Cardiac troponin (Dr.Vishal)

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Transcript of Cardiac troponin (Dr.Vishal)

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A Post Graduate Seminar on Cardiac Troponins As A Emerging Cardiac Biomarker of Choice VPP-691

Speaker: Undhad Vishal V.Reg. No. : 04-1443-2010

Major Advisor: Minor Advisor: Dr. D. J. Ghodasara Dr. A. M. Thaker Associate Professor Professor and Head Dept. of Vet. Pathology Dept. of Vet. Pharmacology And Toxicology

College of Veterinary Science and Animal HusbandryAnand Agricultural UniversityAnand -388 001

IntroductionDefinitionHistory BiochemistryPhysiologySensitivity and Specificity Causes of Elevated Troponin LevelsCauses of False Positive Troponin ResultsTests To Measure Cardiac TroponinAdvantagesLimitationsConclusion

Traditional biomarkers Myoglobin CK CK-MB LDH SGOT Cardiac auscultation Radiography ECG Echocardiography Myocardial damage Infectious Toxic Nutritional TraumaticIntroduction

Measurement of circulating cardiac troponin concentrations is considered the gold standard for the non-invasive diagnosis of myocardial injury.

It has replaced traditionally used cardiac biomarkers such as creatine-kinase and its isoenzymes due to its high sensitivity and specificity for the detection of myocardial injury. (Anita, 2008)

Troponin is a complex of three regulatory proteins that is integral to muscle contraction in skeletal and cardiac muscle, but not smooth muscle.

Cardiac troponin I (cTnI) and cardiac troponin T (cTnT) are uniquely expressed in the myocardium and have been widely recognized as highly sensitive and specific serum markers for the noninvasive diagnosis of increased mayocyte permeability or necrosis.16,18,28,29Definition

In 1950s Clinical reports that transaminases released from dying myocytes could be detected via laboratory testing aiding in the diagnosis of myocardial infarction.

First cTnI in 1987 and later cTnT in 1989 were used as biomarkers of cardiac cell death. (Katus et al., 1989)history

Biochemistry

Troponin C Binds calcium Troponin I Binds actin Troponin T Binds tropomyosin

Troponin ITroponin CTroponin TTropomyosinActin

Types of Troponin

8

Troponin CTroponin ITroponin TMolecular mass(kd)18 22.537 AA residues161181-211185-205Isoforms and specificity Two isoforms(fast and slow skeletal)3 Isoforms: 2 unique for skeletal muscle, 1 for cardiac muscleMultiple isoforms

(Filatov et al., 1999)

The first data on the three-dimensional structure of troponin C appeared in 1985, and a detailed structure with 2 resolution was published in 1988. (Satyshur et al., 1988)

Troponin C has a dumbbell-like structure and made up of 1. Two Globular Domains a. N-Terminal globular domain b. C-Terminal globular domain 2. Long central -helixTroponin C

(Filatov et al., 1999)Three-Dimensional Structure of Troponin C

cTnI has an extra 30 amino acid sequence at the N terminal portion of molecule making it absolutely specific to cardiac muscle.

Troponin I is the inhibition of actomyosin ATPase activity. This inhibition is enhanced in the presence of tropomyosin and is completely abolished in the presence of fully Ca2+ -saturated troponin C. (Perry, 1999)

Troponin I

In the absence of Ca2+ the inhibitory sites of troponin I interact with actin, whereas in the presence of Ca2+ these sites interact with troponin C.

The orientations of the polypeptide chains of troponin I and troponin C are antiparallel. (Farah et al., 1994)

In most muscles troponin T is present in the form of multiple isoforms. (Jin et al., 1992)

Human cardiac muscle contains four troponin T isoforms, three of which are expressed in the fetus, and one isoform is characteristic for adult heart. (Anderson et al., 1995)Troponin T

In the isolated state or inside the thin filament troponin T has the form of a comma or rod with a length of 185-205 . (Flicker, 1982)Troponin T is located in the groove of the actin helix and is extended along the filament.

There are three tropomyosinbinding sites in the troponin T structure.

Troponin T kinase is involved in phosphorylation of troponin T in vivo.

(Filatov et al., 1999)

physiology

In the 1960s it was hypothesized that the contraction of striated muscle is regulated by a special protein complex located on actin filaments this complex was called native Tropomyosin (Ebashi et al., 1968) Native Tropomyosin consists of two parts 1. Tropomyosin 2. Troponin (Bailey, 1946)TROPOMYOSIN is a single long protein strand that winds around the actin filament. TROPONIN is a globular complex of three proteins, and is found in clumps around the Tropomyosin protein.

Thin filaments made up from the proteins actin, tropomyosin and troponin An actin molecule is a globular protein with binding site to which the myosin cross-bridges can attachGroove hold tropomyosin moleculesSmaller, calcium-binding troponin molecules stuck to tropomyosin Thin filaments

Thick filaments made up from the protein 200 to 500 myosin molecules2 entwined golf clubsArranged in a bundle with heads directed outward in a spiral array around the bundled tails

Thick filaments

Actin myosin contraction

http://www.sci.sdsu.edu/movies/actin_myosin.html

Myosin cross bridge attaches to the actin myofilament1234Working strokethe myosin head pivots and bends as it pulls on the actin filament, sliding it toward the M lineAs new ATP attaches to the myosin head, the cross bridge detachesAs ATP is split into ADP and Pi, cocking of the myosin head occursMyosin head (high-energy configuration)Thick filament

Myosin head (low-energy configuration)ADP and Pi (inorganic phosphate) released

Thin filament

Sequential Events of Contraction

In animals without induced myocardial damage cTnT is undetectable (