Myocardial Injury Thresholds for 4 High-Sensitivity Troponin Assays in a Population-Based Sample of US Children and Adolescents.

BACKGROUND: Myocardial injury is an important pediatric diagnosis. Establishing normative data from a representative pediatric sample is vital to provide accurate upper reference limits (URLs) for defining myocardial injury using high-sensitivity cardiac troponin. METHODS: Among participants 1 to 18 years of age in the 1999-2004 National Health and Nutrition Examination Survey, we measured high-sensitivity troponin T using one assay (Roche) and high-sensitivity troponin I using 3 assays (Abbott, Siemens, and Ortho). In a strictly defined healthy subgroup, we estimated 97.5th and 99th percentile URLs for each assay using the recommended nonparametric method. RESULTS: Of 5695 pediatric participants, 4029 met criteria for the healthy subgroup (50% males; mean age 12.6 years). Our 99th percentile URL estimates for all 4 high-sensitivity troponin assays among children and adolescents were lower than the manufacturer-reported URLs (derived from adults). The 99th percentile URLs (95% CI) were 15 ng/L (95% CI, 12-17) for high-sensitivity troponin T, 16 ng/L (95% CI, 12-19) for high-sensitivity troponin I with the Abbott assay, 38 ng/L (95% CI, 25-46) for high-sensitivity troponin I with the Siemens assay, and 7 ng/L (95% CI, 5, 12) for high-sensitivity troponin I with the Ortho assay. The 95% CIs for age-, sex-, and race and ethnicity-specific 99th percentile URLs overlapped. However, the 97.5th percentile URL for each assay was measured with superior statistical precision (ie, tighter 95% CIs) and demonstrated differences by sex. For male compared with female children and adolescents, 97.5th percentile URLs were 11 ng/L (95% CI, 10-12) versus 6 ng/L (95% CI, 6-7) for high-sensitivity troponin T, 9 ng/L (95% CI, 7-10) versus 5 ng/L (95% CI, 4-6) for high-sensitivity troponin I with the Abbott assay, 21 ng/L (95% CI, 18-25) versus 11 ng/L (95% CI, 9-13) for high-sensitivity troponin I with the Siemens assay, and 4 ng/L (95% CI, 3-5) versus 2 ng/L (95% CI, 1-3) for high-sensitivity troponin I with the Ortho assay. In contrast to the 99th percentiles, the point estimates of 97.5th percentile pediatric URLs for high-sensitivity troponin were also much more stable to differences in the analytic approaches taken to estimate URLs. CONCLUSIONS: Because myocardial infarction is rare in children and adolescents, the use of statistically more precise and reliable sex-specific 97.5th percentile high-sensitivity troponin URLs might be considered to define pediatric myocardial injury.

Sample-to-Answer Detection of SARS-CoV-2 Viremia Using Thermally Responsive Alkane Partitions.

The diagnosis of bloodborne viral infections (viremia) is currently relegated to central laboratories because of the complex procedures required to detect viruses in blood samples. The development of point-of-care diagnostics for viremia would enable patients to receive a diagnosis and begin treatment immediately instead of waiting days for results. Point-of-care systems for viremia have been limited by the challenges of integrating multiple precise steps into a fully automated (i.e., sample-to-answer), compact, low-cost system. We recently reported the development of thermally responsive alkane partitions (TRAPs), which enable the complete automation of diagnostic assays with complex samples. Here we report the use of TRAPs for the sample-to-answer detection of viruses in blood using a low-cost portable device and easily manufacturable cassettes. Specifically, we demonstrate the detection of SARS-CoV-2 in spiked blood samples, and we show that our system detects viremia in COVID-19 patient samples with good agreement to conventional RT-qPCR. We anticipate that our sample-to-answer system can be used to rapidly diagnose SARS-CoV-2 viremia at the point of care, leading to better health outcomes for patients with severe COVID-19 disease, and that our system can be applied to the diagnosis of other life-threatening bloodborne viral diseases, including Hepatitis C and HIV.

Determination of Clinically Acceptable Analytical Variation of Cardiac Troponin at Decision Thresholds.

BACKGROUND: Clinical decision-making for risk stratification for possible myocardial infarction (MI) uses high-sensitivity cardiac troponin (hs-cTn) thresholds that range from the limit of detection to several-fold higher than the upper reference limit (URL). To establish a minimum analytical variation standard, we can quantify the effect of variation on the population clinical measures of safety (sensitivity) and effectiveness [proportion below threshold, or positive predictive value (PPV)]. METHODS: From large datasets of patients investigated for possible MI with the Abbott hs-cTnI and Roche hs-cTnT assays, we synthesized datasets of 1 000 000 simulated patients. Troponin concentrations were randomly varied several times based on absolute deviations of 0.5 to 3 ng/L and relative changes of 2% to 20% around the low-risk threshold (5 ng/L) and URLs, respectively. RESULTS: For both assays at the low-risk thresholds, there were negligible differences in sensitivity (<0.3%) with increasing analytical variation. The proportion of patients characterized as low risk reduced by 30% to 29% (Roche) and 53% to 44% (Abbott). At the URL, increasing analytical variation also did not change sensitivity; the PPV fell by less than 3%. For risk stratification, increased delta thresholds (change between serial troponin concentrations) increased sensitivity at the cost of a decreased percentage of patients below the delta threshold, with the largest changes at the greatest analytical variation. CONCLUSIONS: At the low-risk threshold, analytical variation up to 3 ng/L minimally impacted the safety metric (sensitivity) but marginally reduced effectiveness. Similarly, at the URL even relative variation up to 25% minimally impacted safety metrics and effectiveness. Analytical variation for delta thresholds did not negatively impact sensitivity but decreased effectiveness.

Associations of Cardiac Biomarkers With Peripheral Artery Disease and Peripheral Neuropathy in US Adults Without Prevalent Cardiovascular Disease.

BACKGROUND: NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity cardiac troponin T (hs-troponin T), and high-sensitivity cardiac troponin I (hs-troponin I) are increasingly being recommended for risk stratification for a variety of cardiovascular outcomes. The aims of our study were to establish the prevalence and associations of elevated NT-proBNP, hs-troponin T, and hs-troponin I with lower extremity disease, including peripheral artery disease (PAD) and peripheral neuropathy (PN), in the US general adult population without known cardiovascular disease. We also assessed whether the combination of PAD or PN and elevated cardiac biomarkers was associated with an increased risk of all-cause and cardiovascular mortality. METHODS: We conducted a cross-sectional analysis of the associations of NT-proBNP, hs-troponin T, and hs-troponin I with PAD (based on ankle-brachial index <0.90) and PN (diagnosed by monofilament testing) in adult participants aged ≥40 years of age without prevalent cardiovascular disease in NHANES (National Health and Nutrition Examination Survey) 1999 to 2004. We calculated the prevalence of elevated cardiac biomarkers among adults with PAD and PN and used multivariable logistic regression to assess the associations of each cardiac biomarker, modeled using clinical cut points, with PAD and PN separately. We used multivariable Cox proportional hazards models to assess the adjusted associations of cross categories of clinical categories of each cardiac biomarker and PAD or PN with all-cause and cardiovascular mortality. RESULTS: In US adults aged ≥40 years, the prevalence (±SE) of PAD was 4.1±0.2% and the prevalence of PN was 12.0±0.5%. The prevalence of elevated NT-proBNP (≥125 ng/L), hs-troponin T (≥6 ng/L), and hs-troponin I (≥6 ng/L for men and ≥4 ng/L for women) was 54.0±3.4%, 73.9±3.5%, and 32.3±3.7%, respectively, among adults with PAD and 32.9±1.9%, 72.8±2.0%, and 22.7±1.9%, respectively, among adults with PN. There was a strong, graded association of higher clinical categories of NT-proBNP with PAD after adjusting for cardiovascular risk factors. Clinical categories of elevated hs-troponin T and hs-troponin I were strongly associated with PN in adjusted models. After a maximum follow-up of 21 years, elevated NT-proBNP, hs-troponin T, and hs-troponin I were each associated with all-cause and cardiovascular mortality, with higher risks of death observed among adults with elevated cardiac biomarkers plus PAD or PN compared with elevated biomarkers alone. CONCLUSIONS: Our study establishes a high burden of subclinical cardiovascular disease defined by cardiac biomarkers in people with PAD or PN. Cardiac biomarkers provided prognostic information for mortality within and across PAD and PN status, supporting the use of these biomarkers for risk stratification among adults without prevalent cardiovascular disease.

Performance of the European Society of Cardiology 0/1-hour algorithm with high-sensitivity cardiac troponin T at 90 days among patients with known coronary artery disease.

BACKGROUND: The European Society of Cardiology (ESC) 0/1-h high sensitivity troponin T (hs-cTnT) algorithm does not differentiate risk based on known coronary artery disease (CAD: prior myocardial infarction [MI], coronary revascularization, or ≥ 70% coronary stenosis). We recently evaluated its performance among patients with known CAD at 30-days, but little is known about its longer-term risk prediction. The objective of this study is to determine and compare the performance of the algorithm at 90-days among patients with and without known CAD. METHODS: We performed a pre-planned subgroup analysis of the STOP-CP cohort, which prospectively enrolled ED patients ≥21 years old with symptoms suggestive of ACS without ST-elevation on initial ECG across 8 US sites (1/25/2017-9/6/2018). Participants with 0- and 1-h hs-cTnT measures (Roche, Basel, Switzerland) were stratified into rule-out, observe, and rule-in groups using the ESC 0/1-h algorithm. Algorithm performance was tested among patients with or without known CAD, as determined by the treating provider. The primary outcome was cardiac death or MI at 90-days. Fisher's exact tests were used to compare 90-day event and rule-out rates between patients with and without known CAD. Negative predictive values (NPVs) for 90-day cardiac death or MI with exact 95% confidence intervals were calculated and compared using Fisher's exact test. RESULTS: The STOP-CP study accrued 1430 patients, of which 31.4% (449/1430) had known CAD. Cardiac death or MI at 90 days was more common in patients with known CAD than in those without [21.2% (95/449) vs. 10.0% (98/981); p < 0.001]. Using the ESC 0/1-h algorithm, 39.6% (178/449) of patients with known CAD and 66.1% (648/981) of patients without known CAD were ruled-out (p < 0.001). Among rule-out patients, 90-day cardiac death or MI occurred in 3.4% (6/178) of patients with known CAD and 1.2% (8/648) without known CAD (p = 0.09). NPV for 90-day cardiac death or MI was 96.6% (95%CI 92.8-98.8) among patients with known CAD and 98.8% (95%CI 97.6-99.5) in patients without known CAD (p = 0.09). CONCLUSION: Patients with known CAD who were ruled-out using the ESC 0/1-h hs-cTnT algorithm had a high rate of missed 90-day cardiac events, suggesting that the ESC 0/1-h hs-cTnT algorithm may not be safe for use among patients with known CAD. TRIAL REGISTRATION: High-Sensitivity Cardiac Troponin T to Optimize Chest Pain Risk Stratification (STOP-CP; ClinicalTrials.gov: NCT02984436; https://clinicaltrials.gov/ct2/show/NCT02984436).

High-sensitivity troponins and mortality in the general population.

AIMS: Cardiac troponin T and I can be measured using a number of high-sensitivity (hs) assays. This study aimed to characterize correlations between four such assays and test their comparative associations with mortality. METHODS AND RESULTS: Among adults without cardiovascular disease in the 1999-2004 National Health and Nutrition Examination Survey, hs-troponin T was measured using one assay (Roche) and hs-troponin I using three assays (Abbott, Siemens, and Ortho). Cox regression was used to estimate associations with all-cause and cardiovascular mortality. Pearson's correlation coefficients comparing concentrations from each assay ranged from 0.53 to 0.77. There were 2188 deaths (488 cardiovascular) among 9810 participants. Each hs-troponin assay [log-transformed, per 1 standard deviation (SD)] was independently associated with all-cause mortality: hazard ratio (HR) 1.20 [95% confidence interval (CI) 1.13-1.28] for Abbott hs-troponin I; HR 1.10 (95% CI 1.02-1.18) for Siemens hs-troponin I; HR 1.23 (95% CI 1.14-1.33) for Ortho hs-troponin I; and HR 1.31 (95% CI 1.21-1.42) for Roche hs-troponin T. Each hs-troponin assay was also independently associated with cardiovascular mortality (HR 1.44 to 1.65 per 1 SD). Associations of hs-troponin T and all-cause and cardiovascular mortality remained significant after adjusting for hs-troponin I. Furthermore, associations of hs-troponin I remained significant after mutually adjusting for hs-troponin I from the other individual assays: e.g. cardiovascular mortality HR 1.46 (95% CI 1.19-1.79) for Abbott after adjustment for the Siemens assay and HR 1.29 (95% CI 1.09-1.53) for Abbott after adjustment for the Ortho assay. CONCLUSION: This study demonstrates only modest correlations between hs-troponin T and three hs-troponin I assays and that hs-troponin I assays can provide distinct risk information for mortality in the general population.

Derivation and validation of a high sensitivity troponin-T HEART pathway.

BACKGROUND: The HEART Pathway is widely used for chest pain risk stratification but has yet to be optimized for high sensitivity troponin T (hs-cTnT) assays. METHODS: We conducted a secondary analysis of STOP-CP, a prospective cohort study enrolling adult ED patients with symptoms suggestive of acute coronary syndrome at 8 sites in the United States (US). Patients had a 0- and 1-hour hs-cTnT measured and a HEAR score completed. A derivation set consisting of 729 randomly selected participants was used to derive a hs-cTnT HEART Pathway with rule-out, observation, and rule-in groups for 30-day cardiac death or myocardial infarction (MI). Optimal baseline and 1-hour troponin cutoffs were selected using generalized cross validation to achieve a negative predictive value (NPV) >99% for rule out and positive predictive value (PPV) >60% or maximum Youden index for rule-in. Optimal 0-1-hour delta values were derived using generalized cross validation to maximize the NPV for the rule-out group and PPV for the rule-in group. The hs-cTnT HEART Pathway performance was validated in the remaining cohort (n = 723). RESULTS: Among the 1452 patients, 30-day cardiac death or MI occurred in 12.7% (184/1452). Within the derivation cohort the optimal hs-cTnT HEART Pathway classified 36.5% (266/729) into the rule-out group, yielding a NPV of 99.2% (95% CI: 98.2-100) for 30-day cardiac death or MI. The rule-in group included 15.4% (112/729) with a PPV of 55.4% (95% CI: 46.2-64.6). In the validation cohort, the hs-cTnT HEART Pathway ruled-out 37.6% (272/723), of which 2 had 30-day cardiac death or MI, yielding a NPV of 99.3% (95% CI: 98.3-100). The rule-in group included 14.5% (105/723), yielding a PPV of 57.1% (95% CI: 47.7-66.6). CONCLUSIONS: A novel hs-cTnT HEART Pathway with serial 0- and 1-hour hs-cTnT measures has high NPV and moderate PPV for 30-day cardiac death or MI.

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.

Body Composition Measures and N-terminal pro-B-type Natriuretic Peptide (NT-pro-BNP) in US Adults.

BACKGROUND: The associations of N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) with dual energy x-ray absorptiometry (DEXA)-derived measures of body mass and composition are largely unknown. METHODS: We included participants aged ≥20 years from the 1999-2004 National Health and Nutrition Examination Survey with NT-pro-BNP and DEXA-derived body composition (fat and lean mass) measures. We used linear and logistic regression to characterize the associations of measures of body mass and composition (body mass index [BMI], waist circumference [WC], fat mass, and lean mass) with NT-pro-BNP, adjusting for cardiovascular risk factors. RESULTS: We conducted sex-specific analyses among 9134 adults without cardiovascular disease (mean age 44.4 years, 50.8% women, and 72% White adults). The adjusted mean NT-proBNP values were lowest in the highest quartiles of BMI, WC, fat mass, and lean mass. There were large adjusted absolute differences in NT-pro-BNP between the highest and lowest quartiles of DEXA-derived lean mass, -6.26 pg/mL (95% confidence interval [CI], -8.99 to -3.52) among men and -22.96 pg/mL (95% CI, -26.83 to -19.09) among women. Lean mass exhibited a strong inverse association with elevated NT-pro-BNP ≥ 81.4 pg/mL (highest quartile) - odds ratio (OR) 0.58 (95% CI, 0.39-0.86) in men and OR 0.59 (95% CI, 0.47-0.73) in women for highest lean mass quartile vs. lowest quartile. Further adjustment for fat mass, BMI, or WC did not appreciably alter the inverse association of lean mass with NT-pro-BNP. CONCLUSIONS: In a national sample of US adults, lean mass was inversely associated with NT-pro-BNP.

Integrated Bioinformatics Analysis Confirms the Diagnostic Value of Nourin-Dependent miR-137 and miR-106b in Unstable Angina Patients.

The challenge of rapidly diagnosing myocardial ischemia in unstable angina (UA) patients presenting to the Emergency Department (ED) is due to a lack of sensitive blood biomarkers. This has prompted an investigation into microRNAs (miRNAs) related to cardiac-derived Nourin for potential diagnostic application. The Nourin protein is rapidly expressed in patients with acute coronary syndrome (ACS) (UA and acute myocardial infarction (AMI)). MicroRNAs regulate gene expression through mRNA binding and, thus, may represent potential biomarkers. We initially identified miR-137 and miR-106b and conducted a clinical validation, which demonstrated that they were highly upregulated in ACS patients, but not in healthy subjects and non-ACS controls. Using integrated comprehensive bioinformatics analysis, the present study confirms that the Nourin protein targets miR-137 and miR-106b, which are linked to myocardial ischemia and inflammation associated with ACS. Molecular docking demonstrated robust interactions between the Nourin protein and miR137/hsa-miR-106b, involving hydrogen bonds and hydrophobic interactions, with -10 kcal/mol binding energy. I-TASSER generated Nourin analogs, with the top 10 chosen for structural insights. Antigenic regions and MHCII epitopes within the Nourin SPGADGNGGEAMPGG sequence showed strong binding to HLA-DR/DQ alleles. The Cytoscape network revealed interactions of -miR137/hsa-miR--106b and Phosphatase and tensin homolog (PTEN) in myocardial ischemia. RNA Composer predicted the secondary structure of miR-106b. Schrödinger software identified key Nourin-RNA interactions critical for complex stability. The study identifies miR-137 and miR-106b as potential ACS diagnostic and therapeutic targets. This research underscores the potential of miRNAs targeting Nourin for precision ACS intervention. The analysis leverages RNA Composer, Schrödinger, and I-TASSER tools to explore interactions and structural insights. Robust Nourin-miRNA interactions are established, bolstering the case for miRNA-based interventions in ischemic injury. In conclusion, the study contributes to UA and AMI diagnosis strategies through bioinformatics-guided exploration of Nourin-targeting miRNAs. Supported by comprehensive molecular analysis, the hypoxia-induced miR-137 for cell apoptosis (a marker of cell damage) and the inflammation-induced miR-106b (a marker of inflammation) confirmed their potential clinical use as diagnostic biomarkers. This research reinforces the growing role of miR-137/hsa-miR-106b in the early diagnosis of myocardial ischemia in unstable angina patients.

Diagnostic Performance of High-Sensitivity Cardiac Troponin T Strategies and Clinical Variables in a Multisite US Cohort.

BACKGROUND: European data support the use of low high-sensitivity troponin (hs-cTn) measurements or a 0/1-hour (0/1-h) algorithm for myocardial infarction to exclude major adverse cardiac events (MACEs) among patients in the emergency department with possible acute coronary syndrome. However, modest US data exist to validate these strategies. This study evaluated the diagnostic performance of an initial hs-cTnT measure below the limit of quantification (LOQ: 6 ng/L), a 0/1-h algorithm, and their combination with history, ECG, age, risk factors, and initial troponin (HEART) scores for excluding MACE in a multisite US cohort. METHODS: A prospective cohort study was conducted at 8 US sites, enrolling adult patients in the emergency department with symptoms suggestive of acute coronary syndrome and without ST-elevation on ECG. Baseline and 1-hour blood samples were collected, and hs-cTnT (Roche; Basel, Switzerland) was measured. Treating providers blinded to hs-cTnT results prospectively calculated HEART scores. MACE (cardiac death, myocardial infarction, and coronary revascularization) at 30 days was adjudicated. The proportion of patients with initial hs-cTnT measures below the LOQ and risk according to a 0/1-h algorithm was determined. The negative predictive value (NPV) was calculated for both strategies when used alone or with a HEART score. RESULTS: Among 1462 participants with initial hs-cTnT measures, 46.4% (678 of 1462) were women and 37.1% (542 of 1462) were Black with an age of 57.6±12.9 (mean±SD) years. MACEs at 30 days occurred in 14.4% (210 of 1462) of participants. Initial hs-cTnT measures below the LOQ occurred in 32.8% (479 of 1462), yielding an NPV of 98.3% (95% CI, 96.7-99.3) for 30-day MACEs. A low-risk HEART score with an initial hs-cTnT below the LOQ occurred in 20.1% (294 of 1462), yielding an NPV of 99.0% (95% CI, 97.0-99.8) for 30-day MACEs. A 0/1-h algorithm was complete in 1430 patients, ruling out 57.8% (826 of 1430) with an NPV of 97.2% (95% CI, 95.9-98.2) for 30-day MACEs. Adding a low HEART score to the 0/1-h algorithm ruled out 30.8% (441 of 1430) with an NPV of 98.4% (95% CI, 96.8-99.4) for 30-day MACEs. CONCLUSIONS: In a prospective multisite US cohort, an initial hs-cTnT below the LOQ combined with a low-risk HEART score has a 99% NPV for 30-day MACEs. The 0/1-h hs-cTnT algorithm did not achieve an NPV >99% for 30-day MACEs when used alone or with a HEART score. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02984436.

Glycated Albumin for the Diagnosis of Diabetes in US Adults.

BACKGROUND: There is growing interest in using glycated albumin for the diagnosis of diabetes, especially when standard tests (glucose and hemoglobin A1c [Hb A1c]) are unavailable. However, it is unknown how well glycated albumin identifies diabetes in the general population. METHODS: We measured glycated albumin in stored serum samples from the 1999-2004 National Health and Nutrition Examination Survey. We evaluated the ability of glycated albumin to identify undiagnosed diabetes in US adults aged ≥20 (n = 4785), overall and at thresholds corresponding to clinical cut points for Hb A1c and fasting plasma glucose (FPG). We assessed 4 reference definitions for undiagnosed diabetes: increased FPG (≥126 mg/dL) [≥6.99 mmol/L), increased Hb A1c (≥6.5%), either FPG or Hb A1c increased, or both FPG and Hb A1c increased. RESULTS: Among US adults, glycated albumin had excellent diagnostic accuracy across all 4 definitions of undiagnosed diabetes, with the area under the receiver operating characteristic curve (AUC) ranging from 0.824 to 0.951. Performance was generally consistent across patient demographic and clinical characteristics. Glycated albumin cut points of 16.5% and 17.8% were equivalent to an FPG of 126 mg/dL (6.99 mmol/L; 97th percentile) and Hb A1c of 6.5% (98th percentile) and had low to moderate sensitivity (0.273 to 0.707) but high specificity (0.980 to 0.992) for detecting undiagnosed diabetes. CONCLUSION: The excellent diagnostic performance of glycated albumin to identify diabetes defined by either FPG or Hb A1c suggests that glycated albumin may be useful for identifying adults with undiagnosed diabetes when standard tests are unavailable.

Glycated Albumin and Risk of Mortality in the US Adult Population.

BACKGROUND: Glycated albumin is of growing interest as an alternative biomarker of glycemia. However, the association of glycated albumin with long-term outcomes in the general population is uncharacterized. We evaluated the associations of glycated albumin and hemoglobin A1c (HbA1c) with mortality in US adults. METHODS: We conducted a prospective analysis of 12 915 participants in the National Health and Nutrition Examination Survey 1999-2004. We used Cox regression to characterize associations of glycated albumin and HbA1c with all-cause and cardiovascular mortality through 2014. We categorized glycated albumin based on percentiles corresponding to clinical cut-points for HbA1c. No diagnosed diabetes: <5.0% (<12th percentile), 5.0% to 5.6% (12th-82nd percentile, reference), 5.7% to 6.4% (83rd-97th percentile), and ≥6.5% (≥98th percentile). Diagnosed diabetes: <7.0% (<50th percentile), 7.0% to 8.9% (50th-83rd percentile), and ≥9.0% (≥84th percentile). RESULTS: Among US adults (mean age 46 years), the prevalence of diagnosed diabetes was 6.8%. Glycated albumin and HbA1c were highly correlated (r = 0.76). Over the median 16.8 years follow-up, there were 2818 deaths (652 cardiovascular). Adults with diagnosed diabetes and glycated albumin ≥84th percentile had the highest risk for all-cause mortality [hazard ratio (HR) 3.96, 95% CI 3.06-5.13] and cardiovascular mortality (HR 6.80, 95% CI 4.20-11.03). HbA1c had associations with all-cause and cardiovascular mortality that were similar to those for glycated albumin. CONCLUSIONS: Among US adults, increased values of glycated albumin and HbA1c were associated with all-cause and cardiovascular mortality, particularly in persons with diagnosed diabetes. Glycated albumin may be a useful alternative test of glycemia.

Upper Reference Limits for High-Sensitivity Cardiac Troponin T and N-Terminal Fragment of the Prohormone Brain Natriuretic Peptide in Patients With CKD.

RATIONALE & OBJECTIVE: The utility of conventional upper reference limits (URL) for N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hsTnT) in chronic kidney disease (CKD) remains debated. We analyzed the distribution of hsTnT and NT-proBNP in people with CKD in ambulatory settings to examine the diagnostic value of conventional URL in this population. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: We studied participants of the Chronic Renal Insufficiency Cohort (CRIC) with CKD and no self-reported history of cardiovascular disease. EXPOSURE: Estimated glomerular filtration rate (eGFR). OUTCOME: NT-proBNP and hsTnT at baseline. ANALYTICAL APPROACH: We described the proportion of participants above the conventional URL for NT-proBNP (125pg/mL) and hsTnT (14ng/L) overall and by eGFR. We then estimated 99th percentile URL for NT-proBNP and hsTnT. Using quantile regression of the 99th percentile, we modeled the association of eGFR with NT-proBNP and hsTnT. RESULTS: Among 2,312 CKD participants, 40% and 43% had levels of NT-proBNP and hsTnT above the conventional URL, respectively. In those with eGFR <30mL/min/1.73m2, 71% and 68% of participants had concentrations of NT-proBNP and hsTnT above the conventional URL, respectively. Among all CKD participants, the 99th percentile for NT-proBNP was 3,592 (95% CI, 2,470-4,849) pg/mL and for hsTnT it was 126 (95% CI, 100-144) ng/L. Each 15mL/min/1.73m2 decrement in eGFR was associated with a ~40% higher threshold for the 99th percentile of NT-proBNP (1.43 [95% CI, 1.21-1.69]) and hsTnT (1.45 [95% CI, 1.31-1.60]). LIMITATIONS: Study included ambulatory patients, and we could not test the accuracy of the URL of NT-proBNP and hsTnT in the acute care setting. CONCLUSIONS: In this ambulatory CKD population with no self-reported history of cardiovascular disease, a range of 40%-88% of participants had concentrations of NT-proBNP and hsTnT above the conventional URL, depending on eGFR strata. Developing eGFR-specific thresholds for these commonly used cardiac biomarkers in the setting of CKD may improve their utility for evaluation of suspected heart failure and myocardial infarction.

Multiple Cardiac Biomarker Testing Among Patients With Acute Dyspnea From the ICON-RELOADED Study.

BACKGROUND: Among patients with acute dyspnea, concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T, and insulin-like growth factor binding protein-7 predict cardiovascular outcomes and death. Understanding the optimal means to interpret these elevated biomarkers in patients presenting with acute dyspnea remains unknown. METHODS AND RESULTS: Concentrations of NT-proBNP, high-sensitivity cardiac troponin T, and insulin-like growth factor binding protein-7 were analyzed in 1448 patients presenting with acute dyspnea from the prospective, multicenter International Collaborative of NT-proBNP-Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department (ICON-RELOADED) Study. Eight biogroups were derived based upon patterns in biomarker elevation at presentation and compared for differences in baseline characteristics. Of 441 patients with elevations in all 3 biomarkers, 218 (49.4%) were diagnosed with acute heart failure (HF). The frequency of acute HF diagnosis in this biogroup was higher than those with elevations in 2 biomarkers (18.8%, 44 of 234), 1 biomarker (3.8%, 10 of 260), or no elevated biomarkers (0.4%, 2 of 513). The absolute number of elevated biomarkers on admission was prognostic of the composite end point of mortality and HF rehospitalization. In adjusted models, patients with one, 2, and 3 elevated biomarkers had 3.74 (95% confidence interval [CI], 1.26-11.1, P = .017), 12.3 (95% CI, 4.60-32.9, P < .001), and 12.6 (95% CI, 4.54-35.0, P < .001) fold increased risk of 180-day mortality or HF rehospitalization. CONCLUSIONS: A multimarker panel of NT-proBNP, hsTnT, and IGBFP7 provides unique clinical, diagnostic, and prognostic information in patients presenting with acute dyspnea. Differences in the number of elevated biomarkers at presentation may allow for more efficient clinical risk stratification of short-term mortality and HF rehospitalization.

The performance of glycated albumin as a biomarker of hyperglycemia and cardiometabolic risk in children and adolescents in the United States.

OBJECTIVE: Diabetes and prediabetes are growing concerns among US youth. Fasting glucose (FG) and HbA1c are standard diabetes screening tests, but HbA1c may be unreliable in some settings and fasting is burdensome in children. Glycated albumin (GA) is a non-fasting test that was recently cleared for clinical use in the United States, but studies in youth without diabetes are limited. RESEARCH DESIGN AND METHODS: We conducted a cross-sectional analysis in 6826 youth without diabetes aged 8-19 years in the 1999-2004 National Health and Nutrition Examination Survey. We evaluated the associations of GA with HbA1c, FG, and cardiometabolic risk factors. RESULTS: GA was poorly correlated with HbA1c (ρ = 0.074) and FG (ρ = -0.047) and was negatively associated with body mass index (BMI) and cardiometabolic risk factors. Compared to youth in the highest tertile of GA (≥13.5%), those in the lowest GA tertile (<12.4%) had a higher prevalence of obesity (29.9% vs. 7.6%), low high-density lipoprotein cholesterol (29.7% vs. 16.5%), and hypertensive blood pressure (4.0% vs. 2.7%). These inverse associations persisted after adjustment for age, sex, race/ethnicity, serum albumin, and C-reactive protein. CONCLUSIONS: GA was poorly correlated with traditional markers of hyperglycemia in youth without diabetes. Counterintuitively, there was a negative association between GA and BMI. Among youth without diabetes, GA does not identify youth at high cardiometabolic risk, and it does not appear to be an appropriate biomarker for screening of hyperglycemia.

A multicenter performance evaluation of the new Elecsys Vitamin D total III assay versus reference isotope dilution liquid chromatography tandem mass spectrometry and commercially available comparators.

BACKGROUND: Vitamin D deficiency/insufficiency and toxicity are worldwide issues; thus, accurate diagnostic assays are required to measure vitamin D. We evaluated the performance of the new Elecsys® Vitamin D total III assay (Roche Diagnostics International Ltd). METHODS: Repeatability and intermediate precision of the Elecsys Vitamin D total III assay (cobas e 601 analyzer) were evaluated at three sites using five human serum pools (HSPs) and two PreciControls (five-day model, one reagent lot [CLSI-EP05-A3]) and compared against prespecified acceptance criteria. A serum verification panel, with reference isotope dilution liquid chromatography tandem mass spectrometry (ID-LC-MS/MS) values, was used for comparator assay/concordance studies at two sites, assessed using unweighted Deming regression. Testing of serum vs. plasma on the Elecsys assay was conducted at one site using samples from healthy adults; assessed using Passing-Bablok regression. RESULTS: Repeatability (HSP1 [16.8-18.4 ng/ml], SD 0.87-1.07; HSP5 [94.5-98.0 ng/ml], CV 1.58%-2.76%) and intermediate precision (HSP1, SD 1.14-1.77; HSP5, CV 2.00%-4.13%) met acceptance criteria across sites. Agreement was observed between the Elecsys assay and (i) the ID-LC-MS/MS verification panel (slope, 0.936-1.01; Pearson's r, 0.960-0.986) and (ii) comparator assays (slope, 0.921-1.15; Pearson's r, 0.958-0.982). The Elecsys assay correctly assigned the highest combined percentage of samples to deficient (100%) and insufficient (89.5%) vitamin D categories vs. comparator assays and demonstrated comparable performance in serum and plasma (y = 0.103 + 0.984x). CONCLUSIONS: The Elecsys Vitamin D total III assay demonstrated good analytical performance and compared favorably with other assays, supporting its use in clinical practice.

The Effects of Four Doses of Vitamin D Supplements on Falls in Older Adults : A Response-Adaptive, Randomized Clinical Trial.

BACKGROUND: Vitamin D supplementation may prevent falls in older persons, but evidence is inconsistent, possibly because of dosage differences. OBJECTIVE: To compare the effects of 4 doses of vitamin D3 supplements on falls. DESIGN: 2-stage Bayesian, response-adaptive, randomized trial. (ClinicalTrials.gov: NCT02166333). SETTING: 2 community-based research units. PARTICIPANTS: 688 participants, aged 70 years and older, with elevated fall risk and a serum 25-hydroxyvitamin D [25-(OH)D] level of 25 to 72.5 nmol/L. INTERVENTION: 200 (control), 1000, 2000, or 4000 IU of vitamin D3 per day. During the dose-finding stage, participants were randomly assigned to 1 of the 4 vitamin D3 doses, and the best noncontrol dose for preventing falls was determined. After dose finding, participants previously assigned to receive noncontrol doses received the best dose, and new enrollees were randomly assigned to receive 200 IU/d or the best dose. MEASUREMENTS: Time to first fall or death over 2 years (primary outcome). RESULTS: During the dose-finding stage, the primary outcome rates were higher for the 2000- and 4000-IU/d doses than for the 1000-IU/d dose, which was selected as the best dose (posterior probability of being best, 0.90). In the confirmatory stage, event rates were not significantly different between participants with experience receiving the best dose (events and observation time limited to the period they were receiving 1000 IU/d; n = 308) and those randomly assigned to receive 200 IU/d (n = 339) (hazard ratio [HR], 0.94 [95% CI, 0.76 to 1.15]; P = 0.54). Analysis of falls with adverse outcomes suggested greater risk in the experience-with-best-dose group versus the 200-IU/d group (serious fall: HR, 1.87 [CI, 1.03 to 3.41]; fall with hospitalization: HR, 2.48 [CI, 1.13 to 5.46]). LIMITATIONS: The control group received 200 IU of vitamin D3 per day, not a placebo. Dose finding ended before the prespecified thresholds for dose suspension and dose selection were reached. CONCLUSION: In older persons with elevated fall risk and low serum 25-(OH)D levels, vitamin D3 supplementation at doses of 1000 IU/d or higher did not prevent falls compared with 200 IU/d. Several analyses raised safety concerns about vitamin D3 doses of 1000 IU/d or higher. PRIMARY FUNDING SOURCE: National Institute on Aging.

Monocyte chemoattractant protein-1 is not predictive of cardiac events in patients with non-low-risk chest pain.

BACKGROUND: Prior studies suggest monocyte chemoattractant protein-1 (MCP-1) may be useful for risk stratifying ED patients with chest pain. We hypothesise that MCP-1 will be predictive of 90-day major adverse cardiovascular events (MACEs) in non-low-risk patients. METHODS: A case-control study was nested within a prospective multicentre cohort (STOP-CP), which enrolled adult patients being evaluated for acute coronary syndrome at eight US EDs from 25 January 2017 to 06 September 2018. Patients with a History, ECG, Age, and Risk factor score (HEAR score) ≥4 or coronary artery disease (CAD), a non-ischaemic ECG, and non-elevated contemporary troponins at 0 and 3 hours were included. Cases were patients with 90-day MACE (all-cause death, myocardial infarction or revascularisation). Controls were patients without MACE selected with frequency matching using age, sex, race, and HEAR score or the presence of CAD. Serum MCP-1 was measured. Sensitivity and specificity were determined for cut-off points of 194 pg/mL, 200 pg/mL, 238 pg/mL and 281 pg/mL. Logistic regression adjusting for age, sex, race, and HEAR score/presence of CAD was used to determine the association between MCP-1 and 90-day MACE. A separate logistic model also included high-sensitivity troponin (hs-cTnT). RESULTS: Among 40 cases and 179 controls, there was no difference in age (p=0.90), sex (p=1.00), race (p=0.85), or HEAR score/presence of CAD (p=0.89). MCP-1 was similar in cases (median 191.9 pg/mL, IQR: 161.8-260.1) and controls (median 196.6 pg/mL, IQR: 163.0-261.1) (p=0.48). At a cut-off point of 194 pg/mL, MCP-1 was 50.0% (95% CI 33.8% to 66.2%) sensitive and 46.9% (95% CI 39.4% to 54.5%) specific for 90-day MACE. After adjusting for covariates, MCP-1 was not associated with 90-day MACE at any cut-off point (at 194 pg/mL, OR 0.88 (95% CI 0.43 to 1.79)). When including hs-cTnT in the model, MCP-1 was not associated with 90-day MACE at any cut-off point (at 194 pg/mL, OR 0.85 (95% CI 0.42 to 1.73)). CONCLUSION: MCP-1 is not predictive of 90-day MACE in patients with non-low-risk chest pain.

Biomarkers Enhance Discrimination and Prognosis of Type 2 Myocardial Infarction.

BACKGROUND: The observed incidence of type 2 myocardial infarction (T2MI) is expected to increase with the implementation of increasingly sensitive cTn assays. However, it remains to be determined how to diagnose, risk-stratify, and treat patients with T2MI. We aimed to discriminate and risk-stratify T2MI using biomarkers. METHODS: Patients presenting to the emergency department with chest pain, enrolled in the CHOPIN study (Copeptin Helps in the early detection Of Patients with acute myocardial INfarction), were retrospectively analyzed. Two cardiologists adjudicated type 1 MI (T1MI) and T2MI. The prognostic ability of several biomarkers alone or in combination to discriminate T2MI from T1MI was investigated using receiver operating characteristic curve analysis. The biomarkers analyzed were cTnI, copeptin, MR-proANP (midregional proatrial natriuretic peptide), CT-proET1 (C-terminal proendothelin-1), MR-proADM (midregional proadrenomedullin), and procalcitonin. The prognostic utility of these biomarkers for all-cause mortality and major adverse cardiovascular event (a composite of acute myocardial infarction, unstable angina pectoris, reinfarction, heart failure, and stroke) at 180-day follow-up was also investigated. RESULTS: Among the 2071 patients, T1MI and T2MI were adjudicated in 94 and 176 patients, respectively. Patients with T1MI had higher levels of baseline cTnI, whereas those with T2MI had higher baseline levels of MR-proANP, CT-proET1, MR-proADM, and procalcitonin. The area under the receiver operating characteristic curve for the diagnosis of T2MI was higher for CT-proET1, MR-proADM, and MR-proANP (0.765, 0.750, and 0.733, respectively) than for cTnI (0.631). Combining all biomarkers resulted in a similar accuracy to a model using clinical variables and cTnI (0.854 versus 0.884, P=0.294). Addition of biomarkers to the clinical model yielded the highest area under the receiver operating characteristic curve (0.917). Other biomarkers, but not cTnI, were associated with mortality and major adverse cardiovascular event at 180 days among all patients, with no interaction between the diagnosis of T1MI or T2MI. CONCLUSIONS: Assessment of biomarkers reflecting pathophysiologic processes occurring with T2MI might help differentiate it from T1MI. All biomarkers measured, except cTnI, were significant predictors of prognosis, regardless of the type of myocardial infarction.