Lipoprotein (a) does not participate in the early acute phase response to training or extreme physical activity and is unlikely to enhance any associated immediate cardiovascular risk.

AIMS: To investigate the proposal that lipoprotein (a) (Lp(a)) contributes to the acute phase response and thus possibly to the acute cardiac risks associated with major physical effort. METHODS/RESULTS: Fit, healthy, British army recruits were reviewed at the beginning and the end of a 10 week programme of basic training concluding with an intense 48 hour military exercise. Final recruit assessment was staggered over the last week of training, giving rise to six recruit groups, with determination of Lp(a), C reactive protein (CRP), fibrinogen, albumin, and total creatine kinase values from 12 hours to five days after the final exercise. A clear acute phase response was seen following the final exercise, marked by a significant increase in circulating concentrations of fibrinogen and a reduction of albumin, and a trend with non-significant increases in CRP. CONCLUSION: Lp(a) did not behave as an early marker of the acute response. Previous reports may have been confounded by concurrent disease in older subjects and by late sampling. Lp(a) determination for cardiovascular risk profiling is not confounded by associated physical effort. It is also unlikely that the acute risks of major physical effort are enhanced by any process involving Lp(a).

Very low-density lipoprotein apolipoprotein B-100 turnover in glycogen storage disease type Ia (von Gierke disease).

Mixed hyperlipidaemia is a common finding in glycogen storage disease type Ia (GSD Ia). Although cross-sectional studies have demonstrated increases in intermediate-density lipoproteins (IDLs) and reductions in lipoprotein lipase activity, no studies have investigated the dynamics of apolipoprotein B-100 (apo B) metabolism in GSD Ia. This study investigated apoB turnover in GSD Ia using an exogenous labelling method in one sib from a kinship with established GSD Ia. The study demonstrated normal hepatic secretion of very low-density lipoprotein (VLDL), but hypocatabolism of VLDL, probably due to lack of lipoprotein lipase activity. The production rate of IDL was slightly increased, but the turnover rate of low-density lipoprotein was normal. The findings suggest that, as well as a corn starch diet and dietary fat restriction, treatment of severe mixed hyperlipidaemia in GSD Ia and its attendant risk of pancreatitis should possibly involve fibrates that activate lipoprotein lipase and may enhance the clearance of IDL, rather than omega-3 fatty acids, which principally suppress hepatic secretion of VLDL.

Lipoprotein (a) and stroke.

Strokes are one of the most common causes of mortality and long term severe disability. There is evidence that lipoprotein (a) (Lp(a)) is a predictor of many forms of vascular disease, including premature coronary artery disease. Several studies have also evaluated the association between Lp(a) and ischaemic (thrombotic) stroke. Several cross sectional (and a few prospective) studies provide contradictory findings regarding Lp(a) as a predictor of ischaemic stroke. Several factors might contribute to the existing confusion--for example, small sample sizes, different ethnic groups, the influence of oestrogens in women participating in the studies, plasma storage before Lp(a) determination, statistical errors, and selection bias. This review focuses on the Lp(a) related mechanisms that might contribute to the pathogenesis of ischaemic stroke. The association between Lp(a) and other cardiovascular risk factors is discussed. Therapeutic interventions that can lower the circulating concentrations of Lp(a) and thus possibly reduce the risk of stroke are also considered.

A pilot study of garlic consumption shows no significant effect on markers of oxidation or sub-fraction composition of low-density lipoprotein including lipoprotein(a) after allowance for non-compliance and the placebo effect.

Our aim was to define any effects of confirmed garlic supplementation on the resistance of low density lipoprotein (LDL) to oxidation, on LDL sub-fraction composition including levels of lipoprotein(a), and on levels of circulating antibody to oxidised LDL, variables of interest in relation to cardiovascular risk. Additional tests were performed on samples collected from a double blind, randomised 6-month parallel trial in which 900 mg Kwai garlic or placebo was taken by moderately hypercholesterolaemic volunteers. Final data was analysed for 20 garlic and 11 placebo subjects with compliance of at least 75% as determined by repeat tablet counting. EDTA plasma stabilised by sucrose was stored at -70 degrees C for up to 12 months. Lipids and apolipoproteins were determined by standard methods, lipoprotein(a) by an ELISA method and LDL fraction composition by non-gradient gel electrophoresis. Oxidative resistance of LDL purified after isolation by density gradient centrifugation was assessed from oxidative resistance to copper ions determined spectrophotometrically, antibodies to oxidised LDL were determined by a microtitre plate assay and vitamin E content of plasma by HPLC. Overall lipid/lipoprotein profiles including lipoprotein(a) were unchanged as with the parent group. LDL composition showed a trend to less dense material in both placebo and garlic groups, all differences not significant. Lag time as a marker of oxidative resistance also increased in both groups, without change in vitamin E content, all differences not significant and consistent with a placebo effect. Levels of antibodies to oxidised LDL were unchanged. The results of this study do not support the hypothesis that dietary garlic supplementation decreases the susceptibility of isolated LDL to oxidation and that patterns of LDL tractions in plasma might be involved. Levels of lipoprotein(a) in plasma were also not changed. Other mechanisms of cardiovascular benefit are however not excluded.

A first British case of fish-eye disease presenting at age 75 years: a double heterozygote for defined and new mutations affecting LCAT structure and expression.

Fish-eye disease is a familial syndrome with corneal opacification, major high density lipoprotein (HDL) deficiency in plasma, significant cholesterol esterification in plasma on non-HDL lipoproteins, generally without premature coronary disease. This first British male case from unrelated British parents had infarcts when aged 49 and 73 years but was asymptomatic at age 81 years, with plasma cholesterol 4.3-7.1 mmol/litre, triglycerides 1.8-2.2 mmol/litre, HDL cholesterol < 0.1 mmol/litre, apolipoprotein A-I < 0.16 g/litre, lipoprotein(a) 0.61 g/litre. Cholesterol esterification was impaired using HDL-3 and A-I proteoliposomes but not using VLDL/IDL/LDL. The findings are those of LCAT deficiency with the classic fish-eye disease defect. Most of the 22 reported cases were homozygous or heterozygous for a Thr-Ile mutation at codon 123 of the lecithin:cholesterol acyltransferase (LCAT) gene. This patient was a double heterozygote for this mutation and a second new incompletely defined mutation affecting LCAT expression as defined by reduced mass and activity in plasma.

Effect of hypertension and its treatment on lipid, lipoprotein(a), fibrinogen, and bilirubin levels in patients referred for dyslipidemia.

We measured the serum lipid profile, together with plasma fibrinogen and serum lipoprotein(a) (Lp[a]), glucose, bilirubin, and albumin levels in 491 patients (310 men) who were referred for the management of primary dyslipidemia. All these variables have been shown to predict vascular events. The patients were not taking lipid-lowering drugs; hypertension was present in 156 (31.7%) of them. Of the hypertensive patients, 52 (33%) were not receiving any treatment to control their blood pressure. This omission was not due to a lower prevalence of established vascular disease. The treated hypertensives were divided into three groups according to their treatment: 62 were taking lipid-hostile antihypertensives (beta-blockers, thiazides), 37 were taking lipid-neutral antihypertensives (angiotensin converting enzyme inhibitors, Ca-channel blockers, angiotensin II receptor blockers, indapamide sustained release), and five were taking lipid-friendly antihypertensives (doxazosin). Lipid-hostile antihypertensive drugs were associated with a significantly higher fibrinogen concentration when compared with untreated hypertensives or those taking lipid-neutral/lipid-friendly drugs (median values: 383, 353, and 336 mg/dL, respectively; P < .01). Lipid-neutral/lipid-friendly antihypertensive drugs were associated with lower Lp(a) levels when compared with untreated hypertensives (median values: 22 and 45 mg/dL, respectively; P < .05). The serum bilirubin level was significantly lower in the untreated hypertensives when compared with normotensives or the treated hypertensives. There were no significant differences in lipids, glucose, or albumin among the groups of hypertensives or normotensives. The influence of antihypertensive drugs on additional cardiovascular risk factors should be considered when selecting medication to reduce blood pressure.

Statin + fibrate combination therapy fluvastatin with bezafibrate or ciprofibrate in high risk patients with vascular disease.

We evaluated the use of combination therapy (ciprofibrate 100 mg or bezafibrate 400 mg plus fluvastatin 40 mg) in 23 patients (n = 13 in the ciprofibrate group) with established cardiovascular disease. Both treatments achieved a significant (P< or =0.01) decrease in the total cholesterol (TC) (32 and 21%), triglycerides (TG) (53 and 46%) and low-density lipoprotein (LDL) (36 and 26%) levels and the TC/high-density lipoprotein (HDL) (42 and 31%) and LDL/HDL (46 and 35%) ratios. HDL levels were increased (19% for both treatment groups), but this rise only achieved significance (P=0.01) in the ciprofibrate group. Although the two patient groups were not strictly matched, the reduction in serum TC and LDL levels was greater with ciprofibrate (32 and 36%, respectively; P< or =0.001) than with bezafibrate (21 and 26%, respectively; P< or =0.01). There was a significant reduction in plasma fibrinogen levels (36.4 and 13.5% in the ciprofibrate and bezafibrate group, respectively). None of the patients reported myalgia or had abnormal creatine kinase activity or liver function tests. Combination therapy is worth considering in high-risk patients because of the advantages associated with this option. Combination therapy is competitively priced when compared with high doses of statins. An end-point-based trial is needed.

Platelets and lipoprotein (a): a brief overview of their role in the pathogenesis of atherothrombosis.

The relationship between lipids and the haemostatic mechanisms participating in the evolution of the atherosclerotic plaque have been undergoing extensive investigation for over a century. Circulating lipoproteins can enhance platelet activity. Among these lipid fractions, lipoprotein (a) (Lp(a)), a predictor of atherosclerotic disease, has been proposed as a link between lipids and haemostasis. In this review, we briefly consider lipid-platelet, and particularly Lp(a)-platelet, interactions which may be relevant to the pathogenesis of atherosclerotic disease and its complications.

Changing patterns of referral to UK lipid clinics - a ten-year perspective.

OBJECTIVE: To review changing attitudes of British physicians to the significance of lipids and associated cardiovascular risks over the last decade. METHODS: Analysis of annual trends in referrals to specialist UK lipid clinics as recorded in the UK lipid clinics programme computerised database, with data on source, clinical and metabolic status of up to 12932 patients referred from 1986-1995. - RESULTS: Over the decade the proportion of referrals from hospital teams rather than GP s, and with clinical vascular disease has increased. The predominantly male patients have been referred at lower initial cholesterol levels but increasing BMI, with less emphasis on rare disorders. Recorded reductions in total cholesterol on treatment have also fallen from some 20% to 13%. Alcohol and smoking habits have been in accord with national trends. CONCLUSIONS: These changes suggest that awarerness of the significance of cholesterol and particularly of the opportunities available in secondary prevention, and awareness that lipid problems are seen to apply to a much wider patient base than the rare genetic disorders have all increased. However the increasing proportion of cases found at first referral to have lipaemia secondary to other undiagnosed metabolic disturbance suggests that appreciation of such wider influences on lipids remains incomplete.

Usual care dietary practice, achievement and implications for medication in the management of hypercholesterolaemia. Data from the U.K. Lipid Clinics Programme.

AIMS: To evaluate long-term responses to cholesterol-lowering diets in usual care and their associations with responses to lipid medication. METHODS: Analysis of paired data from the U.K. Lipid Clinics Programme computerized database for lipid responses, and associations of weight loss with later response to medication, plus analysis of a questionnaire on clinic dietary practice. RESULTS: Cholesterol, predominantly as low density lipoprotein was reduced in 60% of 2508 patients entered, and maintained long-term. Moderate 5-7% average responses incorporated reductions of at least 0.6 mmol x (-1) in 40% of patients, consistent with a 25% fall in the risk of cardiac events if maintained for 2 years. Responses to medication were greater for up to 2194 patients who previously lost weight on diet, an effect not apparent for 291 patients on statins alone. Physicians worked with dieticians in most clinics, and with individually tailored diets but with incomplete appreciation of the differences between available dietary protocols. CONCLUSIONS: Usual care dietary advice can be effective in lipid management, weight loss is important and associates with greater responses to lipid medication although statin monotherapy may not be affected. However, average responses are modest and physicians are not well informed of the dietary principles involved.

Prothrombotic and lipoprotein variables in patients attending a cardiovascular risk management clinic: response to ciprofibrate or lifestyle advice.

BACKGROUND: Lipid lowering drugs improve survival. However, intervention studies have focused on reducing serum total cholesterol and low density lipoprotein (LDL) concentrations and have not considered that levels of high density lipoprotein (HDL), triglycerides (TG), lipoprotein (a) and fibrinogen also predict risk and outcome. METHODS: A retrospective survey of patients with primary dyslipidaemia attending a cardiovascular risk management clinic (set in a university hospital) was initiated to assess the effect of ciprofibrate, a drug with the potential to modify all these variables. Patients who received ciprofibrate (n = 72) were compared with 64 patients who only received lifestyle advice. Both groups had a similar age and gender distribution. The ciprofibrate group had a higher cardiovascular risk load but both groups shared several other characteristics. Fasting serum total cholesterol, LDL, HDL, TG, lipoprotein (a), glucose and plasma fibrinogen concentrations were measured at baseline and after 2-4 months. RESULTS: Ciprofibrate significantly improved total cholesterol, LDL, HDL, TG, lipoprotein (a) and fibrinogen. In contrast, lifestyle advice only significantly (but less markedly) reduced serum total cholesterol and TG concentrations. CONCLUSIONS: In a clinical setting, ciprofibrate has a broad spectrum of action on several predictors of vascular events. Although our study is not of a double blind randomized design it reflects the conditions in clinical practice. Nevertheless, this type of survey has its limitations.

Corneal arcus, case finding and definition of individual clinical risk in heterozygous familial hypercholesterolaemia.

Premature corneal arcus may identify individuals with hyperlipidaemia and increased cardiovascular risk. We have attempted to quantitate relationships through determination of graded prevalence of corneal arcus with age for 81 males and 73 females suffering from heterozygous familial hypercholesterolaemia (HFH) at presentation, and for 280 male and 353 female unselected patients (age range 16-76 years) attending a country general practice. Some degree of arcus affected 50% of HFH patients by age 31-35 years, and 50% of practice patients by age 41-45 years. Complete full ring arcus affected 50% of the familial hypercholesterolaemia (FH) group by age 50 years, with only 5% similarly affected in the non-FH group. Arcus grade with age was advanced by some 5 years in males versus females. Premature arcus potentially alerting to HFH can be broadly defined for males and females combined, as heavy full ring by age 50 years, or any degree of arcus by age 30-35 years. Arcus grade was not related to the presence of coronary disease. Accelerated development of corneal arcus with age is an indicator of HFH, but premature arcus is not an additional marker of premature coronary disease for individual cases of HFH.

Lipids and stroke: neglect of a useful preventive measure?

The epidemiological studies linking lipid variables and stroke are reviewed. These studies indicate that serum total cholesterol (TC) levels are associated positively with thrombotic and negatively with haemorrhagic strokes. Relationships for other lipid fractions are not as clearly defined. The results of trials with lipid lowering drugs suggest that only statins effectively reduce the incidence of stroke. Differences between trial results may be due to variation in the extent of reduction of TC levels. Possible underlying mechanisms for benefit and the apparent superiority of statins are also discussed. The reduction in the risk of thrombotic stroke with statins is most evident through meta-analyses (p < 0.001) and less impressive in individual trials (p < 0.03). This difference is largely attributable to the small number of events in trials primarily aimed at evaluating ischaemic heart disease (IHD) reduction. This also means that benefit may be limited to those with established IHD. IHD and thrombotic stroke share common risk factors and patients with one condition are at high risk of developing the other. Therefore, one additional reason for using statins in these patients is that these drugs can effectively prevent IHD-related events including deaths.