrates regulate hypertrophy. salutary may also include extra-cardiac modulating immune responses, reducing fibrosis, promoting angiogenesis vasodilation. Additional pleotropic signaling properties AcAc discussed including epigenetic protection against stress. Evidence benefit feasibility examined preclinical clinical studies. Finally, ongoing trials reviewed perspective translation therapeutics
Язык: Английский
Процитировано
72
International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(2), С. 1211 - 1211
Опубликована: Янв. 19, 2024
This comprehensive review explores the critical role of fatty acid (FA) metabolism in cardiac diseases, particularly heart failure (HF), and implications for therapeutic strategies. The heart’s reliance on ATP, primarily sourced from mitochondrial oxidative metabolism, underscores significance metabolic flexibility, with oxidation (FAO) being a dominant source. In HF, shifts occur an altered FA uptake FAO, impacting function contributing to disease progression. Conditions like obesity diabetes also lead disturbances, resulting cardiomyopathy marked by over-reliance dysfunction, lipotoxicity. Therapeutic approaches targeting diseases have evolved, focusing inhibiting or stimulating FAO optimize energetics. Strategies include using CPT1A inhibitors, PPARα agonists, enhancing biogenesis function. However, effectiveness varies, reflecting complexity remodeling HF. Hence, treatment strategies should be individualized, considering that energy is intricate tightly regulated. aim overall function, recognizing pivotal FAs need further research develop effective therapies, promising new improve
Язык: Английский
Процитировано
18
Nature Reviews Cardiology, Год журнала: 2024, Номер 21(10), С. 682 - 700
Опубликована: Май 30, 2024
Язык: Английский
Процитировано
16
Cardiovascular Diabetology, Год журнала: 2025, Номер 24(1)
Опубликована: Янв. 22, 2025
Insulin resistance (IR) plays a pivotal role in the interplay between metabolic disorders and heart failure with preserved ejection fraction (HFpEF). Various non-insulin-based indices emerge as reliable surrogate markers for assessing IR, including triglyceride-glucose (TyG) index, TyG index body mass (TyG-BMI), atherogenic of plasma (AIP), score insulin (METS-IR). However, ability different IR to predict outcome HFpEF patients has not been extensively explored. Patients having were recruited from January 2012 December 2023. The was defined major adverse cardiovascular event (MACE), encompassing all-cause mortality rehospitalization failure. potential linear relationship visualized by restricted cubic spline (RCS) curve. Both univariable multivariable Cox proportional hazards models employed examine association indexes MACE. Furthermore, assess incremental prognostic value we conducted comprehensive analyses using area under curve (AUC), continuous net reclassification (cNRI), integrated discrimination (IDI). A total 8693 met inclusion criteria included final analysis. mean age 70.59 ± 10.6 years, 5045 (58.04%) being male. Kaplan-Meier survival analysis revealed that higher degree four associated risk MACE (all log-rank P < 0.05). When treated variable, showed significant (HR 2.1, 95% CI 1.98–2.23, 0.001 model 1; HR 1.81, 1.73–1.9, 2; 1.68, 1.6–1.76, 3). categorized into quartiles, highest quartile (Q4) significantly 2.48, 2.24–2.76, Similar associations found TyG-BMI, AIP, METS-IR, enhance stratification capability MAGGIC (AUC 0.601 0.666). compared other indicators, exhibited superior abilities predicting Additionally, TyG-BMI U-shaped correlation MACE, indicating both an elevated lower increased risk. All are independently HFpEF. Notably, these predictive accuracy score, widely used assessment tool Among indices, demonstrated discriminatory abilities, providing greatest exhibiting superiority indices. These findings highlight importance particularly management strategies patients. it should be noted our need validated diverse populations ensure their applicability generalizability.
Язык: Английский
Процитировано
2
Journal of Clinical Medicine, Год журнала: 2024, Номер 13(5), С. 1195 - 1195
Опубликована: Фев. 20, 2024
Heart failure with preserved ejection fraction (HFpEF) is increasingly prevalent and now accounts for half of all heart cases. This rise largely attributed to growing rates obesity, hypertension, diabetes. Despite its prevalence, the pathophysiological mechanisms HFpEF are not fully understood. The heart, being most energy-demanding organ, appears have a compromised bioenergetic capacity in failure, affecting phenotypes aetiologies. While metabolic disturbances reduced (HFrEF) been extensively studied, similar insights into limited. review collates evidence from both animal human studies, highlighting dysregulations associated risk factors, such as We discuss how changes substrate utilisation, oxidative phosphorylation, energy transport contribute HFpEF. By delving these pathological shifts myocardial production, we aim reveal novel therapeutic opportunities. Potential strategies include modulating substrates, improving efficiency, enhancing critical pathways. Understanding aspects could be key developing more effective treatments
Язык: Английский
Процитировано
8
Journal of Biological Chemistry, Год журнала: 2024, Номер 300(6), С. 107296 - 107296
Опубликована: Апрель 18, 2024
The modification of nuclear, cytoplasmic, and mitochondrial proteins by O-linked β-N-actylglucosamine (O-GlcNAc) is an essential posttranslational that common in metozoans. O-GlcNAc cycled on off response to environmental physiological stimuli impacting protein function, which, turn, tunes pathways include transcription, translation, proteostasis, signal transduction, metabolism. One class stimulus induces rapid dynamic changes cellular injury, resulting from stress (for instance, heat shock), hypoxia/reoxygenation ischemia reperfusion injury (heart attack, stroke, trauma hemorrhage), sepsis. Acute elevation before or after reduces apoptosis necrosis, suggesting injury-induced O-GlcNAcylation regulate cell fate decisions. However, prolonged reduction leads a maladaptive associated with pathologies such as hypertrophy heart failure. In this review, we discuss the impact both acute models focus biological mechanisms underpin survival.
Язык: Английский
Процитировано
8
Clinical and Translational Medicine, Год журнала: 2025, Номер 15(1)
Опубликована: Янв. 1, 2025
Abstract Introduction Heart failure with preserved ejection fraction (HFpEF) is a complex condition characterized by metabolic dysfunction and myocardial lipotoxicity. The roles of PTEN‐induced kinase 1 (PINK1) peroxiredoxin‐2 (Prdx2) in HFpEF pathogenesis remain unclear. Objective This study aimed to investigate the interaction between PINK1 Prdx2 mitigate cardiac diastolic HFpEF. Methods In vivo, PINK1‐knockout mice cardiac‐specific PINK1‐overexpressing transgenic were used establish an mouse model via high‐fat diet L‐NAME. Myocardial lipotoxicity was induced palmitic acid vitro. Immunoprecipitation, western blotting immunofluorescence analysis performed elucidate molecular mechanisms involved. Results We determined that downregulated model. ablation exacerbated reduction expression, worsening mice. Conversely, overexpression restored levels decreased reactive oxygen species apoptosis, thereby reducing fibrosis inflammation ameliorating vitro, N‐terminal region (amino acids 1–133) identified. expression effectively attenuated acid‐induced apoptosis through c‐Jun amino‐terminal (JNK) mitogen‐activated protein (p38) pathways, whereas siRNA‐mediated knockdown abolished protective effect PINK1. Conclusion alleviates lipotoxicity‐induced improves Prdx2, highlighting as potential therapeutic strategy for Key points Our investigation discloses pivotal relationship context Notably, PINK1, addition its role mitochondrial autophagy, can increase remove ROS attenuate cardiomyocyte modulating JNK p38 alleviating improving function. studies offer valuable insights, opening avenues development innovative strategies prevention treatment
Язык: Английский
Процитировано
1
Nature Communications, Год журнала: 2025, Номер 16(1)
Опубликована: Фев. 15, 2025
Fibroblast growth factor 21 (FGF21), a metabolic hormone with pleiotropic effects, is beneficial for various cardiac disorders. However, FGF21's role in heart failure preserved ejection fraction (HFpEF) remains unclear. Here, we show that elevated circulating FGF21 levels are negatively associated diastolic function patients HFpEF. Global or adipose deficiency exacerbates dysfunction and damage high-fat diet (HFD) plus N[w]-nitro-L-arginine methyl ester (L-NAME)-induced HFpEF mice, whereas these effects notably reversed by replenishment. Mechanistically, enhances the production of adiponectin (APN), which turn indirectly acts on cardiomyocytes, directly targets to regulate pyruvate dehydrogenase kinase 4 (PDK4) activating PI3K/AKT signals, then promoting mitochondrial bioenergetics. Additionally, APN deletion strikingly abrogates protective against HFpEF, while genetic PDK4 inactivation markedly mitigates mice. Thus, protects via fine-tuning multiorgan crosstalk among adipose, liver, heart. The not fully understood. authors it triggering tissue, heart, suggesting could be promising therapeutic target treating
Язык: Английский
Процитировано
1
Current Opinion in Cardiology, Год журнала: 2024, Номер 39(3), С. 148 - 153
Опубликована: Янв. 31, 2024
Purpose of review Incretin-based drugs are potent weight-lowering agents, emerging as potential breakthrough therapy for the treatment obesity-related phenotype heart failure with preserved ejection fraction (HFpEF). In this article, we will discuss contribution weight loss part benefits incretin-based medications in obese patients HFpEF. Furthermore, describe effects glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists on heart, particularly relation to HFpEF pathophysiology. Recent findings STEP-HFpEF trial, GLP-1 agonist semaglutide significantly improved quality life outcomes patients. Whether beneficial merely a consequence body reduction is unclear. Considering availability other strategies (e.g., caloric restriction, exercise training, bariatric surgery) be used patients, answering question crucial provide tailored therapeutic options these subjects. Summary may represent milestone obesity Elucidating overall benefit observed critical management considering that available might alternative
Язык: Английский
Процитировано
7
ESC Heart Failure, Год журнала: 2024, Номер 11(3), С. 1553 - 1566
Опубликована: Янв. 19, 2024
Abstract 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 profiles or entities both are associated clinical and functional echocardiographic parameters HFpEF. Methods results We examined the human lipidome HFpEF patients ( n = 18) left ventricular ≥50% N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) >125 pg/mL control subjects 12) using mass spectrometry‐based shotgun lipidomics. The cohort included 8 women 22 men average age of 67.8 ± 8.6 SD. disease groups were not significantly different respect age, body index, systolic diastolic blood pressure, waist‐to‐hip ratio. group experienced more fatigue P < 0.001), had often coronary artery 0.04), received medications (beta‐blockers, 0.001). levels HFpEF‐relevant parameters, including NT‐proBNP index 0.005), atrial volume filling lower end‐diastolic diameter 0.014), no difference fraction. Significant differences between controls could be detected, significant abundance circulating lipids binned by carbon chain length double bonds, nor at level individual species. However, there was striking correlation selected smoking status independent status, as well specific hyperlipidaemia [with corresponding significance either false discovery rate (FDR) <0.1 FDR 0.01]. In an exploratory network analysis correlations, we observed stronger correlations within from cholesterol ester phosphatidylcholine (PC) classes clinical/echocardiographic such diameters, heart (FDR 0.1). contrast, showed negative 0.1) species PC sphingomyelin pressure. Conclusions did find direct associations lipidomic therefore conclude any biomarkers validation larger needed confidently absence first‐order associations.
Язык: Английский
Процитировано
6