Familial Hypercholesterolemia Among Young Adults With Myocardial Infarction.

BACKGROUND: There are limited data on the prevalence and treatment of familial hypercholesterolemia (FH) among U.S. adults who experience a myocardial infarction (MI) at a young age. OBJECTIVES: This study aimed to evaluate the prevalence of clinically defined FH and examine the rates of statin utilization and low-density lipoprotein cholesterol (LDL-C) achieved 1-year post MI. METHODS: The YOUNG-MI registry is a retrospective cohort study that includes patients who experience an MI at or below age 50 years between 2000 and 2016 at 2 academic centers. Probable or definite FH was defined by the Dutch Lipid Clinic criteria. Outcomes included the proportion of patients classified as probable or definite FH, use of lipid-lowering therapy, and LDL-C achieved 1-year post MI. RESULTS: The cohort consisted of 1,996 adults with a median age of 45 years; 19% were women, and 54% had ST-segment elevation MI. Probable/definite FH was present in 180 (9%) of whom 42.8% were not on statins prior to their MI. Of the 1,966 patients surviving until hospital discharge, 89.4% of FH patients and 89.9% of non-FH patients were discharged on statin therapy (p = 0.82). Among FH patients, 63.3% were discharged on high-intensity statin compared with 48.4% for non-FH patients (p < 0.001). At 1-year follow-up, the percent reduction in LDL-C among FH patients was -44.4% compared with -34.5% (p = 0.006) in non-FH patients. The proportion of patients with LDL-C ≥70 mg/dl was higher among FH patients (82.2%) compared with non-FH patients (64.5%; p < 0.001). CONCLUSIONS: Clinically defined FH was present in nearly 1 of 10 patients with MI at a young age. Only two-thirds of FH patients were discharged on high-intensity statin therapy, and the vast majority had elevated LDL-C at 1 year. These findings reinforce the need for more aggressive lipid-lowering therapy in young FH and non-FH patients post-MI.

Trends in Statin Use Among US Adults With Chronic Kidney Disease, 1999-2014.

Background The 2013 American College of Cardiology/American Heart Association cholesterol guidelines recognize cardiovascular disease and diabetes mellitus but not chronic kidney disease ( CKD ) as high-risk conditions warranting statin therapy. Statin use may be lower for adults with CKD compared with adults with conditions that have guideline indications for statin use. Methods and Results We analyzed data from the National Health and Nutrition Examination Surveys from 1999-2002 through 2011-2014 to determine trends in the percentage of US adults ≥20 years of age with and without CKD taking statins. CKD was defined by an estimated glomerular filtration rate <60 mL/min per 1.73m2 or albumin-to-creatinine ratio ≥30 mg/g. Statin use was identified through a medication inventory. Between 1999-2002 and 2011-2014, the percentage of adults taking statins increased from 17.6% to 35.7% among those with CKD and from 6.8% to 14.7% among those without CKD . After multivariable adjustment, adults with CKD were not more likely to be taking statins compared with those without CKD (prevalence ratio, 1.01; 95% CI] 0.96-1.08). Among adults without a history of cardiovascular disease, those with CKD but not diabetes mellitus were less likely to be taking statins compared with those with diabetes mellitus but not CKD (prevalence ratio, 0.54; 95% CI , 0.44-0.66). Among adults with a history of cardiovascular disease, there was no difference in statin use between those with CKD but not diabetes mellitus versus those with diabetes mellitus but not CKD (prevalence ratio, 0.95; 95% CI , 0.79-1.15). Conclusions CKD does not appear to be a major stimulus for statin use among US adults.

Epoetin Alfa and Outcomes in Dialysis amid Regulatory and Payment Reform.

Erythropoiesis-stimulating agents (ESAs) are commonly used to treat anemia in patients with CKD, including those receiving dialysis, although clinical trials have identified risks associated with ESA use. We evaluated the effects of changes in dialysis payment policies and product labeling instituted in 2011 on mortality and major cardiovascular events across the United States dialysis population in an open cohort study of patients on dialysis from January 1, 2005, through December 31, 2012, with Medicare as primary payer. We compared observed rates of death and major cardiovascular events in 2011 and 2012 with expected rates calculated on the basis of rates in 2005-2010, accounting for differences in patient characteristics and influenza virulence. An abrupt decline in erythropoietin dosing and hemoglobin concentration began in late 2010. Observed rates of all-cause mortality, cardiovascular mortality, and myocardial infarction in 2011 and 2012 were consistent with expected rates. During 2012, observed rates of stroke, venous thromboembolic disease (VTE), and heart failure were lower than expected (absolute deviation from trend per 100 patient-years [95% confidence interval]: -0.24 [-0.08 to -0.37] for stroke, -2.43 [-1.35 to -3.70] for VTE, and -0.77 [-0.28 to -1.27] for heart failure), although non-ESA-related changes in practice and Medicare payment penalties for rehospitalization may have confounded the results. This initial evidence suggests that action taken to mitigate risks associated with ESA use and changes in payment policy did not result in a relative increase in death or major cardiovascular events and may reflect improvements in stroke, VTE, and heart failure.

Trends in anemia management practices in patients receiving hemodialysis and peritoneal dialysis: a retrospective cohort analysis.

BACKGROUND/AIMS: Recent changes in clinical practice guidelines and reimbursement policies may have affected the use of anemia-related medications and red blood cell (RBC) transfusions in peritoneal dialysis (PD) and hemodialysis (HD) patients. We sought to compare patterns of erythropoiesis-stimulating agents (ESA) and intravenous (IV) iron use, achieved hemoglobin levels, and RBC transfusion use in PD and HD patients. METHODS: In quarterly cohorts of prevalent dialysis patients receiving persistent therapy (>3 months), 2007-2011, with Medicare Parts A and B coverage, we assessed ESA and IV iron use and dose, RBC transfusions, and hemoglobin levels. Quarterly transfusion rates were calculated. RESULTS: Observable PD and HD patients numbered 14,958 and 221,866 in Q1/2007 and 17,842 and 256,942 in Q4/2011. Adjusted ESA use was lower in PD (71.4-80.1%) than in HD (86.9-92.0%) patients, decreasing from 80.1% (Q1/2010) to 71.4% (Q4/2011) in PD patients, and from 92.0 to 86.9% in HD patients. The mean adjusted ESA dose decreased by 67.5% in PD and 58.4% in HD patients. IV iron use tended to increase, peaking at 39.3% for PD (Q3/2011) and 80.5% for HD (Q2/2011) patients. Adjusted mean hemoglobin levels fell from 11.7 to 10.6 mg/dl in PD and from 12.0 to 10.7 mg/dl in HD ESA users; adjusted transfusion rates increased from 2.4 to 3.0 per 100 patient-months in PD and from 2.6 to 3.3 in HD patients. CONCLUSIONS: In patients receiving persistent dialysis, dose and frequency of ESA administrations decreased during the period 2007-2011. Mean hemoglobin levels decreased by more than 1 g/dl, while transfusion rates increased by approximately 25%.

Comparative changes in treatment practices and clinical outcomes following implementation of a prospective payment system: the STEPPS study.

BACKGROUND: The aim of the US dialysis Prospective Payment System bundle, launched in January 2011, was reduction and more accurate prediction of costs of services, whilst maintaining or improving patient care. Dialysis facilities could either adopt the bundle completely (100%) in the first year of launch, or phase-in (25%) over four years. Differences in practice patterns and patient outcomes were hypothesized to occur in facilities that phased-in 25% compared to those that did not. METHODS: Data are from STEPPS, a study of 51 small dialysis organization facilities designed to describe trends in dialytic treatment before and after bundle implementation. Baseline was defined as October-December 2010; follow-up as January-December 2011. Facility- and patient-level data were collected at enrollment and regularly thereafter. Cox proportional hazards and linear multi-level models were used to estimate the effect of opting-in 25% (vs. 100%) on practice patterns and clinical outcomes. RESULTS: 12 facilities (patient n = 346) opted-in 25% and 37 facilities (patient n = 1296) opted-in 100% to the dialysis bundle. At baseline, patients at 25% facilities were primarily covered by Medicare, were more likely to be black, and were receiving higher monthly epoetin alfa (EPO) doses. Throughout 2011, patients in 100% facilities received lower monthly EPO doses, and had lower mean hemoglobin concentrations; hospitalization and mortality rates were numerically lower in 25% facilities but not statistically different. CONCLUSIONS: The economic pressure for dialysis providers to work within an expanded composite rate bundle whilst maintaining patient care may be a driver of practice indicator outcomes. Additional investigations are warranted to more precisely estimate clinical outcomes in patients attending facilities enrolling into the bundle 100% relative to the previous fee-for-service framework.

Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption.

Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.

Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations.

Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20-80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ∼50 000 cosmopolitan tagged SNPs across ∼2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10(-6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (ß ± SE, 0.048 ± 0.008, P = 7.7 × 10(-9)) as was rs7302703-G in HOXC10 (ß = 0.044 ± 0.008, P = 2.9 × 10(-7)) and rs936108-C in PEMT (ß = 0.035 ± 0.007, P = 1.9 × 10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (ß = 0.10 ± 0.02, P = 1.9 × 10(-6)) and rs1037575-A in ATBDB4 (ß = 0.046 ± 0.01, P = 2.2 × 10(-6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.

Effect of facility-level hemoglobin concentration on dialysis patient risk of transfusion.

BACKGROUND: Changes in anemia management practices due to concerns about erythropoiesis-stimulating agent safety and Medicare payment changes may increase patient risk of transfusion. We examined anemia management trends in hemodialysis patients and risk of red blood cell (RBC) transfusion according to dialysis facility-level hemoglobin concentration. STUDY DESIGN: Retrospective follow-up study; 6-month study period (January to June), 3-month exposure/follow-up. SETTING & PARTICIPANTS: For each year in 2007-2011, annual cohorts of point-prevalent Medicare primary payer patients receiving hemodialysis on January 1 with one or more hemoglobin measurements during the study period. Annual cohorts averaged 170,000 patients, with 130,000 patients and 3,100 facilities for the risk analysis. PREDICTOR: Percentage of facility patient-months with hemoglobin level<10 g/dL. OUTCOME: Patient-level RBC transfusion rates. MEASUREMENTS: Monthly epoetin alfa and intravenous iron doses, mean hemoglobin levels, and RBC transfusion rates; percentage of facility patient-months with hemoglobin levels<10 g/dL (exposure) and patient-level RBC transfusion rates (follow-up). RESULTS: Percentages of patients with hemoglobin levels<10 g/dL increased every year from 2007 (6%) to 2011 (~11%). Epoetin alfa doses, iron doses, and transfusion rates remained relatively stable through 2010 and changed in 2011. Median monthly epoetin alfa and iron doses decreased 25% and 43.8%, respectively, and monthly transfusion rates increased from 2.8% to 3.2% in 2011, a 14.3% increase. Patients in facilities with the highest prevalence of hemoglobin levels<10 g/dL over 3 months were at ~30% elevated risk of receiving RBC transfusions within the next 3 months (relative risk, 1.28; 95% CI, 1.22-1.34). LIMITATIONS: Possibly incomplete claims data; smaller units excluded; hemoglobin levels reported monthly for patients receiving epoetin alfa; transfusions usually not administered in dialysis units. CONCLUSIONS: Dialysis facility treatment practices, as assessed by percentage of patient-months with hemoglobin levels<10 g/dL over 3 months, were associated significantly with risk of transfusions in the next 3 months for all patients in the facility, regardless of patient case-mix.

Exploring the genetic basis of chronic periodontitis: a genome-wide association study.

Chronic periodontitis (CP) is a common oral disease that confers substantial systemic inflammatory and microbial burden and is a major cause of tooth loss. Here, we present the results of a genome-wide association study of CP that was carried out in a cohort of 4504 European Americans (EA) participating in the Atherosclerosis Risk in Communities (ARIC) Study (mean age-62 years, moderate CP-43% and severe CP-17%). We detected no genome-wide significant association signals for CP; however, we found suggestive evidence of association (P < 5 × 10(-6)) for six loci, including NIN, NPY, WNT5A for severe CP and NCR2, EMR1, 10p15 for moderate CP. Three of these loci had concordant effect size and direction in an independent sample of 656 adult EA participants of the Health, Aging, and Body Composition (Health ABC) Study. Meta-analysis pooled estimates were severe CP (n = 958 versus health: n = 1909)-NPY, rs2521634 [G]: odds ratio [OR = 1.49 (95% confidence interval (CI = 1.28-1.73, P = 3.5 × 10(-7)))]; moderate CP (n = 2293)-NCR2, rs7762544 [G]: OR = 1.40 (95% CI = 1.24-1.59, P = 7.5 × 10(-8)), EMR1, rs3826782 [A]: OR = 2.01 (95% CI = 1.52-2.65, P = 8.2 × 10(-7)). Canonical pathway analysis indicated significant enrichment of nervous system signaling, cellular immune response and cytokine signaling pathways. A significant interaction of NUAK1 (rs11112872, interaction P = 2.9 × 10(-9)) with smoking in ARIC was not replicated in Health ABC, although estimates of heritable variance in severe CP explained by all single nucleotide polymorphisms increased from 18 to 52% with the inclusion of a genome-wide interaction term with smoking. These genome-wide association results provide information on multiple candidate regions and pathways for interrogation in future genetic studies of CP.

Early trends from the Study to Evaluate the Prospective Payment System Impact on Small Dialysis Organizations (STEPPS).

BACKGROUND: Launched in January 2011, the prospective payment system (PPS) for the US Medicare End-Stage Renal Disease Program bundled payment for services previously reimbursed independently. Small dialysis organizations may be particularly susceptible to the financial implications of the PPS. The ongoing Study to Evaluate the Prospective Payment System Impact on Small Dialysis Organizations (STEPPS) was designed to describe trends in care and outcomes over the period of PPS implementation. This report details early results between October 2010 and June 2011. STUDY DESIGN: Prospective observational cohort study of patients from a sample of 51 small dialysis organizations. SETTING & PARTICIPANTS: 1,873 adult hemodialysis and peritoneal dialysis patients. OUTCOMES: Secular trends in processes of care, anemia, metabolic bone disease management, and red blood cell transfusions. MEASUREMENTS: Facility-level data are collected quarterly. Patient characteristics were collected at enrollment and scheduled intervals thereafter. Clinical outcomes are collected on an ongoing basis. RESULTS: Over time, no significant changes were observed in patient to staff ratios. There was a temporal trend toward greater use of peritoneal dialysis (from 2.4% to 3.6%; P = 0.09). Use of cinacalcet, phosphate binders, and oral vitamin D increased; intravenous (IV) vitamin D use decreased (P for trend for all <0.001). Parathyroid hormone levels increased (from 273 to 324 pg/dL; P < 0.001). Erythropoiesis-stimulating agent doses decreased (P < 0.001 for IV epoetin alfa and IV darbepoetin alfa), particularly high doses. Mean hemoglobin levels decreased (P < 0.001), the percentage of patients with hemoglobin levels <10 g/dL increased (from 12.7% to 16.8%), and transfusion rates increased (from 14.3 to 19.6/100 person-years; P = 0.1). Changes in anemia management were more pronounced for African American patients. LIMITATIONS: Limited data were available for the prebundle period. Secular trends may be subject to the ecologic fallacy and are not causal in nature. CONCLUSIONS: In the period after PPS implementation, IV vitamin D use decreased, use of oral therapies for metabolic bone disease increased, erythropoiesis-stimulating agent use and hemoglobin levels decreased, and transfusion rates increased numerically.

Interaction of FTO and physical activity level on adiposity in African-American and European-American adults: the ARIC study.

Physical inactivity accentuates the association of variants in the FTO locus with obesity-related traits but evidence is largely lacking in non-European populations. Here we tested the hypothesis that physical activity (PA) modifies the association of the FTO single-nucleotide polymorphism (SNP) rs9939609 with adiposity traits in 2,656 African Americans (AA) (1,626 women and 1,030 men) and 9,867 European Americans (EA) (5,286 women and 4,581 men) aged 45-66 years in the Atherosclerosis Risk in Communities (ARIC) study. Individuals in the lowest quintile of the sport activity index of the Baecke questionnaire were categorized as low PA. Baseline BMI, waist circumference (WC), and skinfold measures were dependent variables in regression models testing the additive effect of the SNP, low PA, and their interaction, adjusting for age, alcohol use, cigarette use, educational attainment, and percent European ancestry in AA adults, stratified by sex and race/ethnicity. rs9939609 was associated with adiposity in all groups other than AA women. The SNP × PA interaction was significant in AA men (P ≤ 0.002 for all traits) and EA men (P ≤ 0.04 for all traits). For each additional copy of the A (risk) allele, WC in AA men was higher in those with low PA (ß(lowPA): 5.1 cm, 95% confidence interval (CI): 2.6-7.5) than high PA (ß(highPA): 0.7 cm, 95% CI: -0.4 to 1.9); P (interaction) = 0.002). The interaction effect was not observed in EA or AA women. FTO SNP × PA interactions on adiposity were observed for AA as well as EA men. Differences by sex require further examination.

Genome-wide meta-analysis identifies regions on 7p21 (AHR) and 15q24 (CYP1A2) as determinants of habitual caffeine consumption.

We report the first genome-wide association study of habitual caffeine intake. We included 47,341 individuals of European descent based on five population-based studies within the United States. In a meta-analysis adjusted for age, sex, smoking, and eigenvectors of population variation, two loci achieved genome-wide significance: 7p21 (P = 2.4 × 10(-19)), near AHR, and 15q24 (P = 5.2 × 10(-14)), between CYP1A1 and CYP1A2. Both the AHR and CYP1A2 genes are biologically plausible candidates as CYP1A2 metabolizes caffeine and AHR regulates CYP1A2.

China's transition: the effect of rapid urbanization on adult occupational physical activity.

China has recently undergone rapid social and economic change. Increases in urbanization have led to equally rapid shifts toward more sedentary occupations through the acquisition of new technology and transitions away from a mostly agricultural economy. Our purpose was to utilize a detailed measure of urbanicity comprising 10 dimensions of urban services and infrastructure to examine its effects on the occupational physical activity patterns of Chinese adults. Longitudinal data were from individuals aged 18-55 from the years 1991-1997 of the China Health and Nutrition Survey (N=4376 men and 4384 women). Logistic multilevel regression analyses indicated that men had 68% greater odds, and women had 51% greater odds, of light versus heavy occupational activity given the mean change in urbanization over the 6-year period. Further, simulations showed that light occupational activity increased linearly with increasing urbanization. After controlling for individual-level predictors, community-level urbanization explained 54% and 40% of the variance in occupational activity for men and women, respectively. This study provides empirical evidence of the reduction in intensity of occupational activity with modernization. It is likely that urbanization will continue unabated in China and this is liable to lead to further transitions in the labor market resulting in additional reductions in work-related activity. Because occupational activity remains the major source of energy expenditure for adults, unless alternative forms are widely adopted, the Chinese population is at risk of dramatic increases in the numbers of overweight and obese individuals.

Cluster analysis methods help to clarify the activity-BMI relationship of Chinese youth.

OBJECTIVE: To use cluster analysis to create patterns of overall activity and inactivity in a diverse sample of Chinese youth and to evaluate their use in predicting overweight status. RESEARCH METHODS AND PROCEDURES: The study populations were drawn from the 1997 and 2000 years of the longitudinal China Health and Nutrition Survey, comprised of 2702 and 2641 schoolchildren in the 1997 and 2000 cross-sectional samples, respectively, and 1175 children in the longitudinal cohort. Cluster analysis was used to group children into nonoverlapping activity/inactivity "clusters" that were subsequently used in models of prevalent and incident overweight. Results were compared with traditional models, with activity and inactivity coded separately, to assess whether further insight was gained with the cluster analysis methodology. RESULTS: Moderately and highly active youth were shown to have significantly decreased odds of overweight in both cross-sectional and longitudinal analyses using cluster analysis. In incident longitudinal models, youth in the high activity/high inactivity cluster had the lowest odds of overweight [odds ratio=0.12 (0.03, 0.44)]; in contrast, results from traditional models failed to show any significant relationship between overweight and activity or inactivity. DISCUSSION: Cluster analysis methods allow researchers to simultaneously capture activity and inactivity in new ways. In this comparative study, only with the clustering methodology did we find a significant effect of activity on incident overweight, furthering our ability to examine this complex relationship. Interestingly, no effect of increasing levels of inactivity was observed using either method, indicating that activity seems to be the more important determinant of overweight in this population.