Role of Highly Sensitive Cardiac Troponin T Assay in Stable Coronary Artery Disease

Cardiac troponins (cTn) are the preferred biomarkers of myocardial necrosis, usually used for diagnosis and risk stratification in acute coronary syndromes. Highly sensitive troponin T (hs-cTnT) may be elevated in stable coronary artery disease (SCAD), in which subclinical plaque erosion or rupture and distal embolization and subclinical ischemic episode. hs-cTnT may be used as a prognostic marker in SCAD and can predict cardiovascular events and patient’s mortality rate. In this article, plaque characteristic that is linked to hs-cTnT, it’s used as prognostic biomarker and comparison to other indicators are the focus of discussion.


C
ardiac Troponin T and I are components of cardiomyocyte contractile apparatus and the most widely used biomarker of cardiomyocyte necrosis Troponin measured in those with acute coronary syndrome.Studies had shown that even slight increase in cardiac troponin concentration is associated with worse prognosis in those with acute coronary syndrome. 1,2levation of cardiac troponin ≥0,01 µg/liter was associated with increased mortality in those with or without history of cardiovascular events (Table 1).Based on this finding, it is probable that increased level of troponin which does not pass the threshold concentration for positive test (below the limit for detection; very low plasma troponin level) may play a role as predictor of adverse cardiovascular events. 3,4,9lasma cardiac troponin is a sensitive and specific biomarker which is commonly used to diagnose myocardial infarction.The advent of highly sensitive troponin T assay (hs-cTnT) enables not only early detection of myocardial infarction but also serves as a prognostication tool in stable coronary artery disease.It was able to detect the concentration of plasma cardiac troponin 10 times lower compared to conventional assay.Elevation of hs-cTnT above 99 percentiles was found in 1/3 patients with stable coronary artery disease diagnosed through computed tomography angiography. 5,6,7

Cardiac Troponin and Stable Coronary Artery Disease
Concentration of hs-cTnT is higher in those with stable coronary artery disease compared to a normal person.(Figure 1) Subclinical erosion or plaque rupture and distal embolization, subclinical ischemic episode, micro-small vessels occlusion, inflammatory process, cardiomyocyte apoptosis, reduced renal clearance and distention due to pressure or volume overload were hypothesized to be the underlying pathophysiology of increased troponin and worse outcome. 8 study by Torbjorn Omland, et al. conclude that increased concentration of plasma cardiac troponin T measured by hs-cTnT was significantly associated with increased adverse cardiovascular events and heart failure, but not myocardial infarction in patients with stable coronary artery disease.This study showed that very low plasma cardiac troponin T concentration was detectable in the majority of patients with stable coronary artery disease and preserved ejection fraction.After adjustment for other independent prognostic indicators, there was a strong and graded increase in the cumulative incidence of cardiovascular death and of heart failure in the study group.A study by Mirta Diez, et al showed that increased level of highly sensitive cardiac troponin (hs-cTn) was directly proportional to ventricular dysfunction and those with ejection fraction ≤ 45% had higher hs-cTn.Increased level of hs-cTn was associated with poor clinical outcome, low cardiac output, and cardiogenic shock.Cardiomyocyte damage was even more prominent during acute exacerbation of heart failure due to increase in pulmonary capillary pressure, reduced coronary perfusion pressure, increased catecholamine secretion, abnormal calcium metabolism, oxidative stress and inflammation.This study concluded that heart failure caused by coronary artery disease had high hs-cTn level compared with heart failure due to other etiology.The use of hs-cTn for risk stratification      during admission helps in determining those at high risk of death and poor prognosis which helps in guiding a more aggressive and emergent therapy. 7,9aque Characteristic and Highly Sensitive Cardiac Troponin T Elevated hs-cTnT was not associated with type or severity of chest pain and degree of stenosis but has a relationship between plaque composition especially remodeling in area without calcification and smooth or mixed plaque.A study investigated about plaque characteristic in non-culprit coronary artery with the result showing association between segmental plaque volume and virtual histologyderived thin-cap fibroatheroma (VH-TCFA) with elevated concentration of hs-cTnT in patients with stable coronary artery disease. 8VH-TCFA was found in 49% of the patients with hs-cTnT concentration ≥14 pg/mL which means that there was 2 times more frequent compared to those with hs-cTnT <14 pg/mL (adjusted OR 2.35, 95% CI: 1.12-4.91,p = 0.024).VH-TCFA with high lesional plaque volume (lesional plaque volume above the median of all lesions classified as VH-TCFA) was three times more prevalent in those with hs-cTnT concentration ≥14 pg/mL (adjusted OR 3.36, 95% CI: 1.44 -7.84, p = 0.005).Normalized segmental plaque volume and normalized segmental vessel volume were positively correlated with the level of hs-cTnT while there is no association between plaque burden and hs-cTnT concentration. 8

(Table 2)
A study also showed that elevated pre-procedural hs-cTnT concentration ≥14 pg/mL was found in 26% of patients with stable coronary disease undergoing percutaneous coronary intervention and is associated with increased risk of death.It was also an independent predictor of all-cause mortality within one year (HR 5.73; 95% confidence intervals 3.34-9.83;P<0.001; adjusted HR 2.08; 95% confidence interval 1.10-3.92;P=0.024, after adjustment to relevant risk factors including age, gender, and chronic kidney disease). 6levated hs-cTnT was found to be related to cardiaccause mortality (HR 4.68; 95% confidence interval 2.12-10.31;P<0.001). 6(Table 3)

Highly Sensitive Cardiac Troponin T compared to other indicators
Heart and Soul Study compared traditional risk factors (age, gender, body mass index, hypertension, dyslipidemia, and diabetes) and biomarkers (NT-proBNP, hs-cTnT and urine albumin:creatinine ratio) in predicting risk of secondary events (secondary events in those with coronary heart disease) in patient with stable coronary artery disease.The top four indicators were NT-proBNP, hs-cTnT, urine albumin:creatinine ratio, and smoking. 10From traditional and novel biomarker risk factors, elevated hs-cTnT was the second most powerful predictor of cardiovascular Table 2. Association between high-sensitivity cardiac troponin T and plaque characteristics in nonculprit stable coronary artery disease.From: Oemrawsingh RM et al.High-sensitivity troponin T in relation to coronary plaque characteristics in patients with stable coronary artery disease; results of the ATHEROREMO-IVUS study. 8Table 3.One year outcome in patients with and without elevated hs-Table 2. Association between high-sensitivity cardiac troponin T and plaque characteristics in non-culprit stable coronary artery disease.From: Oemrawsingh RM et al.High-sensitivity troponin T in relation to coronary plaque characteristics in patients with stable coronary artery disease; results of the ATHEROREMO-IVUS study. 8events (adjusted HR 1.47, 95% CI 1.18-1.84);p = 0.001) behind smoking.
Prognostic value of hs-cTnT measurement is also influenced by various factors.A study by Carda et al showed that elevated hs-cTnT was associated with increased risk of the primary outcome (RR 2.360; p = 0.001) and heart failure (RR 5.932; p < 0.001) but not with acute ischemic events, however, it's significance is lost after controlling with age.Its significance is also affected by ejection fraction <40%, use of anticoagulant and ACE inhibitor.Carda et al also stated that other studies did not include patients with EF <40% as study sample which means that it's clinical significance are questionable in those with heart failure reduced ejection fraction.(Table 4) Carda et al also stated that their study is in agreement with ESC guideline for management of stable coronary artery disease in which troponin assay has prognostic value but is not enough to be recommended as routine systematic examination in stable coronary artery disease at outpatient settings. 10,11

Conclusion
Subclinical erosion or plaque rupture and distal embolization, subclinical ischemic episode, microsmall vessels occlusion, inflammatory process, cardiomyocyte apoptosis, reduced renal clearance and distention due to pressure or volume overload were hypothesized to be the underlying pathophysiology of increased troponin and worse outcome.Highly sensitive cardiac troponin T is one of the best prognostication tools among traditional and novel risk factors to predict of adverse.It helps in gradation and risk stratification of those with stable coronary artery disease because of its proportionality with degree and complexity of coronary atherosclerosis, adverse cardiovascular event, and mortality rate. 12s-cTnT is also able to predict acute coronary  From: Beatty AL, et al.Traditional risk factors versus biomarkers for prediction of secondary events in patients with stable coronary heart disease: from the heart and soul study. 10yndrome, myocardial infarction and mortality in those with stable coronary artery disease due to its presence in the majority of patients including those who are at low risk.Albeit the promising prospect of hs-cTnT as a prognostication and risk stratification tool for patients with stable coronary artery disease, the evidence is still lacking to be recommended in the guideline and used routinely in clinical practice.

Figure 1 .
Figure 1.Distribution and determinants of cardiac troponin T c coronary artery disease and apparently healthy blood donors.Fr sensitive cardiac troponin T assay in stable coronary artery diseas

Figure 1 .
Figure 1.Distribution and determinants of cardiac troponin T concentration in stable coronary artery disease and apparently healthy blood donors.From: Omland et al.A sensitive cardiac troponin T assay in stable coronary artery disease. 9

Figure 1 .
Figure 1.Distribution and determinants of cardiac troponin T concentration in stable coronary artery disease and apparently healthy blood donors.From: Omland et al.A sensitive cardiac troponin T assay in stable coronary artery disease.9

Table 1 .
Association between high-sensitive cardiac troponin T and cardiovascular outcomes.From Omland et al, A sensitive cardiac troponin T assay in stable coronary artery disease.9IndonesianJ Cardiol • Vol.39, Issue 1 • January -March 2018

Table 1 .
9ssociation between high-sensitive cardiac tr outcomes.From Omland et al, A sensitive cardiac tropon artery disease.9

Table 1 .
9ssociation between high-sensitive cardiac troponin T and cardiovascular outcomes.From Omland et al, A sensitive cardiac troponin T assay in stable coronary artery disease.9

Table 3 .
One year outcome in patients with and without elevated hs-cTnT From: Zanchin T, et al.Preprocedural high-sensitivity cardiac troponin T and clinical outcomes in patients with stable coronary artery

Table 3 .
6ne year outcome in patients with and without elevated hs-cTnTFrom: Zanchin T, et al.Preprocedural high-sensitivity cardiac troponin T and clinical outcomes in patients with stable coronary artery disease undergoing elective coronary intervention.6

Table 4 .
Adjusted multivariable for myocardial infarction, stroke or cardiovascular death in Heart and Soul Risk Model.