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Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke., Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank., Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min -1 ·1.73 m -2 , compared with those with eGFR between 60 and 105 mL·min -1 ·1.73 m -2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min -1 ·1.73 m -2 , with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min -1 ·1.73 m -2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min -1 ·1.73 m -2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD., Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

Purpose: Correlates of physical activity (PA) vary according to type. However, predictors of long-term patterns of PA types into old age are unknown. This study aimed to identify 20-yr trajectories of PA types into old age and their predictors., Methods: Seven thousand seven hundred thirty-five men (age, 40-59 yr) recruited from UK towns in 1978 to 1980 were followed up after 12, 16, and 20 yr. Men reported participation in sport/exercise, recreational activity and walking, health status, lifestyle behaviors and socio-demographic characteristics. Group-based trajectory modeling identified the trajectories of PA types and associations with time-stable and time-varying covariates., Results: Men with ≥3 measures of sport/exercise (n = 5116), recreational activity (n = 5085) and walking (n = 5106) respectively were included in analyses. Three trajectory groups were identified for sport/exercise, four for recreational activity and three for walking. Poor health, obesity and smoking were associated with reduced odds of following a more favorable trajectory for all PA types. A range of socioeconomic, regional and lifestyle factors were also associated with PA trajectories but the magnitude and direction were specific to PA type. For example, men with manual occupations were less likely to follow a favorable sport/exercise trajectory but more likely to follow an increasing walking trajectory compared to men with nonmanual occupations. Retirement was associated with increased PA but this was largely due to increased sport/exercise participation., Conclusions: Physical activity trajectories from middle to old age vary by activity type. The predictors of these trajectories and effects of major life events, such as retirement, are also specific to the type of PA.

Purpose: This study aimed to determine whether higher levels of physical activity (PA) and less sedentary behavior (SB) are associated with less inflammation, indicated by inflammatory and hemostatic biomarkers, in older men., Methods: A cross-sectional study of 1139 men, from the British Regional Heart Study (mean ± SD age = 78 ± 5 yr), and longitudinal analyses of 490 men with two PA measures 1 yr apart were used in this study. Single fasting venous blood samples were analyzed for several biomarkers. PA and SB were measured using ActiGraph GT3X accelerometers. Total time and time spent in bouts of moderate to vigorous PA (MVPA), light PA, and SB were derived. Linear regression analyses were used to investigate associations., Results: Cross-sectionally, higher total PA, daily steps, and MVPA were all associated with lower levels of interleukin 6 (IL-6), C-reactive protein (CRP), tissue plasminogen activator (tPA), von Willebrand factor (vWF), and D-dimer, whereas higher levels of SB were associated with higher levels of IL-6, CRP, and tPA. Each additional 10 min of MVPA was associated with a 3.2% lower IL-6 (95% confidence interval [CI] = -4.5% to -1.8%), 5.6% lower CRP (95% CI = -7.8 to -3.3), 2.2% lower tPA (95% CI = -3.0 to -1.4), 1.2% lower vWF (95% CI = -2.1 to -0.3), and 1.8% lower D-dimer (95% CI = -2.9 to -0.7), and for CRP, vWF, and D-dimer independently of SB. Associations between SB and IL-6 or tPA were independent of MVPA. Longer bouts of PA or SB were not more strongly associated with outcomes than shorter bouts. Longitudinal analyses were inconsistent with these findings, possibly because of power limitations., Conclusion: Although PA (particularly MVPA) was generally associated with inflammatory and hemostatic biomarkers, we found no evidence that longer bouts were more important than shorter bouts.

Background: Smoking is an important cardiovascular disease risk factor, but the mechanisms linking smoking to blood pressure are poorly understood., Methods and Results: Data on 141 317 participants (62 666 never, 40 669 former, 37 982 current smokers) from 23 population-based studies were included in observational and Mendelian randomization meta-analyses of the associations of smoking status and smoking heaviness with systolic and diastolic blood pressure, hypertension, and resting heart rate. For the Mendelian randomization analyses, a genetic variant rs16969968/rs1051730 was used as a proxy for smoking heaviness in current smokers. In observational analyses, current as compared with never smoking was associated with lower systolic blood pressure and diastolic blood pressure and lower hypertension risk, but with higher resting heart rate. In observational analyses among current smokers, 1 cigarette/day higher level of smoking heaviness was associated with higher (0.21 bpm; 95% confidence interval 0.19; 0.24) resting heart rate and slightly higher diastolic blood pressure (0.05 mm Hg; 95% confidence interval 0.02; 0.08) and systolic blood pressure (0.08 mm Hg; 95% confidence interval 0.03; 0.13). However, in Mendelian randomization analyses among current smokers, although each smoking increasing allele of rs16969968/rs1051730 was associated with higher resting heart rate (0.36 bpm/allele; 95% confidence interval 0.18; 0.54), there was no strong association with diastolic blood pressure, systolic blood pressure, or hypertension. This would suggest a 7 bpm higher heart rate in those who smoke 20 cigarettes/day., Conclusions: This Mendelian randomization meta-analysis supports a causal association of smoking heaviness with higher level of resting heart rate, but not with blood pressure. These findings suggest that part of the cardiovascular risk of smoking may operate through increasing resting heart rate., (© 2015 American Heart Association, Inc.)

Background: Physical activity (PA) has many health benefits but may increase falls risk among older adults. We study how objectively measured habitual daily PA is related to falls by exploring the modifying effect of mobility limitations and the mediating roles of fitness and lower-limb strength., Methods: One thousand six hundred fifty-five (53%) of 3137 surviving participants (men age 71-91 yr) in an ongoing UK-population-based cohort study wore an ActiGraph GT3x accelerometer over the hip for 1 wk in 2010-2012 to measure PA (exposure) and reported demographic and health status, including mobility limitations. One year later, 825 men reported falls history (outcome)., Results: Seven hundred of 825 men had ≥600 min·d of accelerometer wear for ≥3 d. Nineteen percent (n = 128) reported falls 1 yr later. Associations between PA and falls differed by presence of mobility limitations. Among 66% (n = 471) of men without mobility limitations, number of falls increased incrementally (for every 30 min of moderate to vigorous PA [MVPA]: incidence rate ratio [IRR], 1.50; 95% confidence interval [CI], 1.10-2.03, adjusted for falls risk factors). Step count was not related to number of falls below 9000 steps per day but was related to number of falls ≥9000 steps per day (for every additional 1000 steps per day: IRR, 1.59; 95% CI, 1.16-2.18). Among 33% (n = 229) of men with mobility limitations, falls risk declined with increasing activity (for every 1000 steps per day: IRR, 0.80; 95% CI, 0.70-0.91; for every 30 min of MVPA: IRR, 0.61; 95% CI, 0.42-0.89; for every additional 30 min of sedentary behavior ≥600 min·d: IRR, 1.22; 95% CI, 1.07-1.40)., Conclusions: Interventions to promote MVPA in older men should incorporate falls prevention strategies. Among adults with mobility limitations, trials should investigate whether increasing MVPA levels can reduce falls risk.

Background: The steep decline in physical activity (PA) among the oldest old is not well understood; there is little information about the patterns of change in PA and sedentary behaviour (SB) in older people. Longitudinal data on objectively measured PA data can give insights about how PA and SB change with age., Methods: Men age 70-90 yr, from a United Kingdom population-based cohort wore a GT3X accelerometer over the hip annually on up to three occasions (56%, 50%, and 51% response rates) spanning 2 yr. Multilevel models were used to estimate change in activity. Men were grouped according to achieving ≥150 min·wk of MVPA in bouts of ≥10 min (current guidelines) at two or three time points., Results: A total of 1419 ambulatory men had ≥600 min wear time on ≥3 d at ≥2 time points. At baseline, men took 4806 steps per day and spent 72.5% of their day in SB, 23.1% in light PA, and 4.1% in moderate-to-vigorous PA (MVPA). Mean change per year was -341 steps, +1.1% SB, -0.7% light PA, and -0.4% MVPA each day (all P < 0.001). A total of 76.3% (n = 1083) never met guidelines ("stable low"), 7.9% (n = 112) consistently met guidelines ("stable high"), 8.2% (n = 116) stopped meeting guidelines by the last occasion ("decreasers"), and 4.9% (n = 69) started meeting guidelines by the last occasion ("increasers"). "Decreasers" spent 69.3% of each day in SB at baseline, which increased by 2% per year (P < 0.005), light activity remained at 23.3% (change, -0.2% per year; P = 0.4), and total MVPA decreased from 7.1% by -1.7% per year, (P < 0.001). The number of sedentary bouts >30 min increased from 5.1 by 0.1 per year (P = 0.02)., Conclusions: Among older adults, the steep decline in total PA occurred because of reductions in MVPA, while light PA is relatively spared and sedentary time and long sedentary bouts increase.

Background: Hyperparathyroidism and low vitamin D status have been implicated in the pathogenesis of heart failure (HF). We examined the prospective associations between parathyroid hormone (PTH), circulating 25-hydroxyvitamin D, and markers of mineral metabolism and risk of incident HF in older men with and without established cardiovascular disease., Methods and Results: Prospective study of 3731 men aged 60 to 79 years with no prevalent HF followed up for a mean period of 13 years, in whom there were 287 incident HF cases. Elevated PTH (≥55.6 pg/mL; top quarter) was associated with significantly higher risk of incident HF after adjustment for lifestyle characteristics, diabetes mellitus, blood lipids, blood pressure, lung function, heart rate, renal dysfunction, atrial fibrillation, forced expiratory volume in 1 second, and C-reactive protein (hazards ratio, 1.66; 95% confidence interval, 1.30-2.13). The increased risk was seen in both men with and without previous myocardial infarction or stroke (hazards ratio, 1.72; 95% confidence interval, 1.07-2.76; hazards ratio, 1.70; 95% confidence interval, 1.25-2.30, respectively). Elevated PTH was significantly associated with N-terminal probrain natriuretic peptide, a marker of left ventricular wall stress. By contrast, 25-hydroxyvitamin D and other markers of mineral metabolism including serum calcium and phosphate showed no significant association with incident HF after adjustment for age., Conclusions: Elevated PTH, but not 25-hydroxyvitamin D or other markers of mineral metabolism, is associated with increased risk of HF in both older men with and without myocardial infarction/stroke. This increased risk was not explained by its association with known risk factors for HF. Further studies are now needed to elucidate the mechanisms underlying this association., (© 2014 American Heart Association, Inc.)

Background and Purpose: Older adults have the highest risks of stroke and the lowest physical activity levels. It is important to quantify how walking (the predominant form of physical activity in older age) is associated with stroke., Methods: A total of 4252 men from a UK population-based cohort reported usual physical activity (regular walking, cycling, recreational activity, and sport) in 1998 to 2000. Nurses took fasting blood samples and made anthropometric measurements., Results: Among 3435 ambulatory men free from cardiovascular disease and heart failure in 1998 to 2000, 195 first strokes occurred during 11-year follow-up. Men walked a median of 7 (interquartile range, 3-12) hours/wk; walking more hours was associated with lower heart rate, D-dimer, and higher forced expiratory volume in 1 second. Compared with men walking 0 to 3 hours/wk, men walking 4 to 7, 8 to 14, 15 to 21, and >22 hours had age- and region-adjusted hazard ratios (95% confidence intervals) for stroke of 0.89 (0.60-1.31), 0.63 (0.40-1.00), 0.68 (0.35-1.32), and 0.36 (0.14-0.91), respectively, P (trend)=0.006. Hazard ratios were somewhat attenuated by adjustment for established and novel risk markers (inflammatory and hemostatic markers and cardiac function [N-terminal pro-brain natriuretic peptide]) and walking pace, but linear trends remained. There was little evidence for a dose-response relationship between walking pace and stroke; comparing average pace or faster to a baseline of slow pace, the hazard ratio for stroke was 0.65 (95% confidence interval, 0.44-0.97), which was fully mediated by time spent walking., Conclusions: Time spent walking was associated with reduced risk of onset of stroke in dose-response fashion, independent of walking pace. Walking could form an important part of stroke-prevention strategies in older people.

Background: Oxidative stress has been implicated in the pathogenesis of heart failure (HF). However, data on the association between antioxidant intakes and circulating levels and risk of incident HF in the older general population are limited. We have examined prospectively the associations between plasma vitamin C and E, dietary intakes of vitamin C and E, and incident HF., Methods and Results: Prospective study of 3919 men aged 60 to 79 years with no prevalent HF followed up for a mean period of 11 years, in whom there were 263 cases with incident HF. Higher plasma vitamin C level was associated with significantly lower risk of incident HF in both men with and without previous myocardial infarction after adjustment for lifestyle characteristics, diabetes mellitus, blood lipids, blood pressure, and heart rate (hazards ratio [95% confidence interval], 0.81 [0.70, 0.93] and 0.75 [0.59, 0.97] for 1 SD increase in log vitamin C, respectively). Plasma vitamin E and dietary vitamin C intake showed no association with HF. High levels of dietary vitamin E intake (which correlated weakly with plasma vitamin E) were associated with increased risk of HF in men with no previous myocardial infarction even after adjustment (adjusted hazards ratio [95% confidence interval], 1.23 [1.06, 1.42] for 1 SD increase)., Conclusions: Higher plasma vitamin C is associated with a reduced risk of HF in older men with and without myocardial infarction. High intake of dietary vitamin E may be associated with increased HF risk. Primary intervention trials assessing the effect of vitamin C supplements on HF risk in the elderly are needed.

Objective: We have examined the association between serum phosphate and alkaline phosphatase (ALP) with incident cardiovascular disease (CVD) outcomes and total mortality in older men., Approach and Results: A prospective study of 3381 men, aged 60 to 79 years, without a history of myocardial infarction or stroke followed up for an average 11 years during which there were 605 major CVD events (fatal coronary heart disease and nonfatal myocardial infarction, stroke, and CVD death) and 984 total deaths. ALP but not serum phosphate was associated with increased risk of coronary heart disease and overall CVD events which persisted after adjustment for CVD risk factors and markers of inflammation and after exclusion of men with chronic kidney disease (adjusted hazard ratio per SD, 1.19 [1.05, 1.34]; P=0.007 and 1.10 [1.01, 1.21]; P=0.04). In contrast, serum phosphate was only associated with increased CVD mortality owing to noncoronary heart disease or stroke causes (adjusted hazard ratio per SD, 1.35 [1.01, 1.83]; P=0.04). Both raised phosphate and ALP were associated with significantly increased total mortality after full adjustment and exclusion of men with chronic kidney disease., Conclusions: ALP but not serum phosphate is associated with coronary heart disease risk in elderly men. High levels of ALP and serum phosphate are both associated with increased total mortality.

Background and Purpose: The association between adiposity and adipocytes and risk of stroke in older adults is uncertain. We have examined the association between adiposity measures and adipocytes (adiponectin and leptin) with incident stroke events in older men., Methods: Prospective study of 3411 men aged 60 to 79 years with no previous diagnosis of myocardial infarction, heart failure, or stroke followed-up for an average of 9 years, during which there were 192 incident major stroke events., Results: In age-adjusted analyses, body mass index and waist circumference were not significantly associated with risk of stroke in older men, although obese men (body mass index >30 kg/m(2)) showed the lowest risk of stroke. Despite the strong positive correlation between leptin and body mass index and waist circumference, risk of stroke was significantly increased in those in the top quartile of the leptin distribution. The increased risk remained after adjustment for potential confounders, including systolic blood pressure (adjusted hazard ratios top quartile versus bottom quartile: 2.03; confidence interval, 1.27-3.27]). Further adjustment for markers of inflammation (c-reactive protein), endothelial dysfunction (von Willebrand factor), fibrinolytic activity (d-dimer), and γ-glutamyl transferase attenuated the increased risk, but risk remained significantly increased (adjusted hazard ratios, 1.73; confidence interval, 1.06-2.83]). By contrast, no association was seen between adiponectin and risk of stroke., Conclusions: Conventional adiposity measures were not associated with increased stroke risk in older men. However, leptin (a good marker of percent fat mass), but not adiponectin, predicted stroke, suggesting a link between fat mass and stroke risk.

Objective: The relationship between γ-glutamyl transferase (GGT) and heart failure (HF) in older adults is unknown. We have examined the relationship between GGT, other markers of hepatic function (alanine aminotransferase, aspartate transaminase, and alkaline phosphatase), and incident HF in older men., Methods and Results: This was a prospective study of 3494 men aged 60 to 79 years with no diagnosed HF or myocardial infarction followed up for a mean period of 9 years, in whom there were 168 incident HF cases. Elevated GGT (top quartile, ≥38 U/L) was associated with significantly increased risk of incident HF in men aged<70 years but not in men aged≥70 years (test for age-GGT interaction, P<0.0001). The increased risk of HF associated with elevated GGT persisted after adjustment for a wide range of established and novel risk factors for HF, including diabetes, stroke, obesity, systolic blood pressure, atrial fibrillation, lung function, inflammation (C-reactive protein), endothelial dysfunction (von Willebrand factor), leptin, and N terminal pro brain natriuretic peptide (adjusted hazard ratio [95% CI], 1.91 [1.07, 3.42]). Other liver function markers showed no significant associations with HF after similar adjustments., Conclusion: Elevated GGT was associated with increased risk of HF in men aged<70 years. Additional studies are now needed to determine the mechanisms responsible.

Background: Physical activity is associated with lower risk of cardiovascular disease, but the mechanisms are uncertain. Hemostatic and inflammatory markers have been linked with risk of cardiovascular disease. We therefore examined the relationship between physical activity and hemostatic and inflammatory variables., Methods and Results: In 1998 to 2000, 20 years after the initial screening of 7735 men 40 to 59 years old from general practices in 24 British towns, 4252 subjects (77% of available survivors, now 60 to 79 old) attended for reexamination. A fasting blood sample was available in 4088 men. All men on warfarin (n=134) and men with incomplete data on physical activity (n=144) were excluded, leaving 3810 men for analysis. Physical activity showed a significant and inverse dose-response relationship with fibrinogen, plasma and blood viscosity, platelet count, coagulation factors VIII and IX, von Willebrand factor, fibrin D-dimer, tissue plasminogen activator antigen, C-reactive protein, and white cell count, even after adjustment for possible confounders. The effects were similar in men with and without prevalent cardiovascular disease. No relationship was seen with activated partial thromboplastin time, activated protein C resistance, hematocrit, or factor VII. An examination of changes in physical activity between baseline and 20 years later showed that inactive men who took up at least light physical activity had levels of blood variables approaching those who remained at least lightly active. Those who became inactive showed levels more similar to those who remained inactive., Conclusions: These data suggest that the benefit of physical activity on cardiovascular disease may be at least partly a result of effects on hemostasis and inflammation.

Background and Purpose: Type 2 diabetes is an established risk factor for stroke, but the relations between asymptomatic hyperglycemia, hyperinsulinemia, and stroke incidence remain uncertain. We have examined the relationship between established diabetes, nonfasting serum glucose and serum insulin concentrations, and subsequent risk of stroke., Methods: We performed a prospective study of 7735 men aged 40 to 59 years drawn from general practices in 24 British towns. Men with missing serum glucose values (n=50) and men on insulin injection (n=36) were excluded, leaving 7649 men available for analysis. Baseline nonfasting serum was analyzed for insulin with a specific enzyme-linked immunosorbent assay method in 18 of the 24 towns (n=5663 men)., Results: During the mean follow-up period of 16.8 years, there were 347 stroke cases (fatal and nonfatal) in the 7649 men. Men who developed diabetes during follow-up (n=320) and men with established type 2 diabetes at screening (n=98) both showed significantly increased risk of stroke, even after adjustment for cardiovascular risk factors, including blood pressure (adjusted relative risk [RR], 2.27; 95% CI, 1.23 to 4.20; RR, 2.07; 95% CI, 1. 44 to 2.98, respectively). In men with no diagnosed diabetes at screening (n=7551), risk of stroke was increased significantly only in the top 2.5% of the nonfasting glucose distribution (>/=8.2 mmol/L), and this persisted even after adjustment for cardiovascular risk factors, including hypertension (RR, 1.86; 95% CI, 1.11 to 3. 13). Exclusion of the 320 men who developed diabetes during follow-up attenuated this risk so that it was no longer significant (RR, 1.56; 95% CI, 0.83 to 2.91). In the 5567 men with insulin measurements and no diagnosis of diabetes at screening, a J-shaped relationship was seen between nonfasting insulin and risk of stroke. Risk was significantly raised in the first quintile and in the fourth quintile and above compared with the second quintile, with all findings of marginal significance. Part of the increased risk at higher levels of insulin was due to men who developed diabetes in the follow-up period., Conclusions: This study confirms the importance of established type 2 diabetes as an independent risk factor for stroke. The increased risk of stroke seen in hyperglycemic subjects and those with elevated serum insulin levels at screening reflected to some extent the high proportion of men who subsequently developed diabetes.

Most prospective studies have shown physical activity to be associated with a reduced risk of stroke. The results of existing studies suggest that this benefit is seen in both men and women, in younger and older subjects and in subjects with and without pre-existing coronary heart disease. Sporting (vigorous) activity does not appear to be essential to achieve this benefit. Moderate levels of physical activity may be sufficient to achieve a significant reduction in stroke risk and overall cardiovascular risk.

Background and Purpose: Elevated serum creatinine has been associated with increased mortality in hypertensive persons, the elderly, and patients with myocardial infarction or stroke in whom cardiovascular disease is the major cause of death. We have examined the relationship between serum creatinine concentration and the risk of major ischemic heart disease and stroke events and all-cause mortality in a general population of middle-aged men., Methods: We present a prospective study of middle-aged men (aged 40 to 59 years) drawn from 24 British towns who have been followed up for an average of 14.75 years. Data on serum creatinine were available for 7690 men in whom there were 287 major stroke events, 967 major ischemic heart disease events, and 1259 deaths from all causes during follow-up., Results: The median serum creatinine concentration was 98 micromol/L (95% range, 76 to 129 micromol/L). Stroke risk was significantly increased at levels above 116 micromol/L (90th percentile) even after adjustment for a wide range of cardiovascular risk factors (relative risk [RR], 1.6; 95% CI, 1.1 to 2.1; > 116 micromol/L versus the rest). Risk of a major ischemic heart disease event was significantly increased at or above 130 micromol/L (97.5 percentile), but this was attenuated after adjustment (RR, 1.2; 95% CI, 0.8 to 1.7; > or = 130 micromol/L versus the rest). There was a weak but significant positive association between diastolic blood pressure and creatinine concentration. However, elevated creatinine concentration (> or = 116 micromol/L) was associated with a significant increase in stroke in both normotensive and hypertensive men. All-cause mortality and overall cardiovascular mortality were significantly increased only above the 97.5 percentile, and no significant association was seen with cancer or other noncardiovascular mortality., Conclusions: A high serum creatinine concentration within the normal range is a marker for increased risk of cerebrovascular disease in both normotensive and hypertensive subjects. These findings support the evidence indicating that subtle impairment of renal function is a factor for increased risk of stroke and suggest mechanisms in the pathogenesis of stroke that warrant further investigation.

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