High Serum Cholesteryl Ester Transfer Rates and Young AMI Patients
High Serum Cholesteryl Ester Transfer Rates and Young AMI Patients
Objectives. Our aim was to characterize cholesteryl ester transfer protein (CETP) activity in the early phase of acute myocardial infarction (MI).
Background. Cholesteryl ester transfer protein catalyzes the transfer of cholesteryl esters from high-density lipoprotein (HDL) donors to apolipoprotein B-containing lipoprotein acceptors.
Methods. The CETP concentration, lipid profiles, and the rate of cholesteryl ester transfer (CET) from a tracer dose of radiolabeledHDL toward endogenous lipoproteins were determined within 24 h after symptom onset.
Results. Among 347 patients with first MI, CETP concentration, triglycerides, and non–HDL-cholesterol increased across tertiles of the CET rate, whereas HDL-cholesterol, HDL, and LDL sizes decreased gradually. Among lipoprotein donors and acceptors, the best predictors of the CET rate were HDL2b and non–HDL-cholesterol, respectively. Mean age at first MI was 8.5 years lower in the patients from the highest CET tertile than in those in the lowest CET tertile. Diagonal stratification according to both non–HDL-cholesterol and HDL2b tertiles revealed that patients in the highest CET group were 18 years younger than patients in the lowest CET group. Parameters of the high CETP mass/high non–HDL-cholesterol/low HDL2b triad were independently associated with the CET rate.
Conclusions. In patients with acute MI, high CET rates are characterized by the presence of the high CETP mass/high non– HDL-cholesterol/low HDL2b triad. The association of high CET rates with young age at first MI lends support to a significant contribution of CETP to the accelerated progression of disease among asymptomatic patients.
Plasma cholesteryl ester transfer protein (CETP) catalyzes the exchange of cholesteryl esters and triglycerides between circulating lipoproteins, leading to the net mass transfer of cholesteryl esters from antiatherogenic high-density lipoproteins (HDL) to proatherogenic apolipoprotein (apo) B-containing lipoproteins (very-low-density lipoproteins [VLDL] and low-density lipoproteins [LDL]). Although the reduction in plasma neutral lipid transfer activity, as a result of either CETP gene mutation or CETP inhibition, is known to produce a major yet unrivaled increase in HDL-cholesterol, its impact on atherosclerosis prevention still remains a matter of debate. In particular, animal studies have provided a mixed picture. Whether modulation of CETP is beneficial or deleterious in the prevention or treatment of cardiovascular disease has recently come to the fore, because an excess of deaths and cardiovascular events has been found in high-risk patients from the ILLUMINATE (Investigation of Lipid Level management to Understand its iMpact IN ATherosclerotic Events) study receiving the CETP inhibitor torcetrapib. This outcome was rather unexpected, at least in the light of 3 distinct but complementary observations. First, elevated CETP mass and activity had been reported in patients with a history of myocardial infarction (MI) in whom CETP-mediated decreases in the levels of large LDL and HDL subfractions correlated with cardiovascular risk. Second, CETP-deficient subjects with high HDL-cholesterol have a lower incidence of coronary heart disease (CHD) than subjects with normal CETP activity, whereas subjects with high CETP concentrations have an increased risk for future CHD. Third, CETP was reported to relate to the progression of atherosclerosis in high-risk populations. It remains plausible that torcetrapib was harmful in the ILLUMINATE study not because of its impact on the lipoprotein profile but because of uncontrolled molecule-specific adverse effects. Based on these observations, the hypothesis of a predominant adverse effect of CETP still deserves attention, at least in high-risk populations.
An independent yet unexplored way to answer the question of the role of CETP in cardiovascular disease would be to assess further whether elevated CETP activity was associated with a younger age at first MI onset. To this end, CETP concentrations and cholesteryl ester transfer (CET) rates were measured in patients with acute MI at the very early phase, during which changes in lipids and CET rates are minimal. The hallmarks of elevated CET rates, including high triglycerides and small LDL and HDL were determined.
Abstract and Introduction
Abstract
Objectives. Our aim was to characterize cholesteryl ester transfer protein (CETP) activity in the early phase of acute myocardial infarction (MI).
Background. Cholesteryl ester transfer protein catalyzes the transfer of cholesteryl esters from high-density lipoprotein (HDL) donors to apolipoprotein B-containing lipoprotein acceptors.
Methods. The CETP concentration, lipid profiles, and the rate of cholesteryl ester transfer (CET) from a tracer dose of radiolabeledHDL toward endogenous lipoproteins were determined within 24 h after symptom onset.
Results. Among 347 patients with first MI, CETP concentration, triglycerides, and non–HDL-cholesterol increased across tertiles of the CET rate, whereas HDL-cholesterol, HDL, and LDL sizes decreased gradually. Among lipoprotein donors and acceptors, the best predictors of the CET rate were HDL2b and non–HDL-cholesterol, respectively. Mean age at first MI was 8.5 years lower in the patients from the highest CET tertile than in those in the lowest CET tertile. Diagonal stratification according to both non–HDL-cholesterol and HDL2b tertiles revealed that patients in the highest CET group were 18 years younger than patients in the lowest CET group. Parameters of the high CETP mass/high non–HDL-cholesterol/low HDL2b triad were independently associated with the CET rate.
Conclusions. In patients with acute MI, high CET rates are characterized by the presence of the high CETP mass/high non– HDL-cholesterol/low HDL2b triad. The association of high CET rates with young age at first MI lends support to a significant contribution of CETP to the accelerated progression of disease among asymptomatic patients.
Introduction
Plasma cholesteryl ester transfer protein (CETP) catalyzes the exchange of cholesteryl esters and triglycerides between circulating lipoproteins, leading to the net mass transfer of cholesteryl esters from antiatherogenic high-density lipoproteins (HDL) to proatherogenic apolipoprotein (apo) B-containing lipoproteins (very-low-density lipoproteins [VLDL] and low-density lipoproteins [LDL]). Although the reduction in plasma neutral lipid transfer activity, as a result of either CETP gene mutation or CETP inhibition, is known to produce a major yet unrivaled increase in HDL-cholesterol, its impact on atherosclerosis prevention still remains a matter of debate. In particular, animal studies have provided a mixed picture. Whether modulation of CETP is beneficial or deleterious in the prevention or treatment of cardiovascular disease has recently come to the fore, because an excess of deaths and cardiovascular events has been found in high-risk patients from the ILLUMINATE (Investigation of Lipid Level management to Understand its iMpact IN ATherosclerotic Events) study receiving the CETP inhibitor torcetrapib. This outcome was rather unexpected, at least in the light of 3 distinct but complementary observations. First, elevated CETP mass and activity had been reported in patients with a history of myocardial infarction (MI) in whom CETP-mediated decreases in the levels of large LDL and HDL subfractions correlated with cardiovascular risk. Second, CETP-deficient subjects with high HDL-cholesterol have a lower incidence of coronary heart disease (CHD) than subjects with normal CETP activity, whereas subjects with high CETP concentrations have an increased risk for future CHD. Third, CETP was reported to relate to the progression of atherosclerosis in high-risk populations. It remains plausible that torcetrapib was harmful in the ILLUMINATE study not because of its impact on the lipoprotein profile but because of uncontrolled molecule-specific adverse effects. Based on these observations, the hypothesis of a predominant adverse effect of CETP still deserves attention, at least in high-risk populations.
An independent yet unexplored way to answer the question of the role of CETP in cardiovascular disease would be to assess further whether elevated CETP activity was associated with a younger age at first MI onset. To this end, CETP concentrations and cholesteryl ester transfer (CET) rates were measured in patients with acute MI at the very early phase, during which changes in lipids and CET rates are minimal. The hallmarks of elevated CET rates, including high triglycerides and small LDL and HDL were determined.
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