Troponin testing, “Answers”

Troponin is a structural protein found in striated muscle and is involved in calcium processing.  Although troponin can be found in many types of muscle, cardiac troponins are structurally different from the variety found in skeletal muscle. Therefore tests can be created to selectively distinguish them.  There are three forms of cardiac troponins: I, T and C. Most troponin is structurally bound but about 3-6% exists in a “cytosolic pool.” This troponin is released immediately upon injury and is detectable within 4-6 hours of coronary occlusion, depending on assay.  Cardiac troponin remains elevated in the serum for up to 10 days (Jaffe 2005).  For the purpose of this summary, we will refer to cardiac troponins simply as “troponins.”EML Troponin testing Answers

It is important to understand that a positive troponin does not diagnose myocardial ischemia/infarction. A positive troponin risk stratifies a patient to an increased likelihood of ischemia or infarction but is not diagnostic.  Currently, a positive troponin is defined as an elevation of troponin above the 99th percentile of normal (ACC/AHA Guidelines, 2007).  However, a troponin can be elevated for a number of reasons some of which are detailed in the following table (Limkakeng, 2012).

Non-CAD Causes of Troponin Elevation
Cardiac Contusion
Aortic Valve Disease
Pulmonary Embolism
Renal Failure
Drug Toxicity

Additionally, a negative troponin does not rule out ischemia or infarction.  If a patient presents very early in their course it is possible that there has been inadequate leakage of troponin into the serum and a first troponin may be negative.  Some patients experiencing unstable angina will not produce positive troponins but are at risk of significant morbidity and mortality. Therefore, a negative troponin simply risk stratifies a person to a lower risk of ischemia or infarction.

1. Do you ever send a single troponin in patients with chest pain?  If so, when?

Acute Coronary Syndrome includes three diagnoses: ST Elevation MI (STEMI), Non-ST Elevation MI (NSTEMI) and Unstable Angina (UA).  Currently, serial EKGs and serial serum cardiac biomarkers are the workhorses of ACS evaluation.  Troponin elevations in patients with ACS symptoms have been shown to predict which patients are at risk of major adverse cardiac events.  In spite of the fact that they are cheap, noninvasive, yield rapid results, and are objective data points, a great deal of controversy surrounds their use, application, and diagnostic utility.  One of the major debates surrounds the use of a single troponin to “rule-out” ACS.

The goal of serial troponin testing is to rule out NSTEMI since STEMI is ruled in/out by presenting EKG.  ACC/AHA guidelines stress that serial troponins are necessary to rule out an acute myocardial infarction (AMI) (ACC/AHA Guidelines, 2007) and should be spaced apart by at least 6 hours (Alpert, 2000).  Serial troponin testing is the standard of care because early on in a patient’s myocardial ischemic event, it is feasible that there has not been adequate leakage of troponin into the serum to be detected by our troponin assays.  Thus, getting a second troponin spaced apart in time would catch these “early presenters.”  Although the current ACC/AHA recommendations support serial troponins at least 6 hours apart, many physicians have narrowed their time between troponin testing.  MacRae, et al., found that the window could be shortened to 3-4 hours in between troponin testing without increasing the number of missed troponin elevations (MacRae, 2006).  Additionally, this research team found that if the patient’s symptom onset was taken into account, serial troponins could be obtained 1 hour apart without missing any delayed elevations as long as at least one troponin was obtained 6 hours after symptom onset (MacRae, 2006).

Based on this logic, a more sensitive troponin assay would allow for the detection of small troponin leakage early in the clinical course and could theoretically “rule out” NSTEMI with a single test.

In September 2011, Body, et al., published an article in the Journal of the American College of Cardiology (JACC) investigating the utility of a High Sensitivity Troponin Assay (hs-cTnT) (Body, 2011).  In their study, they found that no patient with a negative first hs-cTnT assay was found to have an MI by standard serial troponin testing giving a sensitivity of 100%.  The authors concluded that a single negative hs-cTnT would rule out an acute MI.  Unfortunately, the assay had an extremely low specificity (34%) i.e., the majority of patients with a positive hs-cTnT assay were found to not have an acute event.  Raising the cutoff for hs-cTnT assay in an attempt to increase specificity predictably led to an unacceptably low sensitivity (85.4%).

What about single standard troponin assays in patients with atypical symptoms?  This is the more common question that arises in the clinical setting.  The idea of getting a single troponin to rule out an AMI (mainly NSTEMI) definitely runs counter to the traditional teaching.  However, many experts support its use in specific situations.  In patients with low risk historical features (no comorbidities, etc) and constant chest pain for greater than 4-6 hours, or with chest pain that resolved more than 4-6 hours ago, many clinicians will obtain a troponin on presentation and if negative, consider the diagnosis of AMI effectively “ruled out.”  There are no studies or clinical guidelines to support this approach but from a physiologic standpoint, it may make sense. If a patient had chest pain representative of ischemia or infarction lasting for 4-6 hours, you would expect the initial troponin assay to be elevated based on the test’s characteristics.  Similarly, if the patient had an ischemic event 4-6 hours ago (that has now subsided) we would expect the initial troponin to be elevated and reflect this.

While EKGs and troponins can be used to rule out STEMI and NSTEMI, we still haven’t addressed the third part of ACS: UA.  The current standard (as set by the AHA) for determining if a patient’s symptoms are reflective of UA is serial troponins and EKGs followed by evocative testing (i.e. stress test) within 72 hours.  Thus, no number of negative troponins (whether it be 1 or 100) rules out unstable angina since, by definition, it does not cause troponin elevation.  However, there are a number of studies demonstrating that in low risk populations, a single negative standard troponin effectively risk stratifies patients to an extremely low risk of cardiac event at 30 days (0.2%) (Marsan, 2005 Walker, 2001; Lee, 1992).  The low risk population was defined by: Age < 40, Low risk chest pain according to physician judgment, EKG without ST elevations or depressions, vital signs stable, and no history of known heart disease.

So what are our actual conclusions regarding single troponins?  The high-sensitivity troponin assay may help to rule out some patients early on without serial testing.  However, it will lead to many more false positives and the extensive workup that follows a positive assay and overall, cause more harm than good.  Using a single standard troponin to “rule out” AMI has never been validated. However, in the right, low-risk population, a single negative troponin risk stratifies patients to an ultra low-risk group and may help with early discharge from the ED with outpatient follow up.

2. How do you manage patients with end-stage renal disease (ESRD) and chest pain who have equivocal troponins?

How many times have you heard from your admitting consultant, “that troponin is meaningless.  That patient has renal failure.  He always has an elevated troponin.  It doesn’t mean he’s having an ischemic event.”  This is usually followed by a comment on how troponin is renally cleared and that the patient is simply accumulating troponin that would otherwise be urinated out by a person with normal kidney function.  Unfortunately, all of this is untrue.

Troponin is not cleared by the kidneys and thus, is unaffected by dialysis.  It has been hypothesized that chronic troponin elevations in renal failure patients results from ventricular hypertrophy, chronic fluid overload, or endothelial dysfunction (Jaffe, 2005).  Quite to the contrary, renal failure patients with elevated troponins (even asymptomatic ones) have been found to have increased long-term mortality (Apple, 2002; Khan, 2005).  Additionally, multiple studies have found that renal failure patients with chest pain and elevated troponins are at a higher risk of adverse cardiac events and death at 30 days compared to patients with and without ESRD without elevated troponins (Aviles, 2002; Kontos, 2005).

This doesn’t mean that all troponin elevations in patients with renal failure are indicative of myocardial ischemia or infarction.  In fact, patients with renal failure and elevated troponins often have no identifiable coronary disease (Lamb, 2004).   Additionally, a recent study found that 100% of asymptomatic ESRD patients had a positive high-sensitivity troponin assay result (Jacobs, 2009).

Confused?  To recap: Troponins are just one part of risk stratification in patients with chest pain, regardless of renal function.  If a patient with renal failure presents with concerning symptoms and has a positive troponin assay, they should be considered to have an increased likelihood of ischemic event and treated accordingly.  In a patient with questionable symptoms and an elevated troponin level, the clinician can consider getting serial troponins to see if the troponin level is stable or increasing.  The National Academy of Clinical Biochemistry (NACB) recommends a 20% change in troponin concentration for the diagnosis of AMI in patients with ESRD but these recommendations are based on older generation assays (Lamb, 2004).

3. Do you send a troponin on patients with presumed pericarditis?

Pericarditis in and of itself should not cause an elevation in cardiac troponin.  Inflammation of the myocardium or myocarditis leads to a leakage of troponin into serum.  Thus, the presence of an elevated troponin in a patient with pericarditis suggests myocarditis, not more severe pericarditis.  This pathophysiology is markedly different than the pathophysiology of troponin elevation in myocardial ischemia/infarction.  In one study of 69 patients with acute pericarditis, 49% were found to have troponin elevations. Of those who went on to have cardiac catheterizations, none were found to have coronary artery disease (Bonnefoy 2000).  Troponin testing in this disease raises the following question: what are the prognostic and treatment implications of a positive troponin in patients with pericarditis? It has been hypothesized that an elevated troponin may indicate more severe inflammation and may be a prognostic indicator leading some clinicians to obtain troponin levels in all patients with pericarditis.

There is scant evidence to defend this approach.  Imazio, et al., found that of 118 serial cases of pericarditis, 32.2% had elevated troponin I levels.  It appeared that young patients, those with ST elevations, and those with pericardial effusions were more likely to have detectable troponin levels.   At 24-month follow up, the troponin positive group showed no differences in important outcomes (recurrent pericarditis, death) (Imazio, 2003).

While it appears that many patients with pericarditis have elevated troponin levels, it is unclear whether an elevated troponin is a prognostic indicator or should be used to guide treatment.  It does appear clear from the literature that the pathophysiologic mechanism of a troponin elevation in pericarditis does not indicate the presence of underlying coronary artery disease.  The key issue is a good history leading to an accurate diagnosis and initiation of therapy (NSAIDs, cardiology follow up, etc.).  Although there is not yet an evidence basis to guide this, we recommend obtaining a troponin in patients with persistent tachycardia (despite treatment of fever and pain if appropriate) and in patients with pericardial effusions (as these patients may have more severe pericarditis accompanied by myocarditis).

4. Do you send a troponin on patients who present with lone atrial fibrillation and no chest pain or anginal equivalent symptoms?  What about other atrial tachydysrhythmias?

As mentioned earlier, tachydysrhthmias are one of the many non-ischemic causes of elevated troponins.  It is believed that the shortened diastole period seen in tachydysrhythmias causes under-perfusion of coronary arteries leading to subendocardial ischemia (Jeremias, 2005).  There are few recommendations from professional societies on whether patients presenting with atrial tachydysrhythmias should have troponins sent (Camm, 2010; Fuster, 2006). A number of case seres over the last 10 years have shown that atrial tachydysrhythmias frequently result in elevated troponin levels in patients without coronary artery disease on stress test or catheterization (Redfearn, 2005; Zellweger, 2003; Kanjwal, 2008; Nunes, 2004; Miranda, 2006;).

In spite of this, troponins are often sent to diagnose myocardial ischemia or infarction as a possible cause or consequence of the tachydysrhythmia.  Meshkat, et al., found that 86% of patients presenting with AFib/AFlutter had at least a single troponin sent in a retrospective chart review (Meshkat, 2011).  In this study, 13.7% of patients who were tested had elevated troponin levels and 4.9% of the patients were treated for ACS.  Forty percent of the patients had serial troponins.  Overall, only 7 patients out of the group that had positive troponins (n = 53, so 13%) had a positive workup for ACS.  As a retrospective study, this study had many limitations, making it insufficient evidence against troponing testing in atrial tachydysrhytmias.  What this study does demonstrate is the varied approaches to the workup of patients with AFib/AFlutter who present to the ED and suggests the generally low overall yield of troponin testing.

Once again, we have a paucity of good research to inform practice.  In patients with atrial tachydysrhythmias who have ischemic symptoms it seems reasonable to initiate serial troponin testing. In patients with multiple comorbidities who have been tachycardic for a prolonged period of time, serial troponin testing may be useful in risk stratifying patients, although the significance of these elevations is unclear. Finally, in young, healthy patients with new-onset atrial tachydysrhythmias (particularly AFib/AFlutter) and no ischemic symptoms, serial troponin testing does not appear to be beneficial.  Again, there is limited evidence for these recommendations and this represents an area ripe for further research.

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5 Responses to Troponin testing, “Answers”

  1. Pik Mukherji says:

    Very nice as usual. An important caveat for the q1 hr testing in delta troponin is that it’s not only 6 hrs post onset of sx but also in cases where the CP is constant for 4 hrs. The UA spectre is stronger when it’s short episodes.

  2. Ian Welsh, DO says:

    Great, practical review of troponin utility. My question is this: when do you send “delta” troponins and in whom (in efforts to discharge a patient from the ED).


  3. Anand Swaminathan says:

    Pik – great point. Thanks for chiming in on this one.
    @ Ian – I do Delta troponins on patients who are low risk with the thought of discharging them home with outpatient follow up for possible stress. The AHA guidelines say that they should have a stress test within 72 hours- it doesn’t say this has to be done as an inpatient (or observation status as many do). I also think that many times, the PCP can talk to the patient and decide they don’t need a stress because they know more about their patient. If they don’t have a PCP, we set them up with a rapid clinic follow up or arrange the outpatient visit.

  4. Dan Firestone says:

    Great post and important topic!

    Another add on the delta issue: know which assay your hospital runs.

    1) Ultrasensitive (hopefully not) may sway you away from delta’s if they present late enough, although you’ll be admitting a lot of your ankle sprains who someone decided to send a trop on

    2)standard trop’s you’ll need a delta on early presenters and if you’re more aggressive like me you won’t do a second trop on late presenters who are low risk. Or, you will, depending on comfort level, but it’s not necessarily for scientific or CYA reasons.

    The AHA guidelines quote that if the patient presents less than 6 hours you need a second trop at 8-12 hours from symptoms onset. Being agressive, I interpret this as: if they present at 5 hours and 55 minutes from time zero, I’m getting another trop at time 8 hours (2 hours and 5 minutes later). You could also imply that they are allowing a single trop strategy for late presenters who are low risk. A lot of this boils down to how reliable you think the history is and how clinically sure you are with their risk category.

    3) I prefer point of care (POC) troponins for throughput reasons but can only comment on the istat assay whose sensi/speci characteristics I’m familiar with. With these I am more likely to get a delta especially if on the hub of the 6 hour mark, as their sensitivity is a touch lower than standard trops. I also, admittedly, am ok with slightly less sensitive since we over admit these patients as it is. I want to admit true ACS patients. The CP patients with a good story you decide to admit before any tests come back, so even if your trop doesn’t catch the good story patient, you’re admitting them anyway for serial trop’s and a stress test.

    POC trops if used right don’t miss true MI’s, they may simply be later to catch the rise. Over 5 years my group noted a handful of cases a year in which (if both POC and standard trop were ordered at the same time….don’t ask why we’d do this) the POC trop was normal and the standard trop was slightly bumped or “indeterminate”. The second POC trop an hour or 2 later would be positive.

    It was a nice experiment to prove the point–you need to treat each chest pain patient uniquely, based on overall risk of presentation and timing of symptoms. This is more important than which assay I feel.

    We routinely moved on with dispo after one trop for patients who presented after 6 hours, mainly because we could easily get stress tests by day, and at night we routinely admitted for a stress test to an obs unit, with little pushback (lucky, I realize). For those patients who wouldn’t stay or I felt it was overkill or throughput clogging and they could get it done < 72 hours as an outpatient, I'd still do one trop if they were a late presenter, but only in the low risk cohort. Food for thought if your group decides to go with POC trop.

  5. Dan – great points. We’ll have to tackle high-sensitivity troponin in a future post. The literature has been coming so rapidly we figured we’d wait a bit to take it on. Thanks for reading!

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