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PubMed2004

Low-density lipoprotein (LDL) receptor/transferrin fusion protein: in vivo production and functional evaluation as a potential therapeutic tool for lowering plasma LDL cholesterol.

A soluble form of human low-density lipoprotein receptor (LDL-R) fused in frame with rabbit transferrin (LDL-Rs(hu)/Tf(rab)) is assessed in vivo as a therapeutic tool for lowering plasma LDL cholesterol. The cDNA encoding LDL-Rs(hu)/Tf(rab) is expressed in mice, using a hydrodynamics-based gene transfer procedure. The transgene is transcribed in the liver of transduced animals and the corresponding protein is secreted into the bloodstream. Circulating LDL-Rs(hu)/Tf(rab) binds LDL specifically, thus indicating that it is correctly processed through the cellular compartments in vivo. More importantly, the expression of LDL-Rs(hu)/Tf(rab) allows the removal of injected human (125)I-labeled LDL ((123)I-LDL) from the bloodstream of transduced CD1 mice, which show faster LDL plasma clearance, anticipating by approximately 90 min the same clearance value observed in control animals. A similar effect is observed in transduced LDL-R(-/-) mice, in which the clearance of injected human LDL depends solely on the presence of circulating LDL-Rs(hu) /Tf(rab). In these animals the extent of plasma LDL clearance is directly related to the concentration of LDL-Rs(hu)/Tf(rab) in the blood. Finally, LDL-Rs(hu)/Tf(rab) does not alter the pattern of LDL organ distribution: in transduced animals, as well as in control animals, liver and bladder are the predominantly labeled organs after (123)I-LDL injection. However, LDL-Rs(hu)/Tf(rab) has a quantitative effect on LDL tissue deposition: in treated animals LDL-Rs(hu)/Tf(rab) determines an increase in radioactivity in the liver at early times after (123)I-LDL injection and a progressive labeling of the bladder, starting 20 min after injection.

Animals↗

PubMed2001

Intensive surveillance and treatment of dyslipidemia in the postinfarct patient: evaluation of a nurse-oriented management approach.

BACKGROUND: Lowering plasma low density lipoprotein (LDL) cholesterol concentrations in patients with established coronary artery disease is essential if recurrent cardiac events and mortality are to be prevented; however, a large proportion of patients with myocardial infarction (MI) are not screened and treated appropriately in the months immediately following hospital discharge. OBJECTIVES AND METHODS: The CHOlesterol Post-INfarct (CHOPIN) project is a nurse-centred program initiated to close the large gap between nationally centred recognized guidelines for LDL lowering and current actual practice in the secondary prevention of coronary artery disease. RESULTS: The authors report findings in 151 consecutive patients (70 years of age or less) followed for an average of 5.5+/-3.3 months. Three months after an index MI and at a time when patients started being followed in CHOPIN, 46% of patients had LDL in excess of 2.5 mmol/L and 36% had LDL greater than 3.20 mmol/L. LDL-lowering interventions undertaken comprised either consultation with a dietitian (35%) or initiation or modification of lipid-lowering medication (58%). Mean LDL on discharge from CHOPIN was 2.58+/-0.49 mmol/L, and 97% of the patients had LDL cholesterol less than 3.20 mmol/L at discharge. CONCLUSIONS: This experience shows that a nurse-based case management strategy can achieve good control of dyslipidemia in a large proportion of post-MI patients. Because intervention to lower LDL has been prospectively shown to reduce the need for coronary artery bypass and angioplasty, these results suggest that projects configured in the manner of CHOPIN should reduce hospital costs associated with cardiovascular disease.

Aged↗

PubMed2026

Comparative efficacy of LDL-C-lowering therapies in first-time vs. recurrent myocardial infarction prevention: a meta-analysis of large-scale randomized controlled trials.

AIMS: Reducing elevated low-density lipoprotein cholesterol (LDL-C) is central to global efforts to prevent myocardial infarction (MI). While many studies have evaluated LDL-C-lowering therapies in first-time and recurrent MI prevention, direct comparisons of their relative efficacy are lacking. Therefore, we conducted a systematic review and meta-analysis to compare the efficacy of LDL-C-lowering therapies in first-time vs. recurrent MI prevention. METHODS AND RESULTS: We searched three databases until 30 November 2024, for randomized controlled trials (RCTs) with at least 1000 patient-years of follow-up. Efficacy was quantified as relative risk (RR) with 95% confidence intervals (CIs). Differences in benefit magnitude were assessed using Cochran's Q test. Data were pooled with a random-effects model, and heterogeneity was measured using the I2 statistic. Additionally, we applied the Cochrane Risk of Bias Tool to evaluate study quality and utilized the GRADE method to assess the certainty of the evidence. This study included 22 large-scale RCTs involving 180 304 participants. In first-time MI prevention, LDL-C-lowering therapies achieved a remarkable 38% reduction in MI risk [12 RCTs; 79 604 participants; RR, 0.62 (95% CI, 0.55-0.69); P < 0.001]. In recurrent MI prevention, these therapies were associated with a more modest but significant 16% risk reduction [11 RCTs; 100 700 participants; RR, 0.84 (95% CI, 0.80-0.88); P < 0.001]. Importantly, the benefit magnitude between the two groups was significantly different (Q = 22.63; P < 0.001), highlighting the greater relative benefit in first-time MI prevention. Furthermore, the robustness of our findings was consistently supported by leave-one-out analyses, the absence of publication bias, high-quality GRADE evidence, and subgroup and sensitivity analyses. CONCLUSION: Our findings suggest that LDL-C-lowering therapies may offer a greater benefit in preventing first-time MI compared with recurrent MI.

Humans↗

PubMed2006

The role of statins in clinical medicine--LDL--cholesterol lowering and beyond.

In the past years, statins have emerged as the most important class of lipid lowering agents. Through inhibition of HMG-CoA reductase, they restrict the rate-limiting step of cholesterol synthesis, which leads to upregulation of LDL receptors on the cell membrane and thus reduction of atherogenic LDLs. This effect translates into clinical benefit by reducing cardiovascular events both in primary and secondary prevention settings. As an approximate rule, statin therapy leads to a relative risk reduction of 25-30% in most of the large randomised controlled trials. Stroke risk is reduced to a similar degree. Despite initial concerns, the currently available statins have a favourable safety profile; however, potential interactions with other drugs must be considered. Recently, characteristics unrelated to LDL lowering have been intensively studied. These pleiotropic statin effects result from decreased levels of isoprenoid intermediates of cholesterol synthesis. They include--among others--anti-inflammatory, anti-proliferative, and immunomodulatory actions. Pleiotropic effects favourably influence pathomechanisms of plaque formation. Furthermore, they may prove beneficial in the prevention or treatment of diseases unrelated to atherosclerosis, eg rheumatoid arthritis, multiple sclerosis, or cancer.

Cardiovascular Diseases↗

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↗

PubMed1998

Cookies enriched with psyllium or oat bran lower plasma LDL cholesterol in normal and hypercholesterolemic men from Northern Mexico.

BACKGROUND: Psyllium and oat bran have been shown to lower plasma LDL cholesterol levels in different populations. Hypercholesterolemia is prevalent in the Northern part of Mexico and might be associated to dietary habits and sedentary lifestyle. METHODS: Sedentary normal (cholesterol<200 mg/dL) (n=36) and hypercholesterolemic (cholesterol>220 mg/dL) (n=30) men from the Northern part of Mexico aged 20 to 45 years of age participated in an 8-week study to determine the effects of dietary soluble fiber, either psyllium or oat bran, in lowering plasma LDL cholesterol in this population. Fiber was administered by feeding the subjects an amount of cookies (100 g) equivalent to 1.3 or 2.6 g/day of soluble fiber from psyllium or oat bran, respectively. Subjects were randomly allocated to three groups: a control group consuming cookies with wheat bran, a known source of fiber with no cholesterol lowering effects, psyllium, or oat bran. RESULTS: Food frequency questionnaires indicated that subjects from the three groups had similar intakes of foods classified as hypercholesterolemic (p>0.05). Plasma LDL cholesterol concentrations were reduced by an average of 22.6 and 26% in the psyllium and oat bran groups (p<0.001) while a non-significant reduction of 8.4% was observed in the hypercholesterolemic individuals from the control group. No effects on plasma HDL or triglycerides levels were observed among the three dietary treatments except for hypercholesterolemic individuals supplemented with oat bran where a 28% reduction in plasma triglycerides was observed after 8 weeks (p<0.01). CONCLUSION: These results indicate that psyllium and oat bran are efficacious in lowering plasma LDL cholesterol in both normal and hypercholesterolemic individuals from this population.

Adult↗

PubMed2000

The aggressive low density lipoprotein lowering controversy.

Recent clinical trials have provided unequivocal evidence of major cardiovascular benefits from low density lipoprotein (LDL) lowering with statins. However, the three critical unresolved questions about aggressive LDL lowering are the shape of the curve relating cardiac events to LDL, the best surrogate measurement for assessing therapeutic efficacy and the best target for LDL therapy. The relation between cardiac events and LDL is curvilinear, both epidemiologically and during therapy. The benefit of lipid lowering diminishes progressively and becomes difficult to detect at lower LDL levels without a very large sample size. Assessment of the benefits of lipid lowering is further confounded by differences in the level of pretreatment LDL and by the non-LDL lowering effects of statins. Both epidemiologic studies and large randomized clinical trials have produced conflicting results concerning the best LDL target. Failure to reduce the event rate in patients with pretreatment LDL <125 mg (Cholesterol And Recurrent Events [CARE] trial) alerts us to the risk of extrapolating epidemiologic data to clinical practice, yet subset analysis of some clinical trials suggests the greatest benefit appears in those patients with the lowest on-treatment LDL levels (Scandinavian Simvastatin Survival Study [4S]). This controversy should be resolved in the next few years by several important on-going trials. In the face of seemingly contradictory data from current clinical trials, we can only speculate that very aggressive LDL lowering to <80 mg/dl could be accompanied by a modest therapeutic benefit beyond the current recommendations of the National Cholesterol Education Program. If any benefit is observed, it will have to be balanced against a small potential for increased adverse events.

Anticholesteremic Agents↗

PubMed2005

Statins and LDL-cholesterol lowering: an overview.

Statins have become a cornerstone of treatment for dyslipidaemia primarily due to their marked lowering of low-density lipoprotein cholesterol (LDL-C). Studies show that statin treatment typically reduces relative risk of cardiovascular disease by 24-37%, regardless of age, sex, prior history of coronary heart disease (CHD), or other co-morbid conditions. There is also a growing body of evidence that statins can be effective in people whose LDL-C is not considered elevated under current guidelines. In both the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) and the Collaborative Atorvastatin Diabetes Study (CARDS), participants randomised to atorvastatin (10 mg/day) experienced at least a one-third reduction in major cardiovascular events, even though at baseline, their LDL-C was within the normal range. Other studies have also provided evidence that more intensive lipid-lowering regimens could provide additional clinical benefits. In the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial, the first active-control clinical trial of CHD progression, an intensive lipid-lowering regimen using atorvastatin (80 mg/day) decreased atherogenic lipoproteins and atheroma volume in patients with established CHD, compared with a moderate regimen using pravastatin (40 mg/day). Furthermore, relative to baseline, there was no measurable atheroma progression in the atorvastatin group. While statin therapy does offer significant clinical benefit, 60-70% of major cardiovascular events are still not prevented, which underscores the need for alternative interventions. Targeting inflammatory mediators of atherosclerosis such as C-reactive protein (CRP), as well as combination therapy to simultaneously raise high-density lipoprotein cholesterol (HDL-C) and lower LDL-C, are among the promising new strategies for primary and secondary prevention of atherosclerotic disease. This article will summarise data concerning use of statins in patients without markedly elevated LDL-C. The issue of the ideal LDL-C target will also be considered before addressing future treatment options for dyslipidaemia.

Cholesterol, LDL↗

PubMed2006

Plasma lipoprotein(a) levels and LDL-cholesterol lowering response to statin therapy in patients with heterozygous familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is characterised by elevated plasma LDL-cholesterol levels and premature ischemic heart disease. Statin therapy is mandatory in order to prevent atherosclerosis in patients with heterozygous FH. Both genetic and environmental factors affect the statin-induced LDL-cholesterol lowering effect in patients with heterozygous FH. Recently published data suggest that plasma lipoprotein(a) levels may affect the efficacy of statin therapy in patients with nephrotic syndrome. However, no data are available concerning the effect of lipoprotein(a) levels on the efficacy of statin therapy in patients with heterozygous FH. This report demonstrates negative correlation between plasma lipoprotein(a) levels and the LDL-cholesterol lowering effect of statin therapy in 49 patients with heterozygous FH.

Anticholesteremic Agents↗

PubMed1995

Currently available hypolipidaemic drugs and future therapeutic developments.

Dyslipidaemia may be treated with a number of safe and effective pharmacological agents that target specific lipid disorders through a variety of mechanisms. The bile-acid sequestrants--cholestyramine and colestipol--primarily decrease LDL cholesterol by binding bile acids, thereby decreasing intrahepatic cholesterol, and by increasing the activity of LDL receptors. Nicotinic acid lowers LDL cholesterol and triglyceride by decreasing VLDL synthesis and by decreasing free fatty acid mobilization from peripheral adipocytes. The HMG-CoA reductase inhibitors--fluvastatin, lovastatin, pravastatin and simvastatin--lower LDL cholesterol by partially inhibiting HMG-CoA reductase (the rate-limiting enzyme of cholesterol biosynthesis) and by increasing the activity of LDL receptors. The fibric-acid derivatives--bezafibrate, ciprofibrate, clofibrate, fenofibrate and gemfibrozil--primarily decrease triglyceride by increasing lipoprotein lipase activity and by decreasing the release of free fatty acids from peripheral adipose tissue. Probucol decreases LDL cholesterol by increasing non-receptor-mediated LDL clearance; as an anti-oxidant, probucol also decreases LDL oxidation; oxidized LDL which is thought to lead to atherogenesis. Although these agents have been proven safe in clinical trials, like any drug, they carry the risk for adverse effects. The bile-acid sequestrants may cause constipation, reflux oesophagitis, and dyspepsia, and may bind coadministered medications such as digitalis glycosides, beta blockers, warfarin, and exogenous thyroid hormone. Nicotinic acid use is commonly associated with flushing and pruritus and may also cause non-specific gastrointestinal complaints, hepatotoxicity (hepatic necrosis, hepatitis, or elevated liver enzymes), gout, myolysis, decreased glucose tolerance and increased fasting glucose levels, and ophthalmological complications including decreased visual acuity, toxic amblyopia, and cystic maculopathy. The HMG-CoA reductase inhibitors may produce liver enzyme elevations, creatine kinase elevations and rhabdomyolysis. The combination of a reductase inhibitor and a fibrate increases the risk for rhabdomyolysis. Possible adverse effects of the fibric-acid derivatives include abdominal discomfort, nausea, flatulence, increased lithogenicity of bile, liver enzyme elevations and creatine kinase elevations. Probucol may increase the QTc interval and may cause non-specific gastrointestinal complaints.

Anticholesteremic Agents↗

PubMed1992

Plasma cholesterol-lowering potential of edible-oil blends suitable for commercial use.

We tested semihardened blends of edible oils, suitable for commercial food manufacture, with a lower-than-conventional saturated fatty acid content, for their effects on plasma cholesterol. Twenty-six mildly hypercholesterolemic men took part in a double-blind crossover experiment in which two test blends were compared with two control dietary periods [which resembled the Australian fat intake: proportions of polyunsaturated, monounsaturated, and saturated fatty acids (PMS) 0.4:0.9:1]. PMS in the test diets was approximately 0.8:1.3:1 and resulted in significantly lower LDL-cholesterol concentrations (reductions of less than or equal to 7.7%). HDL cholesterol and plasma triglyceride were unchanged. The trans fatty acid (mainly elaidic) content of the blends was 16%, raising its contribution to energy by 4% but without apparent effect on LDL and HDL concentrations. Provided the overall ratio of linoleic acid to palmitic acid in commercial edible-oil blends exceeds that in the prevailing national diet, partial hydrogenation will not negate the LDL-lowering potential.

Adult↗

PubMed2004

Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines.

The Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program issued an evidence-based set of guidelines on cholesterol management in 2001. Since the publication of ATP III, 5 major clinical trials of statin therapy with clinical end points have been published. These trials addressed issues that were not examined in previous clinical trials of cholesterol-lowering therapy. The present document reviews the results of these recent trials and assesses their implications for cholesterol management. Therapeutic lifestyle changes (TLC) remain an essential modality in clinical management. The trials confirm the benefit of cholesterol-lowering therapy in high-risk patients and support the ATP III treatment goal of low-density lipoprotein cholesterol (LDL-C) <100 mg/dL. They support the inclusion of patients with diabetes in the high-risk category and confirm the benefits of LDL-lowering therapy in these patients. They further confirm that older persons benefit from therapeutic lowering of LDL-C. The major recommendations for modifications to footnote the ATP III treatment algorithm are the following. In high-risk persons, the recommended LDL-C goal is <100 mg/dL, but when risk is very high, an LDL-C goal of <70 mg/dL is a therapeutic option, ie, a reasonable clinical strategy, on the basis of available clinical trial evidence. This therapeutic option extends also to patients at very high risk who have a baseline LDL-C < 100 mg/dL. Moreover, when a high-risk patient has high triglycerides or low high-density lipoprotein cholesterol (HDL-C), consideration can be given to combining a fibrate or nicotinic acid with an LDL-lowering drug. For moderately high-risk persons (2+ risk factors and 10-year risk 10% to 20%), the recommended LDL-C goal is <130 mg/dL, but an LDL-C goal <100 mg/dL is a therapeutic option on the basis of recent trial evidence. The latter option extends also to moderately high-risk persons with a baseline LDL-C of 100 to 129 mg/dL. When LDL-lowering drug therapy is employed in high-risk or moderately high-risk persons, it is advised that intensity of therapy be sufficient to achieve at least a 30% to 40% reduction in LDL-C levels. Moreover, any person at high risk or moderately high risk who has lifestyle-related risk factors (eg, obesity, physical inactivity, elevated triglycerides, low HDL-C, or metabolic syndrome) is a candidate for TLC to modify these risk factors regardless of LDL-C level. Finally, for people in lower-risk categories, recent clinical trials do not modify the goals and cutpoints of therapy.

Aged↗

PubMed2004

Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.

The Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program issued an evidence-based set of guidelines on cholesterol management in 2001. Since the publication of ATP III, 5 major clinical trials of statin therapy with clinical end points have been published. These trials addressed issues that were not examined in previous clinical trials of cholesterol-lowering therapy. The present document reviews the results of these recent trials and assesses their implications for cholesterol management. Therapeutic lifestyle changes (TLC) remain an essential modality in clinical management. The trials confirm the benefit of cholesterol-lowering therapy in high-risk patients and support the ATP III treatment goal of low-density lipoprotein cholesterol (LDL-C) <100 mg/dL. They support the inclusion of patients with diabetes in the high-risk category and confirm the benefits of LDL-lowering therapy in these patients. They further confirm that older persons benefit from therapeutic lowering of LDL-C. The major recommendations for modifications to footnote the ATP III treatment algorithm are the following. In high-risk persons, the recommended LDL-C goal is <100 mg/dL, but when risk is very high, an LDL-C goal of <70 mg/dL is a therapeutic option, ie, a reasonable clinical strategy, on the basis of available clinical trial evidence. This therapeutic option extends also to patients at very high risk who have a baseline LDL-C <100 mg/dL. Moreover, when a high-risk patient has high triglycerides or low high-density lipoprotein cholesterol (HDL-C), consideration can be given to combining a fibrate or nicotinic acid with an LDL-lowering drug. For moderately high-risk persons (2+ risk factors and 10-year risk 10% to 20%), the recommended LDL-C goal is <130 mg/dL, but an LDL-C goal <100 mg/dL is a therapeutic option on the basis of recent trial evidence. The latter option extends also to moderately high-risk persons with a baseline LDL-C of 100 to 129 mg/dL. When LDL-lowering drug therapy is employed in high-risk or moderately high-risk persons, it is advised that intensity of therapy be sufficient to achieve at least a 30% to 40% reduction in LDL-C levels. Moreover, any person at high risk or moderately high risk who has lifestyle-related risk factors (eg, obesity, physical inactivity, elevated triglycerides, low HDL-C, or metabolic syndrome) is a candidate for TLC to modify these risk factors regardless of LDL-C level. Finally, for people in lower-risk categories, recent clinical trials do not modify the goals and cutpoints of therapy.

Aged↗

PubMed2004

Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.

The Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program issued an evidence-based set of guidelines on cholesterol management in 2001. Since the publication of ATP III, 5 major clinical trials of statin therapy with clinical end points have been published. These trials addressed issues that were not examined in previous clinical trials of cholesterol-lowering therapy. The present document reviews the results of these recent trials and assesses their implications for cholesterol management. Therapeutic lifestyle changes (TLC) remain an essential modality in clinical management. The trials confirm the benefit of cholesterol-lowering therapy in high-risk patients and support the ATP III treatment goal of low-density lipoprotein cholesterol (LDL-C) <100 mg/dL. They support the inclusion of patients with diabetes in the high-risk category and confirm the benefits of LDL-lowering therapy in these patients. They further confirm that older persons benefit from therapeutic lowering of LDL-C. The major recommendations for modifications to footnote the ATP III treatment algorithm are the following. In high-risk persons, the recommended LDL-C goal is <100 mg/dL, but when risk is very high, an LDL-C goal of <70 mg/dL is a therapeutic option, ie, a reasonable clinical strategy, on the basis of available clinical trial evidence. This therapeutic option extends also to patients at very high risk who have a baseline LDL-C <100 mg/dL. Moreover, when a high-risk patient has high triglycerides or low high-density lipoprotein cholesterol (HDL-C), consideration can be given to combining a fibrate or nicotinic acid with an LDL-lowering drug. For moderately high-risk persons (2+ risk factors and 10-year risk 10% to 20%), the recommended LDL-C goal is <130 mg/dL, but an LDL-C goal <100 mg/dL is a therapeutic option on the basis of recent trial evidence. The latter option extends also to moderately high-risk persons with a baseline LDL-C of 100 to 129 mg/dL. When LDL-lowering drug therapy is employed in high-risk or moderately high-risk persons, it is advised that intensity of therapy be sufficient to achieve at least a 30% to 40% reduction in LDL-C levels. Moreover, any person at high risk or moderately high risk who has lifestyle-related risk factors (eg, obesity, physical inactivity, elevated triglycerides, low HDL-C, or metabolic syndrome) is a candidate for TLC to modify these risk factors regardless of LDL-C level. Finally, for people in lower-risk categories, recent clinical trials do not modify the goals and cutpoints of therapy.

Aged↗

PubMed1995

Mechanisms of LDL-cholesterol lowering action of psyllium hydrophillic mucilloid in the hamster.

Psyllium hydrophillic mucilloid (psyllium) is a soluble fiber that significantly lowers plasma low-density lipoprotein (LDL)-cholesterol levels in humans and experimental animals. These studies were designed to determine whether this action is the result of a reduction in LDL-cholesterol production, an increase in receptor-mediated LDL clearance by the tissues, or a combination of these mechanisms. Adult male Golden Syrian hamsters were fed ad libitum for 30 days a cereal-based diet containing added cholesterol (0.1%) and hydrogenated coconut oil (10%), as well as either microcrystalline cellulose (Avicel) (7.5%) or psyllium (7.5%). In contrast to their Avicel-fed controls, the hamsters given psyllium had markedly lower plasma total (122.1 +/- 4.1 vs. 399.4 +/- 39.4 mg/dl) and LDL-cholesterol (46.0 +/- 2.2 vs. 143.5 +/- 12.0 mg/dl) levels. Psyllium feeding also prevented both the dramatic increase in hepatic total cholesterol levels (2.6 +/- 0.1 vs. 16.6 +/- 1.1 mg/g), and the suppression of hepatic cholesterol synthesis (165.1 +/- 27.1 vs. 26.1 +/- 1.2 nmol/h per g) that occurred in the animals given Avicel. Compared to their controls, the psyllium-fed animals also manifested a 44% lower rate of LDL-cholesterol production (167.6 +/- 8.1 vs. 300.2 +/- 16.0 micrograms/h per 100 g bw), and a 2.2-fold higher rate of hepatic LDL clearance (50.1 +/- 2.3 vs. 22.6 +/- 2.1 microliters/h per g). When expressed as a percentage of corresponding values obtained for hamsters fed the basal diet without any additions, the relative rate of LDL-cholesterol production was 175 +/- 10% and 99 +/- 4% for the Avicel- and psyllium-fed groups, respectively. It was similarly determined that the level of whole animal relative LDL receptor activity was marginally higher in the hamsters given psyllium (55.9 +/- 1.4%) than in those fed Avicel (47.5 +/- 3.3%). Thus, it was concluded that while the LDL-cholesterol lowering action of psyllium in the hamster is mediated through two mechanisms, the major effect is exerted at the level of LDL-cholesterol production.

Animals↗

PubMed2005

LDL-cholesterol lowering or HDL-cholesterol raising for cardiovascular prevention. A lesson from cholesterol turnover studies and others.

A number of reports have indicated that both lowering low density lipoprotein (LDL)-cholesterol and raising high density lipoprotein (HDL)-cholesterol can result in significant cardiovascular benefit, both in terms of reduction of events and also, to a variable extent, of atheromatous lesions. LDL and HDL have opposite roles in body cholesterol regulation and, in theory, both reduced deposition (LDL reduction) and increased removal (raised HDL) can improve vascular disease. A number of reports over the last 30 years have attempted to quantitate with cholesterol balance/turnover studies, the correlations between LDL and HDL levels and body cholesterol pool sizes. More recently, these studies have evaluated the effects of LDL or HDL changes on cholesterol elimination. Data have, at times, been fully consistent with theoretical expectations, whereas at others they have not. Evaluation of these, at times, historical data provides, however, an important clue to the understanding of current results with different medications for the management of lipoprotein disorders.

Anticholesteremic Agents↗

PubMed2005

Implications of emerging risk factors for therapeutic intervention.

Recently, the National Cholesterol Education Panel (NCEP) of the United States of America commented on the implications of new clinical trials for the Adult Treatment Panel III (ATP III) guidelines. In this commentary, new categories of "moderately high" and "very high" coronary risk were proposed with new "therapeutic options" for low-density lipoprotein (LDL) cholesterol of < or = 100 mg/dL and < or = 70 mg/dL respectively. In ATP III, these "moderately high" risk patients had been classified as moderate risk with an LDL treatment goal of < or = 130 mg/dL, while the "very high" risk patients had been classified as high risk with a treatment goal of < or = 100 mg/dL. Risk classification in the new NCEP publication is based essentially on the combination of the Framingham risk score plus counting of classical risk factors. In the present document, the International Task Force for Prevention of Coronary Heart Disease responds to this NCEP commentary and supports the suggestion of more intensive LDL cholesterol lowering in particular cases. However, the Task Force feels that a classification based on a combination of a risk score plus a count of emerging risk factors is a more logical way to identify such patients requiring lower LDL cholesterol levels than a scheme in which classical risk factors are taken into account twice, once in a count and once in a risk score.

Advisory Committees↗

PubMed2000

One-year effects of increasingly fat-restricted, carbohydrate-enriched diets on lipoprotein levels in free-living subjects.

Restriction of all dietary fat is a popular strategy for restricting saturated fat intake to lower LDL cholesterol. Some authorities advise the restriction of fat intake to the extreme of less than 10% of daily energy on the assumption that more fat restriction is better. The two studies described herein address questions relating to whether increasing fat restriction produces proportionally increasing benefit on cardiovascular risk factors in hyperlipidemic subjects. The first study is the Dietary Alternatives Study (DAS). The DAS was conducted in 531 male Boeing employees over a 2-year period. Subjects were defined as hypercholesterolemic (HC) or combined hyperlipidemic (CHL) based on age-specific 75th percentiles for plasma LDL-C and triglyceride levels. Hypothesis test analyses were performed at 1 year. HC subjects were randomized to diets taught to attain fat intakes of 30, 26, 22, and 18% (Diets levels 1-4, respectively). CHL subjects (slightly fewer in number) were randomized to Diets 1-3. After 1 year, subjects' total fat intakes were 27, 26, 25, and 22% of energy (en%), resulting in saturated fat intakes of 8, 7, 7, and 6%, respectively. In HC subjects the greatest LDL-C decrease was with Diet 2 (mean of 13.4%) and in CHL subjects with Diet 1 (7.0%). Surprisingly, plasma triglyceride concentrations rose in HC subjects 20% and 40% above baseline on Diets 3 and 4, respectively, with reciprocal reductions in HDL cholesterol of 2.5% and 3%, respectively. Furthermore, apo B reductions were attenuated below Diet 2 in HC subjects and Diet 1 in CHL subjects, and no further reductions were seen in plasma glucose and insulin concentrations, blood pressure, or body weight. Measurements of plasma total fatty acid composition showed a slight increase in plasma palmitate, whereas stearate decreased slightly, supporting the idea that de novo synthesis of palmitic acid was increased in the chronic high-carbohydrate feeding condition. The second study asked if the most effective diet in HC subjects, Diet 2, has an equivalent effect in women and men. To answer this question, men and women Boeing employees were taught the closely similar National Cholesterol Education Program (NCEP) Step II diet. After 6 and 12 months, equivalent reductions in LDL cholesterol were observed in women compared with men. HDL cholesterol levels in men were unchanged from baseline at 6 and 12 months, but were reduced 8% in HC women, with accompanying decreases of 18% in HDL2-cholesterol and 5% in apoprotein A-I (all P < 0.01). These data indicate that intakes of fat below about 25 en% and carbohydrate intake above approximately 60 en% yield no further LDL-C lowering in HC and CHL male subjects and can be counterproductive to triglyceride, HDL-C, and apo B levels. This lack of benefit appears to be explained by an enhanced endogenous synthesis of palmitic acid, which negates the benefit of further saturated fat restriction. The HDL-C decrease in HC women may have a similar cause and points to an underlying male-female difference. Alternative dietary approaches to limit saturated fat intake deserve intensive study.

Adult↗