Second Paper Supports Concept of Troponin as a Chronic Marker of CVD

December 8, 2010 (Dallas, Texas)— The second study in a month to find that detection of cardiac troponin T--as measured by high-sensitivity assays--is associated with all-cause mortality raises the possibility that testing troponin as a chronic marker of cardiovascular disease might one day become routine in the doctor's office, say the researchers, who publish their findings in the December 8, 2010 issue of the Journal of the American Medical Association [1].

Dr James A de Lemos (University of Texas Southwestern Medical Center, Dallas) and colleagues followed a relatively young population of 30- to 65-year-olds and found that troponin was detectable in approximately 25% of people and was associated with structural heart disease and risk of subsequent all-cause mortality. The findings complement those of a second study, by Dr Christopher R deFilippi (University of Maryland School of Medicine, Baltimore) et al, appearing in the same issue of the journal but published online last month to coincide with a presentation at the American Heart Association meeting. It showed cardiac troponin T detected by high-sensitivity assay was associated with new-onset heart failure and cardiovascular death in adults aged 65 and over.

"The message is that we might have to rethink the way we have considered troponin and perhaps use it more as a chronic marker for disease than as an acute marker of someone having a heart attack. There is a possibility troponin could be used as a screening test," de Lemos told heartwire.

Two Studies Are Better Than One

We might have to rethink the way we have considered troponin and use it more as a chronic marker for disease than as an acute marker of heart attack.
Although raised troponin levels as detected by traditional assays have long been used to indicate myocardial infarction (MI), a new analysis from the PEACE trial published last year showed that almost any troponin detected by high-sensitivity tests was associated with heart failure and death in a stable coronary heart disease population. The new papers are the first to show the same outcome in two general populations without underlying cardiovascular disease, across a wide age spectrum.

"These are highly complementary studies published side-by-side for that reason," de Lemos explained. "Validation is the key to knowing whether results are real or spurious. The mortality findings across the studies are similar." He points out also that the two papers cover different age groups, further strengthening the findings, and that each has its own unique feature: in his own, the detailed assessments done by cardiac magnetic resonance imaging (MRI), and in the other study, the availability of serial measurements of troponin.

Taken together, these new studies and the PEACE analysis from last year "suggest important differences in the pathophysiology of troponin release in the chronic compared with the acute setting," say he and his colleagues.

Adding Troponin Modestly Improved Mortality Models

In their study, de Lemos et al measured troponin levels using both the traditional and new highly sensitive assays (which detect around 10-fold lower levels than standard assays) in 3546 individuals enrolled between 2000 and 2002 in the Dallas Heart Study, a multiethnic population-based cohort with a large proportion of women. The main outcome measures were MRI of cardiac structure and function and mortality through a median of 6.4 years of follow-up.

The prevalence of detectable cardiac troponin T (>0.003 ng/mL) was 25% with the highly sensitive assay vs 0.7% with the standard assay. Prevalence was 37.1% in men vs 12.9% in women and 14% in those younger than 40 vs 57.6% in those 60 and over.

Participants were placed into five categories based on troponin levels. Prevalence of LV hypertrophy increased from 7.5% in the lowest troponin category (<0.003 ng/mL) to 48.1% in the highest (>0.014 ng/mL; p<0.001); prevalence of LV systolic dysfunction and chronic kidney disease also increased across categories (p<0.001 for each).

There were 151 total deaths, including 62 CVD deaths. All-cause mortality increased from 1.9% to 28.4% across higher troponin categories. After adjustment for traditional risk factors, C-reactive protein (CRP), chronic kidney disease, and N-terminal pro-B-type natriuretic peptide (NT-proBNP), troponin remained independently associated with all-cause mortality (adjusted HR 2.8). Adding troponin categories to the fully adjusted mortality model modestly improved model fit (p=0.02) and the integrated discrimination index (p=0.01).

"Our study gives us a mechanism by which the elevation of troponin might be working; it helps explain the 'why' for the heart-failure mortality, which, in many ways, makes perfect sense, because troponin is a structural cardiac protein," says de Lemos.

Education to Aid Doctors in Use of Highly Sensitive Troponin Assays

The results suggest that future studies should be performed to assess whether measurement of troponin with a highly sensitive assay adds value to traditional cardiovascular risk factors as well as measures of renal function and NT-proBNP for risk assessment in the general population, say de Lemos and colleagues.

And the independent and additive associations of troponin and NT-proBNP observed "suggest that combinations of these two markers may perform better than either marker alone," they add.

They note also that this new research has important implications for the use of highly sensitive assays in the hospital, with work needed to educate doctors to avoid false-positive diagnoses of acute MI.

These new highly sensitive assays may add trouble and confusion in the ER but open a whole new world in the doctor's office.
Although de Lemos says there are some obvious indicators that troponin detection is due to MI rather than a chronic, underlying condition--for example, the magnitude of elevation, where "very, very high levels of troponin will still indicate MI," and use of serial measurements to look for acute rises in troponin--this will be "an imperfect science," and not nearly as simple as people might think.

"In Europe, where they are using these new assays, they are setting a higher threshold to diagnose MI that is similar to the old threshold. But then, how do you interpret a value between the old level and new level? We need algorithms. Troponin has always been a yes/no test for a heart attack. These new highly sensitive assays may add trouble and confusion in the ER but open a whole new world in the doctor's office," he concludes.

de Lemos has received research grants from Roche Diagnostics and Biosite/Inverness and consulting fees and/or lecture honoraria from Tethys Biomedical, Johnson & Johnson, Roche Diagnostics, Biosite/Inverness, Siemens, AstraZeneca, Pfizer, Bristol-Myers Squibb/Sanofi-Aventis, and Merck/Schering. Disclosures for the coauthors are listed in the paper.

References
1.de Lemos JA, Drazner MH, Omland T, et al. Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population. JAMA 2010; 304:2503-2512.