CARDIAC TROPONIN and TROPONINS I and T: function, metabolism and normal values

What is Troponin

There troponin it's a complex protein which constitutes the cardiac muscle  is skeletal, the smooth muscle in fact lacks it. The troponin complex is critical for the actin-myosin mediated calcium interaction underlying muscle contraction. Troponin is defined as cardiac enzyme, cardiac marker or myocardiocytolysis index, and is used in the diagnosis ofacute heart attack of the myocardium (MI).

In accordance with the European and American guidelines to define a heart attack it is necessary that the suggestive clinical context (angor, i.e. chest pain, electrocardiogram or ECG, risk factors) is also accompanied by a significant troponin curve (increasing / decreasing) and from troponins above the 99% of the reference limit value compared to the normal population.

Classification of troponins and cardiac enzymes

THE cardiac markers or cardiac markers  therefore they are molecules released into circulation following damage to the cardiac muscle. They are used to aid in the diagnosis and risk stratification of patients with angina and suspected ACS.

Cardiac troponins, in particular, have become the markers of choice in patients with ACS (Acute Coronary Syndrome), whose symptoms such as chest pain, nausea, sensation of cardiac constriction, often accompanied by breathing difficulties, are not always present, nor are they specific to myocardial infarction or cardiac pain, but may also depend on other situations. Therefore, for a correct diagnosis and treatment it is necessary to have laboratory support.

There are three types of troponins, each with their own role:

  • troponin I: inhibits the interaction of myosin with actin,
  • troponin T: binds the components of troponin to tropomyosin,
  • troponin C: contains the binding sites for the Ca2 + essential for the initiation of muscle contraction

The process of muscle contraction begins through the binding of the Ca2 + cation to the C site of the troponin which causes the removal of the I domain from T with consequent slipping of the tropomyosin on the actin filament, thus a conformational change takes place which allows the free actin furrows to sliding, through an inclination of 45 °, on the thick filaments of myosin with finally the muscle contraction.

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Troponin and other cardiac markers

Like others cardiac markers, although less specific than troponin we have at our disposal:

Creatin Kinase or CK

Creatine Kinase (CK) is released from the muscles whenever there is muscle damage.
In particular, there are three forms:

  • Creatin Kinase MB (CK-MB): is the specific CK isoenzyme for the heart.
  • CK-MM mainly located in skeletal muscle and in heart,
  • CK-BB mainly located in the brain and smooth muscle: intestine, uterus and prostate.

So we understand that CK-MB is much less specific than troponins.
The relative index of CK-MB can be obtained from CK-MB / CK ratio, which allows to exclude other causes other than skeletal muscle as a source of origin, however it is less diagnostic than troponins. Total CK-MB in skeletal muscle increases in patients whose conditions cause chronic muscle destruction and regeneration (e.g. muscular dystrophy) or in those who participate in athletic competitions (e.g. marathons) and in those with rhabdomyolysis.

Elevations of CK-MB are found more frequently in ER patients because they are the ones with the highest levels of alcohol abuse and history of trauma. One advantage of the CK-MB is its own short half-life in the circulation, which is useful for evaluating the time to onset of a myocardial infarction (if I have for example high troponin levels but a low CK-MB it is likely that it is a reduced heart attack or a heart attack that occurred a few days ago ).

An increase in CK-MB may be detectable in those who have had a heart attack approximately 3-6 hours after the onset of chest pain. Concentration peaks in 12-24 hours and returns to normal after 48-72 hours. If there is a second heart attack or the damage progresses, then the levels rise again and / or remain high over time. However the high sensitivity troponin has the same function. The dosage of CK-MB is mainly carried out if the troponin test is not available. CK-MB can also be prescribed if CK is high to tell if this is due to muscle or heart damage.

Copeptin

Copeptin (CT-proAVP) is secreted by the pituitary gland at the beginning of a myocardial infarction. It has been studied in combination with troponin in patients with suspected ACS. In the CHOPIN study, a negative dose of copeptin and sensitive troponin evaluated in patients within six hours of onset of symptoms had a negative predictive value of 99.2%. However, a study that evaluated the diagnostic contribution of copeptin 1 hour after the initial dosing did not reveal a greater utility than ultrasensitive troponin I alone.

Myoglobin

Myoglobin, this too, like CK-MB, is not very specific of myocardial damage, it tends to rise with every muscle trauma. In particular, the causes of high myoglobin are muscular dystrophy, accidents, trauma, myositis; on the other hand, low myoglobin is usually found in myasthenia gravis;

FABP and modified albumin

Fatty Acid Binding Protein (FABP) and Ischemic Modified Albumin: have been studied as diagnostic markers, but none are specific to myocardial tissue.

The advent of troponins and in recent years of high sensitivity troponins leaves little room for these other biomarkers, so although in blood tests we find these high enzymes the clinical utility in the diagnosis and prognosis of ACS is limited.

Let's now look at the troponins in detail.

Exam indication: what is it for

The analysis of the blood of the troponins serve to diagnose heart attack in patients with signs and symptoms of heart attack heart pain such as chest pain radiating to shoulders, jaw, neck, pain in the left arm, with difficulty in breathing or those patients whose angina does not go away with rest.
When, after the blood tests, there are altered cardiac enzymes and the troponin curve is significant (increases / decreases), the diagnosis of myocardial infarction is almost certain and further diagnostic tests can be carried out, such as echocardiogram, which allows you to view any impaired contraction cardiac from hypokinesia or akinesia of the walls of the heart resulting from the suffering of the myocardium, and set up the necessary therapies.

Release of troponins in case of heart damage

It is thought that there is a small amount of troponins in the cytoplasm and that another part is contained within the skeletal muscle and that during damage to the heart muscle, depending on its severity, troponins are released from their respective pools. Thus an initial elevation of troponins occurs when they are released from their cytosolic part, while when troponin molecules in the cytosol of the heart muscle diffuse through the sarcolemma into nearby lymphatic and blood vessels, they become detectable in the blood.

As we know myocardial infarction represents damage to the heart muscle due to a discrepancy between the need for O2 and the supply of the same, therefore, if the myocardial suffering progresses, it leads to myocardial necrosis and further troponins are released from the muscle portion. For this the troponin values in myocardial infarction increase significantly.

Troponin normal values

A healthy person usually has no detectable troponins in their blood. The outlier depends on the patient's clinical situation and the assay used. In a patient presenting with chest pain and possible myocardial infarction a troponin move , in particular, an abnormal value is defined as that above 99% compared to the healthy population.

In detail i troponin levels:

  • Normal values of troponin t (tnt): there is a single % value between 0.01-0.03 ng / ml, since there is only one type of assay to validate the cTnT;
  • Normal values of troponin i (tnI): there are numerous assays so the value varies from laboratory to laboratory, so it is important to always check the range of the reference laboratory.

When measured with the old assays, elevated troponin levels could be detected between 6 and 12 hours after the myocardial damage event, peaking at 24 hours followed by a gradual decline after two weeks.

In recent years there has been the introduction of a new type of troponin, troponin to high sensitivity, with different sensitivity and specificity, which made it possible to overcome the large limit of classical troponins of being detectable in the blood only several hours after the ischemic event and which improved the diagnostic accuracy, being able to diagnose subendocardial or transmural infarction with two samples veins performed just 3 hours apart from each other.

It was a remarkable one increase of the sensitivity for IMA (from 63.7% to 90.7%), compared to a slight reduction of the specificity (from 97.2% to 90.7%). However, the tissue specificity of troponin hs for damage to cardiomyocytes, which is always very high, must always be distinguished from clinical specificity for AMI, which can be reduced by increases in hs-cTn not related to ischemic heart disease.

The evaluation of an increase in hs-cTN can be done as soon as the patient arrives in ED and if these are negative then the patient can be discharged, if they are positive, the dosage is repeated at 3 hours and, if an increase has occurred. of 301TP1 Compared to the reference values of troponin, then the patient is hospitalized and the troponins are measured at 6, 12, 18 hours. Otherwise the patient can be discharged.

We can therefore understand the high potential of high sensitivity troponins, which allow on the one hand to detect a heart attack early, and on the other to considerably dispose of the long queues of the PS. One of the main concerns that arose shortly after starting the ultrasensitive troponin dosing was whether or not there was a risk of having too many false positives, given the high sensitivity but reduced specificity, however, numerous studies over the years have agreed that hs-cTNs actually allow for an early diagnosis of heart attack and rapid therapy.

High Troponin

Normal cardiac troponin values can undergo variations for both cardiovascular and extracardiac causes.
Among the causes and symptoms of high troponin we can distinguish cardiovascular causes, such as:

  • Heart attack,
  • Angina pectoris,
  • Inflammatory heart disease,
  • Taking cardiotoxic drugs,
  • Pericarditis, myocarditis,
  • Ventricular arrhythmias such as ventricular tachycardia and ventricular fibrillation,
  • Other tachyarrhythmias: atrial fibrillation with rapid ventricular rate,
  • Chest trauma / cardiac contusion,
  • Aortic dissection,
  • Endocarditis
  • Cardiac surgery

Extracardiac causes:

The presence of high levels of troponins in the blood is also associated with extra-cardiac causes, which require high cardiac output that causes the oxygen demand / supply mismatch underlying ischemia, such as:

  • Septic shock,
  • Hypovolemic shock,
  • Systemic inflammatory response (SIRS),
  • Pulmonary embolism, in this case of great importance the execution of the D-dimer, because the high value of the latter allows to make a diagnosis of PE,
  • Severe kidney dysfunction,
  • Hypothyroidism,
  • Muscle trauma,
  • Neurological emergencies (cerebral haemorrhage, stroke),
  • Renal diseases, in particular, the evaluation of the elevation of troponins in patients with chronic kidney disease in fact in many patients who undergo hemodialysis troponin (especially high troponin t for unknown cause) is elevated. In the absence of clinical features of ischemia, elevated troponins alone can be unreliable and therefore represent a false positive, leading to unnecessary investigations. This is also a confounding factor for the clinician because patients with renal insufficiency are those in whom cardiovascular disease is the primary cause of death and are also the patients at the greatest risk of silent ischemia. However, the elevated troponin level in patients with kidney disease is associated with a poor prognosis.

This image reports various causes of high troponin, for example: renal failure, heart failure, tachy-or bradyarrhythmia, cardiac and non-cardiac surgical procedures that cause cardiac myocyte death and the rise and fall of the troponin enzyme curve. Downloaded from https://academic.oup.com/eurheartj/article-abstract/33/20/2551/447556

 

Low Troponin

So far we have seen that elevated Troponin levels direct the diagnosis towards acute coronary syndrome (ACS) or myocardial infarction depending on the clinic and tests performed.

But what is the significance of low troponin levels?

We distinguish two populations: the healthy one and the population with stable coronary syndrome. In a healthy population, low troponin levels can rule out heart attack or other heart damage. In the second type of population, the PEACE trial showed that very low troponin levels, detectable by the new high sensitivity assays, are associated with the onset of heart failure and death but not with an increased incidence of myocardial infarction.
The study was published in the New England Journal of Medicine in 2009 (see here the Abstract).

Factors that can alter the examination

Even particularly intense physical exertion, such as that which marathon runners or triathletes undergo, can be accompanied by an alteration of troponin in the serum.
Instead, we can say that the test loses sensitivity when it is indiscriminately dosed with a relatively low positive predictive value (around 50%, poor specificity). This leads to erroneous suspicions of acute coronary syndrome and consequently to further inappropriate diagnostic tests and therapies.

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