Kathryn M. Rexrode

Long term effects of dietary sodium reduction on cardiovascular disease outcomes: observational follow-up of the trials of hypertension prevention (TOHP)

Objective To examine the effects of reduction in dietary sodium intake on cardiovascular events using data from two completed randomised trials, TOHP I and TOHP II. Design Long term follow-up assessed 10-15 years after the original trial. Setting 10 clinic sites in 1987-90 (TOHP I) and nine sites in 1990-5 (TOHP II). Central follow-up conducted by post and phone. Participants Adults aged 30-54 years with prehypertension. Intervention Dietary sodium reduction, including comprehensive education and counselling on reducing intake, for 18 months (TOHP I) or 36-48 months (TOHP II). Main outcome measure Cardiovascular disease (myocardial infarction, stroke, coronary revascularisation, or cardiovascular death). Results 744 participants in TOHP I and 2382 in TOHP II were randomised to a sodium reduction intervention or control. Net sodium reductions in the intervention groups were 44 mmol/24 h and 33 mmol/24 h, respectively. Vital status was obtained for all participants and follow-up information on morbidity was obtained from 2415 (77%), with 200 reporting a cardiovascular event. Risk of a cardiovascular event was 25% lower among those in the intervention group (relative risk 0.75, 95% confidence interval 0.57 to 0.99, P=0.04), adjusted for trial, clinic, age, race, and sex, and 30% lower after further adjustment for baseline sodium excretion and weight (0.70, 0.53 to 0.94), with similar results in each trial. In secondary analyses, 67 participants died (0.80, 0.51 to 1.26, P=0.34). Conclusion Sodium reduction, previously shown to lower blood pressure, may also reduce long term risk of cardiovascular events.

Adherence to a DASH-Style Diet and Risk of Coronary Heart Disease and Stroke in Women

BACKGROUND The Dietary Approaches to Stop Hypertension (DASH) diet has been shown to lower blood pressure, but little is known about its long-term effect on cardiovascular end points. Our objective was to assess the association between a DASH-style diet adherence score and risk of coronary heart disease (CHD) and stroke in women. METHODS In this prospective cohort study, diet was assessed 7 times during 24 years of follow-up (1980-2004) with validated food frequency questionnaires. A DASH score based on 8 food and nutrient components (fruits, vegetables, whole grains, nuts and legumes, low-fat dairy, red and processed meats, sweetened beverages, and sodium) was calculated. Lifestyle and medical information was collected biennially with a questionnaire. The Cox proportional hazard model was used to adjust for potential confounders. The study population comprised 88,517 female nurses aged 34 to 59 years without a history of cardiovascular disease or diabetes in 1980. The main outcome measures were the numbers of confirmed incident cases of nonfatal myocardial infarction, CHD death, and stroke. RESULTS We documented 2129 cases of incident nonfatal myocardial infarction, 976 CHD deaths, and 2317 [corrected] cases of stroke. After adjustment for age, smoking, and other cardiovascular risk factors, the relative risks of CHD across quintiles of the DASH score were 1.0, 0.99, 0.86, 0.87, and 0.76 (95% confidence interval, 0.67-0.85) (P<.001 for trend). The magnitude of risk difference was similar for nonfatal myocardial infarction and fatal CHD. The DASH score was also significantly associated with lower risk of stroke (multivariate relative risks across quintiles of the DASH score were 1.0, 0.92, 0.91, 0.89, and 0.82) (P=.002 for trend). Cross-sectional analysis in a subgroup of women with blood samples showed that the DASH score was significantly associated with lower plasma levels of C-reactive protein (P=.008 for trend) and interleukin 6 (P=.04 for trend). CONCLUSION Adherence to the DASH-style diet is associated with a lower risk of CHD and stroke among middle-aged women during 24 years of follow-up.

Abdominal Obesity and the Risk of All-Cause, Cardiovascular, and Cancer Mortality Sixteen Years of Follow-Up in US Women

Background— Accumulating evidence indicates that abdominal adiposity is positively related to cardiovascular disease (CVD) risk and some other diseases independently of overall adiposity. However, the association of premature death resulting from these diseases with abdominal adiposity has not been widely studied, and findings are inconsistent. Methods and Results— In a prospective cohort study of 44 636 women in the Nurses’ Health Study, associations of abdominal adiposity with all-cause and cause-specific mortality were examined. During 16 years of follow-up, 3507 deaths were identified, including 751 cardiovascular deaths and 1748 cancer deaths. After adjustment for body mass index and potential confounders, the relative risks across the lowest to the highest waist circumference quintiles were 1.00, 1.11, 1.17, 1.31, and 1.79 (95% confidence interval [CI], 1.47 to 1.98) for all-cause mortality; 1.00, 1.04, 1.04, 1.28, and 1.99 (95% CI, 1.44 to 2.73) for CVD mortality; and 1.00, 1.18, 1.20, 1.34, and 1.63 (95% CI, 1.32 to 2.01) for cancer mortality (all P<0.001 for trend). Among normal-weight women (body mass index, 18.5 to <25 kg/m2), abdominal obesity was significantly associated with elevated CVD mortality: Relative risk associated with waist circumference ≥88 cm was 3.02 (95% CI, 1.31 to 6.99) and for waist-to-hip ratio >0.88 was 3.45 (95% CI, 2.02 to 6.92). After adjustment for waist circumference, hip circumference was significantly and inversely associated with CVD mortality. Conclusions— Anthropometric measures of abdominal adiposity were strongly and positively associated with all-cause, CVD, and cancer mortality independently of body mass index. Elevated waist circumference was associated with significantly increased CVD mortality even among normal-weight women.

Obesity as Compared With Physical Activity in Predicting Risk of Coronary Heart Disease in Women

Background— The comparative importance of physical inactivity and obesity as predictors of coronary heart disease (CHD) risk remains unsettled. Methods and Results— We followed 88 393 women, 34 to 59 years of age, in the Nurses’ Health Study from 1980 to 2000. These participants did not have cardiovascular disease and cancer at baseline. We documented 2358 incident major CHD events (including nonfatal myocardial infarction and fatal CHD) during 20 years of follow-up, including 889 cases of fatal CHD and 1469 cases of nonfatal myocardial infarction. In a multivariate model adjusting for cardiovascular risk factors, overweight and obesity were significantly associated with increased risk of CHD, whereas increasing levels of physical activity were associated with a graded reduction in CHD risk (P<0.001). In joint analyses of body mass index (BMI) and physical activity in women who had a healthy weight (BMI, 18.5 to 24.9 kg/m2) and were physically active (exercise ≥3.5 h/wk) as the reference group, the relative risks of CHD were 3.44 (95% confidence interval [CI], 2.81 to 4.21) for women who were obese (BMI ≥30 kg/m2) and sedentary (exercise <1 h/wk), 2.48 (95% CI, 1.84 to 3.34) for women who were active but obese, and 1.48 (95% CI, 1.24 to 1.77) for women who had a healthy weight but were sedentary. In combined analyses of waist-hip ratio and physical activity, both waist-hip ratio and physical activity were significant predictors of CHD, and the highest risk was among women in the lowest category of physical activity and the highest tertile of waist-hip ratio (relative risk=3.03; 95% CI, 1.96 to 4.18). Even a modest weight gain (4 to 10 kg) during adulthood was associated with 27% (95% CI, 12% to 45%) increased risk of CHD compared with women with a stable weight after adjusting for physical activity and other cardiovascular risk factors. Conclusions— Obesity and physical inactivity independently contribute to the development of CHD in women. These data underscore the importance of both maintaining a healthy weight and regular physical activity in preventing CHD.

Depression and Risk of Stroke Morbidity and Mortality: A Meta-analysis and Systematic Review

CONTEXT Several studies have suggested that depression is associated with an increased risk of stroke; however, the results are inconsistent. OBJECTIVE To conduct a systematic review and meta-analysis of prospective studies assessing the association between depression and risk of developing stroke in adults. DATA SOURCES A search of MEDLINE, EMBASE, and PsycINFO databases (to May 2011) was supplemented by manual searches of bibliographies of key retrieved articles and relevant reviews. STUDY SELECTION We included prospective cohort studies that reported risk estimates of stroke morbidity or mortality by baseline or updated depression status assessed by self-reported scales or clinician diagnosis. DATA EXTRACTION Two independent reviewers extracted data on depression status at baseline, risk estimates of stroke, study quality, and methods used to assess depression and stroke. Hazard ratios (HRs) were pooled using fixed-effect or random-effects models when appropriate. Associations were tested in subgroups representing different participant and study characteristics. Publication bias was evaluated with funnel plots and Begg test. RESULTS The search yielded 28 prospective cohort studies (comprising 317,540 participants) that reported 8478 stroke cases (morbidity and mortality) during a follow-up period ranging from 2 to 29 years. The pooled adjusted HRs were 1.45 (95% CI, 1.29-1.63; P for heterogeneity <.001; random-effects model) for total stroke, 1.55 (95% CI, 1.25-1.93; P for heterogeneity = .31; fixed-effects model) for fatal stroke (8 studies), and 1.25 (95% CI, 1.11-1.40; P for heterogeneity = .34; fixed-effects model) for ischemic stroke (6 studies). The estimated absolute risk differences associated with depression were 106 cases for total stroke, 53 cases for ischemic stroke, and 22 cases for fatal stroke per 100,000 individuals per year. The increased risk of total stroke associated with depression was consistent across most subgroups. CONCLUSION Depression is associated with a significantly increased risk of stroke morbidity and mortality.

Guidelines for the Prevention of Stroke in Women A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association

Purpose— The aim of this statement is to summarize data on stroke risk factors that are unique to and more common in women than men and to expand on the data provided in prior stroke guidelines and cardiovascular prevention guidelines for women. This guideline focuses on the risk factors unique to women, such as reproductive factors, and those that are more common in women, including migraine with aura, obesity, metabolic syndrome, and atrial fibrillation. Methods— Writing group members were nominated by the committee chair on the basis of their previous work in relevant topic areas and were approved by the American Heart Association (AHA) Stroke Council’s Scientific Statement Oversight Committee and the AHA’s Manuscript Oversight Committee. The panel reviewed relevant articles on adults using computerized searches of the medical literature through May 15, 2013. The evidence is organized within the context of the AHA framework and is classified according to the joint AHA/American College of Cardiology and supplementary AHA Stroke Council methods of classifying the level of certainty and the class and level of evidence. The document underwent extensive AHA internal peer review, Stroke Council Leadership review, and Scientific Statements Oversight Committee review before consideration and approval by the AHA Science Advisory and Coordinating Committee. Results— We provide current evidence, research gaps, and recommendations on risk of stroke related to preeclampsia, oral contraceptives, menopause, and hormone replacement, as well as those risk factors more common in women, such as obesity/metabolic syndrome, atrial fibrillation, and migraine with aura. Conclusions— To more accurately reflect the risk of stroke in women across the lifespan, as well as the clear gaps in current risk scores, we believe a female-specific stroke risk score is warranted.

Prospective Study of Sudden Cardiac Death Among Women in the United States

Background—There are few data regarding the determinants of sudden cardiac death (SCD) in women, primarily because of their markedly lower rate of SCD compared with men. Nonetheless, existing data, although sparse, suggest possible gender differences in risk factors for SCD. Methods and Results—In this prospective cohort of 121 701 women aged 30 to 55 years at baseline, SCD was defined as death within 1 hour of symptom onset. From 1976 to 1998, 244 SCDs were identified. Although the risk of SCD increased markedly with age, the percentage of cardiac deaths that were sudden decreased. Most (69%) women who suffered a SCD had no history of cardiac disease before their death. However, almost all of the women who died suddenly (94%) had reported at least 1 coronary heart disease risk factor. Smoking, hypertension, and diabetes conferred markedly elevated (2.5- to 4.0-fold) risk of SCD, similar to that conferred by a history of nonfatal myocardial infarction (relative risk, 4.1; 95% confidence interval, 2.9 to 6.7). Family history of myocardial infarction before age 60 years and obesity were associated with moderate (1.6-fold) elevations in risk. With regard to mechanism, 88% of SCDs were classified as arrhythmic. In 76% of these, the first rhythm documented was ventricular tachycardia or ventricular fibrillation. Conclusions—These prospective data suggest that, as in men, coronary heart disease risk factors predict risk of SCD in women and that SCD is usually an arrhythmic death. Therefore, prevention of atherosclerosis or ventricular arrhythmias may reduce the incidence of SCD in women.

Primary Prevention of Stroke by Healthy Lifestyle

Background— The combination of healthy lifestyle factors is associated with lower risk of coronary heart disease, diabetes, and total cardiovascular disease. Little is known about the impact of multiple lifestyle factors on the risk of stroke. Methods and Results— We conducted a prospective cohort study among 43 685 men from the Health Professionals Follow-up Study and 71 243 women from the Nurses’ Health Study. Diet and other lifestyle factors were updated from self-reported questionnaires. We defined a low-risk lifestyle as not smoking, a body mass index <25 kg/m2, ≥30 min/d of moderate activity, modest alcohol consumption (men, 5 to 30 g/d; women, 5 to 15 g/d), and scoring within the top 40% of a healthy diet score. We documented 1559 strokes (853 ischemic, 278 hemorrhagic) among women and 994 strokes (600 ischemic, 161 hemorrhagic) among men during follow-up. Women with all 5 low-risk factors had a relative risk of 0.21 (95% confidence interval [CI], 0.12, 0.36) for total and 0.19 (95% CI, 0.09, 0.40) for ischemic stroke compared with women who had none of these factors. Among men, the relative risks were 0.31 (95% CI, 0.19, 0.53) for total and 0.20 (95% CI, 0.10, 0.42) for ischemic stroke for the same comparison. Among the women, 47% (95% CI, 18 to 69) of total and 54% (95% CI, 15 to 78%) of ischemic stroke cases were attributable to lack of adherence to a low-risk lifestyle; among the men, 35% (95% CI, 7 to 58) of total and 52% (95% CI, 19 to 75) of ischemic stroke may have been prevented. Conclusion— A low-risk lifestyle that is associated with a reduced risk of multiple chronic diseases also may be beneficial in the prevention of stroke, especially ischemic stroke.

Baseline characteristics of participants in the Women's Health Study.

The Womens Health Study (WHS) is a randomized, double-blind, placebo-controlled trial designed to evaluate the balance of benefits and risks of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer in women. A total of 39,876 female health professionals, age 45 years or older and without a history of cardiovascular disease or cancer (other than nonmelanoma skin cancer), were randomized in a 2x2 factorial design to one of four treatment groups: active aspirin and vitamin E placebo, aspirin placebo and active vitamin E, both active agents, or both placebos. The process of randomization was successful, as evidenced by the equal distribution of a large number of baseline demographic, lifestyle, and health history characteristics among the four treatment groups. Similar distribution of known potential confounders, as well as the large sample size, provides reassuring evidence that unmeasured or unknown potential confounders are also equally distributed. As expected in a clinical trial, the women in the study are healthier in some respects than the general population, but they have very comparable rates of obesity, hypertension, and elevated cholesterol. With adequate duration of treatment and follow-up, this trial will provide important and relevant information on the balance of benefits and risks of aspirin and vitamin E supplementation in the primary prevention of cardiovascular disease and cancer in women.

Fish and Long-Chain ω-3 Fatty Acid Intake and Risk of Coronary Heart Disease and Total Mortality in Diabetic Women

Background—Although several prospective cohort studies have found an inverse association between fish consumption and risk of coronary heart disease (CHD) or sudden cardiac death in the general population, limited data are available among diabetic patients. Methods and Results—We examined prospectively the association between intake of fish and &ohgr;-3 fatty acids and risk of CHD and total mortality among 5103 female nurses with diagnosed type 2 diabetes but free of cardiovascular disease or cancer at baseline. Between 1980 and 1996 (45 845 person-years of follow-up), we documented 362 incident cases of CHD (141 CHD deaths and 221 nonfatal myocardial infarctions) and 468 deaths from all causes. Compared with women who seldom consumed fish (<1 serving/mo), the relative risks (RRs) (95% CI) of CHD adjusted for age, smoking, and other established coronary risk factors were 0.70 (0.48 to 1.03) for fish consumption 1 to 3 times per month, 0.60 (0.42 to 0.85) for once per week, 0.64 (0.42 to 0.99) for 2 to 4 times per week, and 0.36 (0.20 to 0.66) for 5 or more times per week (P for trend=0.002). Higher consumption of fish was also associated with a significantly lower total mortality (multivariate RR=0.48 [0.29 to 0.80] for ≥5 times per week [P for trend=0.005]). Higher consumption of long-chain &ohgr;-3 fatty acids was associated with a trend toward lower incidence of CHD (RR=0.69 [95% CI 0.47 to 1.03], P for trend=0.10) and total mortality (RR=0.63 [95% CI, 0.45 to 0.88], P for trend=0.02). Conclusions—A higher consumption of fish and long-chain &ohgr;-3 fatty acids was associated with a lower CHD incidence and total mortality among diabetic women.