Major Ischaemic Heart Disease Events Research Articles

Myocardial perfusion imaging in women for the evaluation of stable ischemic heart disease—state-of-the-evidence and clinical recommendations

This document from the American Society of Nuclear Cardiology represents an updated consensus statement on the evidence base of stress myocardial perfusion imaging (MPI), emphasizing new developments in single-photon emission tomography (SPECT) and positron emission tomography (PET) in the clinical evaluation of women presenting with symptoms of stable ischemic heart disease (SIHD). The clinical evaluation of symptomatic women is challenging due to their varying clinical presentation, clinical risk factor burden, high degree of comorbidity, and increased risk of major ischemic heart disease events. Evidence is substantial that both SPECT and PET MPI effectively risk stratify women with SIHD. The addition of coronary flow reserve (CFR) with PET improves risk detection, including for women with nonobstructive coronary artery disease and coronary microvascular dysfunction. With the advent of PET with computed tomography (CT), multiparametric imaging approaches may enable integration of MPI and CFR with CT visualization of anatomical atherosclerotic plaque to uniquely identify at-risk women. Radiation dose-reduction strategies, including the use of ultra-low-dose protocols involving stress-only imaging, solid-state detector SPECT, and PET, should be uniformly applied whenever possible to all women undergoing MPI. Appropriate candidate selection for stress MPI and for post-MPI indications for guideline-directed medical therapy and/or invasive coronary angiography are discussed in this statement. The critical need for randomized and comparative trial data in female patients is also emphasized.

Association of prediabetes, defined by fasting glucose, HbA1c only, or combined criteria, with the risk of cardiovascular disease in Koreans.

The aim of the present study was to compare the association between cardiovascular diseases (CVD) and prediabetes defined by either fasting plasma glucose (FPG), HbA1c, or their combination in a Korean population. In all, 76 434 South Koreans who voluntarily underwent a general health examination in the Health Screening & Promotion Center (Asan Medical Center) were analyzed after excluding patients with a previous history of CVD. Cardiovascular events and death due to CVD during a median follow-up period of 3.1 years (interquartile range 1.9-4.3 years) were identified from the Nationwide Health Insurance Claims Database and death certificates using ICD-10 codes. Age- and sex-adjusted hazard ratios (HRs) for overall CVD events were significantly greater for subjects with prediabetes defined by FPG only (HR 1.19; 95% confidence interval [CI] 1.08-1.31), HbA1c only (HR 1.28; 95% CI 1.16-1.42), and combined criteria (HR 1.20; 95% CI 1.09-1.32) compared with the normoglycemic group. After adjusting for multiple conventional risk factors (e.g. hypertension, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, smoking status, family history of CVD, and BMI), the HRs for overall CVD were significantly increased only for participants with prediabetes defined by HbA1c. Age- and sex-adjusted HRs for major ischemic heart disease events were significantly increased for subjects with prediabetes defined either by HbA1c or combined criteria. Similarly, age- and sex-adjusted HRs for percutaneous coronary intervention were significantly higher for subjects with prediabetes defined by HbA1c only. For diabetes, the multivariate-adjusted HRs for all outcomes were significantly increased by all three criteria. Adding an HbA1c criterion when defining prediabetes in Koreans can help identify individuals with an increased risk of CVD.

One in four major ischaemic heart disease events are fatal and 60% are pre-hospital deaths: a national data-linkage study (ANZACS-QI 8).

The aim of this study is to determine proportions of major ischaemic heart disease (IHD) events that are fatal and where they occur, in an era of rapidly falling IHD mortality. Individual person linkage of national data sets identified all IHD hospitalizations and deaths in New Zealand from December 2008 to November 2010. Outcome measures were proportions of people: (i) hospitalized with IHD and alive at 28 days; (ii) hospitalized with IHD and died within 28 days; (iii) hospitalized for a non-IHD cause and died from IHD within 28 days; and (iv) not hospitalized and died from IHD. Three event definitions were used [broad-balanced: IHD deaths and IHD hospitalizations, unbalanced: IHD deaths and myocardial infarction (MI) hospitalizations, and narrow-balanced: MI deaths and MI hospitalizations]. About 37 867 IHD hospitalizations and 9409 IHD deaths were identified using the broad IHD definition. Approximately one-quarter of IHD events were fatal: 4% were deaths within 28 days of an IHD hospitalization, 6% were IHD deaths within 28 days of a non-IHD hospitalization, and 14% were non-hospitalized IHD deaths. Using different event definitions, overall case fatality varied from 24–25% (broad and narrow balanced) to 37–39% (unbalanced), whereas the proportion of all deaths that were non-hospitalized was approximately 60%. Forty per cent of deaths were first-ever events that manifested as non-hospitalized IHD deaths. About one-quarter of IHD are fatal, although the proportion is dependent on disease definitions and age. About 60% of all IHD deaths occur out of hospital, and of these 60% are in people not previously hospitalized for IHD.

Serum Triglyceride Levels and Cardiovascular Disease Events in Koreans

Objectives: Hypercholesterolemia, especially elevated levels of LDL-cholesterol, is a well-known risk factor for cardiovascular disease (CVD). However, the role of triglycerides in CVD risk remains controversial. Methods: We enrolled 86,476 individuals who had undergone a general health checkup at Asan Medical Center between January 2007 and June 2011. After exclusion criteria were applied to the total cohort, 76,434 participants were included. CVD events and death were gathered from the nationwide health insurance claims database and death certificates using ICD-10 codes. Results: Age- and sex-adjusted odds ratios (ORs) of the higher triglyceride group were significantly increased: 1.52 (95% CI: 1.27-1.82) for major CVD events, 1.53 (95% CI: 1.24-1.88) for major ischemic heart disease events, and 1.49 (95% CI: 1.37-1.63) for overall CVD events. After adjustment for multiple risk factors including HDL-cholesterol, ORs for overall CVD events were significantly increased in the higher triglyceride group. When the analysis was stratified according to BMI, hypertension, and glycemic status at baseline, age- and sex-adjusted ORs for the outcomes were significantly increased in the higher triglyceride group with nonobese, normotensive, or nondiabetic subjects. Conclusions: Hypertriglyceridemia is independently associated with an increased risk for CVD, especially in nonobese, normotensive, or nondiabetic individuals.

Effects of cardiac rehabilitation and exercise training on autonomic regulation in patients with coronary artery disease

Background Although cardiovascular rehabilitation and exercise training have substantial benefits in various ischemic heart disease (IHD) risk factors and subsequent prognosis after major IHD events, there is a paucity of information about its effects on autonomic regulation (such as heart rate variability [HRV] and baroreflex gain), particularly considering its arterial and cardiopulmonary components. Methods We studied 40 patients (aged 60 ± 6 y) after major IHD events, including 29 who underwent a comprehensive phase II cardiac rehabilitation and exercise training program and 11 controls who did not attend cardiac rehabilitation. Specifically, we determined whether active training improves prognostic indices of autonomic regulation of the SA node and whether changes in baroreflex gain could be ascribed to the arterial or to the cardiopulmonary component of the overall arterial pressure/heart period baroreflex. Results Only patients with IHD undergoing active rehabilitation demonstrated a significant increase in R-R interval, in its variance, in overall gain of arterial pressure/heart period baroreflex (7.44 ± 1.20 ms/mm Hg to 12.12 ± 1.48 ms/mm Hg, P <.001) and in peak oxygen consumption (Δ = 2.45 mL/kg/min, P <.001). Separate examination of the selective arterial and cardiopulmonary components showed that only the latter increased significantly (6.17 ± 1.09 ms/mm Hg to 10.62 ± 1.56 ms/mm Hg; P <.01). Conclusions Cardiac rehabilitation is associated with significant improvements in autonomic markers of neural regulation of the SA node, such as increases in R-R variance and the gain of the overall spontaneous baroreflex, with specific improvements in the cardiopulmonary component as opposed to the arterial baroreflex component of this system. These improvements may further explain the reduction in morbidity and mortality noted after formal cardiac rehabilitation and exercise training programs. (Am Heart J 2002;143:977-83.)

Do total and high density lipoprotein cholesterol and triglycerides act independently in the prediction of ischemic heart disease? Ten-year follow-up of Caerphilly and Speedwell Cohorts.

Several studies have suggested that men with raised plasma triglycerides (TGs) in combination with adverse levels of other lipids may be at special risk of subsequent ischemic heart disease (IHD). We examined the independent and combined effects of plasma lipids at 10 years of follow-up. We measured fasting TGs, total cholesterol (TC), and high density lipoprotein cholesterol (HDLC) in 4362 men (aged 45 to 63 years) from 2 study populations and reexamined them at intervals during a 10-year follow-up. Major IHD events (death from IHD, clinical myocardial infarction, or ECG-defined myocardial infarction) were recorded. Five hundred thirty-three major IHD events occurred. All 3 lipids were strongly and independently predictive of IHD after 10 years of follow-up. Subjects were then divided into 27 groups (ie, 3(3)) by the tertiles of TGs, TC, and HDLC. The number of events observed in each group was compared with that predicted by a logistic regression model, which included terms for the 3 lipids (without interactions) and potential confounding variables. The incidence of IHD was 22.6% in the group with the lipid risk factor combination with the highest expected risk (high TGs, high TC, and low HDLC) and 4.7% in the group with the lowest expected risk (P<0.01). A comparison of the predicted number of events in the 27 groups with the number of events observed showed that a logistic regression provided an adequate fit without the need to incorporate interactions between lipids in the model. Conclusions are as follows: (1) Serum TGs, TC, and HDLC are independently predictive of IHD at 10 years of follow-up. (2) Combinations of adverse levels of the 3 major lipid risk factors have no greater impact on IHD than that expected from their individual contributions in a logistic regression model. There was no evidence that men with low HDL/raised TGs were at significantly greater risk than that predicted from the independent effects of the 2 lipids considered individually.

Variability of angina symptoms and the risk of major ischemic heart disease events.

Variability of angina symptoms over a 5-year period was examined in a prospective study, in which 7,109 British middle-aged men completed two chest pain questionnaires, Q1 (1978-1980) and Q5 (1983-1985), and were classified as having no chest pain, nonexertional chest pain, or angina (Q) (exertional chest pain) on each occasion. Within persons, there was considerable variability in response to the chest pain questions at Q1 and Q5. Angina (Q) persistence showed marked associations with previous myocardial infarction, diagnosed angina, electrocardiogram ischemia, and subsequent major ischemic heart disease events from Q5 onward. Compared with men without angina (Q), the age-adjusted hazard ratios were 1.5 (95% confidence interval (CI): 1.1, 2.2) for angina (Q) at Q1 only, 2.6 (95% CI: 2.1, 3.2) for angina (Q) at Q5 only, and 3.4 (95% CI: 2.8, 4.3) for angina (Q) on both occasions. For men without diagnosed ischemic heart disease, for whom apparent remission of angina (Q) was particularly frequent, a similar pattern of association was found between angina (Q) persistence and subsequent major events. In middle-aged men, exertional chest pain is a strong indicator of major coronary risk but frequently appears transient in the longer term. Persistently reported symptoms are associated with severe disease and a poor prognosis.

Explained and unexplained ischemic heart disease risk after renal transplantation.

Whether the high incidence of ischemic heart disease (IHD) among renal transplant patients can be attributed to the same risk factors that have been identified in the general population is unclear. The risk for major IHD events occurring >1 yr after transplantation among 1124 transplant recipients was estimated by using the risk calculated from the Framingham Heart Study (FHS). The FHS risk predicted IHD (relative risk, 1.28; 95% confidence interval, 1.20 to 1.40; P: < 0.001); however, the FHS risk tended to underestimate the risk of IHD for renal transplant recipients. This was largely attributable to increased risks associated with diabetes mellitus and, to a lesser extent, age and cigarette smoking for renal transplant recipients. For men, the relative risks for diabetes mellitus were 2.78 (1.73 to 4.49) and 1.53 for the transplant recipient and FHS populations, respectively; the relative risks for age (in years) were 1.06 (1.04 to 1.08) and 1.05, respectively, and those for smoking were 1.95 (1.20 to 3.19) and 1.69, respectively. For women, the relative risks for diabetes mellitus were 5.40 (2.73 to 10.66) and 1.82, respectively. There was a tendency for the risk associated with cholesterol levels to be higher for transplant recipients, compared with the FHS population, but the risks associated with high-density lipoprotein cholesterol levels and BP appeared to be comparable. Independent of these and other risk factors, the adjusted risk of IHD for the transplant recipient population has decreased. Compared with the era before 1986, transplantation between 1986 and 1992 was associated with a lower relative risk of 0.60 (0.39 to 0.92); transplantation after 1992 was associated with an even lower relative risk of 0.27 (0.11 to 0.63) for IHD. Of concern was the fact that dihydropyridine calcium channel antagonists were associated with an increased risk for IHD (relative risk, 2.26; 95% confidence interval, 1.24 to 4.12; P: = 0. 008), and this association was independent of other antihypertensive agents and risk factors. Therefore, although the FHS risk predicts IHD after renal transplantation, it tends to underestimate the risks, especially the risk associated with diabetes mellitus. The unexpected finding that dihydropyridine calcium channel antagonists were associated with an increased IHD risk merits further evaluation.

Factor VIII, von Willebrand factor and the risk of major ischaemic heart disease in the Caerphilly Heart Study

The relationships of three measurements of the factor VIII/von Willebrand factor (VWF) complex (factor VIII activity, FVIIIc (one-stage assay); VWF antigen, VWF Ag (ELISA); and VWF activity, VWF act, measured by a recently-developed ELISA) to major ischaemic heart disease (IHD) events were studied in 1997 men aged 49-65 years, in the second phase of the Caerphilly Heart Study. These variables were related using logistic regression analysis to myocardial infarction or IHD death, which occurred in 129 men during an average follow-up period of 61 months. All three measurements were highly correlated (r = 0.63-0.77), and each was significantly associated with incident major IHD on univariate analyses (relative odds in highest fifth compared to lowest fifth, 1.68-1.90; P = 0.028-0.006) and on multivariate analyses adjusting for major IHD risk factors and for baseline IHD. Neither FVIIIc nor VWF act was significantly related to incident IHD following adjustment for VWF Ag. We therefore suggest that the associations between these three measurements of the factor VIII/VWF complex and incident IHD might have at least three explanations: VWF Ag is a marker of arterial endothelial disturbance; VWF act promotes platelet adhesion/aggregation and hence the platelet component of arterial thrombosis; and FVIIIc promotes fibrin formation and hence the fibrin component of arterial thrombosis.

Fasting plasma glucose and subsequent macrovascular disease after 10 years follow-up: a collaborative study on two populations.

The American Diabetes Association recently proposed a new, lower, cut-point of 7.0 mmol/l for diagnosis of diabetes mellitus. We examined data from the Caerphilly and Speedwell cohorts to determine possible cut-points of fasting plasma glucose for increased risk of subsequent ischaemic heart disease (IHD). Men (n = 4860) from the general population of a town in South Wales and a practice-based population in Bristol aged 45-63 years were first examined in 1979-83, and re-examined at intervals, and these data relate to follow-up at about 10 years (120 months, Caerphilly) (112 months, Speedwell). Clinically recognized diabetics (n = 94) experienced a higher mortality rate and an excess number of major IHD events. Among non-diabetics, mean blood glucose was 5.0 mmol/l and a significant excess of major IHD events occurred above this point even when the data were fully adjusted for all other IHD risk factors. Risk of major IHD was greatest for non-diabetic men with plasma glucose levels between 7.0 and 7.7 mmol/l. Under 7.0 mmol/l, the excess event rate was modest, however. Glucose levels were not associated with excess all-cause mortality among these non-diabetic men. These data, based on the excess risk of macrovascular disease experienced by a British cohort of non-diabetic men, accord with the proposals to base the diagnosis of diabetes on a cut point of 7.0 rather than 7.8 mmol/l.

Triglyceride as a risk factor for ischaemic heart disease in British men: effect of adjusting for measurement error

Objective: To assess the influence of differential precision in the measurement of the correlated variables total cholesterol and high density lipoprotein (HDL) cholesterol on the estimates of the risk of ischaemic heart disease (IHD) associated with plasma triglyceride levels. Design, setting and participants: The Caerphilly Heart Disease Study (CHDS), a prospective cohort study of 2512 middle-aged men living in the town of Caerphilly, south Wales, UK. The results from two sub-studies were used to estimate the degree of measurement imprecision (laboratory error and within-person variation) in triglycerides, total cholesterol and HDL cholesterol. Main outcome measures: Multivariable risk estimates for major IHD calculated from logistic regression analysis, adjusted and not adjusted for measurement imprecision. Major IHD events were defined as death from IHD, clinical non-fatal myocardial infarction or electrocardiographic myocardial infarction. Results: There were 261 men with major IHD events during follow-up. In age-adjusted analyses, taking measurement imprecision into account strengthened associations with IHD for all lipid factors. The odds ratio (OR) for one S.D. increase in triglycerides, ignoring measurement imprecision, was 1.36 (95% confidence interval [95% CI] 1.20–1.55) but 1.57 (95% CI 1.30–1.89) when taking imprecision into account. The standardised odds ratio for triglycerides adjusted for measurement imprecision and the two other lipid factors was 1.35 (95% CI 1.09–1.69). In this model, the triglyceride level showed a stronger association than total cholesterol (OR 1.28; 95% CI 1.05–1.56) and HDL cholesterol (OR for one S.D. decrease 1.20; 95% CI 0.97–1.49). When adding fasting blood glucose and diastolic blood pressure, however, the effect of triglycerides was reduced and ceased to be statistically significant (OR 1.19; 95% CI 0.95–1.49). This was further attenuated upon inclusion of body mass index, smoking status and history of pre-existing IHD. Total cholesterol remained a statistically significant ( P<0.05) risk factor in all models. Conclusions: In contrast to other cohort studies, triglyceride concentration in the CHDS shows an association with the risk of IHD which is independent of total and HDL cholesterol. This effect was pronounced after adjustment for measurement imprecision. It was reduced, however, when adjusted for other factors. While hypertriglyceridaemia may exert an influence independent of other lipid factors, insulin resistance is probably the underlying metabolic disturbance.

Validity of a Self-reported History of Doctor-diagnosed Angina

The objective of this study was to assess the validity of a self-reported history of doctor-diagnosed angina in population-based studies in men. Subjects were 5789 men from the British Regional Heart Study who reported being without an angina diagnosis at entry (1978–1980) and were alive at the end of 1992, aged 52 to 75 years. In 1992, subjects were asked in a self-administered questionnaire if they recalled ever having had a doctor diagnosis of angina. Self-report of diagnosed angina was compared with general practice (GP) record of angina obtained from reviews of medical records from study entry to the end of 1992. Men were followed for a further 3 years from 1992 for major ischemic heart disease events. The prevalence of diagnosed angina in 1992 was 10.1% according to self-reported history and 8.9% according to GP record review. There was substantial agreement between the two sources of information: 80% of men with a GP record of angina reported their diagnosis, and 70% of men who reported an angina diagnosis had confirmation of this from the record review. When all ischemic heart disease (angina or myocardial infarction) was considered, agreement was higher. Genuine angina was likely in many of the 177 men who had self-reported angina not confirmed by the GP record review: 78 had an ischemic heart disease history (myocardial infarction or coronary revascularization) identified by the review, and 31 had a GP record of angina after 1992. Angina symptoms, nitrate use, cardiological investigation, and surgical intervention for angina compared between agreement groups showed a very consistent pattern. All these indicators of angina were most common in men with both self-report and GP record of angina, least common in men with neither self-report nor GP record of angina, but had a substantially higher prevalence in men with self-reported angina only than in those with GP-recorded angina only. After 3 years follow-up from 1992, 9.5% of men with both self-report and GP record of angina, and 11.3% of men with self-reported angina only had experienced a new major ischemic heart disease event; compared to 5.7% of men with a GP record of angina only and 2.7% of those without angina by either criteria. This pattern of risk remained similar after adjustment for age and previous myocardial infarction. These results suggest that self-reported history of a doctor diagnosis of angina is a valid measure of diagnosed angina in population-based studies in men.

Chest pain on questionnaire and prediction of major ischaemic heart disease events in men.

To examine the prediction of major ischaemic heart disease events by questionnaire-assessed chest pain and other symptoms. Population-based prospective study. 7735 randomly selected men, aged 40-59 years at entry. Symptoms and history of diagnosed ischaemic heart disease were ascertained by administered questionnaire at baseline. Follow-up was for an average of 14.7 years, for first major ischaemic heart disease event. During follow-up, 969 men had a major ischaemic heart disease event. 'Definite' angina (chest pain fulfilling all WHO criteria) and 'possible' angina (exertional chest pain without all other WHO criteria) were associated with similar ischaemic heart disease outcome, and a single combined angina category was used. In the whole cohort, the relative risks (95% CI) of a major ischaemic heart disease event were 2.03 (1.61, 2.57) for angina only, 2.13 (1.72, 2.63) for possible myocardial infarction only and 4.50 (3.57, 5.66) for angina plus possible myocardial infarction, compared to no chest pain. The relative risk for recall of an ischaemic heart disease diagnosis was 3.98 (3.36, 4.71). Only 33% of men with angina or possible myocardial infarction symptoms recalled a previous ischaemic heart disease diagnosis. In men without recall of an ischaemic heart disease diagnosis (in whom 82% of events during follow-up occurred), chest pain symptoms remained predictive of major ischaemic heart disease events with relative risks (95% CI) of 1.69 (1.27, 2.24) for angina only, 1.49 (1.12, 1.97) for possible myocardial infarction only and 2.55 (1.44, 4.53) for angina plus possible myocardial infarction. 'Other chest pain' increased risk of a major ischaemic heart disease event by 1.19 (1.01, 1.40) compared to no chest pain. Symptoms of breathlessness or calf pain on walking increased ischaemic heart disease risk in men with 'other chest pain' and in men without chest pain, but had no further effect on ischaemic heart disease risk in men with symptoms of angina or possible myocardial infarction. In defining angina by chest pain questionnaire, the exertional component is the crucial criterion. When using questionnaire-assessed symptoms to determine ischaemic heart disease risk, information on previous ischaemic heart disease diagnoses should be taken into account. The majority of men with angina or possible myocardial infarction symptoms do not have a diagnosis of ischaemic heart disease, but they remain at significantly increased risk of a major ischaemic heart disease event. The value of breathlessness and calf pain on walking in stratifying ischaemic heart disease risk is restricted to men with 'other chest pain' or no chest pain.

Fibrin D-dimer, Tissue Plasminogen Activator, Plasminogen Activator Inhibitor, and the Risk of Major Ischaemic Heart Disease in the Caerphilly Study

Plasma levels of fibrin D-dimer, tissue plasminogen activator (tPA) and plasminogen activator inhibitor (PAI) have been associated with ischaemic heart disease (IHD). However their associations with incident IHD in samples of the general population are not established. D-dimer antigen, tPA antigen and PAI activity were measured in stored, fasting plasma samples from 1,998 men aged 45-65 examined between 1984 and 1988, during the first re-examination of the Caerphilly Study cohort. These variables were related to major IHD events (myocardial infarction or IHD death) which occurred in 129 men during a follow-up period which averaged 61 months. Mean fibrin D-dimer was higher in men who developed IHD events (90 vs. 71 ng/ml; age-adjusted logarithmic mean difference 0.21; 95% CI 0.11, 0.30; p <0.0001). This association remained after adjusting for baseline IHD and for other risk factors including fibrinogen: the adjusted relative odds of IHD in the highest fifth of D-dimer were 3.5 (95% CI 1.8, 6.9; p = 0.0003). Mean tPA antigen was also higher in men who developed IHD (12.6 vs. 11.6 ng/ml; mean difference 0.9; 95% CI 0.2, 1.7; p = 0.02); however this difference largely disappeared after adjusting for other risk factors. PAI activity was not associated with risk of IHD.

Serum Creatinine Concentration and Risk of Cardiovascular Disease

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. 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. 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. 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.

History of parental death from stroke or heart trouble and the risk of stroke in middle-aged men.

The purpose of this study was to determine the effect of a history of parental death from stroke or heart trouble on the risk of major stroke events (fatal and nonfatal) in middle-aged British men. A prospective study was undertaken of 7735 middle-aged men, drawn at random from general practices in 24 British towns, who were followed up for an average of 14.8 (range, 13.5 to 16.0) years. In the 7683 men providing information on at least one of their parents, there were 278 major stroke events and 947 major ischemic heart disease events. A history of death from stroke or heart trouble in mother or father was associated with a significantly increased risk of stroke independent of other risk factors, including hypertension. The association is due almost entirely to an increased risk of nonfatal stroke. In comparison with men whose parents were still alive or who had no history of parental death from either heart trouble or stroke, the adjusted relative risk of stroke in men with a history of parental stroke death was 1.4 (95% confidence interval [CI], 1.1 to 2.0; P = .02), and in men with parental heart trouble death, the relative risk was 1.3 (95% CI, 1.0 to 1.7; P = .04). The positive relationships were present whether the parental death occurred before or after 70 years of age. A parental death from stroke was not associated with increased risk of an ischemic heart disease event, although the latter was significantly associated with a history of parental death from heart trouble. Although factors such as hypertension and smoking are of major importance in the etiology of stroke, there is a link between a history of parental death from cardiovascular disease (stroke or heart trouble) and the risk of stroke that appears to be independent of the established risk factors.

Serum bilirubin and risk of ischemic heart disease in middle-aged British men

The possibility that low concentrations of serum bilirubin may be associated with increased risk of ischemic heart disease has been examined in a prospective study of 7685 middle-aged British men. During 11.5 years there were 737 major ischemic heart disease (IHD) events. A U-shaped relationship was observed between serum bilirubin and risk of IHD. Low bilirubin was associated with several cardiovascular risk factors, in particular smoking, low concentrations of high-density lipoprotein cholesterol, low forced expiratory volume in 1 s, and low serum albumin. The U-shaped relationship persisted even after adjusting for several risk factors. Compared with men in the lowest fifth of the distribution (bilirubin < 7 mumol/L), those in the middle range (8-9 mumol/L) showed a 30% reduction in relative risk [RR = 0.68 (95% confidence intervals 0.51-0.89)] in IHD, whereas men in the top fifth (> 12 mumol/L) showed similar risk to the lowest fifth [RR = 0.99 (95% confidence intervals 0.73-1.34)], which persisted after exclusion of men with bilirubin > 17 mumol/L. The significance of this U-shaped relationship is unclear, but it could be interpreted as support for the role of endogenous antioxidants in the etiology of IHD.

Factors determining case fatality in myocardial infarction "who dies in a heart attack"?

To examine the determinants of case fatality in the first major ischaemic heart disease event (heart attack) after screening. Prospective study of 7735 middle aged men drawn from general practices in 24 British towns. During 11.5 years follow up there were 743 major ischaemic heart disease events of which 302 (40.6%) were fatal within 28 days of onset. Previous definite myocardial infarction or stroke and age at time of event were most strongly associated with case fatality. In men with no previous myocardial infarction or stroke, after adjustment for a range of risk factors, antihypertensive treatment (odds ratio (OR) = 1.97, P < 0.05), arrhythmia (OR = 1.93, P = 0.06), increased heart rate (OR = 2.03, P = 0.06), and diabetes (OR = 2.61, P = 0.07) were associated with increased case fatality. High levels of physical activity (OR = 0.53, P < 0.05) and moderate drinking (16-42 units/week) (OR = 0.61, P < 0.05) were associated with lower case fatality, although moderate drinking was not associated with a lower incidence of major ischaemic heart disease events. Current smoking, serum total cholesterol, and systolic blood pressure were not significantly associated with case fatality. In men with previous myocardial infarction or stroke, arrhythmia and to a lesser degree antihypertensive treatment, moderate or heavy drinking, and diabetes were associated with higher case fatality. These findings suggest that physical activity may be an important modifiable factor influencing the incidence of ischaemic heart disease and the chance of survival in men without a previous heart attack or stroke. Arrhythmia, increased heart rate, diabetes, and treatment for hypertension are also areas of concern.

Risk factors for sudden cardiac death in middle-aged British men.

Risk factors specific to sudden cardiac death (SCD), ie, death within 1 hour after onset of symptoms, have been poorly identified, although recent findings from the present study incriminate heavy drinking and elevated heart rate. This paper examines the relations between a wide range of established and potential risk factors for ischemic heart disease (IHD) and SCD to identify independent risk factors for SCD and factors that might particularly or specifically relate to SCD. We present a prospective study of a cohort that was drawn from general practices in 24 British towns of 7735 middle-aged men who were followed up for 8 years. During 8 years of follow-up, the men experienced 488 major IHD events (nonfatal and fatal), of which 117 (24%) were classified as SCD. Age, preexisting IHD, arrhythmia, systolic blood pressure, blood cholesterol, elevated heart rate (> or = 90 beats per minute), physical activity (all, P < .05), and, to a lesser extent, smoking (P = .06), HDL cholesterol (P < .07), and elevated hematocrit (> or = 46%, P < .09) emerged as independent risk factors for SCD after adjustment for a wide range of factors. Diabetes was not found to be associated with SCD, and forced expiratory volume in 1 second, body mass index, white blood cell count, and antihypertensive drugs were not associated with risk of SCD after adjustment. When examined in relation to non-sudden IHD deaths and nonfatal myocardial infarction, elevated heart rate, heavy drinking, and arrhythmia emerged as factors that appear to be specific or particular to SCD. These three factors and age and blood cholesterol were associated with an increased risk of SCD in men both with and without preexisting IHD. Physical activity, systolic blood pressure, and current smoking were associated with SCD only in men without preexisting IHD. HDL cholesterol and hematocrit were strong predictors of SCD only in men with preexisting IHD. Three risk factors appear to be specific or particular to the risk of SCD, and these and other risk factors operate differently in patients with versus those without preexisting IHD. These findings have implications for the causes and prevention of SCD.

Asymptomatic hyperglycaemia and major ischaemic heart disease events in Britain.

To examine the association between non-fasting serum glucose concentrations and major ischaemic heart disease (IHD) events (fatal and non-fatal myocardial infarction). A prospective study. A population based sample of 7735 middle aged British men. Known diabetics, men with a glucose concentration > or = 11.1 mmol/l at screening, and hypertensive patients taking regular medication were excluded from the analysis. With exclusions (n = 509) and missing glucose values (n = 49), there were 7177 men available for analysis. Major IHD events (fatal and non-fatal myocardial infarction) during 9.5 years follow up on all men. There were 505 major IHD events, 222 fatal and 283 non-fatal, in the 7177 men studied. There was a non-linear relation between the glucose concentration and the risk (per 1000 men per year) of all major IHD events and fatal IHD events, with the excess risk in the upper quintile of the glucose distribution (> or = 6.1 mmol/l). The unadjusted relative risks (RR) in the upper glucose concentration quintile compared with the first to the fourth quintiles combined were 1.4 (95% CI 1.1, 1.7) for all events and 1.3 (95% CI 1.0, 1.7) for fatal events. Adjustment for age, smoking, occupational status, body mass index, physical activity, systolic blood pressure, total and high density lipoprotein cholesterol, and triglyceride concentrations had a minimal effect on these relative risk estimates. This non-linear relationship between the serum glucose concentration and the risk of a major IHD event was observed in men with no evidence of IHD at screening (n = 5518) but not in men with IHD (n = 1659). In the former group, the RR (adjusted for major coronary risk factors) for all major IHD events in the upper quintile relative to the lower quintiles combined was 1.5 (95% CI 1.2, 2.0) and for fatal IHD events was 1.8 (95% CI 1.1, 2.6). These data suggest that asymptomatic hyperglycaemia is an independent risk factor for major IHD events.