Major risk factors as antecedents of fatal and nonfatal coronary heart disease events

Context  A frequently cited concept is that individual major risk factors for coronary heart disease (CHD) are absent in many patients (perhaps >50%) with CHD. However, prior studies have not systematically evaluated the extent to which CHD patients have previous exposure to at least 1 risk factor, including diabetes, cigarette smoking, or clinically elevated levels of cholesterol or blood pressure. Objective  To determine the frequency of exposure to major CHD risk factors. Design, Setting, and Participants  Three prospective cohort studies were included: the Chicago Heart Association Detection Project in Industry, with a population sample of 35 642 employed men and women aged 18 to 59 years; screenees for the Multiple Risk Factor Intervention Trial, including 347 978 men aged 35 to 57 years; and a population-based sample of 3295 men and women aged 34 to 59 years from the Framingham Heart Study (FHS). Follow-up lasted 21 to 30 years across the studies. Main Outcome Measures  Fatal CHD in all cohorts and nonfatal myocardial infarction (MI) in the FHS, compared by exposure to major CHD risk factors, defined as total cholesterol of at least 240 mg/dL (=" BORDER="0">6.22 mmol/L), systolic blood pressure of at least 140 mm Hg, diastolic blood pressure of at least 90 mm Hg, cigarette smoking, and diabetes. Participants were stratified by sex and age (18-39 vs 40-59 years). Results  For fatal CHD (n = 20 995), exposure to at least 1 clinically elevated major risk factor ranged from 87% to 100%. Among those aged 40 to 59 years at baseline with fatal CHD (n = 19 263), exposure to at least 1 major risk factor ranged from 87% to 94%. For nonfatal MI, prior exposure was documented in 92% (95% CI, 87%-96%) (n = 167) of men aged 40 to 59 years at baseline and in 87% (95% CI, 80%-94%) (n = 94) of women in this age group. Conclusions  Antecedent major CHD risk factor exposures were very common among those who developed CHD, emphasizing the importance of considering all major risk factors in determining CHD risk estimation and in attempting to prevent clinical CHD. These results challenge claims that CHD events commonly occur in persons without exposure to at least 1 major CHD risk factor.      

Retinal arteriolar narrowing and risk of coronary heart disease in men and women. The Atherosclerosis Risk in Communities Study

Context  Microvascular processes have been hypothesized to play a greater role in the development of coronary heart disease (CHD) in women than in men; however, prospective clinical data are limited. Objective  To examine the association between retinal arteriolar narrowing, a marker of microvascular damage from hypertension and inflammation, and incident CHD in healthy middle-aged women and men. Design, Setting, and Participants  The Atherosclerosis Risk in Communities Study, an ongoing prospective, population-based cohort study in 4 US communities initiated in 1987-1989. Retinal photographs were taken in 9648 women and men aged 51 to 72 years without CHD at the third examination (1993-1995). To quantify retinal arteriolar narrowing, the photographs were digitized, individual arteriolar and venular diameters were measured, and a summary arteriole-to-venule ratio (AVR) was calculated. Main Outcome Measure  Risk of CHD associated with retinal arteriolar narrowing. Results  During an average 3.5 years of follow-up, 84 women and 187 men experienced incident CHD events. In women, after controlling for mean arterial blood pressure averaged over the previous 6 years, diabetes, cigarette smoking, plasma lipid levels, and other risk factors, each SD decrease in the AVR was associated with an increased risk of any incident CHD (relative risk [RR], 1.37; 95% confidence interval [CI], 1.08-1.72) and of acute myocardial infarction (RR, 1.50; 95% CI, 1.10-2.04). In contrast, AVR was unrelated to any incident CHD in men (RR, 1.00; 95% CI, 0.84-1.18) or to acute myocardial infarction (RR, 1.08; 95% CI, 0.85-1.38). Conclusion  Retinal arteriolar narrowing is related to risk of CHD in women but not in men, supporting a more prominent microvascular role in the development of CHD in women than in men. Future work is needed to confirm these findings.      

Job strain and risk of acute recurrent coronary heart disease events

Context  There is evidence that job strain increases the risk of a first coronary heart disease (CHD) event. However, little is known about its association with the risk of recurrent CHD events after a first myocardial infarction (MI). Objective  To determine whether job strain increases the risk of recurrent CHD events. Design, Setting, and Patients  Prospective cohort study of 972 men and women aged 35 to 59 years who returned to work after a first MI and were then followed up between February 10, 1996, and June 22, 2005. Patients were interviewed at baseline (on average, 6 weeks after their return to work), then after 2 and 6 years subsequently. Job strain, a combination of high psychological demands and low decision latitude, was evaluated in 4 quadrants: high strain (high demands and low latitude), active (high demands and high latitude), passive (low demands and low latitude), and low strain. A chronic job strain variable was constructed based on the first 2 interviews, and patients were divided into those exposed to high strain at both interviews and those unexposed to high strain at 1 or both interviews. The survival analyses were presented separately for 2 periods: before 2.2 years and at 2.2 years and beyond. Main Outcome Measure  The outcome was a composite of fatal CHD, nonfatal MI, and unstable angina. Results  The outcome was documented in 206 patients. In the unadjusted analysis, chronic job strain was associated with recurrent CHD in the second period after 2.2 years of follow-up (hazard ratio [HR], 2.20; 95% CI, 1.32-3.66; respective event rates for patients exposed and unexposed to chronic job strain, 6.18 and 2.81 per 100 person-years). Chronic job strain remained an independent predictor of recurrent CHD in a multivariate model adjusted for 26 potentially confounding factors (HR, 2.00; 95% CI, 1.08-3.72). Conclusion  Chronic job strain after a first MI was associated with an increased risk of recurrent CHD.      

Parental cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults: a prospective study of parents and offspring

Context  Whether parental cardiovascular disease confers increased risk independent of other risk factors remains controversial. Prior studies relied on offspring report, without complete validation of parental events. Objective  To determine whether parental cardiovascular disease predicts offspring events independent of traditional risk factors, using a prospective design for both parents and offspring, and uniform criteria to validate events. Design  Inception cohort study. Setting  Framingham Heart Study, a US population-based epidemiologic cohort begun in 1948 with the offspring cohort established in 1971. Participants  All Framingham Offspring Study participants (aged =" BORDER="0">30 years) who were free of cardiovascular disease and both parents in the original Framingham cohort. Main Outcome Measures  We examined the association of parental cardiovascular disease with 8-year risk of offspring cardiovascular disease, using pooled logistic regression. Results  Among 2302 men and women (mean age, 44 years), 164 men and 79 women had cardiovascular events during follow-up. Compared with participants with no parental cardiovascular disease, those with at least 1 parent with premature cardiovascular disease (onset age <55 years in father, <65 years in mother) had greater risk for events, with age-adjusted odds ratios of 2.6 (95% confidence interval [CI], 1.7-4.1) for men and 2.3 (95% CI, 1.3-4.3) for women. Multivariable adjustment resulted in odds ratios of 2.0 (95% CI, 1.2-3.1) for men and 1.7 (95% CI, 0.9-3.1) for women. Nonpremature parental cardiovascular disease and parental coronary disease were weaker predictors. Addition of parental information aided in discriminating event rates, notably among offspring with intermediate levels of cholesterol and blood pressure, as well as intermediate predicted multivariable risk. Conclusions  Using validated events, we found that parental cardiovascular disease independently predicted future offspring events in middle-aged adults. Addition of parental information may help clinicians and patients with primary prevention of cardiovascular disease, when treatment decisions may be difficult in patients at intermediate risk based on levels of single or multiple risk factors. These data also support further research into genetic determinants of cardiovascular risk.      

Sex differences in the use of implantable cardioverter-defibrillators for primary and secondary prevention of sudden cardiac death

Context  Previous studies of sex differences in the use of implantable cardioverter-defibrillators (ICDs) predate recent expansions in Medicare coverage and did not provide patient follow-up over multiple years. Objective  To examine sex differences in ICD use for primary and secondary prevention of sudden cardiac death. Design, Setting, and Participants  Analysis of a 5% national sample of research-identifiable files obtained from the US Centers for Medicare & Medicaid Services for the period 1991 through 2005. Patients were those aged 65 years or older with Medicare fee-for-service coverage and diagnosed with acute myocardial infarction and either heart failure or cardiomyopathy but no prior cardiac arrest or ventricular tachycardia (ie, the primary prevention cohort [n = 65 917 men and 70 504 women]), or with cardiac arrest or ventricular tachycardia (ie, the secondary prevention cohort [n = 52 252 men and 47 411 women]), from 1999 through 2005. Main Outcome Measures  Receipt of ICD therapy and all-cause mortality at 1 year. Results  In the 2005 primary prevention cohort, 32.3 per 1000 men and 8.6 per 1000 women received ICD therapy within 1 year of cohort entry. In multivariate analyses, men were more likely than women to receive ICD therapy (hazard ratio [HR], 3.15; 95% confidence interval [CI], 2.86-3.47). Among men and women alive at 180 days after cohort entry, the hazard of mortality in the subsequent year was not significantly lower among those who received ICD therapy (HR, 1.01; 95% CI, 0.82-1.23). In the 2005 secondary prevention cohort, 102.2 per 1000 men and 38.4 per 1000 women received ICD therapy. Controlling for demographic variables and comorbid conditions, men were more likely than women to receive ICD therapy (HR, 2.44; 95% CI, 2.30-2.59). Among men and women alive at 30 days after cohort entry, the hazard of mortality in the subsequent year was significantly lower among those who received ICD therapy (HR, 0.65; 95% CI, 0.60-0.71). Conclusion  In the Medicare population, women are significantly less likely than men to receive ICD therapy for primary or secondary prevention of sudden cardiac death.      

Sibling cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults

Context  While parental cardiovascular disease (CVD) doubles the risk for CVD in offspring, the extent of increased risk associated with sibling CVD is unclear. Objective  To determine, using validated events, whether sibling CVD predicts outcome in middle-aged adults independent of other risk factors. Design, Setting, and Participants  The Framingham Offspring Study, an inception cohort of the Framingham Heart Study, a prospective population-based cohort study initiated in 1948 with the offspring cohort initiated in 1971. Participants (n = 2475) were members of the offspring cohort aged 30 years or older, free of CVD, and with at least 1 sibling in the study; all were followed up for 8 years. Main Outcome Measures  Association of sibling CVD with 8-year personal risk for CVD using pooled logistic regression. A secondary analysis restricted to offspring with both parents in the study assessed the joint impact of parental and sibling CVD occurrence. Results  Among 973 person-examinations in the sibling CVD group (mean age, 57 years) and 4506 person-examinations in the no sibling CVD group (mean age, 47 years), 329 CVD events occurred during follow-up. Baseline risk factors were more prevalent in the sibling CVD group compared with the no sibling CVD group. Sibling CVD was associated with a significantly increased risk for incident CVD (age- and sex-adjusted odds ratio [OR], 1.55; 95% confidence interval [CI], 1.19-2.03). Adjustment for risk factors did not substantially attenuate the risk (adjusted OR, 1.45; 95% CI, 1.10-1.91). In the analysis restricted to persons with both parents in the study, in models adjusting for both sibling and parental CVD, the multivariable-adjusted OR for sibling CVD (1.99; 95% CI, 1.32-3.00) exceeded that for parental CVD (1.45; 95% CI, 1.02-2.05). Conclusion  Using validated events, sibling CVD conferred increased risk of future CVD events above and beyond established risk factors and parental CVD in middle-aged adults.      

Prevalence of conventional risk factors in patients with coronary heart disease

Context  It is commonly suggested that more than 50% of patients with coronary heart disease (CHD) lack any of the conventional risk factors (cigarette smoking, diabetes, hyperlipidemia, and hypertension). This claim implies that other factors play a significant role in CHD and has led to considerable interest in nontraditional risk factors and genetic causes of CHD. Objective  To determine the prevalence of the 4 conventional risk factors among patients with CHD. Design, Setting, and Patients  In 2002-2003, we analyzed data for 122 458 patients enrolled in 14 international randomized clinical trials of CHD conducted during the prior decade. Patients included 76 716 with ST-elevation myocardial infarction, 35 527 with unstable angina/non–ST-elevation myocardial infarction, and 10 215 undergoing percutaneous coronary intervention. Main Outcome Measures  Prevalence of each conventional risk factor and number of conventional risk factors present among patients with CHD, compared between men and women and by age at trial entry. Results  Among patients with CHD, at least 1 of the 4 conventional risk factors was present in 84.6% of women and 80.6% of men. In younger patients (men 55 years and women 65 years) and most patients presenting either with unstable angina or for percutaneous coronary intervention, only 10% to 15% of patients lacked any of the 4 conventional risk factors. This pattern was largely independent of sex, geographic region, trial entry criteria, or prior CHD. Premature CHD was related to cigarette smoking in men and cigarette smoking and diabetes in women. Smoking decreased the age at the time of CHD event (at trial entry) by nearly 1 decade in all risk factor combinations. Conclusions  In direct contrast with conventional thinking, 80% to 90% of patients with CHD have conventional risk factors. Although research on nontraditional risk factors and genetic causes of heart disease is important, clinical medicine, public health policies, and research efforts should place significant emphasis on the 4 conventional risk factors and the lifestyle behaviors causing them to reduce the epidemic of CHD.      

Exercise type and intensity in relation to coronary heart disease in men

Context  Studies have shown an inverse relationship between exercise and risk of coronary heart disease (CHD), but data on type and intensity are sparse. Objective  To assess the amount, type, and intensity of physical activity in relation to risk of CHD among men. Design, Setting, and Participants  A cohort of 44 452 US men enrolled in the Health Professionals' Follow-up Study, followed up at 2-year intervals from 1986 through January 31, 1998, to assess potential CHD risk factors, identify newly diagnosed cases of CHD, and assess levels of leisure-time physical activity. Main Outcome Measure  Incident nonfatal myocardial infarction or fatal CHD occurring during the follow-up period. Results  During 475 755 person-years, we documented 1700 new cases of CHD. Total physical activity, running, weight training, and rowing were each inversely associated with risk of CHD. The RRs (95% confidence intervals [CIs]) corresponding to quintiles of metabolic equivalent tasks (METs) for total physical activity adjusted for age, smoking, and other cardiovascular risk factors were 1.0, 0.90 (0.78-1.04), 0.87 (0.75-1.00), 0.83 (0.71-0.96), and 0.70 (0.59-0.82) (P<.001 for trend). Men who ran for an hour or more per week had a 42% risk reduction (RR, 0.58; 95% CI, 0.44-0.77) compared with men who did not run (P<.001 for trend). Men who trained with weights for 30 minutes or more per week had a 23% risk reduction (RR, 0.77; 95% CI, 0.61-0.98) compared with men who did not train with weights (P = .03 for trend). Rowing for 1 hour or more per week was associated with an 18% risk reduction (RR, 0.82; 05% CI, 0.68-0.99). Average exercise intensity was associated with reduced CHD risk independent of the total volume of physical activity. The RRs (95% CIs) corresponding to moderate (4-6 METs) and high (6-12 METs) activity intensities were 0.94 (0.83-1.04) and 0.83 (0.72-0.97) compared with low activity intensity (<4 METs) (P = .02 for trend). A half-hour per day or more of brisk walking was associated with an 18% risk reduction (RR, 0.82; 95% CI, 0.67-1.00). Walking pace was associated with reduced CHD risk independent of the number of walking hours. Conclusions  Total physical activity, running, weight training, and walking were each associated with reduced CHD risk. Average exercise intensity was associated with reduced risk independent of the number of MET-hours spent in physical activity.      

Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause

Context  The timing of initiation of hormone therapy may influence its effect on cardiovascular disease. Objective  To explore whether the effects of hormone therapy on risk of cardiovascular disease vary by age or years since menopause began. Design, Setting, and Participants  Secondary analysis of the Women's Health Initiative (WHI) randomized controlled trials of hormone therapy in which 10 739 postmenopausal women who had undergone a hysterectomy were randomized to conjugated equine estrogens (CEE) or placebo and 16 608 postmenopausal women who had not had a hysterectomy were randomized to CEE plus medroxyprogesterone acetate (CEE + MPA) or placebo. Women aged 50 to 79 years were recruited to the study from 40 US clinical centers between September 1993 and October 1998. Main Outcome Measures  Statistical test for trend of the effect of hormone therapy on coronary heart disease (CHD) and stroke across categories of age and years since menopause in the combined trials. Results  In the combined trials, there were 396 cases of CHD and 327 cases of stroke in the hormone therapy group vs 379 cases of CHD and 239 cases of stroke in the placebo group. For women with less than 10 years since menopause began, the hazard ratio (HR) for CHD was 0.76 (95% confidence interval [CI], 0.50-1.16); 10 to 19 years, 1.10 (95% CI, 0.84-1.45); and 20 or more years, 1.28 (95% CI, 1.03-1.58) (P for trend = .02). The estimated absolute excess risk for CHD for women within 10 years of menopause was –6 per 10 000 person-years; for women 10 to 19 years since menopause began, 4 per 10 000 person-years; and for women 20 or more years from menopause onset, 17 per 10 000 person-years. For the age group of 50 to 59 years, the HR for CHD was 0.93 (95% CI, 0.65-1.33) and the absolute excess risk was –2 per 10 000 person-years; 60 to 69 years, 0.98 (95% CI, 0.79-1.21) and –1 per 10 000 person-years; and 70 to 79 years, 1.26 (95% CI, 1.00-1.59) and 19 per 10 000 person-years (P for trend = .16). Hormone therapy increased the risk of stroke (HR, 1.32; 95% CI, 1.12-1.56). Risk did not vary significantly by age or time since menopause. There was a nonsignificant tendency for the effects of hormone therapy on total mortality to be more favorable in younger than older women (HR of 0.70 for 50-59 years; 1.05 for 60-69 years, and 1.14 for 70-79 years; P for trend = .06). Conclusions  Women who initiated hormone therapy closer to menopause tended to have reduced CHD risk compared with the increase in CHD risk among women more distant from menopause, but this trend test did not meet our criterion for statistical significance. A similar nonsignificant trend was observed for total mortality but the risk of stroke was elevated regardless of years since menopause. These data should be considered in regard to the short-term treatment of menopausal symptoms. Trial Registration  clinicaltrials.gov Identifier: NCT00000611      

Long-term Intake of Dietary Fiber and Decreased Risk of Coronary Heart Disease Among Women

Context  Epidemiological studies of men suggest that dietary fiber intake protects against coronary heart disease (CHD), but data on this association in women are sparse. Objective  To examine the association between long-term intake of total dietary fiber as well as fiber from different sources and risk of CHD in women. Design and Setting  The Nurses' Health Study, a large, prospective cohort study of US women followed up for 10 years from 1984. Dietary data were collected in 1984, 1986, and 1990, using a validated semiquantitative food frequency questionnaire. Participants  A total of 68,782 women aged 37 to 64 years without previously diagnosed angina, myocardial infarction (MI), stroke, cancer, hypercholesterolemia, or diabetes at baseline. Main Outcome Measure  Incidence of acute MI or death due to CHD by amount of fiber intake. Results  Response rate averaged 80% to 90% during the 10-year follow-up. We documented 591 major CHD events (429 nonfatal MIs and 162 CHD deaths). The age-adjusted relative risk (RR) for major CHD events was 0.53 (95% confidence interval [CI], 0.40-0.69) for women in the highest quintile of total dietary fiber intake (median, 22.9 g/d) compared with women in the lowest quintile (median, 11.5 g/d). After controlling for age, cardiovascular risk factors, dietary factors, and multivitamin supplement use, the RR was 0.77 (95% CI, 0.57-1.04). For a 10-g/d increase in total fiber intake (the difference between the lowest and highest quintiles), the multivariate RR of total CHD events was 0.81 (95% CI, 0.66-0.99). Among different sources of dietary fiber (eg, cereal, vegetables, fruit), only cereal fiber was strongly associated with a reduced risk of CHD (multivariate RR, 0.63; 95% CI, 0.49-0.81 for each 5-g/d increase in cereal fiber). Conclusions  Our findings in women support the hypothesis that higher fiber intake, particularly from cereal sources, reduces the risk of CHD.      

Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring

Context  Atrial fibrillation (AF) is the most common cardiac dysrhythmia in the United States. Whereas rare cases of familial AF have been reported, it is unknown if AF among unselected individuals is a heritable condition. Objective  To determine whether parental AF increases the risk for the development of offspring AF. Design, Setting, and Participants  Prospective cohort study (1983-2002) within the Framingham Heart Study, a population-based epidemiologic study. Participants were 2243 offspring (1165 women, 1078 men) at least 30 years of age and free of AF whose parents had both been evaluated in the original cohort. Main Outcome Measures  Development of new-onset AF in the offspring was prospectively examined in association with previously documented parental AF. Results  Among 2243 offspring participants, 681 (30%) had at least 1 parent with documented AF; 70 offspring participants (23 women; mean age, 62 [range, 40-81] years) developed AF in follow-up. Compared with no parental AF, AF in at least 1 parent increased the risk of offspring AF (multivariable-adjusted odds ratio [OR], 1.85; 95% confidence interval [CI], 1.12-3.06; P = .02). These results were stronger when age was limited to younger than 75 years in both parents and offspring (multivariable-adjusted OR, 3.23; 95% CI, 1.87-5.58; P<.001) and when the sample was further limited to those without antecedent myocardial infarction, heart failure, or valve disease (multivariable-adjusted OR, 3.17; 95% CI, 1.71-5.86; P<.001). Conclusions  Parental AF increases the future risk for offspring AF, an observation supporting a genetic susceptibility to developing this dysrhythmia. Further research into the genetic factors predisposing to AF is warranted.      

Cost-effectiveness of vitamin therapy to lower plasma homocysteine levels for the prevention of coronary heart disease: effect of grain fortification and beyond

Context  A high homocysteine level has been identified as an independent modifiable risk factor for coronary heart disease (CHD) events and death. Since January 1998, the US Food and Drug Administration has required that all enriched grain products contain 140 µg of folic acid per 100 g, a level considered to decrease homocysteine levels. Objectives  To examine the potential effect of grain fortification with folic acid on CHD events and to estimate the cost-effectiveness of additional vitamin supplementation (folic acid and cyanocobalamin) for CHD prevention. Design and Setting  Cost-effectiveness analysis using the Coronary Heart Disease Policy Model, a validated, state-transition model of CHD events in adults aged 35 through 84 years. Data from the third National Health and Nutrition Examination Survey (NHANES III) were used to estimate age- and sex-specific differences in homocysteine levels. Intervention  Hypothetical comparison between a diet that includes enriched grain products projected to increase folic acid intake by 100 µg/d with the same diet without folic acid fortification; and a comparison between vitamin therapy that consists of 1 mg of folic acid and 0.5 mg of cyanocobalamin and the diet that includes grains fortified with folic acid. Main Outcome Measures  Incidence of myocardial infarction and death from CHD, quality-adjusted life-years (QALYs) saved, and medical costs. Results  Grain fortification with folic acid was predicted to decrease CHD events by 8% in women and 13% in men, with comparable reductions in CHD mortality. The model projected that, compared with grain fortification alone, treating all patients with known CHD with folic acid and cyanocobalamin over a 10-year period would result in 310 000 fewer deaths and lower costs. Over the same 10-year period, providing vitamin supplementation in addition to grain fortification to all men aged 45 years or older without known CHD was projected to save more than 300 000 QALYs, to save more than US $2 billion, and to be the preferred strategy. For women without CHD, the preferred vitamin supplementation strategy would be to treat all women older than 55 years, a strategy projected to save more than 140 000 QALYs over 10 years. Conclusions  Folic acid and cyanocobalamin supplementation may be cost-effective among many population subgroups and could have a major epidemiologic benefit for primary and secondary prevention of CHD if ongoing clinical trials confirm that homocysteine-lowering therapy decreases CHD event rates.      

Global risk scores and exercise testing for predicting all-cause mortality in a preventive medicine program

Context  The usefulness of exercise stress test results and global cardiovascular risk systems for predicting all-cause mortality in asymptomatic individuals seen in clinical settings is unclear. Objectives  To determine the validity for prediction of all-cause mortality of the Framingham Risk Score and of a recently described European global scoring system Systematic Coronary Risk Evaluation (SCORE) for cardiovascular mortality among asymptomatic individuals evaluated in a clinical setting and to determine the potential prognostic value of exercise stress testing once these baseline risks are known. Design, Setting, and Participants  Prospective cohort study of 3554 asymptomatic adults between the ages of 50 and 75 years who underwent exercise stress testing as part of an executive health program between October 1990 and December 2002; participants were followed up for a mean of 8 years. Main Outcome Measures  Global risk based on the Framingham Risk Score and the European SCORE. Prospectively recorded exercise stress test result abnormalities included impaired physical fitness, abnormal heart rate recovery, ventricular ectopy, and ST-segment abnormalities. The primary end point was all-cause mortality. Results  There were 114 deaths. The c-index, which corresponds to receiver operating characteristic curve values, and the Akaike Information Criteria found that the European SCORE was superior to the Framingham Risk Score in estimating global mortality risk. In a multivariable model, independent predictors of death were a higher SCORE (for 1% predicted increase in absolute risk, relative risk [RR], 1.07; 95% confidence interval [CI], 1.04-1.09; P<.001), impaired functional capacity (RR, 2.95; 95% CI, 1.98-4.39; P<.001), and an abnormal heart rate recovery (RR, 1.59; 95%, 1.04-2.41; P = .03). ST-segment depression did not predict mortality. Among patients in the highest tertile from the SCORE, an abnormal exercise stress test result, defined as either impaired functional capacity or an abnormal heart rate recovery, identified a mortality risk of more than 1% per year. Conclusion  Exercise stress testing when combined with the European global risk SCORE may be useful for stratifying risk in asymptomatic individuals in a comprehensive executive health screening program.      

Trends in incidence, lifetime risk, severity, and 30-day mortality of stroke over the past 50 years

Context  Prior estimates of long-term trends in the incidence and severity of stroke have varied; trends in lifetime risk have not been reported. Objective  To determine long-term trends in the incidence, lifetime risk, severity, and 30-day mortality of clinical stroke. Design, Setting, and Participants  Prospective evaluation of the community-based Framingham Study original and offspring cohorts. Participants were 9152 men and women free of prevalent stroke and undergoing follow-up for up to 50 years over 3 consecutive periods (1950-1977, 1978-1989, and 1990-2004), with biennial ascertainment of stroke risk factor data and active surveillance for incident clinical stroke and cause-specific mortality. Main Outcome Measures  Incidence (age-adjusted, sex-specific), severity, 30-day mortality, and mortality-adjusted 10-year and lifetime risk of stroke in each of the specified periods. Results  There were 1030 incident clinical strokes (450 [44%] in men, 629 atherothrombotic brain infarctions [61%]) in 9152 persons 55 years or older over 174 917 person-years of follow-up. The age-adjusted incidence of first stroke per 1000 person-years in each of the 3 periods was 7.6, 6.2, and 5.3, respectively, in men (P = .02 for trend) and 6.2, 5.8, and 5.1 in women (P = .01 for trend). The lifetime risk at age 65 years decreased from 19.5% to 14.5% in men (P = .11) and from 18.0% to 16.1% in women (P = .61). Age-adjusted stroke severity did not vary across periods; however, 30-day mortality decreased significantly in men (from 23% to 14%; P = .01) but not significantly in women (from 21% to 20%; P = .32). Conclusions  In this cohort of men and women free of prevalent clinical stroke at initial examination, incidence of stroke has decreased over the past 50 years but the lifetime risk has not declined to the same degree, perhaps due to improved life expectancy. The results of this study suggest that improved control of risk factors has lowered stroke incidence but emphasize the need for continued primary prevention efforts.      

Trends in heart failure incidence and survival in a community-based population

Context  The epidemic of heart failure has yet to be fully investigated, and data on incidence, survival, and sex-specific temporal trends in community-based populations are limited. Objective  To test the hypothesis that the incidence of heart failure has declined and survival after heart failure diagnosis has improved over time but that secular trends have diverged by sex. Design, Setting, and Participants  Population-based cohort study using the resources of the Rochester Epidemiology Project conducted in Olmsted County, Minnesota. Patients were 4537 Olmsted County residents (57% women; mean [SD] age, 74 [14] years) with a diagnosis of heart failure between 1979 and 2000. Framingham criteria and clinical criteria were used to validate the diagnosis Main Outcome Measures  Incidence of heart failure and survival after heart failure diagnosis. Results  The incidence of heart failure was higher among men (378/100 000 persons; 95% confidence interval [CI], 361-395 for men; 289/100 000 persons; 95% CI, 277-300 for women) and did not change over time among men or women. After a mean follow-up of 4.2 years (range, 0-23.8 years), 3347 deaths occurred, including 1930 among women and 1417 among men. Survival after heart failure diagnosis was worse among men than women (relative risk, 1.33; 95% CI, 1.24-1.43) but overall improved over time (5-year age-adjusted survival, 43% in 1979-1984 vs 52% in 1996-2000, P<.001). However, men and younger persons experienced larger survival gains, contrasting with less or no improvement for women and elderly persons. Conclusion  In this community-based cohort, the incidence of heart failure has not declined during 2 decades, but survival after onset of heart failure has increased overall, with less improvement among women and elderly persons.      

Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II)

Context  The Heart and Estrogen/progestin Replacement Study (HERS) found no overall reduction in risk of coronary heart disease (CHD) events among postmenopausal women with CHD. However, in the hormone group, findings did suggest a higher risk of CHD events during the first year, and a decreased risk during years 3 to 5. Objective  To determine if the risk reduction observed in the later years of HERS persisted and resulted in an overall reduced risk of CHD events with additional years of follow-up. Design and Setting  Randomized, blinded, placebo-controlled trial of 4.1 years' duration (HERS) and subsequent unblinded follow-up for 2.7 years (HERS II) conducted at outpatient and community settings at 20 US clinical centers. Participants  A total of 2763 postmenopausal women with CHD and average age of 67 years at enrollment in HERS; 2321 women (93% of those surviving) consented to follow-up in HERS II. Intervention  Participants were randomly assigned to receive 0.625 mg/d of conjugated estrogens and 2.5 mg of medroxyprogesterone acetate (n = 1380), or placebo (n = 1383) during HERS; open-label hormone therapy was prescribed at personal physicians' discretion during HERS II. The proportions with at least 80% adherence to hormones declined from 81% (year 1) to 45% (year 6) in the hormone group, and increased from 0% (year 1) to 8% (year 6) in the placebo group. Main Outcome Measures  The primary outcome was nonfatal myocardial infarction and CHD death. Secondary cardiovascular events were coronary revascularization, hospitalization for unstable angina or congestive heart failure, nonfatal ventricular arrhythmia, sudden death, stroke or transient ischemic attack, and peripheral arterial disease. Results  There were no significant decreases in rates of primary CHD events or secondary cardiovascular events among women assigned to the hormone group compared with the placebo group in HERS, HERS II, or overall. The unadjusted relative hazard (RH) for CHD events in HERS was 0.99 (95% confidence interval [CI], 0.81-1.22); HERS II, 1.00 (95% CI, 0.77-1.29); and overall, 0.99 (0.84-1.17). The overall RHs were similar after adjustment for potential confounders and differential use of statins between treatment groups (RH, 0.97; 95% CI, 0.82-1.14), and in analyses restricted to women who were adherent to randomized treatment assignment (RH, 0.96; 95% CI, 0.77-1.19). Conclusions  Lower rates of CHD events among women in the hormone group in the final years of HERS did not persist during additional years of follow-up. After 6.8 years, hormone therapy did not reduce risk of cardiovascular events in women with CHD. Postmenopausal hormone therapy should not be used to reduce risk for CHD events in women with CHD.      

Obesity and the risk of new-onset atrial fibrillation

Context  Obesity is associated with atrial enlargement and ventricular diastolic dysfunction, both known predictors of atrial fibrillation (AF). However, it is unclear whether obesity is a risk factor for AF. Objective  To examine the association between body mass index (BMI) and the risk of developing AF. Design, Setting, and Participants  Prospective, community-based observational cohort in Framingham, Mass. We studied 5282 participants (mean age, 57 [SD, 13] years; 2898 women [55%]) without baseline AF (electrocardiographic AF or arterial flutter). Body mass index (calculated as weight in kilograms divided by square of height in meters) was evaluated as both a continuous and a categorical variable (normal defined as <25.0; overweight, 25.0 to <30.0; and obese, 30.0). In addition to adjusting for clinical confounders by multivariable techniques, we also examined models including echocardiographic left atrial diameter to examine whether the influence of obesity was mediated by changes in left atrial dimensions. Main Outcome Measure  Association between BMI or BMI category and risk of developing new-onset AF. Results  During a mean follow-up of 13.7 years, 526 participants (234 women) developed AF. Age-adjusted incidence rates for AF increased across the 3 BMI categories in men (9.7, 10.7, and 14.3 per 1000 person-years) and women (5.1, 8.6, and 9.9 per 1000 person-years). In multivariable models adjusted for cardiovascular risk factors and interim myocardial infarction or heart failure, a 4% increase in AF risk per 1-unit increase in BMI was observed in men (95% confidence interval [CI], 1%-7%; P = .02) and in women (95% CI, 1%-7%; P = .009). Adjusted hazard ratios for AF associated with obesity were 1.52 (95% CI, 1.09-2.13; P = .02) and 1.46 (95% CI, 1.03-2.07; P = .03) for men and women, respectively, compared with individuals with normal BMI. After adjustment for echocardiographic left atrial diameter in addition to clinical risk factors, BMI was no longer associated with AF risk (adjusted hazard ratios per 1-unit increase in BMI, 1.00 [95% CI, 0.97-1.04], P = .84 in men; 0.99 [95% CI, 0.96-1.02], P = .56 in women). Conclusions  Obesity is an important, potentially modifiable risk factor for AF. The excess risk of AF associated with obesity appears to be mediated by left atrial dilatation. These prospective data raise the possibility that interventions to promote normal weight may reduce the population burden of AF.      

Major and minor ECG abnormalities in asymptomatic women and risk of cardiovascular events and mortality

Context  Data are sparse regarding the prevalence, incidence, and independent prognostic value of minor and/or major electrocardiographic (ECG) abnormalities in asymptomatic postmenopausal women. There is no information on the effect, if any, of hormonal treatment on the prognostic value of the ECG. Objective  To examine association of minor and major baseline and incident ECG abnormalities with long-term cardiovascular morbidity and mortality. Design, Setting, and Participants  Post-hoc analysis of the estrogen plus progestin component of the Women's Health Initiative study, a randomized controlled primary prevention trial of 14 749 postmenopausal asymptomatic women with intact uterus who received 1 daily tablet containing 0.625 mg of oral conjugated equine estrogen and 2.5 mg of medroxyprogesterone acetate or a matching placebo. Participants were enrolled from 1993 to 1998, and the estrogen plus progestin trial was stopped on July 7, 2002. Main Outcome Measures  The Novacode criteria were used to define minor, major, and incident ECG abnormalities. Cardiovascular end points included incident coronary heart disease (CHD) and cardiovascular disease (CVD) events. Results  Among women with absent (n = 9744), minor (n = 4095), and major (n = 910) ECG abnormalities, there were 118, 91, and 37 incident CHD events, respectively. The incident annual CHD event rates per 10 000 women with absent, minor, or major ECG abnormalities were 21 (95% confidence interval [CI], 18-26), 40 (95% CI, 32-49), and 75 (95% CI, 54-104), respectively. After 3 years of follow-up, 5% of women who had normal ECG at baseline developed new ECG abnormalities with an annual CHD event rate of 85 (95% CI, 44-164) per 10 000 women. The adjusted hazard ratios for CHD events were 1.55 (95% CI, 1.14-2.11) for minor baseline, 3.01 (95% CI, 2.03-4.46) for major baseline, and 2.60 (95% CI, 1.08-6.27) for incident ECG abnormalities. There were no significant interactions between hormone treatment assignment and ECG abnormalities for risk prediction of cardiovascular end points. For prediction of CHD events, the addition of ECG findings to the Framingham risk score increased from 0.69 to 0.74 the area under the receiver operating characteristic curve. Similar findings were found for incident CVD events. Conclusions  Among asymptomatic postmenopausal women, clinically relevant baseline and incident ECG abnormalities are independently associated with increased risk of cardiovascular events and mortality, and the information is incremental to the established method of risk stratification. Trial Registration  clinicaltrials.gov Identifier: NCT00000611      

Plasma homocysteine and risk for congestive heart failure in adults without prior myocardial infarction

Context  Elevated plasma homocysteine levels are associated with increased risk of vascular disease. It is unclear whether elevated homocysteine levels are a risk factor for congestive heart failure (CHF). Objective  To study prospectively the association between nonfasting plasma homocysteine and incidence of CHF. Design, Setting, and Participants  Community-based prospective cohort study of 2491 adults (mean age 72 years, 1547 women) who participated in the Framingham Heart Study during the 1979-1982 and 1986-1990 examinations and were free of CHF or prior myocardial infarction (recognized or unrecognized) at baseline. Main Outcome Measure  Incidence of a first episode of CHF during an 8-year follow-up period. Results  During follow-up, 156 subjects (88 women) developed CHF. In multivariable analyses controlling for established risk factors for CHF including the occurrence of myocardial infarction (recognized or unrecognized) during follow-up, plasma homocysteine levels higher than the sex-specific median value were associated with an adjusted hazards ratio for heart failure of 1.93 in women (95% confidence interval, 1.19-3.14) and 1.84 in men (95% confidence interval, 1.06-3.17). The relation of plasma homocysteine levels to CHF risk was more continuous in women than in men. In analyses restricted to participants without any manifestation of coronary heart disease at baseline, the association of plasma homocysteine levels with risk of CHF was maintained in men and women. Conclusions  An increased plasma homocysteine level independently predicts risk of the development of CHF in adults without prior myocardial infarction. Additional investigations are warranted to confirm these findings.      

Favorable cardiovascular risk profile in young women and long-term risk of cardiovascular and all-cause mortality

Context  For women, impact of cardiovascular risk factors measured in young adulthood, particularly favorable (low-risk) profile, on mortality has been difficult to assess due to low short-term death rates. Objective  To assess the relationship of baseline coronary risk factor status to mortality from coronary heart disease (CHD), cardiovascular diseases (CVDs), and all causes in young women. Design  Prospective cohort study. Setting and Participants  A total of 7302 women aged 18 to 39 years without prior CHD or major electrocardiographic abnormalities screened between 1967 and 1973 for the Chicago Heart Association Detection Project in Industry. Risk groups were defined using national guidelines for values of systolic and diastolic blood pressure, serum cholesterol level, body mass index, presence of diabetes, and smoking status. Participants were divided into 4 groups: low risk, 0 risk factors high but 1 or more unfavorable, 1 only risk factor high, and 2 or more risk factors high. Main Outcome Measures  All-cause mortality, CHD mortality, and CVD mortality; hazard ratio of outcome measures comparing low-risk group with other groups. Results  Only 20% met low-risk criteria; 59% had high levels of 1 or more risk factors. During an average follow-up of 31 years, there were 47 CHD deaths, 94 CVD deaths, and 469 deaths from all causes. The age-adjusted CVD death rate per 10 000 person-years was lowest for low-risk women and increased with the number of risk factors, ie, 1.5, 1.7, 5.0, and 9.1 for low-risk; 0, 1, and 2 or more risk factors high, respectively. Multivariate-adjusted CVD mortality hazard ratio for low-risk women was 0.19 (95% confidence interval, 0.08-0.45) compared with women with 2 or more risk factors high. Similar patterns were observed for CHD and all-cause mortality and for both blacks and whites. Conclusion  For women with favorable levels for all 5 major risk factors at younger ages, CHD and CVD are rare; long-term and all-cause mortality are much lower compared with others.