Troponin

Troponin is a complex of three regulatory proteins that is integral to muscle contraction in skeletal and cardiac muscle, but not smooth muscle. Troponin is attached to the protein tropomyosin and lies within the groove between actin filaments in muscle tissue. In a relaxed muscle, tropomyosin blocks the attachment site for the myosin crossbridge, thus preventing contraction. When the muscle cell is stimulated to contract by an action potential, calcium channels open in the sarcoplasmic reticulum and release calcium into the sarcoplasm. Some of this calcium attaches to troponin, causing a conformational change that moves tropomyosin out of the way so that the cross bridges can attach to actin and produce muscle contraction.

Troponin is found in both skeletal muscle and cardiac muscle, but the specific versions of troponin differ between types of muscle. The main difference is that the TnC subunit of troponin in skeletal muscle has four calcium ion binding sites, whereas in cardiac muscle there are only three.

Discussions of troponin often pertain to its functional characteristics and/or to its usefulness as a diagnostic marker for various heart disorders.

Contents 1 Physiology 2 Diagnostic use 2.1 Cardiac conditions 2.2 Non-cardiac conditions 3 Detection of cardiac troponin 4 Prognostic use 5 Footnotes

Physiology

Both cardiac and skeletal muscles are controlled by changes in the intracellular calcium concentration. When calcium rises, the muscles contract, and when calcium falls the muscles relax.

Troponin is a component of thin filaments (along with actin and tropomyosin), and is the protein to which calcium binds to accomplish this regulation. Troponin has three subunits, TnC, TnI, and TnT. When calcium is bound to specific sites on TnC, tropomyosin rolls out of the way of the actin filament active sites, so that myosin (a molecular motor organized in muscle thick filaments) can attach to the thin filament and produce force and/or movement. In the absence of calcium, tropomyosin interferes with this action of myosin, and therefore muscles remain relaxed.

Troponin I has also been shown to inhibit angiogenesis in vivo and in vitro.^{[citation needed]}

Individual subunits serve different functions:

• 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 troponin-tropomyosin complex in place

Diagnostic use

Cardiac conditions

Certain subtypes of troponin (cardiac troponin I and T) are very sensitive and specific indicators of damage to the heart muscle (myocardium). They are measured in the blood to differentiate between unstable angina and myocardial infarction (heart attack) in patients with chest pain or acute coronary syndrome. A patient who had suffered from a myocardial infarction would have an area of damaged heart muscle and so would have elevated cardiac troponin levels in the blood.^[1] This can also occur in patients with coronary vasospasm.

It is important to note that cardiac troponins are a marker of all heart muscle damage, not just myocardial infarction. Other conditions that directly or indirectly lead to heart muscle damage can also increase troponin levels.^[2][3] Severe tachycardia (for example due to supraventricular tachycardia) in an individual with normal coronary arteries can also lead to increased troponins for example, presumably due to increased oxygen demand and inadequate supply to the heart muscle.

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.

Heart injury with increased troponins also occurs in cardiac contusion, defibrillation and internal or external cardioversion. Increased troponins are commonly increased in several procedures such as cardiac surgery and heart transplantation, closure of atrial septal defects, percutaneous coronary intervention or radiofrequency ablation.

Non-cardiac conditions

The distinction between cardiac and non-cardiac conditions is somewhat artificial; the conditions listed below are not primary heart diseases, but they exert indirect effects on the heart muscle.

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.^[4] 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 anthracycline, cyclophosphamide, 5-fluorouracil and cisplatin). Several toxins and venoms can also lead to heart muscle injury (scorpion venom, snake venom, venom from jellyfish or centipedes). Carbon monoxide poisoning or cyanide poisoning can also be accompanied by release of troponins due to hypoxic cardiotoxic effects. Cardiac injury occurs in about one third of severe CO poisoning cases, and troponin screening is appropriate in these patients.^[5][6]

Some patients with dissection of the ascending aorta have elevated troponins, and increased hemodynamic stress has been suggested as a mechanism.^[7]

In both primary pulmonary hypertension, pulmonary embolism and acute exacerbations of chronic obstructive pulmonary disease (COPD), right ventricular strain with increased wall tension and ischemia. Of course, patients with COPD exacerbations might also have concurrent myocardial infarction or pulmonary embolism, so care has to be taken to attribute increased troponin levels to COPD.

Central nervous system disorders can lead to increased sympathetic tone and/or catecholamine release which lead to cardiac overstimulation. This is seen in subarachnoid hemorrhage, stroke, intracranial hemorrhage and (generalized) seizures (in patients with epilepsy or eclampsia, for example).

Patients with end-stage renal disease can have chronically elevated troponin T levels, which are linked to a poorer prognosis.^[8][9] Troponin I is less likely to be falsely elevated.^[8]

Strenuous endurance exercise such as marathons or triathlons can lead to increased troponin levels in up to one third of subjects, but it is not linked to adverse health effects in these competitors.^[10][11][12] High troponin T levels have also been reported in patients with inflammatory muscle diseases such as polymyositis or dermatomyositis.^[13][14] Troponins are also increased in rhabdomyolysis.

In hypertensive disorders of pregnancy such as preeclampsia, elevated troponin levels indicate some degree of myofibrillary damage.^[15][16]

Cardiac troponin T and I can be used to monitor drug and toxin induced cardiomyocyte toxicity. .^[17]

Detection of cardiac troponin

Cardiac troponin T and I are measured by immunoassay methods.^[18] Due to patent regulations a single manufacturer distributes cTnT. A host of diagnostic companies make cTnI immunoassay methods available on many different immunoassay platforms.^[19]

Prognostic use

Raised troponin levels are prognostically important in many of the conditions in which they are used for diagnosis.

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.^[20]

Footnotes

v • d • e Histology: muscle tissue skeletal muscle/general epimysium, fascicle, perimysium, endomysium, muscle fiber (intrafusal, extrafusal), myofibril sarcomere (a, i, and h bands; z and m lines), myofilaments (thin filament/actin, thick filament/myosin, elastic filament/titin, nebulin), tropomyosin, troponin (T, C, I) costamere (dystrophin, α,β-dystrobrevin, syncoilin, synemin/desmuslin, dysbindin, sarcoglycan, dystroglycan, sarcospan), desmin neuromuscular junction, motor unit, muscle spindle, excitation-contraction coupling, sliding filament mechanism myoblast, satellite cell, sarcoplasm, sarcolemma, sarcoplasmic reticulum, T-tubule cardiac muscle myocardium, intercalated disc, nebulette smooth muscle calmodulin, vascular smooth muscle

v • d • e Proteins of the cytoskeleton Microfilaments Actins - Actin-binding proteins - Actinin - Arp2/3 complex - Cofilin - Destrin - Gelsolin - Myosins - Profilin - Tropomodulin - Troponin (T, C, I) - Tropomyosin - Wiskott-Aldrich syndrome protein Intermediate filaments type 1 and 2 (Cytokeratin, type I, type II) - type 3 (Desmin, GFAP, Peripherin, Vimentin) - type 4 (Internexin, Nestin, Neurofilament, Synemin, Syncoilin) - type 5 (Lamin A, B) Microtubules Dyneins - Kinesins - MAPs (Tau protein, Dynamin) - Tubulins - Stathmin - Tektin Catenins Alpha catenin - Beta catenin - Plakoglobin (gamma catenin) - Delta catenin Nonhuman Major sperm proteins - Prokaryotic cytoskeleton (Crescentin, FtsZ, MreB) Other APC - Dystrophin (Dystroglycan) - plakin (Desmoplakin, Plectin) - Spectrin (SPTA1, SPTAN1, SPTB, SPTBN1, SPTBN2, SPTBN4) - Talin - Utrophin - Vinculin

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