December 2007 Clinical Laboratory News: Diagnostic Profiles

December 2007: Volume 33, Number 12

Study Emphasizes Extra Troponin Testing in Non-ST ACS

Because even mild but persistent minor cTnI elevation can predict mortality during long-term follow-up after a non-ST ACS (NSTACS) episode, further troponin testing is warranted after hospital discharge, suggests a new study (Circulation 2007; 116:1907–1914).

To assess the prevalence and prognostic importance of persistent cTnI elevation in stable patients who have had an NSTACS event, Swedish researchers measured cTnI in 1,092 stabilized patients at 6 weeks, 3 months, and 6 months after enrollment in the FRagmin and Fast Revascularization During InStability in Coronary Artery Disease (FRISC-II) trial. The researchers measured cTnI with the Access AccuTnI assay (Beckman Coulter, Fullerton, Calif.) using different prognostic cutoffs, and assessed outcomes through 5 years.

At 6 weeks, 48% of patients had elevated cTnI levels >0.01 μg/L, while 36% had similar levels at 6 months, and 26% had such levels at all 3 points. cTnI elevation was associated with increased age and other cardiovascular high-risk features. The lowest tested cTnI cutoff (0.01 μg/L) was most useful for prognosis and was independently predicative of mortality (HR 2.1, 95% CI, 1.3—3.3) in multivariable analysis adjusted for cardiovascular risk factors and randomization to an invasive versus noninvasive treatment strategy. But the lowest cutoff was related to myocardial infarction only in univariate analysis. “From a prognostic perspective, cTnI 0.01 μg/L as cutoff performed at least as well as the previously described 99th percentile. In view of these results, the question of how to define ‘troponin elevation’ needs to be addressed,” the researchers wrote. They suggested that when identifying high-risk patients, troponin elevation should be defined by the lowest reliably measurable concentration rather than the 99th percentile.

 Early CRP Measurement Advised in ACS

Because increased baseline concentration of CRP is strongly associated with mortality and heart failure across the ACS spectrum, CRP measurement with index diagnosis-specific cutpoints should occur soon after presentation, according to recent research (Clinical Chemistry 2007; 53: 1800–1807). Researchers from Brigham and Women’s Hospital in Boston, Mass. measured CRP upon admission in 3,225 patients who participated in the Orbofiban in Patients with Unstable Coronary Syndromes (OPUS)—Thrombolysis in Myocardial Infarction (TMI) 16 trial of patients with unstable angina, non- elevation myocardial infarction (NSTEMI), and STEMI. The researchers compared CRP concentrations in patients who suffered an adverse cardiac outcome within 10 months of study entry and in patients who had no adverse events. Samples were collected within 48 hours of symptom onset. Patients in the highest quartile of CRP, compared to those in the lowest quartile, were at increased risk of death at 30 days (adjusted HR 4.6) and at 10 months (adjusted HR 3.9). In patients with unstable angina (NSTEMI), CRP >3.0 mg/ L was associated with 10-month mortality (adjusted HR 2.3), whereas in STEMI, a relationship with mortality was seen at CRP > 10 mg/L (adjusted HR 3.0). Increased concentrations of CRP were strongly associated with the development of heart failure at 30 days (adjusted HR 8.2) and at 10 months (adjusted HR 2.6).

 Low LDL-C Doesn’t Mitigate Risk from High HDL-C Levels

HDL-C levels can predict major cardiovascular events (CVEs) in patients on statins, even among those with LDL-C levels below1.8 mmol/L, according to a recent paper (The New England Journal of Medicine 2007; 357: 1301–1310). While researchers have long known that a low HDL-C level is a powerful predictor of increased cardiovascular risk, it’s been unclear whether a low HDL-C level would remain a significant risk actor in people whose LDL-C has been reduced to very low levels.

In a posthoc analysis of the Treating to New Targets (TNT) study, researchers from seven sites in the U.S., the Netherlands, and France assessed the predictive relationship between HDL-C and clinically evident CHD using time to a first major cardiovascular death as an outcome measure in 9,770 patients age 35 to 75 with clinically evident CHD. In both univariate and multivariate analyses, the research team determined the predictive relationship between both HDL-C levels at the third month of statin treatment and first major cardiovascular event. The team also assessed specific LDL-C strata, including subjects with LDL-C <1.8 mmol/L. The HDL-C levels in patients who received atorvastatin were predictive of major cardiovascular events across the TNT study cohort, both when HDL-C was considered as a continuous variable and when subjects were stratified according to quintiles of HDL-C level. When the analysis was stratified according to LDL-C level, the relationship between HDL-C level and major cardiovascular events was of borderline significance. Even among study subjects with LDL-C levels <1.8 mmol/L, those in the highest quintile of HDL-C were at less risk for major cardiovascular events than those in the lowest quintile.

White Blood Cell Count Linked to Cancer

For the first time, researchers have demonstrated that a high WBC is associated with incident invasive breast, colorectal, endometrial, and lung cancer among postmenopausal women, providing a boost to a hypothesis of a causal link between inflammation and the initiation, promotion, and progression of these tumors (Archives of Internal Medicine 2007; 167: 1837–1844). In a prospective cohort study performed at 40 U.S. clinical centers, researchers examined data from 143,748 postmenopausal women who were free of cancer at baseline, age 50 to 79 and participants in the Women’s Health Initiative. The main outcome measures were incident invasive breast, colorectal, endometrial, and lung cancers.

In multivariate models, researchers observed a graded association of WBC count with incidence of all four types of cancer. Compared with the lowest quartile of WBC count (2.50–4.79 X 109 cells/L), women with WBC counts in the upper quartile (6.80–15.00 X 109 cells/L) had a statistically significantly higher risk of invasive breast cancer (HR 1.15, 95% CI, 1.04–1.26), colorectal cancer (HR 1.19, 95% CI, 1.00–1.41), endometrial cancer (HR 1.42, 95% CI, 1.12–1.79), and lung cancer (HR 1.63, 95% CI, 1.35–1.97). The findings were similar when cancer that occurred during the first 2 years of follow-up was excluded. Statistically significant associations remained for invasive breast cancer and endometrial cancer when the analyses were limited to nonsmokers. The WBC count also was statistically significantly associated with breast cancer, lung cancer, and overall mortality. “Before these finding can be applied clinically, they should be replicated in other populations, preferably with two measures of WBC count, and expanded to include other biomarkers of inflammation that may be more specifically linked to underlying causal mechanisms of neoplasia,” the researchers wrote.

 Uric Acid Linked to Cerebral Ischemia

Even normal elevations of serum uric acid (UA) are associated with increased burden of white matter hyperintense (WMH), a recent study reports. (Neurology 2007; 69: 1418–1423). Researchers from Johns Hopkins University in Baltimore, Md. and Yale University in New Haven, Conn. examined 177 adults ages 20 to 92 in a cross-sectional observational study that examined the relationship between cross-sectional measures of serum uric acid (UA) and the burden of T2-weighted hyperintense signals in the cerebral white matter of healthy adults stratified by age and sex. The researchers hypothesized that elderly adults would be most likely to show a relationship because they are at greatest risk of cerebral ischemia.

Using logistic regression, the researchers tested whether participants with UA concentrations in the highest quartile of the sample—but still normal—would have increased WMH volume. Compared with those with lower levels, participants with high normal serum US were more likely to fall in the highest quartile of WMH volume. The odds ratios (95% CIs) of increased WMH were 2.6 (1.2–5.4), for total, 2.5 (1.2–5.1) for periventricular, and 2.8 (1.4–5.9) for subcortical WMH volume. After controlling for age, sex, race, education, body mass, hypertension, and diabetes, the multivariate-adjusted odds of large total and subcortical WMH volumes remained elevated. Finally, high normal UA increased the odds of having excessive ischemic burden four to five fold in adults over age 60. “This might provide a partial explanation of the previously observed association between high normal serum UA and mild cognitive dysfunction in elderly adults,” researchers wrote. “Current results suggest that determining whether UA lowering medications can reduce ischemic brain disease or improve cognitive functioning in elderly adults with mildly elevated uric acid merits consideration.”

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