Valproic Acid-Associated Hyperammonemia: A Systematic Review.

BACKGROUND: Hyperammonemia is an adverse effect that poses clinical uncertainty around valproic acid (VPA) use. The prevalence of symptomatic and asymptomatic hyperammonemia and its relationship to VPA concentration is not well established. There is also no clear guidance regarding its management. This results in variability in the monitoring and treatment of VPA-induced hyperammonemia. To inform clinical practice, this systematic review aims to summarize evidence available around VPA-associated hyperammonemia and its prevalence, clinical outcomes, and management. METHODS: An electronic search was performed through Ovid MEDLINE, Ovid Embase, Web of Science, and PsycINFO using search terms that identified hyperammonemia in patients receiving VPA. Two reviewers independently performed primary title and abstract screening with a third reviewer resolving conflicting screening results. This process was repeated during the full-text review process. RESULTS: A total of 240 articles were included. Prevalence of asymptomatic hyperammonemia (5%-73%) was higher than symptomatic hyperammonemia (0.7%-22.2%) and occurred within the therapeutic range of VPA serum concentration. Various risk factors were identified, including concomitant medications, liver injury, and defects in carnitine metabolism. With VPA discontinued, most symptomatic patients returned to baseline mental status with normalized ammonia level. There was insufficient data to support routine monitoring of ammonia level for VPA-associated hyperammonemia. CONCLUSIONS: Valproic acid-associated hyperammonemia is a common adverse effect that may occur within therapeutic range of VPA. Further studies are required to determine the benefit of routine ammonia level monitoring and to guide the management of VPA-associated hyperammonemia.

Biventricular Repair in Borderline Left Hearts: Insights From Cardiac Magnetic Resonance Imaging.

Background: Cardiac magnetic resonance imaging (CMR) may augment 2-dimensional (2D) echocardiography in decision-making for biventricular repair in borderline hypoplastic left hearts. Objectives: This study evaluates: 1) the relationship between 2D echocardiography and CMR; 2) imaging variables affecting assignment to biventricular vs non-biventricular management; and 3) variables affecting transplant-free biventricular survival. Methods: We reviewed clinical, echocardiographic, and CMR data in 67 infants, including CMR-determined ascending aortic (AAo) flow and comparable left ventricular end-diastolic volume indexed (LVEDVi) by 2D-echocardiography and CMR. Results: Treatment assignment to biventricular repair was either direct (BV, n = 45) or with a bridging hybrid procedure (H1-BV, n = 12). Echocardiographic LVEDVi was <20 mL/m2 in 83% of biventricular repair infants and underestimated CMR-LVEDVi by 16.8 mL/m2. AAo flows had no/weak correlation with aortic and mitral valve z-scores or LVEDVi. AAo flows differed between BV, H1-BV, and single-ventricle groups (median): 2.1, 1.7, and 0.7 L/min/m2, respectively. Important variables for treatment assignment were presence of endocardial fibroelastosis, AAo flow, and mitral valve z-score. Biventricular repair was achieved in 54. The median follow-up was 8.0 (0.1-16.4) years. Transplant-free biventricular survival was 96%, 82%, and 77% at 1, 5, and 10 years, respectively. Patients without aortic coarctation repair were at higher risk of death, transplantation, or single-ventricle conversion (HR: 54.3; 95% CI: 6.3-47.1; P < 0.001) during follow-up. AAo flow had a smaller nonlinear effect with hazard ratio increasing at lower flows. Conclusions: Historical 2D echocardiographic criteria would have precluded many patients from successful biventricular repair. AAo flow, an integrative index of left heart performance, was important in assigning patients to a biventricular circulation and affected survival. Biventricular survival was strongly associated with the need for aortic coarctation repair.

Current-Era Outcomes of Balloon Aortic Valvotomy in Neonates and Infants.

Background: The optimal initial treatment pathway for aortic valve stenosis remains debated. Objectives: The objective of this study was to review current outcomes of balloon aortic valvotomy (BAV) in neonates and infants. Methods: Neonates and infants with a biventricular circulation treated with BAV between 2004 and 2019 were reviewed. Results: One hundred thirty-nine infants (48% neonates) with median (Q1, Q3) age of 33(7, 84) days and weight 4.0 (3.4, 5.1) kg were followed up for 7.1 (3.3, 11.0) years. BAV reduced peak-to-peak gradient from mean (SD) 52 (16) mmHg to 18 (12) mmHg; P < 0.001. Aortic regurgitation (AI) increased with time after BAV. Three children died during follow-up. Fifty-one reinterventions (26 BAV, 19 aortic valve replacements [AVRs], and 6 surgical valvotomies) were performed on 40 children. Freedom from AVR (95% CI) was 96% (93%-99%) at 1, 91% (86%-96%) at 5, and 86% (79%-93%) at 10 years. The predictors of AVR were a unicommissural valve (hazard ratio [HR] [95% CI]: 3.7 [1.4-9.6]; P = 0.007) and moderate to severe AI after index BAV (HR [95% CI]: 3.3 [1.1-9.7]; P = 0.029). Freedom from reintervention was 84% (78%-90%) at 1, 76% (69%-83%) at 5, and 69% (60-78%) at 10 years. Main predictors of reintervention were age below 1 month (HR [95% CI]: 2.1 [1.1-4.1]; P = 0.032) and postdilation peak-to-peak gradient (per 10-mmHg increase; HR [95% CI]: 1.36 [1.02-1.79]; P = 0.032). Conclusions: BAV is a safe and effective treatment for aortic valve stenosis in neonates and infants. Outcomes are competitive with contemporary published data on aortic valve repair in relation to mortality, gradient relief, long-term AVR, and reintervention rates. In the absence of significant AI, surgery can be reserved for those with gradients resistant to valve dilation.

Palliative Care?! But This Child's Not Dying: The Burgeoning Partnership Between Pediatric Cardiology and Palliative Care.

The field of pediatric cardiology has witnessed major changes over the past few decades that have considerably altered patient outcomes, including decreasing mortality rates for many previously untreatable conditions. Despite this, some pediatric cardiology programs are increasingly choosing to partner with their institutional palliative care teams. Why is this? The field of palliative care also has experienced significant shifts over a similar period of time. Today's palliative care is focused on improving quality of life for any patient with a serious or life-threatening condition, regardless of where they might be on their disease trajectory. Research has clearly demonstrated that improved outcomes can be achieved for a variety of patient cohorts through early integration of palliative care; recent evidence suggests that the same may be true in pediatric cardiology. All pediatric cardiologists need to be aware of what pediatric palliative care has to offer their patients, especially those who are not actively dying. This manuscript reviews the evolution of palliative care and provides a rationale for its integration into the care of children with advanced heart disease. Readers will gain a sense of how and when to introduce palliative care to their families, as well as insight into what pediatric palliative care teams have to offer. Additional research is required to better delineate optimal partnerships between palliative care and pediatric cardiology so that we may promote maximal quality of life for patients concurrently with continued efforts to push the boundaries of quantity of life.

Warfarin Reinitiation After Intracranial Hemorrhage: A Case Series of Heart Valve Patients.

Patients with mechanical heart valves are at high thrombotic risk and require warfarin. Among those developing intracranial hemorrhage, limited data are available to guide clinicians with antithrombotic reinitiation. This 13-patient case series of warfarin-associated intracranial hemorrhages found the time to reinitiate antithrombotic therapy (17 days, interquartile range 21.5 days), and changes to international normalized ratio targets were variable and neither correlated with the type, location, or etiology of bleed, nor the valve and associated thromboembolic risk. The initial presentation significantly impacted prognosis, and diligent assessment and follow-up may support positive long-term outcomes.

A case series of left main coronary artery ostial atresia and a review of the literature.

Left main coronary artery ostial atresia (LMCAOA) is a rare congenital anomaly of the coronary arteries. The published literature regarding the current diagnostic and management recommendations are limited. We present three case series of LMCAOA from our institution, including one with a unique association with anomalous origin of left coronary artery (LCA) from pulmonary artery. In addition, this report includes a review of 50 pediatric and 43 adult cases from literature. The majority of the patients were symptomatic. Sudden cardiac death occurred in 10% of pediatric patients and 7% of adult patients. Almost half of pediatric patients had additional cardiac lesions. At the time of diagnosis, 82% of patients had abnormal exercise stress test and 73% had abnormal myocardial perfusion imaging (MPI). The diagnosis of LMCAOA was suspected by echocardiography in 47% of pediatric patients, while 26% were initially misdiagnosed as anomalous origin of LCA from pulmonary artery. Coronary angiography confirmed the diagnosis in most cases and 70.5% of pediatric patients had small collaterals, while 80.5% of adult patients had large collaterals. Nine pediatric patients had no revascularization surgery with five deaths. Revascularization surgery was performed in 39 pediatric patients with four deaths. After 2005, there is a gradual shift toward performing coronary osteoplasty rather than coronary artery bypass grafting. Eighteen adult patients had revascularization surgery and all survived. Fifteen adult patients had no revascularization surgery, of which there were five deaths. In patients with LMCAOA, revascularization surgery is currently recommended in the presence of symptoms, ischemic changes on electrocardiogram or exercise stress test, myocardial perfusion defect on MPI, global left ventricular systolic dysfunction on echocardiogram, severe mitral regurgitation, or small-sized collaterals in coronary angiography. Short-term and mid-term outcomes are encouraging.

Evaluation of Prescribing Appropriateness and Initiatives to Improve Prescribing of Proton Pump Inhibitors at Vancouver General Hospital.

BACKGROUND: Proton pump inhibitors (PPIs) have proven clinical efficacy for a variety of indications. However, there is emerging evidence of adverse events associated with their long-term use. The emergence of these adverse events has reinforced the need to regularly evaluate the appropriateness of continuing PPI therapy, and to use only the lowest effective dose for the minimally indicated duration. OBJECTIVES: To characterize the appropriateness of PPI orders continued or initiated in the internal medicine and family practice units of Vancouver General Hospital, to detect adverse events associated with PPI use, and to explore the impact of multidisciplinary teaching and provision of educational resources on health care practitioners' views about PPI use. METHODS: A chart review was conducted for patients admitted (for at least 24 hours) between January 1 and December 31, 2015, for whom a hospital formulary PPI was prescribed. An educational initiative, which included interprofessional in-service sessions, a PPI prescribing infographic, a PPI prescribing card, and a patient counselling sheet, was implemented. The impact of these interventions was assessed using a qualitative survey of health care practitioners. RESULTS: Of the 258 patients whose charts were reviewed, 175 had a PPI prescription before hospital admission, and 83 were initiated on PPI therapy during their hospital stay. Overall, 94 (36%) of the patients were receiving PPIs without an appropriate indication. Community-acquired pneumonia and Clostridium difficile infections were the most common adverse events potentially associated with PPI use. In-service sessions and educational resources on PPI prescribing were reported to affect the clinical practice of 24 (52%) of the 46 survey respondents. CONCLUSIONS: The results of this study emphasize the need for ongoing re-evaluation of long-term PPI therapy at the time of admission, during the hospital stay, and upon discharge. Implementing multidisciplinary teaching and providing educational resources may encourage more appropriate prescribing.

CONTEXTE: Les inhibiteurs de la pompe à protons (IPP) ont prouvé leur efficacité clinique pour une gamme d'indications. Cependant, de nouvelles données sur leur utilisation à long terme leur imputent des événements indésirables. L'émergence de ces événements indésirables a renforcé l'idée qu'il est nécessaire d'évaluer régulièrement la pertinence d'un traitement prolongé par IPP et d'employer seulement la plus faible dose efficace pendant la durée indiquée la plus courte. OBJECTIFS: Offrir un portrait de la pertinence des ordonnances d'IPP, renouvelées ou nouvelles, dans les services de médecine interne et de médecine familiale de l'Hôpital général de Vancouver, détecter les événements indésirables liés à l'utilisation des IPP et étudier l'effet qu'ont une formation multidisciplinaire et une fourniture de ressources éducatives sur les points de vue des professionnels de la santé à propos des IPP. MÉTHODES: Une analyse rétrospective de dossiers médicaux a été menée auprès de patients qui ont été admis (pendant au moins 24 heures) entre le 1er janvier et le 31 décembre 2015 et qui se sont vu prescrire un IPP inscrit sur la liste des médicaments de l'hôpital. On a mis en place un programme éducatif comprenant des séances de formation interprofessionnelles internes, un document infographique de prescription des IPP, une carte de prescription des IPP et une fiche de conseils aux patients. L'effet de ces interventions a été évalué à l'aide d'une enquête qualitative auprès des professionnels de la santé. RÉSULTATS: Parmi les 258 patients dont le dossier a été examiné, 175 avaient une ordonnance d'IPP avant l'admission à l'hôpital et 83 ont amorcé un traitement par IPP pendant leur séjour. Dans l'ensemble, 94 (36 %) des patients recevaient un IPP sans indication pertinente. Les infections à Clostridium difficile et les pneumonies extra-hospitalières représentaient les événements indésirables les plus courants potentiellement liés à l'utilisation des IPP. On a signalé que les séances de formation interne et les ressources éducatives sur la prescription des IPP avaient eu un effet sur la pratique clinique de 24 (52 %) des 46 participants à l'enquête. CONCLUSIONS: Les résultats de l'étude font ressortir la nécessité d'une réévaluation continuelle des traitements à long terme par IPP au moment de l'admission, pendant le séjour et lors du congé. La mise en place de formation multidisciplinaire et l'offre de ressources éducatives pourraient favoriser des pratiques de prescription plus adéquates.

Dual effects of hyperglycemia on endothelial cells and cardiomyocytes to enhance coronary LPL activity.

In the diabetic heart, there is excessive dependence on fatty acid (FA) utilization to generate ATP. Lipoprotein lipase (LPL)-mediated hydrolysis of circulating triglycerides is suggested to be the predominant source of FA for cardiac utilization during diabetes. In the heart, the majority of LPL is synthesized in cardiomyocytes and secreted onto cell surface heparan sulfate proteoglycan (HSPG), where an endothelial cell (EC)-releasable ß-endoglycosidase, heparanase cleaves the side chains of HSPG to liberate LPL for its onward movement across the EC. EC glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) captures this released enzyme at its basolateral side and shuttles it across to its luminal side. We tested whether the diabetes-induced increase of transforming growth factor-ß (TGF-ß) can influence the myocyte and EC to help transfer LPL to the vascular lumen to generate triglyceride-FA. In response to high glucose and EC heparanase secretion, this endoglycosidase is taken up by the cardiomyocyte (Wang Y, Chiu AP, Neumaier K, Wang F, Zhang D, Hussein B, Lal N, Wan A, Liu G, Vlodavsky I, Rodrigues B. Diabetes 63: 2643-2655, 2014) to stimulate matrix metalloproteinase-9 expression and the conversion of latent to active TGF-ß. In the cardiomyocyte, TGF-ß activation of RhoA enhances actin cytoskeleton rearrangement to promote LPL trafficking and secretion onto cell surface HSPG. In the EC, TGF-ß signaling promotes mesodermal homeobox 2 translocation to the nucleus, which increases the expression of GPIHBP1, which facilitates movement of LPL to the vascular lumen. Collectively, our data suggest that in the diabetic heart, TGF-ß actions on the cardiomyocyte promotes movement of LPL, whereas its action on the EC facilitates LPL shuttling. NEW & NOTEWORTHY Endothelial cells, as first responders to hyperglycemia, release heparanase, whose subsequent uptake by cardiomyocytes amplifies matrix metalloproteinase-9 expression and activation of transforming growth factor-ß. Transforming growth factor-ß increases lipoprotein lipase secretion from cardiomyocytes and promotes mesodermal homeobox 2 to enhance glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1-dependent transfer of lipoprotein lipase across endothelial cells, mechanisms that accelerate fatty acid utilization by the diabetic heart.

Loss of VEGFB and its signaling in the diabetic heart is associated with increased cell death signaling.

Vascular endothelial growth factor B (VEGFB) is highly expressed in metabolically active tissues, such as the heart and skeletal muscle, suggesting a function in maintaining oxidative metabolic and contractile function in these tissues. Multiple models of heart failure have indicated a significant drop in VEGFB. However, whether there is a role for decreased VEGFB in diabetic cardiomyopathy is currently unknown. Of the VEGFB located in cardiomyocytes, there is a substantial and readily releasable pool localized on the cell surface. The immediate response to high glucose and the secretion of endothelial heparanase is the release of this surface-bound VEGFB, which triggers signaling pathways and gene expression to influence endothelial cell (autocrine action) and cardiomyocyte (paracrine effects) survival. Under conditions of hyperglycemia, when VEGFB production is impaired, a robust increase in vascular endothelial growth factor receptor (VEGFR)-1 expression ensues as a possible mechanism to enhance or maintain VEGFB signaling. However, even with an increase in VEGFR1 after diabetes, cardiomyocytes are unable to respond to VEGFB. In addition to the loss of VEGFB production and signaling, evaluation of latent heparanase, the protein responsible for VEGFB release, also showed a significant decline in expression in whole hearts from animals with chronic or acute diabetes. Defects in these numerous VEGFB pathways were associated with an increased cell death signature in our models of diabetes. Through this bidirectional interaction between endothelial cells (which secrete heparanase) and cardiomyocytes (which release VEGFB), this growth factor could provide the diabetic heart protection against cell death and may be a critical tool to delay or prevent cardiomyopathy.NEW & NOTEWORTHY We discovered a bidirectional interaction between endothelial cells (which secrete heparanase) and cardiomyocytes [which release vascular endothelial growth factor B (VEGFB)]. VEGFB promoted cell survival through ERK and cell death gene expression. Loss of VEGFB and its downstream signaling is an early event following hyperglycemia, is sustained with disease progression, and could explain diabetic cardiomyopathy.

Heparanase Overexpression Induces Glucagon Resistance and Protects Animals From Chemically Induced Diabetes.

Heparanase, a protein with enzymatic and nonenzymatic properties, contributes toward disease progression and prevention. In the current study, a fortuitous observation in transgenic mice globally overexpressing heparanase (hep-tg) was the discovery of improved glucose homeostasis. We examined the mechanisms that contribute toward this improved glucose metabolism. Heparanase overexpression was associated with enhanced glucose-stimulated insulin secretion and hyperglucagonemia, in addition to changes in islet composition and structure. Strikingly, the pancreatic islet transcriptome was greatly altered in hep-tg mice, with >2,000 genes differentially expressed versus control. The upregulated genes were enriched for diverse functions including cell death regulation, extracellular matrix component synthesis, and pancreatic hormone production. The downregulated genes were tightly linked to regulation of the cell cycle. In response to multiple low-dose streptozotocin (STZ), hep-tg animals developed less severe hyperglycemia compared with wild-type, an effect likely related to their ß-cells being more functionally efficient. In animals given a single high dose of STZ causing severe and rapid development of hyperglycemia related to the catastrophic loss of insulin, hep-tg mice continued to have significantly lower blood glucose. In these mice, protective pathways were uncovered for managing hyperglycemia and include augmentation of fibroblast growth factor 21 and glucagon-like peptide 1. This study uncovers the opportunity to use properties of heparanase in management of diabetes.

High glucose facilitated endothelial heparanase transfer to the cardiomyocyte modifies its cell death signature.

AIMS: The secretion of enzymatically active heparanase (HepA) has been implicated as an essential metabolic adaptation in the heart following diabetes. However, the regulation and function of the enzymatically inactive heparanase (HepL) remain poorly understood. We hypothesized that in response to high glucose (HG) and secretion of HepL from the endothelial cell (EC), HepL uptake and function can protect the cardiomyocyte by modifying its cell death signature. METHODS AND RESULTS: HG promoted both HepL and HepA secretion from microvascular (rat heart micro vessel endothelial cells, RHMEC) and macrovascular (rat aortic endothelial cells, RAOEC) EC. However, only RAOEC were capable of HepL reuptake. This occurred through a low-density lipoprotein receptor-related protein 1 (LRP1) dependent mechanism, as LRP1 inhibition using small interfering RNA (siRNA), receptor-associated protein, or an LRP1 neutralizing antibody significantly reduced uptake. In cardiomyocytes, which have a negligible amount of heparanase gene expression, LRP1 also participated in the uptake of HepL. Exogenous addition of HepL to rat cardiomyocytes produced a dramatically altered expression of apoptosis-related genes, and protection against HG and H2O2 induced cell death. Cardiomyocytes from acutely diabetic rats demonstrated a robust increase in LRP1 expression and levels of heparanase, a pro-survival gene signature, and limited evidence of cell death, observations that were not apparent following chronic and progressive diabetes. CONCLUSION: Our results highlight EC-to-cardiomyocyte transfer of heparanase to modulate the cardiomyocyte cell death signature. This mechanism was observed in the acutely diabetic heart, and its interruption following chronic diabetes may contribute towards the development of diabetic cardiomyopathy.

Endothelial cell-cardiomyocyte crosstalk in diabetic cardiomyopathy.

The incidence of diabetes is increasing globally, with cardiovascular disease accounting for a substantial number of diabetes-related deaths. Although atherosclerotic vascular disease is a primary reason for this cardiovascular dysfunction, heart failure in patients with diabetes might also be an outcome of an intrinsic heart muscle malfunction, labelled diabetic cardiomyopathy. Changes in cardiomyocyte metabolism, which encompasses a shift to exclusive fatty acid utilization, are considered a leading stimulus for this cardiomyopathy. In addition to cardiomyocytes, endothelial cells (ECs) make up a significant proportion of the heart, with the majority of ATP generation in these cells provided by glucose. In this review, we will discuss the metabolic machinery that drives energy metabolism in the cardiomyocyte and EC, its breakdown following diabetes, and the research direction necessary to assist in devising novel therapeutic strategies to prevent or delay diabetic heart disease.

Cardiomyocyte-endothelial cell control of lipoprotein lipase.

In people with diabetes, inadequate pharmaceutical management predisposes the patient to heart failure, which is the leading cause of diabetes related death. One instigator for this cardiac dysfunction is change in fuel utilization by the heart. Thus, following diabetes, when cardiac glucose utilization is impaired, the heart undergoes metabolic transformation wherein it switches to using fats as an exclusive source of energy. Although this switching is geared to help the heart initially, in the long term, this has detrimental effects on cardiac function. These include the generation of noxious byproducts, which damage the cardiomyocytes, and ultimately result in increased morbidity and mortality. A key perpetrator that may be responsible for organizing this metabolic disequilibrium is lipoprotein lipase (LPL), the enzyme responsible for providing fat to the hearts. Either exaggeration or reduction in its activity following diabetes could lead to heart dysfunction. Given the disturbing news that diabetes is rampant across the globe, gaining more insight into the mechanism(s) by which cardiac LPL is regulated may assist other researchers in devising new therapeutic strategies to restore metabolic equilibrium, to help prevent or delay heart disease seen during diabetes. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk.

Cardiomyocyte VEGF Regulates Endothelial Cell GPIHBP1 to Relocate Lipoprotein Lipase to the Coronary Lumen During Diabetes Mellitus.

OBJECTIVE: Lipoprotein lipase (LPL)-mediated triglyceride hydrolysis is the major source of fatty acid for cardiac energy. LPL, synthesized in cardiomyocytes, is translocated across endothelial cells (EC) by its transporter glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1). Previously, we have reported an augmentation in coronary LPL, which was linked to an increased expression of GPIHBP1 following moderate diabetes mellitus. We examined the potential mechanism by which hyperglycemia amplifies GPIHBP1. APPROACH AND RESULTS: Exposure of rat aortic EC to high glucose induced GPIHBP1 expression and amplified LPL shuttling across these cells. This effect coincided with an elevated secretion of heparanase. Incubation of EC with high glucose or latent heparanase resulted in secretion of vascular endothelial growth factor (VEGF). Primary cardiomyocytes, being a rich source of VEGF, when cocultured with EC, restored EC GPIHBP1 that is lost because of cell passaging. Furthermore, recombinant VEGF induced EC GPIHBP1 mRNA and protein expression within 24 hours, an effect that could be prevented by a VEGF neutralizing antibody. This VEGF-induced increase in GPIHBP1 was through Notch signaling that encompassed Delta-like ligand 4 augmentation and nuclear translocation of the Notch intracellular domain. Finally, cardiomyocytes from severely diabetic animals exhibiting attenuation of VEGF were unable to increase EC GPIHBP1 expression and had lower LPL activity at the vascular lumen in perfused hearts. CONCLUSION: EC, as the first responders to hyperglycemia, can release heparanase to liberate myocyte VEGF. This growth factor, by activating EC Notch signaling, is responsible for facilitating GPIHBP1-mediated translocation of LPL across EC and regulating LPL-derived fatty acid delivery to the cardiomyocytes.

Lipoprotein lipase and angiopoietin-like 4 - Cardiomyocyte secretory proteins that regulate metabolism during diabetic heart disease.

Cardiac diseases have been extensively studied following diabetes and altered metabolism has been implicated in its initiation. In this context, there is a shift from glucose utilization to predominantly fatty acid metabolism. We have focused on the micro- and macro-environments that the heart uses to provide fatty acids to the cardiomyocyte. Specifically, we will discuss the cross talk between endothelial cells, smooth muscles and cardiomyocytes, and their respective secretory products that allows for this shift in metabolism. These changes will then be linked to alterations in the cardiovascular system and the augmented heart disease observed during diabetes. Traditionally, the heart was only thought of as an organ that supplies oxygen and nutrients to the body through its function as a pump. However, the heart as an endocrine organ has also been suggested. Secreted products from the cardiomyocytes include the natriuretic peptides atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Both have been shown to have vasodilatory, diuretic and antihypertensive effects. These peptides have been extensively studied and their deficiency is considered to be a major cause for the initiation of cardiovascular and cardiometabolic disorders. Another secretory enzyme, lipoprotein lipase (LPL), has been implicated in diabetic heart disease. LPL is a triglyceride-hydrolyzing enzyme that is synthesized within the cardiomyocyte and secreted towards the lumen under various conditions. For example, moderate or short-term hyperglycemia stimulates the release of LPL from the cardiomyocytes towards the endothelial cells. This process allows LPL to contact lipoprotein triglycerides, initiating their break down, with the product of lipolysis (free fatty acids, FA) translocating towards the cardiomyocytes for energy consumption. This mechanism compensates for the lack of glucose availability following diabetes. Under prolonged, chronic conditions of hyperglycemia, there is a need to inhibit this mechanism to avoid the excess delivery of FA to the cardiomyocytes, an effect that is known to induce cardiac cell death. Thus, LPL inhibition is made possible by a FA-induced activation of PPAR ß/δ, which augments angiopoietin-like 4 (Angptl4), an inhibitor of LPL activity. In the current review, we will focus on the mediators and conditions that regulate LPL and Angptl4 secretion from the cardiomyocyte, which are critical for maintaining cardiac metabolic homeostasis.

Direct measurement of aortic regurgitation with phase-contrast magnetic resonance is inaccurate: proposal of an alternative method of quantification.

BACKGROUND: Phase-contrast magnetic resonance (MR) has been widely used for quantification of aortic regurgitation. However there is significant practice variability regarding where and how the blood flow data are acquired. OBJECTIVE: To compare the accuracy of flow quantification of aortic regurgitation at three levels: the ascending aorta at the level of the right pulmonary artery (level 1), the aortic valve hinge points at end-diastole (level 2) and the aortic valve hinge points at end-systole (level 3). MATERIALS AND METHODS: We performed cardiovascular MR in 43 children with aortic regurgitation. By using phase-contrast MR, we measured the systolic forward, diastolic retrograde and net forward flow volume indices at three levels. At each level, the following comparisons were made: (1) systolic forward flow volume index (FFVI) versus left ventricular cardiac index (LVCI) measured by cine ventricular volumetry; (2) retrograde flow volume index (RFVI) versus estimated aortic regurgitation volume index (which equals LVCI minus pulmonary blood flow index [QPI]); (3) net forward flow volume index (NFVI) versus pulmonary blood flow index. RESULTS: The forward flow volume index, retrograde flow volume index and net forward flow volume index measured at each of the three levels were significantly different except for the retrograde flow volume index measured at levels 1 and 3. There were good correlations between the forward flow volume index and the left ventricular cardiac index at all three levels, with measurement at level 2 showing the best correlation. Compared to the forward flow volume indices, the retrograde flow volume index had a lower correlation with the estimated aortic regurgitation volume indices and had widely dispersed data with larger prediction intervals. CONCLUSION: Large variations in systolic forward, diastolic retrograde and net forward flow volumes were observed at different levels of the aortic valve and ascending aorta. Direct measurement of aortic regurgitation volume and fraction is inaccurate and should be abandoned. Instead, calculation of the aortic regurgitation volume from more reliable data is advised. We recommend subtracting pulmonary blood flow from systolic forward flow measured at the aortic valve hinge points at end-diastole as a more accurate and consistent method for calculating the volume of aortic regurgitation.

Endothelial cell regulation of cardiac metabolism following diabetes.

The earliest change that occurs in the diabetic heart is reduced glucose consumption, with a switch to utilization of fatty acids (FA) predominantly as an energy resource. Although this adaptation might be beneficial in the short-term, over a protracted duration, it is potentially catastrophic given the malicious effects produced by high FA in cardiomyocytes. In this review, we describe how the endothelial cell (EC), a "first-responder" to hyperglycemia, communicates with the underlying cardiomyocyte. As this cross-talk is expected to facilitate increased FA delivery to, and utilization by, the cardiomyocyte, understanding this conversationshould assist in devising new therapeutic strategies to prevent or delay diabetic heart disease.

Endothelial cells respond to hyperglycemia by increasing the LPL transporter GPIHBP1.

In diabetes, when glucose uptake and oxidation are impaired, the heart is compelled to use fatty acid (FA) almost exclusively for ATP. The vascular content of lipoprotein lipase (LPL), the rate-limiting enzyme that determines circulating triglyceride clearance, is largely responsible for this FA delivery and increases following diabetes. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein [GPIHBP1; a protein expressed abundantly in the heart in endothelial cells (EC)] collects LPL from the interstitial space and transfers it across ECs onto the luminal binding sites of these cells, where the enzyme is functional. We tested whether ECs respond to hyperglycemia by increasing GPIHBP1. Streptozotocin diabetes increased cardiac LPL activity and GPIHBP1 gene and protein expression. The increased LPL and GPIHBP1 were located at the capillary lumen. In vitro, passaging EC caused a loss of GPIHBP1, which could be induced on exposure to increasing concentrations of glucose. The high-glucose-induced GPIHBP1 increased LPL shuttling across EC monolayers. GPIHBP1 expression was linked to the EC content of heparanase. Moreover, active heparanase increased GPIHBP1 gene and protein expression. Both ECs and myocyte heparan sulfate proteoglycan-bound platelet-derived growth factor (PDGF) released by heparanase caused augmentation of GPIHBP1. Overall, our data suggest that this protein "ensemble" (heparanase-PDGF-GPIHBP1) cooperates in the diabetic heart to regulate FA delivery and utilization by the cardiomyocytes. Interrupting this axis may be a novel therapeutic strategy to restore metabolic equilibrium, curb lipotoxicity, and help prevent or delay heart dysfunction that is characteristic of diabetes.

Endothelial cell heparanase taken up by cardiomyocytes regulates lipoprotein lipase transfer to the coronary lumen after diabetes.

After diabetes, the heart has a singular reliance on fatty acid (FA) for energy production, which is achieved by increased coronary lipoprotein lipase (LPL) that breaks down circulating triglycerides. Coronary LPL originates from cardiomyocytes, and to translocate to the vascular lumen, the enzyme requires liberation from myocyte surface heparan sulfate proteoglycans (HSPGs), an activity that needs to be sustained after chronic hyperglycemia. We investigated the mechanism by which endothelial cells (EC) and cardiomyocytes operate together to enable continuous translocation of LPL after diabetes. EC were cocultured with myocytes, exposed to high glucose, and uptake of endothelial heparanase into myocytes was determined. Upon uptake, the effect of nuclear entry of heparanase was also investigated. A streptozotocin model of diabetes was used to expand our in vitro observations. In high glucose, EC-derived latent heparanase was taken up by cardiomyocytes by a caveolae-dependent pathway using HSPGs. This latent heparanase was converted into an active form in myocyte lysosomes, entered the nucleus, and upregulated gene expression of matrix metalloproteinase-9. The net effect was increased shedding of HSPGs from the myocyte surface, releasing LPL for its onwards translocation to the coronary lumen. EC-derived heparanase regulates the ability of the cardiomyocyte to send LPL to the coronary lumen. This adaptation, although acutely beneficial, could be catastrophic chronically because excess FA causes lipotoxicity. Inhibiting heparanase function could offer a new strategy for managing cardiomyopathy observed after diabetes.