Troponin: more than a marker of infarction?

 

As I’m writing this, I’m travelling back from an excellent conference in London. The BioRemarkable Symposium was sponsored by a company called Singulex. The team at Singulex had decided to hold the event to showcase some of the recent research involving its troponin assay and to bring together some opinion leaders from around the world to discuss the future of troponin testing. I was privileged to be involved and to present the breaking findings of our latest research using the Singulex troponin assay. But the data aren’t published yet – so I won’t discuss that here. Instead, I’d like to pass on details of some of the really exciting discussions we had at the conference. The future of troponin testing could be pretty amazing.

First, a quick word about possible conflicts of interest. Clearly, this was a conference run by a commercial company. They also paid all the speakers a fee, including myself. [I haven’t accepted that yet but it is in the standard contract that we were asked to sign]. I should note that this wasn’t a lavish do though – for example, I waited for 4 hours after the conference to take an off peak train back home. I should also note that I really don’t have any reason to promote the Singulex troponin above any other. If I seem enthusiastic about it, it has nothing to do with any commercial interest. Having seen the details of the assay, I’ve actually been trying to negotiate support to run it since 2011 – and prior to obtaining support from Singulex to evaluate the assay in clinical studies, I had two failed grant applications for public funding.
Now, let’s think about the Singulex troponin assay itself, which is what brought us together to talk about this. This is a new high sensitivity troponin assay, which uses a ‘single molecule counting’ technology. Yes, the test actually counts individual troponin molecules.

You might wonder why that’s helpful, but having even more sensitive troponin tests available would actually offer us some great new possibilities. This new test can detect much lower troponin concentrations than other assays. Just by way of a raw comparison, here’s the limit of detection in comparison with other high sensitivity assays….

  • Roche high sensitivity troponin T: 5ng/L
  • Abbott ARCHITECT high sensitivity troponin I: 1.2ng/L
  • Singulex Clarity high sensitivity troponin I: 0.08ng/L

So, the limit of detection is 60 times lower than the Roche high sensitivity troponin assay – one of the very best tests that we currently use in practice.

The new test is also more precise. The precision of an assay tells us how much the result is likely to vary when we test the same sample several times. We can measure this with something called the co-efficient of variation (CV), which is expressed as a percentage. A CV of <10% is good – and considered acceptable for making diagnoses. The lower your troponin result, the higher the CV tends to be (meaning the test is less precise). So, as another comparison…

  • The CV of the Roche hs-cTnT assay is <10% once you get to 5ng/L or above
  • The CV of the Abbott hs-cTnI assay is also <10% once you get above 5ng/L
  • The CV of the Singulex s-cTnI assay is <10% at 0.5ng/L

So, it’s ten times lower than the best troponin tests we currently have (and we’re only just realising the clinical benefits of those assays). You can check it all out in the updated IFCC troponin tables, here.

Just to emphasise, I’m not telling you this to promote the Singulex troponin assay over anything else. We can’t actually use this test in the ED yet even if we wanted to. The point is to explain what can now be achieved, and then to think about how it might help patients in the near future.

That sounds great but how could it affect patient care? 

Well, the bottom line is that we really don’t yet know If it will. We’ll have to wait for more research to find out for sure. But, in the meantime, here are some of the possibilities…

We could use a blood test to rule out STABLE coronary artery disease

If patients have extremely low troponin levels and a low pre-test probability of coronary artery disease (<30% using a visual analogue scale, assessed by a cardiologist) then a troponin level below 1.5ng/L has 95% sensitivity and 98% negative predictive value for stable coronary artery disease. Christian Mueller’s group published the data in the American Journal of Medicine. The prospective validation is not yet published, but if the validation is successful, just imagine…

Troponin could tell us not just about AMI, but whether a patient has any coronary artery disease

I think that would take troponin testing to a new level. Of course, we don’t know if we need the Singulex test to count single molecules in order to achieve this, other tests could do it too. My point isn’t about promoting any particular assay – the point is that even more sensitive troponin tests might detect such small troponin concentrations that we can even rule out stable coronary disease.

We could tell which patients will benefit most from statins

I’m not talking about measuring cholesterol – but troponin! It might seem crazy but a ‘high’ (>5ng/L) troponin (in health) could tell us which patients will have the best response to statin treatment. Nick Mills has shown that really nicely in the WOSCOPS study from Scotland…

Here’s the reference for you. Again, the point isn’t to favour any one troponin assay, but to show that detecting low concentrations of troponin very precisely could actually help us to tailor treatment to improve patient outcomes.

So what does all this mean for the future?

Now we know that we could have troponin tests that detect extremely tiny concentrations of troponin very precisely. We can use that information to rule in and rule out acute MI – quickly. (We already know that with currently used high sensitivity assays).

So, what could the future hold for troponin testing? Imagine…

  1. When patients develop symptoms of possible stable angina, they might have a simple blood test in primary care. No scans, no angiograms, no long waits.
  2. We could monitor troponin in health. A high baseline troponin shows a poor prognosis. So what? Well, we can target preventative treatments (like statins) to those patients. And we can target lifestyle interventions at those higher risk individuals, then monitor the response, which might include monitoring troponin levels.
  3. If we know patients’ baseline troponin, we can compare the troponin results we see in the ED to those that were measured when the patient was healthy. If we see a change from that, we know something is wrong.

Let’s just think about that last point for a minute. Why do we do serial troponin samples in the ED? It’s so we can know if the troponin is rising (or falling), as it would with AMI. But if we already have a baseline to compare against, many more patients could be ruled in or ruled out with one test – so although a lot of the benefits of measuring such low troponin levels might be outside the ED, it could still help us because we’ll have a patient’s baseline troponin available to compare the result against.

Clearly, there’s a lot of work to do to find out if this will really benefit patients, but the possibilities are really exciting.

Yes, but what if the troponin is still in the normal range?

Well, here’s another thing. Why do we have a one size fits all normal range for troponin? It’s convenient. But we all know it’s not right. A 90 year-old with many co-morbidities is likely to have a much higher baseline troponin than a 20 year-old who’s completely healthy.

But, right now, we have one normal range for both. We could stratify that – by sex, age, renal function, etc. But what if we truly personalized it? Each patient has their own expected normal range. This could really help us to cure ‘troponinitis‘!

[Ed – I know some people hate that word. Please note ‘troponinitis’ is a disease affecting the clinician’s judgement, not the patient. Any troponin rise is important for a patient, whatever the cause]

So, I’ve come back from this meeting feeling quite excited about the possibilities. We don’t know whether we need a test that counts single molecules to achieve all this but clearly having that even higher sensitivity and precision might have advantages. So I think the future of troponin testing might take us down some totally new avenues. There’s so much more we can do with troponin than simply rule in and rule out ACS. Keep your eyes peeled for some really exciting publications coming soon!

Rick

1.
International Federation of Clinical Chemistry Task Force on Clinical Applications of Cardiac Biomarkers: Troponin Table, 2017. International Federation of Clinical Chemistry. http://www.ifcc.org/executive-board-and-council/eb-task-forces/task-force-on-clinical-applications-of-cardiac-bio-markers-tf-cb/. Accessed September 8, 2017.
2.
Tanglay Y, Twerenbold R, Lee G, et al. Incremental value of a single high-sensitivity cardiac troponin I measurement to rule out myocardial ischemia. Am J Med. 2015;128(6):638-646. [PubMed]
3.
Ford I, Shah A, Zhang R, et al. High-Sensitivity Cardiac Troponin, Statin Therapy, and Risk of Coronary Heart Disease. J Am Coll Cardiol. 2016;68(25):2719-2728. [PubMed]
4.
Body R. Understanding cardiac troponin part 1: avoiding troponinitis. Emerg Med J. July 2017. doi:doi: 10.1136/emermed-2017-206812.

2 Comments

  1. andywebster1971

    Thanks Rick for a great blog. The future around troponins will get more and more complicated…going to need a super computer to help us interpret the results (or a troponinologist like yourself)

    Reply
  2. Pingback: Is cMyC the new troponin? - St.Emlyn's

Thanks so much for following. Viva la #FOAMed

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