hs-Troponin in a New Light: Predicting Risk in Absence of MI, ACS

October 25, 2017

STOCKHOLM, SWEDEN — Cardiac troponin T (cTnT) can predict mortality and clinical events even in patients without overt heart disease, suggests a large cohort study that expands on research suggesting that troponins by contemporary high-sensitivity (hs) assays will be useful for risk stratification, not just acute-MI confirmation or rule-out[1].

In the study with almost 20,000 patients presenting with chest pain but without acute MI or other known cardiac disease, elevated but stable levels of hs-cTnT predicted risk over about 3 years. Risk was significantly increased even at hs-cTnT levels "well below" the upper limit of normal and went up in graded fashion at higher levels of the biomarker.

Of note, the small but ongoing hs-cTnT elevations were more closely associated with risk of future heart-failure hospitalization than with future MI.

The study, reported in the October 31, 2017 issue of the Journal of the American College of Cardiology, is only the latest to show that small amounts of troponin-identified myocardial damage can predict future cardiac events. Its added twist is that the cohort excluded anyone with acute coronary syndrome or other known cardiac conditions.

The hs-cTnT elevations probably pointed to previously unidentified, subclinical heart disease, according to senior author Dr Martin J Holzmann (Karolinska University Hospital, Sweden); Dr Andreas Roos (Karolinska University Hospital) is the publication's first author.

"If we were to investigate them, we would find that some of those patients had heart failure that was previously undetected, or left ventricular hypertrophy, or something else that explains the elevations," Holzmann told theheart.org | Medscape Cardiology.

Even in Europe, where the hs-troponin assays have been available longer than in North America, they are used only for confirming or ruling out acute MI, he notes. "But I think in the future, it will be established as a marker of risk of death from cardiovascular disease, definitely. Also maybe in the primary-care setting."

Indeed, the current study "underscores the evolution of cardiac troponin as a powerful continuous marker of subclinical illness rather than solely as a dichotomous test for ACS," according to Dr Marc P Bonaca (Brigham and Women's Hospital, Boston, MA) in an accompanying editorial[2].

"We must begin to interpret hs-cTn in this context as an indicator of important subclinical disease that warrants additional evaluation," he writes.

For that to happen, it will be important to see elevated troponins as something other a sign of acute injury. Although the current cohort was seen in the emergency department, "what you're identifying here is a chronic signal. It's a chronic low-level smoldering myocardial injury," Dr James De Lemos (University of Texas Southwestern Medical Center, Dallas) said in an interview.

"It's a crude measurement, and there can be multiple different causes of that injury in any group of individuals," according to De Lemos, who is not connected with the current study but lauds it for its focus on patients without known heart disease. The cause would have to be sought in further tests; otherwise, "it's sort of like looking at creatinine, then trying to figure out the cause of kidney dysfunction."

The analysis followed 19,460 adults presenting with chest pain to a major center's emergency department over 4 years who did not have acute MI or any other acute conditions known to affect hs-cTnT levels. Of the group, 6.9% died from any cause over a mean of 3.3 years.

The mean follow-up time for cause-specific mortalities was 2.1 years, during which 1.5% of the patients died of cardiovascular causes and 3.2% had noncardiovascular deaths; 35% of all deaths were from cancer and 34% were from CV disease.

Adjusted Hazard Ratio (95% CI)* for Clinical Outcomes by Presenting hs-cTnT Levels in 19,460 Patients With Chest Pain, No MI

End points 5–9 ng/L 10–14 ng/L 15–29 ng/L 30–49 ng/L > 50 ng/L
All-cause mortality 2.00 (1.66–2.42) 2.92 (2.38–3.59) 4.07 (3.28–5.05) 6.77 (5.22–8.78) 9.68 (7.18–13.0)
CV mortality 3.59 (1.93–6.66) 7.32 (3.96–13.5) 9.12 (4.87–17.1) 17.5 (8.86–34.5) 27.0 (13.2–55.4)
Non-CV mortality 1.80 (1.40–2.33) 2.52 (1.89–3.36) 3.49 (2.58–4.71) 5.95 (4.09–8.66) 7.78 (5.02–12.1)
MI 1.18 (0.83–1.67) 2.06 (1.42–3.00) 1.83 (1.20–2.80) 2.66 (1.51–4.68) 2.77 (1.27–6.01)
Heart failure 3.66 (2.46–5.45) 6.04 (3.97–9.19) 10.7 (7.00–16.3) 13.1 (8.03–21.3) 13.3 (7.69–23.1)
*Reference: <5 ng/L. HR adjusted for age, sex, estimated glomerular filtration rate, prior MI, heart failure, stroke,  chronic obstructive pulmonary disease, atrial fibrillation, diabetes, hypertension, and use of aspirin, beta-blockers, ACE inhibitors or angiotensin-receptor blockers, and statins

"There was a strong and graded association between all detectable levels of hs-TnT and risk for MI, heart failure, and cardiovascular and noncardiovascular mortality," the group writes. A similar pattern was seen in a wide-ranging subgroup analysis, with risk going up in graded fashion at all ages, in men and in women, and regardless of renal function.

hs-TnT Is Elevated—Now What?

The data are sufficient now for such stable hs-cTnT elevations in the absence of known causes to prompt further workups, according to Holzmann. "I think we should do at least routine echocardiography—MRI is not very accessible in Sweden, but at least an echocardiography to rule out structural heart disease, like heart failure or left ventricular hypertrophy, that would explain the high troponin levels."

De Lemos agrees. "The simplest thing would be probably an echocardiogram for this group of individuals as a prudent next step, because some subset of them are going to have unrecognized structural heart disease. What they don't appear to need is a big workup for ischemia, because ischemia is not the driver of much of these troponin elevations."

For those found at imaging to have subclinical heart disease, what to do next may be the more challenging question. With the advent of hs-troponins in the emergency department, there are concerns over a possible "deluge of people with basically small elevations, and what that means in terms of overutilization of resources and overconsultation of cardiology," De Lemos observed. "We're all very nervous about that."

But it may be okay, he said, "as long as it's recognized that this is a long-term and not a short-term signal, and these people don't need to stay in the hospital or be evaluated urgently or emergently and can basically be targeted in the same way anybody at long-term risk might be, with a prudent evaluation that might include outpatient echo."

The "simplest strategy," De Lemos said, would be to "use this risk signal to target things we already know work," such as aggressive lipid and blood-pressure control and lifestyle recommendations.

"The same interventions that we use for patients with coronary artery disease, namely high-intensity statin therapy, ACE inhibitors, blood-pressure control, etc, I'm quite convinced that it would work in this group of patients," echoed Holzmann.

"However, we need to do the studies prospectively, with patients randomized to multifactorial intervention as compared with no intervention, in order to know what to do with these patients."

Holzmann discloses consulting for Actelion and Pfizer. Roos reports no relevant financial relationships. Disclosures for the coauthors are listed in the paper. Bonaca reports no relevant financial relationships. De Lemos said he has received grant support in the past from Roche Diagnostics and Abbott Diagnostics and has consulted for Abbott, Roche Diagnostics, Siemen's Health Care, Radiometer, and Ortho Clinical Diagnostics.

Follow Steve Stiles on Twitter: @SteveStiles2. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.

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