High-Normal Troponin Levels May Signal Risk for Fatal CVD

Neil Osterweil

July 31, 2017

INNSBRUCK, AUSTRIA — Cardiac troponin levels that are high but still within the "normal" range appear to be a marker for increased cardiovascular disease (CVD) risk, especially fatal CVD events, results of a systematic review and meta-analysis suggest[1].

Among 154,052 participants in 28 prospective, long-term studies of patients without a history of CVD, patients with the highest third of cardiac troponin levels detected by high-sensitivity cardiac troponin T or troponin I (hs-cTNT/cTNI) assays had a greater than 60% increase in risk for fatal CVD events, a nearly 60% greater likelihood of coronary heart disease (CHD), and a more than 40% rise in overall CVD compared with patients in the lowest third, reported investigators led by Dr Peter Willeit (Medical University of Innsbruck, Austria).

The association between troponin levels and fatal CVD persisted even after adjustment for other CVD risk factors.

"To shed more light on this preliminary finding, future research is needed that evaluates, in a direct comparison, whether the clinical utility of hs-cTnT and hs-cTnI measurements depends on the assay generation or on patient characteristics, including age, sex, and indicators of myocardial stress," they write in the August 1, 2017 issue of Journal of the American College of Cardiology.

However, it's still too early to tell whether the findings will have a significant effect on clinical practice, commented Dr Jennifer E Ho (Massachusetts General Hospital, Boston) in an accompanying editorial[2].

"Although the use of hs-Tn assays in patients with suspected acute coronary syndrome may have been embraced early on, the clinical usefulness of hs-Tn assays when extended to asymptomatic populations without known cardiovascular disease is largely uncharted," she writes.


Willeit et al searched the medical literature for prospective studies reporting on associations between cardiac troponin concentrations and first-ever CVD outcomes, and identified 27 that met their criteria. Two independent reviewers then extracted study-specific estimates, controlling for conventional CVD risk factors.

The investigators then pooled the findings with de novo data from the Pravastatin in Elderly Individuals at Risk of Vascular Disease Study (PROSPER) and created a random effects meta-analysis. Increases were seen across a number of cardiovascular outcomes.

Relative Risks for CVD Events in Meta-analysis of 28 Studies

Outcome Relative risk (top vs bottom third) (95% CI)
CVD 1.43 (1.31–1.56)
Fatal CVD 1.67 (1.50–1.86)
CHD 1.59 (1.38–1.83)
Stroke 1.35 (1.23–1.48)

For the end point of fatal CVD, the investigators found that the associations were significantly stronger for those studies measuring troponin T rather than troponin I (P=0.027) and in studies conducted in North American compared with other regions (P=0.010).

These associations occurred among populations with largely normal troponin values. For example, in PROSPER, which measured troponin T, 87.5% of the 4402 participants had detectable concentrations, with a median of 7 ng/L, and 85% of values were below the high-normal cutoff of 14 ng/L.

Now What?

The results indicate that binary classification of patients as being "troponin-positive" or "troponin-negative" are simplistic and may no longer be meaningful, Ho commented in her editorial.

"The days of 'troponin-positive' patients are likely to end, because hs-Tn assays will need to be considered quantitatively, and underlying etiologies for troponin release will need to be considered. For example, if hs-Tn is driven by cardiac remodeling, fibrosis, and stage B heart failure, prevention strategies could be distinct from hs-Tn release in the setting of atherosclerosis or uncontrolled hypertension," she wrote.

In an interview with theheart.org / Medscape Cardiology, Ho said that high-sensitivity troponin assays have been shown in European trials to be valuable clinical aids when patients present with possible acute coronary syndrome and for ruling out MI early on with a rapid protocol.

"But with respect to measuring high-sensitivity troponins in the general population or in patients who are coming in for outpatient follow-up in the absence of chest pain, that, I think, is entirely unclear. We don't know the clinical implications of measuring troponins in the general population and how that's helpful in terms of taking care of our patients or modifying their risk for future cardiovascular events," she said.

Dr Deepak Bhatt (Brigham & Women's Hospital, Boston, MA), who was not involved in the study, likened the findings to earlier studies showing that serum cholesterol levels that are high but still within the so-called normal range confer greater CVD risk on patients than low or intermediate levels.

"On a population level what they found is definitely true, but how would one apply that as a physician to an individual patient? That's where things get very tricky, because I think that just measuring this troponin and finding that it's a bit higher but with the normal range isn't necessarily actionable," he said.

The US Food and Drug Administration recently granted 501(K) clearance to a high-sensitivity troponin T assay made by Roche Diagnostics.

The study was supported by the Austrian Research Promotion Agency (Agency FFG). Willeit and  coauthors reported no relevant financial relationships. Bhatt previously served on the advisory board of Medscape Cardiology and has received honoraria from WebMD (continued medical education steering committees), among others. Ho is supported in part by a National Institutes of Health grant and a Massachusetts General Hospital Hassenfeld Scholar Award. She reported no relevant financial relationships.

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