Showing papers by "Gerald F. Watts published in 1995"
TL;DR: The St Thomas' Atherosclerosis Regression Study as mentioned in this paper showed that the 6A6A genotype was significantly associated with greater progression of coronary atherosclerosis than other genotypes in patients with baseline percentage diameter stenosis less than 20% (P < 0.05), but not in those with baseline percent of coronary stenosis greater than or equal to 20%.
Abstract: Stromelysin is a member of the family of metalloproteinases that degrade extracellular matrix. In situ hybridisation and histopathological studies suggest that stromelysin activity may be important in the connective tissue remodelling processes associated with atherogenesis and plaque rupture. Single strand conformation polymorphism analysis identified a common polymorphism in the stromelysin gene promoter located 1171 bp upstream from the start of transcription in which one allele has a run of six adenosines (6A) and another has five adenosines (5A). 72 men with coronary heart disease, were genotyped. They were participants in the St Thomas' Atherosclerosis Regression Study who were randomised to receive usual care (UC), dietary intervention (D), or diet plus cholestyramine (DC), with angiography at baseline and at 39 months. In these patients the frequency of the 5A allele was 0.49 (95% CI from 0.41 to 0.57) and was not significantly different from that in a sample of 354 healthy UK men. In the UC group, patients who were homozygous for the 6A allele showed greater progression of angiographic disease than those with other genotypes: the minimum absolute width of coronary segments decreased by 0.04 (SEM 0.10) mm for 5A5A, 0.20 (0.07) mm for 5A6A, and 0.67 (0.19) mm for 6A6A (P < 0.01). The findings were similar but slightly less significant for the change in mean absolute width of coronary segments (P < 0.05). No significant associations were seen in patients in the D or DC groups. In data pooled from the three treatment groups, the 6A6A genotype was significantly associated with greater progression of coronary atherosclerosis than other genotypes in patients with baseline percentage diameter stenosis less than 20% (P < 0.05), but not in those with baseline percentage diameter stenosis greater than or equal to 20%. These results provide the first evidence of a link between genetic variation in stromelysin and progression of coronary atherosclerosis and support the hypothesis that connective tissue remodeling mediated by metalloproteinases contribute to the pathogenesis of atherosclerosis.
241 citations
TL;DR: There is increased hepatic secretion of VLDL apoB which may partly explain the dyslipoproteinaemia seen in the non-insulin-dependent diabetes mellitus (NIDDM), and it is suggested that increased secretion of this apolipoprotein may be a consequence of resistance to the inhibitory effect of insulin.
Abstract: We measured the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 (VLDL apoB) using a stable isotope gas-chromatography mass-spectrometry method in six patients with non-insulin-dependent diabetes mellitus (NIDDM) (four males, two females, age 57.5±2.2 years (mean±SEM), weight 88.2±5.5 kg, glycated haemoglobin (HbA1) 8.5±0.5%, plasma total cholesterol concentration 5.7±0.5 mmol/l, triglyceride 3.8±0.9 mmol/l, high-density lipoprotein (HDL) cholesterol 1.0±0.1 mmol/l) and six non-diabetic subjects matched for age, sex and weight (four males, two females, age 55.7±2.8 years, weight 85.8±5.6 kg, HbA1 6.5±0.1%, plasma total cholesterol concentration 5.7±0.5 mmol/l, triglyceride 1.2±0.1 mmol/l, HDL cholesterol 1.4±0.1 mmol/l). HbA1, plasma triglyceride and mevalpnic acid (an index of cholesterol synthesis in vivo) concentrations were significantly higher in the diabetic patients than in the non-diabetic subjects (p=0.006, p=0.02 and p=0.004, respectively). VLDL apoB absolute secretion rate was significantly higher in the diabetic patients compared with the non-diabetic subjects (2297±491 vs 921±115 mg/day, p<0.05), but there was no significant difference in the fractional catabolic rate of VLDL apoB. There was a positive correlation between VLDL apoB secretion rate and (i) fasting C-peptide (r=0.84, p=0.04) and (ii) mevalonic acid concentration (r=0.83, p<0.05) in the diabetic patients but not in the non-diabetic subjects. There was also a significant positive association between plasma mevalonic acid and plasma C-peptide (r=0.82, p<0.05) concentrations in the diabetic patients. We conclude that in NIDDM, there is increased hepatic secretion of VLDL apoB which may partly explain the dyslipoproteinaemia seen in this condition. We suggest that increased secretion of this apolipoprotein may be a consequence of resistance to the inhibitory effect of insulin on VLDL apoB secretion. Insulin resistance may also be the mechanism by which cholesterol synthesis, a regulator of apoB secretion, is increased in NIDDM.
128 citations
TL;DR: Plasma total cholesterol, triacylglycerol and mevalonic acid (an index of cholesterol synthesis in vivo) concentrations were significantly higher in the obese subjects than in control subjects, but there was no significant difference in the fractional catabolic rate of VLDL apoB.
Abstract: 1. We measured the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 (VLDL apoB) using a stable-isotope gas chromatography-mass spectrometry method in six obese subjects [three males, three females, age 41.5 +/- 3.4 years (mean +/- SEM), weight 105.0 +/- 4.8 kg, plasma total cholesterol concentration 6.2 +/- 0.4 mmol/l, triacylglycerol 2.8 +/- 0.8 mmol/l, high-density lipoprotein cholesterol 1.0 +/- 0.2 mmol/l] and six lean control subjects (three males, three females, age 41.8 +/- 3.7 years, weight 68.2 +/- 4.9 kg, total cholesterol concentration 4.5 +/- 0.3 mmol/l, triacylglycerol 0.8 +/- 0.2 mmol/l, high-density lipoprotein cholesterol 1.3 +/- 0.1 mmol/l). 2. Plasma total cholesterol, triacylglycerol and mevalonic acid (an index of cholesterol synthesis in vivo) concentrations were significantly higher in the obese subjects than in control subjects (P = 0.02, P = 0.03, P = 0.04, respectively). VLDL apoB pool size and absolute secretion rate were significantly higher in the obese subjects than in control subjects (323.4 +/- 99.8 mg versus 53.6 +/- 17.1 mg, P = 0.004; and 42.3 +/- 13.8 mg kg fat-free mass-1 day-1 versus 10.7 +/- 0.4 mg kg fat-free mass-1 day-1, P = 0.01), but there was no significant difference in the fractional catabolic rate of VLDL apoB.(ABSTRACT TRUNCATED AT 250 WORDS)
84 citations
TL;DR: It is concluded that acute hyperinsulinemia decreases the hepatic secretion rate of VLDL apoB in NIDDM, probably in part due to reduction in the delivery of NEFA and glycerol substrate to the liver.
Abstract: In a randomized crossover study, we measured the hepatic secretion rate of very-low-density lipoprotein (VLDL) apolipoprotein B-100 (apoB) in seven patients with well-controlled non-insulin-dependent diabetes mellitus (NIDDM) (HbA1 8.4 +/- 0.4% [mean +/- SE]) on two occasions: during a 13-h hyperinsulinemic (plasma insulin concentration 586 +/- 9.7 pmol/l) euglycemic (plasma glucose concentration 5.2 +/- 0.1 mmol/l) clamp; and during a 13-h saline (control) infusion. After 5 h of the hyperinsulinemic euglycemic clamp (or saline infusion) when a new steady state of apoB turnover was reached, [1-(13)C]leucine was administered by a primed (1 mg/kg), constant 8-h infusion (1 mg.kg-1. h-1). VLDL apoB isotopic enrichment was determined with gas chromatography-mass spectrometry, and a monoexponential model was used to calculate the fractional secretion rate of VLDL apoB. VLDL apoB secretion rate was significantly reduced during the hyperinsulinemic euglycemic clamp compared with the saline study (12.2 +/- 3.6 vs. 24.5 +/- 7.1 mg.kg-1.day-1, P = 0.001), but there was no change in the fractional catabolic rate of VLDL apoB. Concomitantly, plasma concentrations of nonesterified fatty acids (NEFAs), glycerol, and triglycerides (TGs) were significantly lower during the hyperinsulinemic euglycemic clamp compared with the saline study (NEFAs, P < 0.001; glycerol, P = 0.005; TGs P = 0.004). We conclude that acute hyperinsulinemia decreases the hepatic secretion rate of VLDL apoB in NIDDM, probably in part due to reduction in the delivery of NEFA and glycerol substrate to the liver.
77 citations
TL;DR: The findings are consistent with the hypothesis that in FH increased hepatic cholesterol availability (due to increased uptake of LDL-cholesterol via the receptor-independent pathway) stimulates hepatic secretion of VLDL apo B.
66 citations
TL;DR: It is suggested that in vivo cholesterol synthesis is a determinant of hepatic secretion of apo B in normolipidemic subjects.
Abstract: The regulation of apolipoprotein B-100 (apo B) metabolism in man is not fully understood. In vitro studies suggest a key role for the hepatic availability of cholesterol substrate. We therefore examined whether there was a direct association between plasma mevalonic acid (MVA) concentration (an index of in vivo cholesterol synthesis) and hepatic secretion of very-low-density lipoprotein (VLDL) apo B in eight normolipidemic, healthy adult subjects. Hepatic secretion of VLDL apo B was estimated by endogenous labeling of apo B with an 8-hour primed, constant infusion of 1-13C-leucine. Isotopic enrichment of VLDL apo B was measured by gas chromatography—mass spectrometry (GCMS), from which the fractional secretion rate (FSR) was derived by a modified monoexponential function. Plasma concentration of MVA was measured by gas chromatography-electron-capture mass spectrometry in blood samples taken at 9 am. The absolute secretion rate (ASR) of VLDL apo B (mean ± SD) was 9.7 ± 2.6 mg/kg/d, and MVA concentration was 5.0 ± 2.5 ng/mL. There was a highly significant positive correlation between ASR of VLDL apoB and plasma MVA (r = .88, P = .004), which persisted after adjusting for apo E phenotype. The findings suggest that in vivo cholesterol synthesis is a determinant of hepatic secretion of apo B in normolipidemic subjects.
60 citations
TL;DR: The hepatic secretion of VLDL apoB in FH is decreased by simvastatin, which may partly explain the fall in plasma cholesterol, and the effect does not appear to be directly related to the inhibition of cholesterol synthesis.
Abstract: We studied six patients with heterozygous familial hypercholesterolaemia (FH) before and after 8 weeks of treatment with simvastatin (40 mg day -1 ), an inhibitor of 3-hydroxy-3-methylglutaryl-Coenzyme A. Simvastatin decreased plasma low-density lipoprotein (LDL) cholesterol by 43% (P=0.002), triglycerides by 27% (P=0.05) and mevalonic acid (a measure of in vivo cholesterol synthesis) by 20% (P=0.002) ; high-density lipoprotein cholesterol increased by 17% (P=0.02). The hepatic secretion rate of very-low-density lipoprotein apolipoprotein B-100 (VLDL apoB) was measured directly using a primed, constant intravenous infusion of 1-[ 13 C]-leucine with monitoring of the isotopic enrichment of apoB by gas chromatography-mass spectrometry ; fractional secretion rate (FSR) was derived using a monoexponential function. Simvastatin decreased the FSR, ASR and pool size of VLDL apoB by 17% (14.3 (SEM 3.6)) vs. (11.9 (SEM 3.5) pools day -1 , P=0.10), 83% (51.4 (SEM 17.9) vs. (8.6 (SEM 1.4), P=0.007 mg kg -1 day -1 ) and 65% (234.2 (SEM 30.4) vs. 82.6 (SEM 24.0)mg, P=0.02), respectively. The change in the ASR of VLDL apoB was significantly correlated with the change in plasma LDL cholesterol concentration (P=0.04), but not with the change of triglyceride or mevalonic acid. We conclude that the hepatic secretion of VLDL apoB in FH is decreased by simvastatin, which may partly explain the fall in plasma cholesterol. This effect does not appear to be directly related to the inhibition of cholesterol synthesis and may be due to decreased hepatic delivery of cholesterol esters via the LDL receptor-independent pathway, but these mechanisms require further investigation.
51 citations
TL;DR: The findings are consistent with the hypothesis that in CESD increased intrahepatic synthesis of cholesterol stimulates hepatic secretion of VLDL apoB and this may partly account for the dyslipidemia.
Abstract: Using a stable isotope method, we measured the hepatic secretion rate of very-low-density lipoprotein apolipoprotein B-100 (VLDL apoB) in a 26-year-old women who had dyslipidemia due to cholesteryl ester storage disease (CESD) and in five normolipidemic subjects. [1-13C]Leucine was administered by a primed constant intravenous infusion and the enrichment of VLDL apoB was determined by gas chromatography-mass spectrometry. The absolute secretion rate (ASR) of VLDL apoB in the patient was more than twice the mean ASR of the normolipidemic group (17.1 vs 8.0 +/- 0.8 mg/kg body wt. per day). The plasma mevalonic acid concentration, a measure of intrahepatic cholesterol synthesis, was also greater in the patient than in the normolipidemic subjects (8.3 vs 4.4 +/- 1.8 micrograms/L). The findings are consistent with the hypothesis that in CESD increased intrahepatic synthesis of cholesterol stimulates hepatic secretion of VLDL apoB and this may partly account for the dyslipidemia.
47 citations
TL;DR: Plasma Lp(a) is a strong and independent correlate of the extent of angiographie CAD in symptomatic patients with NIDDM, independent of other cardiovascular risk factors, including lipoprotein related variables and glycated hemoglobin.
Abstract: OBJECTIVE To examine the correlation between angiographie coronary artery disease (CAD) and plasma lipoprotein(a) [Lp(a)] concentration in non-insulin-dependent diabetes mellitus (NIDDM).
RESEARCH DESIGN AND METHODS In this cross-sectional study of 36 patients with NIDDM who underwent coronary angiography, CAD was assessed visually using a coronary artery score (CAS), and plasma Lp(a) was measured immunotur-bidimetrically.
RESULTS Lp(a) concentration was significantly higher in patients in the middle and upper tenues of CASs (>4) compared with those in the lower tenue (≤4); geometric mean 0.30 g/l(95% confidence interval [CI] 0.22–0.40) vs. 0.12 g/l (0.08–0.17, P = 0.002). Lp(a) was significantly and positively correlated with the CAS ( R 2 23%, P = 0.006), independent of other cardiovascular risk factors, including lipoprotein related variables and glycated hemoglobin.
CONCLUSIONS Plasma Lp(a) is a strong and independent correlate of the extent of angiographie CAD in symptomatic patients with NIDDM.
33 citations
TL;DR: It is concluded that serial measurement of serum TSA levels may be a useful indicator of the progression of CAD.
Abstract: We measured serum levels of total sialic acid (TSA) by an enzymatic method in 74 men who completed the St Thomas' Atherosclerosis Regression Study (STARS). Coronary artery disease (CAD) was assessed as the change (delta) in mean absolute width of coronary segments (MAWS) over 3 years by a computerized technique. Delta TSA was significantly correlated with delta MAWS (r = -.50, P < .001) after adjusting for age, blood pressure, smoking status, and plasma low-density lipoprotein (LDL) cholesterol. The relative risk of progression of CAD for a delta TSA exceeding 10 mg/dL as compared with a delta TSA not exceeding 10 mg/dL was 4.6 (95% confidence interval, 2.4 to 8.7). We conclude that serial measurement of serum TSA levels may be a useful indicator of the progression of CAD.
33 citations
TL;DR: Test whether serum von Willebrand factor (vWf) would be lower in men with atherosclerosis who had been consuming a lipid‐lowering diet for 3 years than in a control group of men with AtherosclerosisWho had been following their normal diet.
Abstract: . Objectives. To test whether serum von Willebrand factor (vWf) would be lower in men with atherosclerosis who had been consuming a lipid-lowering diet for 3 years than in a control group of men with atherosclerosis who had been following their normal diet.
Design. A randomized, population-based case-control study.
Setting. A tertiary health care referral centre at a University Hospital.
Subjects. Men age less than 66 years with angiographically proven coronary atherosclerosis and a cholesterol level > 6 mmol L−1. Sixty started the study and 50 completed it.
Interventions. Subjects were randomized to a lipid-lowering diet or to taking their normal diet for approximately 3 years.
Main outcome measures. The components of the subjects' diets were assessed and blood was obtained for total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglycerides and for vWf.
Results. Men on the lipid-lowering diet consumed less total, saturated and monounsaturated fats (all P < 0.001), cholesterol and retinol (both P < 0.002) but increased polyunsaturated fats (P < 0.001), fibre, vitamin E (both P < 0.005) and carbohydrate (P < 0.05). Those on the lipid-lowering diet also had lower serum levels of total and LDL cholesterol (P < 0.002 and P < 0.05, respectively), triglycerides (P < 0.02) and vWf (P < 0.05) than the men on their normal diet. There was no difference in HDL cholesterol. Levels of vWf correlated with both total cholesterol (P < 0.005) and inversely with dietary polyunsaturated fats (P < 0.02).
Conclusion. von Willebrand factor, a possible indicator of endothelial cell damage, decreases during long-term compliance with a lipid-lowering diet.
TL;DR: Exercise testing may be useful for identifying normoalbuminuric IDDM patients who are susceptible to the later development of microalbuminuria.
Abstract: OBJECTIVE To determine the association between exercise-induced albuminuria and the development of microalbuminuria over 10 years in subjects with insulin-dependent diabetes mellitus (IDDM) who were initially normoalbuminuric. RESEARCH DESIGN AND METHODS Thirty-two patients with IDDM and a resting urinary albumin/creatinine ratio (U A /U C ) A /U C was determined before and after exercise. The exercise test was considered positive if the U A /U C was >4.3 mg/mmol (>30 μg/min). Results were compared with resting U A /U C after a 10-year follow-up. Persistent microalbuminuria was defined as a U A /U C >2.1 mg/mmol (> 15 μg/min) in each of two early-morning urine collections. RESULTS Five patients developed persistent microalbuminuria after 10 years, and four patients were predicted by a positive exercise test. Two patients with positive exercise tests did not develop persistent microalbuminuria. The sensitivity of the exercise test for the development of microalbuminuria was 80% (95% confidence interval [CI] 65.8–94.2%) and the specificity was 92.9% (95% CI 83.9–100%). The postexercise U A /U C was positively associated with the U A /U C after 10 years ( P = 0.005, R 2 = 0.31). This association was independent of HbA 1 , systolic blood pressure, body mass index, and duration of diabetes, but HbA 1 remained an independent predictor ( P = 0.02) of U A /U C at follow-up. CONCLUSIONS Exercise testing may be useful for identifying normoalbuminuric IDDM patients who are susceptible to the later development of microalbuminuria.
TL;DR: Elevated serum Lp(a) concentration was significantly higher in patients with carotid artery disease severity score above the median value of the sample population compared with those below the median, and may be useful in identifying patients most at risk of stroke.
Abstract: We measured fasting serum lipids, lipoproteins, apolipoproteins and lipoprotein(a) [Lp(a)] in 49 Caucasian patients with transient ischaemic attacks undergoing carotid angiography. The severity of extracranial cerebrovascular disease was assessed visually by a highly reproducible grading system that focused on the internal carotid artery and carotid bifurcation. Compared with a healthy reference group, patients had significantly higher serum concentrations of: total cholesterol (mean +/- SD), 6.2 +/- 1.6 vs. 5.6 +/- 1.0 mmol/l, p = 0.02; apolipoprotein B, 1.4 +/- 0.5 vs. 1.2 +/- 0.3 g/l, p = 0.03; triglyceride [geometric mean(95% CI)], 2.02(1.75-2.32) vs. 1.66(0.67-4.06) mmol/l, p = 0.03; and Lp(a), 0.33(0.26-0.42) vs. 0.17(0.40-0.76) g/l, p < 0.001. Regression analysis showed that of the lipoprotein-related variables, only Lp(a) was significantly related to the severity of carotid artery disease (p = 0.04) in the patients; this association remained significant after adjusting for age, sex, blood pressure, and a history of stroke. Serum Lp(a) concentration was significantly higher in patients with carotid artery disease severity score above the median value of the sample population compared with those below the median: 0.45 vs. 0.24 g/l (95% CI for difference 0.35-0.88), p = 0.01. Elevated serum Lp(a) is a significant determinant of the extent of carotid atherosclerosis and may be useful in identifying patients most at risk of stroke.
Journal Article•
TL;DR: Findings provide further support for a causal role of saturated fats in CAD; restriction of foods containing such fats should be emphasized as part of regimens aimed to reduce progression of coronary atherosclerosis.
TL;DR: “Depurtment of Medicine, Division of’ Cardiovascular Generics, University College London Medical School, The RaJxe Institute, 5 University Street, London, WClE 6JJ”.
TL;DR: It is concluded that renal dysfunction may be a late manifestation of LCAT deficiency and that it may lead to severe chylomicronaemia and acute pancreatitis.
Abstract: A 38-year-old Asian man presented with acute pancreatitis, marked hypertriglyceridaemia and macroproteinuria, 20 years after the diagnosis of lecithin-cholesterol acyltransferase (LCAT) deficiency. After recovery, he exhibited macroproteinuria and chylomicronaemia despite treatment with a very-low-fat diet. Infusion of normal plasma significantly increased the proportion of cholesterol esters in the patient's plasma and significantly lowered chylomicron-triglyceride levels, but not proteinuria. We conclude that renal dysfunction may be a late manifestation of LCAT deficiency and that it may lead to severe chylomicronaemia and acute pancreatitis. Infusion of normal plasma corrects the dyslipidaemia in LCAT deficiency, but in the short term does not improve renal function.
TL;DR: The methodology required to measure, with optimal resolving power, angiographic changes in coronary artery disease was used in a randomized, controlled trial of the effect of lipid-lowering therapy, the St Thomas' Atherosclerosis Regression Study.
TL;DR: This data indicates that LDL cholesterol levels are higher in men than in women, and the relationship between the benefits of lipid‐lowering strategies and changes in HDL levels is still unclear.
Abstract: HDL cholesterol is only one of many risk factors which can be used to predict coronary disease events, and the relationship between the benefits of lipid-lowering strategies and changes in HDL levels is, at present quite unclear.