Faculty Bibliography

BACKGROUND:Few reports have shown an association between access type and inflammatory marker levels in a longitudinal cohort. We investigated the role of access type on serial levels of inflammatory markers and the role of inflammatory markers in mediating the association of access type and risk of mortality in a prospective study of incident dialysis patients. STUDY DESIGN/METHODS:Cohort study, post hoc analysis of the CHOICE (Choices for Healthy Outcomes in Caring for ESRD) Study. SETTING & PARTICIPANTS/METHODS:In 583 participants, inflammation was assessed by measuring serum C-reactive protein (CRP) and interleukin 6 (IL-6) after access placement and at multiple times during 3 years' follow-up. Type of access was categorized as central venous catheter (CVC), arteriovenous graft (AVG), and arteriovenous fistula (AVF), and changes over time were recorded. PREDICTOR/METHODS:Access type, age, sex, race, body mass index, diabetes, cardiovascular disease, and serum albumin level. OUTCOMES/RESULTS:CRP level, IL-6 level, and mortality. MEASUREMENTS/METHODS:We used mixed-effects pattern mixture models to study the association between access type and repeated measurements of inflammation and survival analysis to investigate the association of access type and mortality, adjusting for predictors. RESULTS:In a mixed-effects pattern mixture model, compared with AVFs, the presence of CVCs and AVGs was associated with 62% (P=0.02) and 30% (P=0.05) increases in average CRP levels, respectively. A Cox proportional hazards model yielded nonsignificant associations of CVC and AVG use (vs AVFs) with risk of mortality when adjusted for inflammatory marker levels. Higher CRP levels were associated with increased risk of CVC failure than lower CRP levels. LIMITATIONS/CONCLUSIONS:CRP and IL-6 measurements not performed for all hemodialysis patients. CONCLUSIONS:CVCs, compared with AVFs, are associated with a greater state of inflammation in incident hemodialysis patients, and the association of catheter use and mortality may be mediated by access-induced inflammation. Our findings support recommendations for the early removal or avoidance of CVC placements.

BACKGROUND:Although obesity is an independent risk factor for heart failure (HF), once HF is established, obesity is associated with lower mortality. It is unclear if the weight loss due to advanced HF leads to this paradoxical finding. OBJECTIVES/OBJECTIVE:This study sought to evaluate the prognostic impact of pre-morbid obesity in patients with HF. METHODS:In the ARIC (Atherosclerosis Risk In Communities) study, we used body mass index (BMI) measured ≥6 months before incident HF (pre-morbid BMI) to evaluate the association of overweight (BMI 25 to <30 kg/m(2)) and obesity (BMI ≥30 kg/m(2)) compared with normal BMI (18.5 to <25 kg/m(2)) with mortality after incident HF. RESULTS:Among 1,487 patients with incident HF, 35% were overweight and 47% were obese by pre-morbid BMI measured 4.3 ± 3.1 years before HF diagnosis. Over 10-year follow-up after incident HF, 43% of patients died. After adjustment for demographics and comorbidities, being pre-morbidly overweight (hazard ratio [HR]: 0.72; 95% confidence interval [CI]: 0.58 to 0.90; p = 0.004) or obese (HR: 0.70; 95% CI: 0.56 to 0.87; p = 0.001) had a protective association with survival compared with normal BMI. The protective effect of overweight and obesity was consistent across subgroups on the basis of a history of cancer, smoking, and diabetes. CONCLUSIONS:Our results, for the first time, demonstrate that patients who were overweight or obese before HF development have lower mortality after HF diagnosis compared with normal BMI patients. Thus, weight loss due to advanced HF may not completely explain the protective effect of higher BMI in HF patients.

BACKGROUND:Identifying individuals at risk for sudden cardiac death (SCD) is of critical importance. Electrocardiographic (ECG) deep terminal negativity of P wave in V1 (DTNPV1), a marker of left atrial abnormality, has been associated with increased risk of all-cause and cardiovascular mortality. We hypothesized that DTNPV1 is associated with increased risk of sudden cardiac death (SCD). METHODS AND RESULTS/RESULTS:This analysis included 15 375 participants (54.1±5.8 years, 45% men, 73% whites) from the Atherosclerosis Risk in Communities (ARIC) study. DTNPV1 was defined from the resting 12-lead ECG as presence of biphasic P wave (positive/negative) in V1 with the amplitude of the terminal negative phase >100 μV, or one small box on ECG scale. After a median of 14 years of follow-up, 311 cases of SCD occurred. In unadjusted Cox regression, DTNPV1 was associated with an 8-fold increased risk of SCD (HR 8.21; [95%CI 5.27 to 12.79]). Stratified by race and study center, and adjusted for age, sex, coronary heart disease (CHD), and ECG risk factors, as well as atrial fibrillation (AF), stroke, CHD, and heart failure (HF) as time-updated variables, the risk of SCD associated with DTNPV1 remained significant (2.49, [1.51-4.10]). DTNPV1 improved reclassification: additional 3.4% of individuals were appropriately reclassified into a higher SCD risk group, as compared with traditional CHD risk factors alone. In fully adjusted models DTNPV1 was associated with increased risk of non-fatal events: AF (5.02[3.23-7.80]), CHD (2.24[1.43-3.53]), HF (1.90[1.19-3.04]), and trended towards increased risk of stroke (1.88[0.99-3.57]). CONCLUSION/CONCLUSIONS:DTNPV1 is predictive of SCD suggesting its potential utility in risk stratification in the general population.

BACKGROUND:There is increased interest in using alternative end points for trials of kidney disease progression. The currently established end points of end-stage renal disease and doubling of serum creatinine level, equivalent to a 57% decline in estimated glomerular filtration rate (eGFR), are late events in chronic kidney disease (CKD), requiring large clinical trials with long follow-up. As part of a comprehensive evaluation of lesser declines in eGFR as alternative end points, we describe the consistency of treatment effects of intervention on the alternative and established end points in past trials. STUDY DESIGN/METHODS:Diagnostic test study. SETTING & POPULATION/METHODS:9,488 participants from 37 randomized controlled trials of CKD progression across 5 intervention types. INDEX TEST/METHODS:Alternative end points including percentage change in eGFR from baseline (20%, 30%, 40%, and 57%) throughout study duration and to 12, 18, and 24 months. eGFR change confirmed versus nonconfirmed at the next visit. REFERENCE TEST/METHODS:The historically established end point of time to composite of treated kidney failure (end-stage renal disease), untreated kidney failure (GFR<15mL/min/1.73m(2)), or doubling of serum creatinine level throughout study duration. RESULTS:Over a median of 3.62 years' follow-up, there were 3,070 established end points. Compared to the established end point, the number of alternative end points was greater for smaller versus larger declines in eGFR and longer versus shorter follow-up intervals. There was a general trend toward attenuation of the treatment effect with end points defined by a lesser eGFR decline, with greater attenuation with nonconfirmed end points, except for the low-protein-diet intervention, for which a stronger treatment effect was observed. The ratio (95% credible interval) of the HR for the alternative to established end point for the 5 intervention types ranged from 0.91 (0.64-1.43) to 1.12 (0.89-1.40) for 40% decline and from 0.88 (0.63-1.39) to 1.15 (0.88-1.54) for 30% decline for the overall study duration, indicating consistency of treatment effects. LIMITATIONS/CONCLUSIONS:Limited variety of interventions tested and low statistical power for many CKD clinical trials. CONCLUSIONS:These results provide some support for the use of lesser eGFR declines as a surrogate end point, with stronger support for the 40% than 30% decline.

BACKGROUND:There is interest in surrogate end points for clinical trials of chronic kidney disease progression because currently established end points-end-stage renal disease (ESRD) and doubling of serum creatinine level-are late events, requiring large clinical trials with long follow-up. Doubling of serum creatinine level is equivalent to a 57% decline in estimated glomerular filtration rate (eGFR). We evaluated type 1 error and required sample size for clinical trials using surrogate end points based on lesser eGFR declines. STUDY DESIGN/METHODS:Simulation study. SETTING & PARTICIPANTS/METHODS:Simulations evaluating 3,060 scenarios representative of 19 treatment comparisons in 13 chronic kidney disease clinical trials. INDEX TESTS/METHODS:Surrogate end points defined as composite end points based on ESRD and either 30% or 40% eGFR declines. REFERENCE TEST/METHODS:Clinical outcome (ESRD) for type 1 error. Established end point (composite of ESRD and 57% eGFR decline) for required sample size. RESULTS:Use of the 40% versus 57% eGFR decline end point consistently led to a reduction in sample size > 20% while maintaining risk for type 1 error < 10% in the presence of a small acute effect (<1.25mL/min/1.73m(2)) for: (1) 2-, 3-, or 5-year trials with a high mean baseline eGFR (67.5mL/min/1.73m(2)), and (2) 2-year trials with an intermediate mean baseline eGFR (42.5mL/min/1.73m(2)). Use of the 30% versus the 40% eGFR decline end point often led to moderately larger reductions in sample size in the absence of an acute effect, but not in the presence of acute effects. LIMITATIONS/CONCLUSIONS:The complexity of eGFR trajectories prevented evaluation of all scenarios for clinical trials. CONCLUSIONS:Use of end points based on 30% or 40% eGFR declines is an appropriate strategy to reduce sample size in certain situations. However, risk for type 1 error is increased in the presence of acute effects, particularly for 30% eGFR declines. The decision to use these end points should be made after thorough evaluation of their expected performance under the conditions of specific clinical trials.

BACKGROUND:The currently established end points for clinical trials of progression of chronic kidney disease (CKD) are end-stage renal disease and doubling of serum creatinine level, which approximates a 57% decline in estimated glomerular filtration rate (eGFR). There is increased interest in using alternative end points in clinical trials to shorten trial duration and reduce sample size. As part of an evaluation of using lesser declines in GFR as alternative end points, we examined the associations of various levels of eGFR decline with the subsequent development of established end points and assess the consistency of alternate levels of eGFR decline across varying clinical manifestations of kidney disease and interventions. STUDY DESIGN/METHODS:Observational analysis of randomized controlled trials. SETTING & PARTICIPANTS/METHODS:9,488 participants in 37 randomized controlled trials in CKD. PREDICTOR/METHODS:Alternative end points, defined as 30% and 40% declines in eGFR from baseline to month 12. Effect modification by baseline eGFR, proteinuria, cause of disease, and interventions. OUTCOMES/RESULTS:Established end point, defined as end-stage renal disease, eGFR<15mL/min/1.73m(2), or doubling of serum creatinine level. RESULTS:From baseline to 12 months, 16.1% and 7.8% of participants had eGFR declines of ≥30% or ≥40%, respectively. Over a median follow-up of 2.0 (IQR, 1.2-3.1) years after the 12-month baseline period, 2,661 established end points were observed. A strong linear association was observed between eGFR decline and subsequent established end points. HRs for the established end point for 30% and 40% decreases in eGFR compared to a 0% decline were 9.6 (95% CI, 7.3-12.6) and 20.3 (95% CI, 14.1-29.3), respectively. The associations were consistent regardless of baseline eGFR, proteinuria, causes of disease, and interventions. LIMITATIONS/CONCLUSIONS:Observational study subject to residual confounding. CONCLUSIONS:The strong associations between lesser declines in eGFR and the subsequent development of established end points were consistent across different clinical characteristics of kidney disease and interventions and support implementation of alternative end points in clinical trials of CKD progression.

OBJECTIVES/OBJECTIVE: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/m(2)) 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.

Metabolic syndrome (MetS) has become a health and financial burden worldwide. The MetS definition captures clustering of risk factors that predict higher risk for diabetes mellitus and cardiovascular disease. Our study hypothesis is that additional to genes influencing individual MetS risk factors, genetic variants exist that influence MetS and inflammatory markers forming a predisposing MetS genetic network. To test this hypothesis a staged approach was undertaken. (a) We analyzed 17 metabolic and inflammatory traits in more than 85,500 participants from 14 large epidemiological studies within the Cross Consortia Pleiotropy Group. Individuals classified with MetS (NCEP definition), versus those without, showed on average significantly different levels for most inflammatory markers studied. (b) Paired average correlations between 8 metabolic traits and 9 inflammatory markers from the same studies as above, estimated with two methods, and factor analyses on large simulated data, helped in identifying 8 combinations of traits for follow-up in meta-analyses, out of 130,305 possible combinations between metabolic traits and inflammatory markers studied. (c) We performed correlated meta-analyses for 8 metabolic traits and 6 inflammatory markers by using existing GWAS published genetic summary results, with about 2.5 million SNPs from twelve predominantly largest GWAS consortia. These analyses yielded 130 unique SNPs/genes with pleiotropic associations (a SNP/gene associating at least one metabolic trait and one inflammatory marker). Of them twenty-five variants (seven loci newly reported) are proposed as MetS candidates. They map to genes MACF1, KIAA0754, GCKR, GRB14, COBLL1, LOC646736-IRS1, SLC39A8, NELFE, SKIV2L, STK19, TFAP2B, BAZ1B, BCL7B, TBL2, MLXIPL, LPL, TRIB1, ATXN2, HECTD4, PTPN11, ZNF664, PDXDC1, FTO, MC4R and TOMM40. Based on large data evidence, we conclude that inflammation is a feature of MetS and several gene variants show pleiotropic genetic associations across phenotypes and might explain a part of MetS correlated genetic architecture. These findings warrant further functional investigation.

BACKGROUND:Increased concentrations of circulating fibroblast growth factor 23 (FGF-23) have been associated with higher risk of cardiovascular disease. The association between FGF-23 and the risk of atrial fibrillation (AF), a common arrhythmia, is less defined. Thus, we explored whether FGF-23 concentration was associated with AF incidence in a large community-based cohort. METHODS AND RESULTS/RESULTS:We studied 12 349 men and women enrolled in the Atherosclerosis Risk in Communities (ARIC) study, without prevalent AF at baseline in 1990-1992. Serum intact FGF-23 concentration was measured with the Kainos 2-site ELISA. Incident AF through 2010 was ascertained from study ECGs and hospital discharge codes. Cox proportional hazards models adjusted for potential confounding factors, including kidney function, were used to estimate the association between FGF-23 and AF risk. We identified 1572 AF events during a mean follow-up of 17 years. In multivariable analysis, a difference of 1 SD (16 pg/mL) in baseline FGF-23 was not associated with the risk of AF (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.99, 1.09). Results were similar when FGF-23 was modeled in quartiles (HR, 1.09; 95% CI, 0.94, 1.26, comparing extreme quartiles). Reduced kidney function was associated with increased AF risk across quartiles of FGF-23 levels. CONCLUSION/CONCLUSIONS:In this large community-based cohort, baseline FGF-23 levels were not associated with AF risk independently of kidney function. Our results do not support a major role for FGF-23 as a risk factor for AF or as a mediator of the association between chronic kidney disease and AF.

BACKGROUND:Lower estimated glomerular filtration rate (eGFR) on a single occasion is associated with risk of cardiovascular events; whether the degree of change in eGFR during a 1-year period adds prognostic information is unknown. METHODS AND RESULTS/RESULTS:We included adults who had ≥2 outpatient eGFR measurements (≥6 months apart) during a 1-year accrual period in Alberta, Canada. According to recent guidelines, we used a change in eGFR category (≥90, 60 to 89, 45 to 59, 30 to 44, 15 to 29, and <15 mL/min per 1.73 m(2)), and the presence/absence of a ≥25% change from baseline to classify participants into 5 groups: certain drop, uncertain drop, stable (no change), uncertain rise, and certain rise. We calculated adjusted rates of cardiovascular events (per 10 000 person-years) for each group. We estimated the adjusted risks of cardiovascular events associated with each category of change in eGFR, in reference to stable kidney function. Among the 526 388 participants, 76.1% (n=400 560) had stable, 2.6% (n=13 668) had a certain drop, and 3.3% (n=17 499) had a certain rise in eGFR. Compared with participants with stable kidney function, adjusted risks of myocardial infarction, heart failure, and stroke were 27%, 51%, and 20% higher, respectively, for those with a certain drop in kidney function. After adjusting for the last eGFR at the end of the accrual period, the observed association diminished. CONCLUSION/CONCLUSIONS:Clinically relevant changes in eGFR are associated with increased risk of cardiovascular events. However, most of the apparent increase in risk can be accounted for by assessing comorbidity and baseline kidney function.