On the interdependence of ketone body oxidation, glycogen content, glycolysis and energy metabolism in the heart.

In heart, glucose and glycolysis are important for anaplerosis and potentially therefore for d-β-hydroxybutyrate (βHB) oxidation. As a glucose store, glycogen may also furnish anaplerosis. We determined the effects of glycogen content on βHB oxidation and glycolytic rates, and their downstream effects on energetics, in the isolated rat heart.

Exogenous d-β-hydroxybutyrate lowers blood glucose in part by decreasing the availability of L-alanine for gluconeogenesis.

Background: Interventions that induce ketosis simultaneously lower blood glucose and the explanation for this phenomenon is unknown. Additionally, the glucose-lowering effect of acute ketosis is greater in people with type 2 diabetes (T2D). On the contrary, L-alanine is a gluconeogenic substrate secreted by skeletal muscle at higher levels in people with T2D and infusing of ketones lower circulating L-alanine blood levels.

Cardiac ketone body metabolism.

The 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.

Safety and tolerability of sustained exogenous ketosis using ketone monoester drinks for 28 days in healthy adults.

Throughout history, the only way humans could raise their blood ketone levels was by several days of fasting or by following a strict low-carb, high-fat diet. A recently developed, dietary source of ketones, a ketone monoester, elevates d-β-hydroxybutyrate (βHB) to similar concentrations within minutes, with βHB remaining raised for several hours. To date, the longest human safety study of the exogenous ketone ester was for 5 days, but longer consumption times may be desired.

Gastrointestinal Effects of Exogenous Ketone Drinks are Infrequent, Mild, and Vary According to Ketone Compound and Dose.

Exogenous ketone drinks may improve athletic performance and recovery, but information on their gastrointestinal tolerability is limited. Studies to date have used a simplistic reporting methodology that inadequately represents symptom type, frequency, and severity. Herein, gastrointestinal symptoms were recorded during three studies of exogenous ketone monoester (KME) and salt (KS) drinks.

On the Metabolism of Exogenous Ketones in Humans.

Currently there is considerable interest in ketone metabolism owing to recently reported benefits of ketosis for human health. Traditionally, ketosis has been achieved by following a high-fat, low-carbohydrate "ketogenic" diet, but adherence to such diets can be difficult. An alternative way to increase blood D-β-hydroxybutyrate (D-βHB) concentrations is ketone drinks, but the metabolic effects of exogenous ketones are relatively unknown.

A Ketone Ester Drink Lowers Human Ghrelin and Appetite.

Objective: The ketones d-β-hydroxybutyrate (BHB) and acetoacetate are elevated during prolonged fasting or during a "ketogenic" diet. Although weight loss on a ketogenic diet may be associated with decreased appetite and altered gut hormone levels, it is unknown whether such changes are caused by elevated blood ketones. This study investigated the effects of an exogenous ketone ester (KE) on appetite.

Inhibition of sarcolemmal FAT/CD36 by sulfo-N-succinimidyl oleate rapidly corrects metabolism and restores function in the diabetic heart following hypoxia/reoxygenation.

Aims: The type 2 diabetic heart oxidizes more fat and less glucose, which can impair metabolic flexibility and function. Increased sarcolemmal fatty acid translocase (FAT/CD36) imports more fatty acid into the diabetic myocardium, feeding increased fatty acid oxidation and elevated lipid deposition. Unlike other metabolic modulators that target mitochondrial fatty acid oxidation, we proposed that pharmacologically inhibiting fatty acid uptake, as the primary step in the pathway, would provide an alternative mechanism to rebalance metabolism and prevent lipid accumulation following hypoxic stress.

Incidence, aetiology and outcome of community-acquired acute kidney injury in medical admissions in Malawi.

Background: Epidemiological data on Acute Kidney Injury (AKI) from low-income countries is sparse. The aim of this study was to establish the incidence, severity, aetiology, and outcomes of community-acquired AKI in Malawi.

Methods: We conducted a prospective observational study of general medical admissions to a tertiary hospital in Blantyre between 27 April and 17 July 2015.

On the pivotal role of PPARα in adaptation of the heart to hypoxia and why fat in the diet increases hypoxic injury.

The role of peroxisome proliferator-activated receptor α (PPARα)-mediated metabolic remodeling in cardiac adaptation to hypoxia has yet to be defined. Here, mice were housed in hypoxia for 3 wk before in vivo contractile function was measured using cine MRI. In isolated, perfused hearts, energetics were measured using (31)P magnetic resonance spectroscopy (MRS), and glycolysis and fatty acid oxidation were measured using [(3)H] labeling.

The role of triacylglycerol in cardiac energy provision.

Triacylglycerols (TAGs) constitute the main energy storage resource in mammals, by virtue of their high energy density. This in turn is a function of their highly reduced state and hydrophobicity. Limited water solubility, however, imposes specific requirements for delivery and uptake mechanisms on TAG-utilising tissues, including the heart, as well as intracellular disposition.

Tubulointerstitial nephritis in primary Sjögren syndrome: clinical manifestations and response to treatment.

Background: Primary Sjögren syndrome (pSS) is a common autoimmune condition which primarily affects epithelial tissue, often including the kidney causing either tubulointerstitial nephritis (TIN) or more rarely, an immune complex related glomerulonephritis.

Methods: We describe the clinical, biochemical and histological characteristics of 12 patients with pSS related TIN and their response to treatment with antiproliferative agents. All 12 patients were investigated and treated at the UCL Centre for Nephrology in London.

Varying degrees of ventricular unloading in the heterotopic rat heart transplant model demonstrated by magnetic resonance imaging.

Objective: Left ventricular assist device placement is an increasingly common treatment for cardiac failure, resulting in cardiac unloading and potentially reversing the remodelling changes seen in heart failure. A popular animal model for human ventricular unloading is the rodent heterotopic non-working heart transplant; the volume loading status of this preparation is important to interpreting the resulting reverse remodelling yet has not been previously investigated. This study was designed to assess the variability of left ventricular volume loading in the rodent transplant model.

Changes to both cardiac metabolism and performance accompany acute reductions in functional capillary supply.

Background: The relative importance of arteriole supply or ability to switch between substrates to preserve cardiac performance is currently unclear, but may be critically important in conditions such as diabetes.

Methods: Metabolism of substrates was measured before and after infusion of polystyrene microspheres in the perfused working heart to mimic random capillary loss due to microvascular disease. The effect of acute loss of functional capillary supply on palmitate and glucose metabolism together with function was quantified, and theoretical tissue oxygen distribution calculated from histological samples and ventricular VO(2) estimated.

Antioxidant treatment improves neonatal survival and prevents impaired cardiac function at adulthood following neonatal glucocorticoid therapy.

Glucocorticoids are widely used to treat chronic lung disease in premature infants but their longer-term adverse effects on the cardiovascular system raise concerns. We reported that neonatal dexamethasone treatment in rats induced in the short term molecular indices of cardiac oxidative stress and cardiovascular tissue remodelling at weaning, and that neonatal combined antioxidant and dexamethasone treatment was protective at this time. In this study, we investigated whether such effects of neonatal dexamethasone have adverse consequences for NO bioavailability and cardiovascular function at adulthood, and whether neonatal combined antioxidant and dexamethasone treatment is protective in the adult.

Differential translocation of the fatty acid transporter, FAT/CD36, and the glucose transporter, GLUT4, coordinates changes in cardiac substrate metabolism during ischemia and reperfusion.

Background: Fatty acid and glucose transporters translocate between the sarcolemma and intracellular compartments to regulate substrate metabolism acutely. We hypothesised that during ischemia fatty acid translocase (FAT/CD36) would translocate away from the sarcolemma to limit fatty acid uptake when fatty acid oxidation is inhibited.

Methods And Results: Wistar rat hearts were perfused during preischemia, low-flow ischemia, and reperfusion, using (3)H-substrates for measurement of metabolic rates, followed by metabolomic analysis and subcellular fractionation.

Myocardial substrate metabolism in heart disease.

Cardiac disease is commonly associated with changes in energy substrate metabolism. Fatty acid and glucose represent the main fuels used by the heart, and characteristic alterations in substrate preference and utilisation occur early in many cardiac disease processes. Different substrate classes (lipids, carbohydrates) have different metabolic efficiencies, both in terms of energy (ATP) yield and in terms of oxygen requirement; changes in metabolic efficiency may affect, positively and negatively, cardiac function.

Very-low-density lipoprotein: complex particles in cardiac energy metabolism.

The heart is a major consumer of energy and is able to utilise a wide range of substrates including lipids. Nonesterified fatty acids (NEFA) were thought to be a favoured carbon source, but their quantitative contribution is limited because of their relative histotoxicity. Circulating triacylglycerols (TAGs) in the form of chylomicrons (CMs) and very-low-density lipoprotein (VLDL) are an alternative source of fatty acids and are now believed to be important in cardiac metabolism.

Adenosine monophosphate-activated protein kinase activation, substrate transporter translocation, and metabolism in the contracting hyperthyroid rat heart.

Thyroid hormones can modify cardiac metabolism via multiple molecular mechanisms, yet their integrated effect on overall substrate metabolism is poorly understood. Here we determined the effect of hyperthyroidism on substrate metabolism in the isolated, perfused, contracting rat heart. Male Wistar rats were injected for 7 d with T(3) (0.

Spinal epidural abscess: a rare complication of olecranon bursitis.

Spinal epidural abscess is a rare but potentially fatal condition if left untreated. We report the case of a 67-year old man who presented to the Accident and Emergency department complaining of acute onset of inter-scapular back pain, left leg weakness and loss of sensation in the left foot. On examination he was found to be pyrexial with long tract signs in the left lower leg.

Myocardial metabolism of triacylglycerol-rich lipoproteins in type 2 diabetes.

Cardiac utilisation of very-low-density lipoprotein (VLDL) and chylomicrons (CM) was investigated in the ZDF rat model of type 2 diabetes, in order to define the role of triacylglycerol (TAG) metabolism in the development of contractile dysfunction. Hearts from obese diabetic and lean littermate control rats were perfused with VLDL and CM from diabetic and control rats. Metabolic fate of the lipoprotein TAG and contractile function were examined.

Metabolism of very-low-density lipoprotein and chylomicrons by streptozotocin-induced diabetic rat heart: effects of diabetes and lipoprotein preference.

Very-low-density lipoprotein (VLDL) and chylomicrons (CM) are major sources of fatty acid supply to the heart, but little is known about their metabolism in diabetic myocardium. To investigate this, working hearts isolated from control rats and diabetic rats 2 wk following streptozotocin (STZ) injection were perfused with control and diabetic lipoproteins. Analysis of the diabetic lipoproteins showed that both VLDL and CM were altered compared with control lipoproteins; both were smaller and had different apolipoprotein composition.

Fatty acid transporter levels and palmitate oxidation rate correlate with ejection fraction in the infarcted rat heart.

Objectives: Cardiac fatty acid uptake occurs predominantly via sarcolemmal transporter proteins; fatty acid translocase (FAT/CD36), plasma membrane fatty acid binding protein (FABPpm) and fatty acid transporter proteins (FATP) 1 and 6. We hypothesised that levels of the fatty acid transporters would be reduced in the chronically infarcted rat heart, in parallel with reduced dependence on fatty acid utilisation.

Methods And Results: In vivo left ventricular ejection fractions, measured using echocardiography, were 36% lower in rats six months after coronary artery ligation than in sham-operated control rats.

Utilization of triacylglycerol-rich lipoproteins by the working rat heart: routes of uptake and metabolic fates.

Very-low-density lipoprotein (VLDL) and chylomicrons (CMs) transport triacylglycerol (TAG) to peripheral tissues. Lipoprotein-TAG may gain access to target cells by lipoprotein lipase (LPL) hydrolysis or via receptor-mediated uptake; the principal routes of entry of VLDL and CM into heart are unknown, and different routes of entry may result in different metabolic fates. To examine this, isolated working rat hearts were perfused with rat VLDL and CMs, dual-labelled with [3H]TAG and [14C]cholesterol.