Cardiovascular risk prediction models based on classical risk factors identified in epidemiologic cohort studies are useful in primary prevention of cardiovascular disease in individuals. This article briefly reviews aspects of cardiovascular risk prediction in the United States and efforts to evaluate novel risk factors. Even though many novel risk markers have been found to be associated with cardiovascular disease, few appear to improve risk prediction beyond the powerful, classical risk factors. A recent US consensus panel concluded that clinical measurement of certain novel markers for risk prediction was reasonable, namely, hemoglobin A1c (in all adults), microalbuminuria (in patients with hypertension or diabetes), and C-reactive protein, lipoprotein-associated phospholipase, coronary calcium, carotid intima-media thickness, and ankle/brachial index (in patients deemed to be at intermediate cardiovascular risk, based on traditional risk factors).
risk factors; coronary disease; cardiovascular disease; epidemiology
To evaluate the associations of high sensitivity Troponin T (Hs-TnT), N-terminal pro-brain natriuretic peptide (NT-proBNP), and high sensitivity C-reactive protein (Hs-CRP) with mortality from any cause, cardiovascular disease (CVD), coronary heart disease (CHD), stroke, cancer, and respiratory disease in the Atherosclerosis Risk in Communities (ARIC) cohort.
11193 participants aged 54-74 years, initially free of the conditions being studied, had biomarkers measured and were followed for a mean of 9.9 years.
Hazard ratios (HR), adjusted for multiple risk factors, for mortality in participants in the highest Hs-TnT category compared to those with undetectable levels were: total 3.42 (95% Confidence Interval: 2.75-4.26), CVD 7.34 (4.64-11.6), CHD 6.06 (2.91-12.6), stroke 3.31 (1.26-8.66), cancer 1.60 (1.08-2.38) and respiratory 3.85 (1.39-10.7). Comparing the highest NT-proBNP quintile to those in the lowest quintile, the adjusted HRs for mortality were: total 3.05 (2.46-3.77), CVD 7.48 (4.67-12.0), CHD 4.07 (2.07-7.98) and stroke 10.4 (2.26-47.7). Comparing extreme Hs-CRP quintiles, the adjusted HRs for mortality were: total 1.61 (1.32-1.97), CVD 1.76 (1.19-2.62) and respiratory 3.36 (1.34-8.45). Having multiple markers elevated simultaneously greatly increased cause-specific mortality risks.
Greater levels of Hs-TnT, NT-proBNP and Hs-CRP are associated with increased risk of death, not just from cardiovascular disease but also from some non-cardiovascular causes.
biomarkers; troponin T; B natriuretic peptide; C- reactive protein; mortality
Diabetes is a risk factor for many cancers; chronic hyperglycemia is hypothesized to be, in part, explanatory. We evaluated the association between glycated hemoglobin, a time-integrated glycemia measure, and cancer incidence and mortality in non-diabetic and diabetic men and women. We conducted a prospective study of 12,792 cancer-free participants attending the second visit (1990–1992) of the Atherosclerosis Risk in Communities (ARIC) Study. We measured glycated hemoglobin in whole-blood samples using HPLC. Incident cancers were ascertained from registries and hospital records through 2006. We estimated multivariable-adjusted hazard ratios (HR) of cancer incidence and mortality for non-diabetic participants with values ≥5.7% (elevated), non-diabetic participants with <5.0% (low), and diabetic participants all compared with non-diabetic participants with 5.0–5.6% (normal). We ascertained 2,349 incident cancer cases and 887 cancer deaths. Compared with non-diabetic women with normal glycated hemoglobin, non-diabetic women with elevated values had an increased risk of cancer incidence (HR:1.24; 95% CI:1.07,1.44) and mortality (HR:1.58; 95% CI:1.23,2.05) as did diabetic women (incidence, HR:1.30; 95% CI:1.06,1.60, mortality, HR:1.96; 95% CI:1.40,2.76). Non-diabetic women with low values also had increased risk. Diabetic women with good glycemic control (<7.0%) had a lower cancer risk than those with higher values. Glycated hemoglobin in non-diabetic and diabetic men, and diabetes were not statistically significantly associated with total cancer risk. Our findings support the hypothesis that chronic hyperglycemia, even in the non-diabetic range, increases cancer risk in women. Maintaining normal glycated hemoglobin overall, and good glycemic control among diabetic adults, may reduce the burden of cancer, especially in women.
glycated hemoglobin; diabetes; cancer incidence; cancer mortality
Individual participant time-to-event data from multiple prospective epidemiologic studies enable detailed investigation into the predictive ability of risk models. Here we address the challenges in appropriately combining such information across studies. Methods are exemplified by analyses of log C-reactive protein and conventional risk factors for coronary heart disease in the Emerging Risk Factors Collaboration, a collation of individual data from multiple prospective studies with an average follow-up duration of 9.8 years (dates varied). We derive risk prediction models using Cox proportional hazards regression analysis stratified by study and obtain estimates of risk discrimination, Harrell's concordance index, and Royston's discrimination measure within each study; we then combine the estimates across studies using a weighted meta-analysis. Various weighting approaches are compared and lead us to recommend using the number of events in each study. We also discuss the calculation of measures of reclassification for multiple studies. We further show that comparison of differences in predictive ability across subgroups should be based only on within-study information and that combining measures of risk discrimination from case-control studies and prospective studies is problematic. The concordance index and discrimination measure gave qualitatively similar results throughout. While the concordance index was very heterogeneous between studies, principally because of differing age ranges, the increments in the concordance index from adding log C-reactive protein to conventional risk factors were more homogeneous.
C index; coronary heart disease; D measure; individual participant data; inverse variance; meta-analysis; risk prediction; weighting
This study evaluated the prevalence of ideal cardiovascular (CV) health in the Atherosclerosis Risk in Communities Study and determined its relationship with prevalent retinopathy, wider retinal venular diameters, and narrower arteriolar diameters, which are risk markers for subclinical cerebrovascular disease and are associated with increased stroke and coronary heart disease (CHD) morbidity and mortality.
Methods and Results
We used gradings of fundus photography measurements from the Atherosclerosis Risk in Communities Study to examine the association of retinopathy and retinal arteriolar and venular calibers to the number of ideal CV health metrics. Prevalent retinopathy showed a graded relationship with the CV health categories and number of ideal CV health metrics present: retinopathy prevalence was 2.1% among those with ≥5 ideal CV health metrics compared with 13.1% among those with zero ideal CV health metrics (odds ratio [CI]), 4.8 [2.5 to 8.9]). Central retinal venule equivalent and central retinal arteriolar equivalent diameters also showed graded relationships with CV health categories and number of ideal CV health metrics: after adjustment for age, race, sex, and education, mean central retinal venular equivalent was 187.8 μm (95% CI, 186.9 to 188.6 μm) among those with ≥5 ideal CV health metrics compared with 201.1 μm (95% CI, 199.1 to 203.1 μm) among those with zero ideal CV health metrics. Mean central retinal arteriolar equivalent was 163.8 μm (95% CI, 163.0 to 164.5 μm) among those with ≥5 ideal CV health metrics compared with 157.9 μm (95% CI, 156.1 to 159.7 μm) among those with zero ideal CV health metrics.
Few adults had ideal cardiovascular health. Those with the best level of health were less likely to have retinopathy signs, wide retinal venules, and narrow retinal arterioles, which are associated with increased stroke and coronary heart disease risk.
cardiovascular diseases; cardiovascular health metrics; cerebrovascular circulation; epidemiology; risk factors
The SNP rs11628722 in the SERPINA9 gene was previously associated with incident ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study. Centerin, the protein encoded by SERPINA9, is involved in maturation and maintenance of naïve B cells, which play a role in atherogenesis. We investigated whether 21 tag SNPs in the SERPINA9 gene are associated with features of carotid artery atherosclerotic plaque measured by magnetic resonance imaging (MRI). Carotid MRI data were obtained from 1,282 European Americans and 341 African Americans of the ARIC Carotid MRI study, which recruited participants from ARIC by a stratified sampling plan that over-sampled participants with carotid intima-media thickening. Five MRI measures, focused on carotid wall volume, wall thickness, and lipid core, were analyzed. Genetic associations between the MRI measurements and each of the 21 SNPs were analyzed in linear regression models with adjustment for sample weights and traditional risk factors. Rs11628722 was tested a priori. In African Americans, rs11628722 was significantly associated with carotid wall volume (p < 0.05). Among the other 20 SNPs, adjusted for multiple testing, rs4905204, which encodes an Ala to Val amino acid change, was significantly associated with maximum wall thickness (p < 0.000625) and suggestively associated with total wall volume (p < 0.0026) in European Americans. In conclusion, SNPs in the SERPINA9 gene showed race-specific associations with characteristics of carotid atherosclerotic plaques. Replications in other populations are needed to validate findings of this study and to establish the SERPINA9 gene as a candidate in the etiology of carotid atherosclerosis.
SERPINA9 gene; carotid atherosclerosis; MRI; genetic association
To determine whether the 9p21 SNP association with coronary heart disease is modified by other classical or novel risk markers.
The 9p21 SNP (rs10757274) and multiple risk markers were measured in the Atherosclerosis Risk in Communities Study, and incident coronary disease events were ascertained. Effect modification (interaction) of the 9p21 SNP with risk markers was tested in Cox proportional hazard regression models.
The incidence rates of coronary heart disease per 1000 person-years were 14.4, 17.0, and 18.7 for AA, AG, and GG genotypes, yielding hazard ratios of 1.0, 1.20 (95% CI = 1.07-1.36), and 1.34 (95% CI = 1.16-1.53). There was no meaningful evidence of an interaction (all p-interaction > 0.04) between 9p21 SNP and any of 14 other risk markers for coronary heart disease. These included novel markers not previously explored for 9p21 interaction (e.g., cardiac troponin T and N-terminal pro-brain natriuretic peptide).
Our study extends evidence that the 9p21 SNP association with coronary heart disease is not modified by classical or novel risk markers. Our findings therefore rule out additional plausible pathways by which 9p21 might have increased coronary heart disease risk.
coronary disease; prospective study; 9p21 SNP
Apart from obesity, it remains controversial whether atherosclerosis and its cardiovascular risk disease (CVD) factors are associated with risk of venous thromboembolism (VTE). Using data from the Atherosclerosis Risk in Communities study (ARIC), we evaluated associations between CVD risk factors and incident VTE in a cohort of 15,340 participants who were free a history of VTE and/or anticoagulant use on enrolment. The CVD risk factors were updated during the follow-up period. Over a mean follow-up time of 15.5 years (237,375 person-years), 468 participants had VTE events. Adjusting for demographic variables and body mass index (BMI), current smokers were at greater risk [HR of 1.44 (95% CI: 1.12–1.86)] compared to non-smokers. There was a positive monotonic association between BMI and VTE risk. Individuals with a BMI ≥35 kg/m2 had a HR for VTE of 3.09 (95%CI: 2.26–4.23) compared to those with normal BMI (<25 kg/m2). Greater physical activity was associated with lower VTE risk in a demographic adjusted model; however, this association became non-significant following adjustment for BMI. Alcohol intake, diabetes, hypertension, high-density lipoprotein and low-density lipoprotein cholesterol, and triglycerides were not associated with VTE risk. In conclusion, among the well-established CVD risk factors, only current smoking and obesity were independently associated with VTE risk in this large cohort where risk factors were updated serially during follow-up. This finding corroborates that the pathogenesis of venous disease differs from that of atherosclerotic disease.
Deep-vein thrombosis; pulmonary embolism; risk factors
Based on studies with limited statistical power, lipoprotein(a) [Lp(a)] is not considered a risk factor for cardiovascular disease (CVD) in African Americans. We evaluated associations between Lp(a) and incident CVD events in African Americans and Caucasians in the Atherosclerosis Risk in Communities (ARIC) study.
Methods and Results
Plasma Lp(a) was measured in African Americans (n=3,467) and Caucasians (n=9,851). Hazards ratios (HRs) for incident CVD events (coronary heart disease [CHD] and ischemic strokes) were calculated. Lp(a) levels were higher with wider interindividual variation in African Americans (median [interquartile range]: 12.8 [7.1–21.7] mg/dl) than Caucasians (4.3 [1.7–9.5] mg/dl; p <0.0001). At 20 years of follow-up, 676 CVD events occurred in African Americans and 1,821 events occurred in Caucasians. Adjusted HRs (95% confidence interval [CI]) per race-specific 1-SD–greater log-transformed Lp(a) were 1.13 (1.04–1.23) for incident CVD, 1.11 (1.00–1.22) for incident CHD, and 1.21 (1.06–1.39) for ischemic strokes in African Americans. For Caucasians, the respective HRs (95% CIs) were 1.09 (1.04–1.15), 1.10 (1.05–1.16), and 1.07 (0.97–1.19). Quintile analyses showed that risk for incident CVD was graded but statistically significant only for the highest compared with the lowest quintile (HR [95%CI] 1.35 [1.06–1.74] for African Americans; HR 1.27 [1.10–1.47] for Caucasians). Similar results were obtained using Lp(a) cut-offs of ≤10 mg/dl, >10–≤20 mg/dl, >20–≤30 mg/dl, and >30 mg/dl.
Lp(a) levels were positively associated with CVD events. Associations were at least as strong, with a larger range of Lp(a) concentrations, in African Americans compared with Caucasians.
lipoproteins; cardiovascular diseases; risk factors; race/ethnicity; cardiovascular disease risk factors
Sex steroid hormones have been postulated to involve in blood pressure (BP) regulation. We examine the association of endogenous sex hormone levels with longitudinal change of BP and risk of developing hypertension in initially normotensive postmenopausal women.
We conducted prospective analysis among 619 postmenopausal women free of hypertension at baseline in the Multi-Ethnic Study of Atherosclerosis (MESA). Change of BP and development of incident hypertension were assessed during a mean of 4.8 years follow-up.
After adjusting for age, race/ethnicity, and lifestyle factors, baseline serum estradiol (E2), total and bioavailable testosterone (T), dehydroepiandrosterone (DHEA) were each positively and sex- hormone binding globulin (SHBG) was inversely associated with risk of hypertension. Additional adjustment for body mass index eliminated the associations for E2 and T but only attenuated the associations for DHEA and SHBG. The corresponding multivariable hazard ratios (95% CIs) in the highest quartile were 1.28 (0.83–1.97) for E2, 1.38 (0.89–2.14) for total T, 1.42 (0.90–2.23) for bioavailable T, 1.54 (1.02–2.31) for DHEA, and 0.48 (0.30–0.76) for SHBG. Adjustment for fasting glucose, insulin, and C-reactive protein further attenuated the association for DHEA but not SHBG. Associations of sex hormones with longitudinal BP change were similar.
In postmenopausal women, higher endogenous E2, T, and DHEA and lower SHBG were associated with higher incidence of hypertension and greater longitudinal rise in BP. The associations for E2, T, and DHEA were mostly explained by adiposity, while the association for SHBG was independent of measures of adiposity, insulin resistance, and systemic inflammation.
sex steroid hormones; hypertension; blood pressure; postmenopausal women; prospective study; epidemiology
The incidence of venous thromboembolism (VTE) is increased in patients with albuminuria. However, whether a low serum albumin concentration is associated with increased risk of VTE has been a matter of controversy. We determined the association of serum albumin with VTE incidence in two large, prospective, population-based cohorts: the Atherosclerosis Risk in Communities (ARIC) Study (n = 15,300) and the Cardiovascular Health Study (CHS) (n = 5,400). Validated VTE occurrence (n=462 in ARIC and n=174 in CHS) was ascertained during follow-up. In both studies, after adjustment for age, sex, race, use of hormone replacement therapy, estimated GFR, history of cancer, and diabetes, serum albumin tended to be associated inversely with VTE. The adjusted hazard ratio per standard deviation lower albumin was 1.18 (95% CI = 1.08, 1.31) in ARIC and 1.10 (95% CI = 0.94, 1.29) in CHS. The hazard ratio for albumin below (versus above) the fifth percentile was 1.28 (95% CI = 0.90, 1.84) in ARIC and 1.80 (95% CI = 1.11, 2.93) in CHS. In conclusion, low serum albumin was a modest marker of increased VTE risk. The observed association likely does not reflect cause and effect, but rather that low serum albumin reflects a hyperinflammatory or hypercoagulable state. Whether this association has clinical relevance warrants further study.
albumin; prospective study; pulmonary embolism; venous thrombosis
Since few studies have examined the associations of plasma levels of coagulation factors II, V, IX, X, XI, XII, plasminogen, or α-2 antiplasmin with coronary heart disease (CHD), we sought to examine the associations of these factors with incident CHD in a prospective case-cohort study.
This case-cohort sample consisted of 368 African-American or white incident CHD cases that occurred between 1990–92 and 1998 in the Atherosclerosis Risk in Communities (ARIC) study, and a cohort random sample of n=412. Hemostatic factors were measured in the case-cohort sample using plasma stored at −70°C since 1990–92.
After adjustment for age, sex and race, coagulation factors IX and XI, and α-2 antiplasmin were associated positively with risk of CHD: The hazard ratio [95% confidence interval] for the highest vs lowest quartiles was 1.52 [1.01–2.27] for factor IX; 2.26 [1.47–3.48] for factor XI; and 1.64 [1.05–2.57] for α-2 antiplasmin. However, these hemostatic factors were correlated with classical risk factors, so that after multivariable adjustment their associations with CHD were attenuated and no longer statistically significant. No associations were observed between CHD and factors II, V, X, XII, or plasminogen.
Positive associations of factors IX and XI, and α-2 antiplasmin with incident CHD were not strong and were accounted for by classical coronary risk factors. (213 words/250 limits)
epidemiology; cardiovascular disease; ischemic disease; fibrinolytic factors; blood clotting
Decades-old animal experiments suggested dietary long-chain monounsaturated fatty acids (LCMUFA) caused cardiotoxicity, leading, for example, Canada to develop Canadian-oil-low-in-erucic-acid (Canola) from rapeseed. However, potential cardiotoxicity in humans and contemporary dietary sources of LCMUFA are unknown.
Methods and Results
We prospectively investigated associations of plasma phospholipid LCMUFA (20:1, 22:1, and 24:1), objective biomarkers of exposure, with incidence congestive heart failure (CHF) in two independent cohorts: 3,694 older adults (mean age=75.2±5.2 years) in the Cardiovascular Health Study (CHS, 1992–2006), and 3,577 middle-aged adults (mean age=54.1±5.8 years) in the Atherosclerosis Risk in Communities Study Minnesota subcohort (ARIC, 1987–2008). We further examined dietary correlates of circulating LCMUFA in CHS and ARIC, and US dietary sources of LCMUFA in the 2003–2010 National Health and Nutrition Examination Survey (NHANES). In CHS, 997 CHF events occurred during 39,238 person-years; and in ARIC, 330 events during 64,438 person-years. After multivariable-adjustment, higher levels of 22:1 and 24:1 were positively associated with greater incident CHF in both CHS and ARIC: hazard ratios (95% confidence interval)=1.34 (1.02–1.76) and 1.57 (1.11–2.23) for highest vs. lowest quintiles of 22:1, respectively; and 1.75 (1.23–2.50) and 1.92 (1.22–3.03) for 24:1, respectively (P-trend≤0.03 each). A variety of foods related to circulating LCMUFA in CHS and ARIC, consistent with food sources of LCMUFA in NHANES, including fish, poultry, meats, whole grains, and mustard.
Higher circulating levels of 22:1 and 24:1, with apparently diverse dietary sources, were associated with incident CHF in two independent cohorts, suggesting possible cardiotoxicity of LCMUFA in humans.
congestive heart failure; fatty acids; diet; epidemiology
The role of inflammation in the causation of venous thromboembolism (VTE) is uncertain. In 10,505 participants of the Atherosclerosis Risk in Communities (ARIC) Study, we assessed the association of the systemic inflammation marker, elevated C-reactive protein (CRP), with incidence of VTE (n=221) over a median of 8.3 years of follow-up. Adjusted for age, race, and sex, the hazard ratios of VTE across quintiles of CRP were 1.0, 1.61, 1.16, 1.56, and 2.31 (p for trend p<0.0007). For CRP above the upper 10 percentile (≥8.55 mg/L), compared with the lowest 90% of CRP values, the hazard ratio of VTE was 2.07 (95% CI 1.47, 2.94). Further adjustment for baseline hormone replacement therapy, diabetes, and body mass index attenuated the hazard ratios only slightly. For example, the adjusted hazard ratio of VTE was 1.76 (95% CI 1.23, 2.52) for CRP above versus below the 90th percentile. In conclusion, this prospective, population-based study suggests elevated CRP is independently associated with increased risk of VTE.
C-reactive protein; prospective study; pulmonary embolus; venous thrombosis
The authors sought to examine the relation between serum or dietary magnesium and the incidence of ischemic stroke among blacks and whites. Between 1987 and 1989, 14,221 men and women aged 45–64 years took part in the first examination of the Atherosclerosis Risk in Communities Study cohort. The incidence of stroke was ascertained from hospital records. Higher serum magnesium levels were associated with lower prevalence of hypertension and diabetes mellitus at baseline. During the 15-year follow-up, 577 ischemic strokes occurred. Serum magnesium was inversely associated with ischemic stroke incidence. The age-, sex-, and race-adjusted rate ratios of ischemic stroke for those with serum magnesium levels of ≤1.5, 1.6, 1.7, and ≥1.8 mEq/L were 1.0, 0.78 (95% confidence interval (CI): 0.62, 0.96), 0.70 (95% CI: 0.56, 0.88), and 0.75 (95% CI: 0.59, 0.95) (Ptrend = 0.005). After adjustment for hypertension and diabetes, the rate ratios were attenuated to nonsignificant levels. Dietary magnesium intake was marginally inversely associated with the incidence of ischemic stroke (Ptrend = 0.09). Low serum magnesium levels could be associated with increased risk of ischemic stroke, in part, via effects on hypertension and diabetes.
brain infarction; diet; magnesium; risk factors
Venous thromboembolism (VTE) recurs frequently. Greater height is associated with increased risk of incident VTE, but it is unclear if height is related to risk of VTE recurrence. Recurrent VTE is associated with substantial morbidity and mortality, thus identifying individuals at greatest risk of experiencing a recurrent event, who may benefit from extended anticoagulant therapy, is vitally important. Using data from the Iowa Women’s Health Study we explored whether greater height was associated with increased risk of VTE recurrence. Among 1691 women who experienced an initial VTE event 286 (16.9%) experienced a recurrent event. Risk of recurrence was 76% (95% CI: 16%–186%) higher among women ≥66 inches [~168 centimeters] tall relative to those ≤62 inches [~158 centimeters] tall, after adjustment for age and waist circumference. Future research should evaluate whether body height improves clinical prediction of VTE recurrence risk.
We hypothesized that women with early- and mid-adult life obesity, as well as high mid-adult life waist-to-hip ratios, and high weight gain during adulthood, experience a greater incidence of gout.
We examined the incidence of gout in the Atherosclerosis Risk in Communities (ARIC) Study, a population-based biracial cohort comprised of individuals aged 45–65 years of age at baseline (1987–1989). A total of 6,263 women without prior history of gout were identified. We examined the association of BMI and obesity at cohort entry and at age 25 years, waist-to-hip ratio and weight change, with gout incidence (1996–1998).
Over 9 years of follow-up, 103 women developed gout. The cumulative incidence of gout, by age 70 years, according to BMI category at baseline of <25, 25–29.9, 30–34.9, and ≥ 35 kg/m2, was 1.9, 3.6, 7.9, and 11.8%, respectively (P <0.001). Obese women (BMI≥30) at baseline had an adjusted 2.4-fold greater risk of developing gout than non-obese women (95% confidence interval (CI) 1.53, 3.68). This association was attenuated after further adjustment for urate levels. Further, early adult obesity in women was associated with a 2.8-fold increased risk of gout compared to non-obese women (95% CI 1.33, 6.09), which remained statistically significant after baseline urate adjustment. There was a graded association between each anthropometric measure, including weight gain, with incident gout (each P for trend <0.001). The results were similar in black and white women.
In a large cohort of African American and Caucasian women, obesity in early and mid-adulthood, and weight gain during this interval, were each independent risk factors for incident gout in women.
Gout; Women; Obesity; Weight; Arthritis
A simple and effective Heart Failure (HF) risk score would facilitate the primary prevention and early diagnosis of HF in general practice. We examined the external validity of existing HF risk scores, optimized a 10-year HF risk function, and examined the incremental value of several biomarkers, including NT-proBNP.
Methods and Results
During 15.5 years (210,102 person-years of follow-up), 1487 HF events were recorded among 13,555 members of the bi-ethnic Atherosclerosis Risk in Communities (ARIC) Study cohort. The area under curve (AUC) from the Framingham-published, Framingham-recalibrated, Health ABC HF recalibrated, and ARIC risk scores were 0.610, 0.762, 0.783, and 0.797, respectively. Upon addition of NT-pro-BNP, the optimism corrected AUC of the ARIC HF risk score increased from 0.773 (95% CI: 0.753 – 0.787) to 0.805 (95% CI: 0.792 – 0.820). Inclusion of NT-proBNP improved the overall classification of re-calibrated Framingham, re-calibrated Health ABC, and ARIC risk scores by 18%, 12%, and 13%, respectively. In contrast, Cystatin C or hs-CRP did not add towards incremental risk prediction.
The ARIC HF risk score is more parsimonious yet performs slightly better than the extant risk scores in predicting 10-year risk of incident HF. The inclusion of NT-proBNP markedly improves HF risk prediction. A simplified risk score restricted to a patient’s age, race, gender, and NT-proBNP performs comparably to the full score (AUC = 0.745), and is suitable for automated reporting from laboratory panels and electronic medical records.
heart failure; risk prediction; external validation; NT-proBNP; Cystatin C; hs-CRP; biomarkers
We hypothesized that variants in PCSK9 that lower LDL cholesterol levels are associated with reduced prevalence and incidence of peripheral artery disease (PAD).
The Atherosclerosis Risk in Communities (ARIC) Study assessed risk factors and PCSK9 variants Y142X and C679X (relevant to blacks) and R46L (relevant to whites) in a cohort of 45-64 year olds in 1987-89 (n=13,634). Prevalent PAD (n=619 cases) was defined by an ankle-brachial index <0.9 or a history of leg claudication. Incident PAD (n=895) was identified from 1987 through 1998 by the same PAD criteria or a PAD hospitalization.
As expected, greater LDL cholesterol was a risk factor for prevalent and incident PAD. 2.4% of blacks and 3.1% of whites were carriers of one of the race-specific PCSK9 variants. Carriers had lower prevalence of PAD compared with non-carriers (2.3% vs. 4.6%). The corresponding age- and sex-adjusted odds ratio of PAD was 0.47 (95% confidence interval, 0.24-0.92). In contrast with the cross-sectional findings, there was no association between PCSK9 variants and incident PAD [age- and sex-adjusted hazard ratio, 1.09 (95% confidence interval, 0.76-1.57)].
Our study provides mixed evidence that variation in PCSK9 may contribute to genetic risk of PAD.
Peripheral arterial disease; Prospective study; PCSK9; Total cholesterol; LDL cholesterol
To assess whether markers of acculturation (birthplace, number of U.S. generations) and socioeconomic status (SES) are associated with carotid artery plaque, internal carotid intima-media thickness (IMT), and albuminuria, in four racial/ethnic groups.
Using Multi-Ethnic Study of Atherosclerosis data (n = 6,716; age: 45-84) and race-specific binomial regression models, we computed prevalence ratios, adjusted for demographics and traditional cardiovascular risk factors.
The adjusted U.S. to foreign-born prevalence ratio (99% CI) for carotid plaque was 1.20 (0.97, 1.39) in Whites, 1.91 (0.94, 2.94) in Chinese, 1.62 (1.28, 2.06) in Blacks, and 1.23 (1.15, 1.31) in Hispanics. Greater carotid plaque prevalence was also found among Whites, Blacks, and Hispanics with more generations of US residence (p<0.001). Lower educational attainment and/or income were associated with greater carotid plaque prevalence in Whites and Blacks. Similar associations were observed with IMT. There was also some evidence of an inverse association between albuminuria and SES, in Whites and Hispanics.
Greater U.S. acculturation and lower SES were associated with a higher prevalence of carotid plaque and IMT, while little association was found with albuminuria.
Lp(a); venous thrombosis; pulmonary embolus; risk factors; prospective study; epidemiology
We evaluated whether the addition of carotid intima media thickness and plaque (CIMT-P), and, a single nucleotide polymorphism on chromosome 9p21 (9p21) together improve coronary heart disease (CHD) risk prediction in the ARIC study.
Ten year CHD risk was estimated using the ARIC coronary risk score (ACRS) alone and in combination with CIMT-P and 9p21 individually and together in White participants (n=9338). Area under the receiver operating characteristic curve (AUC), model calibration, net reclassification index (NRI), integrated discrimination index (IDI) and number of individuals reclassified were estimated.
The AUC of the ACRS, ACRS+9p21, ACRS+CIMT-P and ACRS+CIMT-P+9p21 models were 0.748, 0.751, 0.763 and 0.766 respectively. The percentage of individuals reclassified, model calibration, NRI and IDI improved when CIMT-P and 9p21 were added to the ACRS only model (see manuscript).
Addition of 9p21 allele information to CIMT-P minimally improves CHD risk prediction in whites in the ARIC study.
Carotid intima media thickness; Plaque; 9p21; Risk prediction; Coronary heart disease
Dietary intake among other lifestyle factors influence blood pressure. We examined the associations of an “a priori” diet score with incident high normal blood pressure (HNBP; systolic blood pressure (SBP) 120–139 mmHg, or diastolic blood pressure (DBP) 80–89 mmHg and no antihypertensive medications) and hypertension (SBP ≥ 140 mmHg, DBP ≥ 90 mmHg, or taking antihypertensive medication). We used proportional hazards regression to evaluate this score in quintiles (Q) and each food group making up the score relative to incident HNBP or hypertension over nine years in the Atherosclerosis Risk of Communities (ARIC) study of 9913 African-American and Caucasian adults aged 45–64 years and free of HNBP or hypertension at baseline. Incidence of HNBP varied from 42.5% in white women to 44.1% in black women; and incident hypertension from 26.1% in white women to 40.8% in black women. Adjusting for demographics and CVD risk factors, the “a priori” food score was inversely associated with incident hypertension; but not HNBP. Compared to Q1, the relative hazards of hypertension for the food score Q2–Q5 were 0.97 (0.87–1.09), 0.91 (0.81–1.02), 0.91 (0.80–1.03), and 0.86 (0.75–0.98); ptrend = 0.01. This inverse relation was largely attributable to greater intake of dairy products and nuts, and less meat. These findings support the 2010 Dietary Guidelines to consume more dairy products and nuts, but suggest a reduction in meat intake.
diet pattern; healthy food score; hypertension; high normal blood pressure
Guidelines to prevent and treat hypertension advocate the Dietary Approaches to Stop Hypertension (DASH) diet.
We studied whether a greater concordance with the DASH diet is associated with reduced incidence of hypertension (self-reported) and mortality from cardiovascular disease in 20,993 women initially aged 55–69. We created a DASH diet concordance score using food frequency data in 1986 and followed the women for events through 2002.
No woman had perfect concordance with the DASH diet. Adjusted for age and energy intake, incidence of hypertension was inversely associated with the degree of concordance with the DASH diet, with hazard ratios across quintiles of 1.0, 0.91, 0.95, 0.99, and 0.87 (p trend = 0.02). There also were inverse, but not monotonic, associations between better DASH diet concordance and mortality from coronary heart disease, stroke, and all CVD. However, after adjustment for other risk factors, there was little evidence that any endpoint was associated with the DASH diet score.
Our results suggest that greater concordance with DASH guidelines did not have an independent long-term association with hypertension or cardiovascular mortality in this cohort. This implies that very high concordance, as achieved in the DASH trials, may be necessary to achieve the benefits of the DASH diet.
Diet; hypertension; coronary disease; cerebrovascular accident
Knowledge of trends in the incidence of and survival after myocardial infarction (MI) in a community setting is important to understanding trends in coronary heart disease (CHD) mortality rates.
Methods and Results
We estimated race and gender specific trends in the incidence of hospitalized MI, case-fatality and CHD mortality from community-wide surveillance and validation of hospital discharges and of in- and out-of-hospital deaths among 35 to 74 year old residents of four communities in the Atherosclerosis Risk in Communities (ARIC) Study. Biomarker adjustment accounted for change from reliance on cardiac enzymes to widespread use of troponin measurements overtime. Between 1987 and 2008, a total of 30,985 fatal or non-fatal hospitalized acute MI events occurred. Rates of CHD death among persons without a history of MI fell an average 4.7 percent per year among men and 4.3 percent per year among women. Rates of both in- and out-of-hospital CHD death declined significantly throughout the period. Age- and biomarker adjusted average annual rate of incident MI decreased 4.3 percent among white men, 3.8 percent among white women, 2.9 percent among black women, and 1.5 percent among black men. Declines in CHD mortality and MI incidence were greater in the second decade (1997–2008). Failure to account for biomarker shift would have masked declines in incidence, particularly among blacks. Age-adjusted 28-day case-fatality after hospitalized MI declined 4.2 percent per year among white men and 3.6 percent per year among black men, 2.6 percent per year among white women, and 2.4 percent per year among black women.
Although these findings from 4 communities may not directly generalize to blacks and whites in the entire US, we observed significant declines in MI incidence, primarily due to downward trends in rates between 1997 and 2008.
epidemiology; mortality rates; myocardial infarction; surveillance; survival