Emily B. Levitan

Validation of the atherosclerotic cardiovascular disease Pooled Cohort risk equations.

IMPORTANCE The American College of Cardiology/American Heart Association (ACC/AHA) Pooled Cohort risk equations were developed to estimate atherosclerotic cardiovascular disease (CVD) risk and guide statin initiation. OBJECTIVE To assess calibration and discrimination of the Pooled Cohort risk equations in a contemporary US population. DESIGN, SETTING, AND PARTICIPANTS Adults aged 45 to 79 years enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study between January 2003 and October 2007 and followed up through December 2010. We studied participants for whom atherosclerotic CVD risk may trigger a discussion of statin initiation (those without clinical atherosclerotic CVD or diabetes, low-density lipoprotein cholesterol level between 70 and 189 mg/dL, and not taking statins; n = 10,997). MAIN OUTCOMES AND MEASURES Predicted risk and observed adjudicated atherosclerotic CVD incidence (nonfatal myocardial infarction, coronary heart disease [CHD] death, nonfatal or fatal stroke) at 5 years because REGARDS participants have not been followed up for 10 years. Additional analyses, limited to Medicare beneficiaries (n = 3333), added atherosclerotic CVD events identified in Medicare claims data. RESULTS There were 338 adjudicated events (192 CHD events, 146 strokes). The observed and predicted 5-year atherosclerotic CVD incidence per 1000 person-years for participants with a 10-year predicted atherosclerotic CVD risk of less than 5% was 1.9 (95% CI, 1.3-2.7) and 1.9, respectively, risk of 5% to less than 7.5% was 4.8 (95% CI, 3.4-6.7) and 4.8, risk of 7.5% to less than 10% was 6.1 (95% CI, 4.4-8.6) and 6.9, and risk of 10% or greater was 12.0 (95% CI, 10.6-13.6) and 15.1 (Hosmer-Lemeshow χ2 = 19.9, P = .01). The C index was 0.72 (95% CI, 0.70-0.75). There were 234 atherosclerotic CVD events (120 CHD events, 114 strokes) among Medicare-linked participants and the observed and predicted 5-year atherosclerotic CVD incidence per 1000 person-years for participants with a predicted risk of less than 7.5% was 5.3 (95% CI, 2.8-10.1) and 4.0, respectively, risk of 7.5% to less than 10% was 7.9 (95% CI, 4.6-13.5) and 6.4, and risk of 10% or greater was 17.4 (95% CI, 15.3-19.8) and 16.4 (Hosmer-Lemeshow χ2 = 5.4, P = .71). The C index was 0.67 (95% CI, 0.64-0.71). CONCLUSIONS AND RELEVANCE In this cohort of US adults for whom statin initiation is considered based on the ACC/AHA Pooled Cohort risk equations, observed and predicted 5-year atherosclerotic CVD risks were similar, indicating that these risk equations were well calibrated in the population for which they were designed to be used, and demonstrated moderate to good discrimination.

Dietary glycemic index, dietary glycemic load, blood lipids, and C-reactive protein.

Carbohydrate quantity and quality may influence the risk of cardiovascular disease through blood lipid concentrations and inflammation. We measured dietary glycemic index (GI) and dietary glycemic load (GL) among 18137 healthy women > or = 45 years old without diagnosed diabetes using a food-frequency questionnaire. We assayed fasting total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol; LDL/HDL cholesterol ratio; triacylglycerols (TG); and C-reactive protein (CRP). We evaluated associations with dietary GI and GL using a cross-sectional design, adjusting for age, body mass index, lifestyle factors, and other dietary factors. Dietary GI was significantly associated with HDL and LDL cholesterol, LDL/HDL cholesterol ratio, TG, and CRP (comparing top to bottom quintile difference in HDL cholesterol = -2.6 mg/dL, LDL cholesterol = 2.2 mg/dL, LDL/HDL cholesterol ratio = 0.16, TG = 12 mg/dL, and CRP = 0.21 mg/L). Dietary GL was associated with HDL cholesterol, LDL/HDL cholesterol ratio, and TG (comparing top to bottom quintile HDL cholesterol = -4.9 mg/dL, LDL/HDL cholesterol ratio = 0.24, and TG = 13 mg/dL). Differences in blood lipids and CRP between extreme quintiles of dietary GI and GL were small, but may translate into a clinically meaningful difference in cardiovascular risk.

Acute Kidney Injury Reduces Survival in Very Low Birth Weight Infants

Acute kidney injury (AKI) independently predicts mortality in children and adults. Our understanding of the epidemiology of AKI in very LBW (VLBW) infants is limited to retrospective studies. After adjustment for demographics, comorbidities, and interventions, infants with AKI have decreased survival compared with those without AKI. The study was conducted in regional quaternary care NICU of the University of Alabama at Birmingham. VLBW infants were followed prospectively and were classified into a serum creatinine (SCr)-based classification for AKI. Forty-one of 229 (18%) VLBW infants developed AKI. Those with AKI were more likely to have umbilical artery catheters, assisted ventilation, blood pressure medications, and lower 1- and 5-min Apgar scores. Of the infants with AKI, 17 of 41 (42%) died compared with 9 of 188 (5%) of those without AKI (p < 0.001). AKI was associated with mortality with a crude hazard ratio (HR) of 9.3 (95% CI, 4.1–21.0). After adjusting for potential confounders, those with AKI had higher chance of death as the adjusted HR was 2.4 (95% CI 0.95–6.04). AKI is associated with mortality in VLBW infants. Efforts to prevent and ameliorate the impact of AKI may improve the outcomes in this vulnerable population.

Consistency with the DASH diet and incidence of heart failure.

BACKGROUND The Dietary Approaches to Stop Hypertension (DASH) diet effectively reduces blood pressure. In observational studies, the association between diets consistent with DASH and risk of coronary heart disease and stroke has been examined with varying results. We hypothesized that diets consistent with the DASH diet would be associated with a lower incidence of heart failure (HF). METHODS We conducted a prospective observational study in 36 019 participants in the Swedish Mammography Cohort who were aged 48 to 83 years and without baseline HF, diabetes mellitus, or myocardial infarction. Diet was measured using food-frequency questionnaires. We created a score to assess consistency with the DASH diet by ranking the intake of DASH diet components and 3 additional scores based on food and nutrient guidelines. Cox proportional hazards models were used to calculate rate ratios of HF-associated hospitalization or death, determined using the Swedish inpatient and cause-of-death registers between January 1, 1998, and December 31, 2004. RESULTS During 7 years, 443 women developed HF. Women in the top quartile of the DASH diet score based on ranking DASH diet components had a 37% lower rate of HF after adjustment for age, physical activity, energy intake, education status, family history of myocardial infarction, cigarette smoking, postmenopausal hormone use, living alone, hypertension, high cholesterol concentration, body mass index (calculated as weight in kilograms divided by height in meters squared), and incident myocardial infarction. Rate ratios (95% confidence intervals) across quartiles were 1 [Reference], 0.85 (0.66-1.11), 0.69 (0.54-0.88), and 0.63 (0.48-0.81); P(trend) < .001. A similar pattern was seen for the guideline-based scores. CONCLUSION In this population, diets consistent with the DASH diet are associated with lower rates of HF.

Ethnic Differences in Hypertension Incidence Among Middle-Aged and Older Adults The Multi-Ethnic Study of Atherosclerosis

The prevalence of hypertension is higher among blacks than whites. However, inconsistent findings have been reported on the incidence of hypertension among middle-aged and older blacks and whites, and limited data are available on the incidence of hypertension among Hispanics and Asians in the United States. Therefore, this study investigated the age-specific incidence of hypertension by ethnicity for 3146 participants from the Multi-Ethnic Study of Atherosclerosis. Participants, age 45 to 84 years at baseline, were followed for a median of 4.8 years for incident hypertension, defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or the initiation of antihypertensive medications. The crude incidence rate of hypertension, per 1000 person-years, was 56.8 for whites, 84.9 for blacks, 65.7 for Hispanics, and 52.2 for Chinese. After adjustment for age, sex, and study site, the incidence rate ratio (IRR) for hypertension was increased for blacks age 45 to 54 (IRR: 2.05 [95%CI: 1.47 to 2.85]), 55 to 64 (IRR: 1.63 [95% CI: 1.20 to 2.23]), and 65 to 74 years (IRR: 1.67 [95% CI: 1.21 to 2.30]) compared with whites but not for those 75 to 84 years of age (IRR: 0.97 [95% CI: 0.56 to 1.66]). Additional adjustment for health characteristics attenuated these associations. Hispanic participants also had a higher incidence of hypertension compared with whites; however, hypertension incidence did not differ for Chinese and white participants. In summary, hypertension incidence was higher for blacks compared with whites between 45 and 74 years of age but not after age 75 years. Public health prevention programs tailored to middle-aged and older adults are needed to eliminate ethnic disparities in incident hypertension.

Habitual Coffee Consumption and Risk of Heart Failure: A Dose-Response Meta-Analysis

Background— There have been discrepant findings on the association between coffee consumption and risk of incident heart failure. Methods and Results— We conducted a systematic review and a dose-response meta-analysis of prospective studies that assessed the relationship between habitual coffee consumption and the risk of heart failure. We searched electronic databases (MEDLINE, Embase, and CINAHL) from January 1966 through December 2011, with the use of a standardized protocol. Eligible studies were prospective cohort studies that examined the association of coffee consumption with incident heart failure. Five independent prospective studies of coffee consumption and heart failure risk, including 6522 heart failure events and 140 220 participants, were included in the meta-analysis. We observed a statistically significant J-shaped relationship between coffee and heart failure. Compared with no consumption, the strongest inverse association was seen for 4 servings/day and a potentially higher risk at higher levels of consumption. There was no evidence that the relationship between coffee and heart failure risk varied by sex or by baseline history of myocardial infarction or diabetes. Conclusions— Moderate coffee consumption is inversely associated with risk of heart failure, with the largest inverse association observed for consumption of 4 servings per day.Background—There have been discrepant findings on the association between coffee consumption and risk of incident heart failure. Methods and Results—We conducted a systematic review and a dose-response meta-analysis of prospective studies that assessed the relationship between habitual coffee consumption and the risk of heart failure. We searched electronic databases (MEDLINE, Embase, and CINAHL) from January 1966 through December 2011, with the use of a standardized protocol. Eligible studies were prospective cohort studies that examined the association of coffee consumption with incident heart failure. Five independent prospective studies of coffee consumption and heart failure risk, including 6522 heart failure events and 140 220 participants, were included in the meta-analysis. We observed a statistically significant J-shaped relationship between coffee and heart failure. Compared with no consumption, the strongest inverse association was seen for 4 servings/day and a potentially higher risk at higher levels of consumption. There was no evidence that the relationship between coffee and heart failure risk varied by sex or by baseline history of myocardial infarction or diabetes. Conclusions—Moderate coffee consumption is inversely associated with risk of heart failure, with the largest inverse association observed for consumption of 4 servings per day.

Visit-to-Visit Variability of Blood Pressure and Cardiovascular Disease and All-Cause Mortality A Systematic Review and Meta-Analysis

Visit-to-visit variability of blood pressure (BP) has been associated with cardiovascular disease (CVD) and mortality in some but not all studies. We conducted a systematic review and meta-analysis to examine the association between visit-to-visit variability of BP and CVD and all-cause mortality. Medical databases were searched through June 4, 2014, for studies meeting the following eligibility criteria: adult participants; BP measurements at ≥3 visits; follow-up for CVD, coronary heart disease, stroke, or mortality outcomes; events confirmed via database, death certificate, or event ascertainment committee; and adjustment for confounders. Data were extracted by 2 reviewers and pooled using a random-effects model. Overall, 8870 abstracts were identified of which 37 studies, representing 41 separate cohorts, met inclusion criteria. Across studies, visit-to-visit variability of systolic BP and diastolic BP showed significant associations with outcomes in 181 of 312 (58.0%) and 61 of 188 (32.4%) analyses, respectively. Few studies provided sufficient data for pooling risk estimates. For each 5 mm Hg higher SD of systolic BP, the pooled hazard ratio for stroke across 7 cohorts was 1.17 (95% confidence interval [CI], 1.07–1.28), for coronary heart disease across 4 cohorts was 1.27 (95% CI, 1.07–1.51), for CVD across 5 cohorts was 1.12 (95% CI, 0.98–1.28), for CVD mortality across 5 cohorts was 1.22 (95% CI, 1.09–1.35), and for all-cause mortality across 4 cohorts was 1.20 (95% CI, 1.05–1.36). In summary, modest associations between visit-to-visit variability of BP and CVD and all-cause mortality are present in published studies. However, these findings are limited by the small amount of data available for meta-analysis.

Visit-to-Visit Variability of Blood Pressure and Coronary Heart Disease, Stroke, Heart Failure, and Mortality: A Cohort Study

Context It is not clear whether variability in a patients outpatient blood pressure (BP) measurements has prognostic importance. Contribution Patients with greater visit-to-visit variability in BP readings had an increased risk for cardiovascular events and mortality, which was independent of their overall degree of BP control. Implication Further studies are warranted to assess whether reducing visit-to-visit BP variations will alter the risk for adverse cardiovascular outcomes. The prognostic value of blood pressure (BP) is mainly based on measurements obtained in a clinical setting, typically from a few visits (1). Until recently, variability of BP across outpatient visits was dismissed as random fluctuation around a patients true underlying BP (2, 3). Although some studies have reported associations between higher visit-to-visit variability (VVV) of systolic BP (SBP) and an increased risk for stroke and coronary heart disease (CHD), other analyses have failed to show such associations (410). The method applied in estimating VVV of BP varied widely across previous studies. In addition, studies have used as few as 3 visits and as many as 56 visits to estimate the VVV of BP, and the time between visits has ranged from 2 days to as long as 4 years (5, 11, 12). These factors not only influence VVV of BP but could also affect the strength of its association with cardiovascular disease (CVD) outcomes (4, 13). To address the inconsistent findings from previous studies, we did a secondary data analysis of ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) to examine whether VVV of BP is associated with CVD and mortality events. ALLHAT provides the opportunity to evaluate the association between VVV of BP and major clinical outcomes in a large and diverse population with hypertension in which visits were conducted at set time intervals, BP was measured by following a standardized protocol, and outcomes were evaluated over several years of follow-up. Methods Study Design We did a cohort study as a secondary analysis using data from ALLHAT. Figure 1 shows the timeline for assessment of VVV of BP and outcome events within ALLHAT. The primary exposure of interest, VVV of SBP, was ascertained at the 7 study visits conducted between 6 and 28 months after randomization. We studied 4 outcomes: fatal CHD or nonfatal myocardial infarction (MI), all-cause mortality, stroke, and heart failure. Participants were followed from their 28-month visit until the occurrence of an outcome event or the end of active ALLHAT follow-up (October 2001 to March 2002). Participants who had an event before their 28-month visit were excluded from all analyses. Figure 1. Study design evaluating the association between VVV of BP and cardiovascular outcomes and all-cause mortality in ALLHAT. ALLHAT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; BP = blood pressure; DBP = diastolic blood pressure; SBP = systolic blood pressure; VVV = visit-to-visit variability. * Participants were followed for a mean of 2.7 to 2.9 y (maximum, 5.7 y) depending on the outcome after assessment of VVV of BP. ALLHAT was a multicenter, double-blind, randomized clinical trial sponsored by the National Heart, Lung, and Blood Institute of the National Institutes of Health. A complete description of the rationale and design of ALLHAT has been previously published (14). In brief, ALLHAT was designed to determine whether treatment initiated with a calcium-channel blocker (amlodipine), angiotensin-converting enzyme inhibitor (lisinopril), or -blocker (doxazosin)each compared with treatment initiated with a diuretic (chlorthalidone)would lower major cardiovascular outcomes. The primary end point was incidence of fatal CHD or nonfatal MI. A total of 42418 hypertensive adults aged 55 years or older with 1 or more additional risk factor for CVD were enrolled at 623 clinical sites across the United States, Canada, Puerto Rico, and the U.S. Virgin Islands between February 1994 and January 1998. The doxazosin treatment group was discontinued in 2000 because of the small chance of finding a benefit on CHD outcomes and an increased risk for CVD than in the chlorthalidone group (15). The main results comparing participants randomly assigned to chlorthalidone, amlodipine, or lisinopril were published in December 2002 (16). The trial was approved by local institutional review boards, and all participants provided written informed consent. Our current analysis was approved by the Institutional Review Board at the University of Alabama at Birmingham. Study Visits, BP Measurements, and Calculation of VVV of BP To calculate intraindividual VVV of SBP and diastolic BP (DBP), we used data from 7 follow-up visits that occurred 6, 9, 12, 16, 20, 24, and 28 months after randomization. We chose to begin the assessment period at the 6-month follow-up visit to avoid confounding by the initial reduction in BP that occurred between randomization and this visit (SBP, 6 to 10 mm Hg; DBP, approximately 5 mm Hg) due to early medication titration. To increase the precision of estimates, we calculated VVV of BP for participants with BP measurements at 5, 6, or 7 visits conducted between month 6 and 28 after randomization. The VVV of BP was imputed for participants who attended fewer than 5 visits between months 6 and 28. To maximize follow-up time, we did not extend the assessment past the 28-month follow-up visit. At each follow-up visit, BP was measured twice by a trained observer by means of a standardized technique (17). Using the average BP at each visit, we defined VVV of BP by the intraindividual SD across visits. Average real variability (ARV) and SD independent of the mean (SDIM) were calculated as alternative metrics for VVV of BP (Appendix Figure) (18). The VVV of DBP was also calculated in secondary analyses. Appendix Figure. Formulas used to calculate VVV of BP metrics. ARV = average real variability; BP = blood pressure; SDIM = SD independent of the mean; VVV = visit-to-visit variability. Outcome Ascertainment We studied 4 outcomes, including fatal CHD or nonfatal MI, all-cause mortality, stroke, and heart failure. The event ascertainment process is detailed elsewhere (14, 16). Participants were followed from the end of the assessment period to the date of each outcome, their date of death, or the end of active ALLHAT follow-up (1 October 2001 through 31 March 2002). Covariate Information Covariates used for adjustment were selected a priori on the basis of their potential role as confounders. Baseline (before randomization) variables included age, sex, race/ethnicity, education, current cigarette smoking status, body mass index, use of aspirin, high-density lipoprotein cholesterol level less than 0.91 mmol/L (<35 mg/dL) (at 2 occasions in the 5 years before ALLHAT enrollment), total cholesterol level, estimated glomerular filtration rate (eGFR), diabetes, history of MI or stroke, documentation of other atherosclerotic CVD, history of revascularization, atrial fibrillation by electrocardiography, left ventricular hypertrophy (LVH), the presence of ST depression and T-wave inversion, and use of antihypertensive medication before ALLHAT randomization. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation (19). Data collected at visits conducted 6 to 28 months after randomization were used to calculate mean SBP and DBP; pulse pressure; the use of antihypertensive medications beyond the randomization drug; changes in antihypertensive medication regimen (adding, stopping, or changing antihypertensive medications); use of statins; and low adherence, which is defined as a report of a participant receiving less than 80% of the randomization drug at any visit between months 6 and 28. Participants who reported taking 80% or more of their randomization drug at every visit between months 6 and 28 were considered to have high adherence. Statistical Analysis Because of limited follow-up available after the assessment period for participants randomly assigned to receive doxazosin, we restricted our analyses to the 33357 ALLHAT participants randomly assigned to receive chlorthalidone, amlodipine, or lisinopril. We excluded 7543 participants who had CVD events or died before the 28-month visit. We imputed VVV of BP for participants with fewer than 5 visits and BP measurements between months 6 and 28 of follow-up. In addition, missing data for covariates were imputed (Appendix Table 1). Imputation was performed with 10 data sets using chained equations. Appendix Table 1. Percentage of Missing Data for Participants Included in the Current Analyses Characteristics of participants included in the current analyses were calculated after participants were stratified into a quintile of SD of SBP. The KaplanMeier method was used to calculate the cumulative incidence of each outcome by quintile of SD of SBP. Cox proportional hazards regression was used to calculate multivariable-adjusted hazard ratios (HRs) for each outcome associated with a quintile of SD of SBP, with the lowest quintile serving as the reference. Four nested models were constructed. Model 1 included adjustment for age, race/ethnicity, sex, region of residence, and antihypertensive randomization assignment. Model 2 includes the variables in model 1 and additional adjustment for education, smoking status, body mass index, use of aspirin, low high-density lipoprotein cholesterol level, total cholesterol level, eGFR, diabetes, history of MI or stroke, history of other atherosclerotic CVD, history of coronary revascularization, atrial fibrillation by electrocardiography, major ST depression or T-wave inversion, LVH, use of antihypertensive medications before ALLHAT randomization, and statin use during the assessment period (months 6 through 28 of follow-up). Model 3 includes the variables in model 2 and additional adjustment for mean pulse pressure, medic

Adiposity and Incidence of Heart Failure Hospitalization and Mortality: A Population-based Prospective Study

Background—Obesity is associated with heart failure (HF) incidence. We examined the strength of the association of body mass index (BMI) with HF by age and joint associations of BMI and waist circumference (WC). Methods and Results—Women aged 48 to 83 (n=36 873) and men aged 45 to 79 (n=43 487) self-reported height, weight, and WC. HF hospitalization or death (n=382 women, 718 men) between January 1, 1998, and December 31, 2004, was determined through administrative registers. Hazard ratios, from Cox proportional-hazards models, for an interquartile range higher BMI were 1.39 (95% CI, 1.15 to 1.68) at age 60 and 1.13 (95% CI, 1.02 to 1.27) at 75 in women. In men, hazard ratios were 1.54 (95% CI, 1.37 to 1.73) at 60 and 1.25 (95% CI, 1.16 to 1.35) at 75. A 10-cm higher WC was associated with 15% (95% CI, 2% to 31%) and 18% (95% CI, 4% to 33%) higher HF rates among women with BMI 25 and 30 kg/m2, respectively; hazard ratios for 1 kg/m2 higher BMI were 1.00 (95% CI, 0.96 to 1.04) and 1.01 (95% CI, 0.98 to 1.04) for WC 70 and 100 cm, respectively. In men, a 10-cm higher WC was associated with 16% and 18% higher rates for BMI 25 and 30 kg/m2, respectively; a 1 kg/m2 higher BMI was associated with 4% higher HF rates regardless of WC. Conclusions—Strength of the association between BMI and HF events declined with age. In women, higher WC was associated with HF at all levels of BMI. Both BMI and WC were predictors among men.

Fish consumption, marine omega-3 fatty acids, and incidence of heart failure: a population-based prospective study of middle-aged and elderly men.

AIMS Fatty fish and marine omega-3 fatty acids were associated with lower rates of heart failure (HF) among US elderly, but this has not been confirmed in broader age ranges or other populations where source and type of fish may differ. We therefore conducted a population-based, prospective study of 39 367 middle-aged and older Swedish men. METHODS AND RESULTS Diet was measured using food-frequency questionnaires. Men were followed for HF through Swedish inpatient and cause-of-death registers from 1 January 1998 to 31 December 2004. We used proportional hazards models adjusted for age and other covariates to estimate hazard ratios (HR). Compared with no consumption, men who ate fatty fish once per week had an HR of 0.88 (95% CI 0.68-1.13). Hazard ratios for consumption two times per week and > or =3 times per week were 0.99 and 0.97, respectively. Hazard ratios across quintiles of marine omega-3 were 1, 0.94 (95% CI 0.74-1.20), 0.67 (95% CI 0.50-0.90), 0.89 (95% CI 0.68-1.16), 1.00 (95% CI 0.77-1.29). CONCLUSION In this population, moderate intake of fatty fish and marine omega-3 fatty acids was associated with lower rates of HF, though the association for fish intake was not statistically significant; higher intake was not associated with additional benefit.