Metabolic Pathway of Cardiac Troponins and Its Diagnostic Value

Figures & data

Figure 1 Interpretation of possible reasons for myocardial injury and increase of cardiac troponin serum levels.

Notes: Adapted from Thygesen K, Alpert JS, Jaffe AS et al⁶.

Table 1 Current Diagnostic Algorithms for Confirmation/Exclusion of NSTEMI (0 → 1 Hour and 0 → 2 Hours), Approved by the ESC

One-Hour NSTEMI Diagnostic Algorithm
Troponin immunoassay, company (manufacturer)	Biomarker concentration that indicates an extremely low probability of an NSTEMI diagnosis, ng/L	Biomarker concentration that indicates a low probability of an NSTEMI diagnosis, ng/L	Changes in biomarker concentration after 1 hour at which a diagnosis of NSTEMI should be excluded, ng/L	Biomarker concentration that indicates a high probability of an NSTEMI diagnosis, ng/L	Changes in biomarker concentration after 1 hour at which a diagnosis of NSTEMI should be confirmed, ng/L
High-sensitivity cardiac troponin T (Elecsys; Roche)	<5	<12	<3	≥52	≥5
High-sensitivity cardiac troponin I (Architect; Abbott)	<4	<5	<2	≥64	≥6
High-sensitivity cardiac troponin I (Centaur; Siemens)	<3	<6	<3	≥120	≥12
High-sensitivity cardiac troponin I (Access; Beckman Coulter)	<4	<5	<4	≥50	≥15
hs-cTn I (Clarity; Singulex)	<1	<2	<1	≥30	≥6
hs-cTn I (Vitros; Clinical Diagnostics)	<1	<2	<1	≥40	≥4
hs-cTn I (Pathfast; LSI Medience)	<3	<4	<3	≥90	≥20
Two-Hour NSTEMI Diagnostic Algorithm
Troponin immunoassay, company (manufacturer)	Biomarker concentration that indicates an extremely low probability of an NSTEMI diagnosis, ng/L	Biomarker concentration that indicates a low probability of an NSTEMI diagnosis, ng/L	Changes in biomarker concentration after 2 hours at which a diagnosis of NSTEMI should be excluded, ng/L	Biomarker concentration that indicates a high probability of an NSTEMI diagnosis, ng/L	Changes in biomarker concentration after 2 hours at which a diagnosis of NSTEMI should be confirmed, ng/L
hs-сTnT (Elecsys; Roche)	<5	<14	<4	≥52	≥10
hs-сTnI (Architect; Abbott)	<4	<6	<2	≥64	≥15
hs-сTnI (Centaur; Siemens)	<3	<8	<7	≥120	≥20
hs-сTnI (Access; Beckman Coulter)	<4	<5	<5	≥50	≥20
hs-cTn I (Clarity; Singulex)	<1	To be determined	To be determined	≥30	To be determined
hs-cTn I (Vitros; Clinical Diagnostics)	<1	To be determined	To be determined	≥40	To be determined
hs-cTn I (Pathfast; LSI Medience)	<3	To be determined	To be determined	≥90	To be determined

Notes: Adapted with permission from Collet JP, Thiele H, Barbato E et al²⁹.

Table 2 Biological Fluids in Which the Molecules of Cardiac Troponins are Detected and the Diagnostic Value

Biological Fluid	Diagnostic Value of Cardiac Troponins	Sources
Blood (whole, serum, plasma)	It is the main biological fluid used to diagnose AMI and assess the prognosis of patients suffering from non-ischemic cardiac (myocardites, Takotsubo syndrome, cardiomyopathies, etc.) and non-cardiac (sepsis, renal failure, neurogenic pathologies, etc.) pathologies that cause damage to myocardial cells.	[^Citation24^–^Citation28]
Urine	Molecules of cardiac troponins can be detected in this biological fluid via highly sensitive test systems. Increased troponin levels have a high prognostic value in diabetes mellitus and arterial hypertension. The method of obtaining this biological fluid is non-invasive, which has a number of advantages over the use of blood. It should be noted that the possibilities of examination of highly sensitive troponins in urine are still poorly studied and have not been finally validated. Further research is needed before the introduction of this method into clinical practice.	[^Citation34,Citation67,Citation69]
Oral fluid	The levels of cardiac troponins in oral fluid increase in AMI and moderately correlate with serum troponin levels; therefore, further study of this area of non-invasive diagnostics is very promising.	[^Citation35^–^Citation37,Citation68]
Pericardial fluid and cerebrospinal fluid	Molecules of cardiac troponins are detected in pericardial fluid and cerebrospinal fluid via moderately sensitive and highly sensitive test systems and, according to some studies, may correlate with serum levels of cardiac troponins. Increased troponin levels in these biological fluids may reflect the degree of myocardial damage and may be used in forensic medicine to determine the cause of death. However, due to the relative paucity of such studies, further investigation of these possibilities is necessary.	[^Citation72^–^Citation76]
Amniotic fluid	Cardiac troponin molecules can be detected in amniotic fluid via moderately sensitive and highly sensitive immunoassays. Increased troponin levels may indicate chronic fetal hypoxia, abnormal development of the cardiovascular system and fetal myocardial injury, and an increased risk of fetal death during the intrauterine growth period. However, it is worth noting that such studies are few in number. Further research is needed to clarify the diagnostic capabilities of amniotic fluid.	[^Citation77^–^Citation80]

Figure 2 Metabolic pathway of cardiac troponins.

Table 3 Release of Cardiac Troponins from Myocardial Cells: Mechanisms and Diagnostic Value

Mechanism	Diagnostic Value
Myocardial cell necrosis	This is the main proven mechanism underlying the increase in cardiac troponins in AMI. Cardiomyocyte necrosis will result in the release of all molecules (biomarkers) from the cell into the bloodstream.
Release of cardiac troponins as a result of the processes of regeneration and renewal of myocardial cells	The renewal of myocardial cells gradually occurring throughout life, hypothetically, may be associated with normal (less than the upper limit of the 99th percentile) concentrations of cardiac troponins in the bloodstream.
Release of cardiac troponins as a result of apoptosis of myocardial cells	It has been proven that apoptosis of cardiomyocytes (without signs of necrosis) is accompanied by an increase in the serum concentration of cardiac troponins. Thus, any physiological (physical activity, old age) and pathological (heart failure, arterial hypertension, chronic obstructive pulmonary disease, etc.) conditions that enhance apoptosis may be accompanied by the release of cardiac troponins from cardiomyocytes and an increase in serum levels.
Release of cardiac troponins as a result of the formation of membrane vesicles on the surface of myocardial cells	Membrane vesicles (blebbing vesicles) formed on the surface of the plasma membrane of cardiomyocytes, hypothetically, may contain cytoplasmic proteins, including cardiac troponins. The number of membrane vesicles increases during ischemia of myocardial cells and may be associated with the release of cardiac troponins into the bloodstream.
Intracellular proteolytic degradation of cardiac troponin molecules into small fragments and the release of the latter through the intact membrane of myocardial cells	Molecules of cardiac troponins can be fragmented/destroyed by the action of certain proteolytic enzymes: calpain, thrombin, matrix metalloproteinases. As a result of the action of these enzymes, there can form small fragments of troponin molecules, which, due to their size, have a higher probability of release from the cell. This mechanism may have high clinical significance: for example, all those physiological and pathological conditions and/or drugs that affect the activity of these proteolytic enzymes can also affect the release of cardiac troponins and their concentration in the bloodstream.
Release of cardiac troponins as a result of increased membrane permeability of myocardial cells	An increase in the release of cardiac troponin molecules into the bloodstream is observed in case of an increase in the membrane permeability of myocardial cells, which is characteristic of myocardial ischemia, an increase in preload and stretching of the heart wall.
Release of cardiac troponins as a result of small-scale (subclinical) necrosis of cardiomyocytes	The death of a small number of cardiomyocytes may not manifest itself clinically and instrumentally (since these are relatively low-sensitivity methods), but highly sensitive methods of detection can register such subclinical lesions. Possible causes of subclinical necrosis of cardiomyocytes are ischemia, inflammatory-toxic processes and imbalances in the neuroendocrine system.
Release of cardiac troponins from non-cardiac cells	This is a controversial mechanism of increased levels of cardiac troponins in the bloodstream. In the literature, there are works confirming the expression of cardiac troponins in skeletal muscle tissue in patients with CRF and hereditary skeletal myopathies, as well as studies that refute this hypothesis.

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