Hypercholesterolemia In Men Research Articles

MANAGEMENT OF HYPERCHOLESTEROLEMIA

Benefit from the treatment of hyperlipidemia has now been conclusively documented, and this article has focused on the clinical trial data supporting diet and drug therapy in adult patients with different lipoprotein disorders and discussed therapeutic approaches with a focus on reducing plasma concentrations of LDL cholesterol. National guidelines for the use of hypolipidemic drugs are strongly supported by the clinical trials and have appropriately set lower target concentrations of LDL cholesterol for patients with established atherosclerosis or diabetic patients as compared with patients with more than two cardiovascular risk factors or, the lowest risk group, patients without evidence of atherosclerosis and fewer than two known cardiovascular risk factors. The goals of therapy in patients with established atherosclerosis are to prevent further progression and potentially induce regression, whereas in high-risk patients (e.g., those with heterozygous familial hypercholesterolemia) without evidence of atherosclerosis, the aims of therapy are to reduce LDL cholesterol to a concentration at which subclinical atherosclerosis and xanthomas regress and the patient does not develop premature cardiovascular disease. Evidence-based medicine strongly supports clinical benefit from the treatment of hypercholesterolemia in men and women with and without known coronary artery disease, and the main goal should be ensure that patients who could benefit from lipid-lowering therapy are effectively treated and followed to ensure long-term compliance, efficacy, and safety.

Effects of inhibiting cholesterol absorption and synthesis on cholesterol and lipoprotein metabolism in hypercholesterolemic non-insulin-dependent diabetic men.

Effectiveness of a simultaneous inhibition of cholesterol absorption and synthesis, caused by sitostanol ester margarine and pravastatin, was studied to control mild hypercholesterolemia in men with non-insulin-dependent diabetes mellitus (NIDDM) (n = 8). Margarine, 24 g daily, was a basal dietary treatment. Four 7-week intervention periods included margarine, sitostanol (3 g/day) ester margarine, pravastatin (40 mg/day), and sitostanol ester margarine plus pravastatin in a random order. Pravastatin lowered serum total (-32%) and LDL cholesterol (-38%) and apolipoprotein B (-39%) because of enhanced removal (+20%) and decreased production (-26%) of LDL apolipoprotein B, and reduced synthesis (-9%) and turnover (-8%) of cholesterol, which resulted in reduced biliary cholesterol seretion (-18%). Even though serum triglycerides were lowered by 28%, VLDL, IDL, and light and dense LDL became triglyceride-enriched. Despite increasing cholesterol synthesis, sitostanol lowered LDL cholesterol (-14%) by inhibiting cholesterol absorption (-68%) and LDL apolipoprotein B production rate (-20%). Combination of pravastatin and sitostanol ester lowered serum total, VLDL, IDL, and LDL cholesterol and LDL apolipoprotein B by the highest rate, 35%, 50%, 35%, 44%, and 45% from the control margarine period, respectively, because of reduced apolipoprotein B transport rate (but unchanged removal), in both the total and dense LDL subfractions. HDL cholesterol and apolipoprotein A-I kinetics were unchanged. In spite of decreased absorption, cholesterol synthesis was not compensatorily increased. In conclusion, simultaneous inhibition of cholesterol absorption and synthesis lowers LDL cholesterol and apolipoprotein B by 44-45% solely through inhibition of LDL apolipoprotein B production rate in hypercholesterolemic NIDDM patients. A combination of statin to sitostanol ester margarine-resistant patients offers a safe and effective measure to normalize abnormally high cholesterol values, probably with a lowered statin dose.

Relative effects on serum lipids and apolipoproteins of a caprenin-rich diet compared with diets rich in palm oil/palm-kernel oil or butter

Two randomized, blind studies measured changes in serum cholesterol, other serum lipids, and apolipoprotein (apo) concentrations in hypercholesterolemic men consuming caprenin (Cap)-rich diets after either baseline diets enriched in palm oil/palm-kernel oil (PO/PKO) or butter. The triglyceride Cap contains 45% 22:0 and 50% 8:0-10:0. Compared with baseline values established at 3 wk on the PO/PKO diet, the 17 subjects on the Cap diet showed significant reductions after 6 wk in HDL cholesterol (HDL-C), HDL2-C, and HDL3-C and a significant increase in the ratio of total cholesterol, LDL-C, triglycerides, apo B-100, or apo A-I were seen. Compared with baseline values established at 3 wk on the butter diet, after 6 wk the seven subjects receiving the Cap diet showed no significant changes in the lipid and apolipoprotein indexes analyzed. These data show that one or more of 8:0, 10:0, and 22:0 fatty acids can contribute to hypercholesterolemia in men.

Lowering cholesterol for prevention of coronary heart disease?Problems and perspectives

The evidence for aggressive treatment of severe hypercholesterolemia in men in order to reduce the development on a primary basis of the incidence of coronary heart disease is strong; the main benefit is reduction of morbidity. Extrapolation to women or to the management of mild hypercholesterolemia in either gender is not supported by facts. The value of reducing hypercholesterolemia in the young and in the elderly has not been tested. None of the primary or secondary prevention trials have reduced all-cause mortality. There is an inverse relation between cholesterol levels and noncardiovascular disease. The possibility that reducing mild to moderate elevation of cholesterol might be harmful to some people remains unanswered.

Validity of cardiovascular disease risk factors assessed by telephone survey: The behavioral risk factor survey

The Behavioral Risk Factor Surveillance System (BRFSS) collects telephone interview data on behaviors for the leading causes of premature death and disability. Its validity has never been adequately studied. The authors replicated BRFSS methodology to validate self-reported cardiovascular disease (CVD) risk factors. Nine-hundred and eleven subjects from three upstate New York counties were interviewed between 1 89 and 5 90 . Interviewees were offered physical examinations and laboratory testing for CVD risk factors; 282 men and 344 women participated. The authors studied validity by comparing objectively measured to self-reported CVD risk factors. Sensitivities for self-reported hypertension, hypercholesterolemia, obesity, smoking, and diabetes were: 43, 44, 74, 82 and 75%, respectively. Only smoking sensitivity differed by gender: men, 77%; women, 86%. Specificity was >85% for all risk factors, except hypercholesterolemia in men (75%). Prevalence was underreported for hypertension, hypercholesterolemia, obesity, and smoking by 43, 50, 25 and 17%, respectively. Results suggest telephone survey research includes physiologic measurements for blood pressure, cholesterol, height, weight, and smoking to validate self-reported CVD risk factors. When this is impossible, results such as these can be used, in similar samples, to correct risk factor prevalence rates from telephone surveys for misclassifications.

Seasonal Variation in Plasma Cholesterol Distributions: Implications for Screening and Referral

In 3,377 men and 3,900 women who participated in a community-based plasma cholesterol screening program, we found a significant cyclic time-trend in cholesterol levels, with maximum peak in January. The 95% confidence interval (CI) of the peak to trough distance was 5.8-13.8 mg/dL (0.15-0.36 mmol/L) in men, corresponding to 2.6%-6.3% of the average cholesterol level. Corresponding figures for women were 2.0-9.3 mg/dL (0.05-0.24 mmol/L) or 1.0%-4.6%. Applying the cutoff level for high cholesterol risk proposed by the National Cholesterol Education Program (< or = 240 mg/dL [6.21 mmol/L]) to sex-specific bimonthly distributions, we found a statistically significant variation in prevalence, attributable to seasonal trends, in men (P < .01), but not in women. In men, the age-adjusted prevalence in winter (25.4%) was double that in the summer (13.5%). Seasonal variation is an important determinant of the prevalence of hypercholesterolemia in men and should be considered in patient follow-up and screening.

Hypercholesterolemia Impairs Endothelium-Dependent Relaxation of Rabbit Corpus Cavernosum Smooth Muscle

The majority of cases of impotence are associated with vascular risk factors such as diabetes, hypercholesterolemia, hypertension and smoking. These factors induce impairment of endothelium-dependent relaxation of blood vessels in man and in experimental animals. In this study the effects of hypercholesterolemia on the reactivity of rabbit corpus cavernosum smooth muscle strips to endothelium-dependent and endothelium-independent agents were investigated. New Zealand White rabbits (n = 14) were randomly divided into control and treatment groups. The control group (n = 7) received a regular diet while the treatment group (n = 7) was fed a diet of 0.5% cholesterol and 4% peanut oil for 10 weeks. Animals were then sacrificed and the corporal tissue studied in organ chambers for isometric tension measurement. Tissue was contracted with phenylephrine and concentration-dependent relaxation to acetylcholine, in the presence and absence of indomethacin, and to nitroprusside were examined. Blood level of cholesterol in the cholesterol-fed group was significantly higher compared to the control group. Contractions to phenylephrine were similar in both groups. Hypercholesterolemia, however, inhibited relaxation to acetylcholine but did not alter relaxation to nitroprusside, a cyclic guanosine monophosphate (cGMP)-dependent, direct smooth muscle dilator. Indomethacin enhanced the relaxations to acetylcholine in both control and cholesterol-fed groups but did not correct the difference in the relaxation to acetylcholine between both groups. It is concluded that hypercholesterolemia impairs endothelium-mediated relaxation of rabbit corpus cavernosum smooth muscle. The mechanism for the endothelial dysfunction does not appear to involve alteration in cyclooxygenase products of arachidonate or the cGMP-dependent relaxation of corporal smooth muscle. Impairment of endothelium-dependent relaxation of corporal smooth muscle may contribute to the pathophysiology of impotence associated with hypercholesterolemia in man.

Preventive effect of pravastatin sodium, a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on coronary atherosclerosis and xanthoma in WHHL rabbits

In this paper, we examined whether the development of atherosclerosis in the Watanabe heritable hyperlipidemic (WHHL) rabbit, an animal model of familial hypercholesterolemia in man, could be prevented by the reduction of serum cholesterol levels. Pravastatin sodium (the generic name of CS-514), a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, was used as a cholesterol-lowering drug. The drug was administered orally to 12 WHHL rabbits (2–3 months old) at a dose of 50 mg/kg per day for 24 weeks, and 13 animals were given water as control. In the treated group, serum cholesterol, phospholipid and triacylglycerol levels were significantly reduced by 28%, 32% and 16%, respectively, as compared with those of the control group. Although the prevention of development of the aortic atherosclerosis was not significant, the progression of coronary atherosclerosis was significantly prevented. The incidence of atherosclerosis in four main coronary arteries was reduced from 42% (control group) to 19% (treated group, P < 0.01), and the development of lesion of coronary arteries evaluated by area of lesion was reduced from 19.7% (control group) to 9.1% (treated group, P < 0.05). Histopathological findings supported the above observations. In addition, development of xanthoma in digital joints was also reduced from 90.4% (control group) to 58.3% (treated group, P < 0.005). These results suggest that the development of coronary atherosclerosis and xanthoma in WHHL rabbit was reduced by continuous reduction of serum cholesterol levels treated with pravastatin sodium.

WHHL rabbitの動脈硬化に対するCS-514の抑止効果

CS-514, an inhibitor of 3-hydroxy-3-methylglu-taryl coenzyme A reductase, was orally administered to WHHL rabbits (Watanabe heritable hyperlipidemic rabbit), an LDL receptor-deficient animal model for homozygous familial hypercholesterolemia in man. Twelve rabbits 2-3 month-old) were given the drug (50 mg/kg/day) for 24 weeks and 13 rabbits were given the water. In treated group, serum cholesterol level was reduced from 814 to 466mg/dl, which was 28% lower than that in control group (p<0.001). The cholesterol level in VLDL, IDL and LDL was also significantly reduced, while HDL cholesterol was not affected. Although there was no effect on aortic atherosclerosis, the incidence of coronary atherosclerosis in four main branches was 19% in treated group, which was about 23% lower than that in control group (p<0.05), and the ratio of lesion area (lesion area/lumen area) of coronary arteries was 9.2% in treated group, which was about 10% lower than that in control group (p<0.01). The incidence of xanthoma in digital joints was 58.3% in treated group, which was about 30% lower than that in control group (p<0.005).These results suggest that CS-514 has a preventive effect on the development of coronary atherosclerosis and xanthoma in consequence of the reduction of serum cholesterol level.

CS-514, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase: tissue-selective inhibition of sterol synthesis and hypolipidemic effect on various animal species

CS-514 is a tissue-selective inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, a key enzyme in cholesterol synthesis. For the microsomal enzyme from rat liver, the mode of inhibition is competitive with respect to hydroxymethylglutaryl-CoA, and the K i value is 2.3 · 10 -9 M. CS-514 also strongly inhibited the sterol synthesis from [su14C]acetate in cell-free enzyme systems from rat liver and in freshly isolated rat hepatocytes; the concentrations required for 50% inhibition were 0.8 ng/ml and 2.2 ng/ml, respectively. On the other hand, the inhibition by CS-514 was much less in the cells from nonhepatic tissues such as freshly isolated rat spleen cells, and cultured mouse L cells and human skin fibroblasts. In addition, the cellular uptake of 14C-labeled CS-514 by isolated rat spleen cells or mouse L cells was less than one-tenth of that by isolated hepatocytes. These differences between hepatic and nonhepatic cells were further confirmed by the fact that CS-514 orally administered to rats inhibited sterol synthesis selectively in liver and intestine, the major sites of cholesterogenesis. CS-514 markedly reduced serum cholesterol levels in dogs, monkeys and rabbits, including Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model for familial hypercholesterolemia in man, but did not reduce those in rats and mice. In the former case, preferential lowering of atherogenic lipoproteins was observed in all of the animals tested. The biliary neutral sterols significantly decreased, whereas the amount of biliary bile acids was not affected by administration of the drug to dogs.

Prevalence and prognostic significance of hypercholesterolemia in men with hypertension: Prospective data on the primary screenees of the multiple risk factor intervention trial

To assess the impact of serum cholesterol level on the risk of fatal coronary heart disease for men with high blood pressure, the six-year follow-up data from 361,662 men (aged 35 to 57 years) screened in 18 cities in the recruitment effort for the Multiple Risk Factor intervention Trial were evaluated. Of these men, 356,222 reported no history of hospitalization for myocardial infarction; 100,032 of these 356,222 had a baseline mean diastolic blood pressure equal to or greater than 90 mm Hg. For those men with high blood pressure, the overall age-adjusted six-year rate of coronary heart disease death was 79 percent higher than for those with diastolic blood pressure less than 90 mm Hg. Compared with men with diastolic blood pressure less than 90 mm Hg and serum cholesterol below 182 mg/dl, men with diastolic blood pressure equal to or greater than 90 mm Hg had the following relative risks, based on the serum cholesterol level: for those with a serum cholesterol level less than 182 mg/dl, risk was 1.64; for those with a level of 182 to 202 mg/dl, risk was 2.14; for those with a level of 203 to 220 mg/dl, risk was 3.14; for those with a level of 221 to 244 mg/dl, risk was 3.29; and for those with a level equal to or greater than 245 mg/dl, risk was 5.14. Thus, for men with high blood pressure, serum cholesterol related to coronary heart disease risk in a strong, graded way, over the entire distribution of serum cholesterol, from levels of 182 mg/dl and higher. This was the case for hypertensive male smokers and nonsmokers, with cigarette use associated with a further marked increase in risk—at least a doubling of the mortality rate—at any level of serum cholesterol. These data underscore the necessity for a strategy of comprehensive care for persons with high blood pressure, including approaches to both nutritional and hygienic counseling and drug treatment, aimed at controlling all of the established major risk factors influencing prognosis.

遺伝性高脂血症兎(WHHL)に認められた心筋梗塞と冠状動脈硬化

Myocardial infarcts were frequently seen in the homozygous WHHL rabbits that had severe atherosclerotic lesions at radices of main coronary arteries. Normal control rabbits with normolipidemia at the same age had neither atherosclerosis of main coronary arteries nor myocardial infarcts. However, some control and homozygous WHHL rabbits had intimal thickening of small arteries in the myocardium with tiny focal necroses of myocardium around those affected vessels.These findings suggest that intimal thickening of small arteries was related to neither a predisposition of WHHL rabbits nor hyperlipidemia, and that the myocardial infarcts peculiar to the WHHL rabbits were mainly caused by hypercholesterolemia like familial hypercholesterolemia in man. Thus, the WHHL rabbit may be a useful model of human myocardial infarction in general as well as a model of familial hypercholesterolemia.

Stimulation of rat liver 3-hydroxy-3-methylglutaryl-coenzyme a reductase activity by o, p′-DDD

To investigate the mechanism by which o, p′-DDD (2,2-bis[2-chlorophenyl-4-chloro-phenyl]-1,1-dichloroethane; Mitotane) produces hypercholesterolemia in man, we studied the effect of the drug on hepatic 3-hydroxy-3-methylglutaryl-CoA reductase activity in reverse light-cycled rats. o, p′-DDD markedly stimulated reductase activity in vivo and in vitro in a dose-dependent manner. This effect was not associated with demonstrable adrenocortical toxicity or changes in plasma corticosterone concentrations. Thus, o, p′-DDD may elevate circulating cholesterol levels in man by increasing endogenous cholesterol synthesis. In addition, the o, p′-DDD-treated rat may serve as a useful model for testing other agents for the ability to suppress endogenous cholesterol synthesis and lower circulating cholesterol levels.

Biochemical characterization of skin fibroblasts derived from WHHL-rabbit, a notable animal model for familial hypercholesterolemia.

WHHL-rabbit (Watanabe-heritable hyperlipidemic rabbit), a strain of animal with spontaneous hyperlipidemia, is characterized by the remarkable resemblance of the pathology to type II hyperlipoproteinemia in man. In order to understand the biological basis of the disorder in the WHHL-rabbit, the lipid metabolism of cultured skin fibroblasts from the mutant rabbits was studied. Skin fibroblasts from WHHL-rabbits grown in the presence of whole serum showed 12.3-times and 3.5-times higher activities of sterol and fatty acid syntheses from [14C]acetate, respectively, when compared with fibroblasts from normal rabbits. The cholesterol esterification activity, which was measured by the incorporation of [14C]oleate into cholesterol esters, however, was 9-times lower in the mutant cells than the normal cells. The higher sterol-synthesizing capacity of the WHHL-rabbit fibroblasts was attributed to the 5-times-enhanced activity of 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, compared with that in normal cells. In normal cells, the removal of lipoproteins from the culture medium caused a marked enhancement of 3-hydroxy-3-methylglutaryl-CoA reductase activity with a concomitant decrease of cholesterol esterification activity. The incubation of normal cells with low density lipoprotein (LDL) led to a reciprocal decrease in 3-hydroxy-3-methylglutaryl-CoA reductase activity and increase in the esterification activity. In contrast, the high level of 3-hydroxy-3-methylglutaryl-CoA reductase, which was associated with low cholesterol-esterification activity, in the WHHL-rabbit cells was essentially unchanged by removal or addition of LDL, indicating the absence of the functional LDL-mediated regulation system in the mutant cells. The studies using 125I-labeled LDL showed that normal cells possessed the specific receptor for LDL; LDL was bound, internalized by the receptor and degraded within cells. On the other hand, the finding that only 6 % of the receptor activity was present in the mutant cells when compared with normal cells, revealed that the mutant cells were the receptor-defective type. Thus, the primary defect in WHHL-rabbit fibroblasts is the lack of LDL receptor which regulates both 3-hydroxy-3-methylglutaryl-CoA reductase and cholesterol esterification activities. The mode of inheritance of LDL receptor-deficiency in WHHL-rabbit cells was found to be recessive, since all cell lines from the heterozygous rabbits possessed almost the same LDL receptor activities as normal cells. WHHL-rabbit, the first LDL receptor-deficient animal. can be a suitable model for familial hypercholesterolemia in man.

Radioimmunoassay for plasma corticosterone

To investigate the mechanism by which o,p′-DDD (2,2-bis[2-chlorophenyl-4-chloro-phenyl]-1,1-dichloroethane; Mitotane) produces hypercholesterolemia in man, we studied the effect of the drug on hepatic 3-hydroxy-3-methylglutaryl-CoA reductase activity in reverse light-cycled rats. o,p′-DDD markedly stimulated reductase activity in vivo and in vitro in a dose-dependent manner. This effect was not associated with demonstrable adrenocortical toxicity or changes in plasma corticosterone concentrations. Thus, o,p′-DDD may elevate circulating cholesterol levels in man by increasing endogenous cholesterol synthesis. In addition, the o,p′-DDD-treated rat may serve as a useful model for testing other agents for the ability to suppress endogenous cholesterol synthesis and lower circulating cholesterol levels.

In vitro regulation of cholesterol metabolism by low density lipoproteins in skin fibroblasts from hypo- and hyperresponding squirrel monkeys

When squirrel monkeys ( Saimiri sciureus) are fed diets containing cholesterol, some individuals (hyperresponders) become hypercholesterolemic, while others (hyporesponders) are able to maintain nearly normal plasma cholesterol concentrations. Skin fibroblasts were grown from three hyperresponder and three hyporesponder squirrel monkeys, previously characterized on the basis of their plasma cholesterol response to two cholesterol-containing diets and the phenotype of their parents. The rates of cholesterol synthesis and esterification were determined in the cultured fibroblasts incubated with low density lipoproteins isolated from normocholesterolemic squirrel monkeys or hypercholesterolemic rhesus monkeys. Both lipoprotein preparations influenced the metabolic parameters measured in a similar manner in cells from both hypo- and hyperresponder animals. Exposure of skin fibroblasts to low density lipoproteins resulted in a stimulation of cholesterol esterification and a suppression of cholesterol synthesis in cells from both hypo- and hyperresponder animals. When incubated with increasing concentrations of low density lipoprotein cholesterol, up to 50 μg/ml, fibroblasts from both hypo- and hyperresponding animals responded with a similar maximum percentage suppression of sterol synthesis. Thus, hyperresponsiveness to dietary cholesterol in squirrel monkeys, although a heritable characteristic, is not associated with an inability of low density lipoprotein to suppress cholesterol synthesis or stimulate cholesterol esterification as occurs in familial hypercholesterolemia in man.