Research LettersUncoupling proteins in human heart
Summary
Abnormal energetic activity in heart failure correlates inversely with plasma free-fatty-acid concentrations. However, the link between energetic and metabolic abnormalities is unknown. To investigate this association, we obtained blood samples from 39 patients undergoing coronary artery bypass graft surgery. Patients fasted overnight before samples were taken. When plasma free-fatty-acid concentrations were raised, cardiac mitochondrial uncoupling proteins (UCP) increased (isoform UCP2, p<0·0001; isoform UCP3, p=0·0036) and those of glucose transporter (GLUT4) protein decreased (cardiac, p=0·0001; skeletal muscle, p=0·0006). Consequently, energy deficiency in heart failure might result from increased mitochondrial UCPs (ie, less efficient ATP synthesis) and depleted GLUT4 (ie, reduced glucose uptake). New treatment to correct these energy defects would be to simultaneously lower plasma free fatty acids and provide an alternative energy source.
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Cited by (253)
The link between obesity and aging - insights into cardiac energy metabolism
2023, Mechanisms of Ageing and DevelopmentObesity and aging are well-established risk factors for a range of diseases, including cardiovascular diseases and type 2 diabetes. Given the escalating prevalence of obesity, the aging population, and the subsequent increase in cardiovascular diseases, it is crucial to investigate the underlying mechanisms involved. Both aging and obesity have profound effects on the energy metabolism through various mechanisms, including metabolic inflexibility, altered substrate utilization for energy production, deregulated nutrient sensing, and mitochondrial dysfunction. In this review, we aim to present and discuss the hypothesis that obesity, due to its similarity in changes observed in the aging heart, may accelerate the process of cardiac aging and exacerbate the clinical outcomes of elderly individuals with obesity.
Current status and emerging trends of cardiac metabolism from the past 20 years: A bibliometric study
2023, HeliyonAbnormal cardiac metabolism is a key factor in the development of cardiovascular diseases. Consequently, there has been considerable emphasis on researching and developing drugs that regulate metabolism. This study employed bibliometric methods to comprehensively and objectively analyze the relevant literature, offering insights into the knowledge dynamics in this field.
The data source for this study was the Web of Science Core Collection (WoSCC), from which the collected data were imported into bibliometric software for analysis.
The United States was the leading contributor, accounting for 38.33 % of publications. The University of Washington and Damian J. Tyler were the most active institution and author, respectively. The American Journal of Physiology-Heart and Circulatory Physiology, Journal of Molecular and Cellular Cardiology, Cardiovascular Research, Circulation Research, and American Journal of Physiology-Endocrinology and Metabolism were highly influential journals that published numerous high-quality articles on cardiac metabolism. Common keywords in this research area included heart failure, insulin resistance, skeletal muscle, mitochondria, as well as topic words such as cardiac metabolism, fatty acid oxidation, glucose metabolism, and myocardial metabolism. Co-citation analysis has shown that research on heart failure and in vitro modeling of cardiovascular disease has gained prominence in recent years and making it a research hotspot.
Research on cardiac metabolism is steadily growing, with a specific focus on heart failure and the interplay between mitochondrial dysfunction, insulin resistance, and cardiac metabolism. An emerging trend in this field involves the enhancement of maturation in human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) through the manipulation of cardiac metabolism.
Beneficial Effects of Ketone Ester in Patients With Cardiogenic Shock: A Randomized, Controlled, Double-Blind Trial
2023, JACC: Heart FailureCardiogenic shock (CS) is a life-threatening condition with sparse treatment options. The ketone body 3-hydroxybutyrate has favorable hemodynamic effects in patients with stable chronic heart failure. Yet, the hemodynamic effects of exogenous ketone ester (KE) in patients with CS remain unknown.
The authors aimed to assess the hemodynamic effects of single-dose enteral treatment with KE in patients with CS.
In a double-blind, crossover study, 12 patients with CS were randomized to an enteral bolus of KE and isocaloric, isovolumic placebo containing maltodextrin. Patients were assessed with pulmonary artery catheterization, arterial blood samples, echocardiography, and near-infrared spectroscopy for 3 hours following each intervention separated by a 3-hour washout period.
KE increased circulating 3-hydroxybutyrate (2.9 ± 0.3 mmol/L vs 0.2 ± 0.3 mmol/L, P < 0.001) and was associated with augmented cardiac output (area under the curve of relative change: 61 ± 22 L vs 1 ± 18 L, P = 0.044). Also, KE increased cardiac power output (0.07 W [95% CI: 0.01-0.14]; P = 0.037), mixed venous saturation (3 percentage points [95% CI: 1-5 percentage points]; P = 0.010), and forearm perfusion (3 percentage points [95% CI: 0-6 percentage points]; P = 0.026). Right (P = 0.048) and left (P = 0.017) ventricular filling pressures were reduced whereas heart rate and mean arterial and pulmonary arterial pressures remained similar. Left ventricular ejection fraction improved by 4 percentage points (95% CI: 2-6 percentage points; P = 0.005). Glucose levels decreased by 2.6 mmol/L (95% CI: −5.2 to 0.0; P = 0.047) whereas insulin levels remained unaltered.
Treatment with KE improved cardiac output, biventricular function, tissue oxygenation, and glycemic control in patients with CS (Treatment With the Ketone Body 3-hydroxybutyrate in Patients With Cardiogenic Shock [KETO-SHOCK1]; NCT04642768)
Triglyceride–glucose index associates with incident heart failure: A cohort study
2022, Diabetes and MetabolismTriglyceride–glucose (TyG) index has been proposed as a simple surrogate marker of insulin resistance. However, few studies have investigated the association of TyG index with heart failure (HF). We aimed to explore the relationship between TyG index and incident HF.
A total of 138,620 participants from the Kailuan study were included for analysis. TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL) / 2]. Cox proportional hazard models were used to investigate the association between TyG index and the risk of HF. Restricted cubic spline analysis was applied to evaluate the dose-response relationship between TyG index and the risk of HF.
There were 1602 incident HF cases among the 138,620 participants during a median follow-up of 8.78 years. Compared with those in the lowest quartile group of TyG index, participants with the highest quartile of TyG index had a 24% higher risk of HF (HR=1.24, 95%CI=1.07-1.44) after adjusting for other risk factors. Restricted cubic spline analysis showed a significant J-shaped dose-response relationship between TyG index and risk of HF (P for non-linearity < 0.001). The significant association was still observed among the men and participants with or without abdominal obesity in subgroup analyses.
The TyG index was positively associated with the risk of HF, which indicates that the TyG index might be useful to identify people at high-risk for developing HF.
PET imaging of heart diseases by Acetate
2022, Nuclear Medicine and Molecular Imaging: Volume 1-4Acetate has a pivotal role in the intermediary metabolism of living cells. Glucose, fatty acids and other carbon sources for oxidation are converted to acetate before entering the mitochondrial tricarboxylic acid cycle. 11C-acetate PET is an established technique in cardiac imaging since decades and allows accurate estimates of both regional myocardial blood flow (MBF) and oxygen consumption (MVO2) to be obtained simultaneously from a single scan of less than 30 min duration. Image acquisition is based on dynamic imaging and analysis requires kinetic modeling approaches for optimal results. These requirements, as well as the need for an on-site cyclotron for carbon-11 production, so far limited the clinical use to advanced PET facilities. In recent years, myocardial 11C-acetate PET has seen a renewed interest in heart failure research into myocardial external efficiency (MEE). MEE is defined as the ratio of the energy associated with external pressure-volume work (cardiac output x systemic blood pressure, converted to Joule) and chemical energy consumed (MVO2 x left ventricular mass (LVM), converted to Joule). Cardiac output and LVM can be measured by echocardiography, magnetic resonance imaging or directly from the 11C-acetate PET scan, and hence provides a fully non-invasive approach to detailing important aspects of the inner workings of the heart. MEE is increasingly used to evaluate new therapies in heart failure and has been validated for that purpose. MEE has a high reproducibility and might potentially also be of use for early diagnosis of heart failure before symptoms develop.
This chapter describes scanning parameters with image analysis and summarizes the clinical utility of MBF, MVO2 and MEE measurements obtained from 11C-acetate PET.
Cardiac ketone body metabolism
2020, Biochimica et Biophysica Acta - Molecular Basis of DiseaseThe ketone bodies, d-β-hydroxybutyrate and acetoacetate, are soluble 4-carbon compounds derived principally from fatty acids, that can be metabolised by many oxidative tissues, including heart, in carbohydrate-depleted conditions as glucose-sparing energy substrates. They also have important signalling functions, acting through G-protein coupled receptors and histone deacetylases to regulate metabolism and gene expression including that associated with anti-oxidant activity. Their concentration, and hence availability, increases in diabetes mellitus and heart failure. Whilst known to be substrates for ATP production, especially in starvation, their role(s) in the heart, and in heart disease, is uncertain. Recent evidence, reviewed here, indicates that increased ketone body metabolism is a feature of heart failure, and is accompanied by other changes in substrate selection. Whether the change in myocardial ketone body metabolism is adaptive or maladaptive is unknown, but it offers the possibility of using exogenous ketones to treat the failing heart.