Introduction

Cardiac troponin I (cTnI) and cardiac troponin T (cTnT) are cornerstone markers for the diagnosis of acute myocardial infarction (AMI) because they provide important diagnostic and prognostic information.¹ High-sensitivity cardiac troponin assays allow the measurement of very low concentrations of cardiac troponin and appear to facilitate detection of unstable coronary artery disease (CAD).² There are also some data suggesting that cardiac troponin values and particularly high-sensitivity cardiac troponin values are helpful in identifying the high-risk group of patients with putatively stable CAD.

Brief Relevant Biology of Troponin

Myocardial injury is followed by the release of cardiac troponins from affected tissue and their increased concentration in circulation. Mechanisms of release are controversial, but we would argue that release is due to cardiomyocyte death.³ cTnT and cTnI are isoforms mostly bound to the sarcomere, although small amounts of free cTnT and cTnI are present in a less tightly bound form.⁴ Different cardiac troponin fragments may have differential biological activities. Low levels of both cTnT and cTnI circulate in patients with stable ischemic heart disease (SIHD) perhaps related to the CAD, or comorbidities that lead to CAD, which can be detected more easily when probed with high-sensitivity cardiac troponin assays.⁵ Mechanisms for these increases may involve apoptosis and increased myocyte turnover, but myocardial strain, increased preload, increased left ventricular mass, remodeling, or even reversible increases in cardiomyocyte wall permeability may be responsible.⁶ Assays cannot discriminate between ischemic and nonischemic etiologies of circulating cardiac troponins. Most cardiac troponin assays attempt to measure all of the major circulating forms equally. The presence of circulating cardiac troponin auto-antibodies can lead to false high or low results.⁷ Noncardiac sources of cTnT have been also reported in patients with skeletal myopathy.⁸

Use of Troponins in Patients With Putatively SIHD

In healthy individuals, higher high-sensitivity cardiac troponin levels are associated with risk factors for CAD such as hypertension, smoking, obesity, and structural heart disease. These presage an increased risk for long-term heart failure, cardiovascular-related death, and all-cause mortality.⁹ This may be why the most important determinant of a negative stress test when probed with high-sensitivity cTnI assays is a very low value at baseline.¹⁰ This is also likely the reason why patients who present with chest discomfort and have very low levels of high-sensitivity cTnI have a very high negative predictive value exceeding 99% for the diagnosis of AMI (i.e., these patients lack the comorbidities that lead to the development of CAD).¹¹

Most patients with SIHD have very low or undetectable circulating levels of cardiac troponins with conventional assays, though the subset with elevations does have a worse prognosis.¹² This could be due to more extensive or complex CAD or other comorbidities, but to date, studies do not provide information about this critical issue. With the high-sensitivity cardiac troponin assays, higher levels correlate with more extensive and complex coronary atherosclerosis.⁹ For any given level of CAD, women at baseline have lower values of high-sensitivity cardiac troponins.² Thus, some of the prognostic influence of higher high-sensitivity cardiac troponin values may be related to the extent and complexity of CAD. A recent study using computer tomography angiogram identified those with higher high-sensitivity cTnT values as those more apt to have noncalcified plaque and more remodeled plaque.¹³ These findings confirm that acute-appearing lesions exist in patients with putatively SIHD. It could be that having stable disease does not preclude subclinical acute events as manifested by the acute-appearing lesions. Alternatively, because it is thought that CAD progresses via a process of plaque rupture and healing, it may be that these lesions persist and will be identified by computer tomography angiogram more frequently. With regard to the extent and complexity of CAD, these findings likely explain why many studies have found that high-sensitivity cardiac troponin values are potent predictors of risk in patients with SIHD. Thus, when the Heart and Soul Study cohort was interrogated with high-sensitivity cTnT, the predictive value of this approach improved substantially.¹⁴ Notably, the best predictive value was not the 99th percentile upper reference limit (URL) but a much lower value, suggesting that a variety of comorbidities that lead to CAD is often at play.

Omland et al. extended these observations. Initially, his group used the high-sensitivity cTnT assay to determine the association between biomarker levels and incidence of cardiovascular events in a median follow-up period of 5.2 years in the PEACE (Prevention of Events with Angiotensin-Converting Enzyme Inhibitor) trial of 3,679 patients with SIHD. The majority of patients (97.7%) had detectable high-sensitivity cTnT levels, but only 11.1% of them exceeded the 99th percentile URL. Higher values were significantly associated with the incidence of cardiovascular-related death and heart failure but not with myocardial infarction (MI) after adjusting for confounding factors.⁵ It is critical to underline that both values above the 99th percentile URL and values that were increased within the normal range were predictive of adverse events, suggesting that the higher the value the worse the cardiovascular prognosis. The PEACE study population was predominantly white, and more than 80% of the patients were men. Extrapolation of the results to other demographic groups needs to be done cautiously. Subsequently, the authors demonstrated that high-sensitivity cTnI values were associated distinctively with several additional parameters in the PEACE cohort.¹⁵ The presence of prior MI was positively associated with high-sensitivity cTnI levels, and renal insufficiency, age, and sex appeared to be associated with high-sensitivity cTnT. This differential association suggested that although both high-sensitivity cardiac troponins are markers of cardiac injury, they have different biology and might provide distinct signals concerning the nature of cardiac injury. Interestingly, in this cohort, subsequent AMI was also predicted by high-sensitivity cTnI but not with high-sensitivity cTnT. This may be because the high-sensitivity cTnI assay used in this study is much more sensitive based on current metrics.²

The HOPE (Heart Outcomes Prevention Evaluation) study measured cTnI concentrations with both AccuTnI and an investigational high-sensitivity cTnI assay in first aliquot thawed samples from 2,619 subjects with a history of CAD, stroke, diabetes, or peripheral vascular disease with at least one other risk factor. This group was without heart failure, stroke, or AMI within 4 weeks; uncontrolled hypertension; or overt nephropathy and had not received angiotensin-converting enzyme inhibitor or vitamin E previously.¹⁶ The prevalence of cTnI concentrations exceeding the 99th percentile URL in this high-risk population again was not large: 2.4% (95% confidence interval [CI]: 1.9-3.1) using the contemporary AccuTnI assay and 24% (95% CI: 22.4-25.7) using the high-sensitivity cTnI investigational assay. Subjects with values of high-sensitivity cTnI above the receiver operating characteristic cutoff of 6 ng/L were at higher risk for the primary outcome (which was a composite of MI, stroke, and cardiovascular death; hazard ratio [HR]: 2.13; 95% CI: 1.73-2.62) even after adjustments (HR: 1.38; 95% CI: 1.09-1.76). The receiver operating characteristic cutoff was far lower than the 99th percentile URL of 10 ng/L, and the authors suggested that different cutoffs should be used in the non-acute coronary syndrome (ACS) setting for long-term risk stratification.¹⁶ These results are consistent with a previous investigation by Zethelius et al.¹⁷ In patients with SIHD, high-sensitivity cTnT measurement identified those at risk for MI, heart failure, and cardiovascular death.¹⁸ These studies were performed in high-risk populations of stable CAD, thus an inference to other categories of ischemic heart disease cannot be done directly. Different cutoff values and different assays were used, thus emphasizing the need for unifying guidelines.

Koenig et al. assessed the prognostic value of high-sensitivity cTnT on a combined cardiovascular disease end point in 1,050 patients with stable CAD in a median 8.1 years follow-up. An increased high-sensitivity cTnT in these patients was associated with older age, history of hypertension or diabetes, more advanced CAD, and cardiovascular risk factors. High-sensitivity cTnT concentrations in the top quartile compared with the lowest quartile were associated with an HR of 2.83 (95% CI: 1.68-4.79) for the composite end point of cardiovascular death, nonfatal MI, and nonfatal stroke after adjustment for various confounders.¹⁹ Selection bias might have been introduced because the study patients had a better prognosis than general population.

Recently, a study from the BARI 2D (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes) trial measured the high-sensitivity cTnT concentration at baseline in 2285 patients with both type 2 diabetes and SIHD. High-sensitivity cTnT concentrations were strong and independent predictors of death from composite cardiovascular causes, MI, or stroke. Patients with a 25% increase in high-sensitivity cTnT from baseline during follow-up, as compared with those with a stable high-sensitivity cTnT concentration were the ones identified at increased risk even after adjustment for other covariates. An abnormal high-sensitivity cTnT value of 14 ng/L or higher was found in 40% of patients, and many might have anticipated that this group would benefit from an interventional strategy. However, that was not observed in response to random assignment to prompt revascularization. Unfortunately, this is the only evaluation of the impact of invasive therapy, and it lacks the power to detect a treatment effect of revascularization in subgroups such as those defined according to baseline high-sensitivity cTnT concentration. Age and sex may also influence the cutoff value of high-sensitivity cTnT.^20,21

Low values of high-sensitivity cardiac troponin also define a group likely to have negative stress tests. Early studies demonstrated a detectable rise in high-sensitivity cTnI levels in response to stress testing proportionally to the degree of ischemia on perfusion imaging. The high-sensitivity cTnI elevations remained predictive of inducible ischemia, even after adjusting for exercise-limiting angina and the degree of ST depression.²² However, the biomarker elevations were subtle, and the range of values was modest and overlapped significantly between those with and without ischemia. These data could not be recapitulated using the high-sensitivity cTnT assay. Furthermore, Sirivardena et al. have showed that all patients who receive dobutamine elaborate increases in high-sensitivity cTnT,²³ and Turer et al. have concluded that pacing evokes elevations in high-sensitivity cTnT in the coronary sinus and systemically.²⁴ Thus, simply using a change in high-sensitivity cardiac troponin to identify those with CAD is not reliable. More robust is very low value's negative predictive value. It should also be noted that in most trials, the combination of high-sensitivity cardiac troponin with N-terminal pro–B-type natriuretic peptide is superior to an individual biomarker approach.¹⁶

A change in the level of high-sensitivity cardiac troponin in a patient with known SIHD should prompt scrutiny for ACS. Multiple studies have demonstrated that elevated levels of high-sensitivity cardiac troponin are powerful predictors of both cardiac and all-cause mortality in these patients, but the appropriate therapeutic response is still unclear.

Conclusions

Patients with SIHD can have chronic elevations of cardiac troponin, and these elevations define increased risk even with contemporary assays. This approach will be facilitated by the use of high-sensitivity cardiac troponin levels where higher values correlate with the degree and complexity of coronary atherosclerosis. Relying on the 99th percentile URL value will markedly underestimate the predictive value of this approach. Importantly, changes in the level of high-sensitivity cardiac troponin in patients with SIHD should prompt scrutiny for ACS and define a higher risk group. It appears that different values will be optimally predictive in men compared with women.²⁵ Further studies are needed to define potential treatments that might benefit such patients. Adding natriuretic peptide levels improves the predictive accuracy of the approach significantly. Additional basic and population studies are needed before implementing this strategy into clinical practice.

References

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Keywords: Angina, Stable, Acute Coronary Syndrome, Angina Pectoris, Angioplasty, Angiotensin-Converting Enzyme Inhibitors, Apoptosis, Biomarkers, Comorbidity, Confidence Intervals, Coronary Artery Disease, Coronary Sinus, Depression, Diabetes Mellitus, Type 2, Dobutamine, Heart Failure, Hypertension, Muscular Diseases, Myocardial Infarction, Myocardial Ischemia, Myocardium, Myocytes, Cardiac, Natriuretic Peptide, Brain, Obesity, Perfusion Imaging, Peripheral Vascular Diseases, Protein Isoforms, ROC Curve, Renal Insufficiency, Risk Factors, Sarcomeres, Smoking, Stroke, Tomography, Troponin I, Troponin T, Vitamin E

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