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Biomedical subjects

W R Hazzard

Publications and source records attributed to W R Hazzard.

At least 19 recordsLinked to original sources
PubMed1992

Metabolism of apolipoprotein B in members of a family with accelerated atherosclerosis: influence of apolipoprotein E-3/E-2 pattern.

Familial combined hyperlipidemia (FCHL) appears to be the most common, simply inherited hyperlipidemia strongly associated with coronary heart disease. In the family examined in this study, two of the siblings who met diagnostic criteria for FCHL had extensive clinical atherosclerosis before age 30, unusually premature for this form of hyperlipidemia. Lipoproteins and low-density lipoprotein (LDL) apolipoprotein (apo) B metabolism were characterized in these siblings in an attempt to gain insight into the cause of the rapid atherosclerosis in the two siblings so affected. LDL apo B production rates were very high in all three siblings (25 to 30 mg/kg/d), consistent with FCHL. beta-Very-low-density lipoprotein-beta (beta-VLDL) was present in the plasma of both siblings with accelerated atherosclerosis. The isoapolipoprotein E pattern in both of these siblings was E-3/E-2. In the third sibling, who was free of premature clinical atherosclerosis and lacked plasma beta-VLDL, the pattern was E-3/E-3. Thus, the heterozygote apo E-3/E-2 pattern may be related to the accumulation of beta-VLDL in persons with a very high apo B production rate. The abnormal accumulation of beta-VLDL may be one of the possible explanations for the rapid, premature atherosclerosis in the two siblings with FCHL in this kindred. Both male members in this kindred also had low levels of high-density lipoproteins, and thus may have had an additional risk of developing atherosclerosis due to this lipoprotein abnormality as well.

Adult↗
PubMed1992

Dyslipoproteinemia in the elderly. Should it be treated?

No clear consensus has emerged as to whether or not aggressive screening, surveillance, and management of lipid disorders in the elderly is indicated. Informal polling would suggest a highly conservative approach beyond age 70 but near universal support for such therapy below age 60, with gradations of enthusiasm in between. Studies to identify the cardiovascular risk factors in older persons have been initiated, as has been an intervention trial to lower elevated LDL cholesterol levels in older subjects with an HMG CoA reductase inhibitor. By the year 2000, the present, highly individualized and subjective treatment of lipid disorders in elderly patients may be replaced by more objective, uniform guidelines for such management. In the meantime the question remains, "Should dyslipoproteinemia be treated in the elderly?" And the answer remains, "Perhaps."

Aged↗
PubMed1991

A dose-response relationship between sex hormone-induced change in hepatic triglyceride lipase and high-density lipoprotein cholesterol in postmenopausal women.

In previous studies, we have demonstrated a temporal relationship between the postheparin hepatic triglyceride lipase (HTGL) response to sex steroids and the high-density lipoprotein (HDL) cholesterol response. To determine if this relationship is dose-dependent, we compared the effect of three graduated doses of orally administered estradiol and norgestrel in two groups of six postmenopausal women. With estradiol administration, postheparin HTGL activity decreased from 91 +/- 46 to 50 +/- 29 nmol/min/mL, baseline to high dose (P less than .05); HDL cholesterol increased from 54 +/- 6 to 64 +/- 10 mg/dL (P less than .05); HDL2 cholesterol increased from 16 +/- 4 to 23 +/- 7 mg/dL (P less than .05); and HDL3 cholesterol concentration did not change. With norgestrel administration, HTGL activity increased from 79 +/- 19 to 109 +/- 24 nmol/min/mL (P less than .05); HDL cholesterol decreased from 64 +/- 17 to 43 +/- 7 mg/dL (P less than .05); HDL2 cholesterol decreased from 21 +/- 17 to 6 +/- 5 mg/dL (P less than .05); and HDL3 cholesterol concentration decreased from 43 +/- 8 to 38 +/- 8 mg/dL (P less than .05). The HTGL activity response was inversely correlated with estrogen dose (rs = -.733, P = .0001) and directly correlated with progestin dose (rs = .895, P = .0001). The HDL cholesterol response was directly correlated with estrogen dose (HDL: rs = .741, P = .001; HDL2: rs = .586, P = 0.003) and inversely correlated with progestin dose (HDL: rs = -.933, P = .0001; HDL2: rs = -.866, P = .0001; HDL3: rs = -.576, P = .003).(ABSTRACT TRUNCATED AT 250 WORDS)

Cholesterol, HDL↗
PubMed1990

Differential effects of oral estrone versus 17 beta-estradiol on lipoproteins in postmenopausal women.

Toward the definition of optimal postmenopausal estrogen replacement we compared the effects of three graduated doses of two oral estrogens, estrone sulfate and 17 beta-estradiol, on the lipid profiles of two groups of six postmenopausal women. Because of metabolic interconversions equivalent serum concentrations of estrone and estradiol were produced with these regimens. However, differential effects were noted in lipoproteins. 17 beta-Estradiol caused an increase in total plasma cholesterol (from 5.71 +/- 0.36 to 5.99 +/- 0.57 mmol/L, baseline to high dose; P less than 0.02), high density lipoprotein (HDL) cholesterol (from 1.45 +/- 0.15 to 1.78 +/- 0.36 mmol/L; P less than 0.02), HDL2 cholesterol concentration (from 0.41 +/- 0.08 to 0.62 +/- 0.26 mmol/L; P less than 0.01), and triglyceride concentration (from 1.09 +/- 0.29 to 1.24 +/- 0.30 mmol/L; P less than 0.01) without affecting low density lipoprotein (LDL) cholesterol concentration. By contrast, estrone sulfate caused a decrease in total plasma cholesterol (from 6.51 +/- 0.85 to 5.87 +/- 0.41 mmol/L; P less than 0.05) and LDL cholesterol concentration (from 4.34 +/- 0.57 to 3.67 +/- 0.44 mmol/L; P less than 0.01) and an increase in HDL cholesterol (from 1.37 +/- 0.20 to 1.50 +/- 0.26 mmol/L; P less than 0.05) and HDL2 cholesterol concentration (from 0.34 +/- 0.18 to 0.49 +/- 0.18 mmol/L; P less than 0.01), but no change in total triglyceride concentration. We deduce that the differential effect of orally administered estrogens on lipoprotein metabolism in postmenopausal women may be attributed to a first pass effect on hepatic metabolism.

Administration, Oral↗
PubMed1990

Lipoprotein lipids in women with androgen excess: independent associations with increased insulin and androgen.

Concentrations of triglycerides are increased and concentrations of high-density lipoprotein (HDL) cholesterol are low in women with hyperandrogenism. These alterations could be related to excessive androgen or estrogen, to hyperinsulinism, or to a combination of these abnormalities. We examined their independent influences on lipids in 21 women with hyperandrogenism, subgrouped according to apparent source of androgen excess. Results for lipid, androgen, and insulin did not differ among subgroups, so these data were pooled. Free plus albumin-bound testosterone (uT) was correlated with triglycerides (r = 0.69, P less than 0.01) and HDL cholesterol (r = -0.56, P less than 0.01). Both triglycerides (r = 0.66, P less than 0.01) and HDL cholesterol (r = -0.48, P less than 0.05) were also correlated with insulin measured during fasting. Partial correlation revealed that, after adjusting for insulin, lipids were associated with uT. This suggests that androgen excess is independently related to lipid excess. Insulin also was correlated with lipids when adjusted for uT. Free plus albumin-bound estradiol was not associated with any of the lipids. We conclude that altered lipids in women with hyperandrogenism result from the independent effects of androgen and insulin.

Adult↗
PubMed1990

Why women live longer than men: the biologic mechanism of the sex differential in longevity.

1. Exogenous sex steroids appear to influence lipoproteins in a manner that is a caricature of the effects of endogenous sex steroids: Estrogens raise HDL (selectively HDL2) and lower LDL; Androgens lower HDL (selectively HDL2), while raising LDL. 2. Exogenous sex steroids are likely to affect LDL metabolism via effects on the LDL receptor; Estrogens increase LDL receptor activity (in non-human species at both the hepatic cellular and mRNA levels, though this is yet to be confirmed in humans); ??Androgens decrease LDL receptor activity (yet to be tested in either human or non-human species). 3. Exogenous sex steroids appear to alter HDL levels predominantly via modulation of HDL catabolism; Estrogens retard HDL catabolism (33) (and may also increase apo A-I synthesis and HDL production); Androgens accelerate HDL catabolism (30). 4. Modulation of HDL (and possibly LDL) metabolism by sex steroids may be mediated by alterations in hepatic triglyceride lipase (HTGL) activity.

Adolescent↗
PubMed1989

Atherosclerosis and aging: a scenario in flux.

Atherosclerosis is an age-related process that reflects the interaction between aging per se (primary aging) and factors that influence the rate of atherogenesis. Some of the latter are physiologic, notably sex steroid levels and possibly changes in adiposity, whereas others are modulated by diet and other aspects of lifestyle, such as cigarette smoking and hypertension. Recent declines in atherosclerotic disease suggest that the rate of atherogenesis is amenable to both changes in lifestyle and effective pharmacologic management of risk factors, deferring the onset of clinical disease until late in life or preventing its emergence altogether.

Aged↗
PubMed1989

Estrogen replacement and cardiovascular disease: serum lipids and blood pressure effects.

Coronary heart disease, a major cause of morbidity and death, is the leading cause of death in older women, with an incidence that approaches that in men of comparable age. Estrogen favorably alters lipid metabolism and should therefore diminish the risk for coronary heart disease in estrogen users. Epidemiologic data from case-control and prospective cohort studies have suggested that estrogen use may confer protection from cardiovascular disease and decrease all-cause mortality rates in postmenopausal women. Because the age-adjusted mortality rate due to heart disease among American women is approximately four times the combined mortality rate due to endometrial and breast cancers, even modest changes in the risk of fatal heart disease after estrogen use would dramatically impact the overall risk-benefit equation.

Blood Pressure↗
PubMed1989

Why do women live longer than men? Biologic differences that influence longevity.

Women enjoy a natural relative immunity to coronary atherosclerosis compared with their male counterparts because of their sex hormone status, especially in the premenopausal years. This advantage is likely to be extended to the postmenopausal years by the current widespread prescription of estrogen (coupled with cyclic progestin) therapy. Currently available forms of exogenous estrogen preparations do not confer similar benefits on men, nor would their feminizing side effects be acceptable to men. Therefore, to narrow the sex differential in longevity, with its devastating burdens of loneliness and dependency on elderly women and monetary and time burdens on healthcare resources, men must adopt behaviors that reduce their risk of coronary artery disease. Such behaviors are cessation of cigarette smoking, early detection and long-term control of hypertension, and early detection and long-term control of dyslipoproteinemia (as best reflected in the ratio of low-density lipoprotein to high-density lipoprotein cholesterol). Fortunately, the recent advent of effective dietary and, especially, drug therapy for both hypertension and dyslipoproteinemia makes such approaches to reducing male cardiovascular mortality feasible, effective, and of acceptable cost in both economic and personal terms.

Adolescent↗
PubMed1989

Metabolism of chylomicrons in subjects with dysbetalipoproteinaemia (type III hyperlipoproteinaemia).

These studies were conducted to investigate whether subjects with dysbetalipoproteinaemia (type III hyperlipoproteinaemia) can catabolize chylomicrons normally and if chylomicron catabolism is related to the triglyceride pool size. Iodinated postprandial plasma chylomicrons were injected into subjects with dysbetalipoproteinaemia (n = 7), subjects with endogenous hypertriglyceridaemia (n = 4), and normal subjects (n = 5). The subjects with dysbetalipoproteinaemia had VLDL-cholesterol/total triglyceride ratios greater than 0.35 and were deficient in isoapoE-3 and isoapoE-4. The decay of radioactivity in chylomicron apoB was measured and residence times (RT) were calculated by measuring the area under the radioactivity decay curve. The mean RT for chylomicron apoB in subjects with dysbetalipoproteinaemia was 17.4 +/- 3.5 h, which was significantly longer than in both subjects with endogenous hypertriglyceridaemia (4.8 +/- 2.1 h) and also in normal subjects (5.9 +/- 1.6 h). There was no significant correlation between chylomicron apoB RT and triglyceride levels in subjects with dysbetalipoproteinaemia or in other subjects. Thus, chylomicron apoB catabolism is retarded in subjects with dysbetalipoproteinaemia. The slow removal of chylomicron apoB in subjects with dysbetalipoproteinaemia does not seem to be attributable to an increased triglyceride pool size.

Adult↗
PubMed1989

Lipoprotein, apolipoprotein, and lipolytic enzyme changes following estrogen administration in postmenopausal women.

To test whether estrogen can modulate the cholesterolemic response to an Occidental diet, six healthy postmenopausal women were studied for 84 days while ingesting a solid food diet of constant composition high in cholesterol content (995 mg/d). In the middle of the study, estrogen (17 alpha-ethinyl estradiol, 1 microgram/kg per day) was administered orally. Ingestion of the diet for the initial 28 days did not alter lipoprotein lipid or apolipoprotein (apo) levels. However, with just 4 days of estrogen use there were significant decreases in apoE (-36%), low density lipoprotein cholesterol (-26%), and postheparin plasma hepatic triglyceride lipase activity (HTGL) (-61%), and an increase in high density lipoprotein (HDL) triglyceride (72%). These changes persisted throughout the estrogen use. The percent change in HTGL with 4 days of estrogen correlated inversely with the percent change in HDL triglyceride (rs = -0.94). After 28 days of estrogen there were also significant increases in HDL cholesterol (21%), HDL2 cholesterol (42%), apoA-I (37%), and apoA-II (9%), and a decrease in apoB (-11%). The level of apoE at this juncture correlated inversely with the level of HDL cholesterol (rs = -0.90), and the levels of HTGL and apoA-I correlated with HDL2 cholesterol (rs = -0.89 and rs = 0.89, respectively). Thus, HTGL may play a role in both the early estrogen-related changes in HDL triglyceride and apoE and the late estrogen-related changes in HDL cholesterol, apoA-I, and apoA-II.

Aged↗