Self-Rated Health in Middle Age and Risk of Hospitalizations and Death: Recurrent Event Analysis of the ARIC Study.

BACKGROUND: Self-rated health is a simple measure that may identify individuals who are at a higher risk for hospitalization or death. OBJECTIVE: To quantify the association between a single measure of self-rated health and future risk of recurrent hospitalizations or death. PARTICIPANTS: Atherosclerosis Risk in Communities (ARIC) study, a community-based prospective cohort study of middle-aged men and women with follow-up beginning from 1987 to 1989. MAIN MEASURES: We quantified the associations between initial self-rated health with risk of recurrent hospitalizations and of death using a recurrent events survival model that allowed for dependency between the rates of hospitalization and hazards of death, adjusted for demographic and clinical factors. KEY RESULTS: Of the 14,937 ARIC cohort individuals with available self-rated health and covariate information, 34% of individuals reported "excellent" health, 47% "good," 16% "fair," and 3% "poor" at study baseline. After a median follow-up of 27.7 years, 1955 (39%), 3569 (51%), 1626 (67%), and 402 (83%) individuals with "excellent," "good," "fair," and "poor" health, respectively, had died. After adjusting for demographic factors and medical history, a less favorable self-rated health status was associated with increased rates of hospitalization and death. As compared to those reporting "excellent" health, adults with "good," "fair," and "poor" health had 1.22 (1.07 to 1.40), 2.01 (1.63 to 2.47), and 3.13 (2.39 to 4.09) times the rate of hospitalizations, respectively. The hazards of death also increased with worsening categories of self-rated health, with "good," "fair," and "poor" health individuals experiencing 1.30 (1.12 to 1.51), 2.15 (1.71 to 2.69), and 3.40 (2.54 to 4.56) times the hazard of death compared to "excellent," respectively. CONCLUSIONS: Even after adjusting for demographic and clinical factors, having a less favorable response on a single measure of self-rated health taken in middle age is a potent marker of future hospitalizations and death.

Prognostic value of insulin resistance and hyperglycemia biomarkers for long-term risks of cardiometabolic outcomes.

We found that individuals in the top tertile of HOMA-IR and with HbA1c-defined prediabetes have elevated risk of cardiometabolic outcomes.

Prevalence of Elevated NT-proBNP and its Prognostic Value by Blood Pressure Treatment and Control.

BACKGROUND: The prognostic utility of NT-proBNP in the setting of hypertension has not been well-characterized in the general US adult population. METHODS: We measured NT-proBNP in stored blood samples collected from participants 1 year or older who participated in the 1999-2004 National Health and Nutrition Examination Survey. In adults 20 years or older without a history of cardiovascular disease, we assessed the prevalence of elevated NT-pro-BNP by blood pressure (BP) treatment and control categories. We examined the extent to which NT-proBNP identifies participants at higher risk for mortality across BP treatment and control categories. RESULTS: Among US adults without CVD, the prevalence of elevated NT-proBNP (≥125 pg/ml) was 27.2% among those with untreated hypertension, 24.9% among those with treated controlled hypertension, and 43.3% among those with treated uncontrolled hypertension. Over a median follow-up of 17.3 years and after adjusting for demographic and clinical risk factors, US adults with treated controlled hypertension and elevated NT-proBNP had increased risk of all-cause mortality (HR 2.29, 95% CI 1.79, 2.95) and cardiovascular mortality (HR 3.83, 95% CI 2.34, 6.29), compared to adults without hypertension and with low levels of NT-proBNP (<125 pg/ml). Across all levels of SBP and irrespective of antihypertensive medication use, elevated NT-proBNP was associated with an increased risk of mortality, compared to low levels of NT-proBNP. CONCLUSIONS: Among a general population of adults free of CVD, NT-proBNP can provide additional prognostic information within and across categories of BP. Measurement of NT-proBNP may have potential for clinical use to optimize hypertension treatment.

Standing Blood Pressure and Risk of Falls, Syncope, Coronary Heart Disease, and Mortality.

BACKGROUND: ACC/AHA guidelines caution against the use of antihypertensive therapy in the setting of low standing systolic BP (SBP) < 110 mm Hg due to unclear benefits. METHODS: The Atherosclerosis Risk in Communities (ARIC) Study measured supine and standing SBP in adults aged 45-64 years between 1987 and 1989. We used Cox regression to evaluate the associations of low standing SBP (<110 mm Hg) with risk of falls, syncope, coronary heart disease (CHD), and mortality through December 31, 2019. Falls and syncope were ascertained by hospitalization and outpatient claims; CHD events were adjudicated. Associations were examined overall and in strata of hypertension stage, 10-year atherosclerotic cardiovascular disease (ASCVD) risk, age, and sex. RESULTS: Among 12,467 adults followed a median of 24 years (mean age at enrollment 54.1 ±â€…5.8 years, 55% women, 26% Black adults), 3,000 (24%) had a standing SBP < 110 mm Hg. A standing SBP < 110 mm Hg compared to standing SBP ≥ 110 mm Hg was not significantly associated with falls or syncope, and was associated with a lower risk of CHD events and mortality with HRs of 1.02 (95% CI 0.94, 1.11), 1.02 (0.93, 1.11), 0.88 (0.80, 0.97), and 0.91 (0.86, 0.97), respectively. There were no clinically meaningful differences when stratified by hypertension stage, 10-year ASCVD risk, age, and sex. CONCLUSIONS: In this community-based population, low standing SBP was common and not significantly associated with falls or syncope, but was associated with a lower risk of CHD and mortality. These findings do not support screening for low standing BP as a risk factor for adverse events.

Associations of N-terminal pro-B-type natriuretic peptide, estimated glomerular filtration rate, and mortality in US adults.

BACKGROUND: NT-proBNP is an important predictor of mortality but is inversely related to estimated glomerular filtration rate (eGFR). Whether the prognostic value of NT-proBNP is similar at different levels of kidney function is unknown. AIMS: We evaluated the association of NT-proBNP with eGFR and its implications for all-cause and cardiovascular mortality risk in the general population. METHODS: We included adults without prior cardiovascular disease from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004. We used linear regression to characterize the cross-sectional associations of NT-proBNP with eGFR. We used Cox regression to assess the prospective associations of NT-proBNP with mortality across categories of eGFR. RESULTS: Among 11,456 participants (mean age 43 years, 48% female, 71% White, 11% Black), there was an inverse association between NT-proBNP and eGFR, which was stronger in those with more impaired kidney function. Per 15-unit decrease in eGFR, NT-proBNP was 4.3-fold higher for eGFR<30; 1.7-fold higher for eGFR 30 to 60, 1.4-fold higher for eGFR 61 to 90, 1.1-fold higher for eGFR 91 to 120 mL/min/1.73 m2. Over a median 17.6 years of follow-up, 2,275 deaths (622 cardiovascular) occurred. Higher NT-proBNP was associated with higher all-cause (HR per doubling of NT-proBNP: 1.20, 95% CI: 1.16-1.25) and cardiovascular mortality (HR: 1.34, 95% CI 1.25-1.44). Associations were similar across eGFR categories (P-interaction >.10). Adults with NT-proBNP≥450 pg/mL and eGFR<60 mL/min/1.73m2 had 3.4-fold higher all-cause mortality and 5.5-fold higher cardiovascular mortality risk, compared to those with NT-proBNP<125 pg/mL and eGFR>90 mL/min/1.73m2. CONCLUSION: Despite its strong inverse association with eGFR, NT-proBNP has robust associations with mortality across the full range of kidney function in the general US adult population.

Prevalence of Elevated NT-proBNP and its Prognostic Value by Blood Pressure Treatment and Control- National Health and Nutrition Examination Survey, 1999-2004.

Background: The prognostic utility of NT-proBNP in the setting of hypertension has not been well-characterized in the general US adult population. Methods: We measured NT-proBNP among adults aged 20 years who participated in the 1999-2004 National Health and Nutrition Examination Survey. In adults without a history of cardiovascular disease, we assessed the prevalence of elevated NT-pro-BNP by blood pressure (BP) treatment and control categories. We examined the extent to which NT-proBNP identifies participants at higher risk for mortality across BP treatment and control categories. Results: The number of US adults without CVD with elevated NT-proBNP (≥125 pg/ml) was 6.2 million among those with untreated hypertension, 4.6 million among those with treated controlled hypertension, and 5.4 million among those with treated uncontrolled hypertension. After adjusting for age, sex, body mass index, and race/ethnicity, participants with treated controlled hypertension and elevated NT-proBNP had increased risk of all-cause mortality (HR 2.29, 95% CI 1.79, 2.95) and increased risk of cardiovascular mortality (HR 3.83, 95% CI: 2.34, 6.29), compared to those without hypertension and with low levels of NT-proBNP (<125 pg/ml). Among those on antihypertensive medication, those with SBP 130-139 mm Hg and elevated NT-proBNP had increased risk of all-cause mortality, compared to those with SBP<120 mm Hg and low levels of NT-proBNP. Conclusions: Among a general population of adults free of cardiovascular disease, NT-proBNP can provide additional prognostic information within and across categories of BP. Measurement of NT-proBNP may have potential for clinical use to optimize hypertension treatment.

Association Between Subclinical Thyroid Dysfunction and Fracture Risk.

Importance: Clinical hyperthyroidism accelerates bone resorption without compensatory bone formation, reducing bone density and increasing the risk of fracture. The association between subclinical hyperthyroidism and fracture risk is less clear. Objective: To investigate the association of endogenous subclinical thyroid dysfunction and fracture risk, independent of clinical confounders. Design, Setting, and Participants: This cohort study included 10 946 participants from the Atherosclerosis Risk in Communities Study, an ongoing prospective cohort study of community-dwelling individuals conducted from 1987-1989 through December 31, 2019, in Washington County, Maryland; Forsyth County, North Carolina; Jackson, Mississippi; and the suburbs of Minneapolis, Minnesota. Participants were not taking thyroid medications and had no history of fractures. Exposures: Thyrotropin and free thyroxine levels were measured at visit 2 (1990-1992). Subclinical hyperthyroidism was defined as a thyrotropin level lower than 0.56 mIU/L, subclinical hypothyroidism as a thyrotropin level higher than 5.1 mIU/L, and euthyroidism as a thyrotropin level of 0.56 to 5.1 mIU/L, with normal free thyroxine levels from 0.85 to 1.4 ng/dL. Main Outcomes and Measures: Incident fracture was ascertained using hospitalization discharge codes through 2019 and linkage to inpatient and outpatient Medicare claims through 2018. Results: Of 10 946 participants (54.3% women; mean [SD] age, 57 [5.7] years), 93.0% had euthyroidism, 2.6% had subclinical hyperthyroidism, and 4.4% had subclinical hypothyroidism. During a median follow-up of 21 years (IQR, 13.0-27.3 years), there were 3556 incident fractures (167.1 per 10 000 person-years). The adjusted hazard ratios of fracture were 1.34 (95% CI, 1.09-1.65) for those with subclinical hyperthyroidism and 0.90 (95% CI, 0.77-1.05) for those with subclinical hypothyroidism compared with individuals with euthyroidism. Among those with normal free thyroxine levels, thyrotropin levels in the lower-than-normal range were significantly associated with higher fracture-related hospitalization risk; fracture risk was greater among individuals with thyrotropin concentrations below 0.56 mIU/L. Conclusions and Relevance: This community-based cohort study suggests that subclinical hyperthyroidism was an independent risk factor associated with fracture. The increased risk for fracture among individuals with a thyrotropin level lower than 0.56 mIU/L highlights a potential role for more aggressive screening and monitoring of patients with subclinical hyperthyroidism to prevent bone mineral disease.

Cardiovascular Disease Risk Among Cancer Survivors: The Atherosclerosis Risk In Communities (ARIC) Study.

BACKGROUND: More than 80% of adult patients diagnosed with cancer survive long term. Long-term complications of cancer and its therapies may increase the risk of cardiovascular disease (CVD), but prospective studies using adjudicated cancer and CVD events are lacking. OBJECTIVES: The aim of this study was to assess the risk of CVD in cancer survivors in a prospective community-based study. METHODS: We included 12,414 ARIC (Atherosclerosis Risk In Communities) study participants. Cancer diagnoses were ascertained via linkage with state registries supplemented with medical records. Incident CVD outcomes were coronary heart disease (CHD), heart failure (HF), stroke, and a composite of these. We used multivariable Poisson and Cox regressions to estimate the association of cancer with incident CVD. RESULTS: Mean age was 54 years, 55% were female, and 25% were Black. A total of 3,250 participants (25%) had incident cancer over a median 13.6 years of follow-up. Age-adjusted incidence rates of CVD (per 1,000 person-years) were 23.1 (95% CI: 24.7-29.1) for cancer survivors and 12.0 (95% CI: 11.5-12.4) for subjects without cancer. After adjustment for cardiovascular risk factors, cancer survivors had significantly higher risks of CVD (HR: 1.37; 95% CI: 1.26-1.50), HF (HR: 1.52; 95% CI: 1.38-1.68), and stroke (HR: 1.22; 95% CI: 1.03-1.44), but not CHD (HR: 1.11; 95% CI: 0.97-1.28). Breast, lung, colorectal, and hematologic/lymphatic cancers, but not prostate cancer, were significantly associated with CVD risk. CONCLUSIONS: Compared with persons without cancer, adult cancer survivors have significantly higher risk of CVD, especially HF, independent of traditional cardiovascular risk factors. There is an unmet need to define strategies for CVD prevention in this high-risk population.

Glycated Albumin in Pristine and Non-Pristine Stored Samples in the National Health and Nutrition Examination Survey (NHANES) 1999-2004.

BACKGROUND: Glycated albumin is cleared by the Food and Drug Administration (FDA) for clinical use in diabetes care. To understand its performance in the general US population, we conducted measurements in >19 000 samples from the National Health and Nutrition Examination Survey (NHANES). Of these samples, 5.7% had previously undergone at least 2 freeze-thaw cycles and were considered "non-pristine." METHODS: We measured glycated albumin and albumin using the Lucica GA-L (Asahi Kasei) assay in stored serum samples from NHANES 1999-2004. Serum albumin (Roche/Beckman) was previously measured. We examined the correlations of percent glycated albumin with hemoglobin A1C (HbA1c)and fasting glucose in the pristine and non-pristine samples. We also measured cystatin C (Siemens) and compared these to cystatin C (Dade Behring) previously obtained in a subsample. RESULTS: Glycated albumin (%) was significantly lower in pristine vs non-pristine samples (13.8% vs 23.4%, P < 0.0001). The results from the Asahi Kasei albumin assay (g/dL) were highly correlated with albumin originally measured in NHANES (Pearson's correlation coefficient, r = 0.76) but values were systematically higher (+0.25 g/dL, P < 0.0001). Cystatin C (Siemens) was similar to previous cystatin C measurements (r = 0.98) and did not differ by pristine status (P = 0.119). Glycated albumin (%) was highly correlated with HbA1c and fasting glucose in pristine samples (r = 0.78 and r = 0.71, respectively) but not in non-pristine samples (r = 0.11 and r = 0.12, respectively). CONCLUSIONS: The performance of the glycated albumin assay in the pristine samples was excellent. Performance in non-pristine samples was highly problematic. Analyses of glycated albumin in NHANES 1999-2004 should be limited to pristine samples only. These results have major implications for the use of these public data.

Six-year changes in N-terminal pro-brain natriuretic peptide and changes in weight and risk of obesity.

OBJECTIVE: The aim of this study was to study the prospective association between N-terminal pro-brain natriuretic peptide (NT-proBNP) and changes in weight and obesity risk in a community-based population. METHODS: Data from 9,681 participants from the Atherosclerosis Risk in Communities Study were analyzed at two time points 6 years apart. Among people without obesity at baseline, multivariable logistic regression models were used to examine the association between baseline levels of NT-proBNP and incident obesity. A multivariable linear regression model was used to examine the association between changes in NT-proBNP (visit 2 serum and visit 4 plasma samples) and changes in weight. RESULTS: The prevalence of obesity increased from 28% to 35% in the 6-year follow-up period. Compared with individuals in the highest NT-proBNP quartile, those in the lowest were more likely to have obesity at baseline (odds ratio 1.25; 95% CI: 1.08-1.45) and, among people who did not have obesity at baseline, were more likely to develop obesity at follow-up (odds ratio 1.35; 95% CI: 1.07-1.69). Changes in NT-proBNP were inversely associated with weight change. CONCLUSIONS: In this prospective study, lower levels of NT-proBNP were associated with higher risk of obesity, and changes in NT-proBNP were inversely associated with changes in weight. This suggests that natriuretic peptides or their pathways may be potential targets in the treatment of obesity.

Alcohol Consumption and Risk of Hospitalizations and Mortality in the Atherosclerosis Risk in Communities Study.

BACKGROUND: Public health recommendations on the benefits and harms of moderate alcohol intake require a thorough and unbiased understanding of all potential effects of various levels and patterns of alcohol consumption. We seek to evaluate the associations between patterns of current and past alcohol consumption with hospitalizations and mortality. METHODS: Data came from a prospective cohort of 12,327 adults (56% women, 78% white, mean age 60 years) participating in the Atherosclerosis Risk in Communities study visit 3 (1993 to 1995). Current and past alcohol consumption was based on self-report. Hospitalizations and mortality were ascertained through December 31, 2017. Negative binomial and Cox proportional hazards regressions were used. RESULTS: 24.8% of the study population reported never drinking, 48.3% reported currently drinking without a history of heavy drinking, 4.2% reported currently drinking with a history of heavy drinking, 19.2% reported being former drinkers without a history of heavy drinking, and 3.4% reported being former drinkers with a history of heavy drinking. Compared to those who reported drinking ≤1 to 7 drinks/wk, never drinkers (incident rate ratio [IRR]: 1.21 (95% confidence interval 1.13, 1.29) and former drinkers with (IRR: 1.43 [1.26, 1.63]) or without (IRR: 1.21 [1.13, 1.30]) a history of heavy drinking had a positive association with all-cause hospitalization (p < 0.001). Those who reported drinking ≤1 to 7 drinks/wk had the lowest all-cause mortality rate (19.2 per 1,000 person-years [18.4, 20.1]) and former drinkers with a history of heavy drinking had the highest (43.7 per 1,000 person-years [39.0, 49.1]). CONCLUSIONS: The positive associations with hospitalization and mortality were stronger among never and former drinkers compared to those who consume ≤1 to 7 drinks/wk. Former drinkers with a history of heavy drinking had a stronger positive association with adverse health outcomes than former drinkers without a history of heavy drinking, highlighting the impact of this pattern of alcohol consumption.

Associations of Cardiac, Kidney, and Diabetes Biomarkers With Peripheral Neuropathy among Older Adults in the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: The aim of this study was to assess the association of high-sensitivity cardiac troponin (hs-cTnT) and other cardiac, kidney, hyperglycemia, and inflammatory biomarkers with peripheral neuropathy (PN) in a community-based population. METHODS: We conducted a cross-sectional analysis of 3056 black and white participants in the Atherosclerosis Risk in Communities (ARIC) study who underwent standardized monofilament PN testing and had measures of cardiac function (hs-cTnT, N-terminal pro-B-type natriuretic peptide [NT-proBNP], and growth differentiation factor 15 [GDF15]), kidney function (serum creatinine, cystatin C, ß-2 microglobulin, urine albumin-to-creatinine ratio), hyperglycemia (fasting glucose, hemoglobin A1c [Hb A1c], fructosamine, glycated albumin, 1,5-anhydroglucitol), and inflammation (C-reactive protein) assessed at visit 6 (2016-2017; age 71-94 years). We used logistic regression to assess the associations of these biomarkers (modeled in diabetes-specific tertiles) with PN in older adults with and without diabetes after adjusting for traditional risk factors. RESULTS: In total, 33.5% of participants had PN (37.3% with diabetes and 31.9% without diabetes). There was an independent association of hs-cTnT with PN regardless of diabetes status (diabetes T3 vs. T1: odds ratio [OR], 2.15 [95% CI, 1.44-3.22]; no diabetes: OR, 2.31 [95%CI, 1.76-3.03]; P = 0.72 for interaction). Among participants without diabetes, there were also significant associations of NT-proBNP (OR, 1.40 [95% CI, 1.08-1.81]) and urine albumin-to-creatinine ratio (OR, 1.55 [95% CI, 1.22-1.97]) with PN. Associations of hyperglycemia biomarkers including Hb A1c (OR, 1.76 [95% CI, 1.22-2.54]), fructosamine (OR, 1.71 [95% CI, 1.19-2.46]), and glycated albumin (OR, 1.45 [95% CI, 1.03-2.03]) with PN were significant only among participants with diabetes. CONCLUSIONS: Overall, hs-cTnT appears to be a global marker of end organ damage, including PN. Laboratory biomarkers may be able to help us identify those individuals with PN.

Race and sex-based disparities associated with carotid endarterectomy in the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND AND AIMS: The indications for carotid endarterectomy (CEA) are well established. The aim of the current study was to investigate sex and race-based disparities in the incidence of CEA after adjusting for carotid artery stenosis risk factors. METHODS: We conducted a prospective cohort analysis of 14,492 black and white participants in the Atherosclerosis Risk in Communities (ARIC) study without prevalent stroke at baseline (1987-1989). We used Kaplan-Meier curves and Cox proportional hazards models adjusting for sociodemographic, cardiovascular, and disease severity risk factors to quantify the associations of sex and race with incident CEA. RESULTS: CEA was performed in 330 of 14,492 ARIC participants during a median of 27 years of follow-up [incidence rate 1.00 (95% CI 0.90-1.12) per 1000 persons-years]. The crude incidence of CEA varied significantly by sex [female vs. male: HR 0.60 (95% CI 0.48-0.74)] and race [black vs. white: HR 0.65 (95% CI 0.49-0.86)]. Adjustment for sociodemographic and cardiovascular risk factors, carotid intima-media thickness, and symptomatic status attenuated the association of sex with CEA [females vs. males HR 0.96 (0.76-1.22)], but black participants had a lower risk of incident CEA after adjustment [HR 0.68 (95% CI 0.49-0.95)]. CONCLUSIONS: We found significant variation in the incidence of CEA procedures based on race that was independent of traditional risk factors and carotid IMT. Whether this disparity is a reflection of differences in disease presentation or access to care deserves investigation.

Prevalence and Risk Factors of Thyroid Dysfunction in Older Adults in the Community.

Prevalence estimates and evidence informing treatment targets for thyroid dysfunction largely come from studies of middle-aged adults. We conducted a cross-sectional analysis to determine the prevalence of thyroid dysfunction and risk factors for abnormal thyroid tests in participants aged ≥65 in the Atherosclerosis Risk in Communities (ARIC) study (N = 5,392). We measured serum concentrations of triiodothyronine (T3), free thyroxine (FT4), thyroid peroxidase antibody (Anti-TPO), and thyroid stimulating hormone (TSH). In this population (58% women, 22% black), 17% reported medication use for thyroid dysfunction. Among those not on treatment, the prevalence of overt and subclinical hypothyroidism was 0.82% and 6.06%, respectively. Overt and subclinical hyperthyroidism affected 0.26% and 0.78%, respectively. Multivariable adjusted TSH, FT4 and T3 levels were 25%, 1.3% and 3.9% lower in blacks compared to whites, respectively. Men were less likely to be anti-TPO positive compared to women (p < 0.001). Former and never smoking were associated with lower T3 and FT4 levels compared to current smoking. The prevalence of thyroid dysfunction in older adults is nearly 25%. Multiple illnesses can interact to contribute to declines in health. Additional attention to thyroid dysfunction and screening in this age group is recommended.

Confluence of Epidemics of Hepatitis C, Diabetes, Obesity, and Chronic Kidney Disease in the United States Population.

BACKGROUND & AIMS: Obesity, kidney disease, and diabetes are common conditions that can affect outcomes of patients with chronic hepatitis C. The authors aimed to quantify the burden of these comorbid conditions among adults with chronic hepatitis C in the United States and to estimate the risk of death among people with chronic hepatitis C and comorbidities. METHODS: The authors conducted cross-sectional and prospective analyses of 13,726 participants in the third National Health and Nutrition Examination Survey (NHANES III) and 23,691 participants of NHANES 1999-2012. Serum samples were analyzed for the presence of antibodies to hepatitis C virus (anti-HCV); in samples found to be positive for anti-HCV, the authors quantified HCV RNA (viral load). Individuals with anti-HCV and detectable HCV RNA were considered to have chronic hepatitis C. Comorbidities were defined using self-reported, physical examination, and laboratory data, as available. The authors used logistic models and predictive margins to estimate the adjusted prevalence of comorbidities in patients with chronic hepatitis C. The authors used Poisson regression models to estimate adjusted mortality rates based on chronic hepatitis C status, with or without comorbidities. Cox proportional hazards regression models to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause, cardiovascular, and cancer mortality according to chronic hepatitis C status, with and without comorbidities. RESULTS: Among persons with chronic hepatitis C, the demographic-adjusted prevalence estimate of diabetes was 17.9% (95% CI, 11.2%-27.5%) and of obesity was 20.9% (95% CI, 12.4%-29.5%). Overall, 69.6% of persons with chronic hepatitis C had at least 1 major cardiometabolic comorbidity (95% CI, 62.1%-76.2%). Only 38% of adults with chronic hepatitis C reported a diagnosis of liver disease. Chronic hepatitis C was associated with a substantially increased risk of death (HR, 2.45), especially in the presence of diabetes (HR, 3.24) or chronic kidney disease (HR, 4.39). CONCLUSION: In an analysis of NHANES data, the authors found that individuals with chronic hepatitis C have a high burden of major cardiometabolic comorbidities. Diabetes and chronic kidney disease, in particular, are associated with substantial excess mortality in persons with chronic hepatitis C.

Comparative prognostic performance of definitions of prediabetes: a prospective cohort analysis of the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: No consensus on definitions of prediabetes exists among international organisations. Analysis of associations with different definitions and clinical complications can inform the comparative value of different prediabetes definitions. We compared the risk of future outcomes across different prediabetes definitions based on fasting glucose concentration, HbA1c, and 2 h glucose concentration during over two decades of follow-up in the community-based Atherosclerosis Risk in Communities (ARIC) study. We aimed to analyse the associations of definitions with outcomes to provide a comparison of different definitions. METHODS: We did a prospective cohort study of participants in the ARIC study who did not have diagnosed diabetes and who attended visit 2 (1990-92; n=10 844) and who attended visit 4 (1996-98; n=7194). ARIC participants were enrolled from four communities across the USA. Fasting glucose concentration and HbA1c were measured at visit 2 and fasting glucose concentration and 2 h glucose concentration were measured at visit 4. We compared prediabetes definitions based on fasting glucose concentration (American Diabetes Association [ADA] fasting glucose concentration cutoff 5·6-6·9 mmol/L and WHO fasting glucose concentration cutoff 6·1-6·9 mmol/L), HbA1c (ADA HbA1c cutoff 5·7-6·4% [39-46 mmol/mol] and International Expert Committee [IEC] HbA1c cutoff 6·0-6·4% [42-46 mmol/mol]), and 2 h glucose concentration (ADA and WHO 2 h glucose concentration cutoff 7·8-11·0 mmol/L). FINDINGS: Prediabetes defined using the ADA fasting glucose concentration cutoff (prevalence 4112 [38%] of 10 844 people; 95% CI 37·0-38·8) was the most sensitive for major clinical outcomes, whereas using the ADA HbA1c cutoff (2027 [19%] of 10 884 people; 18·0-19·4) and IEC HbA1c cutoff (970 [9%] of 10 844 people; 8·4-9·5), and the WHO fasting glucose concentration cutoff (1213 [11%] of 10 844 people; 10·6-11·8) were more specific. After demographic adjustment, HbA1c-based definitions of prediabetes had higher hazard ratios and better risk discrimination for chronic kidney disease, cardiovascular disease, peripheral arterial disease, and all-cause mortality than did fasting glucose concentration-based definitions (all p<0·05). The C-statistic for incident chronic kidney disease was 0·636 for ADA fasting glucose concentration clinical categories and 0·640 for ADA HbA1c clinical categories (difference -0·005, 95% CI -0·008 to -0·001). The C-statistics were 0·662 for ADA fasting glucose clinical concentration categories and 0·672 for ADA HbA1c clinical categories for atherosclerotic cardiovascular disease, 0·701 for ADA fasting glucose concentration clinical categories and 0·722 for ADA HbA1c clinical categories for peripheral arterial disease, and 0·683 for ADA fasting glucose concentration clinical categories and 0·688 for ADA HbA1c clinical categories for all-cause mortality. Prediabetes defined using the ADA HbA1c cutoff showed a significant overall improvement in the net reclassification index for cardiovascular outcomes and death compared with prediabetes defined with glucose-based definitions. ADA fasting glucose concentration clinical categories, WHO fasting glucose concentration clinical categories, and ADA and WHO 2 h glucose concentrations clinical categories were not significantly different in terms of risk discrimination for chronic kidney disease, cardiovascular outcomes, or mortality outcomes. INTERPRETATION: Our results suggest that prediabetes definitions using HbA1c were more specific and provided modest improvements in risk discrimination for clinical complications. The definition of prediabetes using the ADA fasting glucose concentration cutoff was more sensitive overall. FUNDING: US National Institutes of Health.

Frailty, Kidney Function, and Polypharmacy: The Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Frail individuals are at increased risk for poor outcomes, including adverse drug events. Kidney function is often compromised in frailty and is a key consideration in medication choice and dosing; however, creatinine-based measures of kidney function may be biased in frail individuals. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: 4,987 community-dwelling older men and women with complete data who participated in visit 5 of the Atherosclerosis Risk in Communities (ARIC) Study (2011-2013). PREDICTORS: Kidney measures included glomerular filtration rate (GFR) estimated using serum creatinine (eGFRcr) and serum cystatin C level (eGFRcys) and urine albumin-creatinine ratio. OUTCOME: Frailty, defined using established criteria of 3 or more frailty characteristics (weight loss, slowness, exhaustion, weakness, and low physical activity). RESULTS: 341 (7%) participants were classified as frail, 1,475 (30%) had eGFRcr<60mL/min/1.73m2, 2,480 (50%) had eGFRcys<60mL/min/1.73m2, and 1,006 (20%) had albuminuria with albumin excretion ≥ 30mg/g. Among frail participants, prevalences of eGFRcr and eGFRcys<60mL/min/1.73m2 were 45% and 77%, respectively. Adjusted for covariates, frailty showed a moderate association with eGFRcr and a strong association with eGFRcys and albumin-creatinine ratio. Frail individuals with eGFRcr of 60 to <75mL/min/1.73m2 were frequently reclassified to lower eGFR categories using eGFRcys (49% to 45-<60, 32% to 30-<45, and 3% to <30mL/min/1.73m2). Hyperpolypharmacy (taking ≥10 classes of medications) was more common in frail individuals (54% vs 38% of nonfrail), including classes requiring kidney clearance (eg, digoxin) and associated with falls and subsequent complications (eg, hypnotic/sedatives and anticoagulants). LIMITATIONS: Cross-sectional study design. CONCLUSIONS: Frail individuals had a high prevalence of reduced kidney function, with large discrepancies when reduced kidney function was classified by eGFRcys versus eGFRcr. Given the substantial medication burden and uncertainty in chronic kidney disease classification, confirmation of kidney function with alternative biomarkers may be warranted to ensure careful prescribing practices in this vulnerable population.

Outcomes and worsening renal function in patients hospitalized with heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) has been described as a disease of elderly subjects with female predominance and hypertension. Our clinical experience suggests patients with HFpEF from an urban population are far more heterogenous, with greater co-morbidities and significant inhospital morbidity. There are limited data on the hospitalization course and outcomes in acute decompensated HFpEF. Hospitalizations for acute heart failure at our institution from July 2011 to June 2012 were identified by International Classification of Diseases, Ninth Revision, codes and physician review for left ventricular ejection fraction ≥50% and were reviewed for patient characteristics and clinical outcomes. Worsening renal function (WRF) was defined as creatinine increase of ≥0.3 mg/dl by 72 hours after admission. Hospital readmission and mortality data were captured from electronic medical records and the Social Security Death Index. Of 434 heart failure admissions, 206 patients (47%) with HFpEF were identified. WRF developed in 40%, the highest reported in HFpEF to date, and was associated with higher blood pressure and lower volume of diuresis. Compared to previous reports, hospitalized patients with HFpEF were younger (mean age 63.2 ± 13.6 years), predominantly black (74%), and had more frequent and severe co-morbidities: hypertension (89%), diabetes (56%), and chronic kidney disease (55%). There were no significant differences in 1- and 12-month outcomes by gender, race, or WRF. In conclusion, we found hospitalized patients with HFpEF from an urban population develop a high rate of WRF are younger than previous cohorts, often black, and have greater co-morbidities than previously described.

Metabolomics reveals broad-scale metabolic perturbations in hyperglycemic mothers during pregnancy.

OBJECTIVE To characterize metabolites across the range of maternal glucose by comparing metabolomic profiles of mothers with high and low fasting plasma glucose (FPG). RESEARCH DESIGN AND METHODS We compared fasting serum from an oral glucose tolerance test at ∼28 weeks' gestation from 67 Northern European ancestry mothers from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study with high (>90th percentile) FPG with 50 mothers with low (<10th percentile) FPG but comparable BMI. Metabolic data from biochemical analyses of conventional clinical metabolites, targeted mass spectrometry (MS)-based measurement of amino acids, and nontargeted gas chromatography/MS were subjected to per-metabolite analyses and collective pathway analyses using Unipathway annotation. RESULTS High-FPG mothers had a metabolic profile consistent with insulin resistance including higher triglycerides, 3-hydroxybutyrate, and amino acids including alanine, proline, and branched-chain amino acids (false discovery rate [FDR]-adjusted P < 0.05). Lower 1,5-anhydroglucitol in high-FPG mothers suggested recent hyperglycemic excursions (FDR-adjusted P < 0.05). Pathway analyses indicated differences in amino acid degradation pathways for the two groups (FDR-adjusted P < 0.05), consistent with population-based findings in nonpregnant populations. Exploratory analyses with newborn outcomes indicated positive associations for maternal triglycerides with neonatal sum of skinfolds and cord C-peptide and a negative association between maternal glycine and cord C-peptide (P < 0.05). CONCLUSIONS Metabolomics reveals perturbations in metabolism of major macronutrients and amino acid degradation pathways in high- versus low-FPG mothers.