Troponin

  Troponin is a complex of three 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.

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Functional characteristics

Role of troponins

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.

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

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. 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]

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 therefore increase troponin levels:^[2]

• Cardiac:
  • Cardiac amyloidosis
  • Cardiac contusion
  • Cardiac surgery and heart transplant
  • Defibrillation
  • Closure of atrial septal defects
  • Coronary vasospasm
  • Dilated cardiomyopathy
  • Heart failure
  • Hypertrophic cardiomyopathy
  • Myocarditis
  • Percutaneous coronary intervention
  • Radiofrequency ablation
  • Supraventricular tachycardia
• Non-cardiac:
  • Critical illness, e.g. sepsis
  • High-dose chemotherapy
  • Primary pulmonary hypertension
  • Pulmonary embolism
  • Renal failure
  • Subarachnoid hemorrhage
  • Scorpion venom
  • Stroke
  • Very heavy exercise (marathon)

Detection of cardiac troponin

Cardiac troponin T and I are measured by immunoassay methods. Due to patent regulations a single manufacturer distributes cTnT. A host of diagnostic companies make cTnI immunoassay methods available on many different immunoassay platforms.^[3]

Detection of cardiotoxixity and cardioprotection

Drug-induced cardiotoxicity is common to all classes of therapeutic drugs. It is essential that cardiotoxicity is detected with a high degree of sensitivity and specificity. The newly developed troponins are especially useful in this context^[4]

Similarly, cardioprotective effects of therapeutic intervention is pararmount in preserving myocardial integrity, especially during general surgery. Sensitive assays for cardiac troponin can be used to monitor the protective effects of intervention. ^[5]

Sources

1. ^ Antman EM, Tanasijevic MJ, Thompson B, Schactman M, McCabe CH, Cannon CP, Fischer GA, Fung AY, Thompson C, Wybenga D, Braunwald E. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med 1996;335:1342-9. PMID 8857017.
2. ^ Ammann P, Pfisterer M, Fehr T, Rickli H. Raised cardiac troponins. BMJ 2004;328:1028-9. PMID 15117768.
3. ^ Collinson PO, Boa FG, Gaze DC. Measurement of cardiac troponin. Ann Clin Biochem 2001;38:423-449. PMID 11587122.
4. ^ Gaze DC, Collinson PO. Cardiac troponins as biomarkers of drug- and toxin-induced cardiac toxicity and cardioprotection. Expert Opin Drug Metab Toxicol 2005;1:715-725. PMID 16863435.
5. ^ Gaze DC. The role of existing and novel cardiac biomarkers for cardioprotection. Curr. Opin. Invest. Drugs 2007;8:711-7. PMID 17729182.