Myocardial Uptake of Circulating Triglycerides in Nondiabetic Patients With Heart Disease

Nelson, Robert H.; Prasad, Abhiram; Lerman, Amir; Miles, John M.

doi:10.2337/db06-1552

Cited by 35 publications

(25 citation statements)

References 25 publications

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“…With 55% survival in this series of patients with otherwise non-survivable cardiotoxic insult, ILE is likely to have facilitated survival for these patients. ILE is currently hypothesized to ameliorate drug cardiotoxicity by three mechanisms: provision of a "lipid sink" by providing a separate pharmacologic compartment into which the lipophilic drug may diffuse [6]; delivery of substrate to an energydepleted myocardium [7]; and improving function of select ion channels (e.g., calcium and sodium) present on the cell membrane in order to overcome myocardial conduction delays and poor inotropy [6]. Animal models of drug cardiotoxicity suggest that ILE administration may have superior survival efficacy over classic resuscitative therapies such as epinephrine [1,8] and vasopressin [1].…”

Section: Discussionmentioning

confidence: 99%

Clinical Experience with Intravenous Lipid Emulsion for Drug-Induced Cardiovascular Collapse

2011

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Intravenous lipid emulsion (ILE) is an emerging therapy for refractory cardiotoxicity due to lipid-soluble drugs. The purpose of this study was to assess survival to hospital discharge, effects on hemodynamic parameters, and adverse event occurrence for patients who were treated with ILE as part of the resuscitative effort for drug-induced cardiotoxicity. This is a multicenter retrospective chart review of inpatients at three tertiary referral medical centers receiving ILE for drug-induced cardiotoxicity between November 2007 and March 2009. Nine cases with drug-induced cardiovascular collapse, defined as cardiac arrest or refractory shock, were selected for review if patients received either bolus or infusion of ILE in any combination. No interventions were done. The main outcome measures were survival to hospital discharge, effect on hemodynamic parameters, and adverse event. Hemodynamic vital signs (heart rate, systolic blood pressure, diastolic blood pressure, calculated mean arterial pressure [MAP]) were measured before administration of ILE and up to five measurements (if available) were recorded after administration of ILE. Attribution of adverse events was determined by assignment of Naranjo adverse drug reaction (ADR) likelihood score (3) with adjudication of three medical toxicologists; disagreements were settled by majority consensus. Of nine cases identified based on inclusion criteria (three cardiac arrest, six refractory shock), five (55%) survived to hospital discharge. ILE regimens were bolus alone in five patients and bolus plus infusion in four patients. Hemodynamic trends in response to ILE demonstrated no difference in MAP immediately pre-and post-administration of ILE (p=NS). Administration of infusion (versus boluses alone) did not demonstrate a statistically significant improvement in MAP. Adverse events due to ILE therapy that were categorized as "possible" or "probable" based on Naranjo scores included lipemia, digit amputation, lung injury, renal failure, and deep venous thrombosis. ILE administered to patients with drug-induced cardiovascular collapse was associated with 55% survival but with clinically significant adverse effects. At this time, ILE should be restricted to cardiotoxicity involving cardiac arrest or refractory shock until further prospective studies can better evaluate risks and benefits of ILE therapy.

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Section: Discussionmentioning

confidence: 99%

Clinical Experience with Intravenous Lipid Emulsion for Drug-Induced Cardiovascular Collapse

2011

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“…Although it is generally thought that the majority of FFAs are derived from the action of intracellular lipases on adipose tissue triglycerides, intravascular lipases such as lipoprotein lipase (LPL) can hydrolyze triglycerides in circulating triglyceride-rich lipoproteins and, thus, can be an additional source. It has previously been demonstrated that some fatty acids produced by intravascular lipolysis are released, or "spilled over," into the plasma FFA pool; this phenomenon has been documented in human adipose tissue, forearm tissue, and myocardium (7)(8)(9). A recent study (10) has shown high rates of spillover in the liver and in nonhepatic splanchnic tissues of fasting dogs.…”

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confidence: 99%

Splanchnic Spillover of Extracellular Lipase–Generated Fatty Acids in Overweight and Obese Humans

et al. 2007

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OBJECTIVE-Triglyceride-rich lipoproteins, primarily chylomicrons, can contribute to plasma free fatty acid (FFA) concentrations via spillover of fatty acids during intravascular hydrolysis into the venous effluent of some tissues. The present study was undertaken to determine whether spillover occurs in the splanchnic bed of humans.RESEARCH DESIGN AND METHODS-Arterial and hepatic venous blood was sampled in postabsorptive (n ϭ 6; study A) and postprandial (n ϭ 5; study B) obese humans during infusion of carbon-labeled ( 14 C or 13 C) oleate and 3 H triolein, the latter incorporated into a lipid emulsion as a surrogate for chylomicrons. Spillover was determined by measuring production of 3 H oleate.RESULTS-Splanchnic spillover was higher than nonsplanchnic systemic spillover in both study A (60 Ϯ 7 vs. 24 Ϯ 6%; P Ͻ 0.01) and study B (54 Ϯ 3 vs. 16 Ϯ 5%; P Ͻ 0.005). Because portal vein sampling is not feasible in humans, assumptions regarding actual spillover in nonhepatic splanchnic tissues were required for the spillover calculation. A mathematical model was developed and demonstrated that nonhepatic splanchnic spillover rates in study A and study B of 69 and 80%, respectively, provided the best fit with the data. There was preferential splanchnic uptake of triglyceride fatty acids compared with FFAs in study B (fractional extraction 61 Ϯ 3 vs. 33 Ϯ 2%; P Ͻ 0.005).CONCLUSIONS-These data confirm previous studies indicating that the transport of FFAs and triglyceride fatty acids are partitioned in tissues and indicate that splanchnic spillover from triglyceride-rich lipoproteins may be a significant source of both portal venous and systemic FFAs. Diabetes 56:2878-2884, 2007 E pidemiologic data linking visceral adipose tissue to an increased risk of cardiovascular disease and type 2 diabetes have stimulated considerable study and conjecture as to the mechanism of this relationship. Bjorntorp (1) proposed that increased delivery of free fatty acids (FFAs) to the liver via the portal vein may be the main culprit. Increased portal venous FFAs are thought to lead to increased VLDL triglyceride production (2), to hepatic insulin resistance (3), and to impaired insulin extraction by the liver with subsequent hyperinsulinemia (4).Visceral fat is a known source of portal venous FFAs but only a minor source of peripheral FFAs (5). Upper body fat is known to be metabolically different from lower body fat, characterized by increased lipolysis. Whether visceral fat is hyperlipolytic has been questioned (6). Although it is generally thought that the majority of FFAs are derived from the action of intracellular lipases on adipose tissue triglycerides, intravascular lipases such as lipoprotein lipase (LPL) can hydrolyze triglycerides in circulating triglyceride-rich lipoproteins and, thus, can be an additional source. It has previously been demonstrated that some fatty acids produced by intravascular lipolysis are released, or "spilled over," into the plasma FFA pool; this phenomenon has been documented in human adipose tissue, f...

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“…In this study the myocardium was only a minor contributor to total systemic TAG (VLDL) uptake (~3%) and systemic NEFA production (~0.5%) [2]. Previous studies had also suggested only limited VLDL-TAG utilisation by the human heart with about 10-20% of cardiac energy deriving from VLDL [31]), suggesting that in human heart, at least in the postabsorptive state, NEFAs may be more important cardiac substrates than VLDL-TAG [30,32].…”

Section: Cardiac Vldl-tag Utilisationmentioning

confidence: 84%

“…In the well-fed state it certainly represents the major transport form of endogenous TAG-FA, synthesised by de novo hepatic lipogenesis and exported to adipose tissue for storage; however, in the post-absorptive state it is assembled in the liver from adipose-derived NEFA, and it is unclear why NEFA cannot supply FA direct to oxidative tissues such as heart. Indeed, this pathway certainly occurs, but the issue of the A C C E P T E D M A N U S C R I P T Studies of cardiac A-V (coronary sinus) differences in non-diabetic patients undergoing cardiac catheterisation (usually in the post-absorptive state) found that some hearts extracted plasma (VLDL)TAG but not others (as previously noted [30]) whilst infused labelled TAG was consistently extracted (extraction fraction ~11%) [2]. TAGs and NEFAs accounted for ~17% and ~83%…”

Section: Cardiac Vldl-tag Utilisationmentioning

confidence: 99%

“…Subsequent A-V studies on nondiabetic humans found that TAG-emulsion accounted for only ~ 17% of cardiac FA uptake; moreover, the heart accounted for only 3% of systemic TAG uptake [2]. Studies in dog heart found that 56% myocardial oxygen consumption (mVO 2 ) was accounted for by total (NEFA+TAG) FA oxidation, of which 71% was calculated to be from TAG (hence about 40% of mVO 2 was TAG oxidation) [3].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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The role of triacylglycerol in cardiac energy provision

Evans

Hui‐Kang

2016

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Triacylglycerols (TAG) constitute the main energy storage resource in mammals, by virtue of their high energy density. This in turn is a function of their highly reduced state and hydrophobicity.Limited water solubility, however, imposes specific requirements for delivery and uptake mechanisms on TAG-utilising tissues, including the heart, as well as intracellular disposition. TAGs constitute potentially the major energy supply for working myocardium, both through bloodborne provision and as intracellular TAG within lipid droplets, but also provide the heart with fatty acids (FA) which the myocardium cannot itself synthesise but are required for glycerolipid derivatives with (non-energetic) functions, including membrane phospholipids and lipid signalling molecules. Furthermore they serve to buffer potentially toxic amphipathic fatty acid derivatives.Intracellular handling and disposition of TAGs and their FA and glycerolipid derivatives similarly requires dedicated mechanisms in view of their hydrophobic character. Dysregulation of utilisation can result in inadequate energy provision, accumulation of TAG and/or esterified species, and these may be responsible for significant cardiac dysfunction in a variety of disease states. This review will focus on the role of TAG in myocardial energy provision, by providing FAs from exogenous and endogenous TAG sources for mitochondrial oxidation and ATP production, and how this can change in disease and impact on cardiac function. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 3Key words:heart; triacylglycerol; very-low-density lipoprotein; VLDL; chylomicron; lipid droplet Highlights: Triacylglycerols are supplied to the myocardium within chylomicrons and VLDL  Heart assimilates triacylglycerol-rich lipoproteins by LPL and receptor-mediated routes  Exogenous triacylglycerol-derived fatty acids enter an intracellular lipid pool  Intracardiac triacylglycerol is an important source of fatty acids for oxidation  Dysregulation of triacylglycerol metabolism is associated with cardiac dysfunction

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Myocardial Uptake of Circulating Triglycerides in Nondiabetic Patients With Heart Disease

Cited by 35 publications

References 25 publications

Clinical Experience with Intravenous Lipid Emulsion for Drug-Induced Cardiovascular Collapse

Clinical Experience with Intravenous Lipid Emulsion for Drug-Induced Cardiovascular Collapse

Splanchnic Spillover of Extracellular Lipase–Generated Fatty Acids in Overweight and Obese Humans

The role of triacylglycerol in cardiac energy provision

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