Cardiac troponins- a review.pdf

Journal of Veterinary Emergency and Critical Care 18(3) 2008, pp 235–245

do i : 10 .1111/ j .1476 - 4 4 31. 2 0 0 8 .0 0 3 07. x

State-of-the-Art Review

Cardiac troponins

Scott M. Wells, DVM, DACVECC and Meg Sleeper, VMD, DACVIM (Cardiology)

Abstract

Objective: To review the use of cardiac troponins as biomarkers for myocardial injury in human and

veterinary medicine.

Data sources: Data sources included scientiﬁc reviews and original research publications.

Human data synthesis: Cardiac troponins have been extensively studied in human medicine. Finding an

elevated cardiac troponin level carries important diagnostic and prognostic information for humans with

cardiovascular disease. Troponin assays are used primarily to diagnose acute myocardial infarction in patients

with ischemic symptoms such as chest pain. However, elevated blood levels may be found with any cause of

myocardial injury.

Veterinary data synthesis: Several studies have shown that cardiac troponins are sensitive and speciﬁc for

myocardial damage in veterinary patients and may have utility in diagnosis and prognosis for certain disease

states. Human assays may be used in most animals due to signiﬁcant homology in the troponin proteins

between species.

Conclusions: Cardiac troponins are sensitive and speciﬁc markers of myocardial injury although they do not

give any information regarding the mechanism of injury. They have redeﬁned how acute myocardial

infarction is diagnosed in humans. Their use in the clinical management of veterinary patients is limited at this

time. Further prospective studies are warranted.

(J Vet Emerg Crit Care 2008; 18(3): 235–245) doi: 10.1111/j.1476-4431.2008.00307.x

Keywords: heart disease, infarction, monitoring, myocardial injury

Introduction

have a high sensitivity and speciﬁcity for myocardial

damage and are considered the biomarker of choice for

detection of cardiac cellular injury. 3–6 The purpose of

this paper is to review cardiac troponins and their util-

ity in human and veterinary medicine.

Cardiovascular diseases are commonly encountered in

both human and veterinary medicine. Biological mark-

ers, or biomarkers, are tools used to identify high-risk

individuals, quickly and accurately diagnose disease

states, and determine treatment plans and prognoses.

While the term biomarker was ﬁrst introduced in 1989,

a National Institute of Health group standardized the

deﬁnition in 2001 as ‘a characteristic that is objectively

measured and evaluated as an indicator of normal bi-

ological processes, pathogenic processes, or pharmaco-

logic responses to a therapeutic intervention.’ 1,2

Biomarkers commonly used in the diagnosis of cardio-

vascular disease may include measurements taken from

blood samples, blood pressure, ECG recordings, radio-

graphs, and echocardiograms. Cardiac troponins (cTn)

Physiology

Troponins are regulatory proteins that are part of the

contractile apparatus of skeletal and cardiac muscle

tissue. They are not present in smooth muscle tissue.

With the proteins actin and tropomyosin, they are part

of the thin ﬁlaments within the myoﬁbrils and are es-

sential for the calcium-mediated regulation of muscle

contraction. The troponin complex consists of 3 inter-

acting and functionally distinct proteins (troponin I, T,

and C). 7 Tissue-speciﬁc isoforms exist for each type of

troponin. 8 Within the thin ﬁlament, tropomyosin di-

mers form a continuous chain along the groove of the

actin helix. The troponin complex lies at regular inter-

vals along the ﬁlament. Tropomyosin acts to block the

myosin binding sites on actin. Each troponin protein

has speciﬁc functions that regulate muscle contraction.

From the New England Animal Medical Center, West Bridgewater, MA

(Wells), and Assistant Professor of Cardiology, Section Chief, Cardiology,

Matthew J. Ryan Veterinary Hospital of the University of Pennsylvania,

Philadelphia, PA (Sleeper).

Address correspondence and reprint requests to:

Dr. Scott M. Wells, DVM, Veterinary Specialty Hospital of the Carolinas,

6405 Tryon Road, Cary, NC 27518.

E-mail: scottw@vshcarolinas.com

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S.M. Wells & M. Sleeper

This paper focuses on troponin I and T due to their

speciﬁcity for cardiac injury.

Troponin C (TnC) is present in 2 isoforms. One iso-

form is present in fast-twitch muscle ﬁbers and the

other is present in both cardiac and slow-twitch muscle

ﬁbers. Homology between the cardiac isoform and 1 of

the skeletal muscle isoforms reduces the cardiac spec-

iﬁcity of TnC and therefore limits its diagnostic useful-

ness in heart disease. 9 Troponin C binds calcium to

initiate muscle contraction.

Multiple isoforms of troponin T (TnT) exist in skeletal

muscle. Cardiac troponin T (cTnT) has a molecular

weight of 37,000Da. 10 In human cardiac tissue 4 iso-

forms exist, but only 1 is characteristic of the adult

heart. The other 3 cardiac isoforms are expressed in

fetal tissue. The fetal isoforms may be re-expressed

during heart failure or in damaged skeletal muscle.

Troponin T attaches the troponin complex to tropomy-

osin and actin. 8

Three isoforms exist for troponin I (TnI). Two are

present in skeletal muscle and the other is present only

in cardiac muscle. The cardiac isoform (cTnI), with a

molecular weight of 24,000Da, is larger than the other

isoforms as it contains an additional 32 amino acid N-

terminal peptide. The rest of the protein has greater

than 40% dissimilarity in its amino-acid sequence com-

pared with skeletal muscle TnI. 8,10,11 Unlike cTnT, cTnI

is not expressed in fetal skeletal muscle during devel-

opment, nor after damage and regeneration in adult

skeletal muscle. 12 Troponin I inhibits actomyosin AT-

Pase and prevents the structural interaction of myosin

with actin-binding sites. The binding of calcium to

troponin C displaces troponin I and causes a confor-

mational change in tropomyosin so that it no longer

interferes with myosin/actin binding and muscle con-

traction can occur.

Mutations in the genes encoding for cTnT and cTnI

cause hypertrophic cardiomyopathy in humans. 13,14

Conversely, a knock out cTnI mouse model develops

acute heart failure at 18 days of age. 15

integrity and therefore will not cause leakage of

troponins. 18

Troponin release kinetics are consistent with 2 sep-

arate intracellular populations. After acute cardiac in-

jury, the cytosolic pool is released resulting in an early

rise in blood levels. This is followed by the slower re-

lease of structurally bound troponin that results in a

sustained elevation (see Figure 1). 16,17,19 The half-life of

troponin and its complex in the circulation is about 2

hours. 20 In humans with acute myocardial infarction

(AMI), cTn levels begin to rise 4–12 hours after the in-

farction and reach peak values at 12–48 hours. The lev-

els remain elevated for 7–10 days (cTnI) and 10–14 days

(cTnT). 10,11,21 A canine model of AMI showed release

times similar to those observed in clinical human pa-

tients although the peak was attained earlier (range 10–

16 hours). 22 This earlier peak was hypothesized to be

due to more rapid development of necrosis in the ex-

perimental situation. The sustained elevation of cTn for

several days after AMI is likely due to ongoing release

from damaged myocytes rather than impaired elimina-

tion. 23 The exact mechanism for elimination of tropo-

nins is unknown but it is thought to involve clearance

by the reticuloendothelial system. 24 There is also some

evidence that troponins may be broken down into small

fragments that could be renally excreted. 25 Elevated

cTn levels indicate myocardial damage but do not pro-

vide any information regarding its cause.

ReversibleVersus Irreversible Injury

There has been debate over whether or not cTn is re-

leased after reversible cardiac injury or if it is only

released following irreversible injury. Some investiga-

tors still believe cardiac troponin I release only results

from irreversible membrane injury. Reversible ischemia

after exercise stress testing in humans has not resulted

in cTn elevations. 26 However, several studies have sug-

gested that troponin I can be released in reversible is-

chemia. For example, Feng et al. showed in a porcine

model of ischemic heart disease that reversible is-

chemia was associated with release of cTnI. The source

of troponin is hypothesized to be from the free cytosolic

pool leaking through a reversibly damaged myocyte

membrane. This hypothesis is also supported by clin-

ical observations of 2 protein release patterns in pa-

tients with unstable angina: an early transient pattern

and a persistent pattern. 27–29 Additionally, some studies

involving prolonged strenuous exercise have shown

transient cTn release that is speculated to be from the

cytosolic pool rather than structurally bound cTn. 30,31

The observation that myocardial dysfunction found

during sepsis is reversible also supports the idea of

troponin release associated with reversible injury. 32

TroponinRelease

The troponin protein exists in 2 populations within the

cells. The majority of troponin is structurally bound

within the thin ﬁlaments of the contractile apparatus. A

small percentage of protein remains free in the cytosol.

This percentage is approximately 2–4% for cTnI and

6–8% for cTnT. 16,17 Troponins are considered leakage

markers. Damage to cardiac myocytes resulting in loss

of membrane integrity causes the release of cTn into the

circulation. Apoptosis, a genetically programmed form

of cell death, does not result in loss of cell membrane

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& Veterinary Emergency and Critical Care Society 2008, doi: 10.1111/j.1476-4431.2008.00307.x

Cardiac troponins

However, at this time it is not possible to differentiate

which population of cTn is released so the debate con-

tinues. 33 Also, the clinical signiﬁcance is unknown.

Assays

Troponin levels are determined using enzyme-linked

immunosorbent assays (ELISA). The difference in ami-

no-acid sequences from skeletal muscle and cardiac

troponin I and T has allowed production of antibodies

speciﬁc for cardiac troponins in these assays. 34,35 The

ﬁrst assays for detection of cTn were developed in the

late 1980s. These assays have evolved dramatically

since their introduction with greater sensitivity and

improved precision. The turnaround time for results

has also decreased from several hours to a few minutes.

Point-of-care assays now exist that may be run bedside

or in the ﬁeld. There are multiple assays available from

a variety of manufacturers for cTnI. This has led to

some confusion regarding interpretation of results. The

assays are not standardized so manufacturers may de-

sign the tests using proprietary antibodies that target

varying amino-acid sequences on the cTnI molecule. In

the bloodstream, cTnI can be modiﬁed or complexed to

other proteins, such as cTnC, and the antibodies used in

the assays may have differing speciﬁcity for each cir-

culating form of cTnI. 36,37 There exists no gold standard

assay for cTnI at this time. Comparison studies using a

number of analyzers have concluded with the recom-

mendation that, until assays are standardized, reference

ranges should be established for each individual assay.

Also, absolute values obtained from different assays

cannot be compared. 36,38,39 Serum, heparinized plasma,

or whole blood may be sampled depending on which

cTnI assay is used. Studies in dogs have shown that

cTnI levels do not signiﬁcantly change in serum stored

at room temperature over a 5-day-period nor in serum

that has undergone up to 5 freeze–thaw cycles. 40,41 On-

ly 1 manufacturer produces an assay for cTnT that

eliminates interassay comparison issues for this pro-

tein. The ﬁrst generation cTnT assays used an antibody

that cross-reacted with skeletal muscle troponin T,

thereby decreasing its speciﬁcity for cardiac injury. 42,a

Subsequent generations of cTnT assays have replaced

this antibody with 1 more speciﬁc for cTnT, thereby

eliminated the false positives related to skeletal muscle

leakage. 35 Although sensitivity of the assays for

troponins has improved over the years, concern re-

mains about their precision at low levels. 43 The occur-

rence of false positive troponin results due to

interfering substances in the blood has also been re-

ported. Rheumatoid factor, excess ﬁbrin, heterophile

antibodies, hemolysis, lipemia, elevated alkaline phos-

phatase, and immune complex formation have all been

Figure 1 : Release of cardiac troponins during acute myocardial

infarction. After injury resulting in loss of sarcolemmal membrane

integrity, the free cytoplasmic troponins are released ﬁrst followed

by a more prolonged release of the structurally bound troponin pro-

teins. Reprinted from Antman EM. Decision making with cardiac

troponin tests. NEnglJMed2002;346(26):2080, with permission. 106

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& Veterinary Emergency and Critical Care Society 2008, doi: 10.1111/j.1476-4431.2008.00307.x

S.M. Wells & M. Sleeper

implicated as causes of false positive troponin results. If

a false positive result is suspected and instrument mal-

function is ruled out, then repeating the test on a re-

centrifuged or new blood sample is indicated. The use

of blocking reagents for substances such as rheumatoid

factor and heterophile antibodies may decrease false

results due to these interferences. Alternatively, because

the problem of interference is assay dependent, the

sample may be tested using a different manufacturer’s

assay. 44

While some assays have been speciﬁcally validated

for use in veterinary medicine, it is generally believed

that human assays for cTn can be used to measure

blood levels of cardiac troponins I and T in most species

encountered. 5,6,45,b,c Recently, the genes for canine and

feline cTnI were sequenced proving the protein struc-

ture is highly conserved among these species. Homo-

logy between canine and feline genes and humans was

95% and 96%, respectively. In the region targeted for

detection by most assays, dogs and cats were identical

to each other and humans differed from dogs and cats

by only 1 amino acid. 45 Other studies have shown that

cTnI and cTnT from many mammalian species can be

measured using human assays and that these proteins

are speciﬁc for myocardial injury. 5,6 Species studied in-

clude dogs, mice, rats, pigs, monkeys, sheep, rabbits,

horses, and cows. However, cardiac troponin I mea-

surements appear less useful in birds and useless in ﬁsh

due to a smaller ratio of cardiac to skeletal muscle re-

activities in these species. 6

Normal values for cardiac troponin I and T have been

reported in veterinary species. 46–53 Although each assay

must have its own range established, reports of normal

values for healthy animals have correlated closely. 39

Most normal animals have cTn levels below the thresh-

old of detection for current assays. 46–53 Normal cTnI

ranges for dogs are reported at o 0.03–0.07 ng/mL with

a median of 0.02 ng/mL. 46 For cTnT all normal dogs

had levels below the threshold for detection by the as-

say. 48,51 Cats have ranges of o 0.03–0.16 ng/mL. 46 Are-

port of normal levels in adult horses including pastured

and race trained Thoroughbreds demonstrated a mean

cTnI of 0.047 0.085 ng/mL. 47 There was no signiﬁcant

difference in cTnI concentration between horses under-

going race training and pastured horses. However, as

already stated, normal ranges must be run on each

system and result comparison using different systems

is not possible. 39

medicine is for diagnosis of ischemic heart disease such

as myocardial infarction (MI). MI refers to myocardial

cell death due to ischemia. 55 In humans, MI occurs after

the rupture of an atherosclerotic plaque in the coronary

arteries resulting in platelet aggregation, clotting, and

either large vessel occlusion or distal embolization. 56

For years, according to the World Health Organization

(WHO), MI has been deﬁned as a syndrome requiring

at least 2 of 3 diagnostic criteria. 57 These criteria in-

cluded an appropriate clinical history and presentation,

ECG changes typical for MI, and elevated cardiac en-

zymes, such as total creatine kinase (CK) and its myo-

cardial form (CK-MB), lactate dehydrogenase, and

aspartate aminotransferase. Total CK, lactate dehydro-

genase, and aspartate aminotransferase have poor spec-

iﬁcity for cardiac damage. 55,58 While CK-MB is more

speciﬁc than total CK for injury to the heart, it is not as

cardiac-speciﬁc as the troponins. 3 CK-MB levels also

return to baseline within 48 hours so late diagnosis of

MI is not possible with this marker, whereas troponin

levels remain elevated for approximately 10 days. 59 Be-

cause humans may not have typical clinical signs and

ECG changes may be nondiagnostic, a joint committee

of the European Society of Cardiology and the Amer-

ican College of Cardiology (ESC/ACC) developed a

new deﬁnition for the diagnosis of MI in 2000. 55 This

new deﬁnition was based predominately on the use of

biomarkers such as the troponins in the diagnosis of MI

(see Table 1). Any elevation of troponin above the ref-

erence range is considered abnormal. In humans, the

reference ranges for troponins are set at the 99th per-

centile of the control group (3 SD from the mean). Ow-

ing to the release kinetics of troponins, it is possible that

patients presenting within hours of an acute ischemic

event may not have elevated cTn levels. It is therefore

recommended that samples be taken at the time of ad-

mission, at 6–9 hours, and again 12–24 hours after pre-

sentation. 55 In situations where an early diagnosis is

needed, a biomarker that rises rapidly, such as myogl-

obin or CK-MB, in addition to the later-rising troponin

may be used. 55 Based on the new deﬁnition and use of

Table 1: ESC/ACC criteria for diagnosis of myocardial infarc-

tion in humans proposed in 2000 55

One of the following 2 criteria may be used to diagnose MI:

1. Typical rise and fall of biochemical markers such as troponin or CK-MB

with at least 1 of the following:

Ischemic symptoms (e.g., chest pain)

Development of pathological Q waves on the ECG

ECG indicative of ischemia (ST-segment changes)

Coronary artery intervention (e.g., angioplasty)

2. Pathological ﬁndings of myocardial infarction

Myocardial Infarction

Cardiovascular disease is the leading cause of morbid-

ity and mortality in humans in the United States. 54 The

primary role of cardiac troponin testing in human

ESC/ACC, European Society of Cardiology/American College of Cardi-

ology; MI, myocardial infarction; CK-MB, creatine kinase-MB.

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Cardiac troponins

Table 2: Reported causes of elevated cardiac troponins in humans and animals

Humans 11,30,31,55,70,72–78

Ischemic heart disease (e.g., myocardial infarction, unstable angina)

Hypotension/hypovolemia

Blunt chest trauma resulting in contusions

Renal failure

Trauma during cardiac surgery or myocardial biopsy

Drug toxicity (e.g., doxorubicin)

Electrical cardioversion, pacing, and implantable cardioverter deﬁbrillator

ﬁrings

Snake envenomation

Congestive heart failure

Coronary vasospasm

Hypertrophic cardiomyopathy

Inﬂammatory disease involving the heart (e.g., myocarditis, pericarditis)

Hypertension

Percutaneous coronary intervention

Sepsis

Pulmonary embolism and pulmonary hypertension

Rhabdomyolysis with cardiac injury

Inﬁltrative disease of the myocardium (e.g., sarcoidosis, amyloidosis)

Extreme exercise (marathon runners or Ironman triathlon competitors)

Sympathomimetic activity (e.g., cocaine use, massive catecholamine

release such as in head trauma or stroke)

Abnormal cardiac rhythms (prolonged tachycardias, atrial ﬁbrillation)

Cardiac transplantation

Chronic obstructive pulmonary disease

Animals 22,40,48–53,79–88,d,g–m

Models of myocardial infarction

Ehrlichiosis

Congestive heart failure

Third degree heart block

Canine dilated cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy in Boxers

Mitral valve disease

Blunt chest trauma

Pericardial effusion

Subaortic stenosis

Feline hypertrophic cardiomyopathy

Sepsis

Gastric dilatation-volvulus

Aortic insufﬁciency jet lesions

Toxins (e.g., doxorubicin, cantharadin)

Endurance exercise in dogs and horses

Babesiosis

High dose isoproterenol

Feline hyperthyroidism

Renal insufﬁciency

highly sensitive troponin assays, many patients are

now diagnosed with MI who would not have had that

diagnosis using the previous WHO criteria. In a study

of 2181 patients with chest pain presenting to an emer-

gency department, the implementation of the new deﬁ-

nition resulted in an increase in the diagnosis of MI by

195%. 60 Another study of patients with chest pain pre-

senting to an emergency room showed that cardiac

troponin testing was highly sensitive for the early de-

tection of myocardial injury. 61 In addition, this study

suggested that a negative troponin test at admission

and 6 hours after the onset of symptoms was associated

with a low-risk of a heart-related event and patients

could be discharged early from the hospital. This pro-

vides strong evidence that troponin testing is effective

for rapid triage of emergent patients with chest pain.

may be predicted based on peak cTnI levels or cTnT

levels at 72 hours. 67–69 In addition, elevations of cTn

have prognostic signiﬁcance in other forms of cardio-

vascular disease such as heart failure and pulmonary

thromboembolism. 70,71

OtherCausesof cTnElevations inHumanand

VeterinaryMedicine

MI is a clinical diagnosis and cannot be made based on

troponin elevations alone. While cTn elevations indi-

cate myocardial injury, they do not give any informa-

tion as to the mechanism of injury. Serial samples may

aid in diagnosis because acute injuries such as MI will

have a typical rise and fall of serum values whereas

other cardiac diseases such as chronic congestive heart

failure may result in persistent, relatively lower

troponin elevations. 56 Troponin levels can rise with

very small amounts of myocardial cell necrosis and

most studies show that cTnI levels are more sensitive

than cTnT levels at detecting cardiac damage. 53,61 There

exist many causes of cardiac injury and therefore ele-

vations in cTn (see Table 2).

Prognosis

Cardiac troponins also have a role in establishing prog-

nosis. With MI, any troponin level above the reference

range is associated with an increased risk of adverse

events in both the short- and long-term. 61–64 It has also

been shown that the magnitude of troponin level ele-

vation correlates with risk of future cardiac events or

death and aids the identiﬁcation of patients with great-

er disease severity who may beneﬁt from more aggres-

sive therapy. 64–66

Trauma

Direct trauma to the heart can result in cTn elevations.

This may be secondary to mechanical injuries such as

In fact, the size of the infarcted area

239

& Veterinary Emergency and Critical Care Society 2008, doi: 10.1111/j.1476-4431.2008.00307.x

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