High-Sensitivity Troponins May Help Identify Obstructive CAD in Stable, Symptomatic Patients

Higher concentrations of high-sensitivity troponin I (hsTnI) are associated with a greater prevalence and severity of coronary atherosclerosis among stable, symptomatic outpatients undergoing nonemergent coronary CT angiography, according to an analysis of the PROMISE trial.

High-sensitivity troponins have been evaluated in a wide variety of cardiac patients, and they are well known to be associated with obstructive CAD in patients with more acute presentations like suspected MI. As the assays become more refined, however, researchers are seeking additional uses to better guide and personalize care.

These findings mean that “it's very possible that clinicians might actually utilize highly-sensitive troponins to help decide on a diagnostic and treatment strategy for patients with stable symptoms suggesting possible stable angina,” lead study author James Januzzi Jr, MD (Massachusetts General Hospital, Boston), told TCTMD.

An abnormal high-sensitivity troponin measurement obtained in the office, for example, might indicate the need for an invasive evaluation and more aggressive use of anti-ischemic therapies, “whereas a very low concentration would suggest that coronary disease is not present and that the symptoms may be pursued in other ways,” he said.

For the study, published online March 14, 2018, ahead of print in JACC: Cardiovascular Imaging, Januzzi and colleagues looked at 1,844 stable, symptomatic individuals with suspected CAD who were randomized to undergo coronary CT angiography in the PROMISE trial and had baseline blood samples available for hsTnI  evaluation with a single-molecule counting method (SMC TnI; Singulex, Alameda, CA).

Overall hsTnI concentrations ranged from below the limit of detection (0.5 ng/L) to 1,434.6 ng/L, with measurable levels observed in 98.5% of patients. The median value for all was 1.5 ng/L, and 6.1% of individuals had levels at or above 6 ng/L, the assay’s 99th percentile for patients free of risk factors for CAD or prevalent atherosclerosis, heart failure, or kidney disease.

When study participants were divided into quartiles based on hsTnI concentrations, higher coronary artery calcium (CAC) scores and more prevalent and diffuse CAD were observed in the higher quartiles (P < 0.001 for all). For example, those in the highest quartile had an eightfold higher median CAC score and a near doubling in prevalence of obstructive CAD compared with those in the lowest hsTnI quartile.

Multivariate analysis found age, sex, and CAC score independently predicted hsTnI concentrations (P < 0.05 for all).

Lastly, after adjustment, log-transformed hsTnI levels were linked with obstructive CAD both as defined as ≥ 50% stenosis in any vessel (OR 1.15 per interquartile range; P = 0.02) and as ≥ 70% stenosis in any vessel or ≥ 50% stenosis in the left main (OR 1.25 per interquartile range; P = 0.001).

More Studies Needed

Up until know, the challenge with prior versions of highly-sensitive troponin assays was that they were “not sensitive enough to be able to detect signal in a substantial number of normal patients, or lesser acute patients such as are seen in an office-based environment,” Januzzi explained. With the one used in this study, however, “we found that measurable troponin concentrations were present in the great majority of patients and that higher concentrations well within the normal range . . . of high-sensitive troponin were directly associated with more significant coronary artery calcium scores, as well as more significant presence and severity of obstructive coronary artery disease.”

In fact, the results are in line with a similar analysis of the SCOT-HEART trial published last month in Circulation: Cardiovascular Quality and Outcomes, he said.

That this assay seems to be able to stratify risk of underlying coronary disease “even within what would be perceived as a ‘normal’ range of troponin” reminds Januzzi of “other disease states where higher-sensitivity assays are brought in and replace the previous versions of less-sensitive assays,” he said. For example, when “we started using a more highly-sensitive version of thyroid-stimulating hormone, we began to realize that patients we had previously thought were normal in fact had underlying thyroid disease.”

Although only hypothesis-generating, these findings “[set] the stage for using troponins even in the office-based setting for judging risk, for assessing potentially the presence of coronary disease, and possibly estimating prognosis in these patients,” Januzzi observed. “We can do more studies now in this patient population to see what these measurements might mean for other applications. . . . To the extent that we're moving toward a more precision-based approach for multiple diagnoses in cardiology, it's not hard to envision that this would be part of that approach.”

But going forward, he said, “prospective studies are needed, [and] if we are going to move into the era of precision medicine in cardiology, all of these exceptionally impactful, important results that we are generating with biomarkers need to be applied in a prospective fashion in order to really answer the question: Can we do better than we're already doing?”

A ‘Complementary’ Tool

Commenting on the study for TCTMD, James de Lemos, MD (University of Texas Southwestern Medical Center, Dallas, TX), said although the study does conclude a statistically significant relationship between hsTnI levels and obstructive CAD, it’s “weak.”

“It really is not a useful test to predict who will or will not have obstructive or even nonobstructive atherosclerosis, and that's not surprising because there have been a number of other studies that have looked at similar populations and coronary disease is not one of the major things that leads the troponin to rise in any of these low-level elevations that are detected,” he said. “It's really a measure of the heart muscle and not the arteries. You can have plaque buildup without troponin and troponin buildup without plaque.”

Similarly, Patrick Calvert, MD, PhD (Papworth Hospital NHS Foundation Trust, Cambridge, England), who was also not involved with the study, told TCTMD in an email that the “strength of the association between troponin and extent of coronary artery disease is probably too weak to be of current clinical usage. However, if the relationship could be further refined then there is the potential for troponin to be used to identify higher-risk individuals with stable angina.”

Additionally, de Lemos said, this study “didn't account for some of the things that can explain why the troponin was higher with atherosclerosis, including what's going on in the left ventricle, like if they had left ventricular hypertrophy or left ventricular dysfunction, or even if they had kidney disease, all of which might raise the troponin and would be more common in people with atherosclerosis.”

Rather, he continued, this paper was designed around the other question of: can you use a high-sensitivity troponin assay as a gatekeeper test for atherosclerosis in symptomatic patients to judge whether CT angiography is warranted? “That answer is a definite no from this study,” de Lemos said, adding that hsTnI assays are instead “complementary” tools to CAC scoring and coronary CT angiography.

In the future, Calvert said he would “definitely” like to see studies of high-sensitivity troponins in a stable population of symptomatic patients., noting, “I also think that it would help us understand the mechanism of changes in CAD, which is the fundamental problem with the treatment of CAD—it is not well understood!”