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Biomedical subjects

I J Perry

Publications and source records attributed to I J Perry.

At least 37 records · Page 2Linked to original sources
PubMed1999

The design of a prospective study of Pravastatin in the Elderly at Risk (PROSPER). PROSPER Study Group. PROspective Study of Pravastatin in the Elderly at Risk.

The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) is a randomized, double-blind, placebo-controlled trial designed to test the hypothesis that treatment with pravastatin will diminish risk of subsequent major vascular events in a cohort of men and women (70 to 82 years old) with preexisting vascular disease or significant risk of developing this condition. Five thousand eight hundred four men and women in addition to receiving advice on diet and smoking, have been randomized equally to treatment with 40 mg pravastatin/day or matching placebo in 3 centers (Cork, Ireland, Glasgow, Scotland, and Leiden, The Netherlands). Following an average 3.5-year intervention period, a primary assessment will be made of the influence of this therapy on major vascular events (a combination of coronary heart disease, death, nonfatal myocardial infarction, and fatal and nonfatal stroke). A number of additional analyses will also be conducted on the individual components of the primary end point, on men, on women, and on subjects with and without previous evidence of vascular disease. Finally, an assessment will be made of the effects of treatment on cognitive function, disability, hospitalization or institutionalization, vascular mortality, and all-cause mortality.

Aged↗
PubMed1999

Homocysteine, hypertension and stroke.

The balance of evidence from observational studies suggests that elevated homocysteine levels are associated with increased risk of carotid artery disease and stroke. There is however a paucity of prospective studies. There are also concerns regarding confounding due to factors associated with hyperhomocysteinemia, including renal impairment, an atherogenic diet and cigarette smoking. Homozygosity for a defective thermolabile variant of MTHFR, a common genetic polymorphism which results in hyperhomocysteinemia, has not been consistently linked with stroke or other vascular disease. There is a need for additional prospective studies with data on relevant confounders, sufficient power to characterise the form of the association between homocysteine concentrations and stroke risk, whether linear or threshold, and power to study interactions between homocysteine, other dietary markers and established stroke risk factors such as smoking and hypertension. Similarly, the evidence linking hyperhomocysteinemia with hypertension is limited and inconsistent. Given the biological mechanisms proposed in support of the homocysteine-CVD hypothesis, one would predict a positive association between homocysteine and blood pressure. There is a need to address this hypothesis directly in studies with reliable measurements of both homocysteine and blood pressure. Ultimately, the case for a causal role for elevated homocysteine levels in vascular disease, including hypertension and stroke, will depend on data from randomised controlled trials of homocysteine lowering interventions. Given the high prevalence of hyperhomocysteinemia in apparently well nourished populations and the tendency for homocysteine concentrations to increase with age, modest effects of homocysteine on stroke risk will have profound implications for public health.

Cerebrovascular Disorders↗
PubMed1999

Serum true insulin concentration and the risk of clinical non-insulin dependent diabetes during long-term follow-up.

BACKGROUND: There is considerable evidence that insulin resistance with compensatory hyperinsulinaemia is an early and modifiable defect in the pathogenesis of non-insulin dependent diabetes (NIDDM). Current data, however, are largely based on studies that have used insulin assays which cross-react with proinsulin and other insulin precursors. Using a specific assay, we have addressed the hypothesis that an elevation of serum true insulin concentration, reflecting insulin resistance, is an early event in the pathogenesis of NIDDM. METHODS: We have used a prospective cohort study design in which a group of 5550 non-diabetic men aged 40-59 years, from 18 British towns, have been followed for incident cases of physician-diagnosed NIDDM for an average of period of 14.8 years (range 13.5-15 years). We have estimated the incidence of physician-diagnosed NIDDM by quintile of non-fasting serum true insulin concentration at entry into the study. RESULTS: There were 168 cases of clinically diagnosed NIDDM among the group of 5550 men during follow-up. Mean serum insulin at entry (geometric mean and 95% range, adjusted for time of sampling) was significantly higher in men who subsequently developed NIDDM than in the rest of the cohort, 19.5 mU/l (4.3-88.2) versus 12.2 mU/l (2.7-54.0), P < 0.0001. There was a highly significant linear trend of increasing risk of NIDDM by quintile of serum insulin which was not attenuated substantially after adjustment for age and body mass index (BMI) and additional lifestyle and biological factors associated with serum insulin and risk of NIDDM. However, in men with non-fasting serum glucose > or =6.1 mmol/l at baseline (80th percentile, n = 1125, 82 cases), the risk of NIDDM, adjusted for age and BMI, was higher in the first quintile of serum insulin than in all other quintiles. CONCLUSION: These findings are consistent with the hypothesis that the majority of cases of adult onset NIDDM in this population are characterized by the early development of insulin resistance with compensatory true hyperinsulinaemia.

Adult↗
PubMed1999

Serum total homocysteine and coronary heart disease: prospective study in middle aged men.

OBJECTIVES: To examine the prospective relation between total homocysteine and major coronary heart disease events. DESIGN: A nested case-control study carried out within the British regional heart study, a prospective investigation of cardiovascular disease in men aged 40-59 years at entry. Serum total homocysteine concentrations were analysed retrospectively and blindly in baseline samples from 386 cases who had a myocardial infarct during 12.8 years of follow up and from 454 controls, frequency matched by age and town. RESULTS: Geometric mean serum total homocysteine was slightly higher in cases (14.2 micromol/l) than in controls (13.5 micromol/l), a proportional difference of 5.5% (95% confidence interval (CI) -0.02% to 10.8%, p = 0.06). Age adjusted risk of myocardial infarction increased weakly with log total homocysteine concentration; a 1 SD increase in log total homocysteine (equivalent to a 47% increase in total homo cysteine) was associated with an increase in odds of myocardial infarction of 1.15 (95% CI 1.00 to 1. 32; p = 0.05). The relation was particularly marked in the top fifth of the total homocysteine distribution (values >16.5 micromol/l), which had an odds ratio of 1.77 (95% CI 1.28 to 2.42) compared with lower levels. Adjustment for other risk factors had little effect on these findings. Total homocysteine concentrations more than 16.5 micromol/l accounted for 13% of the attributable risk of myocardial infarction in this study population. Serum total homocysteine among control subjects varied between towns and was correlated with town standardised mortality ratios for coronary heart disease (r = 0.43, p = 0.08). CONCLUSIONS: Serum total homocysteine is prospectively related to increased coronary risk and may also be related to geographical variation in coronary risk within Britain. These results strengthen the case for trials of total homocysteine reduction with folate.

Adult↗
PubMed1999

Nonfasting serum glucose and insulin concentrations and the risk of stroke.

BACKGROUND AND PURPOSE: Type 2 diabetes is an established risk factor for stroke, but the relations between asymptomatic hyperglycemia, hyperinsulinemia, and stroke incidence remain uncertain. We have examined the relationship between established diabetes, nonfasting serum glucose and serum insulin concentrations, and subsequent risk of stroke. METHODS: We performed a prospective study of 7735 men aged 40 to 59 years drawn from general practices in 24 British towns. Men with missing serum glucose values (n=50) and men on insulin injection (n=36) were excluded, leaving 7649 men available for analysis. Baseline nonfasting serum was analyzed for insulin with a specific enzyme-linked immunosorbent assay method in 18 of the 24 towns (n=5663 men). RESULTS: During the mean follow-up period of 16.8 years, there were 347 stroke cases (fatal and nonfatal) in the 7649 men. Men who developed diabetes during follow-up (n=320) and men with established type 2 diabetes at screening (n=98) both showed significantly increased risk of stroke, even after adjustment for cardiovascular risk factors, including blood pressure (adjusted relative risk [RR], 2.27; 95% CI, 1.23 to 4.20; RR, 2.07; 95% CI, 1. 44 to 2.98, respectively). In men with no diagnosed diabetes at screening (n=7551), risk of stroke was increased significantly only in the top 2.5% of the nonfasting glucose distribution (>/=8.2 mmol/L), and this persisted even after adjustment for cardiovascular risk factors, including hypertension (RR, 1.86; 95% CI, 1.11 to 3. 13). Exclusion of the 320 men who developed diabetes during follow-up attenuated this risk so that it was no longer significant (RR, 1.56; 95% CI, 0.83 to 2.91). In the 5567 men with insulin measurements and no diagnosis of diabetes at screening, a J-shaped relationship was seen between nonfasting insulin and risk of stroke. Risk was significantly raised in the first quintile and in the fourth quintile and above compared with the second quintile, with all findings of marginal significance. Part of the increased risk at higher levels of insulin was due to men who developed diabetes in the follow-up period. CONCLUSIONS: This study confirms the importance of established type 2 diabetes as an independent risk factor for stroke. The increased risk of stroke seen in hyperglycemic subjects and those with elevated serum insulin levels at screening reflected to some extent the high proportion of men who subsequently developed diabetes.

Adult↗
PubMed1999

Homocysteine and risk of stroke.

The balance of evidence from observational studies suggests that elevated levels of homocysteine are associated with increased risk of carotid artery disease and stroke. There is, however, a paucity of prospective studies. There are also concerns regarding confounding caused by factors associated with hyperhomocysteinaemia, including renal impairment, an atherogenic diet and cigarette smoking. Homozygosity for a defective thermolabile variant of methylene-tetrahydrofolate reductase, a common genetic polymorphism which results in hyperhomocysteinaemia, has not been consistently linked with stroke or other vascular diseases. Additional prospective studies are required, with sufficient power to characterise the form of the association between homocysteine concentrations and stroke risk, whether linear or threshold, and to study interactions between homocysteine, other dietary markers and established stroke risk factors such as smoking and hypertension. Ultimately, the case for a causal role for elevated levels of homocysteine in vascular disease, including stroke, will depend on data from randomised controlled trials of homocysteine-lowering interventions. Given the high prevalence of hyperhomocysteinaemia in apparently well-nourished populations and the tendency for homocysteine concentrations to increase with age, modest effects of homocysteine on stroke risk will have profound implications for public health.

Arteriosclerosis↗
PubMed1998

Hypertension, serum insulin, obesity and the metabolic syndrome.

BACKGROUND AND AIMS: In recent years it has been proposed that hypertension is part of a cluster of metabolic risk factors (syndrome X) involving hyperlipidaemia and hyperglycaemia, with hyperinsulinaemia as the common link. This study has investigated: (1) the prevalence of the metabolic syndrome and its component variables and their relationship to body mass index (BMI) and non-fasting insulin levels in a general population; and (2) the distribution and clustering of metabolic variables in normotensives and hypertensives. METHODS: Cross-sectional study of 5222 men aged 40-59 years with no history of coronary heart disease (CHD), diabetes mellitus or stroke drawn from general practices in 18 British towns. The men were a subgroup of the 7735 men in the British Regional Heart Study (BRHS) cohort whose baseline non-fasting serum was analysed for insulin, using a specific ELISA method. MAIN OUTCOME MEASURES: Hyperinsulinaemia, hyperglycaemia, high serum total cholesterol, high triglyceride and hyperuricaemia were defined as the top 20% of the distribution in the 5222 men. Low HDL-cholesterol was defined as the bottom 20%. RESULTS: BMI and non-fasting insulin were both significantly and strongly associated with non-diabetic hyperglycaemia, lipid abnormalities (HDL-cholesterol, triglyceride and total cholesterol) and hyperuricaemia. BMI was strongly associated with hypertension whereas non-fasting insulin showed a much weaker relationship which was abolished after adjustment for BMI. However, only 2.9% of men showed the 'full metabolic syndrome' (hypertension, hyperglycaemia and dyslipidaemia) and a large proportion of these men were hyperinsulinaemic (65%) or obese (47%). Dyslipidaemia (any one of low-HDL-cholesterol, high triglyceride or high cholesterol) was common in both normotensives and hypertensives (40.5% vs 46.4%). Hypertensives showed significantly higher levels of total cholesterol, triglyceride, blood glucose, urate and more clustering of hyperglycaemia and dyslipidaemia than normotensives even after adjustment for BMI. CONCLUSION: Hypertensives were more likely to have lipid abnormalities and clustering of risk factors than normotensives even after adjustment for BMI. The metabolic syndrome is more strongly associated with hyperinsulinaemia than with obesity but it is relatively uncommon in men with no history of cardiovascular disease or diabetes. Given the weak relationship between hypertension and hyperinsulinaemia, the latter is unlikely to explain the higher levels of lipid abnormalities and clustering seen in hypertensives. Overweight/obesity may be primarily involved in the pathways to hypertension and lipid abnormalities but the unravelling of these relationships require more specific measures of adipose tissue distribution, composition and function.

Adult↗
PubMed1998

Prospective study of serum gamma-glutamyltransferase and risk of NIDDM.

OBJECTIVE: Serum gamma-glutamyltransferase (GGT) levels are raised in obese individuals, and a particularly strong association with central obesity has been described. We hypothesized that elevated GGT levels are a marker for visceral fat, and specifically for hepatic steatosis (fatty liver), and that hepatic steatosis leads to hepatic insulin resistance. To test this hypothesis, we examined the association between GGT levels and risk of NIDDM. RESEARCH DESIGN AND METHODS: We carried out a prospective cohort study of incident cases of doctor-diagnosed NIDDM in a group of 7,458 nondiabetic men (aged 40-59 years) followed for a mean of 12.8 years (range 11.5-13.0). The men were randomly selected from general practice lists in 24 British towns. Cases of NIDDM were ascertained by repeated postal questionnaires to the men and by regular systematic review of primary care records. RESULTS: A total of 194 men developed NIDDM during follow-up. Mean serum GGT at baseline (geometric mean [95% CI]) was significantly higher in the NIDDM patients than in the rest of the cohort (20.9 [19.3-22.6] vs. 15.3 U/l [15.0-15.6], P < 0.0001). There was a smooth, graded increase in the age-adjusted risk of NIDDM with increasing GGT levels, with a relative risk in the top fifth of the distribution of 6.8 (3.5-12.9) relative to the bottom fifth (trend P < 0.0001). This association was independent of serum glucose and BMI and of other predictors of NIDDM with which GGT is associated, including alcohol intake and physical activity level (adjusted upper to lower fifth relative risk: 4.8 [2.0-11.8], trend P < 0.0001]). CONCLUSIONS: These findings suggest that a raised serum GGT level is an independent risk factor for NIDDM. Serum GGT level may be a simple and reliable marker of visceral and hepatic fat and, by inference, of hepatic insulin resistance.

Adult↗
PubMed1997

Ambulatory blood pressure in pregnancy and fetal growth.

BACKGROUND: Retarded growth in utero has been linked with high blood pressure and other risk factors for cardiovascular disease in adult life. However, the influence on fetal growth of the maternal blood pressure during pregnancy is not well defined. In a prospective study, we examined the relation between maternal ambulatory blood pressure during pregnancy and indices of fetal growth. METHODS: We studied 209 healthy nulliparous pregnant women referred to an inner-city district general hospital (86% of 244 consecutively referred women who met the study criteria). 24 h ambulatory blood-pressure recordings were obtained in early (median 18 weeks [IQR 17-18]) mid (28 weeks [28]), and late (36 weeks [36]) gestation. Eight infants delivered before 32 weeks' gestation were excluded from the analysis. FINDINGS: A 5 mm Hg (1 SD) increase in mean 24 h diastolic blood pressure at 28 weeks' gestation was associated with a 68 g (95% Cl 3-132) decrease in birthweight; a similar change in diastolic pressure at 36 weeks' gestation was associated with a 76 g (24-129) decrease in birthweight. These associations were independent of potential confounders (maternal age, height, weight, cigarette smoking, alcohol intake, ethnic origin, pregnancy hypertension syndromes, and preterm birth). Maternal mean 24 h diastolic blood pressure at 28 weeks' gestation was also inversely associated with the infant's ponderal index at birth in multivariate analysis (p = 0.06). Higher maternal ambulatory blood pressure at 28 weeks' and 36 weeks' gestation also predicted lower head circumference, although these associations were dependent on birthweight. Associations between ambulatory systolic blood pressure and indices of fetal growth were weak and inconsistent and ambulatory blood pressure at 18 weeks' gestation did not predict fetal growth. INTERPRETATION: There is a continuous inverse association between fetal growth and maternal blood pressure, throughout the range seen in normal pregnancy. Maternal blood pressure may be an important confounding factor in the reported associations between fetal growth retardation and adult hypertension and cardiovascular disease.

Adult↗
PubMed1997

Serum creatinine concentration and risk of cardiovascular disease: a possible marker for increased risk of stroke.

BACKGROUND AND PURPOSE: Elevated serum creatinine has been associated with increased mortality in hypertensive persons, the elderly, and patients with myocardial infarction or stroke in whom cardiovascular disease is the major cause of death. We have examined the relationship between serum creatinine concentration and the risk of major ischemic heart disease and stroke events and all-cause mortality in a general population of middle-aged men. METHODS: We present a prospective study of middle-aged men (aged 40 to 59 years) drawn from 24 British towns who have been followed up for an average of 14.75 years. Data on serum creatinine were available for 7690 men in whom there were 287 major stroke events, 967 major ischemic heart disease events, and 1259 deaths from all causes during follow-up. RESULTS: The median serum creatinine concentration was 98 micromol/L (95% range, 76 to 129 micromol/L). Stroke risk was significantly increased at levels above 116 micromol/L (90th percentile) even after adjustment for a wide range of cardiovascular risk factors (relative risk [RR], 1.6; 95% CI, 1.1 to 2.1; > 116 micromol/L versus the rest). Risk of a major ischemic heart disease event was significantly increased at or above 130 micromol/L (97.5 percentile), but this was attenuated after adjustment (RR, 1.2; 95% CI, 0.8 to 1.7; > or = 130 micromol/L versus the rest). There was a weak but significant positive association between diastolic blood pressure and creatinine concentration. However, elevated creatinine concentration (> or = 116 micromol/L) was associated with a significant increase in stroke in both normotensive and hypertensive men. All-cause mortality and overall cardiovascular mortality were significantly increased only above the 97.5 percentile, and no significant association was seen with cancer or other noncardiovascular mortality. CONCLUSIONS: A high serum creatinine concentration within the normal range is a marker for increased risk of cerebrovascular disease in both normotensive and hypertensive subjects. These findings support the evidence indicating that subtle impairment of renal function is a factor for increased risk of stroke and suggest mechanisms in the pathogenesis of stroke that warrant further investigation.

Adult↗