C-reactive protein and incident coronary heart disease in the Atherosclerosis Risk In Communities (ARIC) study

Background Recent evidence implicates inflammation in the pathogenesis of coronary heart disease (CHD). C-reactive protein, a plasma marker of inflammation, is a marker of CHD risk but has been studied in few prospective investigations of the general population. Methods and Results We prospectively examined the association of CRP with incident CHD among middle-aged adults in the Atherosclerosis Risk In Communities (ARIC) study. With the use of a nested case-cohort approach, we measured CRP in stored, baseline blood samples of 2 groups of subjects in whom CHD developed during follow-up (242 incident cases from 1987 to 1993 and 373 from 1990 to 1995) and, for comparison, 2 stratified random samples of noncases. In analyses adjusted for demographic variables and traditional CHD risk factors, the relative risk of CHD across quintiles of CRP was 1.0, 0.8, 1.6, 1.9, and 1.5 for events from 1987 to 1995 (P for trend = .01). As expected, inclusion of fibrinogen, intracellular adhesion molecule-1, and white blood cell count (other potential markers of the inflammatory reaction) attenuated the association of CRP with CHD incidence. In a supplemental cross-sectional analysis, CRP was not associated with carotid intima-media thickness after adjustment for major risk factors. Conclusions C-reactive protein is a moderately strong marker of risk of CHD in this cohort of middle-aged adults, consistent with the role of inflammation in the pathogenesis of CHD events. The association was not specific to CRP because other markers of inflammation could largely account for the finding. (Am Heart J 2002;144:233-8.)     

Prospective study of fibrinolytic factors and incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study

The fibrinolytic system may play a role in the pathogenesis of coronary heart disease (CHD), but existing prospective studies have not consistently shown an independent association between fibrinolytic factors and CHD. None has reported an association between plasminogen and CHD incidence. In the prospective Atherosclerosis Risk in Communities (ARIC) Study of middle-aged adults, we examined the association of incident CHD with several fibrinolytic factors: tissue plasminogen activator antigen, plasminogen activator inhibitor-1, plasminogen, and fibrin fragment D-dimer as well as a marker of coagulation activation (prothrombin fragment F1.2). We measured these in stored baseline plasma samples of 326 subjects who developed CHD and, for comparison, a stratified random sample of the entire cohort (n=720). Tissue plasminogen activator and plasminogen activator inhibitor-1 antigen levels were associated positively with CHD incidence in analyses adjusted for age, race, and sex but were not associated with CHD after adjustment for other risk factors. Plasminogen and D-dimer levels were associated positively and independently with CHD incidence; the multivariable-adjusted relative risks (95% CIs) for the highest versus lowest quintiles were 2.20 (1.2 to 4.2) for plasminogen and 4.21 (1.9 to 9.6) for D-dimer. F1.2 was not associated with CHD incidence. Our findings lend support for a link between fibrinolytic factors and CHD incidence. A positive association between plasminogen and CHD is seemingly opposite the direction expected but may reflect a compensatory response to impaired plasminogen activation in subjects prone to CHD.     

Nontraditional risk factors for coronary heart disease incidence among persons with diabetes: the Atherosclerosis Risk in Communities (ARIC) Study

BACKGROUND: Major risk factors explain much of the excess risk for coronary heart disease produced by diabetes, but nontraditional factors may also relate to incident coronary heart disease. OBJECTIVE: To examine the association of traditional and nontraditional risk factors with incidence of coronary heart disease in adults with diabetes. DESIGN: Prospective cohort study. SETTING: The Atherosclerosis Risk in Communities (ARIC) Study. PARTICIPANTS: 1676 middle-aged persons who had diabetes but no history of prevalent coronary heart disease. MEASUREMENTS: Multiple risk factors were recorded at baseline. Follow-up was from 1987 through 1995. RESULTS: 186 participants developed incident coronary heart disease events during follow-up. As expected, the incidence of coronary heart disease in participants with diabetes was associated positively with traditional risk factors (hypertension, smoking, total cholesterol level, and low high-density lipoprotein [HDL] cholesterol level). After adjustment for sex, age, ethnicity, and ARIC field center, incident coronary heart disease was also significantly associated with waist-to-hip ratio; levels of HDL3 cholesterol, apolipoproteins A-I and B, albumin, fibrinogen, and von Willebrand factor factor VIII activity; and leukocyte count. However, after adjustment for traditional risk factors for coronary heart disease, only levels of albumin, fibrinogen, and von Willebrand factor; factor VIII activity; and leukocyte count remained independently associated with coronary heart disease (P < 0.03). The relative risks associated with the highest compared with lowest groupings of albumin, fibrinogen, factor VIII, and von Willebrand factor values and leukocyte count were 0.64 (95% CI, 0.44 to 0.92), 1.75 (CI, 1.12 to 2.73), 1.58 (CI, 1.02 to 2.42), 1.71 (CI, 1.11 to 2.63), and 1.90 (CI, 1.16 to 3.13), respectively. Adjustment for diabetes treatment status attenuated these associations somewhat. CONCLUSIONS: Levels of albumin, fibrinogen, and von Willebrand factor; factor VIII activity; and leukocyte count were predictors of coronary heart disease among persons with diabetes. These associations may reflect 1) the underlying inflammatory reaction or microvascular injury related to atherosclerosis and a tendency toward thrombosis or 2) common antecedents for both diabetes and coronary heart disease.     

Association between circulating specific leukocyte types and incident chronic kidney disease: the Atherosclerosis Risk in Communities (ARIC) study

Progressive renal fibrosis is a characteristic of all the diseases that cause renal failure and is invariably accompanied by a prominent leukocyte infiltration in the kidney. The goal of this study was to determine the association between the circulating specific leukocyte types and incident chronic kidney disease (CKD). In a cohort of 10,056 middle-aged white and African American adults, levels of circulating neutrophils, lymphocytes, and monocytes were measured at baseline; blood pressure (BP) and serum creatinine were measured and estimated glomerular filtration rate (eGFR) was calculated at baseline and 3 and 9 years later; and surveillance for first hospitalization or death with CKD was carried out over a mean follow-up of 7.4 years (maximum, 11.9 years). Increased neutrophil levels and decreased lymphocyte levels were significantly associated with greater CKD incidence after adjustment for covariates. African Americans tended to have similar but stronger patterns of association between circulating leukocytes and CKD incidence than whites, although the differences between race groups were not statistically significant. We also found that eGFR and BP were higher at each visit in African Americans than whites between ages 45 and 65. These findings support a potential role for circulating specific leukocytes in the pathogenesis of kidney dysfunction, especially in African Americans, indicating the leukocyte-related renal mechanism of essential hypertension (HT).     

Left ventricular architecture and survival in African-Americans free of coronary heart disease (from the Atherosclerosis Risk in Communities [ARIC] study)

Published studies of the prognostic value of left ventricular (LV) hypertrophy and LV geometric pattern in African-Americans were based on referred or hospitalized patients with hypertension or coronary heart disease. All-cause mortality rates and survival associated with LV geometric pattern were determined using echocardiography in a population-based sample of middle-aged and elderly African-American men and women. During the third (1993 to 1995) visit of the ARIC Study, echocardiography was performed at the Jackson, Mississippi, field center on the cohort of 2,445 African-Americans aged 49 to 75 years. M-Mode LV echocardiographic measurements were available for 1,722 persons. Mortality data were available through December 31, 2003. During the follow-up period (median 8.8 years, maximum 10.4), 160 deaths were identified. In men, multivariable-adjusted hazard ratios for all-cause mortality (compared with men with normal LV geometry) were 1.75 (95% confidence interval [CI] 0.71 to 4.33) in those with concentric LV hypertrophy, 0.38 (95% CI 0.08 to 1.88) in those with eccentric LV hypertrophy, and 0.79 (95% CI 0.41 to 1.54) in those with concentric remodeling. In women, multivariable-adjusted hazard ratios for all-cause mortality (compared with women with normal LV geometry) were 1.17 (95% CI 0.48 to 2.84) in those with concentric LV hypertrophy, 1.23 (95% CI 0.46 to 3.28) in those with eccentric LV hypertrophy, and 1.17 (95% CI 0.60 to 2.28) in those with concentric remodeling. In conclusion, in this population-based cohort of middle-aged and elderly African-Americans free of coronary heart disease, adjustment for baseline differences in cardiovascular disease risk factors and LV mass greatly attenuated the strength of the association between LV pattern and all-cause mortality risk in women. In men, an association between concentric LV hypertrophy and mortality risk remained.     

A prospective study of coronary heart disease and the hemochromatosis gene (HFE) C282Y mutation: the Atherosclerosis Risk in Communities (ARIC) study

Increased iron stores may play a role in the development of coronary heart disease (CHD) by increasing lipoprotein oxidation. Recently, mutations have been discovered in the gene (HFE) for hereditary hemochromatosis, an autosomal recessive condition of disordered iron metabolism, absorption, and storage. It is possible that people who carry HFE mutations have increased risk of CHD. We used a prospective case-cohort design (243 CHD cases and 535 non-cases) to determine whether the HFE C282Y mutation was associated with incident CHD in a population-based sample of middle-aged men and women. The frequencies of homozygosity and heterozygosity for the C282Y mutation in the ARIC study population were 0.2% (one homozygous person) and 6%, respectively. The C282Y mutation was associated with nonsignificantly increased risk of CHD (relative risk=1.60, 95% CI 0.9-2.9). After adjusting for other confounding risk factors (age, race, gender, ARIC community, smoking status, diabetes status, hypertension status, LDL cholesterol, HDL cholesterol, and triglycerides), the association became stronger (relative risk=2.70, 95% CI 1.2-6.1). However, a sensitivity analysis showed that this estimate of relative risk was somewhat unstable due to few subjects in some strata. Our prospective findings suggest that individuals carrying the HFE C282Y mutation may be at increased risk of CHD.     

Electrocardiographic predictors of new-onset heart failure in men and in women free of coronary heart disease (from the Atherosclerosis in Communities [ARIC] Study)

We compared the prognostic value of 12 electrocardiographic (ECG) variables in predicting risk of new-onset heart failure (HF) in a subgroup of 13,555 participants of the Atherosclerosis Risk in Communities (ARIC) study who were considered free of coronary heart disease at the onset of the study. Cox proportional hazards models were used to evaluate risk of HF for the highest decile of the distribution of each ECG variable (lowest decile for ST and T amplitudes in lead V(5)), with the remaining deciles as reference groups. Risk models were adjusted for demographic and clinical variables. In univariate Cox regression models, in men 11 and in women 8 of the 12 ECG variables were significant, strong predictors of risk of new-onset HF. Subsequently, 8 ECG variables with low mutual correlations were entered simultaneously into a multivariate Cox regression model. In men, large left ventricular mass by electrocardiogram, QT prolongation, and increased heart rate were the strongest independent predictors of new-onset HF, each with a twofold increased risk. Other independent predictors in men were ST depression in lead V(5), wide QRS/T angle, and old (silent) myocardial infarction, each with a >50% increased risk of incident HF. In women, QRS nondipolar voltage was associated with an 87% increased risk of incident HF, and other independent predictors, as in men, were wide QRS/T angle and increased heart rate. In conclusion, several ECG abnormalities are manifestations of evolving HF in men and women considered free of coronary heart disease.     

Risk prediction of coronary heart disease based on retinal vascular caliber (from the Atherosclerosis Risk In Communities [ARIC] Study)

Recent studies showed that such retinal vascular signs as quantitative retinal vascular caliber were associated with increased risk of incident coronary heart disease (CHD), but whether these retinal vascular signs add to the prediction of CHD over and above traditional CHD risk factors was not addressed. Whether these signs add to the prediction of CHD over and above the Framingham risk score in people (n = 9,155) without diabetes selected from the ARIC Study was investigated. Incident CHD was ascertained using standardized methods, and retinal vascular caliber and other retinal signs were measured from retinal photographs. After a mean of 8.8 years of follow-up, there were 700 incident CHD events. Women with wider retinal venular caliber (hazard ratio 1.27/1-SD increase, 95% confidence interval 1.08 to 1.50) and narrower retinal arteriolar caliber (hazard ratio 1.31/1-SD decrease, 95% confidence interval 1.10 to 1.56) had a higher risk of incident CHD after adjusting for Framingham risk score variables. Area under the receiver operator characteristic curve increased from 0.695 to 0.706 (1.7% increase) with the addition of retinal vascular caliber to the Framingham risk model. Risk prediction models with and without retinal vascular caliber both fitted the data and were well calibrated for women. In men, retinal vascular caliber was not associated with CHD risk after adjustment. Other retinal vascular signs were not associated with 10-year incident CHD in men or women. In conclusion, although retinal vascular caliber independently predicted CHD risk in women, the incremental predictive ability over that of the Framingham model was modest and unlikely to translate meaningfully into clinical practice.     

Glycated haemoglobin and cognitive decline: the Atherosclerosis Risk in Communities (ARIC) study

Aims/hypothesis  

This study aimed to examine the association between diabetes and hyperglycaemia—assessed by HbA_1c—and change in cognitive function in persons with and without diabetes.     

Hypertension, blood pressure, and heart rate variability: the Atherosclerosis Risk in Communities (ARIC) study

Dysregulation of the autonomic nervous system has been implicated in the development of hypertension. Heart rate variability is a noninvasive tool to quantitatively estimate cardiac autonomic activity and has been used to document decreased cardiac autonomic activity in hypertension. The ability of decreased heart rate variability to predict incident hypertension has not been well studied, and there are no studies of whether hypertension leads to changes in heart rate variability. We investigated the temporal sequence linking hypertension, blood pressure, and heart rate variability in a population-based cohort of 11 061 individuals aged 45 to 54 years at baseline. Individuals with hypertension had decreased heart rate variability at baseline, and this association was present across the full blood pressure range. Among 7099 individuals without hypertension at baseline, low heart rate variability predicted greater risk of incident hypertension over 9 years of follow-up. The hazard ratio (95% confidence interval [CI]) for the lowest compared with the highest quartile of the standard deviation of normal-to-normal R-R intervals was 1.24 (95% CI, 1.10-1.40), for the root mean square of successive differences in normal-to-normal R-R intervals was 1.36 (95% CI, 1.21-1.54), and for R-R interval was 1.44 (95% CI, 1.27-1.63). Over 9 years, there was no measurable difference in the rate of change in heart rate variability among those with and without hypertension, although the differences in heart rate variability at follow-up were smaller than those at baseline. These findings thus support the thesis that the autonomic nervous system is involved in the development of hypertension, yet suggest that differences in the autonomic profile of hypertensives and normotensives do not increase with time.     

Plasma fatty acid composition and incidence of coronary heart disease in middle aged adults: the Atherosclerosis Risk in Communities (ARIC) Study

BACKGROUND AND AIM: To prospectively investigate the relation of plasma cholesterol ester (CE) and phospholipid (PL) fatty acid (FA) composition with incidence of coronary heart disease (CHD). METHODS AND RESULTS: 3,591 white participants in the Minneapolis field center of the Atherosclerosis Risk in Communities Study, aged 45-64 years, were studied. Plasma FA composition of CEs and PLs was quantified using gas-liquid chromatography and expressed as percentage of total FAs. Incident CHD was identified during 10.7 years of follow-up. In both CE and PL fractions, the proportions of stearic (18:0) acid, dihomo-gamma-linolenic (20:3n6) acid and total saturated fatty acids (SFAs) were significantly higher while arachidonic (20:4n6) acid and total polyunsaturated fatty acids (PUFAs) were significantly lower among participants who developed incident CHD (n = 282). After adjusting for age, gender, smoking, alcohol drinking, sports activity, and non-FA dietary factors, the incidence of CHD was significantly and positively associated with the proportion of dihomo-gamma-linolenic acid but inversely associated with arachiadonic acid. The multiply-adjusted rate ratios (RRs) of CHD incidence for the highest versus the lowest quintile were 1.31 in CE and 1.44 in PL for dihomo-gamma-linolenic acid (p for trend: 0.05 and 0.017, respectively), 0.59 in CE and 0.65 in PL for arachidonic acid (p: 0.016 and 0.024, respectively). Also significantly and positively associated with incident CHD were PL stearic acid and CE linolenic (18:3n3) acid. Only a borderline significant positive association was observed for total SFAs in CE (multivariate RRs across quintiles: 1.00, 1.15, 1.40, 1.62, 1.32; p = 0.07). Total PUFAs or monounsaturated FA were not independently associated with CHD. CONCLUSIONS: Our study found a weak positive association of SFAs with incident CHD. Our findings also confirm that FA metabolism in the body, such as the activity of delta-5 desaturase, which converts dihomo-gamma-linolenic acid to arachidonic acid, may affect the development of CHD.