Objectives: To measure the frequency of genotypes of the HFE (haemochromatosis) gene in patients recruited to the west of Scotland coronary prevention study (WOSCOPS), and relate them to the subsequent occurrence of coronary clinical events.
Design: Nested case–control study, drawing samples of DNA from the biological bank of a cohort study.
Patients: Men aged 45–64 years in 1989, with moderate hypercholesterolaemia and no evidence of coronary heart disease at baseline.
Interventions: Follow up for a mean period of 4.9 years. Typing for C282Y and H63D mutations of the HFE gene in 482 subjects with a subsequent coronary event and 1104 without an event.
Results: The C282Y mutation was present in 81 of 482 cases (16.8%) and 182 of 1104 controls (16.5%). Comparing the prevalence of gene mutations in the cases and controls, there were no significant differences. The hazard ratio for C282Y heterozygotes was 1.03 (95% confidence interval (CI) 0.77 to 1.36) and for C282Y/H63D compound heterozygotes 1.04 (95% CI 0.50 to 2.14). Prespecified subgroup analyses of the pravastatin, placebo, smoking, and non-smoking groups showed no significant differences between cases and controls. Repeating the analyses after adjusting for possible confounding factors produced no change in the results.
Conclusions: In a population of moderately hypercholesterolaemic middle aged Scottish men who did not have any evidence of coronary heart disease at baseline, the presence of a C282Y mutation in the HFE gene did not predict the occurrence of coronary events over a mean follow up of 4.9 years.
haemochromatosis; genetics; coronary heart disease; iron
Circulating lipoprotein-associated phospholipase A2 (Lp-PLA2) is a marker of inflammation that plays a critical role in atherogenesis; its inhibition may have antiatherogenic effects. Studies from the West of Scotland Coronary Prevention Study (WOSCOPS), Monitoring Trends and Determinants in Cardiovascular Diseases (MONICA) and Rotterdam cohorts have shown that Lp-PLA2 is an independent predictor of coronary heart disease (CHD), and the association is not attenuated upon multivariate analysis with traditional risk factors and other inflammatory markers. Studies in subjects with coronary artery disease (CAD) have also shown associations between Lp-PLA2 and cardiovascular risk. At least two recent studies have shown that Lp-PLA2 is a risk predictor for stroke. Overall, epidemiological studies suggest that measurement of Lp-PLA2 in plasma may be a useful in identifying individuals at high risk for cardiovascular events.
Inflammation; vascular; cardiovascular risk; coronary; stroke
Several lines of evidence support a role for CCL2 (monocyte chemotactic protein-1) and its receptor CCR2 in the development of atherosclerosis. The aim of the present study was to determine the association of the CCR2 Val64Ile polymorphism with the development of coronary artery disease in the WOSCOPS study sample set.
A total of 443 cases and 1003 controls from the West of Scotland Coronary Prevention Study (WOSCOPS) were genotyped for the Val64Ile polymorphism in the CCR2 gene. Genotype frequencies were compared between cases and controls. The CCR2 Val64Ile polymorphism was found not to be associated with coronary events in this study population (odds ratio 1.15, 95% CI 0.82-1.61, p = 0.41).
This case-control study does not support an association of the CCR2 Val64Ile polymorphism with coronary artery disease in the WOSCOPS sample set and does not confirm a possible protective role for CCR2 Val64Ile in the development of coronary artery disease.
Statin therapy reduces the risk of coronary heart disease (CHD), however, the person-to-person variability in response to statin therapy is not well understood. We have investigated the effect of genetic variation on the reduction of CHD events by pravastatin. First, we conducted a genome-wide association study of 682 CHD cases from the Cholesterol and Recurrent Events (CARE) trial and 383 CHD cases from the West of Scotland Coronary Prevention Study (WOSCOPS), two randomized, placebo-controlled studies of pravastatin. In a combined case-only analysis, 79 single nucleotide polymorphisms (SNPs) were associated with differential CHD event reduction by pravastatin according to genotype (P<0.0001), and these SNPs were analyzed in a second stage that included cases as well as non-cases from CARE and WOSCOPS and patients from the PROspective Study of Pravastatin in the Elderly at Risk/PHArmacogenomic study of Statins in the Elderly at risk for cardiovascular disease (PROSPER/PHASE), a randomized placebo controlled study of pravastatin in the elderly. We found that one of these SNPs (rs13279522) was associated with differential CHD event reduction by pravastatin therapy in all 3 studies: P = 0.002 in CARE, P = 0.01 in WOSCOPS, P = 0.002 in PROSPER/PHASE. In a combined analysis of CARE, WOSCOPS, and PROSPER/PHASE, the hazard ratio for CHD when comparing pravastatin with placebo decreased by a factor of 0.63 (95% CI: 0.52 to 0.75) for each extra copy of the minor allele (P = 4.8×10−7). This SNP is located in DnaJ homolog subfamily C member 5B (DNAJC5B) and merits investigation in additional randomized studies of pravastatin and other statins.
Although statin therapy reduces cardiovascular risk, its relationship with the development of diabetes is controversial. The first study (West of Scotland Coronary Prevention Study [WOSCOPS]) that evaluated this association reported a small protective effect but used nonstandardized criteria for diabetes diagnosis. However, results from subsequent hypothesis-testing trials have been inconsistent. The aim of this meta-analysis is to evaluate the possible effect of statin therapy on incident diabetes.
RESEARCH DESIGN AND METHODS
A systematic literature search for randomized statin trials that reported data on diabetes through February 2009 was conducted using specific search terms. In addition to the hypothesis-generating data from WOSCOPS, hypothesis-testing data were available from the Heart Protection Study (HPS), the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study, the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), and the Controlled Rosuvastatin Multinational Study in Heart Failure (CORONA), together including 57,593 patients with mean follow-up of 3.9 years during which 2,082 incident diabetes cases accrued. Weighted averages were reported as risk ratios (RRs) with 95% CIs using a random-effects model. Statistical heterogeneity scores were assessed with the Q and I2 statistic.
In the meta-analysis of the hypothesis-testing trials, we observed a small increase in diabetes risk (RR 1.13 [95% CI 1.03–1.23]) with no evidence of heterogeneity across trials. However, this estimate was attenuated and no longer significant when the hypothesis-generating trial WOSCOPS was included (1.06 [0.93–1.25]) and also resulted in significant heterogeneity (Q 11.8 [5 d.f.], P = 0.03, I2 = 57.7%).
Although statin therapy greatly lowers vascular risk, including among those with and at risk for diabetes, the relationship of statin therapy to incident diabetes remains uncertain. Future statin trials should be designed to formally address this issue.
Objective: To investigate the influence of age and social circumstances on probability of revascularisation among British men.
Design: Prospective population based study
Setting: 24 medium sized British towns, none of which contained a hospital undertaking coronary artery bypass surgery.
Subjects: 5814 surviving participants of the BRHS (British regional heart study), aged 52–73 years, with no history of revascularisation when responding to a questionnaire in November 1992.
Main outcomes: Incident coronary revascularisations, as documented in general practitioner records, over the following 7.1 years and coronary angiography investigations reported by men in a further questionnaire in November 1996.
Results: 160 men underwent at least one revascularisation during this period (4.2/1000 person-years). In multifactorial analysis, which included adjustment for incidence of major coronary heart disease or angina, a lower incidence of revascularisation was found among men aged over 65 years in November 1992 (hazard ratio 0.62, 95% confidence interval (CI) 0.44 to 0.87), among men with manual occupations (0.73, 95% CI 0.53 to 1.02), among men living in households possessing no car (0.44, 95% CI 0.24 to 0.80) or one car (0.60, 95% CI 0.42 to 0.87) compared with two or more cars, among council tenants (0.49, 95% CI 0.25 to 0.97), and among men living outside southern England (0.71, 95% CI 0.51 to 0.99). Only car ownership was related to the incidence of diagnostic angiography: the odds ratio for angiography for those owning fewer than two cars was 0.62 (95% CI 0.42 to 0.89).
Conclusion: During the 1990s, there were major inequalities in the probability of undergoing coronary revascularisation between British men according to socioeconomic status, age, and geographic location.
age group; coronary revascularisation; epidemiology; social inequality
To test whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) was independently associated with, and improved the prediction of, cardiovascular disease (CVD) in a primary prevention cohort.
Methods and results
In the West of Scotland Coronary Prevention Study (WOSCOPS), a cohort of middle-aged men with hypercholesterolaemia at a moderate risk of CVD, we related the baseline NT-proBNP (geometric mean 28 pg/mL) in 4801 men to the risk of CVD over 15 years during which 1690 experienced CVD events. Taking into account the competing risk of non-CVD death, NT-proBNP was associated with an increased risk of all CVD [HR: 1.17 (95% CI: 1.11–1.23) per standard deviation increase in log NT-proBNP] after adjustment for classical and clinical cardiovascular risk factors plus C-reactive protein. N-terminal pro-B-type natriuretic peptide was more strongly related to the risk of fatal [HR: 1.34 (95% CI: 1.19–1.52)] than non-fatal CVD [HR: 1.17 (95% CI: 1.10–1.24)] (P= 0.022). The addition of NT-proBNP to traditional risk factors improved the C-index (+0.013; P < 0.001). The continuous net reclassification index improved with the addition of NT-proBNP by 19.8% (95% CI: 13.6–25.9%) compared with 9.8% (95% CI: 4.2–15.6%) with the addition of C-reactive protein. N-terminal pro-B-type natriuretic peptide correctly reclassified 14.7% of events, whereas C-reactive protein correctly reclassified 3.4% of events. Results were similar in the 4128 men without evidence of angina, nitrate prescription, minor ECG abnormalities, or prior cerebrovascular disease.
N-terminal pro-B-type natriuretic peptide predicts CVD events in men without clinical evidence of CHD, angina, or history of stroke, and appears related more strongly to the risk for fatal events. N-terminal pro-B-type natriuretic peptide also provides moderate risk discrimination, in excess of that provided by the measurement of C-reactive protein.
Clinical trial registration
WOSCOPS was carried out and completed prior to the requirement for clinical trial registration.
NT-proBNP; Natriuretic peptides; Risk factors; Epidemiology
Routinely collected electronic patient records are already widely used in epidemiological research. In this work we investigated the potential for using them to identify endpoints in clinical trials.
The events recorded in the West of Scotland Coronary Prevention Study (WOSCOPS), a large clinical trial of pravastatin in middle-aged hypercholesterolaemic men in the 1990s, were compared with those in the record-linked deaths and hospitalisations records routinely collected in Scotland.
We matched 99% of fatal study events by date. We showed excellent matching (97%) of the causes of fatal endpoint events and good matching (>80% for first events) of the causes of nonfatal endpoint events with a slightly lower rate of mismatching of record linkage than study events (19% of first study myocardial infarctions (MI) and 4% of first record linkage MIs not matched as MI). We also investigated the matching of non-endpoint events and showed a good level of matching, with >78% of first stroke/TIA events being matched as stroke/TIA. The primary reasons for mismatches were record linkage data recording readmissions for procedures or previous events, differences between the diagnoses in the routinely collected data and the conclusions of the clinical trial expert adjudication committee, events occurring outside Scotland and therefore being missed by record linkage data, miscoding of cardiac events in hospitalisations data as ‘unspecified chest pain’, some general miscoding in the record linkage data and some record linkage errors.
We conclude that routinely collected data could be used for recording cardiovascular endpoints in clinical trials and would give very similar results to rigorously collected clinical trial data, in countries with unified health systems such as Scotland. The endpoint types would need to be carefully thought through and an expert endpoint adjudication committee should be involved.
Objective To examine recent trends and social inequalities in age specific coronary heart disease mortality.
Design Time trend analysis using joinpoint regression.
Setting Scotland, 1986-2006.
Participants Men and women aged 35 years and over.
Main outcome measures Age adjusted and age, sex, and deprivation specific coronary heart disease mortality.
Results Persistent sixfold social differentials in coronary heart disease mortality were seen between the most deprived and the most affluent groups aged 35-44 years. These differentials diminished with increasing age but equalised only above 85 years. Between 1986 and 2006, overall, age adjusted coronary heart disease mortality decreased by 61% in men and by 56% in women. Among middle aged and older adults, mortality continued to decrease fairly steadily throughout the period. However, coronary heart disease mortality levelled from 1994 onwards among young men and women aged 35-44 years. Rates in men and women aged 45-54 showed similar flattening from about 2003. Rates in women aged 55-64 may also now be flattening. The flattening of coronary heart disease mortality in younger men and women was confined to the two most deprived fifths.
Conclusions Premature death from coronary heart disease remains a major contributor to social inequalities. Furthermore, the flattening of the decline in mortality for coronary heart disease among younger adults may represent an early warning sign. The observed trends were confined to the most deprived groups. Marked deterioration in medical management of coronary heart disease seems implausible. Unfavourable trends in the major risk factors for coronary heart disease (smoking and poor diet) thus provide the most likely explanation for these inequalities.
OBJECTIVE: To examine the relation between smoking status, clinical need, and likelihood of coronary artery bypass grafting in middle aged men. DESIGN: A prospective study of cardiovascular disease in British men aged 40 to 59 years, screened in 1978-80 and followed until December 1991. SUBJECTS AND SETTING: 7735 men drawn from one general practice in each of 24 British towns. MAIN OUTCOME MEASURE: Coronary artery bypass graft surgery. RESULTS: Of the 3185 current smokers, 38 (1.03/1000/year) underwent coronary artery bypass surgery compared with 47 of 2715 (1.45/1000/year) ex-smokers, and 19 of 1817 (0.85/1000/year) never-smokers. Ex-smokers had a lower incidence of major ischaemic heart disease during follow up than current smokers. After adjustment for incidence of ischaemic heart disease during follow up, the hazard ratio of coronary artery bypass surgery for ex-smokers compared with smokers was 1.52 (95% confidence interval 0.99 to 2.34). Ex-smokers were more likely at screening to recall a doctor diagnosis of ischaemic heart disease than smokers (7.1% v 5.3%), but among those who recalled a doctor diagnosis, smokers were less likely to undergo coronary artery bypass surgery than ex-smokers (9.4% v 3.5%, P = 0.026). By 1992, men defined as smokers at screening were no less likely than ex-smokers to have been referred to a cardiologist (18.5% v 18.8%), nor to report having undergone coronary angiography less frequently than ex-smokers (12.7% v 11.4%). CONCLUSION: Even allowing for the strong relation between coronary artery bypass surgery and clinical need, continuing smokers were less likely to undergo coronary artery bypass surgery than ex-smokers. A complex interplay exists between the men's experience of heart disease, the decision to stop smoking, and the willingness of doctors to consider coronary artery bypass surgery.
Familial hypercholesterolaemia (FH) is an autosomal codominant disorder characterised by high levels of LDL cholesterol and a high incidence of coronary artery disease. Our aims were to track the low density lipoprotein receptor (LDLR) gene in individual families with phenotypic FH and to identify and characterise any mutations of the LDLR gene that may be common in the west of Scotland FH population using single strand conformational polymorphism analysis (SSCP). Patient samples consisted of 80 heterozygous probands with FH, 200 subjects who were related to the probands, and a further 50 normal, unrelated control subjects. Tracking of the LDLR gene was accomplished by amplification of a 19 allele tetranucleotide microsatellite that is tightly linked to the LDLR gene locus. Primers specific for exon 4 of the LDLR gene were used to amplify genomic DNA and used for SSCP analysis. Any PCR products with different migration patterns as assessed by SSCP were then sequenced directly. In addition to identifying probands with a common mutation, family members were screened using a forced restriction site assay and analysed using microplate array diagonal gel electrophoresis (MADGE). Microsatellite D19S394 analysis was informative in 20 of 23 families studied. In these families there was no inconsistency with segregation of the FH phenotype with the LDLR locus. Of the FH probands, 15/80 had a mutant allele as assessed by SSCP using three pairs of primers covering the whole of exon 4 of the LDLR gene. Direct DNA sequencing showed that 7/15 of the probands had a C163Y mutation. Using a PCR induced restriction site assay for the enzyme RsaI and MADGE, it was determined that the C163Y mutation cosegregated with the FH phenotype in family members of the FH probands. This mutant allele was not present in any of the control subjects. Microsatellite analysis has proven useful in tracking the LDLR gene and could be used in conjunction with LDL cholesterol levels to diagnose FH, especially in children and young adults where phenotypic diagnosis can be difficult.
To assess the impact on healthcare resource utilization, costs, and quality of life over 15 years from 5 years of statin use in men without a history of myocardial infarction in the West of Scotland Coronary Prevention Study (WOSCOPS).
Six thousand five hundred and ninety-five participants aged 45–54 years were randomized to 5 years treatment with pravastatin (40 mg) or placebo. Linkage to routinely collected health records extended follow-up for secondary healthcare resource utilization to 15 years. The following new results are reported: cause-specific first and recurrent cardiovascular hospital admissions including myocardial infarction, heart failure, stroke, coronary revascularization and angiography; non-cardiovascular hospitalization; days in hospital; quality-adjusted life years (QALYs); costs of pravastatin treatment, treatment safety monitoring, and hospital admissions.
Five years treatment of 1000 patients with pravastatin (40 mg/day) saved the NHS £710 000 (P < 0.001), including the cost of pravastatin and lipid and safety monitoring, and gained 136 QALYs (P = 0.017) over the 15-year period. Benefits per 1000 subjects, attributable to prevention of cardiovascular events, included 163 fewer admissions and a saving of 1836 days in hospital, with fewer admissions for myocardial infarction, stroke, heart failure and coronary revascularization. There was no excess in non-cardiovascular admissions or costs (or in admissions associated with diabetes or its complications) and no evidence of heterogeneity of effect over sub-groups defined by baseline cardiovascular risk.
Five years' primary prevention treatment of middle-aged men with a statin significantly reduces healthcare resource utilization, is cost saving, and increases QALYs. Treatment of even younger, lower risk individuals is likely to be cost-effective.
Pravastatin; Cardiovascular outcomes; Record linkage; Cost effectiveness; Primary prevention
The Tarim Basin, located on the ancient Silk Road, played a very important role in the history of human migration and cultural communications between the West and the East. However, both the exact period at which the relevant events occurred and the origins of the people in the area remain very obscure. In this paper, we present data from the analyses of both Y chromosomal and mitochondrial DNA (mtDNA) derived from human remains excavated from the Xiaohe cemetery, the oldest archeological site with human remains discovered in the Tarim Basin thus far.
Mitochondrial DNA analysis showed that the Xiaohe people carried both the East Eurasian haplogroup (C) and the West Eurasian haplogroups (H and K), whereas Y chromosomal DNA analysis revealed only the West Eurasian haplogroup R1a1a in the male individuals.
Our results demonstrated that the Xiaohe people were an admixture from populations originating from both the West and the East, implying that the Tarim Basin had been occupied by an admixed population since the early Bronze Age. To our knowledge, this is the earliest genetic evidence of an admixed population settled in the Tarim Basin.
Surveys from several countries have identified the presence of risk factors known to be associated with coronary heart disease in children. Data on the distribution of coronary risk factor variables in British children are scarce. This study was therefore designed to test the feasibility of collecting coronary risk factor data from British children and to conduct a preliminary examination of the problem. One hundred and seven children (mean age 12.8 yr) had their height, weight, triceps skinfold and blood pressure checked. Blood samples for cholesterol and HDL-cholesterol analysis were obtained from 93 children. Peak VO2 was determined on 48 children, 76 children had their daily activity monitored and 59 children's stage of sexual maturity was assessed. The boys' peak VO2 was significantly higher than the girls, whether expressed in l.min-1 (p less than 0.05) or ml.kg.-1min-1 (p less than 0.01). No other significant differences (p greater than 0.05) between the sexes were detected. The results indicate that children have relatively high serum cholesterol levels (boys 4.58 +/- 0.79; girls 4.72 +/- 0.80 mmol.l-1). The willingness and enthusiasm of the children, parents and schools to take part in the study clearly demonstrated the feasibility of a large scale study being successfully pursued in the United Kingdom.
The indications, complexity and capabilities of cardiovascular magnetic resonance (CMR) have rapidly expanded. Whether actual service provision and training have developed in parallel is unknown.
We undertook a systematic telephone and postal survey of all public hospitals on behalf of the British Society of Cardiovascular Magnetic Resonance to identify all CMR providers within the United Kingdom.
Of the 60 CMR centres identified, 88% responded to a detailed questionnaire. Services are led by cardiologists and radiologists in equal proportion, though the majority of current trainees are cardiologists. The mean number of CMR scans performed annually per centre increased by 44% over two years. This trend was consistent across centres of different scanning volumes. The commonest indication for CMR was assessment of heart failure and cardiomyopathy (39%), followed by coronary artery disease and congenital heart disease. There was striking geographical variation in CMR availability, numbers of scans performed, and distribution of trainees. Centres without on site scanning capability refer very few patients for CMR. Just over half of centres had a formal training programme, and few performed regular audit.
The number of CMR scans performed in the UK has increased dramatically in just two years. Trainees are mainly located in large volume centres and enrolled in cardiology as opposed to radiology training programmes.
Objective To examine trends over time in rates of different forms of diagnosed coronary heart disease among British men, during a period in which mortality due to coronary heart disease has been declining.
Design Prospective cohort study covering the period 1978-80 to 1998-2000.
Participants 7735 men, aged 40-59 at entry, randomly selected from one general practice in each of 24 British towns.
Main outcome measures Trends in the rates of major coronary events, first diagnosed angina and first diagnosed coronary heart disease (any fatal or non-fatal documented event or diagnosis). Events were ascertained from NHS central registers and reviews of medical records from general practices.
Results Over the 20 year period, 1561 major coronary events occurred; 1087 and 1816 men had new diagnoses of angina and coronary heart disease, respectively. The age adjusted annual relative changes were -3.6% (95% confidence interval -4.8% to -2.4%, P < 0.001) for all major coronary events, 2.6% (1.1% to 4.0%, P < 0.001) for first diagnosed angina and -0.8% (-1.8% to 0.3%, P = 0.18) for first diagnosed coronary heart disease. The fall in major coronary events occurred across all categories of event (fatal and non-fatal, first and recurrent). Similarly, first diagnosed angina increased for both uncomplicated angina and angina after myocardial infarction. The age adjusted annual relative change in case fatality at 28 days of first major coronary events was -1.4% (-3.1% to 0.4%, P = 0.12).
Conclusions Among British middle aged men, a substantial decline in the rate of major coronary events over the past two decades seems to have been largely offset by an increase in the incidence of diagnosed angina. Overall there was little change in the incidence of first diagnosed coronary heart disease. A continuing need exists for resources and services for coronary heart disease in general, and for new angina in particular.
Objective To establish the predictive accuracy of the Framingham risk score for coronary heart disease in a representative British population.
Design Prospective cohort study.
Setting 24 towns in the United Kingdom.
Participants 6643 British men aged 40-59 years and free from cardiovascular disease at entry into the British regional heart study.
Main outcome measures Comparison of observed 10 year coronary heart disease mortality and event rates with predicted rates for each individual, using the relevant Framingham risk equation.
Results Of 6643 men, 2.8% (95% confidence interval 2.4% to 3.2%) died from coronary heart disease compared with 4.1% predicted (relative overestimation 47%, P < 0.0001). A fatal or non-fatal coronary heart disease event occurred in 10.2% (9.5% to 10.9%) of the men compared with 16.0% predicted (relative overestimation 57%, P < 0.0001). These relative degrees of overestimation were similar at all levels of coronary heart disease risk, so that overestimation of absolute risk was greatest for those at highest risk. A simple adjustment provided an improved level of accuracy. In a “high risk score” approach, most cases occur in the low risk group. In this case, 84% of the deaths from coronary heart disease and non-fatal events occurred in the 93% of men classified at low risk (< 30% in 10 years) by the Framingham score.
Conclusion Guidelines for the primary prevention of coronary heart disease advocate offering preventive measures to individuals at high risk. Currently recommended risk scoring methods derived from the Framingham study significantly overestimate the absolute coronary risk assigned to individuals in the United Kingdom.
OBJECTIVE--To examine the role of insulin as a cardiovascular risk factor in British Asian and white men. DESIGN--Case-controlled study of survivors of first myocardial infarction. SETTING--District general hospital. PATIENTS--Consecutive series of 76 white and 74 Asian men who survived first myocardial infarction compared with 58 white and 61 Asian male controls without coronary artery disease who were randomly sampled from the community. RESULTS--More Asians than white subjects had impaired glucose tolerance or overt diabetes as measured by the two hour glucose tolerance test (23/74 (32%) v 11/76 (15%) (p less than 0.001) among patients; 17/61 (28%) v 3/58 (6%) (p less than 0.001) among controls). Insulin and C peptide concentrations were higher in both patient groups than in respective controls (p less than 0.001) and higher in Asian than in white subjects, irrespective of their glucose tolerance. Triglyceride concentrations were higher in patients than in controls (1.92 (SD 1.05) v 1.43 (0.82) mmol/l among Asian men; 1.65 (0.83) v 1.3 (0.61) mmol/l among white subjects; p less than 0.001). Total cholesterol concentrations were lower in both groups of Asians than in respective white subjects (5.78 (0.99) v 6.22 (1.04) mmol/l (p less than 0.01) among patients; 5.54 (1.01) v 5.65 (1.11) mmol/l (p less than 0.6) among controls). High density lipoprotein cholesterol concentrations were lower in Asian than in white subjects. The ratio of total cholesterol to high density lipoprotein cholesterol was significantly higher (p less than 0.001) in both patient groups (6.69 (1.81) in Asian patients and 6.31 (1.91) in white patients) than in respective controls (5.24 (1.19) and 4.77 (1.43)). Regression analysis identified C peptide concentration and the ratio of total to high density lipoprotein cholesterol as powerful independent predictors of myocardial infarction in Asian and white men. Total cholesterol concentration predicted infarction in white but not in Asian men. CONCLUSIONS--Secretion and hepatic extraction of insulin are high in survivors of myocardial infarction and especially high in British Asians. Tissue resistance to the action of insulin, giving rise to increased pancreatic secretion, may be an important risk factor for coronary artery disease in both ethnic groups and may be partly responsible for the high incidence of diabetes and coronary artery disease in Asian populations.
OBJECTIVE: To estimate the economic efficiency of using pravastatin to prevent the transition from health to cardiovascular disease in men with hypercholesterolaemia. DESIGN: Economic benefit analysis based on data from the West of Scotland coronary prevention study. Treatment specific hazards of developing cardiovascular disease according to various definitions were estimated. Scottish record linkage data provided disease specific survival. Cost estimates were based on extracontractual tariffs and event specific average lengths of stay calculated from the West of Scotland coronary prevention study. SUBJECTS: Men with hypercholesterolaemia similar to the subjects in the West of Scotland coronary prevention study. MAIN OUTCOME: Cost consequences, the number of transitions from health to cardiovascular disease prevented, the number needed to start treatment, and cost per life year gained. RESULTS: If 10,000 of these men started taking pravastatin, 318 of them would not make the transition from health to cardiovascular disease (number needed to treat, 31.4), at a net discounted cost of 20m Pounds over 5 years. These benefits imply an undiscounted gain of 2,460 years of life, and thus 8121 Pounds per life year gained, or 20,375 Pounds per life year gained if benefits are discounted. Restriction to the 40% of men at highest risk reduces the number needed to treat to 22.5 (5601 Pounds per life year gained (undiscounted) and 13,995 Pounds per life year gained (discounted)). CONCLUSIONS: In subjects without evidence of prior myocardial infarction but who have hypercholesterolaemia, the use of pravastatin yields substantial health benefits at a cost that is not prohibitive overall and can be quite efficient in selected high risk subgroups.
It is known that mitochondria play an important role in certain cancers (prostate, renal, breast, or colorectal) and coronary disease. These organelles play an essential role in apoptosis and the production of reactive oxygen species; in addition, mtDNA also reveals the history of populations and ancient human migration. All these events and variations in the mitochondrial genome are thought to cause some cancers, including prostate cancer, and also help us to group individuals into common origin groups. The aim of the present study is to analyze the different haplogroups and variations in the sequence in the mitochondrial genome of a southern European population consisting of subjects affected (n = 239) and non-affected (n = 150) by sporadic prostate cancer.
Methodology and Principal Findings
Using primer extension analysis and DNA sequencing, we identified the nine major European haplogroups and CR polymorphisms. The frequencies of the haplogroups did not differ between patients and control cohorts, whereas the CR polymorphism T16356C was significantly higher in patients with PC compared to the controls (p = 0.029). PSA, staging, and Gleason score were associated with none of the nine major European haplogroups. The CR polymorphisms G16129A (p = 0.007) and T16224C (p = 0.022) were significantly associated with Gleason score, whereas T16311C (p = 0.046) was linked with T-stage.
Conclusions and Significance
Our results do not suggest that mtDNA haplogroups could be involved in sporadic prostate cancer etiology and pathogenesis as previous studies performed in middle Europe population. Although some significant associations have been obtained in studying CR polymorphisms, further studies should be performed to validate these results.
Coronary angiography has been the gold standard for determining the severity, extent and prognosis of coronary atheromatous disease for the past 15–20 years. However, established non‐invasive testing (such as myocardial perfusion scintigraphy and stress echocardiography) and newer imaging modalities (multi‐detector x ray computed tomography and cardiovascular magnetic resonance) now need to be considered increasingly as a challenge to coronary angiography in contemporary practice. An important consideration is the degree to which appropriate use of such techniques impacts on the need for coronary angiography over the next 10–15 years. This review aims to determine the role of the various investigation techniques in the management of coronary artery disease and their resource implications, and should help determine future service provision, accepting that we are in a period of significant technological change.
A detailed analysis of the extent of coronary artery atherosclerosis was made in 92 white subjects (66 men and 26 women) who died suddenly from ischaemic heart disease. Stenoses resulting in loss of greater than or equal to 75% of luminal cross sectional area (significant stenosis) were found in 90 subjects and these were more extensive in the proximal coronary tree than in the distal. Thirty nine per cent had triple vessel disease, 37% had double vessel disease, and 23% had single vessel disease. In addition one man had an isolated significant stenosis affecting the left main coronary artery. The frequency of significant stenoses in the left main coronary artery was greater in men than in women. The arteries that were least affected were the distal branches of the right coronary artery. A notable feature was the widespread nature of the coronary atherosclerosis: only 26 of the total of 1840 segments of coronary artery examined in the 92 victims could be described as having a normal intima (less than or equal to 10% loss of the area within the internal elastic lamina).
Despite regional variations in the prevalence of coronary artery disease (CAD), men are consistently more at risk of developing and dying from CAD than women, and the gender-specific effects of sex hormones are implicated in this inequality. This ‘Perspectives' article reviews the current evidence regarding the cardiovascular effects of testosterone in men including an examination of the age-related decline in testosterone, the relationship between testosterone levels and coronary disease, coronary risk factors and mortality. We also review the vaso-active effects of testosterone, and discuss how these have been used in men with heart failure and angina. We discuss the ‘cause' versus ‘effect' controversy, regarding low testosterone levels in men with coronary heart disease, as well as concerns over the use of testosterone replacement therapy in middle aged and elderly men. The article concludes with a discussion regarding the future direction for work in this interesting area, including the relative merits of screening for, and treating hypogonadism with testosterone replacement therapy in men with heart disease.
atherosclerosis; chronic heart failure; ischaemic heart disease; replacement therapy; testosterone
Epidemiological case-control studies have revealed associations between mitochondrial haplogroups and the onset and/or progression of various multifactorial diseases. For instance, mitochondrial haplogroup T was previously shown to be associated with vascular diseases, including coronary artery disease and diabetic retinopathy. In contrast, haplogroup H, the most frequent haplogroup in Europe, is often found to be more prevalent in healthy control subjects than in patient study groups. However, justifications for the assumption that haplogroups are functionally distinct are rare. Therefore, we attempted to compare differences in mitochondrial function between haplogroup H and T cybrids.
Mitochondrial haplogroup H and T cybrids were generated by fusion of HEK293 cells devoid of mitochondrial DNA with isolated thrombocytes of individuals with the respective haplogroups. These cybrid cells were analyzed for oxidative phosphorylation (OXPHOS) enzyme activities, mitochondrial DNA (mtDNA) copy number, growth rate and susceptibility to reactive oxygen species (ROS). We observed that haplogroup T cybrids have higher survival rate when challenged with hydrogen peroxide, indicating a higher capability to cope with oxidative stress.
The results of this study show that functional differences exist between HEK293 cybrid cells which differ in mitochondrial genomic background.
Coronary heart disease (CHD) mortality in the UK since the late 1970s has declined more markedly among higher socioeconomic groups. However, little is known about changes in coronary risk factors in different socioeconomic groups. This study examined whether changes in established coronary risk factors in Britain over 20 years between 1978–80 and 1998–2000 differed between socioeconomic groups.
Methods and Findings
A socioeconomically representative cohort of 7735 British men aged 40–59 years was followed-up from 1978–80 to 1998–2000; data on blood pressure (BP), cholesterol, body mass index (BMI) and cigarette smoking were collected at both points in 4252 survivors. Social class was based on longest-held occupation in middle-age. Compared with men in non-manual occupations, men in manual occupations experienced a greater increase in BMI (mean difference = 0.33 kg/m2; 95%CI 0.14–0.53; p for interaction = 0.001), a smaller decline in non-HDL cholesterol (difference in mean change = 0.18 mmol/l; 95%CI 0.11–0.25, p for interaction≤0.0001) and a smaller increase in HDL cholesterol (difference in mean change = 0.04 mmol/l; 95%CI 0.02–0.06, p for interaction≤0.0001). However, mean systolic BP declined more in manual than non-manual groups (difference in mean change = 3.6; 95%CI 2.1–5.1, p for interaction≤0.0001). The odds of being a current smoker in 1978–80 and 1998–2000 did not differ between non-manual and manual social classes (p for interaction = 0.51).
Several key risk factors for CHD and type 2 diabetes showed less favourable changes in men in manual occupations. Continuing priority is needed to improve adverse cardiovascular risk profiles in socially disadvantaged groups in the UK.