Clinical Laboratory Strategies: February 11, 2010

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Assessing the Utility of a Highly Sensitive cTn T Assay in Stable Coronary Disease Graded Risk Relationship Suggests New Role for the Biomarker
By Genna Rollins

For at least a decade, cardiac troponin has been recognized by key professional guidelines as the preferred biomarker for diagnosing myocardial infarction and for risk stratification of acute coronary syndrome (ACS). However, a growing body of evidence suggests that even slight troponin elevations indicate risk after ACS and in other lower risk populations. New research described in this issue of Strategies expands on these studies to explore the utility of a novel, highly sensitive cardiac troponin T assay in patients with stable coronary artery disease.

Since 2000, cardiac troponin (cTn I and cTn T) levels above the 99th percentile of a normal reference population and with a CV ≤10% have been recommended by the European Society of Cardiology and the American College of Cardiology as an element of diagnosing myocardial infarction (MI). These groups also have recognized the role of cTn in stratifying risk among patients with acute coronary syndrome (ACS). However, several studies have shown a link between even very small troponin elevations and adverse events in ACS, and with increased mortality after an episode of ACS.

In parallel with these findings, researchers recently developed a novel, highly sensitive cTn T assay that permits cTn T measurement at concentrations up to 10 times lower than existing fourth-generation assays. With this high-sensitivity assay, a team of researchers was able to investigate whether cTn T would be detectable in patients with stable coronary artery disease (CAD) and to determine whether these cTn T levels would be associated with risk of future cardiovascular events (N Engl J Med 2009; 361: 2538-2547).

"Cardiac troponin has been routinely used in patients with suspected acute coronary syndrome, but little has been done in terms of evaluating its use in patients with stable coronary artery disease, mainly because previous assays have not been able to detect circulating troponin at very low levels," explained lead author, Torbjørn Omland, MD, PhD, professor of medicine at the University of Oslo and a cardiologist at Akershus University Hospital in Lørenskog, Norway. "So when we learned that this new highly sensitive assay would be available, we were lucky to be able to use an early, pre-commercial version of it in this setting."

Omland lead this biomarker substudy as part of an international team of investigators in the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial. PEACE involved 8,290 patients with stable CAD and preserved left ventricular systolic function who were randomly assigned to receive either the angiotensin-converting-enzyme inhibitor trandolapril or placebo. The biomarker substudy included 3,679 PEACE subjects from whom baseline EDTA-treated plasma samples had been obtained.

The researchers used the Roche cobas e 411 autoanalyzer to measure cTn T levels. The lower limit of detection for this assay was 0.001 μg/L. In contrast, Roche’s fourth-generation Elecsys cTn T assay has a reported detection limit of 0.01 μg/L, which corresponds to 0.03 μg/L in the novel assay. Other

biochemical measurements included N-terminal pro-brain natriuretic peptide, c-reactive protein, serum cholesterol, and estimated glomerular filtration rate using the Modification of Diet in Renal disease equation.

The investigators found measurable levels of cTn T in nearly all participants (97.7%), with concentrations at or above the 99th percentile (0.0133 μg/L) for apparently healthy individuals in 11.1%. cTn T levels were significantly higher in men than women, with a median of 0.0063 μg/L versus 0.0046 μg/L, respectively. There was a strong and graded relationship between increasing quartiles of cTn T and risk of cardiovascular death, fatal or nonfatal heart failure, and all cardiovascular deaths except those due to heart failure, all of which remained significant after multivariate risk adjustment. A weak association between rising cTn T levels and risk of MI was attenuated after multivariate adjustment and no longer statistically significant.

The findings are particularly notable because with conventional assays, the prevalence of detectable concentrations of cTn T in the general population is only about 0.7%. In addition, whereas this study found an insignificant association between rising cTn T levels and risk of MI, rising levels of cTn T in patients with ACS are considered a specific marker for MI. "I think our study opens a new perspective on cardiac troponins because they have traditionally been used as markers of myocardial ischemia and necrosis. But we were able to demonstrate that cardiac troponin T is actually circulating in a large proportion of patients with stable coronary artery disease," said Omland.

Omland’s findings represent an important step in the progression of science related to cTn T, according to Alan Wu, PhD, director of clinical chemistry and toxicology at the University of California San Francisco. "Troponin has always been used for looking at patients with acute coronary disease and its ability to predict outcomes. This paper suggests that troponin can also be used in stable coronary disease. We’ve not really used troponin in that realm before, although other papers have alluded to using troponin as a marker of chronic disease risk," he explained. "We keep moving the bar up with assays that are more sensitive, and this may be the first paper to have used the next-generation troponin T assay for risk stratification in this group of patients." Wu was not involved in the study.

Wu also pointed out that the findings would need to be replicated in other studies and patient populations before their full significance would be apparent. Omland agreed with this assessment. "What we’d really want to see is if altering therapy based on this assay will improve outcomes, and those data are not available yet," he observed. The assay used in the study has been available in Norway since early 2009, but labs are not reporting the very low levels because their significance has not been clear, according to Omland. The assay has not been FDA-cleared for use in the U.S.

The authors proposed several mechanisms which could account for very low levels of circulating cTn T, including transient, clinically silent ischemic episodes and small vessel occlusions, inflammatory processes, cardiomyocyte apoptosis, and increased myocardial strain due to pressure or volume overload. Wu has had a long-standing hypothesis that cTn T can be elevated in reversible cardiac injury, and he believes the study bolsters that theory.

As the field awaits further research involving highly sensitive cTn T assays, it appears that laboratorians and clinicians will have much to confer about in coming years, according to Omland. "This opens the possibility of a whole new population of patients traditionally not considered for cardiac troponin testing," he said. "Traditionally, some clinicians thought of cardiac troponin almost as a qualitative test, talking about patients being ‘troponin positive’ or ‘troponin negative’. But this study shows that it very much is a quantitative test and that there is much information to be gained from levels below the traditional detection limits."

Dr. Omland has received research support and speakers' honoraria from Roche Diagnostics and Abbott Laboratories.

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