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This analysis assessed the safety of atorvastatin in the 10- to 80-mg dose range using pooled data from 44 completed trials comprising 16,495 dyslipidemic patients treated with atorvastatin (n = 9,416), placebo (n = 1,789), and other statins (n = 5,290). A retrospective analysis was conducted and included treatment-associated adverse events, serious adverse events, and musculoskeletal and hepatic adverse events. Only 3% (n = 241) of atorvastatin-treated patients withdrew from studies due to treatment-associated adverse events, compared with 1% of those (n = 16) on placebo and 4% of those (n = 188) receiving other statins; the most frequently reported treatment-associated adverse events were related to the digestive system. Serious adverse events were rare and seldom led to withdrawal. Persistent elevations in hepatic transaminases to >3 times the upper limit of normal (ULN) were experienced by 0.5% (n = 47) of atorvastatin-treated patients. A persistent elevation in creatine phosphokinase (CPK) (>10 × ULN) was observed in only 1 atorvastatin-treated patient and was not associated with myopathy. The incidence of treatment-associated myalgia was low in the atorvastatin (1.9% [n = 181]), placebo (0.8% [n = 14]), and other statin (2.0% [n = 105]) groups, and was not related to the atorvastatin dose. No cases of rhabdomyolysis or myopathy were reported. Thus, the overall incidence of treatment-associated adverse events observed with atorvastatin did not increase in the 10- to 80-mg dose range, and was similar to that observed with placebo and in patients treated with other statins. Specific analysis of musculoskeletal and hepatic adverse events showed that these occurred infrequently and rarely resulted in treatment discontinuation.

Background: People who are physically active live longer, but it is unclear whether this is because of physical activity in the distant or more recent past. Methods: We assessed activity levels in 5209 men and women in the Framingham Heart Study from 1956 to 1958 and again from 1969 to 1973. We included individuals who were alive and without cardiovascular disease in the period 1969 to 1973. The primary outcome was death from all causes during the 16 years after the 1969 to 1973 assessment. Secondary outcomes were incidence and mortality rate of cardiovascular disease. We used Cox proportional hazards regression to calculate the relative risk of being sedentary, both unadjusted and controlling for smoking, weight, systolic blood pressure, cholesterol, glucose intolerance, left ventricular hypertrophy, chronic obstructive pulmonary disease, and cancer. Results: The overall 16-year mortality rate was 37% for men and 27% for women. When both distant and recent activity levels were included along with major cardiovascular disease risk factors, for recent activity the most active tertile had lower overall mortality rate than the least active tertile for men (risk ratio 0.58, 95% confidence interval, 0.43-0.79) and women (risk ratio 0.61, 95% confidence interval, 0.45-0.82). For distant activity there was no difference in overall mortality rate between the most and least active tertiles either for men or for women. Adjusting for major cardiovascular disease risk factors had little effect on the results. Conclusions: The reduction in overall mortality rates is more associated with recent activity than distant activity. These results suggest that for sedentary patients, it may never be too late to begin exercising. (Am Heart J 1999;138:900-7.)

Abstract —The platelet glycoprotein IIb/IIIa (GP IIb/IIIa) plays a pivotal role in platelet aggregation. Recent data suggest that the Pl A2 polymorphism of GPIIIa may be associated with an increased risk for cardiovascular disease. However, it is unknown if there is any association between this polymorphism and platelet reactivity. We determined GP IIIa genotype and platelet reactivity phenotype data in 1422 subjects from the Framingham Offspring Study. Genotyping was performed using PCR-based restriction fragment length polymorphism analysis. Platelet aggregability was evaluated by the Born method. The threshold concentrations of epinephrine and ADP were determined. Allele frequencies of Pl A1 and Pl A2 were 0.84 and 0.16, respectively. The presence of 1 or 2 Pl A2 alleles was associated with increased platelet aggregability as indicated by incrementally lower threshold concentrations for epinephrine and ADP. For epinephrine, the mean concentrations were 0.9 μmol/L (0.9 to 1.0) for homozygous Pl A1 , 0.7 mmol/L (0.7 to 0.9) for the heterozygous Pl A1 / Pl A2 , and 0.6 μmol/L (0.4 to 1.0) for homozygous Pl A2 individuals, P =0.009. The increase in aggregability induced by epinephrine remained highly significant ( P =0.007) after adjustment for covariates. For ADP-induced aggregation, the respective mean concentrations were 3.1 μmol/L (3.0 to 3.2), 3.0 μmol/L (2.9 to 3.2), and 2.8 μmol/L (2.4 to 3.3); P =0.19 after adjustment for covariates. Our findings indicate that molecular variants of the gene encoding GP IIIa play a role in platelet reactivity in vitro. Our observations are compatible with and provide an explanation for the reported association of the Pl A2 allotype with increased risk for cardiovascular disease.

Men and women with hypertension are at increased risk for cardiovascular disease, especially when left ventricular hypertrophy is present. We examined temporal trends in the use of antihypertensive medications and studied the relation between their use, the prevalence of high blood pressure, and the presence of electrocardiographic evidence of left ventricular hypertrophy.A total of 10,333 participants in the Framingham Heart Study who were 45 to 74 years of age underwent a total of 51,756 examinations from 1950 to 1989. Data were obtained on blood pressure and the use of antihypertensive medications, and electrocardiograms were assessed for left ventricular hypertrophy. The generalized-estimating-equation method was used to test for trends over time.From 1950 to 1989, the rate of use of antihypertensive medications increased from 2.3 percent to 24.6 percent among men and from 5.7 percent to 27.7 percent among women. The age-adjusted prevalence of systolic blood pressure of at least 160 mm Hg or diastolic blood pressure of at least 100 mm Hg declined from 18.5 percent to 9.2 percent among men and from 28.0 percent to 7.7 percent among women. This decline was accompanied by age-adjusted reductions in the prevalence of electrocardiographic evidence of left ventricular hypertrophy, from 4.5 percent to 2.5 percent among men and from 3.6 percent to 1.1 percent among women.Our findings support the notion that the increasing use of antihypertensive medication has resulted in a reduced prevalence of high blood pressure and a concomitant decline in left ventricular hypertrophy in the general population. Our observations may in part explain the considerable decline in mortality from cardiovascular disease observed since the late 1960s.

Background —Atrial fibrillation (AF) causes substantial morbidity. It is uncertain whether AF is associated with excess mortality independent of associated cardiac conditions and risk factors. Methods and Results —We examined the mortality of subjects 55 to 94 years of age who developed AF during 40 years of follow-up of the original Framingham Heart Study cohort. Of the original 5209 subjects, 296 men and 325 women (mean ages, 74 and 76 years, respectively) developed AF and met eligibility criteria. By pooled logistic regression, after adjustment for age, hypertension, smoking, diabetes, left ventricular hypertrophy, myocardial infarction, congestive heart failure, valvular heart disease, and stroke or transient ischemic attack, AF was associated with an OR for death of 1.5 (95% CI, 1.2 to 1.8) in men and 1.9 (95% CI, 1.5 to 2.2) in women. The risk of mortality conferred by AF did not significantly vary by age. However, there was a significant AF-sex interaction: AF diminished the female advantage in survival. In secondary multivariate analyses, in subjects free of valvular heart disease and preexisting cardiovascular disease, AF remained significantly associated with excess mortality, with about a doubling of mortality in both sexes. Conclusions —In subjects from the original cohort of the Framingham Heart Study, AF was associated with a 1.5- to 1.9-fold mortality risk after adjustment for the preexisting cardiovascular conditions with which AF was related. The decreased survival seen with AF was present in men and women and across a wide range of ages.

Background —The objective of this study was to examine the association of Joint National Committee (JNC-V) blood pressure and National Cholesterol Education Program (NCEP) cholesterol categories with coronary heart disease (CHD) risk, to incorporate them into coronary prediction algorithms, and to compare the discrimination properties of this approach with other noncategorical prediction functions. Methods and Results —This work was designed as a prospective, single-center study in the setting of a community-based cohort. The patients were 2489 men and 2856 women 30 to 74 years old at baseline with 12 years of follow-up. During the 12 years of follow-up, a total of 383 men and 227 women developed CHD, which was significantly associated with categories of blood pressure, total cholesterol, LDL cholesterol, and HDL cholesterol (all P Conclusions —Recommended guidelines of blood pressure, total cholesterol, and LDL cholesterol effectively predict CHD risk in a middle-aged white population sample. A simple coronary disease prediction algorithm was developed using categorical variables, which allows physicians to predict multivariate CHD risk in patients without overt CHD.

The influence of blood pressure on the development of cardiovascular disease and mortality rate beyond 75 years of age has been uncertain. A reported inverse relation to mortality rate noted in the very old could reflect poor cardiovascular health. This report examines the impact of blood pressure on cardiovascular morbidity and mortality rates and all-cause mortality rate in those aged 75 to 94 years. For this analysis the data were the Framingham study subjects found free of cardiovascular disease and a second sample of those with cardiovascular disease present on the biennial examinations. Investigation of the relation of systolic and diastolic blood pressures to all causes and cardiovascular morbidity and mortality rates within each 2-year interval for those aged 75 to 94 years was carried out. Over the period of 38 years of follow-up there were increasing cardiovascular morbidity and mortality rates with increasing blood pressure levels for both men and women in the sample free of cardiovascular disease. In those with cardiovascular disease at the biennial examination there was a distinct U-shaped curve of cardiovascular mortality rate in relation to systolic blood pressure in men with a substantial increase in mortality rate below systolic pressures of 120 mm Hg for both men and women. Excess mortality rate reported in elderly persons with low blood pressure appears to be a result of poor cardiovascular health and not from the low pressure itself. The excess mortality rate reported for low blood pressure levels in persons older than 75 years derives from the inclusion of the substantial proportion of this age group who have cardiovascular disease.

Normative data are presented for a neuropsychological test battery (Kaplan-Albert) consisting of subtests from the original Wechsler Adult Intelligence and Memory Scales and the Benton and Hamsher Aphasia Examination. Analyses were based on archival data resulting from administration (1976-1978) of the battery to community residents participating in the Framingham Heart Study, a prospective, longitudinal study of cardiovascular risk factors. Using 3 age groups (55-64, 65-74, and 75-88 years) and 4 education levels (5-8, 9-11, 12, > 12 years), individuals were stratified by age, gender, and education. Multiple linear regression analysis was used to relate main effects (age, education, and gender) and interactions of these effects to 9 test scores and to 2 composite scores identified by factor analysis. The oldest participants who had the fewest years of formal education had the lowest performance levels, with lower levels of performance for men than women in this least educated elderly cohort.

Background Intermittent claudication identifies persons at increased risk for death and disability. Methods and Results Using 38-year follow-up data for the original cohort in the Framingham Heart Study, we developed an intermittent claudication risk profile. Intermittent claudication occurred in a total of 381 men and women. Age, sex, serum cholesterol, hypertension, cigarette smoking, diabetes, and coronary heart disease were associated with an increased risk for claudication and were included in the profile. A pooled logistic regression model was used to compute the probability of intermittent claudication for specified levels of risk factors. Conclusions The intermittent claudication risk profile allows physicians to identify high-risk individuals during a routine office visit and can be used to educate patients about modifiable risk factors, particularly smoking and blood pressure. Improved compliance with risk factor modification strategies may result in a beneficial impact on survival.

Examination of the long-term relation of a single fibrinogen determination to initial and recurrent atherosclerotic cardiovascular events over 20 years of follow-up revealed a powerful and comparably independent impact on initial events in both sexes but an influence on recurrent events only in men.

In very elderly participants of the Framingham Heart Study (mean age 79 years, 276 men and 462 women), interleukin-6 correlated with C-reactive protein (CRP) levels. Interleukin-6, tumour necrosis factor alpha and interleukin-1 production, and CRP were not associated with prevalent cardiovascular disease, and nonsteroidal anti-inflammatory drug use did not influence cytokine or CRP levels. Further studies are warranted to examine the prognostic implications of CRP and related cytokines for CVD in the elderly.

Background and Purpose — Risk of death due to stroke in Japan is more than double the risk in the United States. It remains unknown why some ethnic groups are more prone to stroke than others. Our purpose was to compare the 20-year incidence of hospitalized stroke between Japanese-American men in the Honolulu Heart Program and white men in the Framingham Study. Methods — This was a 20-year follow-up study beginning around 1965, a population-based study on the island of Oahu, Hawaii, and in Framingham, Mass. Participants were 7589 men in Honolulu and 1216 men in Framingham without prevalent coronary heart disease and stroke. Subjects were 45 to 68 years old when follow-up began. Main outcome measures were incident thromboembolic and hemorrhagic stroke. Results — Framingham men had a 40% excess of thromboembolic stroke compared with Honolulu men after adjustment for age and other risk factors (62/1000 versus 45/1000, respectively, P Conclusions — The incidence of thromboembolic stroke requiring hospitalization is markedly less in Honolulu than in Framingham. The difference in stroke incidence rates observed cannot be explained by the traditional risk factors. Further studies are needed to identify factors that protect Japanese-American men in Honolulu from stroke.

The role of C-reactive protein (CRP) as a novel plasma marker of atherothrombotic disease is currently under investigation. Previous studies have mostly related CRP to coronary heart disease, were often restricted to a case-control design, and failed to include pertinent risk factors to evaluate the joint and net effect of CRP on the outcome. We related plasma CRP levels to incidence of first ischemic stroke or transient ischemic attack (TIA) in the Framingham Study original cohort.There were 591 men and 871 women free of stroke/TIA during their 1980 to 1982 clinic examinations, when their mean age was 69.7 years. CRP levels were measured by using an enzyme immunoassay on previously frozen serum samples. Analyses were based on sex-specific CRP quartiles. Risk ratios (RRs) were derived, and series of trend analyses were performed.During 12 to 14 years of follow-up, 196 ischemic strokes and TIAs occurred. Independent of age, men in the highest CRP quartile had 2 times the risk of ischemic stroke/TIA (RR=2.0, P=0.027), and women had almost 3 times the risk (RR=2.7, P=0.0003) compared with those in the lowest quartile. Assessment of the trend in risk across quartiles showed unadjusted risk increase for men (RR=1.347, P=0.0025) and women (RR=1.441, P=0.0001). After adjustment for smoking, total/HDL cholesterol, systolic blood pressure, and diabetes, the increase in risk across CRP quartiles remained statistically significant for both men (P=0.0365) and women (P=0.0084).Independent of other cardiovascular risk factors, elevated plasma CRP levels significantly predict the risk of future ischemic stroke and TIA in the elderly.

Background — Moderate alcohol consumers have lower rates of cardiovascular disease than abstainers. One proposed mechanism is a beneficial effect on hemostatic parameters, but previous studies have provided conflicting results. Methods and Results — We measured levels of fibrinogen, plasma viscosity, von Willebrand factor, factor VII, plasminogen activator inhibitor antigen-1, and tissue plasminogen activator antigen in a cross-sectional analysis of 3223 adults free of cardiovascular disease enrolled in the Framingham Offspring Study. We assessed their alcohol consumption with a standardized questionnaire. Light-to-moderate alcohol consumption was associated with lower levels of fibrinogen, plasma viscosity, von Willebrand factor, and factor VII. This association was most pronounced for consumers of 3 to 7 drinks weekly for viscosity and 7 to 21 drinks weekly for the other hemostatic measures. Alcohol intake of 7 to 21 drinks weekly or more was associated with impaired fibrinolytic potential, reflected by higher levels of plasminogen activator inhibitor antigen-1 and tissue plasminogen activator antigen. Wine drinkers had lower plasminogen activator inhibitor antigen-1 levels than other drinkers, particularly at 3 to 21 drinks weekly, but beverage type did not otherwise consistently affect the results. Conclusions — Light-to-moderate alcohol consumption is associated with lower levels of coagulatory factors, but higher intake is associated with impaired fibrinolytic potential. These findings are consistent with the hypothesis that a balance between hemostatic and fibrinolytic activity may contribute to the complex relation of alcohol use with coronary heart disease.

Background Four large trials have shown cholesterol-reduction therapy to be effective for primary prevention of coronary heart disease (CHD). Methods To determine the generalizability of these trials to a community-based sample, we compared the total cholesterol and high-density lipoprotein cholesterol (HDL-C) distributions of patients in the 4 trials with those of Framingham Heart Study subjects. Lipid profiles that have not been studied were identified. Twelve-year rates of incident CHD were compared between subjects who met eligibility criteria and those who did not. Results The Framingham sample included 2498 men and 2870 women aged 30 to 74 years. Among Framingham men, 23.4% to 42.0% met eligibility criteria for each of the 4 trials based on their lipid levels; 60.2% met eligibility criteria for at least 1 trial. For the 1 trial that included women, 20.2% of Framingham women met eligibility criteria. In general, subjects with desirable total cholesterol levels and lower HDL-C levels and subjects with average total cholesterol levels and average to higher HDL-C levels have not been included in these trials. Among subjects who developed incident CHD during follow-up, 25.1% of men and 66.2% of women would not have been eligible for any trial. Most ineligible subjects who developed CHD had isolated hypertriglyceridemia (>2.25 mmol/L [>200 mg/dL]). Conclusions In our sample, 40% of men and 80% of women had lipid profiles that have not been studied in large trials to date. We observed a large number of CHD events in "ineligible" subjects in whom hypertriglyceridemia was common. Further studies are needed to define the role of lipid-lowering therapy vs other strategies for primary prevention in the general population.

Atrial fibrillation (AF) is strongly associated with thromboembolic complications, although the mechanism for the increased risk has not been fully explained. To determine whether AF might be associated with a hypercoagulable state, we studied hemostatic factors in subjects with or without AF in the Framingham Heart Study. In 3,577 subjects, we measured fibrinogen, von Willebrand factor antigen, tissue plasminogen activator (tPA) antigen, and plasminogen activator inhibitor-1 antigen. Forty-seven subjects had AF at the index clinic examination and 15 had AF on a prior examination, but not on the current examination. Before matching, the 47 subjects with prevalent AF had higher levels of fibrinogen, von Willebrand factor, and tPA antigen than those without AF, all por =0.03. Compared with 167 referent subjects matched for age, sex, and other risk factors, those with AF had higher tPA antigen levels than those without AF, 1 1.8 +/- 4.0 ng/ml versus 10.5 +/- 3.9 ng/ml (p = 0.04). However, when further stratified according to their cardiovascular disease status, the differences in hemostatic factors were no longer significant. We conclude that the prothrombotic profile associated with AF was explained by the risk factors of the subjects and the presence of cardiovascular disease. Nonetheless, the hemostatic changes may contribute toward the propensity for thromboembolic complications in AF. Further prospective studies are needed to evaluate whether measurement of these and other hemostatic factors will identify patients with AF who are at increased risk for thromboembolic complications, and who may therefore benefit from more intensive therapy.

Background —Fibrinogen has been identified as an independent risk factor for cardiovascular disease and associated with traditional cardiovascular risk factors. Also, the role of elevated fibrinogen in thrombosis suggests that it may be on the causal pathway for certain risk factors to exert their effect. These associations remain incompletely characterized. Moreover, the optimal fibrinogen assay for risk stratification is uncertain. Methods and Results —In 2632 subjects from cycle 5 of the Framingham Offspring Population, fibrinogen levels were determined with a newly developed immunoprecipitation test (American Biogenetic Sciences) and the functional Clauss method. With the immunoprecipitation method, there were significant linear trends across fibrinogen tertiles ( P P P =0.035 and P =0.018 for men and women, respectively) but not with the Clauss method. Conclusions —Fibrinogen was associated with traditional cardiovascular risk factors. Elevation of fibrinogen may provide a mechanism for risk factors to exert their effect. Also, fibrinogen levels were higher among subjects with cardiovascular disease compared with those without disease. The immunoprecipitation test showed a stronger association with cardiovascular disease than the Clauss method, suggesting that it may be a useful screening tool to identify individuals at increased thrombotic risk.

Recent studies have indicated that moderate alcohol intake may be beneficial to cognitive functioning in women, although not necessarily in men. Data from the Framingham Heart Study, a large, prospective study of cardiovascular disease in Framingham, Massachusetts, were used to examine the relation between alcohol consumption and cognitive ability. The major research question was whether a different alcohol-cognition relation would be found for male and female drinkers. Men (n = 733) and women (n = 1,053), aged 55-88 years, were queried as to their weekly intake of alcohol, and these data were used to construct groups of abstainers, very light, light, moderate, and heavy drinkers. Data from earlier reports of alcohol consumption were also examined. Participants were administered eight tests which reflect performance in the domains of verbal memory, learning, visual organization and memory, attention, abstract reasoning, and concept formation. Multivariate linear regression analyses were used with statistical adjustment for age, education, occupation, cardiovascular disease, and associated risk factors. Women who drank moderately (2-4 drinks/day) showed superior performance in many cognitive domains relative to abstainers. For men, superior performance was found within the range of 4-8 drinks/day, although fewer significant relations were observed. These results were confirmed by prospective analyses of 24-year drinking history.

Total homocysteine levels are associated with arteriosclerotic outcomes.To determine whether total homocysteine levels predict incident stroke in elderly persons.Prospective population-based cohort study with 9.9 years of follow-up.Framingham, Massachusetts.1947 Framingham Study participants (1158 women and 789 men; mean age +/- SD, 70 +/- 7 years).Baseline total homocysteine levels and 9.9-year stroke incidence.The quartiles of nonfasting total homocysteine levels were as follows: quartile 1, 4.13 to 9.25 micromol/L; quartile 2, 9.26 to 11.43 micromol/L; quartile 3, 11.44 to 14.23 micromol/L; quartile 4, 14.24 to 219.84 micromol/L. During follow-up, 165 incident strokes occurred. In proportional hazards models adjusted for age, sex, systolic blood pressure, diabetes, smoking, and history of atrial fibrillation and coronary heart disease, relative risk (RR) estimates comparing quartile 1 with the other three quartiles were as follows: quartile 2 compared with quartile 1--RR, 1.32 (95% CI, 0.81 to 2.14); quartile 3 compared with quartile 1--RR, 1.44 (CI, 0.89 to 2.34); quartile 4 compared with quartile 1--RR, 1.82 (CI, 1.14 to 2.91). The linear trend across the quartiles was significant (P0.001).Nonfasting total homocysteine levels are an independent risk factor for incident stroke in elderly persons.

Context We devised a risk appraisal function to assess the hazard of heart failure in persons who are predisposed by coronary disease, hypertension, or valvular heart disease. Objective To provide general practitioners and internists with a cost-effective method to select people at high risk who are likely to have impaired left ventricular systolic function and may therefore require further evaluation and aggressive preventive measures. Methods The routinely measured risk factors used in constructing the heart failure profile include age, electrocardiographic left ventricular hypertrophy, cardiomegaly on chest x-ray film, heart rate, systolic blood pressure, vital capacity, diabetes mellitus, evidence of myocardial infarction, and valvular disease or hypertension. Based on 486 heart failure cases during 38 years of follow-up, 4-year probabilities of failure were computed using the pooled logistic regression model for each sex; a simple point score system was employed. A multivariate profile was also produced without the vital capacity or chest x-ray film because these may not be readily available in some clinical settings. Results Using the risk factors that make up the multivariate risk formulation—derived from ordinary office procedures—the probability of developing heart failure can be estimated and compared with the average risk for persons of the same age and sex. Using this risk profile, 60% of events in men and 73% in women occurred in subjects in the top quintile of multivariate risk. Conclusions Using this multivariate risk formulation, it is possible to identify high-risk candidates for heart failure who are likely to have a substantial yield of positive findings when tested for objective evidence of presymptomatic left ventricular dysfunction. The risk profile may also identify candidates who are at high risk for heart failure because of multiple, marginal risk factor abnormalities that might otherwise be overlooked.

The degree of clustering for common metabolic coronary disease risk factors is not well known, the antecedents of clustering are not well studied, and the impact of such clusters on coronary risk has not been assessed systematically.Prospective community sample of 2406 men and 2569 women aged 18 to 74 years at baseline. The 6 metabolically linked risk factors considered were the lowest sex-specific quintile of high-density lipoprotein cholesterol and the highest quintiles of body mass index, systolic blood pressure, triglycerides, glucose, and serum total cholesterol.At baseline the risk factor sum, represented as integer values, ranged from 0 to 6, and clusters of 3 or more risk factors occurred at twice the rate predicted by chance. After adjustment for age and obesity level, a 2.25-kg (5-lb) weight increase over 16 years was associated with an increased risk factor sum in men (+20%; P=.002) and women (+37%; P.001), and a 2.25-kg weight loss was associated with a decreased risk factor sum in men (-48%; P.001) and women (-40%; P.001). Clusters of 3 or more risk factors were associated with a 2.39 (95% confidence interval, 1.56-3.36) and 5.90 (95% confidence interval, 2.54-13.73) times greater risk of coronary heart disease in men and women, respectively (both P.001).Atherogenic risk factor clustering is common in both sexes, worsens with weight gain, and is associated with greatly increased risk of coronary disease risk in both sexes.

A tendency for hypertension to cluster with other risk factors has long been noted in the Framingham Heart Study and elsewhere [1,2]. A metabolic or physiologic basis for this clustering has been postulated [3–5]. Many of the risk factors that tend to cluster with elevated blood pressure also predict its occurrence and greatly influence its impact on the occurrence of atherosclerotic cardiovascular sequelae [1,2]. The population prevalence of risk factor clustering in the presence of hypertension has not been determined. Nor has it been estimated how often coronary events result from hypertension occurring in conjunction with such risk factor clusters.

OBJECTIVE To determine if NIDDM and blood pressure are risk factors for poor cognitive performance and if history and duration of NIDDM and blood pressure interact such that the risk of poor performance is greater for subjects with both NIDDM and hypertension. RESEARCH DESIGN AND METHODS We used a large prospective cohort sample with 187 NIDDM subjects and 1,624 nondiabetic subjects who were followed for 28–30 years. Cognitive function was assessed using eight tests of learning, memory, visual organization, verbal fluency attention, concept formation, and abstract reasoning. A composite score was also calculated. Odds ratios were used to estimate the relative risk of performing below the lower 25th percentile of z scores on these tests. RESULTS NIDDM and blood pressure interacted such that diagnosis and duration of NIDDM were associated with greater risk of poor performance on tests of visual memory and on the composite score for hypertensive subjects. Duration of NIDDM was associated with increased risk for poor performance on tests of verbal memory and concept formation. Insulin-treated NIDDM subjects were at higher risk for poor cognitive performance than those NIDDM subjects treated with oral agents or diet. Blood pressure level was associated independently with a measure of verbal fluency. CONCLUSIONS History and duration of NIDDM and high blood pressure are significant risk factors for poor cognitive performance. Hypertensive people with NIDDM are at greatest risk for poor performance on tests measuring visual organization and memory.

Single measurements of cardiovascular risk factors may not accurately reflect a person's past exposure to those risk factors. We therefore studied the long-term associations of cardiovascular risk factors such as high serum cholesterol levels, high blood pressure, and cigarette smoking with the prevalence of carotid stenosis.We studied cross-sectional and longitudinal information from a sample of 429 men and 661 women in the Framingham Heart Study who underwent B-mode ultrasound measurements of the carotid artery. Their mean age was 75 years, and each had attended most of the biennial clinic examinations over the 34 years before the carotid ultrasound study. We used time-integrated measurements to assess the associations between various cardiovascular risk factors and the degree of carotid stenosis.Moderate carotid stenosis (or =25 percent) was present in 189 men and 226 women. We assessed the odds ratios for this degree of stenosis as compared with minimal stenosis (25 percent) according to increases in risk factors. In the men, the odds ratio for moderate carotid stenosis associated with an increase of 20 mm Hg in systolic blood pressure was 2.11 (95 percent confidence interval, 1.51 to 2.97). The odds ratio for an increase of 10 mg per deciliter (0.26 mmol per liter) in the cholesterol level was 1.10 (95 percent confidence interval, 1.03 to 1.16), and for an increase of five pack-years of smoking it was 1.08 (95 percent confidence interval, 1.03 to 1.13). The results were similar in the women. Time-integrated measurements of diastolic blood pressure showed significant associations with carotid stenosis in men and insignificant associations in women.Over the long term, high systolic blood pressure, high cholesterol levels, and smoking were associated with an increased risk of carotid stenosis in this elderly population.

Cardiac failure is a common lethal outcome of coronary heart disease and left ventricular hypertrophy. The efficacy of forced vital capacity (FVC), measured biennially, in predicting the onset of cardiac failure was explored in 818 Framingham Study subjects with those predisposing conditions, among 324 developed cardiac failure. Among the men and women who had coronary disease or left ventricular hypertrophy, those with FVCs in the lower quartile were at substantially increased risk of developing cardiac failure. For men, comparing the lowest quartile with men whose FVCs were in the highest quartile (2.7 L vs5.6 L), the risk ratio was 1.8; for women with FVCs1.7 L, the risk was 2.3 times those with FVCs ofor = 3.5L. The excess risk of cardiac failure imposed by a low FVC was similar in those with coronary disease and left ventricular hypertrophy. The simple FVC is an inexpensive and robust predictor of cardiac failure in persons predisposed by coronary disease or left ventricular hypertrophy. FVC determination should help identify candidates for cardiac failure needing echocardiographic examination for ventricular dysfunction.

Background Elevated fasting total homocysteine (tHcy) levels were recently shown to confer an independent risk for all-cause and cardiovascular disease (CVD) mortality among selected Norwegian patients with confirmed coronary heart disease. We examined whether elevated fasting plasma tHcy levels were predictive of all-cause and CVD mortality in a large, population-based sample of elderly US women and men. Methods Nonfasting plasma tHcy levels were determined in 1933 elderly participants (mean age, 70 ± 7 years; 58.9% women) from the original Framingham Study cohort, examined between 1979 and 1982, with follow-up through 1992. Unadjusted and adjusted (ie, for age, sex, diabetes, smoking, systolic blood pressure, total and high-density lipoprotein cholesterol, and creatinine) relative risk estimates (with 95% confidence intervals [CIs]) for total and CVD mortality were generated by proportional hazards modeling, with tHcy levels (quartiles) as the independent variable. Results There were 653 total deaths and 244 CVD deaths during a median follow-up of 10.0 years. Proportional hazards modeling revealed that tHcy levels of 14.26 µmol/L or greater (the upper quartile), vs less than 14.26 µmol/L (the lower three quartiles), were associated with relative risk estimates of 2.18 (95% CI, 1.86-2.56) and 2.17 (95% CI, 1.68-2.82) for all-cause and CVD mortality, respectively. The relative risk estimates after adjustment for age, sex, systolic blood pressure, diabetes, smoking, and total and high-density lipoprotein cholesterol levels attenuated these associations, but they remained significant: 1.54 (95% CI, 1.31-1.82) for all-cause mortality; 1.52 (95% CI, 1.16-1.98) for CVD mortality. Conclusion Elevated nonfasting plasma tHcy levels are independently associated with increased rates of all-cause and CVD mortality in the elderly.