Troponin

Troponin, or the troponin complex, is a complex of three

Troponin is found in both

In both cardiac and skeletal muscles, muscular force production is controlled primarily by changes in intracellular calcium concentration. In general, when calcium rises, the muscles contract and, when calcium falls, the muscles relax.^{[citation needed]}

Troponin is a component of thin filaments (along with actin and tropomyosin), and is the protein complex to which calcium binds to trigger the production of muscular force. Troponin has three subunits, TnC, TnI, and TnT, each playing a role in force regulation.^{[citation needed]}. Under resting intracellular levels of calcium, tropomyosin covers the active actin sites to which myosin (a molecular motor organized in muscle thick filaments) binds in order to generate force. When calcium becomes bound to specific sites in the N-domain of TnC, a series of protein structural changes occurs,^{[citation needed]} such that tropomyosin is rolled away from myosin-binding sites on actin, allowing myosin to attach to the thin filament and produce force and shorten the sarcomere.^{[citation needed]}

Individual subunits serve different functions:^{[citation needed]}

• Troponin C binds to calcium ions to produce a conformational change in TnI
• Troponin T binds to tropomyosin, interlocking them to form a troponin-tropomyosin complex
• Troponin I binds to actin in thin myofilaments to hold the actin-tropomyosin complex in place

Smooth muscle does not have troponin.^[11]

Subunits

TnT is a tropomyosin-binding subunit which regulates the interaction of troponin complex with thin filaments; TnI inhibits ATP-ase activity of acto-myosin; TnC is a Ca²⁺-binding subunit, playing the main role in Ca²⁺ dependent regulation of muscle contraction.^[12]

TnT and TnI in cardiac muscle are presented by forms different from those in skeletal muscles. Two isoforms of TnI and two isoforms of TnT are expressed in human skeletal muscle tissue (skTnI and skTnT). Only one tissue-specific isoform of TnI is described for cardiac muscle tissue (cTnI), whereas the existence of several cardiac specific isoforms of TnT (cTnT) are described in the literature. No cardiac specific isoforms are known for human TnC. TnC in human cardiac muscle tissue is presented by an isoform typical for slow skeletal muscle. Another form of TnC, the fast skeletal TnC isoform, is more typical for fast skeletal muscles.^[13] cTnI is expressed only in myocardium. No examples of cTnI expression in healthy or injured skeletal muscle or in other tissue types are known. cTnT is probably less cardiac specific. The expression of cTnT in skeletal tissue of patients with chronic skeletal muscle injuries has been described.^[14]

Inside the cardiac troponin complex the strongest interaction between molecules has been demonstrated for cTnI – TnC binary complex especially in the presence of Ca²⁺ ( KA = 1.5 × 10⁻⁸ M⁻¹).^[15] TnC, forming a complex with cTnI, changes the conformation of cTnI molecule and shields part of its surface. According to the latest data cTnI is released in the blood stream of the patient in the form of binary complex with TnC or ternary complex with cTnT and TnC.^[16] cTnI-TnC complex formation plays an important positive role in improving the stability of cTnI molecule. cTnI, which is extremely unstable in its free form, demonstrates significantly better stability in complex with TnC or in ternary cTnI-cTnT-TnC complex. It has been demonstrated that stability of cTnI in native complex is significantly better than stability of the purified form of the protein or the stability of cTnI in artificial troponin complexes combined from purified proteins.^{[citation needed]}

Research

Cardiac conditions

Subtypes of troponin (cardiac

Cardiac troponins are a marker of all heart muscle damage, not just myocardial infarction, which is the most severe form of heart disorder. However, diagnostic criteria for raised troponin indicating myocardial infarction is currently set by the WHO at a threshold of 2 μg or higher. Critical levels of other cardiac biomarkers are also relevant, such as creatine kinase.^[19] Other conditions that directly or indirectly lead to heart muscle damage and death can also increase troponin levels, such as kidney failure.^[20][21] Severe tachycardia (for example due to supraventricular tachycardia) in an individual with normal coronary arteries can also lead to increased troponins for example, it is presumed due to increased oxygen demand and inadequate supply to the heart muscle.^{[citation needed]}

Coronary artery stent placement can also cause immediate post-procedure elevated serum troponin levels. This can be problematic in a clinical setting as troponin values and guidance protocols become subject to more thoughtful interpretation. Essentially, making it difficult for a clinician to use troponin elevation diagnostically in this patient group. After stenting and related PCI procedures, troponin levels do return to standard levels once the stent has 'settled' and is no longer causing localized cardiac muscle inflammation.^[22]

In patients with non-severe asymptomatic

Troponins are also increased in patients with heart failure, where they also predict mortality and ventricular rhythm abnormalities. They can rise in inflammatory conditions such as myocarditis and pericarditis with heart muscle involvement (which is then termed myopericarditis). Troponins can also indicate several forms of cardiomyopathy, such as dilated cardiomyopathy, hypertrophic cardiomyopathy or (left) ventricular hypertrophy, peripartum cardiomyopathy, Takotsubo cardiomyopathy, or infiltrative disorders such as cardiac amyloidosis.^{[citation needed]}

Heart injury with increased troponins also occurs in

Troponins are increased in around 40% of patients with critical illnesses such as sepsis. There is an increased risk of mortality and length of stay in the intensive-care unit in these patients.^[24] In severe gastrointestinal bleeding, there can also be a mismatch between oxygen demand and supply of the myocardium.

Chemotherapy agents can exert toxic effects on the heart (examples include

In hypertensive disorders of pregnancy such as

Cardiac troponin T and I can be used to monitor drug and toxin-induced cardiomyocyte toxicity. .[36]

In 2020, it was found that patients with severe COVID-19 had higher troponin I levels compared to those with milder disease.^[37]

Prognostic use

Elevated troponin levels are prognostically important in many of the conditions in which they are used for diagnosis.^[38]

In a community-based cohort study indicating the importance of silent cardiac damage, troponin I has been shown to predict mortality and first coronary heart disease event in men free from cardiovascular disease at baseline.^[39] In people with stroke, elevated blood troponin levels are not a useful marker to detect the condition.^[8]

Subunits

First cTnI^[40] and later cTnT^[41] were originally used as markers for cardiac cell death. Both proteins are now widely used to diagnose acute myocardial infarction (AMI), unstable angina, post-surgery myocardium trauma and some other related diseases with cardiac muscle injury. Both markers can be detected in patient's blood 3–6 hours after onset of the chest pain, reaching peak level within 16–30 hours. Elevated concentration of cTnI and cTnT in blood samples can be detected even 5–8 days after onset of the symptoms, making both proteins useful also for the late diagnosis of AMI.^[42]

Detection

Cardiac troponin T and I are measured by immunoassay methods.^[43][44]

• Due to patent regulations, a single manufacturer (
  Roche Diagnostics
  ) distributes cTnT.
• A host of diagnostic companies make cTnI immunoassay methods available on many different immunoassay platforms.^[44][45]

Troponin elevation following cardiac cell necrosis starts within 2–3 hours, peaks in approx. 24 hours, and persists for 1–2 weeks.^[46]

See also

• Calcium-binding protein
• Troponin C
• Troponin I
• Troponin T

References