Variations in common diseases, hospital admissions, and deaths in middle-aged adults in 21 countries from five continents (PURE): a prospective cohort study

BACKGROUND: To our knowledge, no previous study has prospectively documented the incidence of common diseases and related mortality in high-income countries (HICs), middle-income countries (MICs), and low-income countries (LICs) with standardised approaches. Such information is key to developing global and context-specific health strategies. In our analysis of the Prospective Urban Rural Epidemiology (PURE) study, we aimed to evaluate differences in the incidence of common diseases, related hospital admissions, and related mortality in a large contemporary cohort of adults from 21 HICs, MICs, and LICs across five continents by use of standardised approaches. METHODS: The PURE study is a prospective, population-based cohort study of individuals aged 35-70 years who have been enrolled from 21 countries across five continents. The key outcomes were the incidence of fatal and non-fatal cardiovascular diseases, cancers, injuries, respiratory diseases, and hospital admissions, and we calculated the age-standardised and sex-standardised incidence of these events per 1000 person-years. FINDINGS: This analysis assesses the incidence of events in 162 534 participants who were enrolled in the first two phases of the PURE core study, between Jan 6, 2005, and Dec 4, 2016, and who were assessed for a median of 9·5 years (IQR 8·5-10·9). During follow-up, 11 307 (7·0%) participants died, 9329 (5·7%) participants had cardiovascular disease, 5151 (3·2%) participants had a cancer, 4386 (2·7%) participants had injuries requiring hospital admission, 2911 (1·8%) participants had pneumonia, and 1830 (1·1%) participants had chronic obstructive pulmonary disease (COPD). Cardiovascular disease occurred more often in LICs (7·1 cases per 1000 person-years) and in MICs (6·8 cases per 1000 person-years) than in HICs (4·3 cases per 1000 person-years). However, incident cancers, injuries, COPD, and pneumonia were most common in HICs and least common in LICs. Overall mortality rates in LICs (13·3 deaths per 1000 person-years) were double those in MICs (6·9 deaths per 1000 person-years) and four times higher than in HICs (3·4 deaths per 1000 person-years). This pattern of the highest mortality in LICs and the lowest in HICs was observed for all causes of death except cancer, where mortality was similar across country income levels. Cardiovascular disease was the most common cause of deaths overall (40%) but accounted for only 23% of deaths in HICs (vs 41% in MICs and 43% in LICs), despite more cardiovascular disease risk factors (as judged by INTERHEART risk scores) in HICs and the fewest such risk factors in LICs. The ratio of deaths from cardiovascular disease to those from cancer was 0·4 in HICs, 1·3 in MICs, and 3·0 in LICs, and four upper-MICs (Argentina, Chile, Turkey, and Poland) showed ratios similar to the HICs. Rates of first hospital admission and cardiovascular disease medication use were lowest in LICs and highest in HICs. INTERPRETATION: Among adults aged 35-70 years, cardiovascular disease is the major cause of mortality globally. However, in HICs and some upper-MICs, deaths from cancer are now more common than those from cardiovascular disease, indicating a transition in the predominant causes of deaths in middle-age. As cardiovascular disease decreases in many countries, mortality from cancer will probably become the leading cause of death. The high mortality in poorer countries is not related to risk factors, but it might be related to poorer access to health care. (AU)

Impact of rosiglitazone on body composition, hepatic fat, fatty acids, adipokines and glucose in persons with impaired fasting glucose or impaired glucose tolerance: a sub-study of the DREAM trial.

AIMS: Thiazolidinediones reduce ectopic fat, increase adiponectin and reduce inflammatory adipokines, fatty acids and glucose in people with Type 2 diabetes. We aimed to measure these effects in people with impaired fasting glucose and/or impaired glucose tolerance. METHODS: After approximately 3.5 years of exposure to rosiglitazone 8 mg (n = 88) or placebo (n = 102), 190 DREAM trial participants underwent abdominal computed tomography and dual-energy X-ray absorptiometry scans. Visceral and subcutaneous adipose tissue areas, estimated hepatic fat content, total fat and lean mass were calculated and changes in levels of fasting adipokines, free fatty acids, glucose and post-load glucose were assessed. RESULTS: Compared with the placebo, participants on rosiglitazone had no difference in lean mass, had 4.1 kg more body fat (P < 0.0001) and 31 cm(2) more subcutaneous abdominal adipose tissue area (P = 0.007). Only after adjusting for total fat, participants on rosiglitazone had 23 cm² less visceral adipose tissue area (P = 0.01) and an 0.08-unit higher liver:spleen attenuation ratio (i.e. less hepatic fat; P = 0.02) than those on the placebo. Adiponectin increased by 15.0 µg/ml with rosiglitazone and by 0.4 µg/ml with placebo (P < 0.0001). Rosiglitazone's effect on fat distribution was not independent of changes in adiponectin. Rosiglitazone's effects on fasting (-0.36 mmol/l; P = 0.0004) and 2-h post-load glucose (-1.21 mmol/l; P = 0.0008) were not affected by adjustment for fat distribution or changes in adiponectin or free fatty acids. CONCLUSIONS: In people with impaired fasting glucose/impaired glucose tolerance, rosiglitazone is associated with relatively less hepatic and visceral fat, increased subcutaneous fat and increased adiponectin levels. These effects do not appear to explain the glucose-lowering effect of rosiglitazone.

Glucose levels are associated with cardiovascular disease and death in an international cohort of normal glycaemic and dysglycaemic men and women: the EpiDREAM cohort study.

AIMS: In an international prospective cohort study we assessed the relationship between glucose levels and incident cardiovascular events and death. METHODS AND RESULTS: 18,990 men and women were screened for entry into the DREAM clinical trial from 21 different countries. All had clinical and biochemical information collected at baseline, including an oral glucose tolerance test (OGTT), and were prospectively followed over a median (IQR) of 3.5 (3.0-4.0) years for incident cardiovascular (CV) events including coronary artery disease (CAD), stroke, congestive heart failure (CHF) requiring hospitalization, and death. After OGTT screening, 8000 subjects were classified as normoglycaemic, 8427 had impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), and 2563 subjects had newly diagnosed type 2 diabetes mellitus (DM). There were incident events in 491 individuals: 282 CAD, 54 strokes, 19 CHF, and 164 died. The annualized CV or death event rate was 0.79/100 person-years in the overall cohort, 0.51/100 person-years in normoglycaemics, 0.92/100 person-years among subjects with IFG and/or IGT at baseline, and 1.27/100 person-years among those with DM (p for trend <0.0001). Among all subjects, a 1 mmol/l increase in fasting plasma glucose (FPG) or a 2.52 mmol/l increase in the 2-h post-OGTT glucose was associated with a hazard ratio increase in the risk of CV events or death of 1.17 (95% CI 1.13-1.22). CONCLUSIONS: In this large multiethnic cohort, the risk of CV events or death increased progressively among individuals who were normoglycaemic, IFG or IGT, and newly diagnosed diabetics. A 1 mmol/l increase in FPG was associated with a 17% increase in the risk of future CV events or death. Therapeutic or behavioural interventions designed to either prevent glucose levels from rising, or lower glucose among individuals with dysglycaemia should be evaluated.

Glucose levels are associated with cardiovascular disease and death in an international cohort of normal glycaemic and dysglycaemic men and women: the EpiDREAM cohort study

AIMS: In an international prospective cohort study we assessed the relationship between glucose levels and incident cardiovascular events and death.METHODS AND RESULTS: 18,990 men and women were screened for entry into the DREAM clinical trial from 21 different countries. All had clinical and biochemical information collected at baseline, including an oral glucose tolerance test (OGTT), and were prospectively followed over a median (IQR) of 3.5 (3.0-4.0) years for incident cardiovascular (CV) events including coronary artery disease (CAD), stroke, congestive heart failure (CHF) requiring hospitalization, and death. After OGTT screening, 8000 subjects were classified as normoglycaemic, 8427 had impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), and 2563 subjects had newly diagnosed type 2 diabetes mellitus (DM). There were incident events in 491 individuals: 282 CAD, 54 strokes, 19 CHF, and 164 died. The annualized CV or death event rate was 0.79/100 person-years in the overall cohort, 0.51/100 person-years in normoglycaemics, 0.92/100 person-years among subjects with IFG and/or IGT at baseline, and 1.27/100 person-years among those with DM (p for trend <0.0001). Among all subjects, a 1 mmol/l increase in fasting plasma glucose (FPG) or a 2.52 mmol/l increase in the 2-h post-OGTT glucose was associated with a hazard ratio increase in the risk of CV events or death of 1.17 (95% CI 1.13-1.22).CONCLUSIONS: In this large multiethnic cohort, the risk of CV events or death increased progressively among individuals who were normoglycaemic, IFG or IGT, and newly diagnosed diabetics. A 1 mmol/l increase in FPG was associated with a 17% increase in the risk of future CV events or death. Therapeutic or behavioural interventions designed to either prevent glucose levels from rising, or lower glucose among individuals with dysglycaemia should be evaluated.

Intermittent claudication: From its risk factors to its long-term prognosis in men. The Quebec Cardiovascular Study.

BACKGROUND: The natural history of intermittent claudication, from its risk factors to its cardiovascular prognosis, has been reported in few prospective studies. OBJECTIVE: To assess incident intermittent claudication, as well as its risk factors and long-term prognosis in men. METHODS: A random sample of 4376 men 35 to 64 years of age from Quebec City (Quebec), who were free of cardiovascular disease (CVD), was evaluated in 1974 for CVD risk factors and followed until 1998. To assess the prognosis, the event rates between 1985 and 1998 were computed among men with incident claudication without other CVD, incident survivors of a first myocardial infarction (MI) without other CVD and men free of CVD between 1974 and 1985. RESULTS: From 1974 to 1998, 300 men developed intermittent claudication. Tobacco consumption, high systolic blood pressure and diabetes at least doubled the adjusted RR (aRR) of intermittent claudication. In 1985, there were 80 claudicants, 2868 men free of CVD and 68 survivors of a first MI. During the 13-year follow-up, a new CVD occurred in 48.8% of the claudicants, in 18.9% of men without CVD (aRR 2.08; 95% CI 1.48 to 2.90) and in 45.6% of MI survivors (aRR compared with claudicants 1.12; 95% CI 0.69 to 1.79). There was also no significant difference between claudicants and MI survivors for fatal CVD, nonfatal CVD and total mortality. CONCLUSIONS: Men with intermittent claudication are at high risk for CVD that may be equivalent to men with previous MI.

Effects of ramipril and rosiglitazone on cardiovascular and renal outcomes in people with impaired glucose tolerance or impaired fasting glucose: results of the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial.

OBJECTIVE: Impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) are risk factors for diabetes, cardiovascular disease (CVD), and kidney disease. We determined the effects of ramipril and rosiglitazone on combined and individual CVD and renal outcomes in people with IGT and/or IFG in the Diabetes REduction Assessment With ramipril and rosiglitazone Medication (DREAM) trial. RESEARCH DESIGN AND METHODS: A total of 5,269 people aged >or=30 years, with IGT and/or IFG without known CVD or renal insufficiency, were randomized to 15 mg/day ramipril versus placebo and 8 mg/day rosiglitazone versus placebo. A composite cardiorenal outcome and its CVD and renal components were assessed during the 3-year follow-up. RESULTS: Compared with placebo, neither ramipril (15.7% [412 of 2,623] vs. 16.0% [424 of 2,646]; hazard ratio [HR] 0.98 [95% CI 0.84-1.13]; P = 0.75) nor rosiglitazone (15.0% [394 of 2,635] vs. 16.8% [442 of 2,634]; 0.87 [0.75-1.01]; P = 0.07) reduced the risk of the cardiorenal composite outcome. Ramipril had no impact on the CVD and renal components. Rosiglitazone increased heart failure (0.53 vs. 0.08%; HR 7.04 [95% CI 1.60-31.0]; P = 0.01) but reduced the risk of the renal component (0.80 [0.68-0.93]; P = 0.005); prevention of diabetes was independently associated with prevention of the renal component (P < 0.001). CONCLUSIONS: Ramipril did not alter the cardiorenal outcome or its components. Rosiglitazone, which reduced diabetes, also reduced the development of renal disease but not the cardiorenal outcome and increased the risk of heart failure.

The relationship between dysglycaemia and cardiovascular and renal risk in diabetic and non-diabetic participants in the HOPE study: a prospective epidemiological analysis.

AIMS/HYPOTHESIS: Emerging data suggest that different indices of glycaemia are risk factors for clinical events. The aim of this analysis was to investigate the relationship between fasting plasma glucose or glycated haemoglobin (GHb) levels and incident cardiovascular (CV) outcomes, death, heart failure and overt nephropathy in diabetic and non-diabetic individuals enrolled in the Heart Outcomes Prevention Evaluation (HOPE) study. MATERIALS AND METHODS: The adjusted 4.5-year risk of CV events (myocardial infarction or stroke or CV death), heart failure, death and overt nephropathy was analysed in relation to baseline and updated GHb levels (in 3,529 diabetic HOPE study participants) and baseline fasting plasma glucose levels (in 1,937 non-diabetic and 1,013 diabetic participants). RESULTS: In diabetic participants, a 1% absolute rise in the updated GHb predicted future CV events (relative risk [RR]=1.07, 95% CI 1.01-1.13; p=0.014), death (RR=1.12, 95% CI 1.05-1.19; p=0.0004), heart failure (RR=1.20, 95% CI 1.08-1.33; p=0.0008) and overt nephropathy (RR=1.26, 95% CI 1.17-1.36; p<0.0001) after adjusting for age, sex, diabetes duration, blood pressure, WHR, hyperlipidaemia and ramipril. Similarly, a 1 mmol/l rise in fasting plasma glucose was related to an increased risk of CV outcomes (RR=1.09, 95% CI 1.05-1.13; p<0.0001), death (RR=1.06, 95% CI 1.01-1.12; p=0.017), heart failure (RR=1.16, 95% CI 1.06-1.13; p=0.0007) and overt nephropathy (RR=1.34, 95% CI 1.23-1.45; p<0.0001) in the group composed of diabetic and non-diabetic individuals. The significant relationship between fasting plasma glucose and CV outcomes persisted after adjustment for diabetes status (RR=1.06, 95% CI 1.00-1.12; p=0.043). CONCLUSIONS/INTERPRETATION: There is an independent progressive relationship between indices of glycaemia and incident CV events, renal disease and death. Clinical trials of glucose lowering to prevent these outcomes in diabetic and non-diabetic individuals are indicated.

Serum potassium, cardiovascular risk, and effects of an ACE inhibitor: results of the HOPE study.

BACKGROUND: Both hyper- and hypokalemia increase cardiovascular risk. Modest hyperkalemia is common with angiotensin-converting enzyme inhibition. We studied post-hoc the association of an initial, on-treatment serum potassium measurement with subsequent cardiovascular outcomes over 4.5 years in 9297 individuals at high cardiovascular risk, randomized to an ACE inhibitor or to placebo. METHODS: Post-hoc analysis of cardiovascular outcomes, as related to serum potassium levels, in the HOPE (Heart Outcomes and Prevention Evaluation) study which compared ramipril to placebo, and included 692 patients with a serum potassium level >5.0 mM and 137 with a serum potassium level <3.5 mM, defined as hyper- and hypokalemia, respectively. Serum potassium was measured 1 month after start of randomized treatment. RESULTS: With hyperkalemia, the primary event rate was unchanged compared to normokalemia (15.5 vs 15.7%, p > 0.4, respectively), with hypokalemia, the primary event rate was higher (22.6% vs 15.5%, respectively, p = 0.023). The hazard ratio for the primary outcome associated with this initial hypokalemia was 1.44 (1.00-2.06) on multivariate analysis. The combined primary outcome (myocardial infarction, cardiovascular death, stroke) was not different throughout deciles of serum potassium but the lowest and highest deciles included many with normokalemia. Randomized treatment was withheld because of hyperkalemia in 8 and 6 people allocated to ramipril and placebo, respectively. The benefit of ramipril on cardiovascular outcomes was independent of serum potassium, but ramipril reduced hypokalemia in the entire cohort (1.15 vs 1.86% with placebo, p = 0.005), particularly in those participants on diuretics (3.8% vs 6.5%, p = 0.07). CONCLUSIONS: In patients at high cardiovascular risk, modest hypokalemia predicts a less favorable outcome while modest hyperkalemia does not. Ramipril reduces hypokalemia and decreases risk.

Age and duration of follow-up as modulators of the risk for ischemic heart disease associated with high plasma C-reactive protein levels in men.

BACKGROUND: Plasma C-reactive protein (CRP) levels recently have been identified as an emerging risk factor for ischemic heart disease (IHD). However, whether plasma CRP levels predict an increased risk for future IHD beyond traditional risk factors has yet to be evaluated in a large prospective, population-based study. METHODS: The association between elevated plasma CRP levels and the risk for future IHD was investigated in the prospective, population-based cohort of 2037 IHD-free middle-aged men from the Quebec Cardiovascular Study. During a 5-year follow-up, 105 first IHD events were recorded. Baseline plasma CRP levels were measured using a highly sensitive assay. RESULTS: High plasma CRP concentrations (equal to or above vs below the median level of 1.77 mg/L) were associated with a significant 1.8-fold increase in IHD risk (95% confidence interval [CI], 1.2-2.7). This association remained significant after adjustment for lipid risk factors but not when the simultaneous contribution of nonlipid traditional risk factors was taken into account. Multivariate analyses indicated that CRP level predicted short-term risk for IHD (events that occurred < or =2 years after the baseline evaluation), but not long-term risk (>2 years). Moreover, high plasma CRP levels predicted an increased risk for IHD, independent of any other confounder, in younger (< or =55 years) but not in older (>55 years) individuals. CONCLUSION: Plasma CRP levels may provide independent information on IHD risk only in younger middle-aged men and in the case of IHD events that may occur relatively soon after the baseline evaluation.

Total cholesterol/HDL cholesterol ratio vs LDL cholesterol/HDL cholesterol ratio as indices of ischemic heart disease risk in men: the Quebec Cardiovascular Study.

BACKGROUND: Total cholesterol (TC)/high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C)/HDL-C ratios are used to predict ischemic heart disease risk. There is, however, no consensus on which of these 2 indices is superior. The objective of the present study was to present evidence that the LDL-C/HDL-C ratio may underestimate ischemic heart disease risk in overweight hyperinsulinemic patients with high triglyceride (TG)-low HDL-C dyslipidemia. METHODS: A total of 2103 middle-aged men in whom measurements of the metabolic profile were performed in the fasting state were recruited from 7 suburbs of the Quebec metropolitan area. RESULTS: The relationship of LDL-C/HDL-C to TC/HDL-C ratios was examined among men in the Quebec Cardiovascular Study classified into tertiles of fasting TG levels. For any given LDL-C/HDL-C ratio, the TC/HDL-C ratio was higher among men in the top TG tertile (>168 mg/dL [>1.9 mmol/L]) than in men in the first and second TG tertiles. Adjustment of the TC/HDL-C ratio for LDL-C/HDL-C by covariance analysis generated significant differences in average TC/HDL-C ratios among TG tertiles (P<.001). Greater differences in features of the insulin resistance syndrome (insulinemia, apolipoprotein B, and LDL size) were noted across tertiles of the TC/HDL-C ratio than tertiles of the LDL-C/HDL-C ratio. CONCLUSION: Variation in the TC/HDL-C ratio may be associated with more substantial alterations in metabolic indices predictive of ischemic heart disease risk and related to the insulin resistance syndrome than variation in the LDL-C/HDL-C ratio.

Comparison of various electrophoretic characteristics of LDL particles and their relationship to the risk of ischemic heart disease.

BACKGROUND: Several cross-sectional studies and 3 prospective, nested, case-control studies have indicated that individuals with small, dense low density lipoprotein (LDL) particles are at increased risk for ischemic heart disease (IHD). However, whether LDL particle size is an independent risk factor for future IHD events remains controversial. The objective of the present study was to further analyze the cardiovascular risk associated with various electrophoretic characteristics of LDL particles in men. METHODS AND RESULTS: LDL particles were characterized by polyacrylamide gradient gel electrophoresis (PAGGE) in a cohort of 2034 men of the Quebec Cardiovascular Study. All men were initially free of IHD and were followed up for a period of 5 years, during which 108 first IHD events were recorded. Among all LDL characteristics investigated by PAGGE, including LDL peak particle size, the cholesterol concentration in LDL particles with a diameter smaller than 255 A showed the strongest association with the risk of IHD (relative risk=4.6 in men in the third vs first tertile of the distribution, P<0.001). Multivariate logistic and survival models indicated that the relationship between LDL cholesterol levels in particles with a diameter <255 A and IHD risk was independent of all nonlipid risk factors and of LDL cholesterol, high density lipoprotein cholesterol, triglyceride, and lipoprotein(a) levels. CONCLUSIONS: Results from this large, population-based, prospective study suggest that further characterization of LDL particles by PAGGE, in addition to the traditional lipid profile, may improve our ability to predict IHD events in men.

A prospective, population-based study of low density lipoprotein particle size as a risk factor for ischemic heart disease in men.

BACKGROUND: The current interpretation of the increased risk of ischemic heart disease (IHD) associated with reduced low density lipoprotein (LDL) particle size is based entirely on data derived from relatively small case-control studies, with a lack of evidence from large, prospective, population-based cohort data. OBJECTIVES: To investigate the association between LDL particle size and incident IHD on the basis of data from the entire population-based, prospective cohort of men from the Quebec Cardiovascular Study. PATIENTS AND METHODS: Analyses were conducted in a cohort of 2057 men who were all initially free of IHD, and who were followed up over a five-year period, during which 108 first IHD events (myocardial infarction, angina or coronary death) were recorded. LDL particle size was measured by nondenaturing gradient gel electrophoresis. RESULTS: Cox proportional hazards analysis indicated that the relationship between LDL particle size and the risk of future IHD events was not linear. Men with an LDL particle size less than 256.0 A had a significant 2.2-fold increase in the five-year rate of IHD (P<0.001) compared with men having an LDL particle size greater than 256.0 A. Multivariate and subgroup analyses indicated that small, dense LDL particles predicted the rate of IHD independent of LDL cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol, apolipoprotein B and the total cholesterol to HDL cholesterol ratio. Finally, the magnitude of the increase in IHD risk attributed to lipid risk factors was modulated to a significant extent by variations in LDL particle size. CONCLUSIONS: The present study provides the first large scale, population-based, prospective evidence supporting the hypothesis that small, dense LDL particles may be associated with an increased risk of IHD. The results also suggest that information on LDL diameter may improve the ability to predict IHD risk accurately over traditional lipid variables.

Effects of ramipril on coronary events in high-risk persons: results of the Heart Outcomes Prevention Evaluation Study.

BACKGROUND: In trials of patients with left ventricular dysfunction or heart failure, ACE inhibitor use was unexpectedly associated with reduced myocardial infarction (MI). Using the Heart Outcomes Prevention Evaluation (HOPE) trial data, we tested prospectively whether ramipril, an ACE inhibitor, could reduce coronary events and revascularization procedures among patients with normal left ventricular function. METHODS AND RESULTS: In the HOPE trial, 9297 high-risk men and women, >/=55 years of age with previous cardiovascular disease or diabetes plus 1 risk factor, were randomly assigned to ramipril (up to 10 mg/d), vitamin E (400 IU/d), their combination, or matching placebos. During the mean follow-up of 4.5 years, there were 482 (10.4%) patients with clinical MI and unexpected cardiovascular death in the ramipril group compared with 604 (12.9%) in the placebo group [relative risk reduction (RRR), 21% (95% CI) (11,30); P<0.0003]. Ramipril was associated with a trend toward less fatal MI and unexpected death [4.0% versus 4.7%; RRR, 16% (-3, 31)] and with a significant reduction in nonfatal MI [5.6% versus 7.2%; RRR, 23% (9,34)]. Risk reductions in MI were documented in participants taking or not taking beta-blockers, lipid lowering, and/or antiplatelet agents. Although ramipril had no impact on hospitalizations for unstable angina [11.9% versus 12.2%; RRR, 3% (-9,14)], it reduced the risk of worsening and new angina [27.2% versus 30.0%; RRR, 12% (5,18); P<0.0014] and coronary revascularizations [12.5% versus 14.8%; RRR, 18%; (8,26) P<0.0005]. CONCLUSIONS: In this high-risk cohort, ramipril reduced the risk of MI, worsening and new angina, and the occurrence of coronary revascularizations.

Biological profiles in subjects with recurrent acute coronary events compared with subjects with long-standing stable angina.

BACKGROUND: At one end of the clinical spectrum of coronary artery disease (CAD) are subjects who have had repeated acute ischemic events, and at the other end are those with long-standing angina who have never been unstable. This study tests the hypothesis that a specific biological profile can distinguish these 2 extreme groups and predict acute coronary events. METHODS AND RESULTS: Blood levels of lipoprotein(a), homocysteine, tissue plasminogen activator, plasminogen activator inhibitor-1, C-reactive protein (CRP), fibrinogen, and von Willebrand factor were compared in 3 groups of 50 subjects each: (1) those with previous multiple acute coronary events, (2) age-matched subjects with >/=3 years of stable angina and no prior acute coronary events, and (3) matched controls without evidence of atherosclerotic disease and a normal coronary angiogram. All subjects were followed for 4.0 years. Lipoprotein(a), homocysteine, tissue plasminogen activator, and plasminogen activator inhibitor-1 were similar in both CAD groups and significantly higher than in the control group. However, compared with subjects with long-standing stable angina, those with previous multiple coronary events had higher values of CRP (5.7+/-5.4 versus 3.0+/-5.2 mg/L, P=0.012), fibrinogen (3.38+/-0.75 versus 2.92+/-0.64 g/L, P=0.001), and von Willebrand factor (1.60+/-0.55 versus 1.25+/-0.36 U/mL, P=0.0003). On follow-up, myocardial infarction and unstable angina occurred in 42% of the group with multiple events, 4% of the stable angina group (P<0.0001), and none of the control subjects. In the 100 patients with CAD, CRP was 4.9 mg/L in those with and 1.8 mg/L in those without new instability (P<0.0001). In a multivariate analysis, only CRP distinguished those with follow-up acute coronary events (adjusted odds ratio 5.9, 95% CI 2.0 to 17.9; P=0.002). A baseline CRP >3.5 mg/L had a relative risk of 7.6 (2.6 to 21.7, P=0.0002) for subsequent acute events. CONCLUSIONS: An inflammatory biological profile distinguished patients with previous multiple acute coronary events from those with long-standing stable angina and predicted acute coronary instability.

High apolipoprotein B with low high-density lipoprotein cholesterol and normal plasma triglycerides and cholesterol.

Increased numbers of small, dense low-density lipoprotein particles may be present in patients with low high-density lipoprotein cholesterol and normal plasma triglycerides and cholesterol. Measurment of apolipoprotein B is the key to diagnosis and such patients should be considered for statin therapy.

Myocardial perfusion imaging findings and the role of adenosine in the warm-up angina phenomenon.

OBJECTIVES: This study examined the roles of myocardial perfusion and adenosine in warm-up angina. BACKGROUND: In warm-up angina, neither the role of an adenosine-mediated mechanism, as is found in experimental ischemic preconditioning, nor of increased myocardial perfusion is well defined. METHODS: In substudy A, a single-photon emission computed tomography (SPECT)-thallium-201 exercise test was performed by 12 subjects with ischemic heart disease on three occasions one week apart. The third test was preceded by a warm-up test. The extent of the thallium deficit and its intensity on the third test were compared with the baseline tests controlling for the heart rate-systolic blood pressure product (RPP) at thallium injection. In substudy B, 12 similar subjects did two successive exercise tests at two separate sessions and received the adenosine antagonist, aminophylline (intravenous 5 mg/kg bolus and 0.9 mg/kg/h infusion) at one session, and equivalent saline at the other session. Change in ischemic threshold (RPP at 1 mm ST segment depression) and in maximum ST depression adjusted for RPP were analyzed. RESULTS: In substudy A, despite a significant attenuation of electrocardiogram indexes of myocardial ischemia between the baseline and third (warmed-up) tests, the thallium extent deficits (20.8 +/- 15.1% and 16.8 +/- 12.4%) and intensity deficits (41.2 +/- 12.6% and 39.3 +/- 12.6%) did not differ significantly. In substudy B, the increase in ischemic threshold on re-exercise was unaffected by aminophylline. Adjusted maximum ST depression even decreased to a greater extent on re-exercise with aminophylline (by 51 +/- 21%) than with saline (by 32 +/- 19%) (p = 0.012). CONCLUSIONS: While warm-up angina is associated with a significant attenuation of exercise electrocardiogram indexes of ischemia, it is unaccompanied by significant changes in SPECT perfusion and does not appear to be mediated by an adenosine-dependent mechanism since it is not blocked by aminophylline. Thus, its mechanism, which appears distinct from experimental ischemic preconditioning, remains unidentified.

Beta-carotene, vitamin C, and vitamin E and cardiovascular diseases.

Observational studies have shown an inverse relationship between consumption of fruits and vegetables high in beta-carotene, vitamins C and E, and ischemic heart disease (IHD) and stroke. In large observational studies, beta- carotene reduced the risk of IHD events in men, particularly in smokers. In contrast, four large randomized trials did not reveal a reduction in cardiovascular events with beta-carotene use, and may, in fact, increase IHD and total mortality in male smokers. There have been only a few large observational studies and one randomized trial with vitamin C, which have shown no beneficial or deleterious impact of this vitamin on cardiovascular events. Most large observational studies have shown an inverse relationship between vitamin E and IHD. However, a meta-analysis of the four randomized trials done in Europe and America involving a total of 51,000 participants allocated to vitamin E or placebo for 1.4 to 6 years, did not demonstrate a reduction in cardiovascular and IHD mortality and nonfatal myocardial infarction. Currently, there are no data to support the use of these vitamins to reduce the risk of cardiovascular events. Trials are in progress to determine whether a longer duration of administration of vitamin E or the association of vitamin E with cofactors may reduce cardiovascular events.

Psychosocial factors at work, smoking, sedentary behavior, and body mass index: a prevalence study among 6995 white collar workers.

This cross-sectional study examined whether psychosocial factors at work were associated with smoking, sedentary behavior, and body mass index. The study population was composed of 3531 men and 3464 women employed as white collar workers in 21 organizations. Data were collected at worksites. Psychological demands and decision latitude at work were measured with the Karasek 18-item questionnaire. Smoking, sedentary behavior, and mean body mass index were compared by quartiles of decision latitude and psychological demands and by job strain categories. Prevalence of smoking, mean number of cigarettes smoked per day, prevalence of sedentary behavior, and mean body mass index were not consistently associated with decision latitude, psychological demands, or high job strain. However, prevalence of smoking was elevated in women belonging to the highest quartile of psychological demands (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.0 to 1.6) and in the active job strain groups in both men (OR, 1.6; 95% CI, 1.2 to 2.1) and women (OR, 1.4; 95% CI, 1.0 to 2.0). Prevalence of sedentary behavior was elevated in men in the lowest quartile of decision latitude (OR, 1.3; 95% CI, 1.0 to 1.7), in the passive group (OR, 1.3; 95% CI, 1.0 to 1.5), and in the high strain group (OR, 1.2; 95% CI, 1.0 to 1.6). In women, this prevalence was elevated in the third quartile of psychological demand (OR, 1.3; 95% CI, 1.1 to 1.6). These results provide only partial support for an association between some psychosocial factors at work and the prevalence of smoking and sedentary behavior.

Influence of triglyceride concentration on the relationship between lipoprotein cholesterol and apolipoprotein B and A-I levels.

A sample of 2,103 men aged 47 to 76 years from the Québec Cardiovascular Study cohort was examined to quantify the influence of plasma triglyceride (TG) levels on the relationship between plasma lipoprotein cholesterol and either apolipoprotein A-I (apo A-I) or apo B concentrations. Regression analyses between high-density lipoprotein cholesterol (HDL-C) and apo A-I through TG tertiles showed highly significant correlations (.62 < or = r < or = .75, P < .0001) in all TG tertiles between these 2 variables. The associations for plasma apo B versus low-density lipoprotein cholesterol (LDL-C) and non-HDL-C levels were also studied on the basis of TG concentrations, and correlation coefficients between either LDL-C or non-HDL-C and apo B were essentially similar among TG tertiles (.78 < or = r < or = .85 and .83 < or = r < or = .86 for LDL-C and non-HDL-C, respectively, P < .0001). Regression analyses also showed that lower HDL-C levels were found for any given apo A-I concentration among men in the 2 upper TG tertiles, whereas lower LDL-C concentrations were observed at any given apo B level among subjects in the upper TG tertile. We further investigated whether there were synergistic alterations in the HDL-C/apo A-I and LDL-C/apo B ratios as a function of increasing plasma TG. A significant association was noted between these 2 ratios (r = .37; P < .0001). Mean HDL-C/apo A-I and LDL-C/apo B ratios were then calculated across quintiles of plasma TG concentrations. Increased TG concentrations were first associated with a reduced HDL-C/apo A-I ratio, followed by a decreased LDL-C/apo B ratio. These results suggest that a relatively modest increase in TG may rapidly alter the relative cholesterol content of HDL particles. Finally, the cholesterol content of the non-HDL fraction appears to be influenced less by TG levels than HDL-C and LDL-C fractions. Thus, the plasma apo B-containing lipoprotein cholesterol level may provide a better index of number of atherogenic particles than the LDL-C concentration, particularly in the presence of hypertriglyceridemia (HTG).