Sudden, unexpected cardiac or unexplained death in England: a national survey.

BACKGROUND: Post-mortem examinations of adults who were apparently healthy but died suddenly and unexpectedly sometimes reveal no morphological abnormalities to explain their deaths. The frequency of such unexplained deaths in relation to other causes of sudden cardiac death is not known. AIM: To estimate the frequency of sudden unexpected cardiac or unexplained death in England. DESIGN: Prospective survey using a stratified random sample of 83 of the 132 H.M. Coroner's jurisdictions in England. METHODS: Consecutive White Caucasians, aged 16-64 years, with no medical history of cardiac disease, seen alive within 12 h of death, on whom autopsy found either a cardiac or no identifiable cause of death, were included. The coroner's officer sent a copy of the post-mortem report and a completed case registration form to the investigators, with tissue samples. RESULTS: Sixty-seven (81%) coroners participated, each maintaining prospective surveillance for 4 months. Of 692 ascertained cases, case registration forms were received for 650 (94%), post-mortem reports for 682 (99%), blood samples for 569 (82%), myocardial slices for 517 (75%) and whole hearts for 47 (7%). In cases with myocardial tissue, death was ascribed to ischaemic heart disease in 465 (82.4%). In 43.1% the ischaemia was acute, in 19.1% there was myocardial scarring but no acute ischaemia, and 20.2% had coronary atheroma only. Death was due to left ventricular hypertrophy in 32 (5.7%), to other cardiac causes in 30 (5.3%) and in 23 (4.1%) there was no clear cause. Those with cardiac causes were 81% male, median ages 55.9 (male) and 56.6 (female) years. The 23 unexplained deaths were 57% female, median ages 40.5 (male) and 54.9 (female) years. The estimated annual frequency of sudden unexpected death due to cardiac or unidentified causes, in English adults of employment age, was 11/100,000 (3481 annual deaths). DISCUSSION: In 4.1% of sudden unexpected deaths under 65 years, no cause was found. Until it becomes accepted practice to identify these cases by a name, such as Sudden Adult Death Syndrome (SADS), it will not be possible to study their aetiology systematically.

Designing bronchial biopsy studies.

Bronchial biopsy provides valuable information about the inflammatory processes in lung tissue, but optimal results are only achieved if the design of intervention studies is sufficiently rigorous. The parallel-group design has merit, but the cross-over design is statistically superior, providing the wash-out period is effective. Heterogeneity of contributing pathologies in asthma patients results in large inter-patient variability which must be controlled for, for example by using strict inclusion criteria, which should ideally relate to the specific inflammatory marker being studied. The inclusion of a placebo group helps to quantify sample variability. The study must have sufficient statistical power to detect inter-group differences for each variable; appropriate adjustments should be made when multiple tests are used. Studies with larger patient numbers are best performed using a multi-centre design, with one centre analysing all tissue samples to reduce variability. Study duration depends on the type of investigation, but should ideally be short. Longer studies are necessary to evaluate chronic changes such as tissue remodelling. Changes in clinical status and cellular events may follow different time courses after intervention. Biopsy measurements are less reproducible than physiological tests, and diurnal variation in the number and function of inflammatory cells can further complicate measurement. The timing of clinical trial assessments needs to allow for these idiosyncrasies. Finally, a balance must be maintained between the risk, albeit small, and the benefit of performing bronchial biopsies.

The design and analysis of paired cluster randomized trials: an application of meta-analysis techniques.

The statistical issues in clinical trials where clusters, communities or groups rather than individuals are randomized are often not fully appreciated. In this paper we discuss the design and analysis of trials in which pairs of clusters are randomized in the context of one recent trial, the British Family Heart Study. Both sample size calculations and the analysis strategy need to take account of the between-cluster component of variance. The analysis can be considered as a random effects meta-analysis across cluster pairs, and can usefully be presented as such. Techniques developed in the context of meta-analysis can then be used in the analysis, for example using a profile likelihood method to derive a confidence interval for the overall treatment effect which takes into account the variability in the estimate of the between-cluster variance. The methods presented here are contrasted with previously published methods for cluster randomized trials.

Change in coronary risk and coronary risk factor levels in couples following lifestyle intervention. The British Family Heart Study.

OBJECTIVES: To measure the extent to which changes in cardiovascular risk factors were correlated among married couples following a 1-year primary care, family-centered, cardiovascular lifestyle intervention program and to identify couples who benefited most from this prevention program. DESIGN: Observational study. SETTING: Thirteen primary care centers in 13 towns in Britain. PARTICIPANTS: A total of 1477 men aged 40 to 59 years and their female partners who attended a family health checkup in 1991 to 1992 from randomly ordered invitations to registered families. After 1 year, 1204 (82%) partner pairs were rescreened. MAIN OUTCOME MEASURES: One-year changes in cigarette smoking, systolic blood pressure, serum cholesterol level, blood glucose level, and a total coronary risk score. RESULTS: Comparing men and women partners, baseline values and 1-year changes in overall coronary risk score (Pearson r = 0.27 and r = 0.20, respectively), cigarette smoking, body mass index, systolic blood pressure, cholesterol levels, and glucose levels were all positively correlated (all P < .001 except smoking cessation, P = .03). Changes in cholesterol levels and systolic blood pressure were also associated with partner's baseline measurement (P < or = .01 in both men and women). CONCLUSIONS: Men and women who benefit most from risk factor reductions have partners who also tend to benefit most. Conversely, men and women who enjoy little or no benefit have partners who tend to have similarly small benefits. It is likely that lifestyle intervention targeted at men and women as couples rather than as individuals may result in a greater reduction in cardiovascular risk factors, possibly through mutual reinforcement of lifestyle changes.

Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group.

BACKGROUND: Inflammation is an important feature of atherosclerotic lesions, and increased production of the acute-phase reactant. C-reactive protein (CRF), is associated with a poor prognosis in severe unstable angina. We have investigated the existence and possible significance of the acute-phase responses of CRP and another sensitive reactant, serum amyloid A protein (SAA), in patients with unstable or stable angina. METHODS: We used new ultrasensitive immunoassays to measure CRP and SAA concentrations in plasma from 2121 outpatients with angina (1030 unstable, 743 stable, the rest atypical) enrolled in the European Concerted Action on Thrombosis and Disabilities (ECAT) Angina Pectoris Study. All patients underwent coronary angiography and extensive clinical and laboratory assessment at study entry, and were then followed up for 2 years. All suspected coronary events during follow-up were reviewed by an independent endpoint committee. FINDINGS: 75 individuals (41 with unstable, 29 with stable, and 5 with atypical angina) had a coronary event during follow-up. Concentrations of CRP at study entry were associated with coronary events in patients with stable or unstable angina: there was about a two-fold increase in the risk of a coronary event in patients whose CRP concentration was in the fifth quintile (> 3.6 mg/L), compared with the first four quintiles. A third of the events occurred among patients who had a CRP concentration of more than 3.6 mg/L. CRP concentrations were positively correlated with age, smoking, body-mass index, triglycerides, extent of coronary stenosis, history of myocardial infarction, and lower ejection fraction. By contrast, concentrations of SAA were not associated with risk of a coronary event. INTERPRETATION: We found that raised circulating concentrations of CRP are predictors of coronary events in patients with stable or unstable angina. The modest acute-phase responses of CRP were probably not the result of myocardial necrosis. Whatever the underlying mechanisms, the sensitive measurement of CRP as a prognostic marker may be useful in the management of coronary heart disease.

Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. ECAT Study Group. European Concerted Action on Thrombosis and Disabilities.

BACKGROUND: Disturbances of the fibrinolytic system that lead to decreased removal of fibrin deposits may be important risk factors for coronary thrombosis. There is as yet no consensus on the prognostic value of fibrinolytic parameters, which may be attributed in part to the choice of confounding variables controlled for. METHODS AND RESULTS: The ECAT study is a prospective multicenter study of 3043 patients with angina pectoris followed for 2 years. Baseline measurements included 10 fibrinolytic variables. The results were analyzed in relation to the subsequent incidence of myocardial infarction or sudden coronary death. They are presented before and after adjustment for clusters of confounding variables that are markers of different mechanisms: insulin resistance (body mass index, triglyceride, and HDL cholesterol), inflammation (fibrinogen and C-reactive protein), and endothelial cell damage (von Willebrand factor). An increased incidence of events was associated with higher baseline concentrations of tissue plasminogen activator (TPA) antigen (P = .0002), plasminogen activator inhibitor-1 (PAI-1) activity (P = .02), and PAI-1 antigen (P = .001). The associations of PAI-1 activity and PAI-1 antigen with risk of events disappeared after adjustment for parameters reflecting insulin resistance but were not affected by other adjustments. TPA antigen was affected to a similar extent by adjustment for parameters reflecting insulin resistance. Inflammation, or endothelial cell damage, but the risk association disappeared only after combined adjustments. CONCLUSIONS: The prognostic role of PAI-1 in predicting coronary events is related principally to insulin resistance, whereas that of TPA antigen could be explained only by its relationship with different mechanisms, including insulin resistance, inflammation and endothelial cell damage.

Using a coronary risk score for screening and intervention in general practice. British Family Heart Study.

AIM: To investigate whether a risk score proposed by the British Regional Heart Study (BRHS), derived from data collected in 1978-1980, provides an appropriate basis for current coronary risk factor screening and intervention in general practice. METHODS: The BRHS risk score was applied to 1993 men aged 40-59 years and 1353 women aged 35-59 years, from 13 general practices in England, Wales and Scotland, who had health checks during 1991-1992 in the British Family Heart Study (FHS). Modifications to the BRHS risk score were made in order to identify subjects with a current high risk compared with others of the same age and sex. These were validated on 3272 men and 2229 women recruited from different general practices during 1992-1994 in the FHS. RESULTS: Only 9% of men in the FHS fell into the published top (highest risk) quintile of the BRHS score, versus an expected 20%, and 44% fell into the bottom quintile. Scores were, on average, substantially lower in the FHS men than in the BRHS men, principally because of lower measured cholesterol levels (using a Reflotron) and a lower prevalence of cigarette-smoking. The BRHS scores also tended to increase with age, disproportionately identifying older subjects, and were substantially lower in women than in men. Simple age-related modifications to the risk score were therefore devised to overcome these problems. These modifications performed well in the validation. CONCLUSIONS: The substantial difference in risk scores between the BRHS and FHS men may reflect both a real reduction in risk and changes in calibration and methodology. Current use of the BRHS risk score may therefore mislead doctors and patients in the direction of complacency. In addition, the published BRHS risk score has an age-dependence that is undesirable in terms of guiding the intensity of lifestyle intervention which should be offered to an individual patient. The simple modifications proposed provide a more appropriate basis for coronary risk factor screening and intervention in general practice, and one that can be used both for men and for women.

A British Cardiac Society survey of the potential for the secondary prevention of coronary disease: ASPIRE (Action on Secondary Prevention through Intervention to Reduce Events).

OBJECTIVE: To measure the potential for secondary prevention of coronary disease in the United Kingdom. DESIGN: Cross sectional survey of a representative sample of coronary patients from a retrospective review of hospital medical records and patient interview and examination. SETTING: Stratified random sample of 12 specialist cardiac centres and 12 district general hospitals drawn from 34 specialist cardiac centres and 261 district general hospitals in 12 geographic areas in the United Kingdom. SUBJECTS: 2583 patients < or = 70 yr; 25 consecutive males and 25 consecutive females identified retrospectively in each of four diagnostic categories: coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, acute myocardial infarction, and acute myocardial ischaemia without evidence of infarction. MAIN OUTCOME MEASURES: Risk factor recording and management in medical records; the prevalence and control of risk factors at interview six months after the procedure or event. RESULTS: Recording of coronary risk factors in patient's records was incomplete and this varied by risk factor. Smoking habit and blood pressure were most completely recorded, whereas a history of hyperlipidaemia and blood cholesterol concentrations were least complete. Risk factor records were more likely to be complete in cardiac centres than in district hospitals. At interview 10% to 27% of patients were still smoking cigarettes and 75% remained overweight, females more severely so. Up to a quarter of patients remained hypertensive, males more severely so than females. Over three quarters had a total cholesterol > 5.2 mmol/l. In patients on medication for blood pressure, cholesterol or glucose, risk factor profiles were little better than in those who were not. Only about one patient in three was taking a beta blocker after infarction. Up to a fifth of patients who had had acute myocardial ischaemia were not taking aspirin at follow up. CONCLUSIONS: There is considerable potential to reduce the risk of a further major ischaemic event in patients with established coronary disease. This can be achieved by effective lifestyle intervention, the rigorous management of blood pressure and cholesterol, and the appropriate use of prophylactic drugs.

Dietary change after smoking cessation: a prospective study.

A population sample of 375 men and women cigarette smokers were recruited to take part in a prospective study of smoking cessation to test the hypothesis that stopping smoking is associated with an increased consumption of the essential fatty acid linoleic acid, which explains the concomitant reduction in risk of coronary heart disease. Diet was assessed using a 10 d weighed record in 301 smokers at baseline, 153 at 4-month follow-up, of whom twenty-six had quit smoking, and 122 at 1-year follow-up, of whom twenty had quit. Compared with continuing smokers, those who had quit at the 4-month follow-up (mean 10 and 13 weeks for men and women respectively) had statistically significant increases in body weight (5%), energy intake (13%), total dietary fat (24%), all specific types of dietary fat (26% polyunsaturated fat, 26% linoleic acid, 30% eicosapentaenoic acid, 23% monounsaturated fat and 22% saturated fat) and vitamin E intake (19%). The foods which appeared to contribute to increases in energy and fat intakes at the 4-month follow-up were vegetable oils and polyunsaturated margarines, processed meats and meat pies. By follow-up at 1 year (mean time since quitting 31 and 41 weeks for men and women respectively) there were no detectable differences in energy and total fat intakes. However, intakes of eicosapentaenoic acid and pteroylglutamate (folate) were statistically significantly higher in the quitters compared with the continuing smokers (37% for eicosapentaenoic acid and 16% for folate). We conclude that the short-term increase in dietary intake of linoleic acid, which is not sustained by 1 year, cannot explain the reduction in risk of coronary disease following smoking cessation.

Cutaneous leishmaniasis in the Peruvian Andes: an epidemiological study of infection and immunity.

A prospective longitudinal survey of cutaneous leishmaniasis (Leishmania peruviana) was carried out in Peru on a study population of 4716 persons living in 38 villages (Departments of Lima, Ancash and Piura). Demographic and clinical data were collected from all individuals, and a Montenegro skin test (MST) was carried out on 72% (3418) of the study population. Each household was revisited at 3-monthly intervals for up to 2 years to detect new leishmaniasis cases; 497 people received a second MST at the end of the study. Analysis of the epidemiological data indicated that (i) 17% (16/94) of all infections were subclinical, (ii) this percentage increased significantly with age, (iii) clinical infections led to 73.9% protective immunity (95% C.I. 53.0-85.5%) and relatively permanent MST responsiveness (recovery rate = 0.0098/year; 95% C.I. 0.000-0.020/year), (iv) sub-clinical infections led to protective immunity, which was positively correlated with their MST induration size (increasing by 17.9% per mm; P < 0.0001), and a mean MST recovery rate of 0.114/year (4/421 man-months), and (v) recurrent leishmaniasis was dominated by reactivations, not by reinfections.

Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group.

BACKGROUND: Increased levels of certain hemostatic factors may play a part in the development of acute coronary syndromes and may be associated with an increased risk of coronary events in patients with angina pectoris. METHODS: We conducted a prospective multicenter study of 3043 patients with angina pectoris who underwent coronary angiography and were followed for two years. Base-line measurements included the concentrations of selected hemostatic factors indicative of a thrombophilic state or endothelial injury. The results were analyzed in relation to the subsequent incidence of myocardial infarction or sudden coronary death. RESULTS: After adjustment for the extent of coronary artery disease and other risk factors, an increased incidence of myocardial infarction or sudden death was associated with higher base-line concentrations of fibrinogen (mean +/- SD, 3.28 +/- 0.74 g per liter in patients who subsequently had coronary events, as compared with 3.00 +/- 0.71 g per liter in those who did not; P = 0.01), von Willebrand factor antigen (138 +/- 49 percent vs. 125 +/- 49 percent, P = 0.05), and tissue plasminogen activator (t-PA) antigen (11.9 +/- 4.7 ng per milliliter vs. 10.0 +/- 4.2 ng per milliliter, P = 0.02). The concentration of C-reactive protein was also directly correlated with the incidence of coronary events (P = 0.05), except when we adjusted for the fibrinogen concentration. In patients with high serum cholesterol levels, the risk of coronary events rose with increasing levels of fibrinogen and C-reactive protein, but the risk remained low even given high serum cholesterol levels in the presence of low fibrinogen concentrations. CONCLUSIONS: In patients with angina pectoris, the levels of fibrinogen, von Willebrand factor antigen, and t-PA antigen are independent predictors of subsequent acute coronary syndromes. In addition, low fibrinogen concentrations characterize patients at low risk for coronary events despite increased serum cholesterol levels. Our data are consistent with a pathogenetic role of impaired fibrinolysis, endothelial-cell injury, and inflammatory activity in the progression of coronary artery disease.

Variability over time of haemostatic and other cardiovascular risk factors in patients suffering from angina pectoris. ECAT Angina Pectoris Study Group.

The variability of haemostatic factor measurements in patients presenting with angina pectoris is investigated. In all, 219 middle aged patients (almost all men) provided repeat measurements 2.5 years apart on a battery of haemostatic and haematological tests and other cardiovascular risk factors. Correlations between repeat measurements were lower than might be expected in a healthy population, reflecting a relatively large degree of variability within individuals over time. The highest correlations observed for haemostatic factors were for von Willebrand factor related antigen (r = 0.48) and fibrinogen (r = 0.45). The correlations were generally lower amongst patients who had undergone coronary surgery or angioplasty between the two measurements. We conclude that the underlying relationship of fibrinogen to coronary risk must be much greater than is generally appreciated, since even single measurements are found to be important predictors of risk, despite only moderate stability over time. The very low correlations for beta-thromboglobulin (r = 0.10) and platelet factor 4 (r = 0.03) which were observed in this study casts doubt on their potential usefulness as predictors of long-term cardiovascular risk.

Association between circulating antigen and parasite load in a model filarial system, Acanthocheilonema viteae in jirds.

Jirds (Meriones libycus) were infected with various numbers of Acanthocheilonema viteae L3 stage parasites. During the course of the ensuing 16 weeks, blood samples were collected at 2 weekly intervals and the amount of the major parasite excretory-secretory product (E-S 62) and antibodies directed against it measured. After 16 weeks, animals were sacrificed and the size of the mature worm burden established. In spite of interaction between E-S 62 and host antibody, a statistically significant relationship was found to exist between the amount of E-S 62 present in the bloodstream and the size of the parasite load. It is suggested that the detectable antigen level is more influenced by the size of the worm burden than the presence of antibody and that antibody is only likely to affect adversely antigen measurement in situations where the amount released is relatively low. Examples of this are early in infection and in low-level infections. These ideas are discussed in relation to the development and assessment of serological assays which attempt to predict parasite burden in human filarial infections.