- Email: [email protected]
Diurnal triglyceridemia: a surrogate of postprandial lipemia?
Wednesday June 28, 2000: Workshop Abstracts W:20 Triglycerides and CVD
genotype (OR 3.1, 95% CI; 2.24.4, p = 0.0007). whereas those with single infarct did not (OR 2.0, p = 0.15). When subjects were stratified according to homocyst(e)ine levels, MTHFR ‘IT genotype was significantly associated with risk of vascular dementia in hyperhomocyst(e)inemia groups (OR 3.03, 95% CI, 1.80-5.10, p = 0.03), compared to with CT/CC genotype, but not in normohomocysteinemic groups. Conclusions: Findings provide evidence that thermolabile variant of MTHFR enzyme is associated with the severity of cerebral infarction and the occurrence of vascular dementia, furthermore homocyst(e)inemia may not be the only pathogenic factor in MTHFR deficiency. Analysis of both plasma homocyst(e)ine and C677T genotype of MTHFR is probably necessary for the risk evaluation of cerebrovascular disease.
w:20 I WeWl
20
TRIGLYCERIDES
Hypertriglyceridemia
AND CVD
and the metabolic syndrome
S. Grundy. University of Texas Southwestern Medical Center Dallas, Texas, USA Most patients with hypettriglyceridemia have other cardiovascular risk factors that are typical of the metabolic syndrome. These include elevations of apolipoprotein B, remnant lipoproteins and small LDL particles; reduced HDL cholesterol; elevated blood pressure; insulin resistance and glucose intolerance; and coagulation abnormalities. Thus, elevated serum triglycerides are a marker for the metabolic syndrome. This is especially the case when patients have abdominal obesity. Rarely patients will have hypertriglyceridemia in the absence of abdominal obesity and insulin resistance, but such cases are an exception, and not the rule. Hypertriglyceridemia in patients with insulin resistance is usually secondary to fatty liver, which in turn is the result of elevated plasma nonesterified fatty acids (NEFA). Elevations of NEFA can be due either to obesity or to insulin resistance in adipose tissue. In addition to being a marker for the metabolic syndrome, elevated triglycerides may be directly or indirectly atherogenic. Some triglyceride rich lipoproteins, particularly VLDL remnants, appear to be directly atherogenic; also elevated triglycerides give rise to small LDL particles and low HDL levels, both of which may be atherogenic. The primary treatment of hypertriglyceridemia is weight control plus physical activity; both reduce insulin resistance and mitigate the metabolic syndrome. A question of great importance is whether triglyceride-lowering drugs will also reduce risk for coronary heart disease. Several clinical trials give strongly suggestive evidence of risk reduction from these triglyceride-lowering drugs.
IWeW2.20
Twenty-year cardiovascular disease mortality in the familial forms of hypertriglyceridemia
M.A. Austin, B. M&night, K.L. Edwards, C.M. Bradley, M.J. McNeely, B.M. Psaty, J.D. Bmnzell, A.G. Motulsky. University of Washington, Seattle, Washington, USA Background: Familial combined hyperlipidemia (FCHL) and familial hypertriglyceridemia (FHTG) are two of the most common familial forms of hyperlipidemia. The purposes of this study were to estimate 20-year cardiovascular disease (CVD) mortality among relatives in these families, and to evaluate plasma triglyceride as a predictor of CVD mortality. Methods: The study was based on lipid and medical history data from 101 families ascertained in two studies conducted in the early 1970s. Vital status and cause-of-death was determined during 1993-97 for 685 family members, including first degree relatives of the probands and spouse controls. Results: Compared to spouse controls, CVD mortality was increased among sibs and offspring in FCHL (relative risk = 1.7, P = 0.02) after adjustment for baseline covariates. Baseline triglyceride was associated with increased CVD mortality independent of total cholesterol among relatives in FHTG families, (relative risk = 2.7, P = 0.02). but not in FCHL families (relatives risk = 1.5, P = 0.16). after adjustment for baseline covariates. Conclusions: This prospective study establishes that relatives in FCHL families are at increased risk for CVD mortality and that triglyceride predicts CVD mortality among relatives in FHTG families. The findings add to the growing evidence for the importance of hypertriglyceridemia as a risk factor for CVD.
WeW3 20 I
161
Diurnal triglyceridemia: lipemia?
A surrogate of postprandial
M. Castro Cabezas, C.J.M. Halkes, S. Meijssen, D.W. Erkelens. Univ. Hosp. Utrecht, Dpt. of Intern. Med., the Netherlands Background: Postprandial hypertriglyceridemia is regarded as an independent risk factor for atherosclerosis. Large prospective studies have not been performed due to the workload and the costs involved in performing oral fat loading tests. We evaluated the feasibility of determining ambulatory diurnal capillary TG (TGc) profiles compared to standardized oral fat loading tests (OFLT) in 18 subjects and we determined the variability of diurnal triglyceridemia in a larger cohort of 106 subjects. Methods: In 18 subjects with a wide range of fasting plasma TG, results of OFLT (50 g/m*; 10 hrs) were compared to diurnal TGc profiles measured in an out-patient clinic setting. In an observational study, 106 healthy volunteers (54 females and 52 males) measured TGc. Food intake was recorded in a diary and fasting blood was drawn once at inclusion. Diurnal TGc profiles were estimated as the mean area under the TGc curve of 6 time-point measurements on 3 different days. Results: Plasma TG clearance after the acute OFLT correlated well with the diurnal TGc-AUC (r = 0.77; P c 0.01; n = 18). In addition, hyper’IG subjects (plasma TG z 2.0 mM) had a higher diurnal triglyceridemia (49.8 & 15.4 h.mM) as well as a higher response of plasma TG to the OFLT (42.1 f 15.4 h.mM), than the subjects with normal fasting plasma TG (29.8 f 11.8 h.mM [P < 0.051 and 20.8 * 5.9 h.mM [P < O.Ol], respectively). In the cohort of 106 subjects, repeated measurements of diurnal triglyceridemia tended to be less variable than fasting capillary TG (mean coefficients of variation 15% [range: 0.60%-46%] and 25% [range: 1.4%-b-73%], respectively; P = 0.09) for the whole group and in males (19% [0.60%-46%] and 24% [1.4%-58%], respectively; P = 0.07). Stepwise multiple regression analysis with TGc-AUC as dependent variable showed that the best predictors were fasting TGc, gender, systolic blood pressure and mean daily energy intake, explaining 72% of the variation of diurnal triglyceridemia. Conclusion: Diurnal capillary TG profiles may be used to estimate the total daily load of potential atherogenic triglyceride rich particles to which individuals are subjected during the day without the need for metabolic ward studies.
IWeW4.20
Application
of a sandwich ELISA for apo B48
Y. Saikai S. Yamashita’, N. Sakai’, K. Hirano’, Y. Utida*, S. Itou*, -7 Y. Matsuzawa'‘Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University; 2Fujirebio, Inc., Japan
.
Object: Chylomicron (CM) remnants are assumed to play important roles in atherogenesis. However, there have been no appropriate methods to sensitively evaluate the fasting levels of CM remnants. The object of the current study was to raise monoclonal antibodies (mAbs) against human apo B-48 and to establish a sensitive ELISA for measuring serum apo B-48 levels in normolipidemic and hyperlipidemic subjects. Methods and Results: mAbs were raised against human apo B-48 by immunizing synthetic peptides. These mAbs specifically reacted with the C-terminal of apo B-48, but not B-100. Using these mAbs, a sandwich ELISA was established to measure serum apo B-48 levels, using recombinant apo B-48 as a standard (kindly provided by Dr. Yao). The CV of the assay was approximately 10%. After oral fat loading in normolipidemic subjects, serum apo B-48 increased with a peak at 3-4 h. In the normolipidemic subjects (n = 369), fasting serum apo B-48 levels were 41 f 28 (Mean f SD) arbitrary units (AU)/ml (100 AU/ml _ 1 mg/dl). Serum apo B-48 concentration positively correlated with serum triglyceride levels (r = 0.72, p < 0.05). while there was no significant correlation between serum apo B-48 and cholesterol levels. Apo B-48 was detected in ultracentrifugally separated lipoproteins including CM, VLDL, IDL and even LDL. In dyslipidemic subjects with apo E2J2, apo B-48 was extremely increased even if they were normolipidemic. In patients with diabetes mellitus, apo B-48 was also increased, suggesting the impairment of CM metabolism. Furthermore, we used the mAbs to examine the presence or absence of apo B-48 in human aortic tissues. Immunohistochemical analysis demonstrated a strong positive staining of apo B-48 mainly in the extracellular matrices of aterosclerotic aorta. Conclusion: These data suggest that this apo B-48 ELISA provides a useful tool to estimate the impairment of CM metabolism and that the deposition of CM remnants could contribute partly to the pathogenesis of atherosclerosis.
XIIth International Symposium on Atherosclerosis, Stockholm, Sweden, June 25-29, 2000
genotype (OR 3.1, 95% CI; 2.24.4, p = 0.0007). whereas those with single infarct did not (OR 2.0, p = 0.15). When subjects were stratified according to homocyst(e)ine levels, MTHFR ‘IT genotype was significantly associated with risk of vascular dementia in hyperhomocyst(e)inemia groups (OR 3.03, 95% CI, 1.80-5.10, p = 0.03), compared to with CT/CC genotype, but not in normohomocysteinemic groups. Conclusions: Findings provide evidence that thermolabile variant of MTHFR enzyme is associated with the severity of cerebral infarction and the occurrence of vascular dementia, furthermore homocyst(e)inemia may not be the only pathogenic factor in MTHFR deficiency. Analysis of both plasma homocyst(e)ine and C677T genotype of MTHFR is probably necessary for the risk evaluation of cerebrovascular disease.
w:20 I WeWl
20
TRIGLYCERIDES
Hypertriglyceridemia
AND CVD
and the metabolic syndrome
S. Grundy. University of Texas Southwestern Medical Center Dallas, Texas, USA Most patients with hypettriglyceridemia have other cardiovascular risk factors that are typical of the metabolic syndrome. These include elevations of apolipoprotein B, remnant lipoproteins and small LDL particles; reduced HDL cholesterol; elevated blood pressure; insulin resistance and glucose intolerance; and coagulation abnormalities. Thus, elevated serum triglycerides are a marker for the metabolic syndrome. This is especially the case when patients have abdominal obesity. Rarely patients will have hypertriglyceridemia in the absence of abdominal obesity and insulin resistance, but such cases are an exception, and not the rule. Hypertriglyceridemia in patients with insulin resistance is usually secondary to fatty liver, which in turn is the result of elevated plasma nonesterified fatty acids (NEFA). Elevations of NEFA can be due either to obesity or to insulin resistance in adipose tissue. In addition to being a marker for the metabolic syndrome, elevated triglycerides may be directly or indirectly atherogenic. Some triglyceride rich lipoproteins, particularly VLDL remnants, appear to be directly atherogenic; also elevated triglycerides give rise to small LDL particles and low HDL levels, both of which may be atherogenic. The primary treatment of hypertriglyceridemia is weight control plus physical activity; both reduce insulin resistance and mitigate the metabolic syndrome. A question of great importance is whether triglyceride-lowering drugs will also reduce risk for coronary heart disease. Several clinical trials give strongly suggestive evidence of risk reduction from these triglyceride-lowering drugs.
IWeW2.20
Twenty-year cardiovascular disease mortality in the familial forms of hypertriglyceridemia
M.A. Austin, B. M&night, K.L. Edwards, C.M. Bradley, M.J. McNeely, B.M. Psaty, J.D. Bmnzell, A.G. Motulsky. University of Washington, Seattle, Washington, USA Background: Familial combined hyperlipidemia (FCHL) and familial hypertriglyceridemia (FHTG) are two of the most common familial forms of hyperlipidemia. The purposes of this study were to estimate 20-year cardiovascular disease (CVD) mortality among relatives in these families, and to evaluate plasma triglyceride as a predictor of CVD mortality. Methods: The study was based on lipid and medical history data from 101 families ascertained in two studies conducted in the early 1970s. Vital status and cause-of-death was determined during 1993-97 for 685 family members, including first degree relatives of the probands and spouse controls. Results: Compared to spouse controls, CVD mortality was increased among sibs and offspring in FCHL (relative risk = 1.7, P = 0.02) after adjustment for baseline covariates. Baseline triglyceride was associated with increased CVD mortality independent of total cholesterol among relatives in FHTG families, (relative risk = 2.7, P = 0.02). but not in FCHL families (relatives risk = 1.5, P = 0.16). after adjustment for baseline covariates. Conclusions: This prospective study establishes that relatives in FCHL families are at increased risk for CVD mortality and that triglyceride predicts CVD mortality among relatives in FHTG families. The findings add to the growing evidence for the importance of hypertriglyceridemia as a risk factor for CVD.
WeW3 20 I
161
Diurnal triglyceridemia: lipemia?
A surrogate of postprandial
M. Castro Cabezas, C.J.M. Halkes, S. Meijssen, D.W. Erkelens. Univ. Hosp. Utrecht, Dpt. of Intern. Med., the Netherlands Background: Postprandial hypertriglyceridemia is regarded as an independent risk factor for atherosclerosis. Large prospective studies have not been performed due to the workload and the costs involved in performing oral fat loading tests. We evaluated the feasibility of determining ambulatory diurnal capillary TG (TGc) profiles compared to standardized oral fat loading tests (OFLT) in 18 subjects and we determined the variability of diurnal triglyceridemia in a larger cohort of 106 subjects. Methods: In 18 subjects with a wide range of fasting plasma TG, results of OFLT (50 g/m*; 10 hrs) were compared to diurnal TGc profiles measured in an out-patient clinic setting. In an observational study, 106 healthy volunteers (54 females and 52 males) measured TGc. Food intake was recorded in a diary and fasting blood was drawn once at inclusion. Diurnal TGc profiles were estimated as the mean area under the TGc curve of 6 time-point measurements on 3 different days. Results: Plasma TG clearance after the acute OFLT correlated well with the diurnal TGc-AUC (r = 0.77; P c 0.01; n = 18). In addition, hyper’IG subjects (plasma TG z 2.0 mM) had a higher diurnal triglyceridemia (49.8 & 15.4 h.mM) as well as a higher response of plasma TG to the OFLT (42.1 f 15.4 h.mM), than the subjects with normal fasting plasma TG (29.8 f 11.8 h.mM [P < 0.051 and 20.8 * 5.9 h.mM [P < O.Ol], respectively). In the cohort of 106 subjects, repeated measurements of diurnal triglyceridemia tended to be less variable than fasting capillary TG (mean coefficients of variation 15% [range: 0.60%-46%] and 25% [range: 1.4%-b-73%], respectively; P = 0.09) for the whole group and in males (19% [0.60%-46%] and 24% [1.4%-58%], respectively; P = 0.07). Stepwise multiple regression analysis with TGc-AUC as dependent variable showed that the best predictors were fasting TGc, gender, systolic blood pressure and mean daily energy intake, explaining 72% of the variation of diurnal triglyceridemia. Conclusion: Diurnal capillary TG profiles may be used to estimate the total daily load of potential atherogenic triglyceride rich particles to which individuals are subjected during the day without the need for metabolic ward studies.
IWeW4.20
Application
of a sandwich ELISA for apo B48
Y. Saikai S. Yamashita’, N. Sakai’, K. Hirano’, Y. Utida*, S. Itou*, -7 Y. Matsuzawa'‘Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University; 2Fujirebio, Inc., Japan
.
Object: Chylomicron (CM) remnants are assumed to play important roles in atherogenesis. However, there have been no appropriate methods to sensitively evaluate the fasting levels of CM remnants. The object of the current study was to raise monoclonal antibodies (mAbs) against human apo B-48 and to establish a sensitive ELISA for measuring serum apo B-48 levels in normolipidemic and hyperlipidemic subjects. Methods and Results: mAbs were raised against human apo B-48 by immunizing synthetic peptides. These mAbs specifically reacted with the C-terminal of apo B-48, but not B-100. Using these mAbs, a sandwich ELISA was established to measure serum apo B-48 levels, using recombinant apo B-48 as a standard (kindly provided by Dr. Yao). The CV of the assay was approximately 10%. After oral fat loading in normolipidemic subjects, serum apo B-48 increased with a peak at 3-4 h. In the normolipidemic subjects (n = 369), fasting serum apo B-48 levels were 41 f 28 (Mean f SD) arbitrary units (AU)/ml (100 AU/ml _ 1 mg/dl). Serum apo B-48 concentration positively correlated with serum triglyceride levels (r = 0.72, p < 0.05). while there was no significant correlation between serum apo B-48 and cholesterol levels. Apo B-48 was detected in ultracentrifugally separated lipoproteins including CM, VLDL, IDL and even LDL. In dyslipidemic subjects with apo E2J2, apo B-48 was extremely increased even if they were normolipidemic. In patients with diabetes mellitus, apo B-48 was also increased, suggesting the impairment of CM metabolism. Furthermore, we used the mAbs to examine the presence or absence of apo B-48 in human aortic tissues. Immunohistochemical analysis demonstrated a strong positive staining of apo B-48 mainly in the extracellular matrices of aterosclerotic aorta. Conclusion: These data suggest that this apo B-48 ELISA provides a useful tool to estimate the impairment of CM metabolism and that the deposition of CM remnants could contribute partly to the pathogenesis of atherosclerosis.
XIIth International Symposium on Atherosclerosis, Stockholm, Sweden, June 25-29, 2000