Background Cystatin C level predicts mortality more strongly than serum creatinine level. It is unknown whether this advantage extends to other outcomes, such as kidney failure, or whether other ...novel renal filtration markers share this advantage in predicting outcomes. Study Design Observational cohort study. Setting & Participants 9,988 participants in the Atherosclerosis Risk in Communities (ARIC) Study, a population-based study in 4 US communities, followed for approximately 10 years. Predictors Serum creatinine–based estimated glomerular filtration rate calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (eGFRCKD-EPI ) and cystatin C, β-trace protein (BTP), and β2 -microglobulin (B2M) levels. Outcomes Mortality, coronary heart disease, heart failure, and kidney failure. Results Higher cystatin C and B2M concentrations were associated more strongly with mortality (n = 1,425) than BTP level and all were associated more strongly than eGFRCKD-EPI (adjusted HR for the upper 6.7 percentile compared with the lowest quintile: 1.6 95% CI, 1.3-1.9 for eGFRCKD-EPI , 2.9 95% CI, 2.3-3.6 for cystatin C level, 1.9 95% CI, 1.5-2.4 for BTP level, and 3.0 95% CI, 2.4-3.8 for B2M level). Similar patterns were observed for coronary heart disease (n = 1,279), heart failure (n = 803), and kidney failure (n = 130). The addition of cystatin C, BTP, and B2M levels to models including eGFRCKD-EPI and all covariates, including urinary albumin-creatinine ratio, significantly improved risk prediction for all outcomes ( P < 0.001). Limitations No direct measurement of GFR. Conclusions B2M and, to a lesser extent, BTP levels share cystatin C's advantage over eGFRCKD-EPI in predicting outcomes, including kidney failure. These additional markers may be helpful in improving estimation of risk associated with decreased kidney function beyond current estimates based on eGFRCKD-EPI.
Abstract Background Experimental studies in animals suggest that circulating soluble receptor for advanced glycation end products (sRAGE) decrease oxidative stress, inflammation, and fibrosis. The ...association between sRAGE and incident heart failure has not been systematically examined in a prospective study. Methods We conducted a prospective analysis of a subsample of 1,086 participants from the Atherosclerosis Risk in Communities Study who attended visit 2 (1990-1992) without a history of coronary heart disease, stroke, or heart failure and with measured plasma sRAGE levels. Incident heart failure was defined as death from heart failure or hospitalization due to heart failure during a median of 20 years of follow-up. Results In this sample of a community-based population (mean age 63 years, 60% women, 78% white), there were 126 incident cases of heart failure. Lower levels of sRAGE were significantly associated with an increased risk of heart failure; the adjusted hazard ratios (95% CIs) of heart failure were 1.0 (reference), 1.81 (0.94-3.49), 1.57 (0.80-3.08), and 3.37 (1.75-6.50), for fourth, third, second, and first quartiles, respectively ( P for trend = .001). We did not observe significant interactions by diabetes status or by race or obesity status. Conclusions Lower circulating levels of sRAGE are independently associated with the development of heart failure in a community-based population. Our results add to the growing evidence that sRAGE is a valuable predictor of cardiovascular disease.
Objectives The study sought to determine the 99th percentile upper reference limit for the high-sensitivity cardiac troponin T assay (hs-cTnT) in 3 large independent cohorts. Background The presently ...recommended 14 ng/l cut point for the diagnosis of myocardial infarction using the hs-cTnT assay was derived from small studies of presumably healthy individuals, with relatively little phenotypic characterization. Methods Data were included from 3 well-characterized population-based studies: the Dallas Heart Study (DHS), the Atherosclerosis Risk in Communities (ARIC) Study, and the Cardiovascular Health Study (CHS). Within each cohort, reference subcohorts were defined excluding individuals with recent hospitalization, overt cardiovascular disease, and kidney disease (subcohort 1), and further excluding those with subclinical structural heart disease (subcohort 2). Data were analyzed stratified by age, sex, and race. Results The 99th percentile values for the hs-cTnT assay in DHS, ARIC, and CHS were 18, 22, and 36 ng/l (subcohort 1) and 14, 21, and 28 ng/l (subcohort 2), respectively. These differences in 99th percentile values paralleled age differences across cohorts. Analyses within sex/age strata yielded similar results between cohorts. Within each cohort, 99th percentile values increased with age and were higher in men. More than 10% of men 65 to 74 years of age with no cardiovascular disease in our study had cardiac troponin T values above the current myocardial infarction threshold. Conclusions Use of a uniform 14 ng/l cutoff for the hs-cTnT assay may lead to over-diagnosis of myocardial infarction, particularly in men and the elderly. Clinical validation is needed of new age- and sex-specific cutoff values for this assay.
Introduction Structural changes in the heart are known risk factors for atrial fibrillation (AF). An association between high-sensitivity cardiac troponin T (hs-cTnT), a marker of myocardial cell ...damage measured with a high-sensitivity assay, and the risk of AF could have implications for AF risk stratification. Objective To estimate the association between hs-cTnT and the risk of incident AF in the ARIC study, a prospective cohort of middle-aged adults from 4 US communities. Methods Study included 10,584 participants (mean age 62.7 years) free of AF in 1996 to 1998 and followed through 2008. Atrial fibrillation was defined using International Classification of Diseases codes from hospitalizations and death certificates. Participants with undetectable hs-cTnT levels (58%) were assigned the lower limit of measurement (5 ng/L). Net reclassification improvement was used to examine the discriminative ability of hs-cTnT for 10-year AF risk prediction (categories: <5%, 5%-15%, and >15%). Results A total of 920 incident AF cases were observed for 109,227 person-years. After adjustment, a 1-SD difference in ln(hs-cTnT) was associated with a hazard ratio of 1.16 (95% CI 1.10-1.23). Compared with those with undetectable levels, participants with hs-cTnT ≥14 ng/L had a hazard ratio of 1.78 (95% CI 1.43-2.24). Addition of hs-cTnT to known AF predictors did not increase the c statistic appreciably (0.756 vs 0.758) or improve risk stratification (net reclassification improvement 0.4%, 95% CI −1.4% to 2.3%). Conclusions High-sensitivity cTnT level is associated with an increased incidence rate of AF but did not improve risk stratification.
Abstract Objectives The study sought to evaluate the association of obesity with a novel biomarker of subclinical myocardial injury, cardiac troponin T measured with a new high-sensitivity assay ...(hs-cTnT), among adults without clinical cardiovascular disease (CVD). Background Laboratory evidence suggests a relationship between obesity and myocardial injury that may play a role in the development of heart failure (HF), but there is limited clinical data regarding this association. Methods We evaluated 9,507 participants in the ARIC (Atherosclerosis Risk in Communities) study without baseline CVD (Visit 4, 1996 to 1999). We assessed the cross-sectional association of body mass index (BMI) with high (≥14 ng/l) and measurable (≥3 ng/l) hs-cTnT levels after multivariable regression. We further evaluated the independent and combined associations of BMI and hs-cTnT with incident HF. Results Higher BMI was independently associated with a positive, linear increase in the likelihood of high hs-cTnT, with severe obesity (BMI >35 kg/m2 ) associated with an odds ratio of 2.20 (95% confidence interval: 1.59 to 3.06) for high hs-cTnT after adjustment. Over 12 years of follow-up, there were 869 incident HF events. Obesity and hs-cTnT were both independently associated with incident HF, and individuals with severe obesity and high hs-cTnT had a greater than 9-fold higher risk of incident HF (hazard ratio: 9.20 95% confidence interval: 5.67 to 14.93) than individuals with normal weight and undetectable hs-cTnT. Conclusions Among individuals without CVD, higher BMI has an independent, linear association with subclinical myocardial injury, as assessed by hs-cTnT levels. Obesity and hs-cTnT provide independent and complementary prognostic information regarding the risk of incident HF.
Background Serum cystatin C level has been shown to have a stronger association with clinical outcomes than serum creatinine level. However, little is known about the combined association of cystatin ...C–based estimated glomerular filtration rate (eGFRcys ) and albuminuria with clinical outcomes, particularly at levels lower than current chronic kidney disease (CKD) cutoffs. Study Design Prospective cohort. Setting & Participants 10,403 ARIC (Atherosclerosis Risk in Communities) Study participants followed up for a median of 10.2 years. Predictor eGFRcys , albuminuria. Outcomes Mortality, coronary heart disease (CHD), and heart failure, as well as a composite of any of these separate outcomes. Results Both decreased eGFRcys and albuminuria were associated independently with the composite outcome, as well as mortality, CHD, and heart failure. Although eGFRcys of 75-89 mL/min/1.73 m2 in the absence of albuminuria (albumin-creatinine ratio ACR <10 mg/g) or albuminuria with ACR of 10-29 mg/g with normal eGFRcys (90-104 mL/min/1.73 m2 ) was not associated significantly with any outcome compared with eGFRcys of 90-104 mL/min/1.73 m2 and ACR <10 mg/g, the risk of each outcome was significantly higher in those with both eGFRcys of 75-89 mL/min/1.73 m2 and ACR of 10-29 mg/g (for mortality, HR of 1.4 95% CI, 1.1-2.0; for CHD, HR of 1.9 95% CI, 1.4-2.6; for heart failure, HR of 1.8 95% CI, 1.2-2.7). Combining the 2 markers improved risk classification for all outcomes ( P < 0.001), even in those without overt CKD. Limitations Only one measurement of cystatin C. Conclusions Mildly decreased eGFRcys and mild albuminuria independently contributed to the risk of mortality, CHD, and heart failure. Even minimally decreased eGFRcys (75-89 mL/min/1.73 m2 ) is associated with increased risk in the presence of mild albuminuria. Combining the 2 markers is useful for improved risk stratification even in those without clinical CKD.
Background Epidemiologic data for cardiac abnormality predating decreased kidney function are sparse. We investigated the associations of high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal ...pro–brain natriuretic peptide (NT-proBNP) with end-stage renal disease (ESRD) risk in a community-based cohort. Study Design A prospective cohort study. Setting & Participants 10,749 white and black participants at the fourth visit (1996-1998) of the Atherosclerosis Risk in Communities (ARIC) Study with follow-up through 2010. Predictor hs-cTnT (3, 6, 9, and 14 ng/L) and NT-proBNP (41.6, 81.0, 142.5, and 272.5 pg/mL) levels were divided into 5 categories at the same percentiles (32th, 57th, 77th, and 91th; corresponding to ordinary thresholds of hs-cTnT), with the lowest category as a reference. Outcomes Incident ESRD defined as initiation of dialysis therapy, transplantation, or death due to kidney disease. Measurements Relative risk and risk prediction of ESRD according to hs-cTnT and NT-proBNP levels based on Cox proportional hazards models. Results During a median follow-up of 13.1 years, 235 participants developed ESRD (1.8 cases/1,000 person-years). hs-cTnT and NT-proBNP levels were associated with ESRD risk independently of each other and of potential confounders, including kidney function and albuminuria (adjusted HRs for highest category, 4.43 95% CI, 2.43-8.09 and 2.28 95% CI, 1.44-3.60, respectively). For hs-cTnT level, the association was significant even at the third category (HR for 6-8 ng/L of hs-cTnT, 2.74 95% CI, 1.54-4.88). Their associations were largely consistent even among persons without decreased kidney function or history of cardiovascular disease. hs-cTnT and NT-proBNP levels both significantly improved ESRD prediction (C statistic differences of 0.0084 95% CI, 0.0005-0.0164 and 0.0045 95% CI, 0.0004-0.0087, respectively, from 0.884 with conventional risk factors). Limitations Relatively small number of ESRD cases and single measurement of hs-cTnT and NT-proBNP. Conclusions hs-cTnT and NT-proBNP levels independently predicted ESRD risk in the general population, with more evident results for hs-cTnT. These results suggest the involvement of cardiac abnormality, particularly cardiac injury, in the progression of reduced kidney function and/or may reflect the useful property of hs-cTnT as an end-organ damage marker.
Abstract Background The optimal systolic blood pressure (SBP) treatment goal is in question, with SPRINT (Systolic Blood Pressure Intervention Trial) suggesting benefit for 120 mm Hg. However, ...achieving an SBP this low may reduce diastolic blood pressure (DBP) to levels that could compromise myocardial perfusion. Objectives This study sought to examine the independent association of DBP with myocardial damage (using high-sensitivity cardiac troponin-T hs-cTnT) and with coronary heart disease (CHD), stroke, or death over 21 years. Methods The authors studied 11,565 adults from the ARIC (Atherosclerosis Risk In Communities) cohort, analyzing DBP and hs-cTnT associations as well as prospective associations between DBP and events. Results Mean baseline age was 57 years, 57% of patients were female, and 25% were black. Compared with persons who had DBP between 80 to 89 mm Hg at baseline (ARIC visit 2), the adjusted odds ratio of having hs-cTnT ≥14 ng/l at that visit was 2.2 and 1.5 in those with DBP <60 mm Hg and 60 to 69 mm Hg, respectively. Low DBP at baseline was also independently associated with progressive myocardial damage on the basis of estimated annual change in hs-cTnT over the 6 years between ARIC visits 2 and 4. In addition, compared with a DBP of 80 to 89 mm Hg, a DBP <60 mm Hg was associated with incident CHD and mortality, but not with stroke. The DBP and incident CHD association was strongest with baseline hs-cTnT ≥14 ng/l (p value for interaction <0.001). Associations of low DBP with prevalent hs-cTnT and incident CHD were most pronounced among patients with baseline SBP ≥120 mm Hg. Conclusions Particularly among adults with an SBP ≥120 mm Hg, and thus elevated pulse pressure, low DBP was associated with subclinical myocardial damage and CHD events. When titrating treatment to SBP <140 mm Hg, it may be prudent to ensure that DBP levels do not fall below 70 mm Hg, and particularly not below 60 mm Hg.
Objectives The purpose of this study is to describe the proportion of “JUPITER-eligible” (Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) ...individuals and clinical outcomes of individuals based on high-sensitivity C-reactive protein (hs-CRP) and low-density lipoprotein cholesterol (LDL-C) strata in the ARIC (Atherosclerosis Risk in Communities) study. Background Questions remain after the JUPITER study, including whether the observed cardiovascular disease (CVD) event rates would persist with time and how these event rates would compare with other populations (lower hs-CRP and/or higher LDL-C levels). Methods After stratification into 4 groups based on LDL-C and hs-CRP levels, with cutoffs at 130 mg/dl and 2.0 mg/l, respectively, incident CVD events were examined (mean follow-up, 6.9 years) and compared. Results Of 8,907 age-eligible participants, 18.2% (n = 1,621) were JUPITER-eligible (hs-CRP ≥2.0 mg/l, LDL-C <130 mg/dl) and had an absolute CVD risk of ∼10.9% over a mean follow-up of 6.9 years (1.57% per year). If JUPITER hazard ratios were applied to this group, the number needed to treat to prevent 1 CVD event would be estimated at 38 over 5 years and 26 over 6.9 years. Conclusions ARIC participants with elevated hs-CRP and low LDL-C had a CVD event rate of 1.57% per year over 6.9 years, similar to the CVD event rate noted in the JUPITER study placebo group (1.36% per year over 1.9 years). The association of hs-CRP ≥2.0 mg/l with increased CVD risk and mortality regardless of LDL-C provides us a simple method of using age and hs-CRP level for identifying higher risk individuals. (Atherosclerosis Risk in Communities study; NCT00005131 )
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