Editor's Note: This article is based on Turer AT et al. Myocardial ischemia induced by rapid atrial pacing causes troponin T release detectable by a highly sensitive assay: insights from a coronary sinus sampling study. J Am Coll Cardiol. 2011;57:2398-405.

Cardiac troponin (cTn) is currently considered the gold standard marker for identifying myocardial necrosis. Each generation of cTn assays have increased sensitivity compared to the preceding ones, resulting in the ability to detect smaller amounts of myocardial damage. Whether a new highly sensitive cTnT can detect ischemia without necrosis was the objective of the current study in the June 14 issue of the Journal of the American College of Cardiology.⁽¹⁾ A total of 19 patients referred for coronary angiography had a catheter placed in the coronary sinus (CS) to measure cardiac lactate production. Patients then had an atrial pacing wire placed, and heart rate was increased until 1 of 2 end-points was reached: a heart rate of 160 bpm or development of chest pain. Serial CS and peripheral plasma samples were obtained at multiple time points (peak heart rate, 30, 60, and 180 minutes later) for measurement of lactate and cTnT. Patients were separated into 3 groups based on the presence of absence of significant CAD and net lactate elution (arterial-cCS lactate) concentration. Patients who had net lactate elution were considered to have ischemia.

cTnT concentrations in CS blood increased from a median of 6.8 pg/ml prior to pacing to 16 pg/ml 60 min after termination of rapid atrial pacing (p<0.0001), changes that were mirrored at 180 min in peripheral blood (5.1 to 12 pg/ml, p<0.0001). Although peripheral cTnT concentrations tended to be higher at 180 min following pacing for patients with CAD and lactate elution (n=7) when compared with those without either (n=5) (25.0 pg/ml vs. 10.2 pg/ml, p=0.10), relative (1.7-fold vs. 5.2-fold) and absolute (6.8 pg/ml vs. 8.8 pg/ml, p=0.50) changes were not different between groups.

The authors concluded that brief periods of ischemia, without frank infarction, cause low-level cTnT release. In addition, small increases in cTnT were common after periods of increased myocardial work, even among patients without objective evidence of myocardial ischemia or obstructive CAD. These results have important implications for diagnosing myocardial ischemia and infarction in patients with chest pain syndromes.

Commentary

Cardiac troponin (cTn) is the biomarker of choice for diagnosing myocardial infarction because it is the most sensitive and specific marker of myocardial injury/necrosis available. Because its release is thought to require myocyte necrosis, by definition, in patients with ACS, once cTn is detectable, patients are diagnosed MI and not unstable angina.⁽²⁾

The introduction of more sensitive assays for cTn has led to its detection in patients who are asymptomatic and clinically stable.^(3,4) In many cases, these levels are associated with underlying cardiovascular disease, including coronary disease and heart failure, and are associated with worse outcomes.^(3,4) Some of these assays have been able to detect low cTn levels in normal people.⁽⁵⁾

Although in-vitro studies had suggested that cTn could be detected in acute ischemia without infarction, similar data, until recently, was not available in humans. Sabatine et al, using a highly sensitive cTnI assay, found an association with increased cTn in patients with more severe degrees of ischemia as estimated by myocardial perfusion imaging ⁽⁶⁾ (although others did not confirm this finding⁽⁷⁾). The presence of cTn elevations in patients presenting with superventricular tachycardia despite the absence of ECG or clinical evidence of ischemia also suggests that myocardial damage may not always be required for cTn release ⁽⁸⁾

In the current study (1) the authors have extended this finding, demonstrating that cTnT release from the heart was associated with ischemia (as defined by net lactate elution). Elevations were detectable in coronary sinus flow that was subsequently reflected in the blood stream. In addition, a finding that has additional important implications, they found that cTnT increased in patients without ischemia, indicating that cTnT release may not necessarily reflect ongoing infarction, or even ischemia, but may be released as a result of increased cardiac work. The current results are consistent with the association of increased cTnT frequently seen after strenuous exercise.⁽⁹⁾

The rapid release would be consistent with release from the 5% to 8% of cTn that is part of an early releasable pool found in the cytosol.⁽¹⁰⁾ It is possible that in some situations cTn release from this pool may reflect reversible myocyte damage rather than necrosis. As noted by White in his accompanying editorial, there are a variety of potential mechanisms for cTn release.⁽¹¹⁾ These include myocyte necrosis and apoptosis, normal myocyte cell turnover, cellular release of proteolytic troponin degradation products, formation and release of membranous blebs and increased cellular wall permeability. The latter could be a potential contributor in this setting. Myocardial stretch could lead to activation of stretch-responsive integrins⁽¹²⁾, resulting in increased permability, and release of cTn from the cytosolic pool.

It is likely that one or more of these mechanisms, possibly in combination with other yet identified mechanisms, may also have contributed to cTn release. The inability to demonstrate release with ischemia with prior assays is likely due to the relative insensitivity of these assays compared to the newer ones, and the low amounts of cTn that are released.

Finally, a finding that has critical implications for acute chest pain evaluation, serial increases do not appear adequate for differentiating acute ischemia/infarction from non-ischemic etiologies. Three of the 5 patients who had no increase in lactate had a >3-fold increase in baseline cTnT values; in fact, increases were more common in this cohort than in patients with coronary disease. Therefore optimal diagnostic strategies for identifying ACS patients likely will require both serial changes as well as an upper diagnostic threshold.

As with all studies, there were limitations, some of which were acknowledged by the authors. An important limitation was the relatively small sample size. Given that only 19 patients were included, it would have been helpful to be able to see individual patient data. Although cTnT values increased in the CAD-/lactate- patients, the majority still had peak values below the 99th percentile (10.5 vs 14 pg/ml). Determination of appropriate changes and thresholds that would more likely reflect ischemia/infarction rather than stress will be required. It would have been helpful to have concomitant naturietic peptides, as increased cTnT release may have been an effect of myocardial stretch. The duration of pacing was relatively short; it is possible that longer, more sustained increases in heart rate (and/or blood pressure) may have led to larger increases in cTnT.

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References

1. Addo TA et al. Myocardial ischemia induced by rapid atrial pacing causes troponin T release detectable by a highly sensitive assay: insights from a coronary sinus sampling study. J Am Coll Cardiol. 2011;57:2398–2405.
2. Thygesen K, et al. Universal definition of myocardial infarction. Circulation. 2007;116;2634–2653.
3. Otsuka T, et al. Association between high-sensitivity cardiac troponin T levels and the predicted cardiovascular risk in middle-aged men without overt cardiovascular disease. Am Heart J. 2010;159:972–978.
4. de Lemos JA, et al. Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population. JAMA. 2010;304; 2503–2512.
5. Frankenstein L et al. Biological Variation and Reference Change Value of High-Sensitivity Troponin T in Healthy Individuals during Short and Intermediate Follow-up Periods. Clin Chem. 2011;57:1068-71.
6. Sabatine MS, et al, Detection of acute changes in circulating troponin in the setting of transient stress test-induced myocardial ischaemia using an ultrasensitive assay: results from TIMI 35. Eur Heart J. 2009;30:162–169.
7. Kurz K, et al. Highly sensitive cardiac troponin T values remain constant after brief exercise- or pharmacologic-induced reversible myocardial ischemia. Clin Chem. 2008;54:1234–1238.
8. Redfearn DP, et al, Supraventricular tachycardia promotes release of troponin I in patients with normal coronary arteries. Int J Cardiol. 2005;102;521–522.
9. Shave R, et al. Exercise-induced cardiac troponin elevation: evidence, mechanisms, and implications. J Am Coll Cardiol. 2010;56:169–76.
10. Katus HA, ET al., Intracellular compartmentation of cardiac troponin T and its release kinetics in patients with reperfused and nonreperfused myocardial infarction. Am J Cardiol. 1991; 67:1360–1367.
11. White HD. Pathobiology of troponin elevations: do elevations occur with myocardial ischemia as well as necrosis? J Am Coll Cardiol. 2011;57:2406-8.
12. Hessel MH, et al. Release of cardiac troponin I from viable cardiomyocytes is mediated by integrin stimulation. Pflugers Arch. 2008;455;979–986.

Keywords: Angina, Unstable, Coronary Angiography, Coronary Artery Disease, Cytosol, Coronary Sinus, Heart Failure, Infarction, Biomarkers, Myocardial Infarction, Myocardial Ischemia, Myocardial Perfusion Imaging, Troponin

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