Search

This study aims to examine whether greater frequency of depressive symptoms associates with increased risk of incident heart failure (HF).Depressive symptoms associate with adverse prognosis in patients with prevalent HF. Their association with incident HF is less studied, particularly in low-income and minority individuals.We studied 23,937 Black or White Southern Community Cohort Study participants (median age: 53 years, 70% Black, 64% women) enrolled between 2002 and 2009, without prevalent HF, receiving Centers for Medicare and Medicaid Services coverage. Cox models adjusted for traditional HF risk factors, socioeconomic and behavioral factors, social support, and antidepressant medications were used to quantify the association between depressive symptoms assessed at enrollment via the Center for Epidemiologic Studies Depression Scale (CESD-10) and incident HF ascertained from Centers for Medicare and Medicaid Services International Classification of Diseases-9th Revision (ICD-9) (code: 428.x) and ICD-10 (codes: I50, I110) codes through December 31, 2016.The median CESD-10 score was 9 (IQR: 5 to 13). Over a median 11-year follow-up, 6,081 (25%) participants developed HF. The strongest correlates of CESD-10 score were antidepressant medication use, age, and socioeconomic factors, rather than traditional HF risk factors. Greater frequency of depressive symptoms associated with increased incident HF risk (per 8-U higher CESD-10 HR: 1.04; 95% CI: 1.00 to 1.09; P = 0.038) without variation by race or sex. The association between depressive symptoms and incident HF varied by antidepressant use (interaction-P = 0.03) with increased risk among individuals not taking antidepressants.In this high-risk, low-income, cohort of predominantly Black participants, greater frequency of depressive symptoms significantly associates with higher risk of incident HF.

Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values 105 mL·min –1 ·1.73 m –2 , compared with those with eGFR between 60 and 105 mL·min –1 ·1.73 m –2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR –1 ·1.73 m –2 , with a 14% (95% CI, 3%–27%) higher CHD risk per 5 mL·min –1 ·1.73 m –2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min –1 ·1.73 m –2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

Introduction Insulin resistance and obesity are prevalent in chronic kidney disease (CKD) patients. The interaction of body mass index (BMI) and kidney function across the continuum of estimated glomerular filtration rate (eGFR) is unknown. Methods In a cross-sectional study of 139 patients, 52 with CKD stages 3 and 4 and 87 patients with normal eGFR, we measured the insulin sensitivity index (ISI) using the hyperinsulinemic euglycemic clamp and homeostasis model assessment of insulin resistance (HOMA-IR). We investigated the interaction between eGFR and BMI in their association with ISI and HOMA-IR using linear models with robust standard errors. Results Median age was 56 (42, 66) years, 50.4% were female, and 36% were African American. Patients with low eGFR (∼30 ml/min per 1.73 m2) had low ISI (2.3 mg/min per μU/ml) regardless of BMI. Among patients with preserved eGFR (>90 ml/min per 1.73m2), BMI had a greater effect on ISI (6.3 mg/min per μU/ml at a BMI of 20 kg/m2 vs. 4.6 mg/min per μU/ml at a BMI of 30 kg/m2) (P for interaction = 0.046). In models adjusted for demographics, and log transformed interleukin-6, high-sensitivity C-reactive protein, leptin, and adiponectin, a 1-SD (28 ml/min per 1.73 m2) lower eGFR was associated with a statistically significant 1.14-unit decrease in ISI (95% confidence interval = −1.80, −0.48) among nonobese patients. Among obese patients, the effect estimate was −0.25 (95% confidence interval = −0.88, 0.39). The association between BMI and HOMA-IR was stronger in patients with lower eGFR (P for interaction = 0.005). Conclusion Both eGFR and BMI are independently associated with insulin sensitivity, but the strength of the association between BMI and insulin sensitivity varies significantly across eGFR., Graphical abstract

BACKGROUND: Insulin resistance is associated with cardiovascular disease risk and worsened kidney function. Patients with CKD have higher levels of insulin resistance. Elevated levels of copeptin (a surrogate for vasopressin levels) have been associated with an increased incidence and progression of CKD, and with incident diabetes mellitus. The purpose of our study was to examine the relationship between insulin resistance, copeptin, and CKD. METHODS: We performed a cross-sectional study to investigate if insulin resistance was associated with higher copeptin levels in nondiabetic patients with stage 3–4 CKD versus controls. We measured plasma copeptin levels and used data from 52 patients with stage 3–4 CKD and 85 controls (eGFR ≥60 ml/min per 1.73 m(2)) enrolled in the Insulin Resistance in Chronic Kidney Disease (IRCKD) study. We then used a multivariable linear-regression model to assess the independent relationship between peripheral or hepatic insulin resistance and copeptin across levels of eGFR. RESULTS: We found that in patients with CKD (eGFR of 30–60 ml/min per 1.73 m(2)), but not in controls, peripheral insulin resistance was significantly correlated with higher levels of log copeptin (r=−0.21, P=0.04). In patients with CKD, when adjusted for age, sex, BMI, serum osmolality, log IL6, and log leptin/adiponectin ratio, each 1 SD decrease in insulin sensitivity was associated with a 39% increase in serum copeptin levels. The relationship between hepatic insulin resistance, copeptin, and eGFR is similar between controls and patients with reduced eGFR. CONCLUSION: Peripheral insulin resistance is associated with elevated copeptin levels in nondiabetic patients with stage 3–4 CKD. Further research into how the interaction between peripheral insulin resistance and elevated vasopressin affects CKD progression could be of interest.

Common variants in theWe tested associations betweenAmong 648,593 veterans, mean (SD) age was 62 (14) years; 9% were female, 19% Black, and 8% Hispanic. In White patients, the rs4293393Robust associations were observed between

Background: Approximately 13% of black individuals carry 2 copies of the apolipoprotein L1 ( APOL1 ) risk alleles G1 or G2, which are associated with 1.5- to 2.5-fold increased risk of chronic kidney disease. There have been conflicting reports as to whether an association exists between APOL1 risk alleles and cardiovascular disease (CVD) that is independent of the effects of APOL1 on kidney disease. We sought to test the association of APOL1 G1/G2 alleles with coronary artery disease, peripheral artery disease, and stroke among black individuals in the Million Veteran Program. Methods: We performed a time-to-event analysis of retrospective electronic health record data using Cox proportional hazard and competing-risks Fine and Gray subdistribution hazard models. The primary exposure was APOL1 risk allele status. The primary outcome was incident coronary artery disease among individuals without chronic kidney disease during the 12.5-year follow-up period. We separately analyzed the cross-sectional association of APOL1 risk allele status with lipid traits and 115 cardiovascular diseases using phenome-wide association. Results: Among 30 903 black Million Veteran Program participants, 3941 (13%) carried the 2 APOL1 risk allele high-risk genotype. Individuals with normal kidney function at baseline with 2 risk alleles had slightly higher risk of developing coronary artery disease compared with those with no risk alleles (hazard ratio, 1.11 [95% CI, 1.01–1.21]; P =0.039). Similarly, modest associations were identified with incident stroke (hazard ratio, 1.20 [95% CI, 1.05–1.36; P =0.007) and peripheral artery disease (hazard ratio, 1.15 [95% CI, 1.01–1.29l; P =0.031). When both cardiovascular and renal outcomes were modeled, APOL1 was strongly associated with incident renal disease, whereas no significant association with the CVD end points could be detected. Cardiovascular phenome-wide association analyses did not identify additional significant associations with CVD subsets. Conclusions: APOL1 risk variants display a modest association with CVD, and this association is likely mediated by the known APOL1 association with chronic kidney disease.

Introduction The Southern Community Cohort Study is a prospective study of low socioeconomic status (SES) blacks and whites from the southeastern US, where the burden of end-stage renal disease (ESRD) and its risk factors are high. We tested whether the 2.4-fold elevated risk of ESRD we previously observed in blacks compared to whites was explained by differences in baseline kidney function. Methods We conducted a case-cohort study of incident ESRD cases (n = 737) with stored blood and a probability sampled subcohort (n = 4238) and calculated estimated glomerular filtration rate (eGFR) from serum creatinine. 86% of participants were enrolled from community health centers in medically underserved areas and 14% from the general population in 12 states in the southeastern United States. Incident ESRD after entry into the cohort was ascertained by linkage of the cohort with the US Renal Data System (USRDS). Results Median (25th, 75th percentile) eGFR at baseline was 63.3 (36.0, 98.2) ml/min/1.73m2 for ESRD cases and 103.2 (86.0, 117.9) for subcohort. Black ESRD cases had higher median (25th, 75th) eGFR [63.3 (35.9, 95.9)] compared to whites [59.1 (39.4, 99.2)]. In multivariable Cox models accounting for sampling weights, baseline eGFR was a strong predictor of ESRD risk, and an interaction with race was detected (P = 0.029). The higher ESRD risk among blacks relative to whites persisted (hazard ratio: 2.58; 95% confidence interval: 1.65, 4.03) after adjustment for eGFR. Conclusion In this predominantly lower SES cohort, the racial disparity in ESRD risk is not explained by differences in baseline kidney function. Electronic supplementary material The online version of this article (10.1186/s12882-019-1502-z) contains supplementary material, which is available to authorized users.

Apparent treatment-resistant hypertension (ATRH) has been linked to end-stage kidney disease (ESKD) and cardiovascular disease. We tested the hypothesis that the effect of ATRH on ESKD is greater in Black patients than in White patients and investigated the effect of ATRH on ESKD independent of APOL1 genotype. In a retrospective cohort of 139 685 hypertensive veterans (22% Black, 5% women) in the Million Veteran Program, ATRH was defined as failure to achieve outpatient blood pressure P -interactionAPOL1 genotype. Patients with ATRH experienced excess ESKD and cardiovascular disease risk. This excess ATRH-related ESKD risk was magnified among Black patients independently of APOL1 genotype. Targeted treatment of ATRH could curtail ESKD and cardiovascular disease incidence.

Introduction: Reproductive factors might have an effect on the development of heart failure (HF). Early age at menopause has been linked with increased risk of cardiovascular disease; however, there is limited evidence on the relationship between early menopause and HF. Hypothesis: We assessed the hypothesis that earlier age at menopause is associated with increased risk of incident HF among women in the southeastern United States. Methods: The Southern Community Cohort Study enrolled ~86,000 low-income black and white adults in 12 southeastern states (2002-2009). Participants for this analysis were 11,948 women who were postmenopausal at enrollment, had no history of HF, and were using Centers for Medicare or Medicaid Services (CMS). HF events were ascertained using International Classification of Diseases , Ninth Revision, codes 428.x via linkage of the cohort with CMS Research Identifiable Files through December 31, 2016. Early menopause was defined as self-reported age at menopause less than 45 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed from multivariable Cox regression models, overall and by race, adjusting for demographic, lifestyle, and reproductive factors, including reason for menopause. Results: At baseline, median age was 58 years and 65% of participants were black. Among women with early menopause, 76% (n=4,836) had menopause due to hysterectomy or oophorectomy. In women with later menopause, 74% (n=4,102) reported natural menopause. During a median follow-up of 9.5 years (interquartile range 6.0-11.8), 3,808 incident HF events occurred. Compared to women with later onset of menopause, those with early menopause had increased HF risk (HR: 1.13, 95% CI: 1.04-1.23). Risk of HF associated with early menopause differed between white and black women (p-value for interaction: 0.02). In stratified analyses, white women with early menopause had an increased risk of HF compared to those with later onset of menopause (HR: 1.26, 95% CI: 1.11-1.43), although there was no association between early age at menopause and risk of HF in black women (HR: 1.07, 95% CI: 0.98-1.18). Conclusions: In conclusion, in this largely low-income population, early menopause is associated with an increased risk of developing HF and associations differ by race. Women with early menopause represent a potential target population for future interventions aimed to decrease risk of HF and cardiovascular risk factors.

Introduction: Approximately 10-20% of treated hypertensive patients have apparent treatment-resistant hypertension (ATRH), which is associated with adverse cardiovascular outcomes. Our goal was to develop a prediction model for ATRH that combines clinical data and a genetic risk score (GRS) for ATRH. Methods: Study participants were 232,925 patients with hypertension (HTN) enrolled in the Million Veteran Program receiving care at the VA from 2004 to 2017. 21% were black and 6% were women. Incident ATRH was defined as failure to achieve outpatient blood pressure (BP) Results: Over a 13.5-year follow-up, 20,536 and 2,247 incident ATRH cases were observed in the training and test data. In the training data, the clinical model had reasonable discriminant ability (C=0.706) and good calibration (Brier score = 0.085). Age, diabetes, and SBP were the strongest predictors of ATRH. In the test dataset, a 1-IQR increase in the GRS was associated with a 10% (95%CI: 1.04-1.17) higher odds of ATRH. In the test dataset, the LR χ 2 , C-statistic and Brier score for the clinical model were 1075, 0.705 and 0.077 respectively. In the GRS-enriched model, these values were 1107, 0.708 and 0.077. The net reclassification improvement was 1.5% (95% CI: 0.3-2.8, p=0.02). The GRS-enriched model had excellent calibration with an optimism-corrected calibration slope of 0.95. Conclusion: Augmenting a clinical prediction model for ATRH with a GRS comprising GWAS-significant SNPs improved model fit but not discriminant ability. Future work will evaluate whether models incorporating polygenic risk scores with a larger number of variants may refine ATRH risk prediction and stratification and evaluate race-specific performance.

Objectives The purpose of this study was to examine race- and sex-based variation in the associations between modifiable risk factors and incident heart failure (HF) among the SCCS (Southern Community Cohort Study) participants. Background Low-income individuals in the southeastern United States have high HF incidence rates, but relative contributions of risk factors to HF are understudied in this population. Methods We studied 27,078 black or white SCCS participants (mean age: 56 years, 69% black, 63% women) enrolled between 2002 and 2009, without prevalent HF, receiving Centers for Medicare and Medicaid Services. The presence of hypertension, diabetes mellitus, physical underactivity, high body mass index, smoking, high cholesterol, and poor diet was assessed at enrollment. Incident HF was ascertained using International Classification of Diseases-9th revision, codes 428.x in Centers for Medicare and Medicaid Services data through December 31, 2010. Individual risk and population attributable risk for HF for each risk factor were quantified using multivariable Cox models. Results During a median (25th, 75th percentile) 5.2 (3.1, 6.7) years, 4,341 (16%) participants developed HF. Hypertension and diabetes were associated with greatest HF risk, whereas hypertension contributed the greatest population attributable risk, 31.8% (95% confidence interval: 27.3 to 36.0). In black participants, only hypertension and diabetes associated with HF risk; in white participants, smoking and high body mass index also associated with HF risk. Physical underactivity was a risk factor only in white women. Conclusions In this high-risk, low-income cohort, contributions of risk factors to HF varied, particularly by race. To reduce the population burden of HF, interventions tailored for specific race and sex groups may be warranted.

ObjectiveTo examine whether lifestyle factors, including sedentary time and physical activity, could independently contribute to risk of end-stage renal disease (ESRD).Study designCase-cohort study.SettingSouth-eastern USA.ParticipantsThe Southern Community Cohort Study recruited ~86 000 black and white participants from 2002 to 2009. We assembled a case cohort of 692 incident ESRD cases and a probability sample of 4113 participants.PredictorsSedentary time was calculated as hours/day from daily sitting activities. Physical activity was calculated as metabolic equivalent (MET)-hours/day from engagement in light, moderate and vigorous activities.OutcomesIncident ESRD.ResultsAt baseline, among the subcohort, mean (SD) age was 52 (8.6) years, and median (25th, 75th centile) estimated glomerular filtration rate (eGFR) was 102.8 (85.9–117.9) mL/min/1.73 m2. Medians (25th–75th centile) for sedentary time and physical activity were 8.0 (5.5–12.0) hours/day and 17.2 (8.7–31.9) MET-hours/day, respectively. Median follow-up was 9.4 years. We observed significant interactions between eGFR and both physical activity and sedentary behaviour (p2. The inverse association is most pronounced at physical activity levels >27 MET-hours/day. High levels of sitting time were associated with increased ESRD risk only among those with reduced kidney function (eGFR ≤30 mL/min/1.73 m2); this association was attenuated after excluding the first 2 years of follow-up.ConclusionsIn a population with a high prevalence of chronic kidney disease risk factors such as hypertension and diabetes, physical activity appears to be associated with reduced risk of ESRD among those with preserved kidney function. A positive association between sitting time and ESRD observed among those with advanced kidney disease is likely due to reverse causation.

Chronic kidney disease (CKD), defined by low estimated glomerular filtration rate (eGFR), contributes to global morbidity and mortality. Here we conduct a transethnic Genome-Wide Association Study of eGFR in 280,722 participants of the Million Veteran Program (MVP), with replication in 765,289 participants from the Chronic Kidney Disease Genetics (CKDGen) Consortium. We identify 82 previously unreported variants, confirm 54 loci, and report interesting findings including association of the sickle cell allele of betaglobin among non-Hispanic blacks. Our transcriptome-wide association study of kidney function in healthy kidney tissue identifies 36 previously unreported and nine known genes, and maps gene expression to renal cell types. In a Phenome-Wide Association Study in 192,868 MVP participants using a weighted genetic score we detect associations with CKD stages and complications and kidney stones. This investigation reinterprets the genetic architecture of kidney function to identify the gene, tissue, and anatomical context of renal homeostasis and the clinical consequences of dysregulation., Persistently low levels of estimated glomerular filtration rate (eGFR) are a biomarker of chronic kidney disease. Here, the authors reinterpret the genetic architecture of kidney function across ancestries, to identify not only genes, but the tissue and anatomical contexts of renal homeostasis.

Background: Patients with chronic kidney disease (CKD) are at high risk of cardiovascular disease (CVD) and premature death. Insulin resistance (IR) is prevalent in CKD and is one of the most important nontraditional CV risk factors in CKD. We investigated the association between practical insulin sensitivity (IS) indices and the gold standard hyperinsulinemic euglycemic clamp (HEGC) among CKD (estimated GFR = 15-59ml/min) and non-CKD persons. Methods: The relationship of insulin sensitivity in kidney disease (RISKD) study was a cross-sectional investigation involving 140 nondiabetic patients (52 CKD and 88 non-CKD). Insulin sensitivity was assessed by the HEGC-derived insulin sensitivity index (ISI), homeostatic model assessment for insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), McAuley index, and leptin-adiponectin ratio (LAR). Spearman correlation (rs) and multivariable linear models were used to investigate the association between the practical indices and ISI. Results: Compared to non-CKD controls, CKD patients had a higher prevalence of IR based on published cut-points for practical IS markers (HOMA-IR: 83% vs. 32%, p Conclusion: Patients with CKD had a higher prevalence of IR. While all IS indices showed significant correlations with clamp-derived ISI, HOMA-IR performed best in CKD patients while McAuley performed best in non-CKD persons. These data suggest that HOMA-IR is the preferred practical index to be used to assess insulin sensitivity in large cohort investigations involving CKD patients. Disclosure B.C. McMullan: None. E.A. Akwo: None. A.M. Hung: None. Funding U.S. Department of Veterans Affairs (I01CX000982 to A.M.H.)

Background The myocardial contraction fraction (MCF: stroke volume to myocardial volume) is a volumetric measure of left ventricular myocardial shortening. We examined the relationship of MCF, measured by cardiac magnetic resonance imaging (cMRI), to incident cardiovascular (CV) events within the Multi-Ethnic Study of Atherosclerosis (MESA). Methods Participants (n = 5000, aged 45–84 years) underwent cMRI. Primary outcome: CVD events (myocardial infarction, resuscitated cardiac arrest, stroke, coronary heart disease: CHD death, and stroke death). Secondary outcomes: CHD and heart failure (HF) events. Cox proportional hazards regression was used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for outcomes. Results There were 299 incident CVD, 188 CHD, and 151 HF events over 10.2 years. The lowest MCF quartile was associated with an increased risk for incident CVD [HR 2.42, CI: 1.58–3.72], CHD [HR 2.32, CI: 1.36–3.96] and HF events [HR 1.99, CI: 1.15–3.44]. In a model adjusted for demographics, CV risk factors, antihypertensive and lipid-lowering medication use, each standard deviation decrease in MCF was associated with incident CVD [HR 1.42, CI: 1.23–1.64], CHD [HR 1.40, CI: 1.17–1.67] and HF [HR 1.58, CI: 1.30–1.94]. In a subgroup analysis of participants with preserved ejection fraction and without left ventricular hypertrophy, the lowest MCF quartile and each standard deviation decrease in MCF was also associated with an increased risk for incident CVD in fully-adjusted analyses. Conclusions MCF is a novel measure that can be measured using cMRI. In this multi-ethnic cohort, MCF is a measure that can be used to predict incident CVD events.

International audience; In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.

OBJECTIVES/GOALS: Early age at menopause has been linked to increased risk of cardiovascular disease; however, there is limited evidence for a relationship between early menopause and heart failure (HF). We examined whether early menopause is associated with incident HF among women in the southeastern United States. METHODS/STUDY POPULATION: The Southern Community Cohort Study enrolled ~86,000 low-income black and white adults from 2002 to 2009. Participants for this analysis were 11,948 women who were postmenopausal at enrollment, had no history of HF, and were on Medicaid or Medicare. HF events were ascertained using ICD-9 codes 428.x via linkage of the cohort with CMS Research Identifiable Files through December 31, 2010. Early menopause was defined as self-reported age at menopause less than 45 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed from multivariable Cox regression models, overall and by race, adjusting for demographic, lifestyle, and reproductive factors, including reason for menopause. RESULTS/ANTICIPATED RESULTS: At baseline, mean age was 58±9 years, and 65% of participants were black. Among women with early menopause, 76% (n = 4,836) had menopause due to hysterectomy or oophorectomy. In women with later menopause, 74% (n = 4,102) reported natural menopause. During a median follow-up of 5.0 years (range 3.1-6.7), 2,157 incident HF events occurred. Compared with women with later onset of menopause, those with early menopause had increased HF risk (HR: 1.27, 95% CI: 1.10–1.47). Risk of HF associated with early menopause was similar in white and black women (p-value for interaction: 0.13). DISCUSSION/SIGNIFICANCE OF IMPACT: In this largely low-income population, early menopause was associated with an increased risk of developing HF. Women with early menopause represent a potential target population for future interventions to decrease risk of HF and cardiovascular risk factors.

OBJECTIVES/GOALS: African-Americans have a 3-fold higher risk of end-stage kidney disease (ESKD) compared to Whites due in part to APOL1 risk alleles. Whether resistant hypertension (RH) magnifies the risk of ESKD among African Americans beyond APOL1 is not known. We examined the interaction between RH and race on ESKD risk and the independent effect of RH beyond APOL1. METHODS/STUDY POPULATION: We designed a retrospective cohort of 240,038 veterans with HTN, enrolled in the Million Veteran Program with an estimated glomerular filtration rate (eGFR) >30 ml/min/1.73m2. The primary exposure was incident RH (time-varying). The primary outcome was incident ESKD during a 13.5 year follow up: 2004-2017. Secondary outcomes were myocardial infarction (MI), stroke, and death. Incident RH was defined as failure to achieve outpatient blood pressure (BP) APOL1 genotype. Multivariable Cox models (with Fine-Gray competing-risks models as sensitivity analyses) were used to examine independent effects. RESULTS/ANTICIPATED RESULTS: The cohort comprised 235,046 veterans; median age was 60 years; 21% were African-American and 6% were women, with 23,010 incident RH cases observed over a median follow-up time of 10.2 years [interquartile range, 5.6-12.6]. Patients with RH had higher incidence rates [per 1000 person-years] of ESKD (4.5 vs. 1.3), myocardial infarction (6.5 vs. 3.0), stroke (16.4 vs. 7.6) and death (12.0 vs. 6.9) than non-resistant hypertension (NRH). African-Americans with RH had a 2.6-fold higher risk of ESKD compared to African-Americans with NRH; 3-fold the risk of Whites with RH, and 9.6-fold the risk of Whites with NRH [p-interactionAPOL1 genotype and in the subset of African-Americans with no APOL1 risk alleles, RH was associated with an adjusted 2.75-fold (95% CI: 2.00-3.50) higher risk of incident ESKD. DISCUSSION/SIGNIFICANCE OF IMPACT: RH was independently associated with a higher risk of ESKD and cardiovascular outcomes, especially among African-Americans. This elevated risk is independent of APOL1 genotype. Interventions that achieve BP targets among patients with RH could curtail the incidence of ESKD and cardiovascular outcomes in this high-risk population. CONFLICT OF INTEREST DESCRIPTION: None.

OBJECTIVES/SPECIFIC AIMS: The main aim of this study was to investigate the interaction between glomerular filtration rate (GFR) and body mass index (as well as serum leptin) as determinants of peripheral and central insulin sensitivity (IS). METHODS/STUDY POPULATION: This was a cross-sectional investigation of 140 nondiabetic participants – 56 with CKD (GFR = 15-59 ml/min/1.73m2) and 94 with normal GFR (≥ 60 ml/min/1.73m2) – recruited as part of the relationship of insulin sensitivity in kidney disease and vascular health (RISKD) study. Peripheral (skeletal muscle) and central (hepatic) IS were assessed with the hyperinsulinemic euglycemic glucose clamp (HEGC) and homeostasis assessment of insulin resistance (HOMA-IR) respectively. Creatinine-based estimated GFR (eGFR) was obtained using the CKD-EPI equation and body mass index (BMI) was computed from baseline weight and height measurements. Linear regression models with robust standard errors (to relax homoscedasticity assumptions) and interaction terms were used to investigate GFR and BMI as predictors of HEGC-derived insulin sensitivity index (ISI) and HOMA-IR. RESULTS/ANTICIPATED RESULTS: The mean (SD) age was 53.9 (14.5) years; 50.7% were female and 36.7% were African-American. Compared to controls, CKD patients had significantly lower mean (SD) ISI [5.4 (3.2) vs. 3.1 (1.6), p < 0.0001]. Log ISI was positively correlated (r = 0.39, p < 0.0001) with eGFR and inversely correlated (−0.30, p < 0.0001) with BMI and log leptin (−0.42, p < 0.0001). In multivariable models adjusted for age, sex and race, a 10 ml/min/1.73m2 lower eGFR was associated with a greater decrease in ISI among non-obese (0.48; 95% CI: −0.25, −0.70) compared to obese participants (−0.18; 95% CI: −0.02, −0.35) (p-interaction = 0.04). Patients with low eGFR (in particular, the lower margin of the CKD stage 3 range, 30ml/min) had lower ISI even with BMI within normal range (Figure 1a). At higher eGFR, BMI had a greater impact on ISI. P-interaction = 0.046, for differential BMI effects at lower vs. higher eGFR. Log HOMA-IR was inversely correlated with eGFR (r = - 0.49, p < 0.0001) and positively correlated with BMI (r = 0.52, p < 0.0001) and log leptin (0.46, p < 0.0001). HOMA-IR was lower for persons with higher GFR compared to lower GFR, at any BMI value. For example, at a BMI of 30 and a GFR of 120, HOMA-IR was 1.2 compared to 4.8 at a GFR of 30 (Figure 1b). Also, persons with high GFR had low HOMA-IR even with BMI in the obese range. BMI had a greater effect on HOMA-IR at lower eGFR. P-interaction = 0.005, for differential BMI effects at lower vs. higher eGFR. Similar findings were obtained when using log leptin in lieu of BMI in models for ISI and HOMA-IR. DISCUSSION/SIGNIFICANCE OF IMPACT: Measures of adiposity (BMI and leptin) and GFR were independently predictive of insulin sensitivity (IS) but the magnitude of the effect of BMI (or leptin) on IS varied significantly across GFR levels and type of IS (peripheral versus central). The effect of BMI on central IS (HOMA-IR) was more pronounced at lower GFR with small changes in BMI translating into greater variations in IS. Conversely, at low GFR, peripheral IS (ISI) is less affected by BMI. Persons with GFR at the lower margin of the CKD stage 3 range were significantly insulin resistant (low ISI) regardless of their BMI. More studies are required to further elucidate these interaction patterns for central and peripheral IS.

Background and aims Consumption of polyunsaturated fatty acids (PUFA), especially the n3-series, may protect against cardiovascular disease (CVD), but recent randomized studies have failed to demonstrate these benefits. One of the prevailing hypotheses is that PUFA intake may not confer benefits beyond those provided by statins, but studies comparing statin users to non-users with regard to effects of PUFA are lacking. Methods and results Black and white men and women (n = 69,559) in the Southern Community Cohort Study were studied. Cox regression models adjusting for age, sex, race, BMI, recruitment site, education, income, smoking, diabetes, and dietary variables were used. Results At baseline the mean ± SD age was 52 ± 9 years, 60% of participants were women, 54% had hypertension and 16% used statins. We observed modest inverse associations between n3-PUFA and n6-PUFA intake with mortality among non-statin users but not among statin users. In adjusted analyses, the HRs (95% CIs) for all-cause mortality (6,396 deaths over a median of 6.4 years) comparing the highest to the lowest quintile were 0.90 (0.82–1.00) for n3-PUFA and 0.80 (0.70–0.92) for n6-PUFA among non-statin users, whereas they were 1.06 (0.87–1.28) and 0.96 (0.78–1.19) for n3-PUFA and n6-PUFA, respectively, among statin users. Conclusions Our results suggest potential benefits of PUFA consumption on mortality which are only apparent in the absence of statin therapy. It seems prudent to consider the potential benefit of PUFA consumption in the primary prevention of CVD among patients who are not candidates for statin therapy but are at increased risk for CVD and mortality.

Background Cardiac rehabilitation (CR) is underutilized in the United States, with fewer than 20% of eligible patients participating in CR programs. Individual socioeconomic status is associated with CR utilization, but data regarding neighborhood characteristics and CR are sparse. We investigated the association of neighborhood socioeconomic context with CR participation in the SCCS (Southern Community Cohort Study). Methods and Results The SCCS is a prospective cohort study of 84 569 adults in the southeastern United States from 2002 to 2009, 52 117 of whom have Medicare or Medicaid claims. Using these data, we identified participants with hospitalizations for myocardial infarction, percutaneous coronary intervention, or coronary artery bypass surgery and ascertained their CR utilization. Neighborhood socioeconomic context was assessed using a neighborhood deprivation index derived from 11 census‐tract level variables. We analyzed the association of CR utilization with neighborhood deprivation after adjusting for individual socioeconomic status. A total of 4096 SCCS participants (55% female, 57% black) with claims data were eligible for CR. CR utilization was low, with 340 subjects (8%) participating in CR programs. Study participants residing in the most deprived communities (highest quintile of neighborhood deprivation) were less than half as likely to initiate CR (odds ratio 0.42, 95% confidence interval, 0.27–0.66, P P Conclusions Lower neighborhood socioeconomic context was associated with decreased CR participation independent of individual socioeconomic status. These data invite research on interventions to increase CR access in deprived communities.

Background Recent data suggest that neighborhood socioeconomic environment predicts heart failure (HF) hospital readmissions. We investigated whether neighborhood deprivation predicts risk of incident HF beyond individual socioeconomic status in a low-income population. Methods and Results Participants were 27 078 whites and blacks recruited during 2002 to 2009 in the SCCS (Southern Community Cohort Study), who had no history of HF and were using Centers for Medicare or Medicaid Services. Incident HF diagnoses through December 31, 2010, were ascertained using International Classification of Diseases , Ninth Revision, codes 428.x via linkage with Centers for Medicare or Medicaid Services research files. Participant residential information was geocoded and census tract determined by a spatial join to the US Census Bureau TIGER/Line Shapefiles. The neighborhood deprivation index was constructed using principal components analysis based on census tract-level socioeconomic variables. Cox models with Huber–White cluster sandwich estimator of variance were used to investigate the association between neighborhood deprivation index and HF risk. The study sample was predominantly middle aged (mean, 55.5 years), black (69%), female (63%), low income (70% earned 50% of participants lived in the most deprived neighborhoods (third neighborhood deprivation index tertile). Over median follow-up of 5.2 years, 4300 participants were diagnosed with HF. After adjustment for demographic, lifestyle, and clinical factors, a 1 interquartile increase in neighborhood deprivation index was associated with a 12% increase in risk of HF (hazard ratio, 1.12; 95% confidence interval, 1.07–1.18), and 4.8% of the variance in HF risk (intraclass correlation coefficient, 4.8; 95% confidence interval, 3.6–6.4) was explained by neighborhood deprivation. Conclusions In this low-income population, scant neighborhood resources compound the risk of HF above and beyond individual socioeconomic status and traditional cardiovascular risk factors. Improvements in community resources may be a significant axis for curbing the burden of HF.

Background— There is a paucity of data on heart failure (HF) incidence among low-income and minority populations. Our objective was to investigate HF incidence and post-HF survival by race and sex among low-income adults in the southeastern United States. Methods and Results— Participants were 27 078 white and black men and women enrolled during 2002 to 2009 in the SCCS (Southern Community Cohort Study) who had no history of HF and were receiving Centers for Medicare and Medicaid Services. Incident HF diagnoses through December 31, 2010 were ascertained using International Classification of Diseases 9th Revision codes 428.x via linkage with Centers for Medicare and Medicaid Services research files. Most participants were black (68.8%), women (62.6%), and earned Conclusions— In this low-income population, HF incidence was higher for all race–sex groups than previously reported in other cohorts. The SCCS is a unique resource to investigate determinants of HF risk in a segment of the population underrepresented in other existing cohorts.

OBJECTIVES/SPECIFIC AIMS: The main aim of this study was to investigate the relationship between measures of adiposity and FGF-23 in a sample of patients with CKD stages 3-4. METHODS/STUDY POPULATION: This study was a clinic-based cross-sectional investigation of 71 CKD patients who underwent body composition and anthropometric assessments as part of the relationship of insulin sensitivity in kidney disease and vascular health (RISKD) study. Dual energy x-ray absorptiometry (DEXA) scans were used to measure total fat mass and body mass index (BMI) was computed using baseline weight and height measurements. Biomarkers included serum FGF-23 (C-terminal), serum leptin, high sensitivity C-reactive protein (hsCRP), serum triglycerides, high density lipoprotein (HDL) cholesterol and total cholesterol. Creatinine-based estimated glomerular filtration rate (eGFR) was computed using the CKD-EPI equation. Multiple linear regression with robust standard errors was used to investigate the relationship between FGF2-3 and measures of adiposity (BMI, total fat mass and serum leptin). Log-transformation was performed for variables (FGF-23, hsCRP and serum lipids) with considerable skewness. RESULTS/ANTICIPATED RESULTS: The median age of the study participants was 68 (IQR: 60, 73) years; 26% were female and 23% were African-American. Median eGFR was 46.9 ml/min/1.73m2 (IQR: 41.9, 52.8), median BMI was 31 kg/m2 (IQR: 27, 35). Log FGF-23 had a significant positive correlation with BMI (r = 0.27, p = 0.02), total fat mass (r = 0.30, p = 0.01) and serum leptin (r = 0.43, p < 0.0001). After full adjustment for age, sex, race, eGFR, log hsCRP, log HDL and log triglycerides, a 50% increase in FGF-23 was associated with a 1 kg/m2 [95% CI: 0.1, 1.9; p = 0.03] increase in BMI, a 2.5 kg [95% CI: 0.2, 4.8; p = 0.03] increase in total fat mass and a 6.7 ng/mL [95% CI: 1.0, 12.4; p = 0.02] increase in serum leptin. DISCUSSION/SIGNIFICANCE OF IMPACT: In this sample of patients with moderate-to-severe CKD, we found a significant independent association between higher FGF-23 levels and higher adiposity (BMI, total fat mass and the pro-atherogenic adipocytokine, leptin). The underlying causes and the implications of these associations − particularly in bone and vascular health − need to be further investigated.

The relationship between body mass index (BMI) and end-stage renal disease (ESRD) may differ between blacks and whites due to underlying metabolic differences. We conducted a nested case–control study of 631 incident ESRD cases and 1,897 matched controls within the Southern Community Cohort Study. Current weight, height, and weight at age 21 were reported at enrollment. Occurrence of ESRD was ascertained by linkage with the United States Renal Data System. With normal BMI (18.5–24.9 kg/m2) as reference, conditional logistic regression was used to calculate adjusted odds ratios (OR) and corresponding 95 % confidence intervals (CI) for ESRD across other BMI categories by race. In subsequent analysis, BMI at age 21 was modeled using restricted cubic splines with 5 knots. Predicted probabilities of incident ESRD were computed from the multivariable logistic models and plotted against BMI at age 21. Among blacks, odds of ESRD were significantly increased among those who were overweight (OR: 1.41; 95 % CI: 1.09, 1.83) or obese (OR: 2.56; 95 % CI: 1.88, 3.47) at age 21. Among whites, the association between ESRD and BMI at age 21 was more pronounced, with corresponding ORs of 2.13 (95 % CI: 0.92, 4.93) and 7.46 (95 % CI: 2.90, 19.21; p-interaction 0.05). Only among whites was high BMI at enrollment associated with ESRD risk; OR for BMI ≥ 40 kg/m2, was 3.31 (95 % CI: 1.08, 10.12). The plot of the predicted probabilities of incident ESRD vs BMI at age 21 showed a monotonic increase in the probability of ESRD after a BMI cutoff ≈ 25Kg/m2 in both whites and blacks but the slope of the curve for whites appeared greater. Our results suggest racial differences in the relationship between BMI, both in early adulthood and middle age, and ESRD. These findings warrant further research into understanding the underlying metabolic differences that may explain these differences.

Reason for Withdrawal This protocol was withdrawn because finishing the project within adequate deadlines could not be achieved To view the published versions of this article, please click the 'Other versions' tab.

Aim We investigated the association of HLA DRB1 and DQB1 alleles, haplotypes and genotypes with unprovoked antibody-negative ketosis-prone atypical diabetes (A − KPD) in comparison to type 2 diabetes (T2D). Methods A − KPD and T2D sub-Saharan African patients aged 19–63 years were consecutively recruited. Patients positive for cytoplasmic islet cell, insulin, glutamic acid decarboxylase or islet antigen-2 autoantibodies were excluded. Odds ratios were obtained via logistic regression after considering alleles with a minimum frequency of 5% in the study population. Bonferroni correction was used in the case of multiple comparisons. Results Among the 130 participants, 35 (27%) were women and 57 (44%) were A − KPD. DRB1 and DQB1 allele frequencies were similar for both A − KPD and T2D patients; they did not confer any substantial risk even after considering type 1 diabetes susceptibility and resistance alleles. We found no association between A − KPD and the derived DRB1*07-DQB1*02:02 (OR: 0.55 [95%CI: 0.17–1.85], P = 0.336); DRB1*11-DQB1*03:01 (OR: 2.42 [95%CI: 0.79–7.42], P = 0.123); DRB1*15-DQB1*06:02 (OR: 0.87 [95%CI: 0.39–1.95], P = 0.731) and DRB1*03:01-DQB1*02:01 (OR: 1.48 [95%CI: 0.55–3.96], P = 0.437) haplotypes. Overall, we did not find any evidence of susceptibility to ketosis associated with DRB1 and DQB1 genotypes (all P > 0.05) in A − KPD compared to T2D. Similar results were obtained after adjusting the analysis for age and sex. Conclusion Factors other than DRB1 and DQB1 genotype could explain the propensity to ketosis in A − KPD. These results need to be confirmed in a larger population with the perspective of improving the classification and understanding of the pathophysiology of A − KPD.

Background: Numerous prospective studies suggest inverse associations between intake of polyunsaturated fatty acids (PUFA) and cardiovascular outcomes. However, recent randomized studies have failed to demonstrate these benefits. One of the prevailing hypotheses is that the beneficial effects of PUFA may now be masked by the widespread use of statins, which lower lipids and blood pressure and are potent modulators of cardiovascular risk. Hypothesis: We tested the hypothesis that the association between PUFA and hypertension varies by statin use. Methods and Results: We conducted a cross-sectional analysis based on 74,658 black and white men and women in the Southern Community Cohort Study. Intake of PUFA was assessed by a food-frequency questionnaire, while history of diagnosed hypertension and statin use were self-reported. The mean±SD age was 52±9 years, body mass index was 30±8 kg/m 2 , and energy intake from PUFA was 8.0±1.8%. Sixty percent of the participants were women and 68% were African Americans. Hypertension (55%), statin use (16%), smoking (40%) and alcohol use (55%) were common in this cohort. In an adjusted logistic model with hypertension as the dependent variable, there was no interaction between PUFA intake and statin therapy ( P =0.13), whereas a significant inverse association was evident between PUFA intake and hypertension among non-statin users ( P for trend = 0.03) but not among statin users ( P for trend = 0.36) ( Table ). Conclusion: In conclusion, these results support a beneficial effect of PUFA consumption on hypertension, which is only apparent in the absence of statin therapy. These findings underscore the need to stratify by statin therapy when randomizing participants to cardiovascular interventions and support the notion that PUFA may be important in cardiovascular risk reduction in patients where statin therapy is not an option.

This study compared the clinical and biochemical characteristics and microvascular complications found in three groups of type 2 diabetes (T2D) patients: Africans living in Africa; African immigrants living in France; and Caucasians living in France.Diagnosed T2D Africans living in Cameroon (n=100) were compared with 98 African migrants diagnosed with T2D after having moved to France, and a group of 199 T2D Caucasian patients living in France. All underwent clinical and biochemical evaluations, and all were assessed for microvascular complications.The median duration of stay of the migrants in France was 15years before being diagnosed with diabetes. Despite similar durations of diagnosis, they were 8.9years younger at the time of diagnosis than Africans living in Cameroon (P0.001). Caucasians and African immigrants in France had lower HbA1c values than Africans in Cameroon (P0.001); they were also more aggressively treated for hypertension and dyslipidaemia and, therefore, had significantly lower blood pressure levels and better lipid profiles. Diabetic nephropathy and retinopathy rates were higher in Cameroon than in the two other groups. After adjusting for age, diabetes duration, HbA1c, hypertension and other covariates, only the prevalence of diabetic nephropathy (OR: 5.61, 95% CI: 2.32-13.53; P0.0001) was higher in Cameroon compared with those living in France.Our results suggest that Africans who emigrate to France may develop diabetes earlier than those staying in their home country. However, the latter may be a reflection of late diagnosis of diabetes. Also, the less adequate diabetes and hypertension control in the latter would explain their higher rates of nephropathy. Large-scale cohorts are now warranted to substantiate these observations.

Background: Persons with diabetes mellitus (DM) have altered cardiac structure and function, which increases heart failure (HF) risk. Myocardial contraction fraction (MCF) is an echocardiographic global measure of fractional shortening recently applied to cardiac MRI. We sought to determine if MCF differed by DM status and if MCF predicts HF in the Multi-Ethnic Study of Atherosclerosis, a cohort which enrolled ethnically diverse adults aged 45-84 who were free of clinical CVD. Methods: Analyses included 4991 with MRI data for whom DM status could be ascertained. Left ventricle (LV) volumes and mass (LVM) were calculated by the summation of disks method from cine short axis images. Ejection fraction (EF) is defined as LV stroke volume (SV) / end diastolic luminal volume. MCF is defined as LV SV/ end diastolic myocardial volume. DM was defined as using hypoglycemic drugs or a fasting glucose>125mg/dl. Linear regression was utilized for cross sectional analyses of the association between MCF and DM status, adjusting for age, gender, race/ethnicity, BMI, systolic BP, BP drugs, and smoking. Cox proportional hazards modeling was used to compare MCF, EF and LV mass quartiles as predictors of HF, adjusting for the above variables and DM. Results: At baseline the mean age was 61.5 (SD 10), 52% were female, 39% white, and 61% minorities; 13% had impaired fasting glucose (IFG) and 12% DM. The table indicates LV measurements. After adjustment, DM status remained associated with a lower MCF (IFG -0.02, 95% CI -0.03,-0.01; DM -0.032, 95%CI -0.04, -0.02). There were 96 incident HF events. Compared to the 4 th quartile, the 1 st MCF quartile was associated with HF (adjusted HR 2.2; 95%CI 1.13, 4.43) as was 1 st EF quartile (adjusted HR 2.9; 95%CI 1.6, 5.2) and 4 th quartile LVM (adjusted HR 5.4; 95%CI 2.2, 13.2). Among those with DM, 39% were in the 1 st MCF quartile, compared to 27% in the 1 st EF and 33% in the 4 th LVM quartile. Conclusions: Incident HF is predicted by MCF. MCF may be a more sensitive marker for diabetic cardiomyopathy than EF or LVM. Ventricular Measures by Diabetes Status Glucose Category Parameter Normal 100-125 mg/dl Diabetes p-value MCF 0.66 (0.14) 0.61 (0.14) 0.59 (0.14) EF, % 69 (7) 69 (8) 68 (9) 0.11 SV (ml) 87 (20) 86 (19) 86 (19) 0.05 LMV (g) 142 (38) 153 (41) 157 (43) Mean (Std Dev)

Cochrane review protocol.

Objectif La prevalence du diabete de type 2 est superieure dans les populations migrantes par rapport a celles observees dans le pays d’origine ou d’accueil. Le but de notre etude etait de comparer les caracteristiques du diabete de type 2 (DT2) chez des patients originaires d’Afrique sub-saharienne ayant migre en France a l’âge adulte a celles des patients africains vivant en Afrique sub-saharienne et a celles des patients caucasiens vivant en France. Patients et Methodes Nous avons realise de novembre 2005 a decembre 2006 une etude transversale multicentrique dans laquelle ont ete recrutes consecutivement des patients DT2 suivis dans les services de Diabetologie de l’hopital Central de Yaounde au Cameroun et de l’hopital St Louis a Paris. Les parametres releves etaient l’âge a l’inclusion dans l’etude et au diagnostic du diabete, l’IMC, l’HbA1c, et les complications microvasculaires. Les immigres africains devaient avoir developpe leur diabete au moins un an apres leur arrivee en France. Resultats Nous avons inclus 98 patients d’Afrique Sub-saharienne vivant a Paris (AP), 100 patients africains suivis a Yaounde (AY) et 199 patients caucasiens vivant a Paris (CP). L’âge moyen a l’inclusion [49 ± 11 (DS) (AP), 58 ± 10 (AY) et 61 ± 12 ans (CP)] et celui au diagnostic du diabete [43 ± 9 (AP), 52 ± 9 (AY) et 48 ± 11 ans (CP)] etaient significativement differents dans les 3 groupes (p Conclusion La migration d’Afrique Sub-saharienne est associee a un âge au diagnostic du diabete plus precoce, a un meilleur equilibre glycemique et a une plus faible prevalence des complications microangiopathiques. L’âge au diagnostic plus precoce chez les immigres que chez les caucasiens pourrait etre lie a des facteurs genetiques ou environnementaux en rapport avec la migration.