High Sensitivity Cardiac Troponin
Written by Joseph Kummer, MD, FACC
Bryan Health recently transitioned our Troponin assay to high sensitivity cardiac Troponin (hs-cTn). Several of you are already familiar with the high sensitivity test, as it has been used in various communities in Bryan’s outreach area during the past few years. The transition to any new test always involves some educational needs, but this new assay offers significant improvements over the conventional test. It is quickly becoming the standard of care for the evaluation of coronary ischemia. High sensitivity Troponin assays were not approved in the United States until 2017, but have been the mainstay of cardiac biomarkers in Europe and several other countries for over 10 years.
Cardiac Biomarkers
Cardiac biomarkers have long been a critical component in the evaluation of chest pain and instrumental in the diagnosis of a myocardial infarction. Historically, there have been several biomarkers used, with each iteration being more accurate than the one before. For most practicing clinicians, Troponin has been the primary lab test used for the majority of their career. Troponin is a regulatory protein that controls the interaction of actin and myosin in cardiac muscle. Troponin T and Troponin I are commonly assessed and both are extremely specific for a cardiac etiology. Troponin I tends to be the favored test since there is a minimal amount of measurable Troponin T in skeletal muscle, whereas Troponin I is almost exclusively found in cardiac muscle.
By definition, Troponin is invariably released from cardiac myocytes in the setting of an acute myocardial infarction. There are many other situations that can also cause an increase in the level of circulating Troponin, but it should also be noted that almost everyone has at least a very small amount of Troponin in their blood at all times.
This may be due to:
- Apoptosis
- Changes in cellular membrane permeability or
- Possibly even normal myocyte cell maintenance and turnover
Deciphering Troponin Values
The “conventional” Troponin assays that have been used in the United States for over 20 years have values designated to be normal in 99% of healthy subjects, which conveniently parallels the lower limit of detection for these assays. In other words, the Troponin value will be reported as simply “undetectable” for 99% of healthy individuals, and that value is usually reported numerically as something similar to <0.04 ng/mL. There is simplicity in this, as it generates a binary “positive” or “negative” value.
High sensitivity assays can detect levels of Troponin that are about a thousand times lower than conventional assays. Although not precise, a good rule of thumb when seeing a value for these tests is to divide the number by one thousand to estimate the value that would be expected with a conventional Troponin measurement. Another way to look at this, is that the conventional Troponin value was reported as nanograms per Milliliter, whereas high sensitivity assays report nanograms per Liter.
A large majority of the 99% of healthy individuals who have an unmeasurable conventional Troponin value will have a measurable high sensitivity Troponin value. The range in values will be relatively wide, with a “high normal” value being up to 15 times higher than a “low normal” value. To further complicate things, gender differences are observed at this level of sensitivity. For Bryan Health’s new assay, the upper limit of the reference range for women is 53.7 ng/L and for men, it’s 78.5 ng/L. Although most of our hearts will skip a beat the first few times we see a Troponin value of 50, eventually we will get accustomed to the fact that this is an entirely normal value. Clearly, though, the simple binary “positive” vs. “negative” distinction is no longer present.
Sensitivity and Specificity
The other important change that Bryan Health has made with this new test is the elimination of other cardiac biomarkers in the chest pain panel. In particular, you will no longer see CK, CK-MB, or Myoglobin. For several years now, the Universal Definition of Acute Myocardial Infarction mandates a Troponin level above the 99th percentile as a requirement to diagnose a myocardial infarction. No other cardiac biomarker may be substituted for this purpose. There is very good rational behind this. Troponin is simply more sensitive AND more specific for myocardial injury than any other biomarker. An abnormal CK-MB with a normal Troponin value is essentially never due to a myocardial infarction and likely offers no additional clinical benefit in evaluating for myocardial ischemia.
With the high sensitivity Troponin assay, abnormal values can be detected very early following an ischemic event. Myoglobin is often detectable before conventional Troponin tests, but that is generally not the case with high sensitivity Troponin. Since any currently available biomarker offers less sensitivity and less specificity than hs-cTn, including these in a chest pain panel will only increase cost and resource utilization without adding clinical benefit.
Like CK and CK-MB, LDH and AST are less sensitive and less specific than Troponin and thus no longer used. CRP has prognostic value in the setting of an acute MI, but it is also less sensitive and less specific than Troponin. There are other biomarkers under investigation that do appear to have very good sensitivity for myocardial injury.
These include:
- Heart-type fatty acid binding protein (HT-FABP)
- Copeptin
- Glycogen phosphorylase BB
These have limited or no availability in the United States at this time, but there is a small chance that there may be a role for them in the future. In short, these are less specific for myocardial injury than Troponin, but their sensitivities actually appear to be comparable. High sensitivity cardiac Troponin is still certainly preferred due to its superior specificity, but there may be a narrow role for one of these. For instance, HT-FABP may have slightly better sensitivity than even hs-cTn within only the first hour or two after myocardial injury. Nonetheless, any benefit would be very limited, so I suspect that hs-cTn will soon become the only recommended and utilized cardiac biomarker.
Troponin in the ED
One of the major advantages of high sensitivity Troponin is the ability to expedite chest pain evaluation in the emergency room. With an acute coronary syndrome, early detection and emergent intervention can be life-saving and even short delays are associated with worse outcomes. On the other hand, early “rule-out” of chest pain patients in the ED can potentially save substantial amounts of cost and resources by shortening the chest pain rule-out timeline. As we all know, conventional Troponin measurements are often normal for three or more hours after onset of an acute coronary syndrome, known as the “Troponin-blind” period. High sensitivity assays, on the other hand, are often abnormal and levels are measurably increasing much earlier than with conventional Troponin testing.
Due to its ability to detect even very small quantities of Troponin as well as very minimal changes in its value, hs-cTn has been widely used in chest pain evaluation protocols with great success. There are several validated protocols, many of which use two important measures.
- The first is simply the initial absolute Troponin value and
- The second is the amount of change in the value after one, two, or three hours
Bryan’s protocol will generally recommend checking three sets of hs-cTn values at presentation, two hours, and four hours.
Note that a very low value of around less than 5 ng/L is associated with an extremely low rate of future adverse cardiac events. A commonly used algorithm in Europe has shown that if chest pain has been present for three hours or more and a patient has a hs-cTn value of less than 5 ng/L, this by itself had a 100% negative predictive value for an acute coronary syndrome.1 In fact, it was both 100% sensitive and 100% specific for ruling out MI in this study of 3,267 patients. This protocol assesses hs-cTn at presentation and one hour. For those with an initial hs-cTn value < 12 mg/L and a value one hour later that did not increase by 3 ng/L or more, the negative predictive value was 99.8% with a sensitivity of 99.6%. This algorithm was able to rule out MI in 61% of patients within one hour.
This represents a marked change in the way we use this test. If the initial Troponin value is within the normal range, a rise in the value on subsequent testing will change the recommendation for how to proceed with patient disposition, even if the second value is still within the normal range.
Example Troponin Evaluation
Let’s imagine that identical twins arrive in the ED with chest pain, normal EKGs, and similar cardiac risk profiles. Each of their initial hs-cTn values is 20 ng/L with 50 ng/L being the upper limit of normal. If Twin A’s next hs-cTn is 18 ng/L, she can be sent home with an extremely low risk for cardiac events at 30 days. If Twin B’s second value is still normal but rises to 40 ng/L, then most guidelines would recommend observation, further biomarker testing and often non-invasive risk stratification prior to discharge.
Note that with high sensitivity testing, there is no change in the actual Troponin itself being measured nor its concentration in the bloodstream. The only change is the ability to detect and quantitate it. Therefore, you can expect every limitation with conventional Troponin testing to still apply. For example, levels will still be significantly higher in patients who have severe concomitant illnesses such as sepsis, hypoxia, heart failure, pneumonia, etc. Type I and Type II myocardial infarctions will be diagnosed in the same manner as prior. As with conventional Troponin testing, patients with renal insufficiency will often have higher circulating baseline levels.
Looking Forward
As you can see, there is a lot of potential benefit to making this change. It will help us as clinicians by providing us with the most sensitive and the most specific test available. It will help the hospital system by decreasing unnecessary testing and by increasing ED throughput. Most importantly, this will help our patients by expediting the diagnosis, treatment and disposition of our patients with potential myocardial ischemia.
Despite the benefits, we certainly expect and understand that it will take time for us to adapt to this new test. Of course, we at Bryan Heart are 100% ready and willing to help you with utilization and interpretation of this new but exciting test. Please contact us with any questions or concerns that may arise.
We look forward to our continued work together to deliver the highest level of cardiac care in your communities.
Source:
- Clinical Use of High-Sensitivity Cardiac Troponin in Patients with Suspected Myocardial Infarction. Twerenbold R, Boeddinghaus J, et al. J Am Coll Cardiol. 2017 Aug, 70 (8) 996–1012
