Troponin
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Editors-in-Chief: Allen Jeremias, M.D., SUNY; C. Michael Gibson, M.S., M.D. [1]
Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
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Overview
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.
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]
Normal 0 false false false EN-US X-NONE X-NONE
Absence of Troponin Elevation in the General Population
Among 3,557 individuals in the general population, only 0.7% of patients had a troponin ≥0.01 microg/L, which is > than the 99th percentile of the reference range. The underlying disease state in those individuals with elevated troponins included chronic kidney disease, heart failure, left ventricular hypertrophy and diabetes.[2]
"False Positive" Troponin Elevations That Are Not Due to Thrombotic Coronary Occlusion
It is important to note that cardiac troponins are a marker of all heart muscle damage, not just myocardial infarction due to coronary thrombosis. There are other "false positive" causes of troponin elevation that directly or indirectly lead to heart muscle damage in the absence of thrombotic disease can also therefore increase troponin levels.[3] [4] [5] Troponin release in the context of coronary thrombosis and vessel occlusion is due to irreversible damage (myocyte necrosis or cell death) with the release of the intracardiac enzymes into the bloodstream as the myocyte's cell membranes break down. However, in the absence of thrombotic occlusion of a coronary artery, troponin can also be released from myocytes in the absence of necrosis or cell death. This release can occur as a result of changes in the permeability of the cell membrane. Sepsis for instance can cause the breakdown of troponin to lower-molecular-weight fragments that can then leak into the bloodstream through a myocyte membrane that is also rendered more porous by sepsis. [6] The fact that patients who survive sepsis do not have an irreversible decline in LV function supports this mechanism as well. [7] Among patients who have an elevated troponin and a normal angiogram, a very small study of 21 patients identified the following as the underlying causes [8]:
- 47% No clear precipitant
- 28% Tachycardia
- 10% Strenuous exercise
- 10% Pericarditis
- 5% Congestive heart failure
Non-Thrombotic Cardiac Causes of Troponin Elevation
- Ablation procedures to treat arrhythmias
- Amyloidosis and other cardiac infiltrative disorders
- Aortic dissection
- Atrial septal defect closure
- Cardiac contusion
- Cardiac surgery and heart transplant
- Cardioversion
- Defibrillation and defibrillator implantation
- Congestive heart failure
- Coronary artery vasospasm
- Dilated cardiomyopathy
- Endomyocardial biopsy
- Heart block
- Heart failure
- Hypertrophic cardiomyopathy
- Hypotension
- Kawasaki disease
- Myocarditis
- Percutaneous coronary intervention
- Pericarditis
- Pulmonary hypertension
- Radiofrequency ablation
- Stress cardiomyopathy (Apical ballooning syndrome, Takotsubo Cardiomyopathy)
- Supraventricular tachycardia including atrial fibrillation
- Transplant vasculopathy
Non-cardiac Causes of Troponin Elevation
- Burns, especially if it affects >25 percent of body surface area
- Critical illness, e.g. sepsis
- Drug toxicity such as high-dose chemotherapy and compounds such as adriamycin, 5-flurouracil, herceptin, snake venom
- Exercise (e.g. marathon)
- Hypovolemia
- Infiltrative disorders like amyloidosis, hemochromatosis, sarcoidosis, and scleroderma
- Pulmonary embolism
- Intracranial hemorrhage
- Pulmonary hypertension
- Renal failure
- Respiratory failure
- Rhabdomylysis with cardiac injury
- Subarachnoid hemorrhage
- Scorpion venom
- Stroke
- Sympathomimetic ingestion
Technical Aspects
Cardiac troponin T (cTnT) and I (cTnI) are measured by immunoassay methods. A single manufacturer distributes cTnT but a host of diagnostic companies make cTnI methods available on many different immunoassay platforms.[9]
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[10]
References
- ↑ 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.
- ↑ Normal 0 false false false EN-US X-NONE X-NONE Wallace, TW, Abdullah, SM, Drazner, MH, et al. Prevalence and determinants of troponin T elevation in the general population. Circulation 2006; 113:1958.
- ↑ Jeremias A, Gibson CM (2005). "Narrative review: alternative causes for elevated cardiac troponin levels when acute coronary syndromes are excluded". Ann. Intern. Med. 142 (9): 786–91. PMID 15867411. Unknown parameter
|month=ignored (help) - ↑ Ammann P, Pfisterer M, Fehr T, Rickli H. Raised cardiac troponins. BMJ 2004;328:1028-9. PMID 15117768.
- ↑ Higgins, JP, Higgins, JA. Elevation of cardiac troponin I indicates more than myocardial ischemia. Clin Invest Med 2003; 26:133.
- ↑ Wu, AH. Increased troponin in patients with sepsis and septic shock: myocardial necrosis or reversible myocardial depression?. Intensive Care Med 2001; 27:959.
- ↑ Parrillo, JE. Pathogenetic mechanisms of septic shock. N Engl J Med 1993; 328:1471.
- ↑ Normal 0 false false false EN-US X-NONE X-NONE Bakshi, TK, Choo, MK, Edwards, CC, et al. Causes of elevated troponin I with a normal coronary angiogram. Intern Med J 2002; 32:520
- ↑ Collinson PO, Boa FG, Gaze DC. Measurement of cardiac troponin. Ann Clin Biochem 2001;38:423-449. PMID 11587122.
- ↑ 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.