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Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management.

Chapman MJ, Ginsberg HN, Amarenco P, Andreotti F, Borén J, Catapano AL, Descamps OS, Fisher E, Kovanen PT, Kuivenhoven JA, Lesnik P, Masana L, Nordestgaard BG, Ray KK, Reiner Z, Taskinen MR, Tokgözoglu L, Tybjærg-Hansen A, Watts GF, European Atherosclerosis Society Consensus Pan - Eur. Heart J. (2011)

Bottom Line: If inadequately corrected, adding niacin or a fibrate, or intensifying LDL-C lowering therapy may be considered.Treatment decisions regarding statin combination therapy should take into account relevant safety concerns, i.e. the risk of elevation of blood glucose, uric acid or liver enzymes with niacin, and myopathy, increased serum creatinine and cholelithiasis with fibrates.These recommendations will facilitate reduction in the substantial cardiovascular risk that persists in patients with cardiometabolic abnormalities at LDL-C goal.

View Article: PubMed Central - PubMed

Affiliation: European Atherosclerosis Society, INSERM UMR-S939, Pitié-Salpetriere University Hospital, Paris 75651, France. john.chapman@upmc.fr

ABSTRACT
Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high-density lipoprotein cholesterol (HDL-C) as cardiovascular risk factors, and (ii) to advise on therapeutic strategies for management. Current evidence supports a causal association between elevated TRL and their remnants, low HDL-C, and cardiovascular risk. This interpretation is based on mechanistic and genetic studies for TRL and remnants, together with the epidemiological data suggestive of the association for circulating triglycerides and cardiovascular disease. For HDL, epidemiological, mechanistic, and clinical intervention data are consistent with the view that low HDL-C contributes to elevated cardiovascular risk; genetic evidence is unclear however, potentially reflecting the complexity of HDL metabolism. The Panel believes that therapeutic targeting of elevated triglycerides (≥ 1.7 mmol/L or 150 mg/dL), a marker of TRL and their remnants, and/or low HDL-C (<1.0 mmol/L or 40 mg/dL) may provide further benefit. The first step should be lifestyle interventions together with consideration of compliance with pharmacotherapy and secondary causes of dyslipidaemia. If inadequately corrected, adding niacin or a fibrate, or intensifying LDL-C lowering therapy may be considered. Treatment decisions regarding statin combination therapy should take into account relevant safety concerns, i.e. the risk of elevation of blood glucose, uric acid or liver enzymes with niacin, and myopathy, increased serum creatinine and cholelithiasis with fibrates. These recommendations will facilitate reduction in the substantial cardiovascular risk that persists in patients with cardiometabolic abnormalities at LDL-C goal.

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Metabolic pathways for HDL and triglyceride-rich lipoprotein remnants highlight their close interrelationship. De novo production of nascent HDL (discs) occurs in the liver and small intestine through the production of apo A-I (the major HDL protein) and lipidation (with cholesterol and phospholipids) of this protein by the ATP-binding cassette transporter (ABCA1) in these organs. Upon secretion, lecithin: cholesterol acyltransferase (LCAT) esterifies cholesterol on these discs which mature into spherical particles (due to the formation of a hydrophobic core resulting from generation of cholesteryl esters by LCAT). HDL undergoes extensive interconversion through triglyceride lipolysis (hepatic lipase, HL), phospholipid hydrolysis (endothelial lipase, EL), fusion (phospholipid transfer protein, PLTP), and lipid exchange among the HDL subpopulations (cholesteryl ester transfer protein, CETP). CETP also mediates major lipid transfer and exchange between HDL and triglyceride-rich lipoproteins (VLDL, chylomicrons) and their remnants [VLDL remnants = intermediate-density lipoproteins (IDLs), chylomicron remnants]. During this process, cholesteryl esters are transfered from HDL to VLDL and triglycrides move from VLDL to HDL.24 Chylomicrons also act as cholestery ester acceptors from LDL and HDL during the post-prandial phase.25 A second route that contributes to the plasma HDL pool involves hydrolysis of triglycerides in VLDL, IDL, and chylomicrons. In this process which is catalysed by lipoprotein lipase (LPL), phospholipids, as well as several apolipoproteins (such as apo CI, CII, CIII, AV) are transferred to HDL. PLTP contributes significantly to this remodelling process.
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EHR112F2: Metabolic pathways for HDL and triglyceride-rich lipoprotein remnants highlight their close interrelationship. De novo production of nascent HDL (discs) occurs in the liver and small intestine through the production of apo A-I (the major HDL protein) and lipidation (with cholesterol and phospholipids) of this protein by the ATP-binding cassette transporter (ABCA1) in these organs. Upon secretion, lecithin: cholesterol acyltransferase (LCAT) esterifies cholesterol on these discs which mature into spherical particles (due to the formation of a hydrophobic core resulting from generation of cholesteryl esters by LCAT). HDL undergoes extensive interconversion through triglyceride lipolysis (hepatic lipase, HL), phospholipid hydrolysis (endothelial lipase, EL), fusion (phospholipid transfer protein, PLTP), and lipid exchange among the HDL subpopulations (cholesteryl ester transfer protein, CETP). CETP also mediates major lipid transfer and exchange between HDL and triglyceride-rich lipoproteins (VLDL, chylomicrons) and their remnants [VLDL remnants = intermediate-density lipoproteins (IDLs), chylomicron remnants]. During this process, cholesteryl esters are transfered from HDL to VLDL and triglycrides move from VLDL to HDL.24 Chylomicrons also act as cholestery ester acceptors from LDL and HDL during the post-prandial phase.25 A second route that contributes to the plasma HDL pool involves hydrolysis of triglycerides in VLDL, IDL, and chylomicrons. In this process which is catalysed by lipoprotein lipase (LPL), phospholipids, as well as several apolipoproteins (such as apo CI, CII, CIII, AV) are transferred to HDL. PLTP contributes significantly to this remodelling process.

Mentions: Cholesterol, in both free and esterified forms, and triglycerides are the two main lipids in plasma. They are transported in lipoproteins, pseudomicellar lipid–protein complexes, in which the main apolipoproteins, apo B-100/48, apo A-I, apo A-II, apo E, and the apo Cs, are integral components. Apo B is a component of all atherogenic lipoproteins (chylomicron remnants, VLDL and their remnants, IDL, lipoprotein(a) [Lp(a)] and LDL), whereas apo A-I and apo A-II are components of HDL. The apo B-containing lipoproteins and the apo A-I/A-II lipoprotein classes are closely interrelated via several metabolic pathways (Figure 2).23–25Figure 2


Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management.

Chapman MJ, Ginsberg HN, Amarenco P, Andreotti F, Borén J, Catapano AL, Descamps OS, Fisher E, Kovanen PT, Kuivenhoven JA, Lesnik P, Masana L, Nordestgaard BG, Ray KK, Reiner Z, Taskinen MR, Tokgözoglu L, Tybjærg-Hansen A, Watts GF, European Atherosclerosis Society Consensus Pan - Eur. Heart J. (2011)

Metabolic pathways for HDL and triglyceride-rich lipoprotein remnants highlight their close interrelationship. De novo production of nascent HDL (discs) occurs in the liver and small intestine through the production of apo A-I (the major HDL protein) and lipidation (with cholesterol and phospholipids) of this protein by the ATP-binding cassette transporter (ABCA1) in these organs. Upon secretion, lecithin: cholesterol acyltransferase (LCAT) esterifies cholesterol on these discs which mature into spherical particles (due to the formation of a hydrophobic core resulting from generation of cholesteryl esters by LCAT). HDL undergoes extensive interconversion through triglyceride lipolysis (hepatic lipase, HL), phospholipid hydrolysis (endothelial lipase, EL), fusion (phospholipid transfer protein, PLTP), and lipid exchange among the HDL subpopulations (cholesteryl ester transfer protein, CETP). CETP also mediates major lipid transfer and exchange between HDL and triglyceride-rich lipoproteins (VLDL, chylomicrons) and their remnants [VLDL remnants = intermediate-density lipoproteins (IDLs), chylomicron remnants]. During this process, cholesteryl esters are transfered from HDL to VLDL and triglycrides move from VLDL to HDL.24 Chylomicrons also act as cholestery ester acceptors from LDL and HDL during the post-prandial phase.25 A second route that contributes to the plasma HDL pool involves hydrolysis of triglycerides in VLDL, IDL, and chylomicrons. In this process which is catalysed by lipoprotein lipase (LPL), phospholipids, as well as several apolipoproteins (such as apo CI, CII, CIII, AV) are transferred to HDL. PLTP contributes significantly to this remodelling process.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3105250&req=5

EHR112F2: Metabolic pathways for HDL and triglyceride-rich lipoprotein remnants highlight their close interrelationship. De novo production of nascent HDL (discs) occurs in the liver and small intestine through the production of apo A-I (the major HDL protein) and lipidation (with cholesterol and phospholipids) of this protein by the ATP-binding cassette transporter (ABCA1) in these organs. Upon secretion, lecithin: cholesterol acyltransferase (LCAT) esterifies cholesterol on these discs which mature into spherical particles (due to the formation of a hydrophobic core resulting from generation of cholesteryl esters by LCAT). HDL undergoes extensive interconversion through triglyceride lipolysis (hepatic lipase, HL), phospholipid hydrolysis (endothelial lipase, EL), fusion (phospholipid transfer protein, PLTP), and lipid exchange among the HDL subpopulations (cholesteryl ester transfer protein, CETP). CETP also mediates major lipid transfer and exchange between HDL and triglyceride-rich lipoproteins (VLDL, chylomicrons) and their remnants [VLDL remnants = intermediate-density lipoproteins (IDLs), chylomicron remnants]. During this process, cholesteryl esters are transfered from HDL to VLDL and triglycrides move from VLDL to HDL.24 Chylomicrons also act as cholestery ester acceptors from LDL and HDL during the post-prandial phase.25 A second route that contributes to the plasma HDL pool involves hydrolysis of triglycerides in VLDL, IDL, and chylomicrons. In this process which is catalysed by lipoprotein lipase (LPL), phospholipids, as well as several apolipoproteins (such as apo CI, CII, CIII, AV) are transferred to HDL. PLTP contributes significantly to this remodelling process.
Mentions: Cholesterol, in both free and esterified forms, and triglycerides are the two main lipids in plasma. They are transported in lipoproteins, pseudomicellar lipid–protein complexes, in which the main apolipoproteins, apo B-100/48, apo A-I, apo A-II, apo E, and the apo Cs, are integral components. Apo B is a component of all atherogenic lipoproteins (chylomicron remnants, VLDL and their remnants, IDL, lipoprotein(a) [Lp(a)] and LDL), whereas apo A-I and apo A-II are components of HDL. The apo B-containing lipoproteins and the apo A-I/A-II lipoprotein classes are closely interrelated via several metabolic pathways (Figure 2).23–25Figure 2

Bottom Line: If inadequately corrected, adding niacin or a fibrate, or intensifying LDL-C lowering therapy may be considered.Treatment decisions regarding statin combination therapy should take into account relevant safety concerns, i.e. the risk of elevation of blood glucose, uric acid or liver enzymes with niacin, and myopathy, increased serum creatinine and cholelithiasis with fibrates.These recommendations will facilitate reduction in the substantial cardiovascular risk that persists in patients with cardiometabolic abnormalities at LDL-C goal.

View Article: PubMed Central - PubMed

Affiliation: European Atherosclerosis Society, INSERM UMR-S939, Pitié-Salpetriere University Hospital, Paris 75651, France. john.chapman@upmc.fr

ABSTRACT
Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high-density lipoprotein cholesterol (HDL-C) as cardiovascular risk factors, and (ii) to advise on therapeutic strategies for management. Current evidence supports a causal association between elevated TRL and their remnants, low HDL-C, and cardiovascular risk. This interpretation is based on mechanistic and genetic studies for TRL and remnants, together with the epidemiological data suggestive of the association for circulating triglycerides and cardiovascular disease. For HDL, epidemiological, mechanistic, and clinical intervention data are consistent with the view that low HDL-C contributes to elevated cardiovascular risk; genetic evidence is unclear however, potentially reflecting the complexity of HDL metabolism. The Panel believes that therapeutic targeting of elevated triglycerides (≥ 1.7 mmol/L or 150 mg/dL), a marker of TRL and their remnants, and/or low HDL-C (<1.0 mmol/L or 40 mg/dL) may provide further benefit. The first step should be lifestyle interventions together with consideration of compliance with pharmacotherapy and secondary causes of dyslipidaemia. If inadequately corrected, adding niacin or a fibrate, or intensifying LDL-C lowering therapy may be considered. Treatment decisions regarding statin combination therapy should take into account relevant safety concerns, i.e. the risk of elevation of blood glucose, uric acid or liver enzymes with niacin, and myopathy, increased serum creatinine and cholelithiasis with fibrates. These recommendations will facilitate reduction in the substantial cardiovascular risk that persists in patients with cardiometabolic abnormalities at LDL-C goal.

Show MeSH
Related in: MedlinePlus