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Biomedical subjects

G F Watts

Publications and source records attributed to G F Watts.

At least 145 records · Page 8Linked to original sources
PubMed1993

Metabolism of apoB-100-containing lipoproteins in familial hyperchylomicronemia.

The metabolism of apolipoprotein B-100 was studied in three patients with familial hyperchylomicronemia (type I hyperlipoproteinemia) using a very low density lipoprotein (VLDL) dual-tracer technique. Radioiodinated VLDL1 (Sf 60-400) and VLDL2 (Sf 20-60) were injected and their catabolism and rate of the transfer of apoB into VLDL2, intermediate density lipoprotein (IDL) (Sf 12-20), and low density lipoprotein (LDL) (Sf 0-12) were compared in patients and in five normolipidemic controls. The rates of delipidation of large triglyceride-rich VLDL1 to VLDL2 (0.26-0.54 pools/day vs. 2.5-5.2 pools/day in controls) and VLDL1 direct catabolism (0.33-0.92 pools/day vs. 4.2-14.7 pools/day in controls) were found to be significantly reduced in type I patients resulting in a tenfold increase of VLDL1 pool size. ApoB synthesis into this density interval was, however, normal as was that into smaller VLDL2. the circulating apoB mass in VLDL2 was not increased. In fact, apart from a modest decrease in the rate of VLDL2 delipidation to IDL and LDL, the behavior of apoB in this density interval was similar in hyperchylomicronemic and normal subjects. Likewise, the transfer of apoB through the IDL and LDL density ranges was not significantly different from normal. Pool sizes of these fractions, however, were reduced, the latter significantly (354-491 mg vs. 1,160-2,505 mg in controls) due to increased direct catabolism in hyperchylomicronemic patients. The results of this study indicate that lipoprotein lipase deficiency primarily affects VLDL1 metabolism, both its delipidation and direct removal from plasma. Lipolysis further down the delipidation cascade is not dependent on this enzyme. Hypercatabolism rather than a failure of synthesis of IDL and LDL was responsible for the decreased pools for both lipoproteins.

Adult↗
PubMed1992

Impaired endothelium-dependent vasodilation of forearm resistance vessels in hypercholesterolaemia.

Endothelium-dependent vasodilation in response to acetylcholine is impaired in the coronary microvasculature of hypercholesterolaemic subjects. Outside the coronary circulation, however, it has been suggested that hypercholesterolaemia results in a functional abnormality of vascular smooth muscle rather than in endothelial dysfunction. We examined vasodilator responses to acetylcholine, methacholine, and the endothelium-independent vasodilator sodium nitroprusside in the forearm resistance vessels of 12 men with primary hypercholesterolaemia and 12 normocholesterolaemic male controls. Endothelium-dependent vasodilation in response to acetylcholine was impaired in hypercholesterolaemic patients compared with controls: at the highest dose of drug (15 micrograms per min) mean blood flow in the forearms of the hypercholesterolaemic group was only 52% (95% Cl 31-88%) of that in the control group. Responses to sodium nitroprusside and to methacholine in the two study groups were not significantly different. These results indicate that endothelial dysfunction in hypercholesterolaemic subjects is generalised and extends to vascular beds outside the coronary circulation. Selective impairment to acetylcholine suggests that, at a molecular level, the defect is limited to a specific pathway.

Acetylcholine↗
PubMed1992

Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St Thomas' Atherosclerosis Regression Study (STARS)

To assess the effect of dietary reduction of plasma cholesterol concentrations on coronary atherosclerosis, we set up a randomised, controlled, end-point-blinded trial based on quantitative image analysis of coronary angiograms in patients with angina or past myocardial infarction. Another intervention group received diet and cholestyramine, to determine the effect of a greater reduction in circulating cholesterol concentrations. 90 men with coronary heart disease (CHD), who had a mean (SD) plasma cholesterol of 7.23 (0.77) mmol/l were randomised to receive usual care (U, controls), dietary intervention (D), or diet plus cholestyramine (DC), with angiography at baseline and at 39 (SD 3.5) months. Mean plasma cholesterol during the trial period was 6.93 (U), 6.17 (D), and 5.56 (DC) mmol/l. The proportion of patients who showed overall progression of coronary narrowing was significantly reduced by both interventions (U 46%, D 15%, DC 12%), whereas the proportion who showed an increase in luminal diameter rose significantly (U 4%, D 38%, DC 33%). The mean absolute width of the coronary segments (MAWS) studied decreased by 0.201 mm in controls, increased by 0.003 mm in group D, and increased by 0.103 mm in group DC (p less than 0.05), with improvement also seen in the minimum width of segments, percentage diameter stenosis, and edge-irregularity index in intervention groups. The change in MAWS was independently and significantly correlated with LDL cholesterol concentration and LDL/HDL cholesterol ratio during the trial period. Both interventions significantly reduced the frequency of total cardiovascular events. Dietary change alone retarded overall progression and increased overall regression of coronary artery disease, and diet plus cholestyramine was additionally associated with a net increase in coronary lumen diameter. These findings support the use of a lipid-lowering diet, and if necessary of appropriate drug treatment, in men with CHD who have even mildly raised serum cholesterol concentrations.

Angina Pectoris↗
PubMed1992

Lipolysis of triglyceride-rich lipoproteins activates coagulant factor XII: a study in familial lipoprotein-lipase deficiency.

A high factor VII coagulant activity (VIIc), a marker of increased risk of coronary heart disease, is frequently found in types IIb and IV hyperlipidaemia, but its cause is not fully understood. Factor VII can be activated by factor XIIa, generated from factor XII upon activation of the contact system of coagulation. Ten patients with familial lipoprotein-lipase (LPL) deficiency and 10 healthy control subjects were therefore compared to explore the hypothesis that high concentrations of unesterified fatty acids (UFA), released from triglyceride-rich lipoproteins by LPL, are a source of factor XII activation and hence the increased VIIc that is observed post-prandially and in non-LPL-deficient hypertriglyceridaemic states. Mean plasma cholesterol and triglyceride concentrations were, respectively, 1.5- and 19-fold higher in the patients than controls, due to increases in very-low-density lipoproteins and chylomicrons. The concentration and composition of plasma UFA were similar in both groups. In conformity with the hypothesis, VIIc was not increased in the LPL-deficient group, despite their massive hypertriglyceridaemia. Furthermore, when the patients' plasma was treated with LPL, factor XII was activated promptly and substantially, whereas no similar effect was observed in the controls. These results suggest that high concentrations of circulating triglyceride-rich lipoproteins will increase VIIc in the presence of LPL.

Adult↗
PubMed1992

Aortic compliance in young patients with heterozygous familial hypercholesterolaemia.

1. Aortic compliance and plasma lipid and lipoprotein levels were measured in 20 young patients with heterozygous familial hypercholesterolaemia and in 20 age- and sex-matched control subjects. 2. Patients with familial hypercholesterolaemia had significantly higher plasma cholesterol, low-density lipoprotein-cholesterol and triacylglycerol levels than control subjects (P < 0.001, P < 0.001 and P < 0.005, respectively). The patients with familial hypercholesterolemia also had significantly more compliant (distensible) aortas than the control subjects (P < 0.001), a significant inverse correlation being observed between compliance and age (r = 0.73, P < 0.001) and between compliance and mean blood pressure (r = -0.60, P < 0.005). 3. When the effects of age and sex on aortic compliance were corrected for, the blood pressure effect disappeared, significant correlations being observed between normalized compliance and cholesterol (r = 0.50, P < 0.03), low-density lipoprotein-cholesterol (r = 0.54, P < 0.01), high-density lipoprotein-cholesterol (r = -0.44, P < 0.05), low-density lipoprotein-/high-density lipoprotein-cholesterol ratio (r = 0.60, P < 0.0006) and duration of disease (r = 0.67, P < 0.002). Multivariate regression analysis showed that the low-density lipoprotein-/high-density lipoprotein-cholesterol ratio (P < 0.03) and duration of disease (P < 0.04) were the best predictors of normalized compliance. 4. We suggest that the measurement of aortic compliance in young patients with familial hypercholesterolaemia may potentially be a useful, non-invasive, research tool for assessing their susceptibility to atheroma.

Adolescent↗
PubMed1992

One year experience in the treatment of familial hypercholesterolaemia with simvastatin.

Patients with heterozygous familial hypercholesterolaemia (FH) have a substantially increased risk of atherosclerosis due to very high plasma levels of cholesterol. Recent evidence has shown that coronary heart disease in these patients may regress with lipid-lowering therapy. In this study the efficacy and safety of simvastatin, an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A, was investigated in 30 patients with FH over a period of one year. Substantial reductions in the plasma concentrations of total cholesterol (-28%), low-density lipoprotein (LDL) cholesterol (-32%), intermediate-density lipoprotein (IDL) cholesterol and apolipoprotein (apo) B (-33%) were achieved with 20 mg/day of simvastatin; there were no significant changes in triglycerides high-density lipoprotein cholesterol or apo A. In contrast to previous studies, 40 mg/day of simvastatin did not result in a further statistically significant fall in LDL cholesterol, IDL cholesterol or apo B in the group as a whole. The drug was well tolerated and no adverse clinical or laboratory events were recorded. In particular, no ophthalmological, hepatic or renal disorders were observed and there were no sleep disturbances. We conclude that simvastatin is an efficacious and safe drug to treat patients with heterozygous FH and that rarely will the dose need to be increased above 20 mg/day.

Adult↗
PubMed1992

The immunogenetics of early nephropathy in insulin-dependent diabetes mellitus: association between the HLA-A2 antigen and albuminuria.

One-hundred and seventy-two normotensive, insulin-dependent diabetic patients without clinical proteinuria (Albustix negative) were typed for the major histocompatibility complex class I (HLA-A, -B) and class II (HLA-DR) antigens. Urinary albumin excretion was measured as the albumin:creatinine ratio (UA/UC, mg/mmol) in an early morning sample. Patients expressing the HLA-A2 antigen had significantly higher UA/UC values than those not expressing the antigen. The observed ratio of geometric means was 1.77 (95 per cent confidence interval (CI) 1.18-2.67; p < 0.01); the relative risk of microalbuminuria (UA/UC > 3.0 mg/mmol) associated with expression of HLA-A2 was 2.52 (95 per cent CI 1.11-5.73; p < 0.05). There was no significant association between UA/UC and HLA-B8, -B15, -DR3, -DR4 or other antigens. Patients were re-studied after a mean period of 5.3 years: multiple linear regression analysis showed that the UA/UC at this time was positively related to the initial glycosylated haemoglobin level (p < 0.01) and expression of the HLA-A2 antigen (p < 0.05), but not to blood pressure or creatinine clearance. Fifteen patients developed macroalbuminuria at follow-up (UA/UC > 45.5 mg/mmol). Compared with a group matched for age, sex, duration of diabetes, and glycosylated haemoglobin who did not develop macroalbuminuria, macroalbuminuric patients had a higher frequency of HLA-A2 (p < 0.01). The odds ratio of progressing to macroalbuminuria associated with HLA-A2 had a 95 per cent CI of 1.71 to infinity. We conclude that an immunogenetic factor may play a role in the development of early diabetic nephropathy and that the risk associated with expression of the HLA-A2 antigen is independent of metabolic control and blood pressure.

Adolescent↗
PubMed1991

Comparison of the real-time use of glycosylated haemoglobin and plasma fructosamine in the diabetic clinic.

The within-clinic use of glycosylated haemoglobin (HbA1) and plasma fructosamine results in assessing blood glucose control and clinical management was compared in 1030 diabetic patients. The physician initially reviewed the patient with one randomly allocated measure (HbA1 or fructosamine) and completed a questionnaire concerning perception of blood glucose control, alteration to diet, alteration to medication, referral for diabetes education, and follow-up interval. The patient was then re-assessed using the second measure and the questionnaire repeated. Discordance rates for the study end-points, judged as binary outcomes, were: blood glucose control 15%; alteration to diet 7%; alteration to medication 9%; referral for education 3%; follow-up interval 4%. A significantly greater number of patients were rated as poorly controlled with HbA1 than with fructosamine (p less than 0.001) and were, in consequence, more frequently recommended alteration to diet and medication, referral for education and shorter follow-up interval; the rate of discordance for at least one of the management decisions was 16%. Multifactorial analysis showed that discordant management was dependent on the reviewing physician (p less than 0.001) and a history of cardiovascular disease (p less than 0.01); but neither type of diabetes, nor presence of nephropathy or variant haemoglobins, nor plasma glucose concentration, significantly influenced the likelihood of a discordance. Replacing HbA1 with fructosamine in the diabetic clinic may result in significant differences in the physician's perception of blood glucose control and in the management of patients.

Adult↗
PubMed1991

The determinants of early nephropathy in insulin-dependent diabetes mellitus: a prospective study based on the urinary excretion of albumin.

A four-year prospective study of the factors predicting albuminuria was carried out in 172 normotensive, insulin-dependent diabetic patients without overt nephropathy. Urinary albumin excretion was estimated as the urinary albumin:creatinine ratio (UA/UC) in an early morning sample. Multivariate analysis showed that UA/UC on the return visit was positively associated with the UA/UC (p less than 0.001) and glycosylated haemoglobin (HbA1; p less than 0.001) at initial examination; weaker associations were found with a history of hospital admission (p less than 0.05) and smoking (p less than 0.05), and with treatment of blood pressure (p less than 0.05). Neither initial blood pressure, heart rate, nor creatinine clearance were significant predictors of the UA/UC. Two patients died from coronary heart disease, both of whom had raised albumin excretion at initial examination. Eleven (6.8 per cent) of the 160 patients who were studied repeatedly developed macroalbuminuria (UA/UC greater than 45.5 mg/mmol): they had a significantly higher initial UA/UC (p less than 0.005), HbA1 (p less than 0.05) and a greater frequency of retinopathy (p less than 0.05) than patients matched for age, sex and duration of diabetes who did not develop macroalbuminuria. Simultaneous measurements of the UA/UC and HbA1 should be used when screening for microalbuminuria in diabetes mellitus: patients with a high UA/UC (e.g. greater than 3.5 mg/mmol) and HbA1 (e.g. greater than 13 per cent) should be closely monitored even when blood pressure is normal.

Albuminuria↗
PubMed1989

Effects of exercise and fat ingestion on high density lipoprotein production by peripheral tissues.

The peripheral production of high density lipoprotein (HDL) cholesterol and of the subclasses HDL2 and HDL3 was assessed by measurement of the arteriovenous fluxes across the human forearm, at rest and after 20 min isometric exercise in the forearm. Eight subjects were studied twice--fasting and after a high-fat meal--and one other subject was studied only after fat loading. In the fasted state the net fluxes of HDL2 and HDL3 cholesterol were slightly negative in the resting forearm, but they became positive during exercise, indicating greater production during short-term muscular activity. The effect of exercise, particularly that on HDL3 cholesterol, was greatly increased by a high-fat meal; the difference in HDL3 cholesterol arteriovenous flux between rest and exercise was significant (-0.06 [SEM 0.05] vs 0.51 [0.17] mumol/100 ml forearm/min). By contrast, there was no peripheral production of HDL2 or HDL3 cholesterol during exercise in two patients with lipoprotein lipase deficiency. These findings suggest that formation of HDL3 during lipolysis by lipoprotein lipase in the muscle capillary bed is influenced by the supply of chylomicrons and other lipoprotein substrates for this enzyme. Muscle blood flow may therefore be an important determinant of HDL production by this mechanism. The effect of exercise in raising HDL cholesterol, and the inverse relation between exercise and coronary heart disease, may be partly the result of this process.

Adult↗
PubMed1989

An acceptable exercise test to study microalbuminuria in type 1 diabetes.

A modified test for studying the response of urinary albumin excretion (UAV) to exercise in diabetic patients is described. It is designed to produce a standardized increase in pulse rate (by 90-110%) rather than a standardized workload. Thirty-three normotensive Type 1 diabetic patients with normal pre-exercise UAV (less than 10 micrograms min-1) on the day of the test were compared with 25 non-diabetic subjects matched for age and sex. The patients developed a significantly greater increase in the median UAV (p less than 0.05) and systolic blood pressure (p less than 0.01) during exercise, despite the use of lower workloads (p less than 0.05). During exercise, the albumin excretion in the patients was not related to their heart rate, blood pressure, workload or fall in blood glucose; nor was it related to duration of diabetes, glycosylated haemoglobin or insulin dose. An exercise UAV greater than 15 micrograms min-1 was found in 10 of the 33 patients; it was significantly correlated (p less than 0.01) with the frequency of previous overnight microalbuminuria (greater than 10 micrograms min-1), and was associated with a greater progression of microalbuminuria (p less than 0.05) over a mean period of 24 months. Retinol-binding protein excretion rate was also measured as an indicator of proximal tubular function and did not increase in either group.

Adult↗