John J. Albers

Regression of Coronary Artery Disease as a Result of Intensive Lipid-Lowering Therapy in Men with High Levels of Apolipoprotein B

BACKGROUND AND METHODS The effect of intensive lipid-lowering therapy on coronary atherosclerosis among men at high risk for cardiovascular events was assessed by quantitative arteriography. Of 146 men no more than 62 years of age who had apolipoprotein B levels greater than or equal to 125 mg per deciliter, documented coronary artery disease, and a family history of vascular disease, 120 completed the 2 1/2-year double-blind study, which included arteriography at base line and after treatment. Patients were given dietary counseling and were randomly assigned to one of three treatments: lovastatin (20 mg twice a day) and colestipol (10 g three times a day); niacin (1 g four times a day) and colestipol (10 g three times a day); or conventional therapy with placebo (or colestipol if the low-density lipoprotein [LDL] cholesterol level was elevated). RESULTS The levels of LDL and high-density lipoprotein (HDL) cholesterol changed only slightly in the conventional-therapy group (mean changes, -7 and +5 percent, respectively), but more substantially among patients treated with lovastatin and colestipol (-46 and +15 percent) or niacin and colestipol (-32 and +43 percent). In the conventional-therapy group, 46 percent of the patients had definite lesion progression (and no regression) in at least one of nine proximal coronary segments; regression was the only change in 11 percent. By comparison, progression (as the only change) was less frequent among patients who received lovastatin and colestipol (21 percent) and those who received niacin and colestipol (25 percent), and regression was more frequent (lovastatin and colestipol, 32 percent; niacin and colestipol, 39 percent; P less than 0.005). Multivariate analysis indicated that a reduction in the level of apolipoprotein B (or LDL cholesterol) and in systolic blood pressure, and an increase in HDL cholesterol correlated independently with regression of coronary lesions. Clinical events (death, myocardial infarction, or revascularization for worsening symptoms) occurred in 10 of 52 patients assigned to conventional therapy, as compared with 3 of 46 assigned to receive lovastatin and colestipol and 2 of 48 assigned to receive niacin and colestipol (relative risk of an event during intensive treatment, 0.27; 95 percent confidence interval, 0.10 to 0.77). CONCLUSIONS In men with coronary artery disease who were at high risk for cardiovascular events, intensive lipid-lowering therapy reduced the frequency of progression of coronary lesions, increased the frequency of regression, and reduced the incidence of cardiovascular events.

Changes in plasma lipids and lipoproteins in overweight men during weight loss through dieting as compared with exercise.

We studied separately the influence of two methods for losing fat weight on the levels of plasma lipids and lipoproteins in overweight sedentary men--decreasing energy intake without increasing exercise (diet), and increasing energy expenditure without altering energy intake (exercise, primarily running)--in a one-year randomized controlled trial. As compared with controls (n = 42), dieters (n = 42) had significant loss of total body weight (-7.8 +/- 0.9 kg [mean +/- SE]), fat weight (-5.6 +/- 0.8 kg), and lean (non-fat) weight (-2.1 +/- 0.5 kg) (P less than 0.001 for each variable), and exercisers (n = 47) had significant loss of total body weight (-4.6 +/- 0.8 kg) and fat weight (-3.8 +/- 0.7 kg) (P less than 0.001 for both variables) but not lean weight (-0.7 +/- 0.4 kg). Fat-weight loss did not differ significantly between dieters and exercisers. All subjects were discouraged from altering their diet composition; however, dieters and exercisers had slight reductions in the percentage of kilojoules derived from fat. As compared with the control group, both weight-loss groups had significant increases (P less than 0.01) in plasma concentrations of high-density lipoprotein (HDL) cholesterol (diet vs. exercise, 0.13 +/- 0.03 vs. 0.12 +/- 0.03 mmol per liter), HDL2 cholesterol (0.07 +/- 0.02 vs. 0.07 +/- 0.02 mmol per liter), and HDL3 cholesterol (0.07 +/- 0.02 vs. 0.06 +/- 0.02 mmol per liter) and significant decreases (P less than 0.05) in triglyceride levels (diet vs. exercise, -0.35 +/- 0.14 vs. -0.24 +/- 0.12 mmol per liter). Levels of total and low-density lipoprotein cholesterol were not significantly changed, relative to values in controls. None of these changes were significantly different between dieters and exercisers. Thus, we conclude that fat loss through dieting or exercising produces comparable and favorable changes in plasma lipoprotein concentrations.

Increased exercise level and plasma lipoprotein concentrations: A one-year, randomized, controlled study in sedentary, middle-aged men☆

Eighty-one sedentary but healthy men aged 30-55 participated in a 1 yr randomized study of the effects of exercise on plasma lipoprotein concentrations. Forty-eight were assigned to a running program, while 33 remained as sedentary controls (an approximately 3:2 ratio). After 1 yr the running group had become significantly fitter and leaner than the control group. Lipoprotein concentration changes in the runners (vs. controls) uniformly favored reduced risk of coronary heart disease, but were not significant when all 46 participants with complete data were included. However, the 25 men who averaged at least eight miles (12.9 kilometers) per wk of running increased their plasma high-density-lipoprotein (HDL) cholesterol level by 4.4 mg/dl (p = 0.045) and their HDL2 mass level by 33 mg/dl (p = 0.059), vs. controls. Significant correlations were found for distance run per wk vs. change in plasma HDL-cholesterol (r = 0.48), HDL2 (r = 0.41), and low-density-lipoprotein cholesterol (r = -0.31). Changes in percent body fat and in HDL-cholesterol were correlated (r = -0.47) in runners. There appears to be a threshold at about 8 miles per wk above which a 1-yr running program leads to beneficial lipoprotein changes.

The Measurement of Apolipoprotein A-I and A-II Levels in Men and Women by Immunoassay

To study apolipoprotein A-II, a simple, precise, and accurate immunodiffusion assay was developed and applied in a population sample of industrial employees. Apolipoprotein A-II (A-II) did not increase with age in men (r = -0.20, n = 172), but showed a slight increase with age in women (0.1 mg/dl per yr, r = 0.20, n = 188). A-II correlated significantly with apolipoprotein A-I (A-I) (r = 0.71) and high density lipoprotein (HDL) cholesterol (men, r = 0.64; women, r = 0.49). The A-I/A-II ratio was significantly related to HDL cholesterol (men, r = 0.29; women, r = 0.44). Women on no medication (n = 92) had A-II levels similar to men (34+/-5 and 33+/-5 mg/dl, mean+/-SD, respectively), whereas women on oral contraceptives or estrogens had significantly higher levels (39+/-6 mg/dl, n = 75, P < 0.01). The plasma A-I/A-II weight ratio was 3.6+/-0.4 for men and 3.8+/-0.5 for women. In the d = 1.10-1.21 subfraction, both males and females had similar A-I, A-II, and HDL cholesterol levels (men: mean, 97, 27, and 32 mg/dl, respectively; women: mean, 104, 28, and 36 mg/dl, respectively). Women had approximately twice the amount of A-I, A-II, and HDL cholesterol than men in the d = 1.063-1.10 fraction (men: mean, 10, 2, and 10 mg/dl, respectively; women: mean, 24, 4, and 19 mg/dl, respectively). The A-I/A-II weight ratio in the d = 1.063-1.10 fraction (men, 5.1+/-0.7; women, 6.1+/-1.3) was significantly greater (P < 0.01) than that in the d = 1.10-1.21 fraction (men, 3.7+/-0.2; women, 3.8+/-0.2). Furthermore, the weight ratio of cholesterol to total apoprotein A in the d = 1.063-1.10 fraction (men, 0.75+/-0.09; women, 0.67+/-0.05) was significantly higher (P < 0.01) than that found in the d = 1.10-1.21 fraction (men, 0.26+/-0.04, women, 0.28+/-0.05). Thus, the compositions of HDL hydrated density subclasses are significantly different from each other. These results suggest that the differences in HDL between men and women are due primarily to differences in the relative proportions of HDL subclasses rather than to the intrinsic differences in HDL structure.

Quantitation of apolipoprotein A-I of human plasma high density lipoprotein.

High density lipoproteins (HDL) may be controlled via their major apolipoprotein, A-I. To study this apolipoprotein, a simple, precise, and accurate immunodiffusion assay for A-I was developed and applied in a sample of Bell Telephone Company employees. A-I showed a slight increase with age in men (r=0.11, n=263) and women (r=0.15, n=257). A-I correlated closely with HDL cholesterol (r=0.72). It was weakly related to total triglyceride in women (r=0.24) but was inversely related in men (r=-0.17). Women on estrogen had the highest A-I levels (149 mg/dl +/- 26, x +/- S.D., n=29, p is less than 0.05), followed by women on combination oral contraceptives (141 +/- 26, n=80) whereas women on no medication had lower levels (129 +/- 25, n=99, p is less than 0.01) but men had the lowest levels (120 +/- 20, p is less than 0.01) In a separate group of 14 women given estrogen for 2 wks (1 mug/kg/day), A-I increased by 24%. Thus A-I is increased by exogenous and, most likely, endogenous estrogen, Among hyperlipidemic referral subjects, those with hypercholesterolemia (n=43) and hypertriglyceridemic women (n=33) had normal A-I levels. Among hypertriglyceridemic men both A-I and HDL cholesterol values were decreased (115 +/- 20, p is less than 0.01 and 37 +/- 3, p is less than 0.01, respectively, n=68) but were significantly lower among a group of myocardial infarction survivors (107 +/- 16, p is less than 0.01, and 27 +/- 6, p is less than 0.01, respectively, n=24). High density lipoprotein levels and the content of cholesterol in HDL associated with A-I appear to be decreased in coronary heart disease.

Isolation and characterization of human plasma lipid transfer proteins.

A highly purified protein that facilitates the exchange and net mass transfer of cholesteryl ester (CE), and trlacylglycerol (TG), and the transfer of phosphatldylchollne (PC), between plasma llpoprotelns was isolated from the d-1.21-1.25 g/ml plasma fraction. Transfer activities showed similar distributions through ultracentrlfugatlon, phenyl-Sepharose, DEAE-Sepharose, CM-cellulose, and hydroxyapatlte chromatography. The lipid transfer protein appears to be an acidic protein with an apparent molecular weight of 64,000 ± 1600 (n = 4) on sodium dodecyl sulfate polyacrylamlde gel electrophoresls and an apparent molecular weight of 65,000 by gel filtration chrcmatography, and has a pi of 5.0 ± 0.2 (n = 5) by both analytical Isoelectrlcfocusing and chromatofocusing. The purified transfer protein facilitated the net mass transfer of CE from high density lipoproteln (HDL) or low density llpoproteln (LDL) to very low density lipoprotein (VLDL) and the net mass transfer of TG from VLDL to LDL or HDL. Chromatography of lipid transfer protein fractions on a heparln-Sepharose column yielded two separate fractions with PC transfer activity. The first fraction did not bind to heparin column, was relatively resistant to elevated temperature (at 58°C, only 5% activity was lost in 1 hour) and eluted with the CE and TG transfer activities which were also temperature-resistant. The second PC transfer activity bound to the heparin column and was temperature-sensitive (at 58°C, 90% activity was lost In 1 hour). Addition of the temperature-resistant lipid transfer fraction (LTP-1) and purified lecithin cholesterol acyltransferase (LCAT) to whole plasma stimulated the endogenous plasma cholesterol esterlfication rate by approximately 50%, whereas addition of either LTP-1 or LCAT only slightly enhanced the esterification rate. The transfer of CE, TG, and PC was mediated by a temperature-resistant plasma protein or proteins with very similar properties. Plasma also contained a distinct lipid transfer protein which was temperature-sensitive and facilitated the transfer of PC, but not CE or TG.

Very low density lipoprotein overproduction in genetic forms of hypertriglyceridaemia

Abstract. Very low density lipoprotein kinetic parameters were compared in familial hypertriglyceridaemia and familial combined hyperlipidaemia, two distinct genetic forms of hypertriglyceridaemia. Very low density lipoprotein apoprotein B turnover rate was greater in hypertriglyceridaemic subjects with familial combined hyperlipidaemia (099±0–27 mg/kg/h; n= 5; P < 0005) and also in familial hypertriglyceridaemia (0–74±0–10; n= 6; P < 0–005) than in age and weight matched non‐hyperlipidaemic controls (0–54±0–21; n= 6), suggesting that the hypertriglyceridaemia seen in both genetic disorders was due to very low density lipoprotein overproduction. Very low density lipoprotein apoprotein B turnover rate was greater in familial combined hyperlipidaemia than in familial hypertriglyceridaemia while plasma triglyceride turnover was higher in familial hypertriglyceridaemia. This disparity in the turnover rates of apoprotein B and triglyceride between these disorders was accompanied by a higher very low density lipoprotein triglyceride/apoprotein B ratio in familial hypertriglyceridaemia than in familial combined hyperlipidaemia (P < 0001) and in normals (P < 0–005).

Contrasting effects of unmodified and time-release forms of niacin on lipoproteins in hyperlipidemic subjects: Clues to mechanism of action of niacin

To minimize the cutaneous flushing symptoms associated with niacin use, a time-release capsule form of niacin has been formulated. Thus study compares the effects of time-release niacin with those of unmodified niacin on lipoprotein lipids, including HDL2 and HDL3, apoproteins A-I and A-II, clinical chemistries, symptomatic side effects, and adherence to the medication regimen. Seventy-one primarily hypercholesterolemic subjects were randomized to either unmodified niacin or time-release niacin ad took medication for a six-month period. The two groups were closely matched on anthropomorphic and lipid variables. Adherence to the therapeutic regimen at a dose of 1.5 g/d in the first month of treatment was similar in the two groups. Thereafter, at a dose of 3.0 g/d, adherence was in excess of 90% among subjects taking unmodified niacin but only 64% among those taking time-release niacin, chiefly because of aggravated gastrointestinal symptoms; cutaneous flushing side effects, however, were slightly less common with time-release niacin. At these levels of adherence, LDL cholesterol (C) was reduced 21% by unmodified niacin and 13% by the time release form. Plasma total triglyceride was reduced more with unmodified niacin (27%) than with time-release niacin (8% maximum), and HDL-C and HDL2-C were increased significantly with unmodified niacin (26% and 36%) and were not significantly changed by time-release niacin. Increased to a similar degree on both regimens were HDL3-C (approximately 35%) and apoA-I (approximately 12%). ApoA-II was not affected by either drug regimen.(ABSTRACT TRUNCATED AT 250 WORDS)

Apoproteins B and A-I and coronary artery disease in humans.

T review initially will consider the association between premature coronary artery disease and abnormal lipoprotein cholesterol levels, but then focus on recent evidence linking the apoproteins of lipoproteins to atherosclerosis. This evidence suggests that although cholesterol is the major component common to the plasma and the arterial wall, plasma apoproteins may serve as a better marker of risk for atherosclerosis.

Immunochemical quantification of human plasma Lp(a) lipoprotein

The Lp(a) lipoprotein was purified from human plasma by ultracentrifugation and gel filtration on 6% agarose. It contained 27% protein, 65% lipid, and 8% carbohydrate. Quantification of the Lp(a) lipoprotein was performed by radial immunodiffusion. Both within-assay and between-assay coefficients of variation were inversely concentration dependent, decreasing from 20% and 27%, respectively, at 3 mg/100 ml to 7% and 12%, respectively, at concentrations above 8 mg/100 ml. The lower limit of sensitivity of the assay was 1.5 mg/100 ml. Of 340 unrelated fasting subjects tested, 81% had levels of the Lp(a) lipoprotein exceeding this lower limit. The distribution of Lp(a) concentrations in this population was skewed with a mean of 14 mg/100 ml and a median of 8 mg/100 ml. Lp(a) lipoprotein was not significantly correlated with age, sex, or cholesterol or glyceride concentrations.