Preventing heart attack and death in patients with coronary disease.
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Coronary Disease↗
Biomedical subjects
S M Grundy
Publications and source records attributed to S M Grundy.
Efficacy of low-dose cholesterol-lowering drug therapy in men with moderate hypercholesterolemia.
OBJECTIVE: To test the potency of low-dose cholesterol-lowering drug therapy in patients with moderate hypercholesterolemia and to evaluate the effectiveness for cholesterol lowering of a safe regimen to be used in primary prevention of coronary heart disease. DESIGN: The efficacy of three drug regimens (cholestyramine resin, 8 g/d; cholestyramine resin, 8 g/d, plus lovastatin, 5 mg/d; and lovastatin, 20 mg/d) was tested in 26 men aged 31 to 70 years with moderate hypercholesterolemia after a Step-One cholesterol-lowering diet. Each drug period was 3 months in duration, interspersed by a 1-month period of the Step-One diet only. Blood for lipid and lipoprotein measurements was obtained on 5 different days during the last 2 weeks of each drug and diet-only period. RESULTS: Cholestyramine resin therapy at 8 g/d achieved a significant reduction in low-density lipoprotein cholesterol levels from 4.47 mmol/L (173 mg/dL) to 3.90 mmol/L (151 mg/dL) (P < .005). The addition of 5 mg of lovastatin to cholestyramine therapy achieved even lower levels, averaging 3.39 mmol/L (131 mg/dL) (P < .005). Lovastatin therapy at 20 mg/d produced lowering of low-density lipoprotein cholesterol levels similar to that of the low-dose combination. CONCLUSIONS: Low-dose combination drug therapy for the management of hypercholesterolemia appears to be an effective means of lowering cholesterol levels that remain persistently elevated after dietary therapy, at the same time, it should carry a low risk of toxic effects.
Adult↗
Atherogenic dyslipidemia: lipoprotein abnormalities and implications for therapy.
Atherogenic dyslipidemia is a lipoprotein profile combining 4 specific abnormalities: borderline-high total cholesterol levels; high triglyceride concentrations; small, dense, low-density lipoprotein (LDL) particles; and low high-density lipoprotein (HDL) concentrations. It is a predisposing factor to premature coronary artery disease (CAD), although separating and calculating the contribution of each abnormality to the risk of CAD is difficult, especially since the abnormalities often appear in this combination. The ratio of total cholesterol to HDL cholesterol is currently the most powerful single predictor of risk in dyslipidemic patients. Therapy for atherogenic dyslipidemia includes dietary changes aimed at decreasing intake of cholesterol-raising fatty acids and achieving weight reduction; exercise, which confers many of the benefits of weight reduction; and, when those measures fail to correct the lipid and lipoprotein profile, drug therapy. Nicotinic acid reduces triglyceride and cholesterol levels while raising HDL concentrations, but up to half of patients cannot tolerate its adverse effects. Fibric acids effectively lower triglyceride levels and are generally well tolerated but have little beneficial effect on the cholesterol profile. Statins offer marked reductions in total, LDL, and very low-density lipoprotein cholesterol levels and cause modest increases in HDL concentration. Combination therapy can enhance the efficacy of the individual drugs.
Arteriosclerosis↗
AHA consensus panel statement. Preventing heart attack and death in patients with coronary disease. The Secondary Prevention Panel.
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Coronary Disease↗
Metabolism of low density lipoproteins in nephrotic dyslipidemia: comparison of hypercholesterolemia alone and combined hyperlipidemia.
High levels of low-density lipoprotein cholesterol (LDL) (hypercholesterolemia) are commonly present in the nephrotic syndrome. Another pattern of dyslipidemia in nephrotic patients is an elevation of both cholesterol and triglyceride levels (combined hyperlipidemia). It has been postulated that the underlying cause of nephrotic dyslipidemia is an hepatic overproduction of apolipoprotein B (apo B)-containing lipoproteins. To examine this hypothesis, the metabolism of LDL-apo B was compared between nephrotic patients with hypercholesterolemia and with combined hyperlipidemia. Thirteen patients (7 with hypercholesterolemia, and 6 with combined hyperlipidemia) underwent measurements of turnover rates of autologous LDL apo B. The results were compared to normolipidemic controls and to patients with primary combined hyperlipidemia previously studied in our laboratory. Nephrotic patients with hypercholesterolemia generally had: (a) lower fractional catabolic rates of LDL apo B than normolipidemic healthy individuals; (b) LDL particles enriched in cholesterol; but (c) no overproduction of LDL apo B. In contrast, patients with combined hyperlipidemia were found to have: (a) high fractional catabolic rates for LDL apo B compared to normolipidemic controls; (b) cholesterol-poor LDL particles; and (c) markedly elevated production rates for LDL. Also, for the group as a whole, there was a positive correlation between plasma triglyceride levels and fractional catabolic rates. These data indicate that the metabolism of LDL is strikingly different between the two forms of nephrotic dyslipidemia. Although there may be common mechanisms contributing to LDL levels in nephrotic patients, there also appears to be a divergence of mechanisms depending on whether hypertriglyceridemia is associated with hypercholesterolemia.
Adolescent↗
Relation between cholesterol ester transfer protein activities and lipoprotein cholesterol in patients with hypercholesterolemia and combined hyperlipidemia.
Cholesterol ester transfer protein (CETP) promotes the transfer of cholesterol esters among different lipoprotein classes-high-density lipoproteins (HDL), very-low-density lipoproteins, intermediate-density lipoproteins, and low-density lipoproteins (LDL). The current study was carried out to determine whether CETP activities are correlated with lipoprotein cholesterol levels in a large number of patients having elevated LDL cholesterol and normal triglycerides (hypercholesterolemia) and elevated LDL cholesterol and high triglycerides (combined hyperlipidemia). Compared with 50 normolipidemic male patients, 113 hypercholesterolemic patients had a 42% higher mean activity of CETP, and approximately 60% of these patients had CETP activities outside the normal range. A similar elevation of CETP was observed in 47 patients with combined hyperlipidemia. Furthermore, in those with combined hyperlipidemia, CETP activities were highly correlated with LDL cholesterol, non-HDL cholesterol, and non-HDL/HDL ratios. Similar high correlations were obtained by combining normotriglyceridemic patients with and without elevated LDL cholesterol. Since patients with elevated LDL cholesterol had a significantly lower mean level of HDL cholesterol, a high CETP activity also was related to a reduced HDL cholesterol level. Our results are consistent with this concept, although they do not constitute final proof that high CETP activities contribute to elevated cholesterol concentrations and reduced HDL cholesterol levels in patients with hypercholesterolemia and in those with combined hyperlipidemia.
Aged↗
Bimodal distribution of cholesteryl ester transfer protein activities in normotriglyceridemic men with low HDL cholesterol concentrations.
Increased plasma activities of cholesteryl ester transfer protein (CETP) theoretically could lower HDL cholesterol levels due to enhanced transfer of cholesteryl esters from HDL to apo B-containing lipoproteins. To determine whether high CETP activities are associated with isolated hypoalphalipoproteinemia, CETP activities were measured in 109 adult men with HDL cholesterol < 35 mg/dL, plasma triglycerides < 200 mg/dL, and LDL cholesterol < 160 mg/dL; the results were compared with those of 50 normolipidemic (HDL cholesterol > 40 mg/dL) male subjects. CETP activities were assayed in vitro and expressed as the percent of [3H]cholesteryl ester transferred from HDL3 to LDL during a 16-hour incubation. In addition, postheparin plasma activities of lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) were determined in 71 patients with a low HDL cholesterol level. Distributions of CETP activities were unimodal in control subjects (mean +/- SD, 23.1 +/- 5.0%), but they were bimodal in the low-HDL patients. Among the latter, 27 patients had elevated CETP activities (40.8 +/- 4.6%), whereas 82 patients had CETP activities that overlapped the normal range (26.14 +/- 7.6%). Low-HDL patients with normal CETP activities had 20% lower LPL activities (P = .01), 25% higher HTGL activities (P = .03), and 63% lower LPL/HTGL ratios (P < .001) than those of low-HDL patients with increased CETP activity. Furthermore, mean LPL and HTGL activities in the low-HDL patients with elevated CETP activities were in the normal range. Another important distinction between the two subgroups with low HDL was that the subgroup with high CETP activity had only a 30% prevalence of coronary heart disease compared with a 70% prevalence in the subgroup with normal CETP activity (P < .01). These findings suggest that elevated CETP activity may be a significant factor in causing low HDL cholesterol levels in a distinct subgroup of normolipidemic patients with low HDL cholesterol levels.
Adult↗
Relationships of generalized and regional adiposity to insulin sensitivity in men.
The relative impacts of regional and generalized adiposity on insulin sensitivity have not been fully defined. Therefore, we investigated the relationship of insulin sensitivity (measured using hyperinsulinemic, euglycemic clamp technique with [3-3H]glucose turnover) to total body adiposity (determined by hydrodensitometry) and regional adiposity. The latter was assessed by determining subcutaneous abdominal, intraperitoneal, and retroperitoneal fat masses (using magnetic resonance imaging) and the sum of truncal and peripheral skinfold thicknesses. 39 healthy middle-aged men with a wide range of adiposity were studied. Overall, the intraperitoneal and retroperitoneal fat constituted only 11 and 7% of the total body fat. Glucose disposal rate (Rd) and residual hepatic glucose output (rHGO) values during the 40 mU/m2.min insulin infusion correlated significantly with total body fat (r = -0.61 and 0.50, respectively), subcutaneous abdominal fat (r = -0.62 and 0.50, respectively), sum of truncal skinfold thickness (r = -0.72 and 0.57, respectively), and intraperitoneal fat (r = -0.51 and 0.44, respectively) but not to retroperitoneal fat. After adjusting for total body fat, the Rd and rHGO values showed the highest correlation with the sum of truncal skinfold thickness (partial r = -0.40 and 0.33, respectively). We conclude that subcutaneous truncal fat plays a major role in obesity-related insulin resistance in men, whereas intraperitoneal fat and retroperitoneal fat have a lesser role.
Adipose Tissue↗
Immunotoxicity of polyunsaturated fatty acids in serum-free medium.
To test the effect of purified polyunsaturated fatty acids on immune cells in vitro, human peripheral blood mononuclear cells and murine spleen cells were incubated in Opti-MEM medium without serum or even albumin and with 2-mercapto-ethanol, insulin, transferrin and selenium as supplements. The human cells were stimulated with phytohemagglutinin and the murine cells were stimulated with Concanavalin A or lipopolysaccharide. Both human and murine cells were stimulated with recombinant human interleukin-2 to generate lymphokine activated killer cells. Linoleic and linolenic acids inhibited all of the immune responses tested, whereas docosahexaenoic and eicosapentaenoic acids did not. Similar effects were observed with cultured B16 F10 murine melanoma cells. Mixtures of linoleic and docosahexaenoic or eicosapentaenoic acids also inhibited the mitogenic response to phytohemagglutinin. Inhibition of lipid mediator production by indomethacin, quercetin, rutin, or nordihydroguariaretic acid, and addition of vitamins C and E with anti-oxidant activity failed to reverse the effects of linoleic acid. Thus, linoleic and linolenic acids appear to directly inhibit immune and tumor cells, at least under these conditions.
Animals↗
Rationale for cholesterol-lowering strategies.
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Cholesterol↗
Lipoprotein-cholesterol responses in healthy infants fed defined diets from ages 1 to 12 months: comparison of diets predominant in oleic acid versus linoleic acid, with parallel observations in infants fed a human milk-based diet.
A prospective study in healthy infants predefining both diet fatty acid and cholesterol, from birth to age 1 year, compared response of cholesterol fractions in three groups: random assignment to 1) monounsaturated-(Hi-Mono) (n = 20), or 2) polyunsaturated-(Hi-Poly) (n = 22) fatty acid-enriched diets, or 3) non-randomized selection to breast feeding (Human Milk) (n = 25). In each group, designated weaning foods and supplements maintained fatty acid and cholesterol intake similar to that of each group's defined formulas, with long-term compliance confirmed by plasma phospholipid fatty acid concentrations. By 12 months, total cholesterol was significantly lower in the Hi-Poly group compared to either of the other groups (P < 0.05). Low density lipoprotein (LDL)- and high density lipoprotein (HDL)-cholesterol concentrations were significantly lower by 12 months in the Hi-Poly group, compared to the Hi-Mono groups. However, at the earlier 4-month interval, total cholesterol and LDL-cholesterol in both Hi-Mono and Hi-Poly groups were not different from each other, although each was significantly lower than the parallel Human Milk-group (P < 0.05). The Hi-Mono group increased gradually in total and LDL-cholesterol such that, after 12 months' feedings, all lipid fractions of this Hi-Mono group were no different from those of the Human Milk group. In independent group comparisons, there were no significant differences in HDL-cholesterol concentrations after 4 and 9 months on these diets. Independent of diet, HDL-cholesterol showed a falling trend as an overall time-effect across all groups (P < 0.001). These data suggest that prolonged feeding of a diet enriched in polyunsaturated acids in early infancy has a significant cholesterol-lowering effect compared to monounsaturates. These differences in total, LDL-, and HDL-cholesterol plasma concentrations between polyunsaturates and monounsaturates were not significantly evident until feedings had continued for a year.
Cholesterol, HDL↗
Role of low-density lipoproteins in atherogenesis and development of coronary heart disease.
There is a strong association between increased blood concentrations of low-density lipoprotein (LDL) and severity of coronary atherosclerosis. Multiple mechanisms affect hypercholesterolemia, e.g., diet, aging, hormones, and genetics. LDL receptors apparently are also important--through down-regulation, defects in structure, or decreased numbers--as are changes in LDL binding characteristics caused by alterations in apolipoprotein B content or structure. Current concepts of LDL metabolism are extensively reviewed, including the role of modified or oxidized LDL in atherogenesis.
Arteriosclerosis↗
Triglyceride levels in sons of patients with coronary artery disease.
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Coronary Disease↗
Cholestyramine therapy for dyslipidemia in non-insulin-dependent diabetes mellitus. A short-term, double-blind, crossover trial.
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-blind, crossover study of cholestyramine (8 g twice daily) compared with placebo for a period of 6 weeks each. SETTING: Metabolic Unit and the Lipid and Diabetes Clinics at the Department of Veterans Affairs Medical Center, Dallas, Texas. PATIENTS: 21 patients with NIDDM that was well controlled using either glyburide or insulin therapy and with low-density lipoprotein (LDL) cholesterol levels more than 3.36 mmol/L (130 mg/dL) and fasting plasma triglyceride levels less than 3.4 mmol/L (300 mg/dL). MEASUREMENTS: During the last week of each period, for 5 consecutive days fasting plasma lipids and lipoproteins were measured, and plasma glucose levels were determined at 3, 7, and 11 a.m. and at 4 and 8 p.m. Daily urinary glucose excretion was measured for 3 days and glycosylated hemoglobin concentrations were determined on days 28 and 38 of the study periods. RESULTS: In this short-term study, when compared with placebo, cholestyramine reduced total cholesterol by 18% (95% CI, 14% to 22%) and LDL cholesterol by 28% (CI, 21% to 35%). Although cholestyramine therapy increased plasma triglyceride levels by 13.5% (CI, 1% to 26%), very-low density lipoprotein cholesterol and high-density lipoprotein cholesterol levels remained unchanged. Cholestyramine therapy improved glycemic control; mean plasma glucose values were lower by 13% (CI, 5% to 21%), a median reduction in urinary glucose excretion of 0.22 g/d was observed (P < 0.001), and a tendency to lower glycosylated hemoglobin concentration was noted. The doses of glyburide and insulin did not change during the study, and body weight remained stable. Constipation was the main side effect, and two patients dropped out of the study because of cholestyramine intolerance. CONCLUSIONS: In carefully selected male patients with NIDDM and high LDL cholesterol and normal triglyceride levels, cholestyramine therapy effectively reduces LDL levels and also may improve glycemic control. The long-term efficacy of cholestyramine therapy in patients with NIDDM needs further evaluation.
Adult↗
Effects of varying carbohydrate content of diet in patients with non-insulin-dependent diabetes mellitus.
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 < .0001) and 23% (P = .0001), respectively, and increased daylong plasma triglyceride, glucose, and insulin values by 10% (P = .03), 12% (P < .0001), and 9% (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.
Adult↗
Excess body weight. An under-recognized contributor to dyslipidemia in white American women.
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 cross-sectional data from the Second National Health and Nutrition Examination Survey. Mean lipid levels were determined for six different categories of BMI: (1) 21.0 or less; (2) 21.1 to 23.0; (3) 23.1 to 25.0; (4) 25.1 to 27.0; (5) 27.1 to 30.0; and (6) more than 30.0, 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 0.46 mmol/L (18 mg/dL) higher total cholesterol levels, 0.68 mmol/L (26 mg/dL) higher non-high-density lipoprotein (HDL) cholesterol levels, and 0.44 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 0.16 and 0.16 mmol/L (6 and 5 mg/dL), non-HDL of 0.24 and 0.20 mmol/L (9 and 8 mg/dL), and LDL levels of 0.13 and 0.03 mmol/L (5 and 1 mg/dL). More impressively, rising BMI was associated with consistently higher triglyceride levels of 0.54 to 0.40 mmol/L (48 to 35 mg/dL) and consistently lower HDL levels of 0.23 to 0.13 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 weight-associated 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.
Adult↗
Influence of stearic acid on cholesterol metabolism relative to other long-chain fatty acids.
Stearic acid is a long-chain saturated fatty acid. However, in contrast with other saturated fatty acids, stearic acid apparently does not raise serum cholesterol concentrations. Studies carried out three decades ago provided strong suggestive evidence that this was the case. More recent investigations that specifically compared stearic acid with other fatty acids in human studies have confirmed that stearic acid is not hypercholesterolemic. Stearic acid was shown not to raise low-density-lipoprotein cholesterol relative to oleic acid, which is known to be neutral in its effects on cholesterol concentrations. In contrast, palmitic acid, another long-chain saturated fatty acid, definitely raises cholesterol concentrations. For this reason, fats rich in stearic acid might be used in place of those high in palmitic acid in cholesterol-lowering diets.
Animals↗
Variation at the hepatic lipase and apolipoprotein AI/CIII/AIV loci is a major cause of genetically determined variation in plasma HDL cholesterol levels.
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.
Apolipoprotein A-I↗