Advances in Metabolic Remodeling and Intervention Strategies in Heart Failure.

The heart is the most energy-demanding organ throughout the whole body. Perturbations or failure in energy metabolism contributes to heart failure (HF), which represents the advanced stage of various heart diseases. The poor prognosis and huge economic burden associated with HF underscore the high unmet need to explore novel therapies targeting metabolic modulators beyond conventional approaches focused on neurohormonal and hemodynamic regulators. Emerging evidence suggests that alterations in metabolic substrate reliance, metabolic pathways, metabolic by-products, and energy production collectively regulate the occurrence and progression of HF. In this review, we provide an overview of cardiac metabolic remodeling, encompassing the utilization of free fatty acids, glucose metabolism, ketone bodies, and branched-chain amino acids both in the physiological condition and heart failure. Most importantly, the latest advances in pharmacological interventions are discussed as a promising therapeutic approach to restore cardiac function, drawing insights from recent basic research, preclinical and clinical studies.

Increased Serum Soluble Transferrin Receptor Levels Were Associated With High Prevalence of Cardiovascular Diseases: Insights From the National Health and Nutrition Examination Survey 2017-2018.

Background: Iron deficiency is common in cardiovascular diseases (CVD), e.g., heart failure and coronary heart disease. Soluble transferrin receptor (sTfR) is a promising marker representing unmet cellular iron demands. However, whether higher serum sTfR is associated with increased risk of CVDs needs further investigation. Methods: In the present cross-sectional study, we analyzed data of 4,867 adult participants of the National Health and Nutrition Examination Survey (NHANES) 2017-2018. Linear regression models were employed to identify possible correlations between sTfR and other characteristics. The association between sTfR and CVDs was assessed with univariable and multivariable logistics regression models. Results: The prevalence of CVDs was 9.5% among participants, and higher sTfR levels were found in participants with CVDs (p < 0.001). Linear regression models revealed positive associations between sTfR and age, body mass index, systolic blood pressure, glycated hemoglobulin A1c, and insulin resistance (all p < 0.001). In the multivariable logistics regression model, the adjusted odds ratio of sTfR for CVDs was 2.05 (per 1 log2 mg/L, 95% confidence interval: 1.03∼4.05, p = 0.046). Further subgroup analysis identified the associations of sTfR and CVDs were only significant in participants ≥60 years old, or with hypertension (all p < 0.05). Conclusion: Our study demonstrated that increased serum sTfR levels were associated with a high prevalence of cardiovascular diseases.

Phosphoenolpyruvate carboxykinase in cell metabolism: Roles and mechanisms beyond gluconeogenesis.

BACKGROUND: Phosphoenolpyruvate carboxykinase (PCK) has been almost exclusively recognized as a critical enzyme in gluconeogenesis, especially in the liver and kidney. Accumulating evidence has shown that the enhanced activity of PCK leads to increased glucose output and exacerbation of diabetes, whereas the defects of PCK result in lethal hypoglycemia. Genetic mutations or polymorphisms are reported to be related to the onset and progression of diabetes in humans. SCOPE OF REVIEW: Recent studies revealed that the PCK pathway is more complex than just gluconeogenesis, depending on the health or disease condition. Dysregulation of PCK may contribute to the development of obesity, cardiac hypertrophy, stroke, and cancer. Moreover, a regulatory network with multiple layers, from epigenetic regulation, transcription regulation, to posttranscription regulation, precisely tunes the expression of PCK. Deciphering the molecular basis that regulates PCK may pave the way for developing practical strategies to treat metabolic dysfunction. MAJOR CONCLUSIONS: In this review, we summarize the metabolic and non-metabolic roles of the PCK enzyme in cells, especially beyond gluconeogenesis. We highlight the distinct functions of PCK isoforms (PCK1 and PCK2), depict a detailed network regulating PCK's expression, and discuss its clinical relevance. We also discuss the therapeutic potential targeting PCK and the future direction that is highly in need to better understand PCK-mediated signaling under diverse conditions.

Serum Free Fatty Acids Independently Predict Adverse Outcomes in Acute Heart Failure Patients.

Background: Perturbation of energy metabolism exacerbates cardiac dysfunction, serving as a potential therapeutic target in congestive heart failure. Although circulating free fatty acids (FFAs) are linked to insulin resistance and risk of coronary heart disease, it still remains unclear whether circulating FFAs are associated with the prognosis of patients with acute heart failure (AHF). Methods: This single-center, observational cohort study enrolled 183 AHF patients (de novo heart failure or decompensated chronic heart failure) in the Second Affiliated Hospital, Zhejiang University School of Medicine. All-cause mortality and heart failure (HF) rehospitalization within 1 year after discharge were investigated. Serum FFAs were modeled as quartiles as well as a continuous variable (per SD of FFAs). The restricted cubic splines and cox proportional hazards models were applied to evaluate the association between the serum FFAs level and all-cause mortality or HF rehospitalization. Results: During a 1-year follow-up, a total of 71 (38.8%) patients had all-cause mortality or HF rehospitalization. The levels of serum FFAs positively contributed to the risk of death or HF rehospitalization, which was not associated with the status of insulin resistance. When modeled with restricted cubic splines, the serum FFAs increased linearly for the incidence of death or HF rehospitalization. In a multivariable analysis adjusting for sex, age, body-mass index, coronary artery disease, diabetes mellitus, hypertension, left ventricular ejection fraction and N-terminal pro-brain natriuretic peptid, each SD (303.07 µmol/L) higher FFAs were associated with 26% higher risk of death or HF rehospitalization (95% confidence interval, 2-55%). Each increasing quartile of FFAs was associated with differentially elevated hazard ratios for death or HF rehospitalization of 1 (reference), 1.71 (95% confidence interval, [0.81, 3.62]), 1.41 (95% confidence interval, [0.64, 3.09]), and 3.18 (95% confidence interval, [1.53, 6.63]), respectively. Conclusion: Serum FFA levels at admission among patients with AHF were associated with an increased risk of adverse outcomes. Additional studies are needed to determine the causal-effect relationship between FFAs and acute cardiac dysfunction and whether FFAs could be a potential target for AHF management.