Showing papers by "Scott M. Grundy published in 1994"

Modification of low density lipoprotein by advanced glycation end products contributes to the dyslipidemia of diabetes and renal insufficiency

Abstract: Atherosclerosis develops rapidly in patients with diabetes or renal insufficiency. Plasma lipoprotein profiles are frequently abnormal in these conditions and reflect an elevation in the level of the apoprotein B (ApoB)-containing components very low density lipoprotein (VLDL) and low density lipoprotein (LDL). High levels of circulating advanced glycation end products (AGEs) also occur in diabetes and end-stage renal disease (ESRD). These products arise from glucose-derived Amadori products and include AGE-modified peptides (AGE-peptides) which result from the catabolism of AGE-modified tissue proteins. AGE-peptides have been shown to crosslink protein amino groups and to accumulate in plasma as a consequence of renal insufficiency. To address potential mechanisms for the dyslipidemia of diabetes and ESRD, we investigated the possibility that circulating AGEs react directly with plasma lipoproteins to prevent their recognition by tissue LDL receptors. AGE-specific ELISA showed a significantly increased level of AGE-modified LDL in the plasma of diabetic or ESRD patients compared with normal controls. AGE-LDL formed readily in vitro when native LDL was incubated with either synthetic AGE-peptides or AGE-peptides isolated directly from patient plasma. LDL which had been modified by AGE-peptides in vitro to the same level of modification as that present in the plasma of diabetics with renal insufficiency exhibited markedly impaired clearance kinetics when injected into transgenic mice expressing the human LDL receptor. These data indicate that AGE modification significantly impairs LDL-receptor-mediated clearance mechanisms and may contribute to elevated LDL levels in patients with diabetes or renal insufficiency. This hypothesis was further supported by the observation that the administration of the advanced glycation inhibitor aminoguanidine to diabetic patients decreased circulating LDL levels by 28%.

Effects of Varying Carbohydrate Content of Diet in Patients With Non—Insulin-Dependent Diabetes Mellitus

Abstract: Objective. —To study effects of variation in carbohydrate content of diet on glycemia and plasma lipoproteins in patients with non—insulin-dependent diabetes mellitus (NIDDM). Design. —A four-center randomized crossover trial. Setting. —Outpatient and inpatient evaluation in metabolic units. Patients. —Forty-two NIDDM patients receiving glipizide therapy. Interventions. —A high-carbohydrate diet containing 55% of the total energy as carbohydrates and 30% as fats was compared with a high—monounsaturated-fat diet containing 40% carbohydrates and 45% fats. The amounts of saturated fats, polyunsaturated fats, cholesterol, sucrose, and protein were similar. The study diets, prepared in metabolic kitchens, were provided as the sole nutrients to subjects for 6 weeks each. To assess longer-term effects, a subgroup of 21 patients continued the diet they received second for an additional 8 weeks. Main Outcome Measures. —Fasting plasma glucose, insulin, lipoproteins, and glycosylated hemoglobin concentrations. Twenty-four-hour profiles of glucose, insulin, and triglyceride levels. Results. —The site of study as well as the diet order did not affect the results. Compared with the high—monounsaturated-fat diet, the high-carbohydrate diet increased fasting plasma triglyceride levels and very low-density lipoprotein cholesterol levels by 24% ( P P =.0001), respectively, and increased daylong plasma triglyceride, glucose, and insulin values by 10% ( P =.03), 12% ( P P =.02), respectively. Plasma total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels remained unchanged. The effects of both diets on plasma glucose, insulin, and triglyceride levels persisted for 14 weeks. Conclusions. —In NIDDM patients, high-carbohydrate diets compared with high—monounsaturated-fat diets caused persistent deterioration of glycemic control and accentuation of hyperinsulinemia, as well as increased plasma triglyceride and very-low-density lipoprotein cholesterol levels, which may not be desirable. ( JAMA . 1994;271:1421-1428)

Cholestyramine therapy for dyslipidemia in non-insulin-dependent diabetes mellitus. A short-term, double-blind, crossover trial.

Abstract: Objective: To assess clinical efficacy and tolerability of cholestyramine therapy in patients with dyslipidemia and non–insulin-dependent diabetes mellitus (NIDDM). Design: A randomized, double-bli...

Excess body weight. An under-recognized contributor to dyslipidemia in white American women.

Abstract: Background: Whether the association between excess body weight and dyslipidemia is consistent across different age ranges in women has yet to be determined Methods: The relationship between body weight adjusted for height as calculated by body mass index (BMI; kilograms per square meter) and serum lipid and lipoprotein levels in white women was examined using crosssectional data from the Second National Health and Nutrition Examination Survey Mean lipid levels were determined for six different categories of BMI: (1) 210 or less; (2) 211 to 230; (3) 231 to 250; (4) 251 to 270; (5) 271 to 300; and (6) more than 300, and three age groups: premenopausal women, 20 through 44 years; perimenopausal women, 45 through 59 years; and postmenopausal women, 60 through 74 years Results: Compared with BMI category 2, a BMI in category 5 for premenopausal women was associated with 046 mmol/L (18 mg/dL) higher total cholesterol levels, 068 mmol/L (26 mg/dL) higher non—high-density lipoprotein (HDL) cholesterol levels, and 044 mmol/L (17 mg/ dL) higher low-density lipoprotein (LDL) cholesterol levels For perimenopausal women and postmenopausal women the same change in BMI was associated with much smaller differences in total cholesterol of 016 and 016 mmol/L (6 and 5 mg/dL), non-HDL of 024 and 020 mmol/L (9 and 8 mg/dL), and LDL levels of 013 and 003 mmol/L (5 and 1 mg/dL) More impressively, rising BMI was associated with consistently higher triglyceride levels of 054 to 040 mmol/L (48 to 35 mg/dL) and consistently lower HDL levels of 023 to 013 mmol/L (9 to 5 mg/dL), in all three age groups Conclusion: For young women, excess body weight was associated with higher total, non-HDL and LDL-cholesterol levels, higher triglyceride levels, and lower HDL-cholesterol levels In older women, although similar differences in triglyceride levels and HDL-cholesterol levels were observed, excess body weight was associated with smaller differences in total, non-HDL, and LDL cholesterol More striking than the weightassociated differences in total, non-HDL, and LDL-cholesterol levels were the differences in these lipid parameters observed with age alone Specifically, age category differences were twofold to eightfold greater than differences observed between categories of BMI within a given age Nevertheless, because the lower HDL cholesterol concentrations associated with excess body weight were age independent, total cholesterol-HDL cholesterol ratios were highest in obese postmenopausal women Although age and hormonal status are important affecters of lipoprotein risk factors, body weight also worsens the degree of dyslipidemia in white women (Arch Intern Med 1994;154:401-410)

Variation at the hepatic lipase and apolipoprotein AI/CIII/AIV loci is a major cause of genetically determined variation in plasma HDL cholesterol levels.

Abstract: Genetic factors have been shown to play an important role in determining interindividual variation in plasma HDL-C levels, but the specific genetic determinants of HDL cholesterol (HDL-C) levels have not been elucidated. In this study, the effects of variation in the genomic regions encoding hepatic lipase, apolipoprotein AI/CIII/AIV, and the cholesteryl ester transfer protein on plasma HDL-C levels were examined in 73 normotriglyceridemic, Caucasian nuclear families. Genetic factors accounted for 56.5 +/- 13% of the interindividual variation in plasma HDL-C levels. For each candidate gene, adjusted plasma HDL-C levels of sibling pairs who shared zero, one, or two parental alleles identical-by-descent were compared using sibling-pair linkage analysis. Allelic variation in the genes encoding hepatic lipase and apolipoprotein AI/CIII/AIV accounted for 25 and 22%, respectively, of the total interindividual variation in plasma HDL-C levels. In contrast, none of the variation in plasma HDL-C levels could be accounted for by allelic variation in the cholesteryl ester transfer protein. These findings indicate that a major fraction of the genetically determined variation in plasma HDL-C levels is conferred by allelic variation at the hepatic lipase and the apolipoprotein AI/CIII/AIV gene loci.

Lp(a) Lipoprotein Is an Independent, Discriminating Risk Factor for Premature Peripheral Atherosclerosis Among White Men

Abstract: Background: Elevated plasma levels of Lp(a) lipoprotein have been linked to the development of premature atherosclerosis in the coronary circulation (coronary artery disease [CAD]). Although Lp(a) lipoprotein has been implicated as a risk factor for premature atherosclerosis in other locations, the patient populations described were not carefully screened for the coexistence of premature CAD. The purpose of this prospective study was to determine whether carefully screened patients with premature peripheral vascular disease (PVD) have elevated plasma levels of Lp(a) lipoprotein and to test the relative strength of Lp(a) lipoprotein level as a risk factor for premature PVD. Methods: We studied 55 consecutive white men with premature PVD (onset at 45 years of age or earlier) presenting to our vascular laboratory. Study subjects were substratified into 17 with PVD only and 38 with combined PVD and CAD (PVD + CAD). Two comparison groups included 26 age-matched white men with premature CAD recruited from the Cardiology Service after cardiac catheterization and 32 age-matched white male controls recruited from outpatient clinics. Results: Mean plasma apolipoprotein B-100 levels were higher in the CAD group than in controls ( P =.013). Mean plasma Lp(a) lipoprotein levels were higher among the 17 patients with PVD only than among controls ( P =.008). The covariance-adjusted mean Lp(a) lipoprotein levels were higher among all 55 patients with PVD than among controls ( P =.014). Logistic regression analysis demonstrated two variables to be significantly related to premature PVD: Lp(a) lipoprotein level greater than 30 mg/dL (odds ratio, 3.9; 95% confidence interval, 1.1 to 13.7) and apolipoprotein B level greater than 95 mg/dL (odds ratio, 3.2; 95% confidence interval, 1.0 to 10.0). Conclusions: Lp(a) lipoprotein level is an independent, discriminating risk factor for premature PVD among white men. (Arch Intern Med. 1994;154:801-806)

Individual Responses to a Cholesterol-Lowering Diet in 50 Men With Moderate Hypercholesterolemia

Abstract: Background: Dietary modification is the recommended first step in the treatment of hypercholesterolemia. However, the efficacy of the National Cholesterol Education Program Step 1 Diet in outpatients with hypercholesterolemia has been debated. Methods: Fifty normotriglyceridemic men whose ad libitum low-density lipoprotein (LDL) cholesterol levels were 4.14 to 5.69 mmol/L (160 to 220 mg/dL) participated in a two-period outpatient diet counseling study that used a 1-month high-fat, high—saturated fatty acid period (Hi-Sat) and a 4-month low-fat, low—saturated fatty acid period (Step 1 Diet). Lipid, lipoprotein levels, and plasma triglyceride fatty acids were measured five times during the last 2 weeks of each dietary period and averaged for each patient. Dietary intake was assessed by 7-day food records. During the Hi-Sat period, an LDL turnover study was done to determine the fractional catabolic rate of LDL. Results: The mean reduction in total and LDL cholesterol levels achieved by diet was 0.54 mmol/L (21 mg/ dL) and 0.39 mmol/L (15 mg/dL), respectively. These responses equaled those predicted from metabolic ward investigations. While dietary responsiveness was normally distributed, there was marked individual variation in response. The mean (±SD) for quartiles of LDL responsiveness were +0.41±0.21 mmol/L (+16±8 mg/dL), —0.16±0.13 mmol/L (—6±5 mg/dL), —0.57±0.16 mmol/L (—22±6 mg/dL), and —1.16±0.26 mmol/L (—45±10 mg/ dL). These differences in response were partially explained by dietary adherence, baseline fractional catabolic rates of LDL, and the change in plasma triglyceride palmitate level. Conclusions: The Step 1 Diet is effective in lowering LDL cholesterol levels for many hypercholesterolemic men, and with appropriate counseling, outpatients can achieve results predicted by inpatient metabolic diet studies. Nonetheless, the responsiveness for individuals is highly variable, and this variability is influenced by both compliance and biologic factors. Since many men achieved LDL cholesterol levels low enough to remove the need for drug therapy in primary prevention for coronary heart disease, dietary therapy should remain the initial approach to the treatment of hypercholesterolemia. (Arch Intern Med. 1994;154:317-325)

Hypercholesterolemia in postmenopausal women. Metabolic defects and response to low-dose lovastatin.

Abstract: Objective. —To determine the metabolic mechanisms underlying hypercholesterolemia in postmenopausal women and to determine whether a low dose of lovastatin will correct this abnormality. Design. —In the first part of the study, turnover rates of autologous low-density lipoprotein (LDL) were measured in hypercholesterolemic and control women. In the second part, hypercholesterolemic women participated in a placebo-controlled, randomized, double-blind study using lovastatin as the therapeutic agent. Setting. —The General Clinical Research Center of the University of Texas Southwestern Medical Center, Dallas, utilizing inpatient and outpatient facilities, and the Veterans Affairs Medical Center, Dallas, Tex. Patients. —For the LDL turnover study, 26 postmenopausal women with moderate hypercholesterolemia (mean±SD LDL cholesterol, 4.78±0.59 mmol/L [185 ±23 mg/dL]) and 13 postmenopausal women with normal levels of plasma lipids and lipoproteins (mean±SD LDL cholesterol, 3.31 ±0.39 mmol/L [128±15 mg/dL]) were studied. Sixteen postmenopausal women participated in the drug study. Interventions. —In the drug study, patients received blindly both lovastatin (10 mg/d) and placebo. Main Outcome Measures. —In the first study, kinetic parameters of LDL metabolism; in the second study, response in lipids and lipoproteins to lovastatin therapy. Results. —In the LDL turnover study, mean (±SD) input (production) rates for LDL apolipoprotein B (apo B) were similar for hypercholesterolemic women and control women (12.4 [±3.2] mg/kg per day and 11.1 [±2.2] mg/kg per day, respectively). In contrast, mean (±SD) fractional catabolic rates for LDL apo B in hypercholesterolemic women (0.29 [±0.04] pools per day) were significantly lower than those in normolipidemic women (0.35 [±0.03] pools per day). In the drug trial, lovastatin therapy reduced mean (±SD) total cholesterol and LDL cholesterol from 7.03 (±1.16) mmol/L (272 [±45] mg/dL) and 4.42 (±0.80) mmol/L (171 [±31] mg/dL, respectively, to 5.70 (±1.03) mmol/L (221 [±40] mg/dL) and 3.46 (±0.85) mmol/L (134 [±33] mg/dL). Conclusions. —The turnover data suggest that hypercholesterolemia in postmenopausal women is primarily attributable to a reduced activity of LDL receptors. In accord, the hypercholesterolemia in these women was effectively lowered by low doses of lovastatin. Thus, a low dose of lovastatin appears highly effective for treatment of moderate hypercholesterolemia in most postmenopausal women, presumably because it reverses the reduction in LDL receptor activity associated with menopause. (JAMA. 1994;271:453-459)

Lipoprotein responses to treatment with lovastatin, gemfibrozil, and nicotinic acid in normolipidemic patients with hypoalphalipoproteinemia

Abstract: Background: The lipoprotein responses to conventional lipid-modifying drugs have not been adequately evaluated in normolipidemic patients with hypoalphalipoproteinemia (low levels of high-density lipoproteins). The purpose of this study was to compare responses to lovastatin, gemfibrozil, and nicotinic acid in such patients. Methods: The first phase of the study compared lipoprotein responses to lovastatin and gemfibrozil in 61 middle-aged men with low levels of high-density lipoproteins. In the second phase, 37 patients agreed to take nicotinic acid; 27 patients finished this phase at a dose of 4.5 g/d. Nicotinic acid results were compared with those with lovastatin and gemfibrozil in the same patients. Results: In the first phase, both drugs effectively lowered triglyceride levels. Gemfibrozil therapy increased high-density lipoprotein cholesterol levels by 10% and lovastatin by 6%, but lovastatin was much more effective for reducing low-density lipoprotein levels. Nicotinic acid did not significantly lower low-density lipoprotein levels in the second phase, but it raised high-density lipoprotein levels by 30%. Conclusions: Gemfibrozil therapy produced the least favorable response of the three drugs. Lovastatin markedly lowered low-density lipoprotein levels but only modestly raised levels of high-density lipoprotein, whereas nicotinic acid had the opposite effect. Consequently, the latter two drugs similarly reduced low-density lipoprotein— high-density lipoprotein ratios, although these effects were obtained in different ways. Between these two drugs, lovastatin therapy was more likely to reduce low-density lipoprotein cholesterol levels to below 2.6 mmol/L (100 mg/dL), and in view of recent recommendations, it may be preferable to nicotinic acid for many normolipidemic patients with established coronary heart disease. (Arch Intern Med. 1994;154:73-82)

Concentrations of apolipoprotein A-I-containing particles in patients with hypoalphalipoproteinemia.

Abstract: This study was performed to determine relations among concentrations of high-density lipoprotein (HDL) apolipoprotein (apo) A-I and apoA-II and lipoproteins with apoA-I only (LpA-I) and with both apoA-I and apoA-II (LpA-I:A-II) in patients with low plasma levels of HDL cholesterol. Seventy-seven middle-aged men with low HDL cholesterol levels ( 40 mg/dL). Low-HDL patients were divided into those with normotriglyceridemia (triglycerides or = 250 mg/dL; n = 28). Total apoA-I and apoA-II concentrations and apoA-I levels in LpA-I were significantly lower in the two low-HDL groups compared with control subjects. Although low-HDL patients' apoA-I levels were numerically lower in LpA-I:A-II compared with control subjects' levels, the differences were not statistically significant. Thus, there is a preferential reduction in apoA-I levels of LpA-I compared with LpA-I:A-II in patients with low HDL cholesterol. This preferential reduction in LpA-I levels was observed in both normotriglyceridemic and hypertriglyceridemic patients. However, among low-HDL patients levels of apoA-I in LpA-I did not distinguish between those with and without coronary heart disease.

Hypercholesterolemia in postmenopausal women: Metabolic defects and response to low-dose lovastatin

Abstract: OBJECTIVE To determine the metabolic mechanisms underlying hypercholesterolemia in postmenopausal women and to determine whether a low dose of lovastatin will correct this abnormality. DESIGN In the first part of the study, turnover rates of autologous low-density lipoprotein (LDL) were measured in hypercholesterolemic and control women. In the second part, hypercholesterolemic women participated in a placed-controlled, randomized, double-blind study using lovastatin as the therapeutic agent. SETTING The General Clinical Research Center of the University of Texas Southwestern Medical Center, Dallas, utilizing inpatient and outpatient facilities, and the Veterans Affairs Medical Center, Dallas, Tex. PATIENTS For the LDL turnover study, 26 postmenopausal women with moderate hypercholesterolemia (mean +/- SD LDL cholesterol, 4.78 +/- 0.59 mmol/L [185 +/- 23 mg/dL]) and 13 postmenopausal women with normal levels of plasma lipids and lipoproteins (mean +/- SD LDL cholesterol, 3.31 +/- 0.39 mmol/L [128 +/- 15 mg/dL]) were studied. Sixteen postmenopausal women participated in the drug study. INTERVENTIONS In the drug study, patients received blindly both lovastatin (10 mg/d) and placebo. MAIN OUTCOME MEASURES In the first study, kinetic parameters of LDL metabolism; in the second study, response in lipids and lipoproteins to lovastatin therapy. RESULTS In the LDL turnover study, mean (+/- SD) input (production) rates for LDL apolipoprotein B (apo B) were similar for hypercholesterolemic women and control women (12.4 [+/- 3.2] mg/kg per day and 11.1 [+/- 2.2] mg/kg per day, respectively). In contrast, mean (+/- SD) fractional catabolic rates for LDL apo B in hypercholesterolemic women (0.29 [+/- 0.04] pools per day) were significantly lower than those in normolipidemic women (0.35 [+/- 0.03] pools per day). In the drug trial, lovastatin therapy reduced mean (+/- SD) total cholesterol and LDL cholesterol from 7.03 (+/- 1.16) mmol/L (272 [+/- 45] mg/dL) and 4.42 (+/- 0.80) mmol/L (171 [+/- 31] mg/dL, respectively, to 5.70 (+/- 1.03) mmol/L (221 [+/- 40] mg/dL) and 3.46 (+/- 0.85) mmol/L (134 [+/- 33] mg/dL). CONCLUSIONS The turnover data suggest that hypercholesterolemia in post-menopausal women is primarily attributable to a reduced activity of LDL receptors. In accord, the hypercholesterolemia in these women was effectively lowered by low doses of lovastatin. Thus, a low dose of lovastatin appears highly effective for treatment of moderate hypercholesterolemia in most postmenopausal women, presumably because it reverses the reduction in LDL receptor activity associated with menopause.

Effect of combined supplementation with α-tocopherol, ascorbate and beta carotene on low-density lipoprotein oxidation

Abstract: BackgroundData continue to accumulate supporting a proatherogenic role for oxidized low-density lipoprotein (Ox-LDL). Antioxidant micronutrients such as ascorbate, a-tocopherol, and beta carotene, levels of which can be favorably manipulated by dietary measures without side effects, could be a safe approach in inhibiting LDL oxidation. In fact, in vitro studies have shown that all three antioxidants can inhibit LDL oxidation. The present study was undertaken to ascertain both the safety and antioxidant effect of combined supplementation with a-tocopherol, ascorbate, and beta carotene on LDL oxidation. Methods and ResultsThe effect of combined supplementation with a-tocopherol (800 IU/d) plus ascorbate (1.0 g/d) and beta carotene (30 mg/d) on copper-catalyzed LDL oxidation was tested in a randomized, placebo-controlled study in two groups of 12 male subjects over a 3-month period. Blood samples for the lipoprotein profile, antioxidant levels, and LDL isolation were obtained at baseline and at 3 months. Neither placebo nor combined antioxidant therapy resulted in any side effects or exerted an adverse effect on the plasma lipoprotein profile. Compared with placebo, combined antioxidant therapy resulted in a significant increase in plasma ascorbate and lipid standardized a-tocopherol and beta carotene levels (2.6-, 4.1-, and 16.3-fold, respectively). At baseline, there were no significant differences in the time course curves and kinetics of LDL oxidation as evidenced by the thiobarbituric acid reacting substances (TBARS) assay and the formation of conjugated dienes. However, at 3 months, combined supplementation resulted in a twofold prolongation of the lag phase and a 40% decrease in the oxidation rate. The combined antioxidant group was also compared with a group that received 800 IU of a-tocopherol only. Although the combined antioxidant group had significantly higher ascorbate and beta carotene levels than the group supplemented with a-tocopherol alone, there were no significant differences between the two groups with respect to LDL oxidation kinetics. ConclusionsCombined supplementation with ascorbate, beta carotene, and tr-tocopherol is not superior to high-dose cy-tocopherol alone in inhibiting LDL oxidation. Hence, a-tocopherol therapy should be favored in future coronary prevention trials involving antioxidants.

Lipoprotein Responses to Treatment with Lovastatin, Gemfibrozil and Nicotinic Acid in Normolipidemic Patients with Hypoalphalipoproteinemia

Abstract: Background: The lipoprotein responses to conventional lipid-modifying drugs have not been adequately evaluated in normolipidemic patients with hypoalphalipoproteinemia (low levels of high-density lipoproteins). The purpose of this study was to compare responses to lovastatin, gemfibrozil, and nicotinic acid in such patients. Methods: The first phase of the study compared lipoprotein responses to lovastatin and gemfibrozil in 61 middle-aged men with low levels of high-density lipoproteins. In the second phase, 37 patients agreed to take nicotinic acid; 27 patients finished this phase at a dose of 4.5 g/d. Nicotinic acid results were compared with those with lovastatin and gemfibrozil in the same patients. Results: In the first phase, both drugs effectively lowered triglyceride levels. Gemfibrozil therapy increased high-density lipoprotein cholesterol levels by 10% and lovastatin by 6%, but lovastatin was much more effective for reducing low-density lipoprotein levels. Nicotinic acid did not significantly lower low-density lipoprotein levels in the second phase, but it raised high-density lipoprotein levels by 30%. Conclusions: Gemfibrozil therapy produced the least favorable response of the three drugs. Lovastatin markedly lowered low-density lipoprotein levels but only modestly raised levels of high-density lipoprotein, whereas nicotinic acid had the opposite effect. Consequently, the latter two drugs similarly reduced low-density lipoprotein— high-density lipoprotein ratios, although these effects were obtained in different ways. Between these two drugs, lovastatin therapy was more likely to reduce low-density lipoprotein cholesterol levels to below 2.6 mmol/L (100 mg/dL), and in view of recent recommendations, it may be preferable to nicotinic acid for many normolipidemic patients with established coronary heart disease. (Arch Intern Med. 1994;154:73-82)

Triglyceride levels in sons of patients with coronary artery disease.

Abstract: In this issue, the report by Uiterwaal and colleagues [1] indicates that healthy young sons of fathers with established coronary artery disease have a greater postprandial triglyceride response than do sons of fathers without this disease. This finding appears to be the result of a carefully conducted study, and although the difference in responses between the two groups is not great, it is statistically significant. Two alternative explanations could account for the difference in response in the two types of offspring: The difference could be either acquired or genetic. Both possibilities must be considered. An acquired difference might be one of two kinds. First, sons may have acquired habits from their fathers before their fathers developed coronary artery disease. For example, they might have acquired their fathers' eating and exercise habits or attitudes toward work and stress. Although no definite evidence was obtained about these acquired habits, they could be subtle and difficult to detect without more extensive testing. If present, they could have affected the postprandial triglyceride response. A second possibility is that sons were psychologically affected by their fathers' heart attacks and consequently these sons modified their behavior in an attempt to decrease their own risk. This is a strong possibility. We know that having a myocardial infarction is a strong motivating factor for changes in lifestyle (for example, stopping smoking and changing the diet) in affected patients, and some of this motivation probably rubs off on their offspring. An example of this effect is the lower fat intake in sons of fathers with coronary artery disease when compared with sons in the control group. A low-fat diet could induce an increased postprandial response by slightly increasing fasting triglyceride concentrations. This was not detected in the study by Uiterwaal and colleagues, but larger studies have shown that lower-fat diets increase triglyceride levels. Such an effect, therefore, cannot be excluded. The alternative mechanism contributing to a difference in postprandial triglyceride response is a genetic difference, either monogenic or polygenic. If parents were heterozygous for a monogenic disorder of triglyceride metabolism, only half the sons should have inherited the defect; thus, only half would have shown an excessive response. Of course, the response in affected sons would have been bimodal. This possibility is not mentioned in Uiterwaal and colleagues' study, but it should have been examined. All affected parents certainly were not heterozygous for a monogenic defect in triglyceride metabolism. Thus, if a monogenic defect exists that affects triglyceride metabolism, it must have been much more marked in a few sons to make the average response statistically significant. It should have been relatively easy to identify such sons, but this was not done in Uiterwaal and colleagues' study. The second alternative is that an increased postprandial response is polygenic. For example, fathers with coronary artery disease had higher levels of total cholesterol and low-density lipoprotein (LDL) cholesterol than did control fathers, and, on the average, they had polygenic hypercholesterolemia. It is interesting to note that this polygenic phenotype was diluted out in the sons or had not yet become manifest; sons of fathers with coronary artery disease did not have higher total cholesterol and LDL levels than did control sons. Perhaps it is possible that fathers with coronary artery disease had polygenic postprandial hypertriglyceridemia, and enough abnormal genes, albeit diluted by one half, were transmitted to allow this trait to be observed in their sons. Fathers with coronary artery disease certainly had higher fasting triglyceride levels than did control fathers, and therefore they very possibly could have had polygenic hypertriglyceridemia. Consequently, some of the hypertriglyceridemic genes may have been transmitted to their sons. If so, what are some of these abnormal genes? They could have been a host of different genes affecting triglyceride and lipoprotein metabolism, such as those controlling hepatic lipid regulation; lipoprotein lipase; apolipoproteins B, Es, Cs, and As; and LDL receptors, to mention only a few. Increasing evidence suggests that inheritance of a constellation of genes having particular patterns of genetic variation can lead to mild to moderate dyslipidemia, which in turn predisposes to premature coronary artery disease. Because fathers with coronary artery disease definitely had a polygenic form of dyslipidemia, some of the abnormal genes undoubtedly were transmitted to their sons. Thus, findings in this study are compatible with the concept that genetic factors contribute to the mild to moderate dyslipidemia found in patients with premature coronary artery disease. It must be remembered, however, that a confounding effect of acquired characteristics cannot be excluded, which may have contributed to the postprandial responses noted in Uiterwaal and colleagues' study. Does an increased postprandial response mean that increased levels of triglycerides are a risk factor for coronary artery disease? The evidence relating triglycerides to risk for coronary artery disease is complex, and there is not universal agreement on the meaning of this evidence. In my view, available data indicate that increased levels of triglycerides have an atherogenic effect, but this effect may be mediated through other mechanisms (for example, the presence of very-low-density lipoprotein remnants, small LDL particles, decreased levels of high-density lipoprotein cholesterol, and a thrombogenic tendency) [2]. This study sheds little light on the mechanisms involved. Nonetheless, the results are consistent with the possibility that triglyceride-rich lipoproteins have atherogenic potential. This assumes that the entire effect is not explained by modified behavior in sons after their fathers developed clinical evidence of coronary artery disease.