David A. Reaveley

Relation of serum lipoprotein(a) concentration and apolipoprotein(a) phenotype to coronary heart disease in patients with familial hypercholesterolemia

Familial hypercholesterolemia carries a marked increase in the risk of coronary heart disease (CHD), but there is considerable variation between individuals in susceptibility to CHD. To investigate the possible role of lipoprotein(a) as a risk factor for CHD, we studied the association between serum lipoprotein(a) levels, genetic types of apolipoprotein(a) (which influence lipoprotein(a) levels), and CHD in 115 patients with heterozygous familial hypercholesterolemia. The median lipoprotein(a) level in the 54 patients with CHD was 57 mg per deciliter, which is significantly higher than the corresponding value of 18 mg per deciliter in the 61 patients without CHD. According to discriminant-function analysis, the lipoprotein(a) level was the best discriminator between the two groups (as compared with all other lipid and lipoprotein levels, age, sex, and smoking status). Phenotyping for apolipoprotein(a) was performed in 109 patients. The frequencies of the apolipoprotein(a) phenotypes and alleles differed significantly between the patients with and those without CHD. The allele LpS2, which is associated with high lipoprotein(a) levels, was found more frequently among the patients with CHD (0.33 vs. 0.12). In contrast, the LpS4 allele, which is associated with low lipoprotein(a) levels, was more frequent among those without CHD (0.27 vs. 0.15). We conclude that an elevated level of lipoprotein(a) is a strong risk factor for CHD in patients with familial hypercholesterolemia, and the increase in risk is independent of age, sex, smoking status, and serum levels of total cholesterol, triglyceride, or high-density lipoprotein cholesterol. The higher level of lipoprotein(a) observed in the patients with CHD is the result of genetic influence.

Effects of Xanthine Oxidase Inhibition With Allopurinol on Endothelial Function and Peripheral Blood Flow in Hyperuricemic Patients With Chronic Heart Failure: Results From 2 Placebo-Controlled Studies

Background—In patients with chronic heart failure (CHF), hyperuricemia is a common finding and is associated with reduced vasodilator capacity and impaired peripheral blood flow. It has been suggested that the causal link of this association is increased xanthine oxidase (XO)–derived oxygen free radical production and endothelial dysfunction. We therefore studied the effects of XO inhibition with allopurinol on endothelial function and peripheral blood flow in CHF patients after intra-arterial infusion and after oral administration in 2 independent placebo-controlled studies. Methods and Results—In 10 CHF patients with normal serum uric acid (UA) levels (315±42 &mgr;mol/L) and 9 patients with elevated UA (535±54 &mgr;mol/L), endothelium-dependent (acetylcholine infusion) and endothelium-independent (nitroglycerin infusion) vasodilation of the radial artery was determined. Coinfusion of allopurinol (600 &mgr;g/min) improved endothelium-dependent but not endothelium-independent vasodilation in hyperuricemic patients (P <0.05). In a double-blind, crossover design, hyperuricemic CHF patients were randomly allocated to allopurinol 300 mg/d or placebo for 1 week. In 14 patients (UA 558±21 &mgr;mol/L, range 455 to 743 &mgr;mol/L), treatment reduced UA by >120 &mgr;mol/L in all patients (mean reduction 217±15 &mgr;mol/L, P <0.0001). Compared with placebo, allopurinol improved peak blood flow (venous occlusion plethysmography) in arms (+24%, P =0.027) and legs (+23%, P =0.029). Flow-dependent flow improved by 58% in arms (P =0.011). Allantoin, a marker of oxygen free radical generation, decreased by 20% after allopurinol treatment (P <0.001). There was a direct relation between change of UA and improvement of flow-dependent flow after allopurinol treatment (r =0.63, P <0.05). Conclusions—In hyperuricemic CHF patients, XO inhibition with allopurinol improves peripheral vasodilator capacity and blood flow both locally and systemically.

The effect of nicotinic acid and acipimox on lipoprotein(a) concentration and turnover.

This study examines the effect of nicotinic acid (1 g t.d.s.) on serum Lp(a) concentration in a group of patients with type II hyperlipidaemia selected on the basis of a plasma Lp(a) concentration greater than 30 mg/dl. Reductions in total cholesterol, triglyceride, LDL-cholesterol and Lp(a) were 16.3%, 25.5%, 23.7% and 36.4%, respectively, with an increase in HDL cholesterol of 37.3%. The reduction in Lp(a) concentration did not correlate with any other lipoprotein changes. In order to establish the mechanism of the fall in Lp(a) concentration, in vivo turnover of autologous Lp(a) was studied in three subjects before and whilst taking nicotinic acid. The fractional catabolic rate in Lp(a) was unaltered in the subjects on therapy, indicating that nicotinic acid did not increase catabolism of Lp(a) but decreased the synthetic rate. Since nicotinic acid was poorly tolerated we examined the effect of acipimox, an analogue of nicotinic acid on lipoproteins using a placebo controlled double-blind crossover design in a group of hyperlipidaemic patients again selected with plasma Lp(a) concentration greater than 30 mg/dl. Acipimox was better tolerated than nicotinic acid but the percentage changes in lipoprotein concentrations were smaller.

Assay of serum allantoin in humans by gas chromatography-mass spectrometry.

BACKGROUND The small amount of allantoin present in human serum results from free radical (FR) action on urate and may provide a stable marker of free radical activity in vivo. We describe a gas chromatography-mass spectrometry (GC-MS) assay for serum allantoin and report a reference range in healthy individuals. METHODS Fasting blood samples were obtained from 134 healthy middle-aged volunteers (56 men, mean age 55, range 45-72; 78 women, mean age 55, range 50-72) Allantoin was assayed using 15N(2) allantoin as an internal standard. After isolation from aqueous standards or serum by extraction onto an anion exchange column (AG-MP1), allantoin was derivatised with N-methyl-N-(tert-butyldimethylsilyl) trifluoroacetamide (MTBSTFA). Derivatives were injected onto an HP-1 column and analysed using a Mass Selective Detector with Single Ion Monitoring at 398 and 400 m/z. RESULTS The distribution of serum allantoin concentrations in men and women was non-Gaussian and log transformation was used for the analysis of data. Women (10.8 +/- 1.7 micromol/l (mean +/- S.D.)) had significantly lower serum allantoin levels than men (13.4 +/- 1.6 micromol/l, p=0.015). Reference ranges (95% CI) for middle-aged healthy subjects were 7.4-46.8 micromol/l (men) and 3.7-31.2 micromol/l (women). CONCLUSION Gas chromatography-mass spectrometry provides a reliable and accurate method for the determination of serum allantoin.

The effect of change of renal replacement therapy on plasma lipoprotein (a) concentration

Lipoprotein (a) [Lp(a)] is an independent atherogenic risk factor. Lp(a) levels are elevated in patients on renal replacement therapy (RRT). This study looked at the effect of change of RRT on serum lipid and Lp(a) levels. Three groups were identified: (1) patients on dialysis who were transplanted; (2) those who had lost their transplants through immunorejection; (3) those who changed from continuous ambulatory peritoneal dialysis (CAPD) to hemodialysis (HD). All Lp(a) measurements were taken at least 3 months after the change of therapy. Our results were as follows: Group A (n = 21): 8 CAPD and 13 HD patients were transplanted. Median Lp(a) levels fell posttransplantation in the CAPD group (15.6 mg/dL vs 11.4 mg/dL, p = 0.04). The HD group showed a rise in cholesterol, low-density (LDL) and high-density lipoprotein (HDL) levels, with no change in Lp(a) levels. Group B (n = 11): 7 patients started CAPD and 4 HD. Overall, there was a marked increase in Lp(a) levels: median 38.2 mg/dL vs 55.9 mg/dL (p = 0.04), reflecting an increase in those starting CAPD (27.8 mg/dL vs 60.0 mg/dL, p = 0.01), with little change in the HD group (40.45 mg/dL vs 40.05 mg/dL). However, there was a decrease in cholesterol (7.4 mmol/L vs 5.1 mmol/L, p = 0.002) and LDL (5.5 mmol/L vs 3.3 mmol/L, p = 0.004). Group C (n = 16): 16 patients changed from CAPD to HD. Lp(a) levels were higher while on CAPD, as compared to when on HD (58.9 mg/dL vs 49 mg/dL, p = 0.03). Cholesterol (6.62 mmol/L vs 5.26 mmol/L, p = 0.006) and LDL (4.48 mmol/L vs 3.40 mmol/L, p = 0.004) were also higher when on CAPD. In conclusion, serum Lp(a) levels are clearly affected by the mode of the RRT, being highest in CAPD, and decline after transplantation or conversion to HD. Atherogenic risk is thus likely to differ between the modes of RRT and may be greatest for those on CAPD.