Lessons from KEEPS: the Kronos Early Estrogen Prevention Study.

The Kronos Early Estrogen Prevention Study (KEEPS) was a randomized, double-blind, placebo-controlled trial designed to determine the effects of hormone treatments (menopausal hormone treatments [MHTs]) on the progression of carotid intima-medial thickness (CIMT) in recently menopausal women. Participants less than 3 years from menopause and without a history of overt cardiovascular disease (CVD), defined as no clinical CVD events and coronary artery calcium < 50 Agatston units, received either oral conjugated equine estrogens (0.45 mg/day) or transdermal 17ß-estradiol (50 µg/day), both with progesterone (200 mg/day for 12 days/month), or placebo pills and patches for 4 years. Although MHT did not decrease the age-related increase in CIMT, KEEPS provided other important insights about MHT effects. Both MHTs versus placebo reduced the severity of menopausal symptoms and maintained bone density, but differed in efficacy regarding mood/anxiety, sleep, sexual function, and deposition of ß-amyloid in the brain. Additionally, genetic variants in enzymes for metabolism and uptake of estrogen affected the efficacy of MHT for some aspects of symptom relief. KEEPS provides important information for use of MHT in clinical practice, including type, dose, and mode of delivery of MHT recently after menopause, and how genetic variants in hormone metabolism may affect MHT efficacy on specific outcomes.

Using basic science to design a clinical trial: baseline characteristics of women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS).

Observational and epidemiological studies suggest that menopausal hormone therapy (MHT) reduces cardiovascular disease (CVD) risk. However, results from prospective trials showed neutral or adverse effects most likely due to differences in participant demographics, such as age, timing of initiation of treatment, and preexisting cardiovascular disease, which reflected in part the lack of basic science information on mechanisms of action of hormones on the vasculature at the time clinical trials were designed. The Kronos Early Estrogen Replacement Study (KEEPS) is a prospective, randomized, controlled trial designed, using findings from basic science studies, to test the hypothesis that MHT when initiated early in menopause reduces progression of atherosclerosis. KEEPS participants are younger, healthier, and within 3 years of menopause thus matching more closely demographics of women in prior observational and epidemiological studies than women in the Women's Health Initiative hormone trials. KEEPS will provide information relevant to the critical timing hypothesis for MHT use in reducing risk for CVD.

KEEPS: The Kronos Early Estrogen Prevention Study.

Observational studies have indicated that hormone therapy given at or after menopause is linked to substantial reduction in cardiovascular disease and its risk factors. Recent findings from the Women's Health Initiative (WHI) clinical trial, however, indicate that combined estrogen plus progestin hormone therapy, as well as estrogen-alone hormone therapy (given to women without a uterus), is ineffective in preventing the new onset of cardiac events in previously healthy late menopausal women. Further, the secondary prevention trial, the Heart and Estrogen/progestin Replacement Study (HERS), also failed to demonstrate any benefit of initiation of hormone therapy in women with established coronary heart disease. In light of these results, a hypothesis has arisen that early initiation of hormone therapy, in women who are at the inception of their menopause, will delay the onset of subclinical cardiovascular disease in women. The rationale that earlier intervention than that performed in the WHI and HERS trials will provide cardiovascular benefit to women is the driving force behind the Kronos Early Estrogen Prevention Study, or KEEPS. KEEPS is a multicenter, 5-year clinical trial that will evaluate the effectiveness of 0.45 mg of conjugated equine estrogens, 50 microg weekly transdermal estradiol (both in combination with cyclic oral, micronized progesterone, 200 mg for 12 days each month), and placebo in preventing progression of carotid intimal medial thickness and the accrual of coronary calcium in women aged 42-58 years who are within 36 months of their final menstrual period. A total of 720 women are planned to be enrolled in 2005, with an anticipated close-out of the trial in 2010. This overview summarizes the recruitment and methodology of the KEEPS trial.

Heterozygosity for ABCA1 gene mutations: effects on enzymes, apolipoproteins and lipoprotein particle size.

A cohort of 13 female and 14 male heterozygotes for ATP binding cassette A1 (ABCA1) gene defects was directly compared with 13 and 14 unaffected female and male family members of almost exact same age. The activities of three proteins that play key roles in HDL metabolism were measured in addition to extensive lipid and (apo) lipoprotein subfraction analysis. Compared to controls, LCAT activity was reduced by 15% in affected subjects (P < 0.001) while PLTP activity was unaffected. Interestingly, CETP activity was elevated by 50% in the heterozygote siblings of one kindred but was unaffected in heterozygotes of the three other families. With respect to lipids, the heterozygotes had normal total cholesterol (TC), and LDL-cholesterol concentrations but presented with a trend towards increased triglyceride levels (13%; P = 0.08). HDL metabolism, by contrast, was severely affected as illustrated by 40% reductions in HDL-cholesterol (P < 0.001) with concomitant reductions in apoAI (25%; P < 0.001) levels and in lipoprotein subfraction LpAI (28%; P < 0.001), LpAI:AII (24%; P=0.014), and LpCIII:nonB (34%; P < 0.001) concentrations. We furthermore observed reduced average HDL particle size (5%; P = 0.004; 16% in female and 3.6% in male) and reduced plasma apoCIII concentration (15%; P = 0.006) while apoAII, apoAIV, apoE and apoB levels were unchanged. In conclusion, heterozygosity for ABCA1 defects was associated with reduced LCAT activity in absence of effects on PLTP activity. Of special interest was our finding that the effects of compromised ABCA1 function on HDL were more pronounced in women than in men.

Newer HMG-CoA reductase inhibitor (statin) therapies.

Although most patients can achieve their National Cholesterol Education Program goal with a reduction of < or =30% in low-density lipoprotein cholesterol (LDL-C) levels available with all statins, some patients need greater LDL-C lowering. Furthermore, new study data suggest that greater clinical event reduction may be obtained with more aggressive LDL-C lowering and/or with treatment of factors beyond LDL-C. New formulations of statins. including extended-release preparations, are achieving greater reductions in LDL-C levels as well as favorable modification of high-density lipoprotein cholesterol and triglyceride concentrations while maintaining an excellent safety profile.

Alcohol consumption raises HDL cholesterol levels by increasing the transport rate of apolipoproteins A-I and A-II.

BACKGROUND: Moderate alcohol intake is associated with lower atherosclerosis risk, presumably due to increased HDL cholesterol (HDL-C) concentrations; however, the metabolic mechanisms of this increase are poorly understood. METHODS AND RESULTS: We tested the hypothesis that ethanol increases HDL-C by raising transport rates (TRs) of the major HDL apolipoproteins apoA-I and -II. We measured the turnover of these apolipoproteins in vivo in paired studies with and without alcohol consumption in 14 subjects. The fractional catabolic rate (FCR) and TR of radiolabeled apoA-I and -II were determined in the last 2 weeks of a 4-week Western-type metabolic diet, without (control) or with alcohol in isocaloric exchange for carbohydrates. Alcohol was given as vodka in fixed amounts ranging from 0.20 to 0.81 g. kg(-1). d(-1) (mean+/-SD 0.45+/-0.19) to reflect the usual daily intake of each subject. HDL-C concentrations increased 18% with alcohol compared with the control (Wilcoxon matched-pairs test, P=0.002). The apoA-I concentrations increased by 10% (P=0.048) and apoA-II concentrations increased by 17% (P=0.005) due to higher apoA-I and -II TRs, respectively, whereas the FCR of both apoA-I and -II did not change. The amount of alcohol consumed correlated with the degree of increase in HDL-C (Pearson's r=0.66, P=0.01) and apoA-I TR (r=0.57, P=0.03). The increase in HDL-C also correlated with the increase in apoA-I TR (r=0.61, P=0.02). CONCLUSIONS: Alcohol intake increases HDL-C in a dose-dependent fashion, associated with and possibly caused by an increase in the TR of HDL apolipoproteins apoA-I and -II.

The role of fibric acid derivatives in the secondary prevention of coronary heart disease.

Fibric acid derivatives effectively lower triglycerides and raise high-density lipoprotein (HDL) cholesterol, but their effect on low-density lipoprotein (LDL) cholesterol is weakly beneficial (small decreases) to adverse (small increases) and varies according to the triglyceride level. Early primary prevention studies of atherosclerosis using the fibric acid derivative clofibrate showed only modest effects on atherosclerosis and an alarming increase in mortality in the intervention group. Although the Helsinki Heart Study later demonstrated that gemfibrozil decreased cardiac endpoints in primary prevention without increasing total mortality, the efficacy of fibric acid derivatives in both primary and secondary prevention of atherosclerosis has remained widely in doubt. Nevertheless, many patients with atherosclerosis have normal or even low LDL cholesterol, but elevated triglyceride, and low HDL cholesterol; furthermore, even aggressive LDL cholesterol lowering with HMG Co-A (3-hydroxy 3-methylglutaryl coenzyme A) reductase inhibitors (statins) fails to prevent the majority of atherosclerotic events. These findings have kindled increased interest in the use of fibric acid derivatives in atherosclerosis prevention, especially through treatment of non-LDL dyslipidemias. Recent studies with angiographic and clinical end-points have now provided evidence for a beneficial effect of at least some drugs in this class in the secondary prevention of atherosclerosis.

Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease: the ADMIT study: A randomized trial. Arterial Disease Multiple Intervention Trial.

CONTEXT: Although niacin increases low levels of high-density lipoprotein cholesterol (HDL-C), which frequently accompany diabetes, current guidelines do not recommend use of niacin in patients with diabetes because of concerns about adverse effects on glycemic control; however, this is based on limited clinical data. OBJECTIVE: To determine the efficacy and safety of lipid-modifying dosages of niacin in patients with diabetes. DESIGN AND SETTING: Prospective, randomized placebo-controlled clinical trial conducted in 6 clinical centers from August 1993 to December 1995. PARTICIPANTS: A total of 468 participants, including 125 with diabetes, who had diagnosed peripheral arterial disease. INTERVENTIONS: After an active run-in period, participants were randomly assigned to receive niacin (crystalline nicotinic acid), 3000 mg/d or maximum tolerated dosage (n = 64 with diabetes; n = 173 without diabetes), or placebo (n = 61 with diabetes; n = 170 without diabetes) for up to 60 weeks (12-week active run-in and 48-week double-blind). MAIN OUTCOME MEASURES: Plasma lipoprotein, glucose, hemoglobin A(1c) (HbA(1c)), alanine aminotransferase, and uric acid levels; hypoglycemic drug use; compliance; and adverse events, in patients with diabetes vs without who were receiving niacin vs placebo. RESULTS: Niacin use significantly increased HDL-C by 29% and 29% and decreased triglycerides by 23% and 28% and low-density lipoprotein cholesterol (LDL-C) by 8% and 9%, respectively, in participants with and without diabetes (P<.001 for niacin vs placebo for all). Corresponding changes in participants receiving placebo were increases of 0% and 2% in HDL-C and increases of 7% and 0% in triglycerides, and increases of 1% and 1% in LDL-C. Glucose levels were modestly increased by niacin (8.7 and 6.3 mg/dL [0.4 and 0.3 mmol/L]; P =.04 and P<.001) in participants with and without diabetes, respectively. Levels of HbA(1c) were unchanged from baseline to follow-up in participants with diabetes treated with niacin. In participants with diabetes treated with placebo, HbA(1c) decreased by 0.3% (P =.04 for difference). There were no significant differences in niacin discontinuation, niacin dosage, or hypoglycemic therapy in participants with diabetes assigned to niacin vs placebo. CONCLUSIONS: Our study suggests that lipid-modifying dosages of niacin can be safely used in patients with diabetes and that niacin therapy may be considered as an alternative to statin drugs or fibrates for patients with diabetes in whom these agents are not tolerated or fail to sufficiently correct hypertriglyceridemia or low HDL-C levels. JAMA. 2000;284:1263-1270

Postmenopausal hormone replacement improves proteinuria and impaired creatinine clearance in type 2 diabetes mellitus and hypertension.

OBJECTIVE: To determine whether hormone replacement therapy can reverse established renal microvascular damage in type 2 diabetes and hypertension. DESIGN: Prospective, single centre clinical trial. SETTING: Outpatient clinics. PARTICIPANTS: Sixteen diabetic and hypertensive postmenopausal women (age 47-57 years) METHODS: Administration of a cyclic combination of oestradiol and norgestrel orally for 3.5 monthly cycles. RESULTS: Comparing the baseline values, mean (SD) 24-hour urine protein excretion was reduced from 0.452 g (0039) to 0.370 g (0.047) (P < 0.01) and creatinine clearance was increased from 1.68 mL/sec (0.11) to 1.77 mL/sec (0.08) (P < 0.05). Fasting plasma glucose also improved from 6.92 mmol/L (0.47) to 6.51 mmol/L (0.28) (P < 0.05), as did serum total cholesterol from 7.26 mmol/L (0.28) to 6.65 mmol/L (0.14) (P < 0.05). Blood pressure did not change significantly. Univariate linear regression analysis showed no significant correlation between the individual changes in blood pressure, fasting plasma glucose or serum cholesterol and the individual changes in proteinuria or creatinine clearance. CONCLUSIONS: This study shows that hormone replacement therapy may reduce proteinuria, and even improve creatinine clearance, in diabetic and hypertensive postmenopausal women. These effects are additive to nephroprotective therapy, and the mechanisms appear unrelated to conventional risk factors for vascular complications, such as high blood pressure, elevated plasma glucose or serum cholesterol.

Cardiovascular effects of droloxifene, a new selective estrogen receptor modulator, in healthy postmenopausal women.

Selective estrogen receptor modulators, like tamoxifen and related compounds, have mixed estrogen agonistic/antagonistic effects. Tamoxifen may confer significant cardiovascular benefits without the estrogen-associated risks of endometrial and breast cancer. Droloxifene, a structural analogue of tamoxifen, has estrogen agonistic effects on bone and antagonistic effects on endometrial and breast tissue. Its cardiovascular effects in women are unknown. We enrolled 24 healthy postmenopausal women in a randomized, double-blind, 2-period crossover trial comparing the effects of droloxifene (60 mg/d) with conjugated estrogen (0.625 mg/d). Plasma lipids, coagulation and fibrinolytic factors, and brachial flow-mediated vasodilator responses were measured at the beginning and end of each treatment period. Droloxifene and estrogen resulted in 16.6% and 12.0% reductions, respectively, in low density lipoprotein cholesterol (P<0.001) and 13.2% and 9.5% reductions, respectively, in lipoprotein(a) (P<0.05). In contrast, estrogen, but not droloxifene, increased high density lipoprotein (18.5%, P<0.001). Droloxifene also reduced fibrinogen by 17.8% versus a 7.3% reduction with estrogen (P=0.004) but produced no estrogen-like changes in plasminogen, plasminogen activator inhibitor-1, or tissue plasminogen activator. Droloxifene and estrogen produced 36.4% and 27.3% increases, respectively, in flow-mediated vasodilation (percent change from baseline, P<0.05 for both). Droloxifene has estrogen agonistic properties regarding low density lipoprotein and lipoprotein(a) metabolism, certain coagulation factors, and endothelium-dependent vasodilation but, unlike estrogen, has no effect on high density lipoprotein/triglyceride metabolism and the fibrinolytic cascade. It remains unknown whether droloxifene can confer a true cardiovascular benefit.

Very small apolipoprotein A-I-containing particles from human plasma: isolation and quantification by high-performance size-exclusion chromatography.

BACKGROUND: Very small apolipoprotein (apo) A-I-containing lipoprotein (Sm LpA-I) particles with pre-beta electrophoretic mobility may play key roles as "nascent" and/or "senescent" HDL; however, methods for their isolation are difficult and often semiquantitative. METHODS: We developed a preparative method for separating Sm LpA-I particles from human plasma by high-performance size-exclusion chromatography (HP-SEC), using two gel permeation columns (Superdex 200 and Superdex 75) in series and measuring apo A-I content in column fractions in 30 subjects with HDL-cholesterol (HDL-C) concentrations of 0.4-3.83 mmol/L. RESULTS: Three major sizes of apo A-I-containing particles were detected: an approximately 15-nm diameter ( approximately 700 kDa) species; a 7. 5-12 nm (100-450 kDa) species; and a 5.8-6.3 nm species (40-60 kDa, Sm LpA-I particles), containing 0.2-3%, 80-96%, and 2-15% of plasma total apo A-I, respectively. Two subjects with severe HDL deficiency had increased relative apo A-I content in Sm LpA-I: 25% and 37%, respectively. The percentage of apo A-I in Sm LpA-I correlated positively with fasting plasma triglyceride concentrations (r = 0. 581; P <0.0005) and inversely with total apo A-I (r = -0.551; P <0. 0013) and HDL-C concentrations (r = -0.532; P <0.0017), although the latter two relationships were largely attributable to extremely hypoalphalipoproteinemic subjects. The percentage of apo A-I in Sm LpA-I correlated with that in pre-beta-migrating species by crossed immunoelectrophoresis (r = 0.98; P <0.0001; n = 24) and with that in the d >1.21 kg/L fraction by ultracentrifugation (r = 0.86; P <0. 001; n = 20). Sm LpA-I particles, on average, appear to contain two apo A-I and four phospholipid molecules but little or no apo A-II, triglyceride, or cholesterol. CONCLUSIONS: We present a new HP-SEC method for size separation of native HDL particles from plasma, including Sm Lp A-I, which may play important roles in the metabolism of HDL and in its contribution(s) to protection against atherosclerosis. This method provides a basis for further studies of the structure and function of Sm Lp A-I.

Hormone replacement therapy reduces mean 24-hour blood pressure and its variability in postmenopausal women with treated hypertension.

BACKGROUND: The rate and severity of hypertension increase dramatically after menopause. Complications seem to be more frequent and marked in hypertensive patients with greater blood pressure (BP) variability, and antihypertensive treatment does not easily reduce this variability. The effect of hormone replacement therapy (HRT) on BP and its variability is not well understood in moderate to severe hypertension, but estrogen may have calcium channel-blocking properties. Cardiovascular events occur more frequently in the morning, likely in part because of a rise in BP. DESIGN: We prospectively studied 34 postmenopausal women with treated hypertension (mean age = 53 years) and receiving a cyclic combination of estradiol and norgestrel for 19 weeks with 24-h ambulatory BP monitoring. RESULTS: Mean daily BP and its variability decreased significantly with HRT (149.3 +/- 6.1 mm Hg vs. 140.3 +/- 8.5 mm Hg [p < 0.001]; diastolic: 95.4 +/- 4.7 mm Hg vs. 92.4 +/- 7.2 mm Hg [p < 0.05]). There was also a significant decrease in the early morning BP values after HRT (154.0 +/- 6.9 mm Hg vs. 145.6 +/- 11.0 mm Hg [p < 0.001]; diastolic: 98.0 +/- 4.8 mm Hg vs. 95.1 +/- 10.0 mm Hg [p < 0.05]). Subjects who were taking calcium channel blockers (n = 11) had only half the reduction in 24-h systolic BP compared with those who were not taking calcium channel blockers (5.3 mm Hg vs. 10.5 mm Hg), and the reduction in those who were taking calcium channel blockers failed to reach statistical significance. CONCLUSIONS: Our results demonstrate that HRT may have a role in decreasing the severity of hypertension, and the mechanism of its action might be through calcium channels.

Metabolic and genetic determinants of HDL metabolism and hepatic lipase activity in normolipidemic females.

The metabolic and genetic determinants of HDL cholesterol (HDL-C) levels and HDL turnover were studied in 36 normolipidemic female subjects on a whole-food low-fat metabolic diet. Lipid, lipoprotein, and apolipoprotein levels, lipoprotein size, and apolipoprotein turnover parameters were determined, as were genetic variation at one site in the hepatic lipase promoter and six sites in the apolipoprotein AI/CIII/AIV gene cluster. Menopause had no significant effect on HDL-C or turnover. Stepwise multiple regression analysis revealed that HDL-C was most strongly correlated with HDL size, apolipoprotein A-II (apoA-II), and apolipoprotein A-I (apoA-I) levels, which together could account for 90% of the variation in HDL-C. HDL size was inversely correlated with triglycerides, body mass index, and hepatic lipase activity, which together accounted for 82% of the variation in HDL size. The hepatic lipase promoter genotype had a strong effect on hepatic lipase activity and could account for 38% of the variation in hepatic lipase activity. The apoA-I transport rate (AI-TR) was the major determinant of apoA-I levels, but AI-TR was not associated with six common genetic polymorphism in the apoAI/CIII/AIV gene cluster.A simplified model of HDL metabolism is proposed, in which A-I and apoA-II levels combined with triglycerides, and hepatic lipase activity could account for 80% of the variation in HDL-C.

Amputation prevention by vascular surgery and podiatry collaboration in high-risk diabetic and nondiabetic patients. The Operation Desert Foot experience.

OBJECTIVE: To describe a unique multidisciplinary outpatient intervention for patients at high risk for lower-extremity amputation. RESEARCH DESIGN AND METHODS: Patients with foot ulcers and considered to be high risk for lower-extremity amputation were referred to the High Risk Foot Clinic of Operation Desert Foot at the Carl T. Hayden Veterans Affairs' Medical Center in Phoenix, Arizona, where patients received simultaneous vascular surgery and podiatric triage and treatment. Some 124 patients, consisting of 90 diabetic patients and 34 nondiabetic patients, were initially seen between 1 October 1991 and 30 September 1992 and followed for subsequent rate of lower-extremity amputation. RESULTS: In a mean follow-up period of 55 months (range 3-77), only 18 of 124 patients (15%) required amputation at the level of the thigh or leg. Of the 18 amputees, 17 (94%) had type 2 diabetes. The rate of avoiding limb loss was 86.5% after 3 years and 83% after 5 years or more. Furthermore, of the 15 amputees surviving longer than 2 months, only one (7%) had to undergo amputation of the contralateral limb over the following 12-65 months (mean 35 months). Compared with nondiabetic patients, patients with diabetes had a 7.68 odds ratio for amputation (95% CI 5.63-9.74) (P < 0.01). CONCLUSIONS: A specialized clinic for prevention of lower-extremity amputation is described. Initial and contralateral amputation rates appear to be far lower in this population than in previously published reports for similar populations. Relative to patients without diabetes, patients with diabetes were more than seven times as likely to have a lower-extremity amputation. These data suggest that aggressive collaboration of vascular surgery and podiatry can be effective in preventing lower-extremity amputation in the high-risk population.

Oral estrogen replacement therapy in postmenopausal women selectively raises levels and production rates of lipoprotein A-I and lowers hepatic lipase activity without lowering the fractional catabolic rate.

To characterize the apolipoprotein (apo) subfraction specificity of the increase in high density lipoprotein (HDL) levels that is induced by oral estrogen and to explore the metabolic mechanisms thereof, six healthy, postmenopausal women were studied during each of two 5-week periods of a low-fat diet with and without ethinyl estradiol 0.05 mg/d. With estrogen, HDL cholesterol levels increased 36% (mean+/-SD, 47+/-15 versus 63+/-18 mg/dL, basal versus estrogen periods, respectively; P=.004), plasma levels of apo A-I increased by 27% (147+/-24 versus 186+/-34 mg/dL; P=.003), and apo A-II levels increased 17% (39+/-5 versus 46+/-4 mg/dL; P=.0003). Apo A-I mass in particles that contained apo A-I but no apo A-II (ie, Lp A-I) increased 66% (43+/-13 versus 71+/-17 mg/dL; P=.002) while the sum of apo A-I and apo A-II mass in particles with both apo A-I and apo A-II (ie, Lp A-I/A-II) showed only a nonsignificant 14% increase (144+/-23 versus 163+/-29 mg/dL; P=.12). In radioiodinated-protein turnover studies the production rate (PR) of each species changed in proportion to the change in its plasma concentration: Lp A-I PR increased 76% (4.7+/-1.8 versus 8.2+/-2.5 mg x kg(-1) x day(-1); P=.001) while Lp A-I/A-II PR showed only a nonsignificant increase of 22% (14.1+/-1.8 versus 17.2+/-5.4 mg x kg(-1) x day(-1); P=.2). Hepatic lipase (HL) activity in postheparin plasma decreased 66% with estrogen (10.4+/-4.3 versus 3.5+/-0.8 micromol x mL(-1) x h(-1); P=.005) while lipoprotein lipase activity was unchanged (7.1+/-1.6 versus 7.6+/-1.6 micromol x mL(-1) x h(-1); P>.2). Despite the large decrease in HL activity, the fractional catabolic rate of Lp A-I did not decrease (0.241+/-0.048 versus 0.258+/-0.066 pool/d; P=.2), nor was that of Lp A-I/A-II lessened (0.221+/-0.030 versus 0.233+/-0.053 pool/d; P>.2). Thus, oral estrogen replacement therapy has a novel and potentially antiatherogenic effect: a large and selective increase in Lp A-I levels. The metabolic mechanism of the estrogen-induced increase in Lp A-I concentration appears to be the increase in its PR. Although the ability of estrogen to suppress HL activity has been confirmed, surprisingly this decrease was not accompanied by any decrease in the fractional catabolic rate of Lp A-I or Lp A-I/A-II. This suggests that HL may not play a major role in regulating HDL protein catabolism during suppression of HL by estrogen.

Human HDL cholesterol levels are determined by apoA-I fractional catabolic rate, which correlates inversely with estimates of HDL particle size. Effects of gender, hepatic and lipoprotein lipases, triglyceride and insulin levels, and body fat distribution.

High-density lipoprotein (HDL) cholesterol (HDL-C) levels are a strong inverse predictor of atherosclerosis risk, but the physiological determinants of HDL-C levels are poorly understood. We selected 57 human subjects (30 women and 27 men) with a broad range of HDL-C levels and performed turnover studies of apolipoprotein (apo)A-I and apoA-II, the two major apolipoproteins of HDL, to measure the fractional catabolic rate (FCR) and production or transport rate (TR) of these proteins. We also measured several other parameters known to correlate with HDL-C levels to test for their interrelations and to postulate mechanisms of regulation of HDL-C levels. As expected, the women had higher levels of HDL-C (56.7 +/- 21.4 versus 45.1 +/- 16.3 mg/dL, mean +/- SD; P = .03) and apoA-I (147 +/- 32 versus 126 +/- 29 mg/dL, P = .01) than men and did not differ in apoA-II levels (34.5 +/- 7.4 versus 33.3 +/- 7.5 mg/dL, P > .2). The FCR of apoA-I tended to be lower in the women (0.248 +/- 0.077 versus 0.277 +/- 0.069 pools/d, P = .1), although the difference was not statistically significant. The FCR of apoA-II was also lower (0.184 +/- 0.043 versus 0.216 +/- 0.056 pools/d, P = .02). In contrast, the apoA-I TR was equal in women and men (12.0 +/- 1.6 versus 12.1 +/- 2.8 mg/kg per day, P > .2), and there was a trend toward lower apoA-II TR in women (2.19 +/- .62 versus 2.61 +/- 1.06 mg/kg per day, P = .07). Linear regression analysis revealed a strong inverse correlation between HDL-C levels and the FCRs of apoA-I and apoA-II (r = -.81 and -.76, respectively; P < .0001 for both). In contrast, there was little or no association between HDL-C and the TRs of apoA-I and apoA-II (r = .06 and -.35, P = not significant and .01, respectively). In stepwise multiple linear regression analysis, apoA-I FCR alone accounted for 66% of the variability in HDL-C; two other variables accounted for an additional 7%. Due to the importance of apoA-I FCR, its determinants were sought among the remaining variables.(ABSTRACT TRUNCATED AT 400 WORDS)

Polymorphism in the human apolipoprotein A-I gene promoter region. Association of the minor allele with decreased production rate in vivo and promoter activity in vitro.

We investigated a common polymorphism in the human apolipoprotein A-I gene promoter at a position 76 bp upstream of the transcriptional start site. 54 human subjects, whose apoAI production rates had been determined by apoAI turnover studies, were genotyped at this polymorphic position by a novel technique using polymerase chain reaction followed by primer extension. 35 subjects were homozygous for a guanosine (G) at this locus and 19 were heterozygous with a guanosine and adenosine (A). The apoAI production rates were significantly lower (by 11%) in the G/A heterozygotes than in the G homozygotes (P = 0.025). In spite of the apparent effect of this apoAI gene promoter polymorphism on the apoAI production rate, there was no effect on HDL cholesterol or apoAI levels. To investigate whether the observed difference in apoAI production rates was related to differential gene expression of the two alleles, promoters containing either allele were linked to the reporter gene chloramphenicol acetyltransferase, and relative promoter efficiencies were determined after transfection into the human HepG2 hepatoma cell line. The A allele expressed only 68% +/- 5% as well as the G allele, a result consistent with the in vivo apoAI production rate data.

Hypertriglyceridemia in patients with psoriasis treated with cyclosporine.

Eight patients received cyclosporine at doses of 2.0 to 7.5 mg/kg/day. Seven of these patients had increased fasting plasma triglyceride levels with cyclosporine therapy compared with pretreatment values, which peaked after 1 month of therapy. Four patients experienced elevations in fasting triglycerides, over the upper limits for age- and sex-matched controls, which were at least two times higher than their baseline values. It was striking that all four of these patients had previously had hypertriglyceridemia while using etretinate and three of these patients had preexisting hypertriglyceridemia before both etretinate and cyclosporine therapy. Triglyceride elevation did not correlate with cyclosporine levels. Thus cyclosporine, similar to etretinate, unmasks a latent tendency for mild to moderate hypertriglyceridemia. Fasting triglyceride levels should be monitored during cyclosporine therapy, especially after 1 to 2 months of use, and in patients with preexisting increased triglycerides and/or a history of etretinate use.