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Background: It is unknown whether dietary intake of polyunsaturated fatty acids (PUFA) modifies the cardiovascular disease (CVD) risk associated with a family history of CVD. We assessed interactions between biomarkers of low PUFA intake and a family history in relation to long-term CVD risk in a large consortium., Methods: Blood and tissue PUFA data from 40 885 CVD-free adults were assessed. PUFA levels ≤25th percentile were considered to reflect low intake of linoleic, alpha-linolenic, and eicosapentaenoic/docosahexaenoic acids (EPA/DHA). Family history was defined as having ≥1 first-degree relative who experienced a CVD event. Relative risks with 95% CI of CVD were estimated using Cox regression and meta-analyzed. Interactions were assessed by analyzing product terms and calculating relative excess risk due to interaction., Results: After multivariable adjustments, a significant interaction between low EPA/DHA and family history was observed (product term pooled RR, 1.09 [95% CI, 1.02-1.16]; P =0.01). The pooled relative risk of CVD associated with the combined exposure to low EPA/DHA, and family history was 1.41 (95% CI, 1.30-1.54), whereas it was 1.25 (95% CI, 1.16-1.33) for family history alone and 1.06 (95% CI, 0.98-1.14) for EPA/DHA alone, compared with those with neither exposure. The relative excess risk due to interaction results indicated no interactions., Conclusions: A significant interaction between biomarkers of low EPA/DHA intake, but not the other PUFA, and a family history was observed. This novel finding might suggest a need to emphasize the benefit of consuming oily fish for individuals with a family history of CVD., Competing Interests: Disclosures Dr Murphy reports having worked as a consultant for Pharmavite (until 2021). The remaining authors have reported no relationships relevant to the contents of this article. Dr Psaty serves on the steering committee of the Yale Open Data Access Project, funded by Johnson and Johnson.

Background The major risk factors for atherosclerotic cardiovascular disease differ by race or ethnicity but have largely been defined using populations of European ancestry. Despite the rising prevalence of cardiovascular disease in Africa there are few related data from African populations. Therefore, we compared the association of established cardiovascular risk factors with carotid-intima media thickness (CIMT), a subclinical marker of atherosclerosis, between African, African American, Asian, European, and Hispanic populations. Methods and Results Cross-sectional analyses of 34 025 men and women drawn from 15 cohorts in Africa, Asia, Europe, and North America were undertaken. Classical cardiovascular risk factors were assessed and CIMT measured using B-mode ultrasound. Ethnic differences in the association of established cardiovascular risk factors with CIMT were determined using a 2-stage individual participant data meta-analysis with beta coefficients expressed as a percentage using the White population as the reference group. CIMT adjusted for risk factors was the greatest among African American populations followed by Asian, European, and Hispanic populations with African populations having the lowest mean CIMT. In all racial or ethnic groups, men had higher CIMT levels compared with women. Age, sex, body mass index, and systolic blood pressure had a significant positive association with CIMT in all races and ethnicities at varying magnitudes. When compared with European populations, the association of age, sex, and systolic blood pressure with CIMT was weaker in all races and ethnicities. Smoking (beta coefficient, 0.39; 95% CI, 0.09-0.70), body mass index (beta coefficient, 0.05; 95% CI, 0.01-0.08) and glucose (beta coefficient, 0.13; 95% CI, 0.06-0.19) had the strongest positive association with CIMT in the Asian population when compared with all other racial and ethnic groups. High-density lipoprotein-cholesterol had significant protective effects in African American (beta coefficient, -0.31; 95% CI, -0.42 to -0.21) and African (beta coefficient, -0.26; 95% CI, -0.31 to -0.19) populations only. Conclusions The strength of association between established cardiovascular risk factors and CIMT differed across the racial or ethnic groups and may be due to lifestyle risk factors and genetics. These differences have implications for race- ethnicity-specific primary prevention strategies and also give insights into the differential contribution of risk factors to the pathogenesis of cardiovascular disease. The greatest burden of subclinical atherosclerosis in African American individuals warrants further investigations.

The added value of incorporating information from repeated blood pressure and cholesterol measurements to predict cardiovascular disease (CVD) risk has not been rigorously assessed. We used data on 191,445 adults from the Emerging Risk Factors Collaboration (38 cohorts from 17 countries with data encompassing 1962-2014) with more than 1 million measurements of systolic blood pressure, total cholesterol, and high-density lipoprotein cholesterol. Over a median 12 years of follow-up, 21,170 CVD events occurred. Risk prediction models using cumulative mean values of repeated measurements and summary measures from longitudinal modeling of the repeated measurements were compared with models using measurements from a single time point. Risk discrimination (C-index) and net reclassification were calculated, and changes in C-indices were meta-analyzed across studies. Compared with the single-time-point model, the cumulative means and longitudinal models increased the C-index by 0.0040 (95% confidence interval (CI): 0.0023, 0.0057) and 0.0023 (95% CI: 0.0005, 0.0042), respectively. Reclassification was also improved in both models; compared with the single-time-point model, overall net reclassification improvements were 0.0369 (95% CI: 0.0303, 0.0436) for the cumulative-means model and 0.0177 (95% CI: 0.0110, 0.0243) for the longitudinal model. In conclusion, incorporating repeated measurements of blood pressure and cholesterol into CVD risk prediction models slightly improves risk prediction., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Background: The relation of a single risk factor with atherosclerosis is established. Clinically we know of risk factor clustering within individuals. Yet, studies into the magnitude of the relation of risk factor clusters with atherosclerosis are limited. Here, we assessed that relation., Methods: Individual participant data from 14 cohorts, involving 59,025 individuals were used in this cross-sectional analysis. We made 15 clusters of four risk factors (current smoking, overweight, elevated blood pressure, elevated total cholesterol). Multilevel age and sex adjusted linear regression models were applied to estimate mean differences in common carotid intima-media thickness (CIMT) between clusters using those without any of the four risk factors as reference group., Results: Compared to the reference, those with 1, 2, 3 or 4 risk factors had a significantly higher common CIMT: mean difference of 0.026 mm, 0.052 mm, 0.074 mm and 0.114 mm, respectively. These findings were the same in men and in women, and across ethnic groups. Within each risk factor cluster (1, 2, 3 risk factors), groups with elevated blood pressure had the largest CIMT and those with elevated cholesterol the lowest CIMT, a pattern similar for men and women., Conclusion: Clusters of risk factors relate to increased common CIMT in a graded manner, similar in men, women and across race-ethnic groups. Some clusters seemed more atherogenic than others. Our findings support the notion that cardiovascular prevention should focus on sets of risk factors rather than individual levels alone, but may prioritize within clusters.

Although atherosclerosis starts in early life, evidence on risk factors and atherosclerosis in individuals aged <45 years is scarce. Therefore, we studied the relationship between risk factors, common carotid intima-media thickness (CIMT), and first-time cardiovascular events in adults aged <45 years. Our study population consisted of 3067 adults aged <45 years free from symptomatic cardiovascular disease at baseline, derived from 6 cohorts that are part of the USE-IMT initiative, an individual participant data meta-analysis of general-population-based cohort studies evaluating CIMT measurements. Information on risk factors, CIMT measurements, and follow-up of the combined end point (first-time myocardial infarction or stroke) was obtained. We assessed the relationship between risk factors and CIMT and the relationship between CIMT and first-time myocardial infarction or stroke using a multivariable linear mixed-effects model and a Cox proportional-hazards model, respectively. During a follow-up of 16.3 years, 55 first-time myocardial infarctions or strokes occurred. Median CIMT was 0.63 mm. Of the risk factors under study, age, sex, diastolic blood pressure, body mass index, total cholesterol, and high-density lipoprotein cholesterol related to CIMT. Furthermore, CIMT related to first-time myocardial infarction or stroke with a hazard ratio of 1.40 per SD increase in CIMT, independent of risk factors (95% confidence interval, 1.11-1.76). CIMT may be a valuable marker for cardiovascular risk in adults aged <45 years who are not yet eligible for standard cardiovascular risk screening. This is especially relevant in those with an increased, unfavorable risk factor burden., (© 2015 American Heart Association, Inc.)

Carotid intima-media thickness (CIMT) is a marker of cardiovascular risk. It is unclear whether measurement of mean common CIMT improves 10-year risk prediction of first-time myocardial infarction or stroke in individuals with elevated blood pressure. We performed an analysis among individuals with elevated blood pressure (i.e., a systolic blood pressure ≥140 mm Hg and a diastolic blood pressure ≥ 90 mm Hg) in USE-IMT, a large ongoing individual participant data meta-analysis. We refitted the risk factors of the Framingham Risk Score on asymptomatic individuals (baseline model) and expanded this model with mean common CIMT (CIMT model) measurements. From both models, 10-year risks to develop a myocardial infarction or stroke were estimated. In individuals with elevated blood pressure, we compared discrimination and calibration of the 2 models and calculated the net reclassification improvement (NRI). We included 17 254 individuals with elevated blood pressure from 16 studies. During a median follow-up of 9.9 years, 2014 first-time myocardial infarctions or strokes occurred. The C-statistics of the baseline and CIMT models were similar (0.73). NRI with the addition of mean common CIMT was small and not significant (1.4%; 95% confidence intervals, -1.1 to 3.7). In those at intermediate risk (n=5008, 10-year absolute risk of 10% to 20%), the NRI was 5.6% (95% confidence intervals, 1.6-10.4). There is no added value of measurement of mean common CIMT in individuals with elevated blood pressure for improving cardiovascular risk prediction. For those at intermediate risk, the addition of mean common CIMT to an existing cardiovascular risk score is small but statistically significant.

Background: The degree of fatty acid (FA) unsaturation as a determinant of lipid peroxidation has been inadequately studied., Methods: We examined associations of plasma free F2α-isoprostanes (F2-IsoPs), an indicator of in-vivo lipid peroxidation, with the levels/intake of FAs, adjusted for the risk factors of cardiovascular disease (CVD) in 1211 Finnish men and women, of whom 50% were hypertensive, aged 59.3 ± 8.3 years, mean ± SD., Results: Elevated age- and sex-adjusted plasma free levels of omega-6 and omega-3 polyunsaturated Fas (PUFAs), saturated FAs (SFAs), and the PUFA/SFA and the omega-6/omega-3 PUFA ratios were all associated with decreased F2-IsoPs. High dietary SFA intake was associated with elevated F2-IsoP concentrations. In a multivariable regression (with clinical, nutritional, and behavioral CVD risk factors), female gender, body mass index (BMI), serum apolipoprotein A1, and NT-proBNP (natriuretic peptide) were positively associated with the F2-IsoPs, whereas the dietary PUFA/SFA ratio, plasma β-carotene, the omega-6/omega-3 PUFA ratio, and protein intake showed inverse associations., Conclusions: We propose that elevated lipid peroxidation is associated with several risk factors of CVD, such as a low PUFA/SFA ratio, whereas the FA precursors of lipid peroxidation, i.e. omega-3 and omega-6 PUFAs are associated with attenuated F2-IsoP levels. These findings provide mechanistic support for earlier observations linking PUFA to improved cardiovascular health.

Background: There is debate about the value of assessing levels of C-reactive protein (CRP) and other biomarkers of inflammation for the prediction of first cardiovascular events., Methods: We analyzed data from 52 prospective studies that included 246,669 participants without a history of cardiovascular disease to investigate the value of adding CRP or fibrinogen levels to conventional risk factors for the prediction of cardiovascular risk. We calculated measures of discrimination and reclassification during follow-up and modeled the clinical implications of initiation of statin therapy after the assessment of CRP or fibrinogen., Results: The addition of information on high-density lipoprotein cholesterol to a prognostic model for cardiovascular disease that included age, sex, smoking status, blood pressure, history of diabetes, and total cholesterol level increased the C-index, a measure of risk discrimination, by 0.0050. The further addition to this model of information on CRP or fibrinogen increased the C-index by 0.0039 and 0.0027, respectively (P<0.001), and yielded a net reclassification improvement of 1.52% and 0.83%, respectively, for the predicted 10-year risk categories of "low" (<10%), "intermediate" (10% to <20%), and "high" (≥20%) (P<0.02 for both comparisons). We estimated that among 100,000 adults 40 years of age or older, 15,025 persons would initially be classified as being at intermediate risk for a cardiovascular event if conventional risk factors alone were used to calculate risk. Assuming that statin therapy would be initiated in accordance with Adult Treatment Panel III guidelines (i.e., for persons with a predicted risk of ≥20% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), additional targeted assessment of CRP or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years., Conclusions: In a study of people without known cardiovascular disease, we estimated that under current treatment guidelines, assessment of the CRP or fibrinogen level in people at intermediate risk for a cardiovascular event could help prevent one additional event over a period of 10 years for every 400 to 500 people screened. (Funded by the British Heart Foundation and others.).

Context: The evidence that measurement of the common carotid intima-media thickness (CIMT) improves the risk scores in prediction of the absolute risk of cardiovascular events is inconsistent., Objective: To determine whether common CIMT has added value in 10-year risk prediction of first-time myocardial infarctions or strokes, above that of the Framingham Risk Score., Data Sources: Relevant studies were identified through literature searches of databases (PubMed from 1950 to June 2012 and EMBASE from 1980 to June 2012) and expert opinion., Study Selection: Studies were included if participants were drawn from the general population, common CIMT was measured at baseline, and individuals were followed up for first-time myocardial infarction or stroke., Data Extraction: Individual data were combined into 1 data set and an individual participant data meta-analysis was performed on individuals without existing cardiovascular disease., Results: We included 14 population-based cohorts contributing data for 45,828 individuals. During a median follow-up of 11 years, 4007 first-time myocardial infarctions or strokes occurred. We first refitted the risk factors of the Framingham Risk Score and then extended the model with common CIMT measurements to estimate the absolute 10-year risks to develop a first-time myocardial infarction or stroke in both models. The C statistic of both models was similar (0.757; 95% CI, 0.749-0.764; and 0.759; 95% CI, 0.752-0.766). The net reclassification improvement with the addition of common CIMT was small (0.8%; 95% CI, 0.1%-1.6%). In those at intermediate risk, the net reclassification improvement was 3.6% in all individuals (95% CI, 2.7%-4.6%) and no differences between men and women., Conclusion: The addition of common CIMT measurements to the Framingham Risk Score was associated with small improvement in 10-year risk prediction of first-time myocardial infarction or stroke, but this improvement is unlikely to be of clinical importance.

Context: The value of assessing various emerging lipid-related markers for prediction of first cardiovascular events is debated., Objective: To determine whether adding information on apolipoprotein B and apolipoprotein A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 to total cholesterol and high-density lipoprotein cholesterol (HDL-C) improves cardiovascular disease (CVD) risk prediction., Design, Setting, and Participants: Individual records were available for 165,544 participants without baseline CVD in 37 prospective cohorts (calendar years of recruitment: 1968-2007) with up to 15,126 incident fatal or nonfatal CVD outcomes (10,132 CHD and 4994 stroke outcomes) during a median follow-up of 10.4 years (interquartile range, 7.6-14 years)., Main Outcome Measures: Discrimination of CVD outcomes and reclassification of participants across predicted 10-year risk categories of low (<10%), intermediate (10%-<20%), and high (≥20%) risk., Results: The addition of information on various lipid-related markers to total cholesterol, HDL-C, and other conventional risk factors yielded improvement in the model's discrimination: C-index change, 0.0006 (95% CI, 0.0002-0.0009) for the combination of apolipoprotein B and A-I; 0.0016 (95% CI, 0.0009-0.0023) for lipoprotein(a); and 0.0018 (95% CI, 0.0010-0.0026) for lipoprotein-associated phospholipase A2 mass. Net reclassification improvements were less than 1% with the addition of each of these markers to risk scores containing conventional risk factors. We estimated that for 100,000 adults aged 40 years or older, 15,436 would be initially classified at intermediate risk using conventional risk factors alone. Additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1%; lipoprotein(a), 4.1%; and lipoprotein-associated phospholipase A2 mass, 2.7% of people to a 20% or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines., Conclusion: In a study of individuals without known CVD, the addition of information on the combination of apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 mass to risk scores containing total cholesterol and HDL-C led to slight improvement in CVD prediction.

Aims: Dyslipidaemia and hypertension are features of the metabolic syndrome, but the role of dyslipidaemia in the development of hypertension is less clear. We assessed the association of dyslipidaemia with incident hypertension during a 7-year follow-up in a population-based cohort of middle-aged men without hypertension at baseline., Methods and Results: In all, 88 of 311 men developed hypertension during the follow-up. A 1-SD increment in triglyceride concentrations was associated with a 1.6-fold [95% CI(confidence interval) 1.2-2.3] increased risk of developing hypertension, independently of features related to the metabolic syndrome. In separate multivariable models, the triglyceride content of high-density lipoprotein (HDL) cholesterol and apolipoprotein B concentrations were also associated with new-onset hypertension. In a stepwise backwards logistic regression model, concentrations of low-density lipoprotein (LDL) cholesterol [odds ratio (OR) 1.3, 95% CI 1.0-1.7 for a 1-SD change] and triglyceride content of HDL cholesterol (OR) 1.5, 95% CI 1.1-1.9) were positively associated with incident hypertension, whereas HDL concentrations (OR 0.7, 95% CI 0.5-0.9) seemed protective. In factor analyses, elevated triglyceride levels and related disturbances in lipid and cholesterol metabolism were associated with new-onset hypertension., Conclusion: Dyslipidaemia characteristic of the metabolic syndrome predicts the development of hypertension during a 7-year follow-up of eastern Finnish men, independently of features related to insulin resistance. The recognition of dyslipidaemia and initiation of lifestyle treatment even in the absence of hypertension is likely to reduce the long-term burden of cardiovascular disease.

The role of flavonoids in CVD, especially in strokes, is unclear. Our aim was to study the role of flavonoids in CVD. We studied the association between the intakes of five subclasses (flavonols, flavones, flavanones, flavan-3-ols and anthocyanidins), a total of twenty-six flavonoids, on the risk of ischaemic stroke and CVD mortality. The study population consisted of 1950 eastern Finnish men aged 42-60 years free of prior CHD or stroke as part of the prospective population-based Kuopio Ischaemic Heart Disease Risk Factor Study. During an average follow-up time of 15.2 years, 102 ischaemic strokes and 153 CVD deaths occurred. In the Cox proportional hazards model adjusted for age and examination years, BMI,systolic blood pressure, hypertension medication, serum HDL- and LDL-cholesterol, serum TAG, maximal oxygen uptake, smoking, family history of CVD, diabetes, alcohol intake, energy-adjusted intake of folate, vitamin E, total fat and saturated fat intake (percentage of energy), men in the highest quartile of flavonol and flavan-3-ol intakes had a relative risk of 0.55 (95% CI 0.31, 0.99) and 0.59 (95% CI 0.30, 1.14) for ischaemic stroke, respectively, as compared with the lowest quartile. After multivariate adjustment, the relative risk for CVD death in the highest quartile of flavanone and flavone intakes were 0.54 (95% CI 0.32, 0.92) and 0.65 (95% CI 0.40, 1.05), respectively. The present results suggest that high intakes of flavonoids may be associated with decreased risk of ischaemic stroke and possibly with reduced CVD mortality.

Objective: In culture studies matrix metalloproteinase (MMP)-8 thins the protecting fibrous cap of the atherosclerotic plaque thereby increasing its vulnerability. Results on the association of serum MMP-8 concentrations and cardiovascular diseases (CVD) are, however, scarce and contradictory., Methods and Results: We analyzed the association between CVD or subclinical atherosclerosis and serum MMP-8 and tissue inhibitor of metalloproteinase-1 (TIMP-1) concentrations of 1018 men with the follow-up time of 10 years. MMP-8 concentrations or MMP-8/TIMP-1 ratios were higher in men with prevalent CVD or subclinical atherosclerosis at baseline than those without. In men free of CVD at baseline, MMP-8 concentrations associated with acute myocardial infarction, death from coronary heart disease (CHD), CVD, or from any cause with relative risks (RR) (95% CI) of 1.138 (1.009 to 1.284), 1.188 (1.034 to 1.365), 1.171 (1.026 to 1.338), and 1.136 (1.018 to 1.269), respectively, and MMP-8/TIMP-1 ratio with CHD death with an RR of 1.206 (1.028 to 1.414) per standard deviation (SD) increase. In men with no prevalent CVD but with subclinical atherosclerosis at baseline, elevated serum MMP-8 concentration predicted CVD death with an RR of 3.03 (1.09 to 8.44). TIMP-1 concentrations alone had no predictive value., Conclusions: The results indicate that serum MMP-8 concentrations are elevated in prevalent or subclinical atherosclerosis and associate with the worst cardiovascular outcome.

The magnitude of work an individual is able to perform at the heart rate (HR) of 100 beats/min (WL(100)) is a simple, integrated measure of HR at rest, HR response to light dynamic exercise, as well as cardiorespiratory performance. Because a high HR at rest and a low cardiorespiratory performance are previously established risk factors for cardiovascular disease (CVD) mortality, it can be deduced that WL(100) is a potential predictor of CVD and coronary heart disease (CHD) mortality. The aim of the present study was to investigate whether WL(100) independently predicts CVD and CHD mortality in middle-aged men. The subjects were a representative sample of 1,314 middle-aged men who did not have CHD and did not use HR-lowering medication at baseline. The association of WL(100) with CVD and CHD mortality was examined by Cox regression models with backward stepwise selection, including numerous known risk factors for CVD death. During an average follow-up of 11.5 years, there were 51 CVD deaths, of which 35 were due to CHD. In Cox multivariable models, CVD mortality increased by 72% (95% confidence interval 27% to 138%, p = 0.001) and CHD mortality by 89% (95% confidence interval 28% to 178%, p = 0.001) with 1 SD (31 W) decrement in WL(100). WL(100) improved the predictive power of the adjusted Cox models, including other HR-derived and exercise test variables. In conclusion, WL(100) predicts CVD and CHD mortality in men without previous CHD. The association of WL(100) with CVD and CHD mortality is not explained by maximal cardiorespiratory performance.

Aims: The objective is to study whether a heart rate (HR) response during exercise test independently predicts cardiovascular disease (CVD) mortality., Methods and Results: The subjects were a representative sample of 1378 men, 42-61 years of age, from eastern Finland with neither prior coronary heart disease (CHD) nor use of beta-blockers at baseline. HR was measured at rest and during a maximal, symptom-limited exercise test at 20, 40, 60, 80, and 100% of maximal workload. During an average follow-up of 11.4 years, there were 56 deaths due to CVD. The slope of HR increase during exercise test was steeper in survivors when compared with those who died due to CVD during follow-up (P<0.001), and the difference in the steepness of HR slope between the groups was the strongest at interval 40-100% (P<0.001). In Cox-multivariable models, maximal HR-HR at 40% workload as a continuous variable was inversely associated with CVD (P=0.04), CHD (P=0.004), and all-cause (P=0.002) mortality after adjustment for known risk factors for CVD death., Conclusion: By considering an HR response throughout an exercise test, we found that a blunted HR increase at 40-100% of maximal workload was associated with increased CVD mortality.

Aims: Cut-offs for C-reactive protein concentrations have been recommended for risk stratification, but little is known about how these cut-offs predict cardiovascular risk in population-based cohorts. We therefore assessed the association of C-reactive protein levels with cardiovascular mortality in a population-based cohort of 2321 middle-aged men stratified by the presence of cardiovascular disease (CVD) at baseline., Methods and Results: C-reactive protein concentrations were categorized according to current recommendations (1 and 3 mg/L). During the 15 year follow-up, 77 men without CVD and 121 men with CVD at baseline died of CVD. In men without CVD at baseline (n=1476), age-adjusted cardiovascular mortality was 4.1-fold higher (95% CI 2.1-8.2) for C-reactive protein levels between 3.0 and 9.9 mg/L at baseline than for C-reactive protein levels <1.0 mg/L. In men with CVD at baseline (n=845), the corresponding age-adjusted cardiovascular mortality was 3.3-fold higher (95% CI 2.0-5.3). Adjustment for conventional CVD risk factors attenuated the risk somewhat. Further adjustment for dietary and lifestyle factors and factors related to insulin resistance did not affect the association. Classification of C-reactive protein by tertiles gave qualitatively similar results, but identified twice as many men at high risk. C-reactive protein levels also predicted overall mortality., Conclusion: Currently, recommended cut-offs for C-reactive protein levels identify men at risk for cardiovascular and overall death independently of conventional and other risk factors in a population-based sample of middle-aged men with and without CVD at baseline. Lower cut-offs may better identify men at high risk for cardiovascular death, but improvement of current recommendations will require standardization of C-reactive protein assays.

Background: The echocardiographic identification of subclinical risk markers may enhance risk stratification for the development of cardiovascular outcomes in the general population. Although echocardiography is widely used in the evaluation of cardiac structures and function, the prognostic value of echocardiographic assessment of left atrium (LA) size for risk stratification of cardiovascular death is unknown., Methods: Left ventricular (LV) mass and LA size were measured by using M-mode echocardiography in a representative population-based sample of 830 men (age, 42-61 years) from eastern Finland. There were 54 deaths due to cardiovascular disease during an average follow-up of 13 years., Results: The strongest risk factors for cardiovascular death were smoking, family history of coronary heart disease, low exercise capacity, elevated blood pressure, exercise-induced myocardial ischemia, and large LA diameter. Men in the highest tertile of LA diameter (>43 mm) had a 2.3-fold (95% confidence interval, 1.1-5.0) risk of cardiovascular death compared with men in the lowest tertile of LA diameter (<39 mm), after adjusting for other risk factors and the use of antihypertensive medications. The excess risk for cardiovascular mortality appeared to reside largely in the highest tertile of LA size. After additional adjustment for LV mass, the relation between LA size and mortality did not remain statistically significant (relative risk, 1.5; 95% confidence interval, 0.8-4.1; P = .15) in this group., Conclusions: This prospective population-based study shows that echocardiographically defined LA diameter was directly related to the risk of cardiovascular death. The association of LA enlargement to cardiovascular death appears to be partially related to LV hypertrophy.

Background: Substitution of dietary polyunsaturated for saturated fat has long been recommended for the primary prevention of cardiovascular disease (CVD), but only a few prospective cohort studies have provided support for this advice., Methods: We assessed the association of dietary linoleic and total polyunsaturated fatty acid (PUFA) intake with cardiovascular and overall mortality in a population-based cohort of 1551 middle-aged men. Dietary fat composition was estimated with a 4-day food record and serum fatty acid composition., Results: During the 15-year follow-up, 78 men died of CVD and 225 of any cause. Total fat intake was not related to CVD or overall mortality. Men with an energy-adjusted dietary intake of linoleic acid (relative risk [RR] 0.39; 95% confidence interval [CI], 0.21-0.71) and PUFA (RR, 0.38; 95% CI, 0.20-0.70) in the upper third were less likely to die of CVD than men with intake in the lower third after adjustment for age. Multivariate adjustment weakened the association somewhat. Mortality from CVD was also lower for men with proportions of serum esterified linoleic acid (RR, 0.42; 95% CI, 0.21-0.80) and PUFA (RR, 0.25; 95% CI, 0.12-0.50) in the upper vs lower third, with some attenuation in multivariate analyses. Serum and to a lesser extent dietary linoleic acid and PUFA were also inversely associated with overall mortality., Conclusions: Dietary polyunsaturated and more specifically linoleic fatty acid intake may have a substantial cardioprotective benefit that is also reflected in overall mortality. Dietary fat quality seems more important than fat quantity in the reduction of cardiovascular mortality in men.

Objective: Mercury has been suggested to have negative effects on cardiovascular health. We investigated the effects of high mercury content in hair on the risk of acute coronary events and cardiovascular and all-cause mortality in men from eastern Finland., Methods and Results: The population-based prospective Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) cohort of 1871 Finnish men aged 42 to 60 years and free of previous coronary heart disease (CHD) or stroke at baseline was used. During an average follow-up time of 13.9 years, 282 acute coronary events and 132 cardiovascular disease (CVD), 91 CHD, and 525 all-cause deaths occurred. Men in the highest third of hair mercury content (>2.03 microg/g) had an adjusted 1.60-fold (95% CI, 1.24 to 2.06) risk of acute coronary event, 1.68-fold (95% CI, 1.15 to 2.44) risk of CVD, 1.56-fold (95% CI, 0.99 to 2.46) risk of CHD, and 1.38-fold (95% CI, 1.15 to 1.66) risk of any death compared with men in the lower two thirds. High mercury content in hair also attenuated the protective effects of high-serum docosahexaenoic acid plus docosapentaenoic acid concentration., Conclusions: High content of mercury in hair may be a risk factor for acute coronary events and CVD, CHD, and all-cause mortality in middle-aged eastern Finnish men. Mercury may also attenuate the protective effects of fish on cardiovascular health.

Aims: Few data exist to show if the prognostic value of peak exercise oxygen consumption (VO2peak) for fatal and non-fatal coronary events is different among men with low and high pre-test probability for cardiovascular disease (CVD). Our objective was to determine whether VO2peak could predict fatal and non-fatal cardiac events in 2361 men aged 42-60 years with and without conventional risk predictors of CVD or with documented CVD during a 13-year follow-up., Methods and Results: Maximal oxygen consumption (ml/kg/min) was measured directly by using respiratory gas exchange in a cycle ergometer exercise test. Of 204 CVD deaths, 153 were due to coronary disease and 51 were due to other CVDs. A total of 323 non-fatal coronary events occurred during the follow-up. One metabolic equivalent (MET) increment in VO2peak was related to a decreased risk of coronary death in both healthy (RR=0.82, 95% CI 0.66-0.99) and unhealthy (RR=0.72, 95% CI 0.63-0.82) men. VO2peak was predictive of non-fatal and fatal cardiac events among men with or without known risk factors. In subjects with or without common risk factors, one MET increment amounted to an average decrease of 17-29% in non-fatal and 28-51% in fatal cardiac events, after adjustment for age. VO2peak and smoking represented two strongest independent and consistent risk predictors., Conclusions: VO2peak can be used as a very powerful predictor of future fatal cardiac events beyond that predicted by many conventional risk factors. On the prognostic consideration, unfit men with unfavourable risk profiles or underlying chronic disease are the risk groups that will benefit most from preventive measures.

Background: Despite abundant epidemiologic evidence, the role of elevated serum uric acid level as a cardiovascular risk factor is controversial. We assessed the predictive value of serum uric acid levels for cardiovascular and overall mortality., Methods: A population-based prospective cohort study was performed of 1423 middle-aged Finnish men initially without cardiovascular disease, cancer, or diabetes. The main outcome measure was death from cardiovascular disease and any cause., Results: The mean follow-up was 11.9 years. There were 157 deaths during follow-up, of which 55 were cardiovascular. In age-adjusted analyses, serum uric acid levels in the upper third were associated with a greater than 2.5-fold higher risk of death from cardiovascular disease than levels in the lower third. Taking into account cardiovascular risk factors and variables commonly associated with gout increased the relative risk to 3.73. Further adjustment for factors related to the metabolic syndrome strengthened the risk to 4.77. Excluding the 53 men using diuretics did not alter the results. In age-adjusted analyses, men with serum uric acid levels in the upper third were 1.7-fold more likely to die of any cause than men with levels in the lower third. Adjustment for further risk factors strengthened the association somewhat., Conclusions: Serum uric acid levels are a strong predictor of cardiovascular disease mortality in healthy middle-aged men, independent of variables commonly associated with gout or the metabolic syndrome. Serum uric acid measurement is an easily available and inexpensive risk marker, but whether its relationship to cardiovascular events is circumstantial or causal remains to be answered.

Context: The metabolic syndrome, a concurrence of disturbed glucose and insulin metabolism, overweight and abdominal fat distribution, mild dyslipidemia, and hypertension, is associated with subsequent development of type 2 diabetes mellitus and cardiovascular disease (CVD). Despite its high prevalence, little is known of the prospective association of the metabolic syndrome with cardiovascular and overall mortality., Objective: To assess the association of the metabolic syndrome with cardiovascular and overall mortality using recently proposed definitions and factor analysis., Design, Setting, and Participants: The Kuopio Ischaemic Heart Disease Risk Factor Study, a population-based, prospective cohort study of 1209 Finnish men aged 42 to 60 years at baseline (1984-1989) who were initially without CVD, cancer, or diabetes. Follow-up continued through December 1998., Main Outcome Measures: Death due to coronary heart disease (CHD), CVD, and any cause among men with vs without the metabolic syndrome, using 4 definitions based on the National Cholesterol Education Program (NCEP) and the World Health Organization (WHO)., Results: The prevalence of the metabolic syndrome ranged from 8.8% to 14.3%, depending on the definition. There were 109 deaths during the approximately 11.4-year follow-up, of which 46 and 27 were due to CVD and CHD, respectively. Men with the metabolic syndrome as defined by the NCEP were 2.9 (95% confidence interval [CI], 1.2-7.2) to 4.2 (95% CI, 1.6-10.8) times more likely and, as defined by the WHO, 2.9 (95% CI, 1.2-6.8) to 3.3 (95% CI, 1.4-7.7) times more likely to die of CHD after adjustment for conventional cardiovascular risk factors. The metabolic syndrome as defined by the WHO was associated with 2.6 (95% CI, 1.4-5.1) to 3.0 (95% CI, 1.5-5.7) times higher CVD mortality and 1.9 (95% CI, 1.2-3.0) to 2.1 (95% CI, 1.3-3.3) times higher all-cause mortality. The NCEP definition less consistently predicted CVD and all-cause mortality. Factor analysis using 13 variables associated with metabolic or cardiovascular risk yielded a metabolic syndrome factor that explained 18% of total variance. Men with loadings on the metabolic factor in the highest quarter were 3.6 (95% CI, 1.7-7.9), 3.2 (95% CI, 1.7-5.8), and 2.3 (95% CI, 1.5-3.4) times more likely to die of CHD, CVD, and any cause, respectively., Conclusions: Cardiovascular disease and all-cause mortality are increased in men with the metabolic syndrome, even in the absence of baseline CVD and diabetes. Early identification, treatment, and prevention of the metabolic syndrome present a major challenge for health care professionals facing an epidemic of overweight and sedentary lifestyle.

Low intake or tissue concentrations of the n -6 PUFA, especially to the major n -6 PUFA linoleic acid (LA), and low exercise cardiac power (ECP) are both associated with CVD risk. However, associations of the n -6 PUFA with ECP are unknown. The aim of the present study was to explore cross-sectional associations of the serum total n -6 PUFA, LA, arachidonic acid (AA), γ -linolenic acid (GLA) and dihomo- γ -linolenic acid (DGLA) concentrations with ECP and its components. In total, 1685 men aged 42–60 years from the Kuopio Ischaemic Heart Disease Risk Factor Study and free of CVD were included. ANCOVA was used to examine the mean values of ECP (maximal oxygen uptake (VO2max)/maximal systolic blood pressure (SBP)) and its components in quartiles of the serum total and individual n -6 PUFA concentrations. After multivariable adjustments, higher serum total n -6 PUFA concentration was associated with higher ECP and VO2max (for ECP, the extreme-quartile difference was 0·77 ml/mmHg (95 % CI 0·38, 1·16, P for trend across quartiles < 0·001) and for VO2max 157 ml/min (95 % CI 85, 230, P for trend < 0·001), but not with maximal SBP. Similar associations were observed with serum LA concentration. Higher serum AA concentration was associated with higher ECP but not with VO2max or maximal SBP. The minor serum n -6 PUFA GLA and DGLA were associated with higher maximal SBP during exercise test and DGLA also with higher VO2max but neither with ECP. In conclusion, especially LA concentration was associated with higher ECP. This may provide one mechanism for the cardioprotective properties of, especially, LA. [ABSTRACT FROM AUTHOR]

Background Previous studies investigating protein intake in relation to mortality have provided conflicting results. Objective We investigated the associations of dietary protein and protein sources with risk of disease death in the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study. Methods The study population consisted of 2641 Finnish men, aged 42–60 y at baseline in 1984–1989. We estimated protein intakes with 4-d dietary records at baseline and collected data on disease deaths from the national Causes of Death Register. Cox proportional hazards regression models were used to estimate HRs and 95% CIs. Results During the average follow-up of 22.3 y, we observed 1225 deaths due to disease. Higher intakes of total protein and animal protein had borderline statistically significant associations with increased mortality risk: multivariable-adjusted HR (95% CI) in the highest compared with the lowest quartile for total protein intake = 1.17 (0.99, 1.39; P -trend across quartiles = 0.07) and for animal protein intake = 1.13 (0.95, 1.35; P -trend = 0.04). Higher animal-to-plant protein ratio (extreme-quartile HR = 1.23; 95% CI: 1.02, 1.49; P -trend = 0.01) and higher meat intake (extreme-quartile HR = 1.23; 95% CI: 1.04, 1.47; P -trend = 0.01) were associated with increased mortality. When evaluated based on disease history at baseline, the association of total protein with mortality appeared more evident among those with a history of type 2 diabetes, cardiovascular disease, or cancer (n  = 1094) compared with those without disease history (n  = 1547) (P -interaction = 0.05 or 0.07, depending on the model). Intakes of fish, eggs, dairy, or plant protein sources were not associated with mortality. Conclusions Higher ratio of animal to plant protein in diet and higher meat intake were associated with increased mortality risk. Higher total protein intake appeared to be associated with mortality mainly among those with a predisposing disease. This trial was registered at clinicaltrials.gov as NCT03221127. [ABSTRACT FROM AUTHOR]

BACKGROUND: Methylmercury (MeHg), a worldwide contaminant found in fish and seafood, has been linked to an increased risk of cardiovascular mortality. OBJECTIVE: We examined 42 Faroese whaling men (30--70 years of age) to assess possible adverse effects within a wide range of MeHg exposures from consumption of pilot whale meat. METHODS: We assessed exposure levels from mercury analysis of toenails and whole blood (obtained at the time of clinical examination), and a hair sample collected 7 years previously. Outcome measures included heart rate variability (HRV), blood pressure (BP), common carotid intima-media thickness (IMT), and brainstem auditory evoked potentials (BAEP). We carried out multiple regression and structural equation model (SEM) analyses to determine the confounder-adjusted effect of mercury exposure. Taking into account correlations among related measures, we categorized exposure and outcomes in groups to derive latent exposure and response variables in SEMs. We used multiple regression analysis to compare the predictive validity of individual exposure biomarkers and the latent exposure variable on individual and latent outcomes. RESULTS: The toenail mercury concentrations varied widely and had a geometric mean of 2.0 µg/g; hair concentrations averaged about 3-fold higher. Mercury exposure was significantly associated with increased BP and IMT. This effect was reflected by SEMs, but mercury in toenails tended to be the best effect predictor. CONCLUSIONS: The results support the notion that increased MeHg exposure promotes the development of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Abstract: Background and aim: Homocysteine, a methionine metabolite, is suggested to be a risk factor for cardiovascular diseases (CVD). To date, the effects of dietary intake of methionine, the key amino acid in homocysteine metabolism, on CVD have not been studied. Our aim was to examine the effects of dietary methionine intake on the risk of acute coronary events. Methods and results: We examined the effects of dietary methionine intake, assessed with 4-d food record, on acute coronary events in a prospective cohort study consisting of 1981 coronary disease free men from eastern Finland, aged 42–60years at baseline in 1984–89, in the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study. During an average follow-up time of 14.0years, 292 subjects experienced an acute coronary event. In a Cox proportional hazards model adjusting for age, examination years, BMI, urinary nicotine metabolites and protein intake (excluding methionine) the relative risks of acute coronary event in the three highest quarters of dietary methionine intake were 1.31 (95% CI: 0.92, 1.86), 1.31 (95% CI: 0.88, 1.96) and 2.08 (95% CI: 1.31, 3.29) as compared with the lowest quarter. Further adjustments did not change the results. However, opposite association was observed with total protein intake, which tended to decrease the risk. Conclusions: The main finding of this study is that long-term, moderately high dietary methionine intake may increase the risk of acute coronary events in middle-aged Finnish men free of prior CHD. More prospective research is needed to confirm the role of dietary methionine in the development of CVD, and whether its effects are independent of homocysteine. [Copyright &y& Elsevier]

Diets rich in fruits and vegetables have been of interest because of their potential health benefits against chronic diseases such as cardiovascular disease (CVD) and cancer. The aim of this work was to assess the association of the dietary intake of a food group that includes fruits, berries and vegetables with all-cause, CVD-related and non-CVD-related mortality. The subjects were Finnish men aged 42-60 y examined in 1984-1989 in the prospective Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study. Dietary intakes were assessed by 4-d food intake record during the baseline phase of the KIHD Study. The risk of all-cause and non-CVD-related deaths was studied in 2641 men and the risk of CVD-related death in 1950 men who had no history of CVD at baseline. During a mean follow-up time of 12.8 y, cardiovascular as well as noncardiovascular and all-cause mortality were lower among men with the highest consumption of fruits, berries and vegetables. After adjustment for the major CVD risk factors, the relative risk for men in the highest fifth of fruit, berry and vegetable intake for all-cause death, CVD-related and non-CVD-related death was 0.66 [95% confidence interval (CI) 0.50-0.88], 0.59 (0.33-1.06), and 0.68 (0.46-1.00), respectively, compared with men in the lowest fifth. These data show that a high fruit, berry and vegetable intake is associated with reduced risk of mortality in middle-aged Finnish men. Consequently, the findings of this work indicate that diets that are rich in plant-derived foods can promote longevity. [ABSTRACT FROM AUTHOR]

Examines the relations of cardiorespiratory fitness and mortality in men. Patient demographics; Risk factors associated with cardiovascular disease (CVD) related mortality; Link maximum oxygen uptake and maintenance of physical activity; Inverse relationship of exercise test duration and CVD-related and non-CVD related mortality.

Objectives. This study examined whether heightened cardiovascular reactivity and low socioeconomic status had synergistic effects on the progression of carotid atherosclerosis in a population of eastern Finnish men. Methods. Data from the Kuopio Ischemic Heart Disease Risk Factor Study were used to measure 4-year progression of intima-media thickness in 882 men according to cardiovascular reactivity and socioeconomic status. Associations were examined in relation to risk factors and were stratified by base-line levels of atherosclerosis and prevalent ischemic heart disease. Results. The effect of reactivity on atherosclerotic progression depended on socioeconomic status. Men who had heightened cardiovascular responsiveness to stress and were born into poor families, received little education, or had low incomes had the greatest atherosclerotic progression. Conclusions. An understanding of associations between individual risk factors and disease should be based on etiologic hypotheses that are conceived at the population level and involve fundamental social and economic causes of disease. This study demonstrates how examining the interaction of an individual biological predisposition with low socioeconomic status over the life course is etiologically informative for understanding the progression of atherosclerotic vascular disease. (Am J Public Health. 1998;88:389-394) [ABSTRACT FROM AUTHOR]

Because high body iron stores have been suggested as a risk factor for acute myocardial infarction, donation of blood could theoretically reduce the risk by lowering body iron stores. For this reason, the authors tested the hypothesis that voluntary blood donation is associated with reduced risk of acute myocardial infarction in a prospective epidemiologic follow-up study in men from eastern Finland. The subjects are all participants of the Kuopio Ischaemic Heart Disease Risk Factor Study. A cohort of 2, 862 men aged 42–60 years were followed for an average of almost 9 years. One man (0.7%) out of 153 men who had donated blood in 24 months preceding the baseline examination experienced an acute myocardial infarction during 1984 to 1995, whereas 316 men (12.5%) of 2, 529 non-blood donors had an acute myocardial infarction (p < 0.0001 for difference between proportions). In a Cox proportional hazards model adjusting for age, examination years and all other predictive coronary disease risk factors, blood donors had a 88% reduced risk (relative hazard = 0.12, 95% confidence interval 0.02–0.86, p = 0.035) of acute myocardial infarction, compared with non-blood donors. These findings suggest that frequent blood loss through voluntary blood donations may be associated with a reduced risk of acute myocardial infarction in middle-aged men. Am J Epidemiol 1998; 148: 445–51. [ABSTRACT FROM AUTHOR]

Cynical hostility has been associated with increased cardiovascular morbidity and mortality; yet few studies have investigated this relation in population-based samples, and little is known about underlying mechanisms. This study examined the association between hostility, measured by the eight-item Cynical Distrust Scale, and risk for all-cause and cardiovascular mortality and incident myocardial infarction. Subjects were 2,125 men, ages 42–60 years, from the Kuopio lschemic Heart Disease Risk Factor Study, a longitudinal study of unestablished and traditional risk factors for ischemic heart disease, mortality, and other outcomes. There were 177 deaths (73 cardiovascular) in 9 years of follow-up. Men with hostility scores in the top quartile were at more than twice the risk of all-cause mortality (relative hazards (RH) 2.30, 95% confidence interval (Cl) 1.47–3.59) and cardiovascular mortality (RH 2.70, 95% Cl 1.27–5.76), relative to men with scores in the lowest quartile. Among 1,599 men without previous myocardial infarction or angina, high scorers also had an increased risk of myocardial infarction (RH 2.18, 95% CI 1.01–4.70). Biologic and socioeconomic risk factors, social support, and prevalent diseases had minimal impact on these associations, whereas adjustments for the behavioral risk factors of smoking, alcohol consumption, physical activity, and body mass index substantially weakened the relations. Simultaneous risk factor adjustment eliminated the observed associations. Results show that high levels of hostility are associated with increased risk of all-cause and cause-specific mortality and incident myocardial infarction and that these effects are mediated primarily through behavioral risk factors. Am J Epidemiol 1997;146:142-52. [ABSTRACT FROM AUTHOR]

Much remains to be understood about how low socioeconomic status (SES) increases cardiovascular disease and mortality risk. Data from the Kuopio Ischemic Heart Disease Risk Factor Study (1984–1993) were used to estimate the associations between acute myocardial infarction and income, all-cause mortality, and cardiovascular mortality in a population-based sample of 2, 272 Finnish men, with adjustment for 23 biologic, behavioral, psychologic, and social risk factors. Compared with the highest income quintile, those in the bottom quintile had age-adjusted relative hazards of 3.14 (95% confidence interval (Cl) 1.77–5.56), 2.66 (95% Cl 1.25–5.66), and 4.34 (95% Cl 1.95–9.66) for all-cause mortality, cardiovascular mortality, and AMI, respectively. After adjustment for risk factors, the relative hazards for the same comparisons were 1.32 (95% Cl 0.70–2.49), 0.70 (95% Cl 0.29–1.69), and 2.83 (95% Cl 1.14–7.00). In the lowest income quintile, adjustment for risk factors reduced the excess relative risk of all-cause mortality by 85%, that of cardiovascular mortality by 118%, and that of acute myocardial infarction by 45%. These data show how the association between SES and cardiovascular mortality and all-cause mortality is mediated by known risk factor pathways, but full “explanations” for these associations will need to encompass why these biologic, behavioral, psychologic, and social risk factors are differentially distributed by SES. Am J Epidemiol 1996; 144: 934-42. [ABSTRACT FROM AUTHOR]

Abstract: To test whether the cardiovascular disease declines in North Karella were accompanied by subjective improvements in health, we analyzed responses to two questions about perceived risk of heart disease and health status on independent random population samples surveyed to years apart. Age stratified perceived risk of heart disease declined significantly more (p < .01) and age stratified perceived health status improved significantly more in North Karelia than in the reference area (p < .005). [ABSTRACT FROM AUTHOR]

Evidence suggests that low serum enterolactone concentration might be an independent risk factor for acute coronary events. Enterolactone is a lignan, which is formed by intestinal bacteria from precursors in plant foods. Due to the biphenolic structure of enterolactone, it could act as an antioxidant and through this contribute to cardiovascular health. The aim of this study was to test the hypothesis that a low serum enterolactone concentration is associated with increased in vivo lipid peroxidation, assessed by plasma F2-isoprostane concentrations. We investigated this association in a subset of participants in ‘The Antioxidant Supplementation in Atherosclerosis Prevention’ (ASAP) study. Out of 256 male participants a subsample of 100 consecutive men from baseline was selected for F2-isoprostane assays. The mean serum enterolactone concentration was 16.6 nmol/l and that of F2-isoprostanes 29.6 ng/l. The correlation coefficient for association between serum enterolactone and F2-isoprostane concentrations was −0.30 (P<0.003). Plasma F2-isoprostane levels decreased linearly across quintiles of serum enterolactone concentration (P=0.008 for a linear trend). In a multivariate model, enterolactone persisted as a significant predictor after adjustment for vitamins and other variables, with the strongest associations with F2-isoprostanes. Our present data suggest that low serum enterolactone concentration is associated with enhanced in vivo lipid peroxidation in men. [Copyright &y& Elsevier]

Cardiovascular responses to psychological events may mediate the influence of stress on cardiovascular disease. In this study the authors asked whether cardiovascular responses to psychological challenge changed with age and whether such changes were intrinsic to aging or could be attributed to the influence of disease and medications. Cardiovascular reactivity to mental challenge was examined in 902 men ranging in age from 46 to 64 years who participated in the Kuopio Ischemic Heart Disease Risk Factor Study. A battery of 4 tasks was used to induce cardiovascular responses. Current disease status, age, and medication use were entered into hierarchical regression analyses to assess their relation with measures of cardiovascular reactivity. Age and hypertension contributed independent, approximately equal, but small amounts of variance in the cardiac and vascular reactivity indexes. Medications also influenced reactivity independently of age and disease. Performance on the tasks was more consistently altered by age than by disease or medication. Cardiac and vascular reactivity increased with increasing age and the presence of hypertension. The authors conclude that both age and disease state must be considered when examining cardiovascular reactivity as a risk factor for disease. [ABSTRACT FROM AUTHOR]