Search

Aims: Impaired energy metabolism has been implicated in the pathogenesis of heart failure. Hyperpolarized (13)C magnetic resonance (MR), in which (13)C-labelled metabolites are followed using MR imaging (MRI) or spectroscopy (MRS), has enabled non-invasive assessment of pyruvate metabolism. We investigated the hypothesis that if we serially examined a model of heart failure using non-invasive hyperpolarized [(13)C]pyruvate with MR, the profile of in vivo pyruvate oxidation would change throughout the course of the disease.Methods and Results: Dilated cardiomyopathy (DCM) was induced in pigs (n = 5) by rapid pacing. Pigs were examined using MR at weekly time points: cine-MRI assessed cardiac structure and function; hyperpolarized [2-(13)C]pyruvate was administered intravenously, and (13)C MRS monitored [(13)C]glutamate production; (31)P MRS assessed cardiac energetics [phosphocreatine (PCr)/ATP]; and hyperpolarized [1-(13)C]pyruvate was administered for MRI of pyruvate dehydrogenase complex (PDC)-mediated pyruvate oxidation via [(13)C]bicarbonate production. Early in pacing, the cardiac index decreased by 25%, PCr/ATP decreased by 26%, and [(13)C]glutamate production decreased by 51%. After clinical features of DCM appeared, end-diastolic volume increased by 40% and [(13)C]bicarbonate production decreased by 67%. Pyruvate dehydrogenase kinase 4 protein increased by two-fold, and phosphorylated Akt decreased by half. Peroxisome proliferator-activated receptor-α and carnitine palmitoyltransferase-1 gene expression decreased by a half and a third, respectively.Conclusion: Despite early changes associated with cardiac energetics and (13)C incorporation into the Krebs cycle, pyruvate oxidation was maintained until DCM developed, when the heart's capacity to oxidize both pyruvate and fats was reduced. Hyperpolarized (13)C MR may be important to characterize metabolic changes that occur during heart failure progression. [ABSTRACT FROM AUTHOR]

Objective: It is recognized that there is a remarkable variability in the systemic response to high-fat (HF) diets that cannot be completely explained by genetic factors. In addition, pregnancy complications leading to intrauterine growth restriction (IUGR) have been associated with an increased risk of developing metabolic syndrome (MetS) later in life. Thus, we hypothesized that offspring born with IUGR exhibit permanent metabolic changes that make them more susceptible to HF diet-induced MetS.Research Design and Methods: SD rats born normal (control) or with hypoxia-induced IUGR were randomized to low-fat (10% fat) or HF (45% fat) diets. After 9 weeks of feeding, physiological and molecular pathways involved in the MetS were evaluated.Results: IUGR offspring exhibited decreased energy intake and physical activity relative to controls. In offspring fed a HF diet, IUGR was associated with decreased total body fat content, a relative increase in intra-abdominal fat deposition and adipocyte size, an increase in fasting plasma concentrations of leptin, triglyceride and free fatty acids, and an increased concentration of triglycerides and ceramides in both liver and skeletal muscle. These changes in lipid homeostasis were accompanied by in vivo insulin resistance and impaired glucose tolerance and associated with increased phosphorylation of protein kinase C , inhibition of insulin receptor substrate 1, and a decreased activation of protein kinase B (PKB; also known as Akt) in liver and skeletal muscle in response to insulin.Conclusions: IUGR enhances specific deleterious metabolic responses to a HF diet. Our results suggest that offspring born with IUGR may require special attention and follow-up to prevent the early onset of MetS. [ABSTRACT FROM AUTHOR]

Objective: The sodium-calcium exchanger isoform 1 (NCX1) regulates cytoplasmic calcium (Ca(2+)(c)) required for insulin secretion in beta-cells. NCX1 is alternatively spliced, resulting in the expression of splice variants in different tissues such as NCX1.3 and -1.7 in beta-cells. As pharmacological inhibitors of NCX1 splice variants are in development, the pharmacological profile of beta-cell NCX1.3 and -1.7 and the cellular effects of NCX1 inhibition were investigated.Research Design and Methods: The patch-clamp technique was used to examine the pharmacological profile of the NCX1 inhibitor KB-R7943 on recombinant NCX1.3 and -1.7 activity. Ca(2+) imaging and membrane capacitance were used to assess the effects of KB-R7943 on Ca(2+)(c) and insulin secretion in mouse and human beta-cells and islets.Results: NCX1.3 and -1.7 calcium extrusion (forward-mode) activity was approximately 16-fold more sensitive to KB-R7943 inhibition compared with cardiac NCX1.1 (IC(50s) = 2.9 and 2.4 vs. 43.0 micromol/l, respectively). In single mouse/human beta-cells, 1 micromol/l KB-R7943 increased insulin granule exocytosis but was without effect on alpha-cell glucagon granule exocytosis. KB-R7943 also augmented sulfonylurea and glucose-stimulated Ca(2+)(c) levels and insulin secretion in mouse and human islets, although KB-R7943 was without effect under nonstimulated conditions.Conclusions: Islet NCX1 splice variants display a markedly greater sensitivity to pharmacological inhibition than the cardiac NCX1.1 splice variant. NCX1 inhibition resulted in glucose-dependent increases in Ca(2+)(c) and insulin secretion in mouse and human islets. Thus, we identify beta-cell NCX1 splice variants as targets for the development of novel glucose-sensitive insulinotropic drugs for type 2 diabetes. [ABSTRACT FROM AUTHOR]

A voltage reference has been developed to bias ring electrodes of two Penning traps between -90 and 0 V. For output voltages near -90 V, the Allan deviation of the system’s voltage instability is less than 1 part in 108 over all time scales shorter than 104 s. For averaging times longer than several seconds, the system’s stability is determined almost completely by the noise, drift, and aging of the zener diodes in the array of voltage reference integrated circuits. For shorter averaging times, active filters built into the new system significantly reduce the intrinsic noise of the zener diodes. The system makes it possible to continuously adjust the ring voltages for frequency locking the axial motion in the two Penning traps. By keeping electrical noise highly correlated between the two traps, measurement uncertainty should be reduced for precision experiments such as Penning trap mass spectrometry. [ABSTRACT FROM AUTHOR]

The University of Washington Penning Trap Mass Spectrometer (UW-PTMS) is now producing measurements with uncertainties approaching 10 parts per trillion (ppt). We have recently published (Van Dyck, Jr. et al., Int J Mass Spectrom 251:231–242, ) detailed analysis of several systematic shifts which can be important at this level of accuracy. Experimental studies of these effects in our older PTMS, combined with preliminary analysis of 2H data, and re-analysis of the previously reported 4He (Van Dyck, Jr. et al., Phys Rev Lett 92:220802/1, ) and 16O (Van Dyck, Jr. et al., Hyperfine Interact 132:163–175, ) data, gives more accurate atomic mass values for 16O, 4He, and 2H. Currently we are taking data for a new measurement of the 3He atomic mass, and working on some improvements to the PTMS, including a new amplifier system for phase-sensitive detection of the ion’s axial motion, and a new computer-controlled ultra-stable voltage source for the Penning trap’s ring electrode, used to adjust the ion’s axial frequency. These new systems will allow us to simultaneously manipulate individual ions in two nearby Penning traps, and some sources of noise will be the same for both traps. We plan to investigate several techniques which should reduce measurement time and improve accuracy by working with the two ions simultaneously. [ABSTRACT FROM AUTHOR]

Describes a custom-designed magnet/cryostat system that has demonstrated improved field stability over previous designs. Shielding from external magnetic noise; Remote sensing of changes in magnetic field; Basic superconducting solenoid's inclusion of a passive flux-stabilizing coil; Stabilization of internal field shifts; Composite shielding factor of the whole system.

Aims: Measures of structural and functional remodelling of the left atrium (LA) are emerging as useful biomarkers in heart failure (HF). We hypothesized that LA volume and its contribution to stroke volume (SV) would predict a composite endpoint of HF hospitalization or death in patients with HF., Methods and Results: We recruited 57 controls and 86 patients with HF, including preserved and reduced left ventricular ejection fraction (LVEF). Cardiac magnetic resonance imaging was used to evaluate LA volumes and contribution to LV SV. Plasma mid-region pro-atrial natriuretic peptide (MR-proANP) was evaluated. LA volume was negatively correlated with LVEF (P = 0.001) and positively correlated with LV mass in HFrEF (P < 0.001) but not in HFpEF. LA volume at end-diastole was associated with the composite endpoint in HFrEF (hazard ratio 1.26, 95% confidence interval 1.01-1.54; P = 0.044), but not HFpEF (1.06, 0.85-1.30; P = 0.612), per 10 mL/m increase. Active contribution to SV was negatively associated with the composite endpoint in HFpEF (0.32, 0.14-0.66; P = 0.001), but not HFrEF (0.91, 0.38-2.1; P = 0.828) per 10% increase. MR-proANP was associated with the composite endpoint in HFpEF (1.46, 1.03-1.94; P = 0.034), but not in HFrEF (1.14, 0.88-1.37; P = 0.278), per 100 pM increase., Conclusion: We found different relationships between LA remodelling and biomarkers in HFrEF and HFpEF. Our results support the hypothesis that the pathophysiologic underpinnings of HFpEF and HFrEF are different, and atrial remodelling encompasses distinct components for each HF subtype., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Aims: Heart failure with a preserved ejection fraction (HF-PEF) remains a difficult clinical diagnosis. The aim of this study was to test the utility of established criteria to classify patients with HF-PEF. We prospectively enrolled patients into one of five groups across a spectrum of cardiac disease and applied three different criteria for HF-PEF and calculated diagnostic metrics., Methods and Results: A total of 565 patients were included in the analysis, including 170 patients with an adjudicated diagnosis of HF-PEF, 152 patients with heart failure with reduced ejection fraction, 152 patients at risk for heart failure, and 91 age-matched healthy controls. For the diagnosis of HF-PEF, the positive likelihood ratios were 6.1, 6.9, and 4.8 for the Zile, European Society of Cardiology (ESC) 2007, and ESC 2016 criteria, respectively. The negative likelihood ratios were 0.58, 0.60, and 0.42 for the Zile, ESC 2007, and ESC 2016 criteria, respectively. All three criteria lacked sensitivity to detect HF-PEF (46.5%, 44.1%, and 51.8%, respectively) but were highly specific (92.4%, 93.9%, and 89%, respectively). We further evaluated the criteria to distinguish HF-PEF from other diagnoses after excluding heart failure with reduced ejection fraction; the results were similar., Conclusions: In this community based cohort, the likelihood ratios of the existing criteria for HF-PEF were not at the level necessary to be considered diagnostic. Improved criteria for the diagnosis of patients with HF-PEF are needed., (© 2017 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

We investigated whether treatment of mice with established pressure overload-induced heart failure (HF) with the naturally occurring polyphenol resveratrol could improve functional symptoms of clinical HF such as fatigue and exercise intolerance. C57Bl/6N mice were subjected to either sham or transverse aortic constriction surgery to induce HF. Three weeks postsurgery, a cohort of mice with established HF (%ejection fraction <45) was administered resveratrol (~450 mg·kg -1 ·day -1 ) or vehicle for 2 wk. Although the percent ejection fraction was similar between both groups of HF mice, those mice treated with resveratrol had increased total physical activity levels and exercise capacity. Resveratrol treatment was associated with altered gut microbiota composition, increased skeletal muscle insulin sensitivity, a switch toward greater whole body glucose utilization, and increased basal metabolic rates. Although muscle mass and strength were not different between groups, mice with HF had significant declines in basal and ADP-stimulated O 2 consumption in isolated skeletal muscle fibers compared with sham mice, which was completely normalized by resveratrol treatment. Overall, resveratrol treatment of mice with established HF enhances exercise performance, which is associated with alterations in whole body and skeletal muscle energy metabolism. Thus, our preclinical data suggest that resveratrol supplementation may effectively improve fatigue and exercise intolerance in HF patients. NEW & NOTEWORTHY Resveratrol treatment of mice with heart failure leads to enhanced exercise performance that is associated with altered gut microbiota composition, increased whole body glucose utilization, and enhanced skeletal muscle metabolism and function. Together, these preclinical data suggest that resveratrol supplementation may effectively improve fatigue and exercise intolerance in heart failure via these mechanisms., (Copyright © 2017 the American Physiological Society.)

Since left ventricular hypertrophy (LVH) increases the susceptibility for the development of other cardiac conditions, pharmacotherapy that mitigates pathological cardiac remodeling may prove to be beneficial in patients with LVH. Previous work has shown that the activation of the energy-sensing kinase AMP-activated protein kinase (AMPK) can inhibit some of the molecular mechanisms that are involved in LVH. Of interest, metformin activates AMPK through its inhibition of mitochondrial complex I in the electron transport chain and can prevent LVH induced by pressure overload. However, metformin has additional cellular effects unrelated to AMPK activation, raising questions about whether mitochondrial complex I inhibition is sufficient to reduce LVH. Herein, we characterize the cardiac effects of a novel compound (R118), which is a more potent complex I inhibitor than metformin and is thus used at a much lower concentration. We show that R118 activates AMPK in the cardiomyocyte, inhibits multiple signaling pathways involved in LVH, and prevents G q protein-coupled receptor agonist-induced prohypertrophic signaling. We also show that in vivo administration of R118 prevents LVH in a mouse model of hypertension, suggesting that R118 can directly modulate the response of the cardiomyocyte to stress. Of importance, we also show that while R118 treatment prevents adaptive remodelling in response to elevated afterload, it does so without compromising systolic function, improves myocardial energetics, and prevents a decline in diastolic function in hypertensive mice. Taken together, our data suggest that inhibition of mitochondrial complex I may be worthy of future investigation for the treatment of LVH. NEW & NOTEWORTHY Inhibition of mitochondrial complex I by R118 reduces left ventricular hypertrophy (LVH) and improves myocardial energetics as well as diastolic function without compromising systolic function. Together, these effects demonstrate the therapeutic potential of complex I inhibitors in the treatment of LVH, even in the presence of persistent hypertension., (Copyright © 2017 the American Physiological Society.)

Previous studies have shown that loss of CD36 protects the heart from dysfunction induced by pressure overload in the presence of diet-induced insulin resistance and/or obesity. The beneficial effects of CD36 ablation in this context are mediated by preventing excessive cardiac fatty acid (FA) entry and reducing lipotoxic injury. However, whether or not the loss of CD36 can prevent pressure overload-induced cardiac dysfunction in the absence of chronic exposure to high circulating FAs is presently unknown. To address this, we utilized a tamoxifen-inducible cardiomyocyte-specific CD36 knockout (icCD36KO) mouse and genetically deleted CD36 in adulthood. Control mice (CD36 floxed/floxed mice) and icCD36KO mice were treated with tamoxifen and subsequently subjected to transverse aortic constriction (TAC) surgery to generate pressure overload-induced cardiac hypertrophy. Consistent with CD36 mediating a significant proportion of FA entry into the cardiomyocyte and subsequent FA utilization for ATP production, hearts from icCD36KO mice were metabolically inefficient and displayed signs of energetic stress, including activation of the energetic stress kinase, AMPK. In addition, impaired energetics in icCD36KO mice contributed to a rapid progression from compensated hypertrophy to heart failure. However, icCD36KO mice fed a medium-chain FA diet, whereby medium-chain FAs can enter into the cardiomyocyte independent from CD36, were protected from TAC-induced heart failure. Together these data suggest that limiting FA uptake and partial inhibition of FA oxidation in the heart via CD36 ablation may be detrimental for the compensated hypertrophic heart in the absence of sufficiently elevated circulating FAs to provide an adequate energy source. NEW & NOTEWORTHY Limiting CD36-mediated fatty acid uptake in the setting of obesity and/or insulin resistance protects the heart from cardiac hypertrophy and dysfunction. However, cardiomyocyte-specific CD36 ablation in the absence of elevated circulating fatty acid levels accelerates the progression of pressure overload-induced cardiac hypertrophy to systolic heart failure., (Copyright © 2017 the American Physiological Society.)

Introduction: This study on mild cognitive impairment (MCI) in heart failure (HF) compares the utility of Montreal Cognitive Assessment (MoCA) to the Mini-Mental Status Exam (MMSE) for diagnosing MCI in a HF population when compared to the golden standard European Consortium Criteria (ECC)., Methods: Participants were recruited from the Alberta HEART study at the Mazankowski Alberta Heart Institute in Edmonton and St. Mary's hospital in Camrose. This study enrolled 53 community adults aged>50years: 33 HF and 20 controls. Participants were assessed using both the MMSE and MoCA for MCI. MCI was diagnosed using the golden standard, European Consortium Criteria. Sensitivity and specificity analysis, positive and negative predictive values, likelihood ratios and kappa statistic were calculated., Results: The mean age was 72.8years (SD 8.4), 60.4% were females and 34% had underlying ischemic heart disease. Overall, two thirds of patients (22/33, 66%) with HF had MCI. In comparison to European Consortium Criteria, the sensitivity and specificity of MoCA were 82% and 91% in identifying individuals with MCI, and MMSE were 9% and 91%, respectively. The positive and negative predictive values for MoCA were 95% and 71%, and for MMSE were 67% and 33%, respectively. Kappa statistics showed good agreement between MoCA and consortium criteria (kappa=0.68) and a low agreement between MMSE and consortium criteria (kappa=0.07)., Conclusion: Cognitive dysfunction is common in patients with HF. Overall, the MoCA seems to be a better screening tool than MMSE for MCI in HF patients., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Although insulin resistance (IR) is a key factor in the pathogenesis of type 2 diabetes (T2D), the precise role of insulin in the development of IR remains unclear. Therefore, we investigated whether chronic basal insulin infusion is causative in the development of glucose intolerance., Methods: Normoglycemic lean rats surgically instrumented with i.v. catheters were infused with insulin (3mU/kg/min) or physiological saline for 6weeks. At infusion-end, plasma insulin levels along with glucose tolerance were assessed., Results: Six weeks of insulin infusion induced glucose intolerance and impaired insulin response in healthy rats. Interestingly, the effects of chronic insulin infusion were completely normalized following 24h withdrawal of exogenous insulin and plasma insulin response to glucose challenge was enhanced, suggesting improved insulin secretory capacity. As a result of this finding, we assessed whether the effects of insulin therapy followed by a washout could ameliorate established glucose intolerance in obese rats. Obese rats were similarly instrumented and infused with insulin or physiological saline for 7days followed by 24h washout. Seven day-insulin therapy in obese rats significantly improved glucose tolerance, which was attributed to improved insulin secretory capacity and improved insulin signaling in liver and skeletal muscle., Conclusion: Moderate infusion of insulin alone is sufficient to cause glucose intolerance and impair endogenous insulin secretory capacity, whereas short-term, intensive insulin therapy followed by insulin removal effectively improves glucose tolerance, insulin response and peripheral insulin sensitivity in obese rats., General Significance: New insight into the link between insulin and glucose intolerance may optimize T2D management., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Oral administration of resveratrol is able to improve glucose homeostasis in obese individuals. Herein we show that resveratrol ingestion produces taxonomic and predicted functional changes in the gut microbiome of obese mice. In particular, changes in the gut microbiome were characterized by a decreased relative abundance of Turicibacteraceae, Moryella, Lachnospiraceae, and Akkermansia and an increased relative abundance of Bacteroides and Parabacteroides Moreover, fecal transplantation from healthy resveratrol-fed donor mice is sufficient to improve glucose homeostasis in obese mice, suggesting that the resveratrol-mediated changes in the gut microbiome may play an important role in the mechanism of action of resveratrol., (© 2017 by the American Diabetes Association.)

Perturbations in cardiac energy metabolism are major contributors to a number of cardiovascular pathologies. In addition, comorbidities associated with cardiovascular disease (CVD) can alter systemic and myocardial metabolism, often contributing to the worsening of cardiac function and health outcomes. State-of-the-art metabolomic technologies give us the ability to measure thousands of metabolites in biological fluids or biopsies, providing us with a metabolic fingerprint of individual patients. These metabolic profiles may serve as diagnostic and/or prognostic tools that have the potential to significantly alter the management of CVD. Herein, the authors review how metabolomics can assist in the interpretation of perturbed metabolic processes, and how this has improved our ability to understand the pathology of ischemic heart disease, atherosclerosis, and heart failure. Taken together, the integration of metabolomics with other "omics" platforms will allow us to gain insight into pathophysiological interactions of metabolites, proteins, genes, and disease states, while advancing personalized medicine., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Cellular energy homeostasis is a fundamental process that governs the overall health of the cell and is paramount to cell survival. Central to this is the control of ATP generation and utilization, which is regulated by a complex myriad of enzymatic reactions controlling cellular metabolism. In the cardiomyocyte, ATP generated from substrate catabolism is used for numerous cellular processes including maintaining ionic homeostasis, cell repair, protein synthesis and turnover, organelle turnover, and contractile function. In many instances, cardiovascular disease is associated with impaired cardiac energetics and thus the signalling that regulates pathways involved in cardiomyocyte metabolism may be potential targets for pharmacotherapy designed to help treat cardiovascular disease. An important regulator of cardiomyocyte energy homeostasis is adenosine monophosphate-activated protein kinase (AMPK). AMPK is a serine-threonine kinase that functions primarily as a metabolic sensor to coordinate anabolic and catabolic activities in the cell via the phosphorylation of multiple proteins involved in metabolic pathways. In addition to the direct role that AMPK plays in the regulation of cardiomyocyte metabolism, AMPK can also either directly or indirectly influence other cellular processes such as regulating mitochondrial function, post-translation acetylation, autophagy, mitophagy, endoplasmic reticulum stress, and apoptosis. Thus, AMPK is implicated in the control of a wide variety of cellular processes that can influence cardiomyocyte health and survival. In this review, we will discuss the important role that AMPK plays in regulating cardiac metabolism, as well as the additional cellular processes that may contribute to cardiomyocyte function and survival in the healthy and the diseased heart. This article is part of a Special Issue entitled: The role of post-translational protein modifications on heart and vascular metabolism edited by Jason R.B. Dyck & Jan. F.C. Glatz., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The goals of the current study were to compare leg blood flow, oxygen extraction and oxygen uptake (VO2) after constant load sub-maximal unilateral knee extension (ULKE) exercise in patients with heart failure with reduced ejection fraction (HFrEF) compared to those with preserved ejection fraction (HFpEF). Previously, it has been shown that prolonged whole body VO2 recovery kinetics are directly related to disease severity and all-cause mortality in HFrEF patients. To date, no study has simultaneously measured muscle-specific blood flow and oxygen extraction post exercise recovery kinetics in HFrEF or HFpEF patients; therefore it is unknown if muscle VO2 recovery kinetics, and more specifically, the recovery kinetics of blood flow and oxygen extraction at the level of the muscle, differ between HF phenotypes. Ten older (68±10yrs) HFrEF (n = 5) and HFpEF (n = 5) patients performed sub-maximal (85% of maximal weight lifted during an incremental test) ULKE exercise for 4 minutes. Femoral venous blood flow and venous O2 saturation were measured continuously from the onset of end-exercise, using a novel MRI method, to determine off-kinetics (mean response times, MRT) for leg VO2 and its determinants. HFpEF and HFrEF patients had similar end-exercise leg blood flow (1.1±0.6 vs. 1.2±0.6 L/min, p>0.05), venous saturation (42±12 vs. 41±11%, p>0.05) and VO2 (0.13±0.08 vs. 0.11±0.05 L/min, p>0.05); however HFrEF had significantly delayed recovery MRT for flow (292±135sec. vs 105±63sec., p = 0.004) and VO2 (95±37sec. vs. 47±15sec., p = 0.005) compared to HFpEF. Impaired muscle VO2 recovery kinetics following ULKE exercise differentiated HFrEF from HFpEF patients and suggests distinct underlying pathology and potential therapeutic approaches in these populations., Competing Interests: The authors have declared that no competing interests exist.

Since the heart has one of the highest energy requirements of all organs in the body, it requires a constant and plentiful supply of fuel to function properly. Mitochondrial oxidation of lipids provides a major source of ATP for the heart, and the cellular processes that regulate lipid uptake and utilization are important contributors to maintaining proper myocardial energetic status. Although numerous proteins are coordinately regulated in order to ensure proper fatty acid utilization in the cardiomyocyte, a key first step in this process is the entry of fatty acids into the cell. An important protein involved in the transport of fatty acids into the cardiomyocyte is the plasma membrane-associated protein known as fatty acid translocase (FAT; also known as CD36). While multiple proteins are involved in facilitating fatty acid uptake in the heart, CD36 accounts for approximately 50-70% of the total fatty acid taken up in cardiomyocytes. As such, myocardial metabolism of fatty acids may depend upon proper CD36 function. Consistent with this, changes in CD36 levels/function have been implicated in the alteration of myocardial metabolism in the pathophysiology of certain cardiovascular diseases. As such, a better understanding of the role and function of CD36 in the heart may provide important insights for the development of new treatments for specific cardiovascular diseases. Herein, we review the role of CD36 in myocardial lipid metabolism in the healthy heart and describe how CD36-mediated alterations in lipid metabolism may contribute to cardiovascular disease. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Impaired skeletal muscle mitochondrial fatty acid oxidation (mFAO) has been implicated in the etiology of insulin resistance. Carnitine palmitoyltransferase-1 (CPT1) is a key regulatory enzyme of mFAO whose activity is inhibited by malonyl-CoA, a lipogenic intermediate. Whereas increasing CPT1 activity in vitro has been shown to exert a protective effect against lipid-induced insulin resistance in skeletal muscle cells, only a few studies have addressed this issue in vivo. We thus examined whether a direct modulation of muscle CPT1/malonyl-CoA partnership is detrimental or beneficial for insulin sensitivity in the context of diet-induced obesity. By using a Cre-LoxP recombination approach, we generated mice with skeletal muscle-specific and inducible expression of a mutated CPT1 form (CPT1mt) that is active but insensitive to malonyl-CoA inhibition. When fed control chow, homozygous CPT1mt transgenic (dbTg) mice exhibited decreased CPT1 sensitivity to malonyl-CoA inhibition in isolated muscle mitochondria, which was sufficient to substantially increase ex vivo muscle mFAO capacity and whole body fatty acid utilization in vivo. Moreover, dbTg mice were less prone to high-fat/high-sucrose (HFHS) diet-induced insulin resistance and muscle lipotoxicity despite similar body weight gain, adiposity, and muscle malonyl-CoA content. Interestingly, these CPT1mt-protective effects in dbTg-HFHS mice were associated with preserved muscle insulin signaling, increased muscle glycogen content, and upregulation of key genes involved in muscle glucose metabolism. These beneficial effects of muscle CPT1mt expression suggest that a direct modulation of the malonyl-CoA/CPT1 partnership in skeletal muscle could represent a potential strategy to prevent obesity-induced insulin resistance., (Copyright © 2016 the American Physiological Society.)

Background: Cardiac fibrosis attributed to excessive deposition of extracellular matrix proteins is a major cause of heart failure and death. Cardiac fibrosis is extremely difficult and challenging to treat in a clinical setting due to lack of understanding of molecular mechanisms leading to cardiac fibrosis and effective anti-fibrotic therapies. The objective in this study was to examine whether unfolded protein response (UPR) pathway mediates cardiac fibrosis and whether a pharmacological intervention to modulate UPR can prevent cardiac fibrosis and preserve heart function., Methodology/principal Findings: We demonstrate here that the mechanism leading to development of fibrosis in a mouse with increased expression of calreticulin, a model of heart failure, stems from impairment of endoplasmic reticulum (ER) homeostasis, transient activation of the unfolded protein response (UPR) pathway and stimulation of the TGFβ1/Smad2/3 signaling pathway. Remarkably, sustained pharmacologic inhibition of the UPR pathway by tauroursodeoxycholic acid (TUDCA) is sufficient to prevent cardiac fibrosis, and improved exercise tolerance., Conclusions: We show that the mechanism leading to development of fibrosis in a mouse model of heart failure stems from transient activation of UPR pathway leading to persistent remodelling of cardiac tissue. Blocking the activation of the transiently activated UPR pathway by TUDCA prevented cardiac fibrosis, and improved prognosis. These findings offer a window for additional interventions that can preserve heart function.

Aging is associated with the development of chronic diseases such as insulin resistance and type 2 diabetes. A reduction in mitochondrial fat oxidation is postulated to be a key factor contributing to the progression of these diseases. Our aim was to investigate the contribution of impaired mitochondrial fat oxidation toward age-related disease. Mice deficient for malonyl CoA decarboxylase (MCD(-/-)), a mouse model of reduced fat oxidation, were allowed to age while life span and a number of physiological parameters (glucose tolerance, insulin tolerance, indirect calorimetry) were assessed. Decreased fat oxidation in MCD(-/-) mice resulted in the accumulation of lipid intermediates in peripheral tissues, but this was not associated with a worsening of age-associated insulin resistance and, conversely, improved longevity. This improvement was associated with reduced oxidative stress and reduced acetylation of the antioxidant enzyme superoxide dismutase 2 in muscle but not the liver of MCD(-/-) mice. These findings were recapitulated in aged mice treated with an MCD inhibitor (CBM-3001106), and these mice also demonstrated improvements in glucose and insulin tolerance. Therefore, our results demonstrate that in addition to decreasing fat oxidation, MCD inhibition also has novel effects on protein acetylation. These combined effects protect against age-related metabolic dysfunction, demonstrating that MCD inhibitors may have utility in the battle against chronic disease in the elderly., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Aims: Impaired cardiac substrate metabolism plays an important role in heart failure (HF) pathogenesis. Since many of these metabolic changes occur at the transcriptional level of metabolic enzymes, it is possible that this loss of metabolic flexibility is permanent and thus contributes to worsening cardiac function and/or prevents the full regression of HF upon treatment. However, despite the importance of cardiac energetics in HF, it remains unclear whether these metabolic changes can be normalized. In the current study, we investigated whether a reversal of an elevated aortic afterload in mice with severe HF would result in the recovery of cardiac function, substrate metabolism, and transcriptional reprogramming as well as determined the temporal relationship of these changes., Methods and Results: Male C57Bl/6 mice were subjected to either Sham or transverse aortic constriction (TAC) surgery to induce HF. After HF development, mice with severe HF (% ejection fraction < 30) underwent a second surgery to remove the aortic constriction (debanding, DB). Three weeks following DB, there was a near complete recovery of systolic and diastolic function, and gene expression of several markers for hypertrophy/HF were returned to values observed in healthy controls. Interestingly, pressure-overload-induced left ventricular hypertrophy (LVH) and cardiac substrate metabolism were restored at 1-week post-DB, which preceded functional recovery., Conclusions: The regression of severe HF is associated with early and dramatic improvements in cardiac energy metabolism and LVH normalization that precede restored cardiac function, suggesting that metabolic and structural improvements may be critical determinants for functional recovery., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

This study was undertaken to determine whether perinatal maternal resveratrol (Resv)--a phytoalexin known to confer cardiovascular protection--could prevent the development of hypertension and improve vascular function in adult spontaneously hypertensive rat offspring. Dams were fed either a control or Resv-supplemented diet (4 g/kg diet) from gestational day 0.5 until postnatal day 21. Indwelling catheters were used to assess blood pressure and vascular function in vivo; wire myography was used to assess vascular reactivity ex vivo. Perinatal Resv supplementation in dams had no effect on fetal body weights, albeit continued maternal treatment postnatally resulted in growth restriction in offspring by postnatal day 21; growth restriction was no longer evident after 5 weeks of age. Maternal perinatal Resv supplementation prevented the onset of hypertension in adult offspring (-18 mm Hg; P=0.007), and nitric oxide synthase inhibition (with L-NG-nitroarginine methyl ester) normalized these blood pressure differences, suggesting improved nitric oxide bioavailability underlies the hemodynamic alterations in the Resv-treated offspring. In vivo and ex vivo, vascular responses to methylcholine were not different between treatment groups, but prior treatment with L-NG-nitroarginine methyl ester attenuated the vasodilation in untreated, but not Resv-treated adult offspring, suggesting a shift toward nitric oxide-independent vascular control mechanisms in the treated group. Finally, bioconversion of the inactive precursor big endothelin-1 to active endothelin-1 in isolated mesenteric arteries was reduced in Resv-treated offspring (-28%; P<0.05), and this difference could be normalized by L-NG-nitroarginine methyl ester treatment. In conclusion, perinatal maternal Resv supplementation mitigated the development of hypertension and causes persistent alterations in vascular responsiveness in spontaneously hypertensive rats., (© 2016 American Heart Association, Inc.)

Background & Aims: Abnormal iron metabolism and hepatic iron-overload is a major cause of liver injury and in the development of chronic liver diseases. Iron-overload-mediated liver disease leads to end-stage cirrhosis and/or hepatocellular carcinoma., Methods: Using a genetic hemochromatosis (hemojuvelin knockout mice) and non-genetic (secondary iron-overload) murine models of hepatic iron-overload, we elucidated the mechanism of hepatic iron injury and the therapeutic effects of resveratrol., Results: Hepatic iron-overload was associated with hepatosplenomegaly, increased oxidative stress, hepatic fibrosis, and inflammation, and a pro-apoptotic state which was markedly corrected by resveratrol therapy. Importantly our aging studies with the hemojuvelin knockout mice showed advanced liver disease in association with steatosis in the absence of a diabetic state which recapitulates the essential pathological features seen in clinical iron-overload. Chronic hepatic iron-overload showed increased nuclear localization of acetylated Forkhead fox-O-1 (FoxO1) transcription factor whereas resveratrol dietary intervention reversed the acetylation of FoxO1 in association with increased SIRT1 levels which together with its pleotropic antioxidant properties are likely key mechanisms of its therapeutic action. Importantly, resveratrol treatment did not affect the degree of hepatic iron-overload but rather direct protects the liver from iron-mediated injury., Conclusions: Our findings illustrate a novel and definitive therapeutic action of resveratrol and represent an economically feasible therapeutic intervention to treat hepatic iron-overload and liver disease., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Iron-overload cardiomyopathy is a prevalent cause of heart failure on a world-wide basis and is a major cause of mortality and morbidity in patients with secondary iron-overload and genetic hemochromatosis. We investigated the therapeutic effects of resveratrol in acquired and genetic models of iron-overload cardiomyopathy. Murine iron-overload models showed cardiac iron-overload, increased oxidative stress, altered Ca(2+) homeostasis and myocardial fibrosis resulting in heart disease. Iron-overload increased nuclear and acetylated levels of FOXO1 with corresponding inverse changes in SIRT1 levels in the heart corrected by resveratrol therapy. Resveratrol, reduced the pathological remodeling and improved cardiac function in murine models of acquired and genetic iron-overload at varying stages of iron-overload. Echocardiography and hemodynamic analysis revealed a complete normalization of iron-overload mediated diastolic and systolic dysfunction in response to resveratrol therapy. Myocardial SERCA2a levels were reduced in iron-overloaded hearts and resveratrol therapy restored SERCA2a levels and corrected altered Ca(2+) homeostasis. Iron-mediated pro-oxidant and pro-fibrotic effects in human and murine cardiomyocytes and cardiofibroblasts were suppressed by resveratrol which correlated with reduction in iron-induced myocardial oxidative stress and myocardial fibrosis. Resveratrol represents a clinically and economically feasible therapeutic intervention to reduce the global burden from iron-overload cardiomyopathy at early and chronic stages of iron-overload.

It is well known that exercise has a major impact on substrate metabolism for many hours after exercise. However, the regulatory mechanisms increasing lipid oxidation and facilitating glycogen resynthesis in the post-exercise period are unknown. To address this, substrate oxidation was measured after prolonged exercise and during the following 6 h post-exercise in 5´-AMP activated protein kinase (AMPK) α2 and α1 knock-out (KO) and wild-type (WT) mice with free access to food. Substrate oxidation was similar during exercise at the same relative intensity between genotypes. During post-exercise recovery, a lower lipid oxidation (P < 0.05) and higher glucose oxidation were observed in AMPKα2 KO (respiratory exchange ratio (RER) = 0.84 ± 0.02) than in WT and AMPKα1 KO (average RER = 0.80 ± 0.01) without genotype differences in muscle malonyl-CoA or free-carnitine concentrations. A similar increase in muscle pyruvate dehydrogenase kinase 4 (PDK4) mRNA expression in WT and AMPKα2 KO was observed following exercise, which is consistent with AMPKα2 deficiency not affecting the exercise-induced activation of the PDK4 transcriptional regulators HDAC4 and SIRT1. Interestingly, PDK4 protein content increased (63%, P < 0.001) in WT but remained unchanged in AMPKα2 KO. In accordance with the lack of increase in PDK4 protein content, lower (P < 0.01) inhibitory pyruvate dehydrogenase (PDH)-E1α Ser(293) phosphorylation was observed in AMPKα2 KO muscle compared to WT. These findings indicate that AMPKα2 regulates muscle metabolism post-exercise through inhibition of the PDH complex and hence glucose oxidation, subsequently creating conditions for increased fatty acid oxidation., (© 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.)

Modulator of apoptosis 1 (MOAP-1) is a BH3-like protein that plays key roles in cell death or apoptosis. It is an integral partner to the tumor suppressor protein, Ras association domain family 1A (RASSF1A), and functions to activate the Bcl-2 family pro-apoptotic protein Bax. Although RASSF1A is now considered a bona fide tumor suppressor protein, the role of MOAP-1 as a tumor suppressor protein has yet to be determined. In this study, we present several lines of evidence from cancer databases, immunoblotting of cancer cells, proliferation, and xenograft assays as well as DNA microarray analysis to demonstrate the role of MOAP-1 as a tumor suppressor protein. Frequent loss of MOAP-1 expression, in at least some cancers, appears to be attributed to mRNA down-regulation and the rapid proteasomal degradation of MOAP-1 that could be reversed utilizing the proteasome inhibitor MG132. Overexpression of MOAP-1 in several cancer cell lines resulted in reduced tumorigenesis and up-regulation of genes involved in cancer regulatory pathways that include apoptosis (p53, Fas, and MST1), DNA damage control (poly(ADP)-ribose polymerase and ataxia telangiectasia mutated), those within the cell metabolism (IR-α, IR-β, and AMP-activated protein kinase), and a stabilizing effect on microtubules. The loss of RASSF1A (an upstream regulator of MOAP-1) is one of the earliest detectable epigenetically silenced tumor suppressor proteins in cancer, and we speculate that the additional loss of function of MOAP-1 may be a second hit to functionally compromise the RASSF1A/MOAP-1 death receptor-dependent pathway and drive tumorigenesis., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Despite existing therapies, patients with heart failure have a very poor quality of life and a high 1-year mortality rate. Given the impact of this syndrome on health outcomes, research is being directed toward identifying novel strategies to treat heart failure symptoms as well as to prolong survival. One molecule that has been tested in animal models for this purpose is resveratrol. Resveratrol is a naturally occurring polyphenol found in several plants, and administration of resveratrol has been shown to prevent and/or slow the progression of heart failure in animal models of heart failure induced by myocardial infarction, pressure overload, myocarditis, and chemotherapy-induced cardiotoxicity. In addition, some animal studies have shown that resveratrol improves cardiac function and survival when administered as a treatment for established heart failure. Furthermore, as heart failure induces alterations in skeletal muscle and vasculature that also contribute to certain heart failure symptoms, such as fatigue and exercise intolerance, it has also been shown that resveratrol acts on these peripheral tissues to improve skeletal muscle and endothelial/vascular function. Therefore, if these animal studies translate to humans, resveratrol may prove to be a novel therapy for the treatment of heart failure., (© 2015 New York Academy of Sciences.)

Aims: AMP-activated protein kinase (AMPK) is thought to be a central player in regulating myocardial metabolism and its activation has been shown to inhibit cardiac hypertrophy. Recently, mice with muscle-specific deletion of AMPK β1/β2 subunits (AMPKβ1β2-deficient mice, β1β2M-KO) have been generated and possess <10% of normal AMPK activity in muscle. However, how/if dramatic AMPK deficiency alters cardiac metabolism, function, or morphology has not been investigated. Therefore, the aim of this study was to determine whether a significant loss of AMPK activity alters cardiac function, metabolism, and hypertrophy, and whether this may play a role in the pathogenesis of heart failure., Methods and Results: β1β2M-KO mice exhibit an approximate 25% reduction in systolic and diastolic function compared with wild-type (WT) littermates. Despite the well-documented role of AMPK in controlling myocardial energy metabolism, there was no difference in basal glucose and fatty acid oxidation rates between β1β2M-KO and WT mice. However, there was reduced AMPK-mediated phosphorylation of troponin I in β1β2M-KO and reduced ventricular cell shortening in the presence of low Ca(2+), which may explain the impaired cardiac function in these mice. Interestingly, β1β2M-KO mice did not display any signs of compensatory cardiac hypertrophy, which could be attributed to impaired activation of p38 MAPK., Conclusions: β1β2M-KO mice display evidence of dilated cardiomyopathy. This is the first mouse model of AMPK deficiency that demonstrates cardiac dysfunction in the absence of pathological stress and provides insights into the role of AMPK in regulating myocardial function, metabolism, hypertrophy, and the progression to heart failure., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)