Clinical Laboratory Strategies: September 11, 2008

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Identifying Subclinical Heart Disease
Very Low cTn, High NT-proBNP Levels Predict Mortality

By Phil Kibak

Elevations of the cardiac troponin T help guide risk stratification, prognosis, and therapeutic management of patients who have acute coronary syndrome. Similarly, the natriuretic peptides, BNP and NT-proBNP, have taken on a prominent role in identifying heart failure. Little is known, however, about the clinical significance of minimally elevated cardiac troponin T and the long-term prognostic value of NT-proBNP in apparently healthy older adults. This issue of Strategies examines a recent study that assessed the predictive significance of very low, yet detectable levels, of cardiac troponin T along with increases in NT-proBNP in older adults.

A consensus document of the European Society of Cardiology and the American College of Cardiology issued in 2000 recommends that, in the appropriate clinical setting, cTn levels ≥ 0.01 ng/mL may indicate that an MI is in progress. Clinicians also know that elevated levels of natriuretic peptides are useful in diagnosing heart failure. But only a few studies have looked at the predictive effects of minimally detectable levels of cTn combined with elevated levels of NT-proBNP on mortality. Now, results of a new investigation suggest that even small amounts of cTn or higher levels of NT-proBNP are associated with an increased risk of death from all causes. The study suggests that this risk is even higher if both markers meet certain criteria (JACC 2008; 52(6)450-459).

Magnitude of Risk Higher Than Expected

“One thing that’s important to note is that this study identified an association between the levels of these proteins and mortality, and not a cause-and-effect process,” noted Lori Daniels, MD, assistant professor of medicine at the University of California, San Diego and lead author of the study. “My colleagues and I had hypothesized we would see this association, but I was somewhat surprised as to the magnitude of risk associated with these markers. I also was surprised that the results were largely independent of other known cardiovascular risk factors.”

The study population included 957 adults from the Rancho Bernardo Study, a prospective, population-based study analyzing the epidemiology of chronic diseases associated with aging. Plasma cTn and NT-proBNP levels were assessed on blood that was drawn between 1997 and 1999, and the study population was followed through June 2006. At baseline, the age of participants ranged from 60 to 97 years. The researchers divided participants into groups based on cTn levels—undetectable in 917 and detectable in 39. Those with detectable levels were further divided into two groups—< 0.03 ng/mL and ≥ 0.03 ng/mL. Thirty of the 39 participants with detectable cTn had levels of the biomarker of 0.01–0.02 ng/mL. Study subjects also were grouped according to NT-proBNP levels—758 had plasma levels < 450 pg/mL, and 199 had levels ≥ 450 pg/mL. This cut point corresponds to the recommended decision threshold for the general age group represented in the Rancho Bernardo Study, the researchers said.

cTn and NT-proBNP Triple Risk of Death

A total of 220 participants died during the follow-up period, which averaged 6.8 years. Of those, 11% had detectable cTn levels—between 0.01 and 0.07 ng/mL—compared with only 2% of survivors. In addition 40% of those who died during follow-up had levels of NT-proBNP ≥ 450 pg/mL compared with 15% of survivors.

The researchers found that subjects with detectable cTn had a significantly higher risk of both all-cause mortality and cardiovascular mortality (adjusted hazard ratio 2.06 for both) compared to participants with no detectable cTn. Subjects with elevated NT-proBNP also had a significantly higher risk of both all-cause mortality (adjusted hazard ratio 1.85 per log-unit increase) and cardiovascular mortality (adjusted hazard ratio 2.51 per log-unit increase). Participants with both detectable cTn and elevated NT-proBNP had an even higher risk of dying from any cause (adjusted hazard ratio 3.2).

More than 60% of those with detectable cTn did not have known prior heart disease. Only 30% of those with elevated NT-proBNP levels had a history of coronary heart disease at the beginning of the study.

Implications for the Future

Daniels reported that each biomarker probably identifies a distinct physiology, either of which confers increased risk. Furthermore, she added, both may prove clinically useful in identifying a high-risk population with subclinical CVD who may warrant aggressive preventive measures.

“This is a well-done study that confirms previous data showing that minor elevations in troponin do occur—absent acute heart disease—that they are prognostic, and that they’re helpful clinically,” said Allan Jaffe, MD, professor of cardiology and laboratory medicine at the Mayo Clinic in Rochester, Minn. “It also provides further substantiation that a rising pattern of troponin should be used to help clinicians distinguish people who appear asymptomatic but have subclinical disease.”

Both researchers also agree that additional research needs to be done before these assays are used for widespread screening. “These results don’t yet justify using these markers routinely as screening methods for heart disease,” Daniels said. “There are a number of criteria you need to satisfy for something to be considered a good screening test. For example, what you’re screening for has to be prevalent in a certain amount of the target population and there has to be some kind of cost-effective intervention you can apply. I don’t know that these biomarkers have met those criteria yet.”

Before these markers can be used for widespread screening, Jaffe said there are two issues that need to be addressed. “First, we need to know how many patients truly have occult disease before we recommend this as a screening procedure. The second issue highlights the fact that there are patients with chronic cardiovascular disease, and that most of them with elevated cTn also have cardiovascular comorbidities but they appear stable. So, we’ll need to be able to distinguish these patients from those who present to the ER. That will require looking for a rising pattern of troponin to distinguish the chronic and short-term risk populations.”

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