Low-density lipoprotein particle size and coronary atherosclerosis in subjects belonging to hypertensive sibships

BACKGROUND: Dyslipidemia in hypertensive sibships may be characterized by atherogenic small low-density lipoprotein (LDL) particles. Whether LDL particle size is associated with the extent of coronary atherosclerosis in hypertensive sibships is unknown. METHODS: Subjects (n = 792, mean age 62 years, 60% women) were ascertained through sibships containing at least two individuals with essential hypertension diagnosed before age 60 years. The LDL particle size was measured by polyacrylamide gel electrophoresis. Coronary artery calcium (CAC) was measured noninvasively by electron beam computed tomography, and CAC score was calculated using the method of Agatston et al. Sex-specific multiple regression models were used to assess independent predictors of LDL particle size and the association of LDL particle size with CAC. RESULTS: In all, 76% of women and 77% of men were hypertensive. In each sex, independent predictors of smaller LDL particle size were total cholesterol, triglycerides, and lower HDL cholesterol. In women, greater age was an additional predictor of smaller LDL particle size. After adjustment for age and statin use, LDL particle size was significantly associated with the amount of CAC in women but not in men. After further adjustment for HDL cholesterol, triglycerides, diabetes, smoking, and hypertension, LDL particle size was not independently associated with CAC in either sex. CONCLUSIONS: After adjustment for age and statin use, LDL particle size was found to be significantly related to CAC quantity in women but not in men belonging to hypertensive sibships. In women, LDL particle size may mediate some of the atherogenic effects of low-HDL cholesterol-high-triglyceride dyslipidemia, but does not appear to be independently associated with the extent of coronary atherosclerosis in either sex.     

Low-density lipoprotein size and cardiovascular prevention

Low-density lipoprotein (LDL) size appears to be an important predictor of cardiovascular events and progression of coronary artery disease, and the predominance of small, dense LDL has been accepted as an emerging cardiovascular risk factor by the National Cholesterol Education Program Adult Treatment Panel III. Yet, other authors have suggested that LDL subclass measurement does not add independent information to that conferred generically by LDL concentration and other standard risk factors. Therefore, the debate continues as to whether to measure LDL particle size for cardiovascular prevention and, if so, in which categories of patients. Since the therapeutic modulation of distinct LDL subspecies is of great benefit in reducing the risk of cardiovascular events, LDL size measurement should be extended as much as possible to patients at high risk of cardiovascular diseases.     

Low-density lipoprotein particle size, triglycerides, and high-density lipoprotein cholesterol as risk factors for coronary heart disease in older Japanese-American men

Decreased low-density lipoprotein (LDL) particle size is associated with coronary heart disease (CHD) risk among middle-aged Caucasian populations, and has been consistently correlated with increased plasma levels of triglyceride and decreased levels of high-density lipoprotein (HDL) cholesterol. This study examines whether these risk factors predict CHD among older Japanese-American men. With use of the Honolulu Heart Program Lipoprotein Exam 3 (1980 to 1982) as baseline, and 12-year follow-up for CHD events, a nested, case-control study was designed. One hundred forty-five incident CHD cases were identified and matched to 2 controls each. LDL particle diameter (size) was determined by gradient gel electrophoresis. A 10-angstrom (A) decrease in LDL size at baseline was associated with increased risk of incident CHD (relative risk 1.28, 95% confidence interval 1.01 to 1.63). After adjustment for baseline risk factors, the LDL size association was no longer statistically significant (relative risk 1.13, 95% confidence interval 0.86 to 1.49). When principal components analysis was used to define a composite variable for LDL size, triglycerides, and HDL cholesterol, this component predicted CHD independent of smoking, alcohol consumption, physical activity, body mass index, hypertension, diabetes, and beta-blocker use (p <0.01). Therefore, this prospective analysis of data from older, Japanese-American men demonstrated that decreased LDL size is a univariate predictor of incident CHD, and that a composite risk factor of LDL size, triglyceride, and HDL cholesterol was a risk factor for CHD independent of other risk factors.     

Low-density lipoprotein particle size and coronary artery disease in a childhood-onset type 1 diabetes population

Low-density lipoprotein (LDL) cholesterol has been widely recognized as a strong predictor of coronary artery disease (CAD). Recently, studies have examined the influence of LDL particle size (an integral part of the insulin resistance syndrome) on the development of CAD in the general population. This report examines the correlates of LDL particle size and its association with CAD in a type 1 diabetes population. We evaluated the interrelationships between LDL particle size and the presence of CAD in a cohort of childhood-onset type 1 diabetic subjects using the Pittsburgh Epidemiology of Diabetes Complications (EDC) study. LDL particle size was measured in 337 subjects (mean age, 35.6 years; mean diabetes duration, 27.2 years) who underwent the 8-year follow-up examination. LDL particle size was determined by vertical polyacrylamide gel (2% to 16%) electrophoresis. Subjects with the small dense LDL particle phenotype (<235.5 angstroms) [corrected] had a longer diabetes duration, higher cholesterol, triglyceride, LDL, fibrinogen, waist to hip ratio (WHR), and hemoglobin A1 (HbA1), and lower high-density lipoprotein (HDL) cholesterol compared with subjects with the large LDL particle phenotype (>257 angstroms) [corrected]. Males were also more likely to have an increased body mass index (BMI) and CAD, while females were more likely to have hypertension and a family history of type 2 diabetes (a potential marker of insulin resistance and CAD risk). The odds ratio ([OR] 95% confidence, interval [CI]) using logistic regression analysis for LDL particle size in association with CAD was 0.79 (0.60 to 1.04). Multivariate modeling indicated that the duration of type 1 diabetes, depressive symptomatology, and triglycerides were independently associated with the presence of CAD. We conclude that although small dense LDL particle size is associated with CAD in our type 1 diabetes population, its borderline association can largely be explained by the triglyceride concentration. However, as in the general population, LDL particle size is associated with many elements of the insulin resistance syndrome, including a family history of type 2 diabetes, and is likely an important element in the contribution of insulin resistance to the development of CAD in type 1 diabetes.     

Low-density lipoprotein particle diameter in normal pregnancy and preeclampsia

We investigated the changes of low-density lipoprotein (LDL) size and serum lipids during pregnancy and postpartum not only in normal pregnant women but also in preeclampsia. Serum triglyceride (TG) and total cholesterol levels as well as serum high-density lipoprotein (HDL)-cholesterol, apolipoprotein (Apo) A1, B, E and remnant-like particle (RLP)-cholesterol levels were increased in normal pregnant women. The LDL peak particle diameter (PPD) in normal pregnant women was decreased during pregnancy and that at 37 weeks of gestation showed significant decrease compared with the women at 4 weeks after delivery (25.8 +/- 1.0 vs.26.8 +/- 0.7 nm, p < 0.05). The LDL-PPD in the preeclamptic women at admission (mean gestational age: 36 +/- 2.4 weeks) was significantly lower than that in normal pregnancy at 37 weeks of gestation (24.7 +/- 1.2 vs. 25.8 +/- 1.0 nm, p < 0.05). Moreover, the LDL-PPD in the preeclamptic women was significantly higher after delivery compared with the level at admission (27. +/- 0.7 vs. 24.7 +/- 1.2 nm, p < 0.05) accompanied by an improvement in plasma lipids profile. These findings suggest that the predominance of small, dense LDL, a potential contributor to endothelial dysfunction, may be a possible predictor of preeclampsia.     

Low-density lipoprotein particle number and risk for cardiovascular disease

The key role played by low-density lipoprotein (LDL) particles in the pathogenesis of coronary heart disease (CHD) is well accepted, as is the benefit of lowering LDL in high-risk patients. What remains controversial is whether we are using the best measure(s) of LDL to identify all individuals who would benefit from therapy. Many studies have shown that, at a given level of LDL cholesterol, individuals with predominantly small LDL particles (pattern B) experience greater CHD risk than those with larger-size LDL. However, it is not clear from this observation that small LDL particles are inherently more atherogenic than large ones because, at a given level of LDL cholesterol, individuals with small LDL have more LDL particles in total. The phenotype of small LDL particle size co-segregates with a cluster of metabolic factors, including elevated triglycerides and reduced HDL cholesterol, and in multivariate analyses has generally been found not to be independently associated with CHD risk. In contrast, LDL particle number measured by nuclear magnetic resonance has consistently been shown to be a strong, independent predictor of CHD.     

Low-density lipoprotein particle size, triglyceride-rich lipoproteins, and glucose tolerance in non-diabetic men with essential hypertension

The aim of the study is to investigate serum lipoproteins abnormalities including low-density lipoprotein (LDL) particle size, and their relationship with other cardiovascular risk factors in men with essential hypertension. Plasma glucose and serum insulin levels during oral glucose tolerance test (OGTT), serum lipoprotein(a), apolipoprotein (apo) A-I. apo B. cholesterol and triglycerides in serum and in lipoproteins, and LDL particle diameter were measured in thirty-eight consecutive newly-diagnosed non-diabetic untreated hypertensive men and 38 healthy male controls. Plasma glucose at baseline, 60 and 120 min during OGTT was significantly higher in patients than controls whereas serum insulin levels did not differ between patients and controls. Serum apo B and triglycerides were significantly raised in patients compared with controls (1.08 +/- 0.17 g/L [mean +/- SD] vs 0.97 +/- 0.22 g/L. p < 0.05, and 1.56 +/- 0.90 mmol/L vs 1.15 +/- 0.57 mmol/L, p < 0.05, respectively). Very-low-density lipoprotein (VLDL) triglycerides and LDL-cholesterol were increased in patients compared with controls (0.89 +/- 0.79 mmol/L and 0.54 +/- 0.35 mmol/L, p < 0.05, and 4.08 +/- 0.85 mmol/L and 3.60 +/- 0.92 mmol/L, p < 0.05, respectively) whereas high-density lipoprotein (HDL) cholesterol was lower in patients compared with controls 0.95 +/- 0.22 mmol/L and 1.07 +/- 0.20 mmol/L, p < 0.05). Adjustment for body mass index, abdominal/hip perimeter ratio and area under the glucose curve did not attenuate the relationship between hypertension and VLDL-triglycerides. Six patients and two controls had a mean LDL diameter < or = 25.5 nm and in the former serum triglycerides ranged from 1.86 mmol/L to 2.37 mmol/L. Mean LDL particle diameter in both patients and controls showed an inverse relationship with log-transformed serum triglycerides (r = - 0.51, p < 0.001 and r = - 0.47, p < 0.005, respectively). Among patients, those with serum triglycerides > or = [corrected] 1.58 mmol/L had a lesser mean LDL diameter than those with triglycerides above this threshold (25.78 +/- 0.47 nm vs 26.30 +/- 0.35 nm, p < 0.001). Higher plasma glucose, serum apo B and LDL-cholesterol as well as the decrease in serum HDL-cholesterol in patients with hypertension are consistent with high coronary heart disease risk. Not only mild hypertriglyceridemia but also high-normal serum triglycerides in themselves or as a surrogate of a predominance of small dense LDL particles in plasma convey an additional risk for cardiovascular disease in hypertensive patients even though routine plasma lipids are within or near normal range.     

Low-density lipoprotein particle size, insulin resistance, and proinsulin in a population sample of 58-year-old men

The relationship between insulin sensitivity and low-density lipoprotein (LDL) peak particle size was examined in 104 clinically healthy 58-year-old men recruited from the general population. Insulin sensitivity was measured by the euglycemic hyperinsulinemic clamp method with adjustment for lean body mass. LDL peak particle size was determined by gradient gel electrophoresis, and insulin, proinsulin, and 32,33 split proinsulin were determined by 2-site immunoradiometric assays. The results showed that 16 subjects (15%) had pattern B, with a predominance of small LDL particles. These cases and a small LDL peak particle size were characterized by the features of the insulin resistance syndrome, ie, general and central obesity, elevated diastolic blood pressure, low serum concentrations of high-density lipoprotein (HDL) and apolipoprotein A1 (apoA1), increases in serum triglycerides and circulating insulin peptides, and low insulin-mediated glucose uptake. The correlation between insulin sensitivity and LDL peak particle size was significant (r = .33, P = .001) and independent of obesity. In a traditional multiple regression analysis, LDL peak particle size was independently associated not with insulin-mediated glucose uptake but with circulating triglycerides and HDL cholesterol, which together explained 67% of the variability in LDL particle size (P = .000). Of all insulin peptides, only proinsulin showed an independent relation to LDL peak particle size, but it disappeared after adjustment for other variables. We conclude that a small LDL particle size was associated with insulin resistance among these clinically healthy men, but this was not independent of serum triglycerides and HDL cholesterol. Serum proinsulin was more directly related to LDL particle size than insulin.     

Low-density lipoprotein size,high-density lipoprotein concentration,and endothelial dysfunction in non-insulin-dependent diabetes

We examined endothelial function (nitric-oxide mediated) in 29 men with diet-treated non-insulin-dependent (Type 2) diabetes mellitus (NIDDM) and 18 male age-matched controls. Forearm blood flow was measured by venous occlusive plethysmography during intra-arterial administration of acetylcholine (ACh, 7.5 and 15 μg min⁻¹) and sodium nitroprusside (SNP, 3 and 10 μg min⁻¹). LDL particle size was estimated by non-denaturing gel electrophoresis. Serum lipids, blood pressure, and glycated haemoglobin were also measured. LDL particle size was smaller (p = 0.048) in the diabetic patients than controls. In the diabetic patients, LDL particle size was a significant positive predictor (p = 0.01) of the area under the dose–response curve for ACh, after adjusting for age, HbA_1c, systolic BP, and cholesterol (R² 0.20). In stepwise regression including serum lipid and lipoprotein concentrations and LDL particle size, decreased HDL cholesterol was the best predictor of an impaired vasodilatory response to ACh. Vasodilatory responses to sodium nitroprusside were not significantly correlated with LDL particle size or serum lipid and lipoprotein concentrations. We conclude that in men with NIDDM, small, dense LDL particle size is associated with abnormal endogenous release of nitric oxide. The contribution of small, dense LDL particles to the development of endothelial dysfunction and early diabetic vasculopathy may not, however, be as great as decreased HDL cholesterol. © 1997 John Wiley & Sons, Ltd.     

Diet and low-density lipoprotein particle size

Small, dense low-density lipoprotein (LDL) particles are being increasingly recognized as an important risk factor for cardiovascular disease. This paper provides an overview of how different diets and macronutrients modulate the LDL size phenotype. Data reviewed indicated that several components of the LDL size phenotype should be measured concurrently in order to fully appreciate the impact of diet on this complex trait. Data also suggested that numerous dietary elements have a significant impact on several characteristics of the LDL size phenotype, thus providing further evidence to the concept that specific dietary modifications can beneficially alter cardiovascular disease risk beyond their known and demonstrated effects on plasma LDL cholesterol concentrations.     

Low-density lipoprotein particle size, central obesity, cardiovascular fitness, and insulin resistance syndrome markers in obese youths

OBJECTIVE: (1) To determine the prevalence of small dense low-density lipoprotein (SDLDL) particles in obese youths and (2) to compare youths with SDLDL and large buoyant LDL (LBLDL) subclass phenotypes in total body and abdominal fatness, cardiovascular (CV) fitness, and markers of the insulin resistance syndrome (IRS). DESIGN: For group comparisons, subjects were dichotomized into either SDLDL phenotype group or LBDL phenotype group based on LDL particle size. SUBJECTS: Obese 13 to 16-y-olds (n=80) who had a triceps skinfold greater than the 85th percentile for gender, ethnicity, and age. MEASUREMENTS: LDL particle size, plasma lipids and lipoprotein concentrations, plasma glucose and insulin concentrations, and blood pressures; percentage body fat, visceral adipose tissue (VAT); VO(2) at a heart rate of 170 bpm as an index of CV fitness. RESULTS: The prevalence of the SDLDL phenotype was 54% among the 80 obese youths. Although overall body fatness (ie BMI and percentage body fat) and CV fitness were similar between the two LDL phenotype groups, the SDLDL phenotype group had significantly higher weight, waist circumference and VAT than the LBLDL phenotype group. With respect to the IRS markers, youths with the SDLDL phenotype had significantly higher triacylglycerol (TAG), very low-density lipoprotein cholesterol (VLDLC), apolipoprotein B (apo B), and total cholesterol-to-high-density lipoprotein ratio (TC/HDLC) than youths with the LBLDL phenotype. LDL particle size as a continuous variable was significantly correlated with TAG, VLDLC, apo B, HDLC, and TC/HDLC. Plasma TAG and HDLC concentrations were independent predictors of LDL particle size. CONCLUSION: (1) The SDLDL phenotype was common in obese youths and (2) the relationships of LDL particle size with several of the IRS markers suggested that already in adolescence the expression of the SDLDL phenotype might be an important risk factor for future coronary heart disease mortality and morbidity.     

Low density lipoprotein particle size and risk factors of insulin resistance syndrome

The present study aimed to examine the association between low density lipoprotein (LDL) particle size and glucose and insulin variables and with other risk factors that have been related to insulin resistance syndrome. LDL particle size was determined in two groups of subjects who participated in the first examination of the Jerusalem Diabetes Study and who were invited to be re-examined after 8-10 years. The first group were non-diabetic subjects who were found to have at the first examination high insulin levels (above the sex and age specific 90th percentile of the 2 h post-glucose load insulin distribution). The second group was a random sample of individuals who had normal insulin and glucose levels at baseline. Sex-, Age- and body mass index (BMI) mean adjusted LDL-cholesterol (C), triglyceride (TG) and high density lipoprotein cholesterol (HDL-C) levels were significantly different among the LDL subclass groups. Fasting glucose levels and hemoglobin A(1c) did not differ statistically by LDL subclasses. Fasting and 2-h post load insulin levels were significantly higher in persons with LDL subclasses III and IV (small LDL), intermediate in those with LDL subclass II, and lowest in those with LDL subclass I (large LDL). Insulin resistance had an effect on the association between lipids, lipoproteins and LDL particle size. Multivariate analyses indicated that LDL-C, HDL-C and TG were independently associated with LDL particle size variability. The addition of 'insulin resistance' or insulin and glucose levels had no independent effects on LDL particle size. In conclusion, an association of LDL particle size with the cluster of risk factors that characterize the insulin resistance syndrome has been demonstrated. The association of 'insulin resistance' and LDL particle diameter, however, is not mediated directly through the level of insulinemia but via alterations in lipid metabolism.     

The effect of insulin resistance and obesity on low-density lipoprotein particle size in children

Objective: In adults, it was shown that obesity and insulin resistance affect low−density lipoprotein (LDL) particle size and small dense (sd) LDL is associated with cardiovascular diseases. In this study, we investigated the effect of obesity and insulin resistance on LDL particle size.Methods: Twenty−six obese children (13 girls, 13 boys) with a median age of 10.5 years and 27 healthy control subjects (17 girls, 10 boys) with a median age of 11.5 were enrolled in the study.Results: The number of patients with insulin resistance in the obese group was 15 out of 26. In the control group, there was no subject with insulin resistance. Serum triglyceride and very LDL (VLDL) levels were higher and serum high−density lipoprotein levels (HDL) were lower in the obese patients than in the controls. There was no statistical difference in the LDL particle size between the two groups (medians: 26.6 vs. 26.7 nm (p=0.575)). The size of LDL particle was not correlated with body mass index (BMI) standard deviation score (SDS), homeostasis model assessment of insulin resistance (HOMA−IR), or serum lipids.Conclusion: Measurement of LDL particle size as a routine procedure is not necessary in childhood obesity.Conflict of interest:None declared.     

Low-density lipoprotein particle size is inversely related to plasminogen activator inhibitor-1 levels. The Insulin Resistance Atherosclerosis Study

High levels of plasminogen activator inhibitor-1 (PAI-1) and preponderance of small dense low-density lipoproteins (LDL) have both been associated with atherosclerotic disease and with the insulin resistance syndrome (IRS). In vitro studies have shown a stimulatory effect of various lipoproteins on PAI-1 release from different cells, including endothelial cells and adipocytes. The authors sought to investigate the relation of PAI-1 to LDL particle size in a large tri-ethnic population (n=1549) across different states of glucose tolerance. LDL size was determined by gradient gel electrophoresis, and PAI-1 was measured by a 2-site immunoassay, sensitive to free PAI-1. PAI-1 was inversely related to LDL size in the overall population (r=-0.21, P<0.0001), independent of gender and ethnicity. However, the authors found a significant interaction with glucose tolerance status (P=0.035). In univariate analysis, the association between PAI-1 and LDL size was most pronounced in subjects with normal glucose tolerance (NGT, r=-0.22, P<0.0001) and weaker in impaired glucose tolerance (IGT, r=-0.12, P=0.03) and type-2 diabetes (r=-0.10, P=0.02). After adjustment for demographic variables and metabolic variables known to influence PAI-1 levels (triglyceride and insulin sensitivity), a significant inverse relation of LDL size to PAI-1 levels was only present in NGT (P=0. 023). In subjects with IGT or overt diabetes, who usually have elevated PAI-1 levels, additional factors other than LDL size seem to contribute more importantly to PAI-1 levels. The demonstrated inverse relation of LDL size and PAI-1 levels provides one possible explanation for the atherogeneity of small dense LDL particles.     

Low-density lipoprotein metabolism in cerebrotendinous xanthomatosis

Cerebrotendinous xanthomatosis (CTX) is a rare disorder characterized by a defect in conversion of cholesterol into bile acids, increased plasma levels of cholestanol, and accumulations of sterols in tendons, brain, and coronary arteries. Despite the presence of tendon xanthomas, patients with CTX frequently have low levels of plasma cholesterol and low density lipoproteins (LDL). The mechanisms for a low LDL are not understood. The present study, therefore, was carried out to examine the metabolism of LDL in a 58-year-old black man with CTX. This particular patient had an LDL-cholesterol in the mid-normal range (149 +/- 6 mg/dL). Nonetheless, his fractional catabolic rate (FCR) for LDL-apolipoprotein (apo-LDL) was 0.45 pools/d, which was increased compared to 15 aged-matched men (FCR, 0.30 +/- 0.01 pools/d). His production rate for apo-LDL (18.5 mg/kg-d) also was increased compared to those of middle-aged men (13.5 +/- 2.5 mg/kg-d). Since the underlying defect in CTX can be reversed by administration of chenodeoxycholic acid (chenodiol), the patient was treated with chenodiol (250 mg 4X daily), and measurements of LDL kinetics were repeated. During chenodiol therapy, his LDL-cholesterol concentration rose significantly to 165 +/- 12 mg/dL; his FCR for apo-LDL fell to 0.29 pools/d; and his production rate of apo-LDL declined to 14.4 mg/kg-d. We postulate that chenodiol suppressed the excessive synthesis of cholesterol and bile acids, which had two effects. It curtailed both the overproduction of LDL and the excessive synthesis of LDL receptors, the latter being responsible for the high FCR of apo-LDL in the untreated state.     

Low-density lipoprotein cholesterol and mortality in older people

OBJECTIVES: To investigate the role of low-density lipoprotein cholesterol (LDL-C) as a predictor of mortality in elderly subjects. DESIGN: Population-based prospective cohort study. SETTING: Two communities in northern Italy. PARTICIPANTS: Three thousand one hundred twenty Caucasian subjects aged 65 and older recruited in for the Cardiovascular Study in the Elderly and followed up for 12 years. MEASUREMENTS: Anthropometric measures: fasting plasma total cholesterol, triglyceride, high-density lipoprotein cholesterol, LDL-C, glucose, creatinine, and body mass index. Clinical measures: medical assessment, diabetes mellitus, hypertension, stroke, coronary disease, heart failure, and smoking and drinking habits. Vital status measures: death certificates from the Registry Office and causes of death according to the International Classification of Diseases. After plotting mortality rates using quartiles of LDL-C, relative hazard rates (RHRs) were calculated using multivariate Cox regression analyses. When the trend was nonlinear, the RHRs were further calculated for the 25th, 50th, and 75th percentiles of the distribution to confirm curvilinearity. RESULTS: The distribution of risk of total mortality in women and of fatal heart failure in all subjects was curvilinear (non J-shaped), decreasing nonlinearly with LDL-C. For total mortality in men and cardiovascular mortality in both sexes, the relationship with LDL-C was J-shaped. The risk of fatal myocardial infarction was J-shaped in men, whereas it increased linearly with higher LDL-C in women. In both sexes, the association between stroke mortality and LDL-C was not significant. CONCLUSION: This study adds to the uncertainty of the role of elevated levels of LDL-C as a risk factor for mortality in old people.