Frank H. Wians

Prevalence and Determinants of Troponin T Elevation in the General Population

Background— The prevalence and determinants of cardiac troponin T (cTnT) elevation in the general population are unknown, and the significance of minimally increased cTnT remains controversial. Our objective was to determine the prevalence and determinants of cTnT elevation in a large, representative sample of the general population. Methods and Results— cTnT was measured from stored plasma samples in 3557 subjects of the Dallas Heart Study, a population-based sample. cTnT elevation (≥0.01 &mgr;g/L) was correlated with clinical variables and cardiac MRI findings. The sample weight-adjusted prevalence of cTnT elevation in the general population was 0.7%. In univariable analyses, cTnT elevation was associated with older age, black race, male sex, coronary artery calcium by electron beam CT, a composite marker of congestive heart failure (CHF), left ventricular hypertrophy (LVH), diabetes mellitus (DM), and chronic kidney disease (CKD) (P<0.001 for each). Subjects with minimally increased (0.01 to 0.029 &mgr;g/L) and increased (≥0.03 &mgr;g/L) cTnT had a similar prevalence of these characteristics. In multivariable logistic regression analysis, LVH, CHF, DM, and CKD were independently associated with cTnT elevation. Conclusions— In the general population, cTnT elevation is rare in subjects without CHF, LVH, CKD, or DM, suggesting that the upper limit of normal for the immunoassay should be <0.01 &mgr;g/L. Even minimally increased cTnT may represent subclinical cardiac injury and have important clinical implications, a hypothesis that should be tested in longitudinal outcome studies.

Impact of body mass and body composition on circulating levels of natriuretic peptides: results from the Dallas Heart Study.

Background— The association between higher body mass index (BMI) and lower B-type natriuretic peptide (BNP) level is thought to be mediated by expression of the natriuretic peptide clearance receptor (NPR-C) in adipose tissue. To explore this association, we tested 2 hypotheses: (1) that N-terminal (NT)-proBNP, which is not believed to bind NPR-C, would not be associated with BMI and (2) that lower BNP would be more closely associated with fat mass than with lean mass. Methods and Results— Measurements of BNP, NT-proBNP, and body composition by direct dual energy x-ray absorptiometry (DEXA) were performed in 2707 subjects from the Dallas Heart Study. The associations between obesity and low BNP (<4 ng/L) or low NT-proBNP (lowest sex-specific quartile) were evaluated with multivariable logistic regression models stratified by sex and adjusted for age, race/ethnicity, hypertension, left ventricular mass, and end-diastolic volume. Higher BMI was independently associated with lower BNP and NT-proBNP (all P<0.001). When BMI was replaced with both DEXA-derived lean and fat mass, greater lean mass, but not fat mass, was associated with low BNP and NT-proBNP levels. Conclusions— In a large, population-based cohort, we confirm the previously described association between higher BMI and lower BNP and demonstrate a similar inverse association between BMI and NT-proBNP. Interestingly, both BNP and NT-proBNP are more closely associated with lean mass than with fat mass. These findings do not support the hypothesis that the lower BNP levels seen in obesity are driven by enhanced BNP clearance mediated via NPR-C.

Short- and Long-Term Biological Variation in Cardiac Troponin I Measured with a High-Sensitivity Assay: Implications for Clinical Practice

BACKGROUND The improved detection limit and precision in new-generation commercial assays for cardiac troponin I (cTnI) have lowered the 99th-percentile cutoff value, yielding higher frequencies of positive test results. Because serial testing is important in interpreting low concentrations, we evaluated the biological variation of cTnI in both the short (hours) and long (weeks) terms and determined reference change values (RCVs) and the index of individuality (II) for cTnI. METHODS To assess short- and long-term variation, we collected blood from 12 healthy volunteers hourly for 4 h and from 17 healthy individuals once every other week for 8 weeks, measured cTnI with a high-sensitivity assay (detection limit, 0.2 ng/L), and computed analytical, intraindividual, interindividual, and total CVs (CV(A), CV(I), CV(G), and CV(T), respectively; CV(T) = CV(A) + CV(I) + CV(G)) as well as the II. Because of the slight right-skewness of the data, RCVs were calculated with a lognormal approach. RESULTS Within-day CV(A), CV(I), and CV(G) values were 8.3%, 9.7%, and 57%, respectively; the corresponding between-day values were 15%, 14%, and 63%. Within- and between-day IIs were 0.21 and 0.39, respectively. Lognormal within-day RCVs were 46% and -32%, respectively; the corresponding between-day values were 81% and -45%. CONCLUSIONS The low II indicates that population-based reference intervals are less useful for interpreting cTnI values than following serial changes in values in individual patients. This criterion is particularly important for interpreting results from patients who show cTnI increases at low concentrations measured with very high-sensitivity assays, from patients presenting with chest pain (short term), and for evaluating drugs for cardiotoxicity (long term).

Relationship Between C-Reactive Protein and Subclinical Atherosclerosis The Dallas Heart Study

Background— Elevated levels of C-reactive protein (CRP) are associated with increased risk for incident cardiovascular events on the basis of observations from several prospective epidemiological studies. However, less is known regarding the relationship between CRP levels and atherosclerotic burden. Methods and Results— We measured CRP in 3373 subjects 30 to 65 years of age who were participating in the Dallas Heart Study, a multiethnic, population-based, probability sample. Electron-beam CT scans were used to measure coronary artery calcification (CAC) in 2726 of these subjects, and MRI was used to measure aortic plaque in 2393. CRP levels were associated with most traditional cardiovascular risk factors. Subjects with CAC had higher median CRP levels than those without CAC (men: median, 2.4 versus 1.8 mg/L, P<0.001; women: median, 5.2 versus 3.6 mg/L, P<0.001), and there was a modest trend toward increasing CRP levels with increased CAC levels in men (P for trend=0.003) but not in women (P for trend=0.08). Male subjects with aortic plaque also had higher CRP levels than those without (median, 2.3 versus 1.8; P<0.001). In multivariate analysis adjusted for traditional cardiovascular risk factors, body mass index, and estrogen and statin medication use, the associations between CRP levels and CAC and CRP levels and aortic plaque were no longer statistically significant. Conclusions— In a large, population-based sample, subjects with higher CRP levels had a modest increase in the prevalence of subclinical atherosclerosis, but this association was not independent of traditional cardiovascular risk factors. CRP is a poor predictor of atherosclerotic burden.

Assessment of HER-2/neu status in breast cancer. Automated Cellular Imaging System (ACIS)-assisted quantitation of immunohistochemical assay achieves high accuracy in comparison with fluorescence in situ hybridization assay as the standard.

This retrospective study of formalin-fixed infiltrating breast cancer specimens compared manual immunohistochemical assay with a new image analyzer-assisted immunohistochemical quantitation method, using fluorescence in situ hybridization assay (FISH) as the standard. Following the manual immunohistochemical assay, 189 cases, including most manual immunohistochemically positive and some random negative cases, were analyzed by FISH assay for Her-2/neu gene amplification and by the Automated Cellular Imaging System (ACIS) for immunohistochemical staining. Using the FISH standard, the ACIS immunohistochemical assay attained a higher concordance rate and sensitivity than the manual immunohistochemical assay (91.0% and 88% vs 85.7% and 71%, respectively), with only a slight decrease in specificity (93% vs 96%, respectively). In particular, the ACIS immunohistochemical assay resulted in a higher correlation with the FISH assay in the manual immunohistochemical assay 2+ cases. The ACIS immunohistochemical assay achieved higher accuracy than the manual method according to receiver operating characteristic curve analysis. The ACIS method represents a substantial improvement over the manual method for objective evaluation of the HER-2/neu status.

The variability of results between point-of-care testing glucose meters and the central laboratory analyzer.

CONTEXT Point-of-care testing glucose meters are strongly recommended in the management of diabetes and are increasingly being used for making therapeutically important decisions. Thus, it is essential that their results correlate well with those of laboratory analyzers. OBJECTIVES To test the reliability of point-of-care testing glucose meters. DESIGN Two studies were performed: (1), an in-house study comparing accuracy of point-of-care testing glucose meters with a reference analyzer using fresh whole blood specimens (2), a real-time comparison of (a) 2 successive glucose meter readings and (b) glucose meter reading to central laboratory analyzer reading. SETTING (1), Seven glucose meters from 4 manufacturers were compared with the Yellow Springs YSI 2300 blood glucose analyzer using whole blood without preservative. (2), (a) Whole blood samples were read within 5 minutes of each other using Accu-Chek meters and (b) between a glucose meter and a Hitachi laboratory analyzer. RESULTS (1) Within the Accu-Chek group of glucose meters, fresh, preservative-free whole blood samples showed the lowest bias. (2) At the hypoglycemic level, successive glucose meter readings agreed well, but there was considerable disagreement between glucose meter and central laboratory values. Because laboratory analyzers are of proven accuracy, they are used as the reference. In the glucose meter-central laboratory analyzer correlation, for both hypoglycemic and hyperglycemic values, readings in which the differences were greater than 10% occurred more than 61% of the time. In the hypoglycemic range, differences greater than 20% occurred 57% of the time. CONCLUSIONS One should scrutinize point-of-care testing glucose meter readings at the hypoglycemic and hyperglycemic levels and whenever possible to corroborate these clinical results with central laboratory analyzers.

Biological Variation and Reference Change Value of High-Sensitivity Troponin T in Healthy Individuals during Short and Intermediate Follow-up Periods

BACKGROUND Acute myocardial infarction is defined by a troponin concentration >99th percentile with an acute increase and/or decrease, the magnitude of which has not yet been well defined. To aid the interpretation of changes in cardiac troponin concentration, we sought to establish biological variation and reference change values (RCVs) by applying both the normal and lognormal approaches for cardiac troponin T (cTnT) sampled at hourly and weekly intervals in healthy individuals and measured on the Roche E 170 and Elecsys® 2010 automated platforms. METHODS High-sensitivity cTnT (hsTnT) was measured at baseline, and after 1, 2, 3, and 4 h and after 1, 2, 3, and 4 weeks in 20 and 17 healthy individuals, respectively. A healthy status was established by physical examination, MRI analysis at rest and during dobutamine stress, lung function testing, and blood sample testing. RESULTS Hourly total and within-individual CVs were 18% and 15%, respectively, for the E 170 assay, and 24% and 21%, respectively, for the Elecsys 2010 assay. Weekly total and within-individual CVs for these assays were 32% and 31%, respectively, for the E 170 assay, and 32% and 30%, respectively, for the Elecsys 2010 assay. The RCVs for the E 170 and Elecsys 2010 assays were ±46% and ±62% (hourly), respectively, and ±87% and ±86% (weekly), respectively. The corresponding lognormal values were +64%/-39% and +90%/-47% (hourly), and +138%/-58% and +135%/-58% (weekly). CONCLUSIONS RCVs appear attractive for interpreting hsTnT results. The short-term biological variation of hsTnT is low but becomes somewhat more important at intermediate sampling intervals. Knowledge of this variation is important for interpreting results from patients in whom cTnT values increase from low concentrations.

Plasma concentration of Gc-globulin is associated with organ dysfunction and sepsis after injury.

ObjectiveClinical and experimental studies suggest that the proteins of the extracellular actin scavenger system have a role in the pathophysiological processes taking place in critically ill and injured patients. Circulating levels of Gc-globulin and gelsolin are reduced shortly after severe trauma, and admission levels of Gc-globulin are associated with survival. Herein, we sought to measure the association between admission levels of Gc-globulin and postinjury organ dysfunction and infection. We also wanted to describe the serial changes in Gc-globulin in these severely injured patients. DesignProspective cohort. SettingIntensive care unit at a county hospital that serves as a level one trauma center. PatientsNinety-eight consecutive trauma victims admitted to the intensive care unit for >24 hrs during a 4-month period. Measurements and Main ResultsCirculating levels of Gc-globulin were measured by using immunonephelometry. All patients were evaluated daily to obtain the necessary data for assessment of organ dysfunction and sepsis. The median Gc-globulin concentration at admission was 127 mg/L in patients who developed severe multiple organ dysfunction compared with 184 mg/L in patients who did not (p = .001). The admission level of Gc-globulin was comparable to known risk factors such as age and injury severity score, regarding development of organ dysfunction. Plasma concentrations of Gc-globulin remained significantly lower in patients who developed respiratory failure and sepsis, compared with patients who did not develop these complications (p = .02 and p = .015, respectively). ConclusionsAdmission plasma concentration of Gc-globulin is lower in patients who develop organ dysfunction and sepsis after traumatic injury. These data, combined with the work of others, support the hypothesis that actin release and depletion of the extracellular actin scavenger system proteins are associated with, and may contribute in part to, the complications of sepsis and organ dysfunction, particularly respiratory failure and thrombocytopenia.

Discriminating Between Iron Deficiency Anemia and Anemia of Chronic Disease Using Traditional Indices of Iron Status vs Transferrin Receptor Concentration

We compared the ability of soluble serum transferrin receptor (TfR) concentration, quantified using the R&D Systems (Minneapolis, MN) enzyme-linked immunosorbent TfR assay, with other, more traditional indicators of iron status (total iron binding capacity [TIBC], mean corpuscular volume [MCV], percent transferrin saturation [%TS], RBC distribution width [RDW], and serum iron concentration [SIC]) for discriminating between patients with iron deficiency anemia (IDA) or anemia of chronic disease (ACD). The TfR concentration was determined in 72 serum samples selected from men and nonpregnant women classified biochemically on the basis of ferritin concentration as having IDA (n = 41) or ACD (n = 31). By using receiver operating characteristic curve analysis, the diagnostic accuracy of the various indicators of iron status that we evaluated for discriminating between IDA and ACD decreased in the following order: TIBC > TfR > MCV > (%TS = RDW) > SIC. There was no significant difference between the diagnostic accuracy of TIBC and TfR. Thus, the routine measurement of TfR offers no advantage over TIBC for discriminating between people with biochemically defined IDA or ACD.

Maternal cardiac troponin I levels during normal labor and delivery

OBJECTIVE Diagnosis of myocardial infarction in pregnant women on the basis of changes in biochemical markers is complicated by the release of some of these markers from noncardiac tissue sources. We compared troponin I levels with those of other markers in normal pregnant women. STUDY DESIGN In 51 healthy women at term in labor, cardiac troponin I, myoglobin, creatine kinase, and creatine kinase MB levels were determined at admission, during the second stage of labor, and within 30 minutes, 12 hours, and 24 hours after delivery. RESULTS Mean admission levels for all markers were below the upper limit of normal. Mean concentrations of myoglobin, creatine kinase, and creatine kinase MB mass were increased nearly twofold within 30 minutes after delivery. The highest level of troponin I (0.134 ng/mL) at all time points was below the cutoff value (0.15 ng/mL) for discriminating myocardial infarction. CONCLUSIONS Because only troponin I levels remained undetectable during and after delivery, it is potentially the most useful biochemical marker for monitoring pregnant women for myocardial injury.