Evaluating possible acute coronary syndrome in primary care: the value of signs, symptoms, and plasma heart-type fatty acid-binding protein (H-FABP). A diagnostic study.

Background: Additional diagnostic means could be of added value when evaluating possible acute coronary syndrome (ACS) in primary care.

Aim: To determine whether heart-type fatty acid-binding protein (H-FABP)-based point-of-care (POC) biomarker testing, embedded in a clinical decision rule (CDR), is helpful to the GP when evaluating possible ACS.

Design & Setting: A prospective, non-randomised, double-blinded, diagnostic derivation study was undertaken, with a delayed-type cross-sectional diagnostic model among GPs in the Netherlands and Belgium.

Frequency of chest pain in primary care, diagnostic tests performed and final diagnoses.

Objective: Observational study of patients with chest pain in primary care: determination of incidence, referral rate, diagnostic tests and (agreement between) working and final diagnoses.

Methods: 118 general practitioners (GPs) in the Netherlands and Belgium recorded all patient contacts during  2weeks. Furthermore, patients presenting with chest pain were registered extensively.

Small heterodimer partner (SHP) contributes to insulin resistance in cardiomyocytes.

Small heterodimer partner (SHP) is an atypical nuclear receptor expressed in heart that has been shown to inhibit the hypertrophic response. Here, we assessed the role of SHP in cardiac metabolism and inflammation. Mice fed a high-fat diet (HFD) displayed glucose intolerance accompanied by increased cardiac mRNA levels of Shp.

From fat to FAT (CD36/SR-B2): Understanding the regulation of cellular fatty acid uptake.

The molecular mechanisms underlying the cellular uptake of long-chain fatty acids and the regulation of this process have been elucidated in appreciable detail in the last decades. Two main players in this field, each discovered in the early 1990s, are (i) a membrane-associated protein first identified in adipose ('fat') tissue and referred to as putative fatty acid translocase (FAT)/CD36 (now officially designated as SR-B2) which facilitates the transport of fatty acids across the plasma membrane, and (ii) the family of transcription factors designated peroxisome proliferator-activated receptors (PPARα, PPARγ, and PPARβ/δ) for which fatty acids and fatty acid metabolites are the preferred ligand. CD36/SR-B2 is the predominant membrane protein involved in fatty acid uptake into intestinal enterocytes, adipocytes and cardiac and skeletal myocytes.

A new leptin-mediated mechanism for stimulating fatty acid oxidation: a pivotal role for sarcolemmal FAT/CD36.

Leptin stimulates fatty acid oxidation in muscle and heart; but, the mechanism by which these tissues provide additional intracellular fatty acids for their oxidation remains unknown. We examined, in isolated muscle and cardiac myocytes, whether leptin, via AMP-activated protein kinase (AMPK) activation, stimulated fatty acid translocase (FAT/CD36)-mediated fatty acid uptake to enhance fatty acid oxidation. In both mouse skeletal muscle and rat cardiomyocytes, leptin increased fatty acid oxidation, an effect that was blocked when AMPK phosphorylation was inhibited by adenine 9-β-d-arabinofuranoside or Compound C.

Post-translational modifications of CD36 (SR-B2): Implications for regulation of myocellular fatty acid uptake.

The membrane-associated protein CD36, now officially designated as SR-B2, is present in various tissues and fulfills multiple cellular functions. In heart and muscle, CD36 is the main (long-chain) fatty acid transporter, regulating myocellular fatty acid uptake via its vesicle-mediated reversible trafficking (recycling) between intracellular membrane compartments and the cell surface. CD36 is subject to various types of post-translational modification.

Signaling pathways involved in cardiac energy metabolism.

Various signaling pathways coordinate energy metabolism and contractile function in the heart. Myocardial uptake of long-chain fatty acids largely occurs by facilitated diffusion, involving the membrane-associated protein, CD36. Glucose uptake, the rate-limiting step in glucose utilization, is mediated predominantly by the glucose transporter protein, GLUT4.

Novel Biomarkers to Improve the Prediction of Cardiovascular Event Risk in Type 2 Diabetes Mellitus.

Background: We evaluated the ability of 23 novel biomarkers representing several pathophysiological pathways to improve the prediction of cardiovascular event (CVE) risk in patients with type 2 diabetes mellitus beyond traditional risk factors.

Methods And Results: We used data from 1002 patients with type 2 diabetes mellitus from the Second Manifestations of ARTertial disease (SMART) study and 288 patients from the European Prospective Investigation into Cancer and Nutrition-NL (EPIC-NL). The associations of 23 biomarkers (adiponectin, C-reactive protein, epidermal-type fatty acid binding protein, heart-type fatty acid binding protein, basic fibroblast growth factor, soluble FMS-like tyrosine kinase-1, soluble intercellular adhesion molecule-1 and -3, matrix metalloproteinase [MMP]-1, MMP-3, MMP-9, N-terminal prohormone of B-type natriuretic peptide, osteopontin, osteonectin, osteocalcin, placental growth factor, serum amyloid A, E-selectin, P-selectin, tissue inhibitor of MMP-1, thrombomodulin, soluble vascular cell adhesion molecule-1, and vascular endothelial growth factor) with CVE risk were evaluated by using Cox proportional hazards analysis adjusting for traditional risk factors.

Regulation of the subcellular trafficking of CD36, a major determinant of cardiac fatty acid utilization.

Myocardial uptake of long-chain fatty acids largely occurs by facilitated diffusion, involving primarily the membrane-associated protein CD36. Other putative fatty acid transporters, such as FABPpm, FATP1 and FATP4, also play a role, but their quantitative contribution is much smaller or their involvement is rather permissive. Besides its sarcolemmal localization, CD36 is also present in intracellular compartments (endosomes).

Assessing Cardiac Metabolism: A Scientific Statement From the American Heart Association.

In a complex system of interrelated reactions, the heart converts chemical energy to mechanical energy. Energy transfer is achieved through coordinated activation of enzymes, ion channels, and contractile elements, as well as structural and membrane proteins. The heart's needs for energy are difficult to overestimate.

The interaction between AMPKβ2 and the PP1-targeting subunit R6 is dynamically regulated by intracellular glycogen content.

AMP-activated protein kinase (AMPK) is a metabolic stress-sensing kinase. We previously showed that glucose deprivation induces autophosphorylation of AMPKβ at Thr-148, which prevents the binding of AMPK to glycogen. Furthermore, in MIN6 cells, AMPKβ1 binds to R6 (PPP1R3D), a glycogen-targeting subunit of protein phosphatase type 1 (PP1), thereby regulating the glucose-induced inactivation of AMPK.

Effects of high-fat feeding on ectopic fat storage and postprandial lipid metabolism in mouse offspring.

Objective: Parental high-fat feeding was proposed to negatively impact metabolic health in offspring. Here, the ectopic fat storage in heart and liver in offspring was investigated, and the effects on mitochondrial function, de novo lipogenesis, and postprandial lipid metabolism were explored in detail.

Methods: Male and female mice received either a high-fat (HF) or standard chow (LF) diet during mating, gestation and lactation.

Fatty acid transport and transporters in muscle are critically regulated by Akt2.

Muscle contains various fatty acid transporters (CD36, FABPpm, FATP1, FATP4). Physiological stimuli (insulin, contraction) induce the translocation of all four transporters to the sarcolemma to enhance fatty acid uptake similarly to glucose uptake stimulation via glucose transporter-4 (GLUT4) translocation. Akt2 mediates insulin-induced, but not contraction-induced, GLUT4 translocation, but its role in muscle fatty acid transporter translocation is unknown.

Extremely rapid increase in fatty acid transport and intramyocellular lipid accumulation but markedly delayed insulin resistance after high fat feeding in rats.

Aims/hypothesis: The mechanisms for diet-induced intramyocellular lipid accumulation and its association with insulin resistance remain contentious. In a detailed time-course study in rats, we examined whether a high-fat diet increased intramyocellular lipid accumulation via alterations in fatty acid translocase (FAT/CD36)-mediated fatty acid transport, selected enzymes and/or fatty acid oxidation, and whether intramyocellular lipid accretion coincided with the onset of insulin resistance.

Methods: We measured, daily (on days 1-7) and/or weekly (for 6 weeks), the diet-induced changes in circulating substrates, insulin, sarcolemmal substrate transporters and transport, selected enzymes, intramyocellular lipids, mitochondrial fatty acid oxidation and basal and insulin-stimulated sarcolemmal GLUT4 and glucose transport.

Cardiac contraction-induced GLUT4 translocation requires dual signaling input.

Contraction-induced translocation of glucose transporter type-4 (GLUT4) to the sarcolemma is essential to stimulate cardiac glucose uptake during increased energy demand. As such, this process is a target for therapeutic strategies aiming at increasing glucose uptake in insulin-resistant and/or diabetic hearts. AMP-activated protein kinase (AMPK) and its upstream kinases form part of a signaling axis essential for contraction-induced GLUT4 translocation.

MRS: a noninvasive window into cardiac metabolism.

A well-functioning heart requires a constant supply of a balanced mixture of nutrients to be used for the production of adequate amounts of adenosine triphosphate, which is the main energy source for most cellular functions. Defects in cardiac energy metabolism are linked to several myocardial disorders. MRS can be used to study in vivo changes in cardiac metabolism noninvasively.

Suspected acute coronary syndrome in the emergency room: Limited added value of heart type fatty acid binding protein point of care or ELISA tests: The FAME-ER (Fatty Acid binding protein in Myocardial infarction Evaluation in the Emergency Room) study.

Background: Timely recognition of acute coronary syndrome remains a challenge as many biomarkers, including troponin, remain negative in the first hours following the onset of chest pain. We assessed the diagnostic accuracy of heart-type fatty acid binding protein (H-FABP), a cardiac biomarker with potential value immediately post symptom onset.

Methods And Results: Prospective monocentre diagnostic accuracy study of H-FABP bedside point of care (CardioDetect®) and ELISA tests in acute coronary syndrome suspected patients presenting within 24 hours of symptom onset to the emergency department, in addition to clinical findings, electrocardiography and the currently recommended biomarker high sensitivity troponin-T (hs-cTnT).

Good and bad consequences of altered fatty acid metabolism in heart failure: evidence from mouse models.

The shift in substrate preference away from fatty acid oxidation (FAO) towards increased glucose utilization in heart failure has long been interpreted as an oxygen-sparing mechanism. Inhibition of FAO has therefore evolved as an accepted approach to treat heart failure. However, recent data indicate that increased reliance on glucose might be detrimental rather than beneficial for the failing heart.

Heart-type fatty acid binding protein (H-FABP) in patients in an emergency department setting, suspected of acute coronary syndrome: optimal cut-off point, diagnostic value and future opportunities in primary care.

Background: Most patients presenting chest complaints in primary care are referred to secondary care facilities, whereas only a few are diagnosed with acute coronary syndrome (ACS).

Objective: The aim is to determine the optimal cut-off value for a point-of-care heart-type fatty acid binding protein (H-FABP) test in patients presenting to the emergency department and to evaluate a possible future role of H-FABP in safely ruling out ACS in primary care.

Methods: Serial plasma H-FABP (index test) and high sensitivity troponin T (hs-cTnT) (reference test) were determined in patients with any new-onset chest complaint.

Rapidly rule out acute myocardial infarction by combining copeptin and heart-type fatty acid-binding protein with cardiac troponin.

Background: The rapid exclusion of acute myocardial infarction in patients with chest pain can reduce the length of hospital admission, prevent unnecessary diagnostic work-up and reduce the burden on our health-care systems. The combined use of biomarkers that are associated with different pathophysiological aspects of acute myocardial infarction could improve the early diagnostic assessment of patients presenting with chest pain.

Methods: We measured cardiac troponin I, copeptin and heart-type fatty acid-binding protein concentrations in 584 patients who presented to the emergency department with acute chest pain.

Marine omega-3 fatty acids prevent myocardial insulin resistance and metabolic remodeling as induced experimentally by high insulin exposure.

Insulin resistance is an important risk factor for the development of several cardiac pathologies, thus advocating strategies for restoring insulin sensitivity of the heart in these conditions. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), mainly eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3), have been shown to improve insulin sensitivity in insulin-sensitive tissues, but their direct effect on insulin signaling and metabolic parameters in the myocardium has not been reported previously. The aim of this study was therefore to examine the ability of EPA and DHA to prevent insulin resistance in isolated rat cardiomyocytes.

Protein kinase-D1 overexpression prevents lipid-induced cardiac insulin resistance.

In the insulin resistant heart, energy fuel selection shifts away from glucose utilization towards almost complete dependence on long-chain fatty acids (LCFA). This shift results in excessive cardiac lipid accumulation and eventually heart failure. Lipid-induced cardiomyopathy may be averted by strategies that increase glucose uptake without elevating LCFA uptake.