Showing papers by "Scott M. Grundy published in 1986"
TL;DR: A diet rich in monounsaturated fatty acids appears to be at least as effective in lowering plasma cholesterol as a diet low in fat and high in carbohydrate in short-term studies in which liquid diets are used and body weight is kept constant.
Abstract: To examine the effects of dietary fatty acids and carbohydrate on plasma lipids and lipoproteins, 11 patients with a mean plasma total cholesterol level of 251 +/- 10 mg per deciliter were studied on a metabolic ward during three dietary periods, each lasting four weeks. A liquid diet rich in monounsaturated fatty acids ("High-Mono") and a diet low in fat ("Low-Fat") were compared with a diet high in saturated fatty acids ("High-Sat"). The High-Sat and High-Mono diets contained 40 percent of their total calories as fat and 43 percent as carbohydrate; the Low-Fat diet had 20 percent fat and 63 percent carbohydrate. Body weight was kept constant by adjusting total caloric intake. As compared with the High-Sat diet, both the High-Mono and Low-Fat diets lowered plasma total cholesterol (by 13 percent and 8 percent, respectively) and low-density lipoprotein cholesterol (by 21 percent and 15 percent, respectively). As compared with the High-Sat diet, the Low-Fat diet raised triglyceride levels and significantly reduced plasma high-density lipoprotein cholesterol. In contrast, the High-Mono diet had no effect on levels of triglycerides or high-density lipoprotein cholesterol. The ratio of low-density to high-density lipoprotein cholesterol was also significantly lower when the High-Mono diet rather than the Low-Fat diet was followed. Therefore, in short-term studies in which liquid diets are used and body weight is kept constant, a diet rich in monounsaturated fatty acids appears to be at least as effective in lowering plasma cholesterol as a diet low in fat and high in carbohydrate.
753 citations
TL;DR: A new class of cholesterollowering drugs, namely, competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis, has been shown to markedly lower cholesterol levels.
Abstract: SEVERAL important developments have recently given new impetus to prevention of coronary heart disease (CHD) through control of the plasma cholesterol level. Three advances have been particularly dramatic. First, the Nobel prize in medicine was awarded in 1985 to Drs Joseph Goldstein and Michael Brown for their discovery of cell-surface receptors for low-density lipoproteins (LDLs); their finding was fundamental to our understanding of how plasma cholesterol levels are controlled. Second, the Lipid Research Clinics (LRC) Coronary Primary Prevention Trial (CPPT)1reported that lowering of the plasma cholesterol level by bile acid sequestrants reduces the frequency of several manifestations of CHD, including myocardial infarction. And third, a new class of cholesterollowering drugs, namely, competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis, has been shown to markedly lower cholesterol levels.2-4Although these inhibitors are not yet approved for clinical use, they reveal the potential for
434 citations
TL;DR: In this paper, simultaneous turnover rates of autologous and normal homologous LDL were determined in 15 patients with primary moderate hypercholesterolemia, and the turnover rates for both types of LDL were indistinguishable.
Abstract: The causes of primary moderate hypercholesterolemia are not understood, but some patients have reduced fractional clearance rates (FCRs) for low density lipoproteins (LDL). This could be due to either decreased activity of LDL receptors or to a defect in structure (or composition) of LDL that reduces its affinity for receptors. To distinguish between these causes, simultaneous turnover rates of autologous and normal homologous LDL were determined in 15 patients with primary moderate hypercholesterolemia. In 10, turnover rates of both types of LDL were indistinguishable, which indicated that autologous LDL was cleared as efficiently as normal homologous LDL. In five others, FCRs for autologous LDL were significantly lower than for homologous LDL. Two of the latter five were treated with mevinolin, and although FCRs for both types of LDL rose during treatment, differences in FCRs between the two types of LDL persisted. In these five patients, autologous LDL appeared to be a poor ligand for LDL receptors.
198 citations
TL;DR: The data indicate there are multiple abnormalities in structure and metabolism of VLDL in non-insulin-dependent diabetics and control of hyperglycemia with sulfonylureas has the capability of reversing some of these abnormalities.
Abstract: To evaluate mechanisms of diabetes-induced changes in very-low-density lipoprotein (VLDL), VLDL triglyceride (TG) and VLDL apolipoprotein B (apoB) metabolism were studied in 12 obese Pima Indian control subjects and in 15 Pima Indian obese non-insulin-dependent diabetics. Eleven of the diabetics were restudied after reduction of hyperglycemia with oral sulfonylurea therapy. In addition, adipose, muscle, and postheparin lipoprotein lipase and postheparin hepatic lipase activities were measured in all subjects. Obese diabetics as compared with obese controls showed a trend toward increased production of VLDL TG (46 ± 4 vs. 35 ± 6 g/day, P = .10) but not of VLDL apoB (1595 ± 106 vs. 1597 ± 164 mg/day, NS); production of VLDL TG declined to control levels (33 ± 4 g/day, P P P P P −1 · h −1 P P P P P
173 citations
TL;DR: For the limited number of patients in this study, the diet recommended for the general public appeared as effective for lowering of cholesterol levels as diets containing more polyunsaturates or more carbohydrates.
Abstract: Saturated fatty acids and cholesterol in the diet raise the plasma cholesterol concentration, and a reduction in these constituents is recommended widely. However, there is not general agreement as to which nutrients should replace saturated fatty acids. Several different substitute nutrients are possible. In this study, three cholesterol-lowering diets were compared in nine men living in a domiciliary. On a typical American diet at baseline, cholesterol levels were in the normal range. One replacement diet was high in polyunsaturated fatty acids (High Poly); another had 30% fat and corresponded to the American Heart Association's (AHA) recommended diet for the general public (AHA phase I); the third diet had 20% fat, equivalent to the AHA phase III diet for treatment of hypercholesterolemia. Compared with baseline levels, all diets caused similar reductions in total cholesterol and low-density lipoprotein cholesterol levels, but the High Poly and AHA phase III diets lowered the high-density lipoprotein cholesterol level more than the AHA phase I diet. Thus, for the limited number of patients in this study, the diet recommended for the general public appeared as effective for lowering of cholesterol levels as diets containing more polyunsaturates or more carbohydrates. ( JAMA 1986;256:2351-2355)
106 citations
TL;DR: The present results add strong evidence to the concept that the primary metabolic defect in CTX is a deficiency of C27-steroid 26-hydroxylase, as demonstrated in cultured skin fibroblasts from healthy individuals.
Abstract: 26-Hydroxylation of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol and other C27-steroids was demonstrated in cultured skin fibroblasts from healthy individuals. Activities in skin fibroblasts were approximately 5-10% of those previously found in human liver homogenates, and were inhibited by CO. The apparent Km was lowest for 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol (1.3 mumol/liter) and highest for 5-cholestene-3 beta, 7 alpha-diol (12 mumol/liter). The rate of 26-hydroxylation was highest with 7 alpha-hydroxy-4-cholesten-3-one. These characteristics are similar to those of hepatic mitochondrial C27-steroid 26-hydroxylase. In skin fibroblasts from three patients with cerebrotendinous xanthomatosis (CTX), 26-hydroxylation of C27-steroids proceeded at a rate of only 0.2-2.5% of healthy controls. No accumulation of endogenous 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol could be demonstrated in these cells, and the lowered formation of radioactive, 26-hydroxylated products could not be explained by dilution of the labeled exogenous substrate. The present results add strong evidence to the concept that the primary metabolic defect in CTX is a deficiency of C27-steroid 26-hydroxylase.
101 citations
TL;DR: The results were similar to those obtained in European open trials of fenofibrate and were better than the lipid changes seen at comparable times in the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) cholestyramine study.
Abstract: Of 240 patients with Type IIa and IIb hypercholesterolemia recruited in 11 centers, 227 were randomized to double-blind treatment with either fenofibrate (100 mg three times daily) or matching placebo for 24 weeks. A group of 192 of these patients were studied for a further 24 weeks during which all received fenofibrate in open label fashion. For the 92 Type IIa patients receiving fenofibrate in the double-blind phase, there were significant reductions (p less than 0.01 compared to baseline) in total plasma cholesterol (-18%), LDL-cholesterol (-20%), VLDL-cholesterol (-38%) and total triglycerides (-38%). Mean plasma HDL-cholesterol in these patients increased by 11% (p less than 0.01). With the exception of LDL, which was not high before treatment, similar changes were seen in the 24 fenofibrate-treated Type IIb subjects. Lipid parameters of placebo-treated patients did not change significantly. This pattern of change was repeated in the open period for the 94 patients previously on placebo, while the 98 who had been on fenofibrate remained stable with small further reductions in total and LDL cholesterol (-38% and -5.5% respectively). Adverse effects were some allergic-type skin reactions early in treatment and an occasional increase in transaminases, BUN, or creatinine. The results were similar to those obtained in European open trials of fenofibrate and were better than the lipid changes seen at comparable times in the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) cholestyramine study.
80 citations
TL;DR: Patients with primary moderate hypertriglyceridemia often have distinct subfraction that have different turnover rates, and for patients with mild hypertrlglyceridemia, the LDL is more homogenous, and Its subfractions are kinetically similar.
Abstract: The kinetics of two subfractions of low density lipoproteins (LDL) were examined in nine patients with primary hypertriglyceridemia. LDL was subjected to equilibrium ultracentrifugation, and three patterns of LDL subfractions were noted. The LDL of five patients with moderate hypertriglyceridemia (plasma triglycerides (TG) ranging from 333 to 580 mg/dl) appeared to contain two distinct subfractions. One was less dense and had a high TG content; the other was more dense and had a reduced content of all lipids, particularly cholesterol. Each subfraction was labeled separately and was reinjected into the patient. Of the two subfractions, the more dense LDL usually had a higher fractional catabolic rate (FCR), although the turnover rates of both subfractions for these hypertriglyceridemic patients were higher than normal. Two other patients with mild hypertriglyceridemia had only a single LDL after gradient equilibrium ultracentrifugation. This fraction was divided into less dense and more dense subfractions, and their FCR was determined. In both patients, turnover rates of the two subfractions were similar and both were in the normal range. Finally, two more patients with mildly elevated TG had a very dense LDL, besides having a single, less dense band. For both patients, the FCR for the less dense and very dense subfractions were similar, although the denser LDL had a greater fraction in the extravascular compartment. Thus, patients with primary moderate hypertriglyceridemia often have distinct subfractions that have different turnover rates. For patients with mild hypertriglyceridemia, the LDL is more homogeneous, and its subfractions are kinetically similar.
69 citations
59 citations
TL;DR: In this study, mevinolin markedly lowered both VLDL remnants and LDL in a patient with type 3 HLP, presumably by increasing the activity of LDL receptors.
Abstract: Type 3 hyperlipoproteinemia (HLP) results from the accumulation in plasma of remnants of very low density lipoproteins (VLDL) due to a defect in apolipoprotein E. Current data suggest that VLDL remnants can be removed by the same receptors that remove low density lipoproteins (LDL). Mevinolin has been shown to enhance clearance of LDL by LDL receptors. In this study, mevinolin markedly lowered both VLDL remnants and LDL in a patient with type 3 HLP, presumably by increasing the activity of LDL receptors.
51 citations
TL;DR: The combination of liver transplantation and lovastatin restored total and LDL cholesterol levels to normal in this patient with homozygous familial hypercholesterolemia.
Abstract: Patients with homozygous familial hypercholesterolemia produce no normal low-density lipoprotein (LDL) receptors, and as a result, LDL accumulates in plasma, causing severe premature atherosclerosis. Two years ago, liver transplantation was performed in a child with homozygous familial hypercholesterolemia, restoring LDL receptor activity to about 60% of normal and reducing the LDL cholesterol level by 81%. However, the patient's lipoprotein levels remained significantly elevated for her age and sex. Treatment with lovastatin (mevinolin) one year after transplantation produced a marked improvement in the patient's lipoprotein profile. The total and LDL cholesterol levels fell 40% and 49%, respectively, to values within the normal range. The level of very low-density lipoprotein cholesterol fell 41 %, and the level of total triglycerides declined 28%. While lovastatin therapy decreased the production rate of LDL by 35%, it did not affect the LDL fractional clearance rate. Thus, the combination of liver transplantation and lovastatin restored total and LDL cholesterol levels to normal in this patient with homozygous familial hypercholesterolemia. ( JAMA 1986;256:2843-2848)
TL;DR: It is indicated that body position at time of blood withdrawal significantly influences lipid and lipop protein levels, and, depending on the absolute concentration values of total or high-density lipoprotein cholesterol, can alter the predictive risk for coronary heart disease.
TL;DR: Lecithin feeding had no influence on levels of plasma cholesterol and triglycerides, or lipoprotein-cholesterol, transport of VLDL-triglyceride, or total steroid balance, but did significantly increase the molar percent of bile acids and decrease themolar percent lecithin in gallbladder bile suggesting that it has a systemic effect.
TL;DR: Nondiabetics generally tolerated SPE better than diabetics, and in nondiabetic patients caloric restriction + SPE produced a decrease in total cholesterol and in LDL-cholesterol of 20% and 26%, respectively.
TL;DR: In this paper, factors regulating the concentrations of plasma low density lipoproteins (LDL), apolipoprotein B metabolism was studied in nine Pima Indians (25 +/- 2 yr, 191 +/- 20% ideal wt) with low LDL cholesterol and apoB (60 +/- 4 mg/dl) and in eight age-and weight-matched Caucasians with similar very lowdensity lipoprotein (VLDL) concentrations, but higher LDL (cholesterol = 104 +/- 18; apoprotein B = 82 +/- 10; P less than 0.05).
TL;DR: Chronic plasmapheresis therapy every two weeks for 3.4 years reduced plasma low-density lipoprotein cholesterol 54% but had little effect on the rate of cholesterol biosynthesis, and over the decade of study, neutral steroid excretion/kg declined 61% whereas bile acid excretion /kg was unchanged.
Abstract: Synthesis of cholesterol was measured in a familial hypercholesterolemia homozygote on four occasions from age 1.1 to 9.9 years by the sterol balance technique. Both the fecal neutral steroid and fecal bile acid components of sterol balance were elevated initially. Over the decade of study, neutral steroid excretion/kg declined 61% whereas bile acid excretion/kg was unchanged. Chronic plasmapheresis therapy every two weeks for 3.4 years reduced plasma low-density lipoprotein cholesterol 54% but had little effect on the rate of cholesterol biosynthesis.