Article

Troponin in Non-ischaemic Dilated Cardiomyopathy

Abstract

Non-ischaemic dilated cardiomyopathy (DCM) is a disease characterised by progressive left ventricular remodelling and dysfunction. DCM represents a major cause of morbidity and mortality. Cardiac troponins are sensitive biohumoral markers of myocyte injury that are used for diagnostic purposes in acute coronary syndromes but that are also detected in DCM. Several pathophysiological factors (wall stress, neurohormonal activation, inflammation, metabolic dysfunction, microvascular ischaemia) have been advocated to explain subtle ongoing necrosis in DCM. In particular, new ultrasensitive assays expand the detection range toward physiological cardiac troponin levels, allowing accurate biohumoral characterisation of myocardial remodelling from the early stages of DCM. Moreover, several clinical studies have demonstrated that increased cardiac troponin plasma levels are associated with worse prognosis and that further increases in cardiac troponin over time contribute to additional risk. Serial plasma cardiac troponin evaluation represents an accurate marker of disease evolution and risk stratification in DCM, identifying high-risk patients who need strict follow-up and enhanced therapeutic effort.

Disclosure: The authors have no conflicts of interest to declare.

Received:

Accepted:

Citation:European Cardiology 2011;7(3):220–4

Correspondence: Andrea Barison, Scuola Superiore Sant'Anna and Fondazione G Monasterio CNR-Regione Toscana, Via Giuseppe Moruzzi 1, 56124 Pisa, Italy. E: barison@sssup.it

Acknowledgements: The authors are very grateful to Dr Michele Emdin and Dr Claudio Passino for their constant support and their precious advice in writing this review.

Open access:

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Among the various cardiovascular diseases, non-ischaemic dilated cardiomyopathy (DCM) represents a major cause of morbidity and mortality.1 DCM is characterised by the presence of left ventricular dilatation and systolic dysfunction in the absence of coronary artery disease or abnormal loading conditions (hypertension, valvular disease).2 It originates from several aetiologies and includes heterogeneous patients with diverse propensities to ventricular remodelling and different prognoses. Therefore, it is crucial to identify high-risk patients who need strict follow-up and enhanced therapeutic effort using a comprehensive clinical, biohumoral, and instrumental evaluation.

Although characteristics such as ventricular dimension, left ventricular ejection fraction, New York Heart Association (NYHA) functional class, cardiopulmonary exercise performance and haemodynamic measurements are helpful to estimate the risk for adverse cardiac events, the assessment of prognosis in individual patients with DCM remains difficult and would benefit from a more accurate marker of disease activity.1 New imaging techniques, such as magnetic resonance provide unique information, especially about cardiac fibrosis and remodelling, but costs and availability limit their use in the daily management of patients with DCM. Alternatively, several plasma biomarkers of cardiac overload, such as B-type natriuretic peptide (BNP), or of injury, such as cardiac troponins, provide additional independent risk stratification from the early stages of DCM.3 In addition to advantages over imaging techniques in terms of cost and feasibility, both BNP and cardiac troponins have been shown to have superior diagnostic accuracy than echocardiography from the asymptomatic or paucisymptomatic phases of heart failure, especially in the setting of systemic inflammatory/infiltrative diseases (amyloidosis, sarcoidosis) and in cardiotoxic cardiomyopathy.4,5

Ventricular remodelling in DCM consists of myocyte hypertrophy and slippage, loss of myocytes, myocardial interstitial fibrosis and a decrease in myofibril content. Serial measurements of reliable biochemical markers of myocyte injury would be helpful to monitor disease progression. Cardiac troponins are very sensitive and specific markers of myocyte necrosis and play a crucial role in risk stratification and revascularisation planning in acute coronary syndromes.

However, myocyte necrosis with subsequent cardiac troponin release occurs not only in ischaemic conditions but also in several other cardiac conditions, such as acute myocarditis, pericarditis, cardiac contusion, cardiomyopathies and heart failure, even without clinical evidence of myocardial ischaemia or myocarditis.6,7 Moreover, cardiac troponin plasma levels also rise in several non-cardiac disorders, such as pulmonary embolism, sepsis, hypothyroidism, and renal failure (see Table 1). While the pivotal role of cardiac troponins in acute coronary syndromes is well established, their value in DCM remains controversial although promising, in particular after the introduction of high-sensitivity troponin assays.

Physiology of Troponins

Cardiac troponins are part of the troponin–tropomyosin complex in the thin actin filaments of heart-muscle myofibrils. This complex consists of troponin C (cTnC), cardiac troponin I (cTnI), cardiac troponin T (cTnT) and tropomyosin (see Figure 1). Although troponins are found in both skeletal and cardiac muscle, there are specific cTnI and cTnT isoforms in the heart.8 The troponin–tropomyosin complex is responsible for the Ca2+-induced contraction–relaxation cardiac cycle occurring between actin and myosin filaments.9

Troponin mutations promote cardiac hypertrophy, disarray, enlargement and interstitial fibrosis by impairing Ca2+ sensitivity, cellular metabolism and contractility or by promoting myocyte stress with subsequent activation of stress responses.10–13 Mutations in cardiac troponins have been proved to cause familial hypertrophic, dilated, or restrictive cardiomyopathy. Moreover, a single mutation in a codon of cTnI has been demonstrated to induce multiple cardiomyopathic phenotypes (restrictive or hypertrophic).

Troponin Release in Plasma

Troponins are intracellular proteins; therefore, their presence in blood is a sensitive and peculiar indicator of heart cell damage. cTnI and cTnT are currently considered the most sensitive and specific biochemical markers of myocardial damage.14,15 However, cardiac troponins are heart-specific but are not disease-specific biomarkers.

Following cardiomyocyte necrosis and proteolysis of contractile proteins, both single peptides (free troponin subunits, fragments of troponin subunits) and peptidic complexes (such as TnT–TnI–TnC [TIC] complex and TnI–TnC [IC] complex) are released. The total concentration of cTnI is five to 12 times greater than the concentration of free cTnI and TIC complex quickly disintegrates to cTnT and IC complex. Therefore, following myocyte death, free cTnT, IC complex and a certain amount of free cTnI appear in the blood.12

Nevertheless, some studies have demonstrated cardiac troponin release even in the absence of lethal sarcolemma disruption, either through proteolysis and subsequent release of cellular cardiac troponin or through reversible damage to cardiomyocyte membranes without cellular necrosis16 (see Figure 1).

Plasma Troponin Assays

Troponin tests are immunoassays that are susceptible to common interference with antibody recognition and binding. The first generation of cTnT immunoassays encountered false-positive results due to a cross-reaction with skeletal troponin T.17 However, a second generation of immunoassay methods based on more specific antibodies has solved this problem of interference with skeletal muscle isoforms and has showed comparable results to cTnI assays.18 Nevertheless, current commercial cardiac troponin immunoassays still present several limitations, such as inter-assay variability (due to different antibody specificity and different calibration and quantification methods)19 and susceptibility to several immunological interferences. In particular, analytic false-positive cardiac troponin results may be caused by fibrin microclots, heterophile antibodies such as human anti-mouse antibodies and rheumatoid factor (several cardiac troponin assays use murine reagents, so that heterophile antibodies can cross-react with test components and cause false-positive results in the absence of circulating cardiac troponin), or macrocomplexes of cardiac troponin with an immunoglobulin (clearance of Ig–cardiac troponin macrocomplexes is reduced, extending the lifetime of cardiac troponin in circulation).20,21

A new generation of cTnI and cTnT high-sensitivity assays has been developed by manufacturers to improve the analytic performance and standardisation of cardiac troponin assays in accordance with international guidelines, which recommend a 10 % variability coefficient for values corresponding to the 99th upper reference limit.16,19,22 These high-sensitivity troponin assays have made it possible to measure concentrations 10-fold lower than the lower limit of traditional assays, providing the opportunity for a more comprehensive biohumoral and pathophysiological evaluation of both ischaemic and non-ischaemic heart disease. In particular, ultrasensitive cTnI assays present an analytic sensitivity of 6 ng/l, corresponding to myocardial tissue damage lower than 1 mg (cTnI cardiomyocyte content being about 70 mg/g),23 therefore allowing detection of parcellar necrosis, as expected during cardiac remodelling in DCM patients.

Troponin Release in Healthy Subjects

Highly sensitive immunoassays can detect cardiac troponin even in the plasma of healthy subjects, in particular after strenuous physical exercise or in aged people.16 Troponin could be released because of either cardiomyocyte rupture or increased sarcolemmal permeability, probably representing a very sensitive maker of physiological renewal or remodelling of human myocardium.16 Troponin release in healthy older adults could be the result of increased remodelling of myocardial tissue, consisting of myocyte loss with hypertrophy of the remaining cells. Similarly, plasma cardiac troponin after exercise could reflect mechanical stretch, reversible myocardial stunning, transient myocardial ischaemia with cell damage, or even true irreversible focal necrosis. Indeed, cardiac troponin has been detected in the plasma of endurance athletes after marathons. This is associated with either preserved biventricular function24 or transient right ventricular mild systolic dysfunction,25 but without evidence of myocardial oedema or fibrosis at cardiac magnetic resonance, suggesting that cardiac troponin could be released from cardiomyocytes after reversible sarcolemmal damage. On the other hand, chronic exposure to repetitive bouts of endurance exercise has been demonstrated to promote myocardial fibrosis both in animal and in human post mortem studies and has been correlated to an increased prevalence of complex arrhythmias in veteran athletes.26

Pathological Causes of Troponin Release

Cardiomyopathies present by definition a non-ischaemic aetiology: genetic, inflammatory, toxic, immune, or neuroendocrine.2 Nevertheless, myocardial necrosis and apoptosis play a major role in the pathophysiology of primitive cardiomyopathies, promoting further ventricular remodelling and impairment of systolic and diastolic function. The first description of troponin release in patients with heart failure (both ischaemic and non-ischaemic in origin) was reported in 1995 by Missov et al.27

The mechanisms believed to be responsible for ongoing myocyte injury and/or cell death in heart failure include activation of adrenergic, renin–angiotensin–aldosterone, or endothelin signalling pathways, calcium-handling abnormalities, inflammatory cytokines, nitric oxide, oxidative stress, and mechanical stress. Each of these factors, alone or in combination, can promote either myocyte necrosis or myocyte apoptosis through activation of specific genetic pathways. Even repetitive bouts of ischaemia have been advocated in the pathophysiology of DCM: although not representing the primary cause of disease, they may promote myocyte death, replacement fibrosis and further remodelling.28,29

Several in vitro studies have identified a relationship between myocardial wall stretch and myocyte injury,30 with increased troponin proteolysis in volume-overloaded rat hearts,31 while other studies support the relationship between myocardial wall stress and subendocardial ischaemia, even in the absence of coronary artery disease.28,32

Several works have also demonstrated a correlation between myocyte injury and biochemical markers associated with neurohormonal and flogistic activation in patients with heart failure.33 Adrenergic activation is a hallmark of heart failure, promoting irreversible contraction band lesions in myocardial cells with coagulative myocytolysis (Zenker necrosis).34 Adrenergic effects seem to derive from cyclic adenosine monophosphate (cAMP)-mediated calcium overload, as well as from microcirculatory dysfunction.35 Also, angiotensin II can induce cardiomyocyte necrosis36 and apoptosis of neonatal and adult ventricular myocytes37 independently of adrenergic activation and haemodynamic overload.

DCM patients present elevated levels of inflammatory biomarkers, which are associated with troponin increase. Cytokines have been demonstrated to reduce cardiac contractility in a concentration-dependent manner,38 promote cardiomyocyte death via the Fas/FasL system,39 and predict worse prognosis. Septic shock, a condition of extreme cytokine overexpression, is always accompanied by troponin release: cardiac ischaemia and cardiac metabolic disorders have both been excluded in its pathogenesis, while microvascular thrombosis seems to play a role.40

All of these mechanisms, in particular adrenergic activation and haemodynamic overload, have been demonstrated to increase during effort- and stress-related situations in everyday life, determining phasic bouts of troponin release and disease progression. Moreover, it has been hypothesised that the more the myocardium is remodelled, the more it is susceptible to cardiac damage; in other words, troponin increases following cardiac damage (adrenergic activation, haemodynamic overload, and inflammation), in particular in the advanced stages of cardiac disease when the heart is weaker and more susceptible to mechanical and neurohormonal stress.

Several studies have investigated the role of autoimmunity response to troponin. Administration of monoclonal antibodies to cTnI induces heart dysfunction and dilation by chronic stimulation of Ca2+ influx in cardiomyocytes.41 In a murine model, a complete autoimmune response to troponin (humoral and cellular) led to severe inflammation and fibrosis of the myocardium, resulting in increased end-systolic and end-diastolic diameters, decreased fractional shortening and reduced survival.42 In DCM, troponin release could implicate a vicious cycle through autoimmunity, contributing to disease progression, even though other studies have excluded a pathological role of antitroponin autoantibodies.43 Further studies are needed to fully elucidate the mechanisms of inflammation- and autoimmunity-mediated cardiac damage.44

Imaging Myocardial Necrosis

The association between cardiac troponin release and myocardial necrosis in DCM is supported by autoptic and imaging studies. Replacement fibrosis is a reparative process caused by myocyte death and scar formation, and is reported in as many as 57 % DCM patients in post mortem studies.45

Similarly, contrast-enhanced cardiac magnetic resonance allows the detection and quantification of fibrosis with a delayed enhancement technique: in DCM patients, myocardial fibrotic areas are associated with higher cardiac troponin plasma levels,46 more advanced ventricular remodeling, and worse outcome.47,48 Moreover, cardiac magnetic resonance allows detection of myocardial oedema with T2-weighted imaging, but the association between myocardial oedema and cardiac troponin release has not been extensively described so far. Similarly, ongoing myocyte injury in DCM has been documented in nuclear imaging by 111-Indium antimyosin antibodies, and has been correlated with worse left ventricular function and worse prognosis.49

Prognostic Role of Troponins

Several clinical studies have demonstrated the negative prognostic role of increased plasma levels of cardiac troponin in DCM (see Table 2). Sato et al.50 demonstrated that persistently increased values of cTnT in DCM patients indicate progressive myocyte degeneration and deterioration of the patient’s clinical condition. Indeed, in 60 DCM patients, they reported three evolutionary patterns of cTnT concentrations during a follow-up of 16 months: 33 patients had cTnT concentrations <0.02 ng/ml (group 1), 10 patients had high initial cTnT concentrations (>0.02 ng/ml; group 2) which then decreased to <0.02 ng/ml, and 17 had persistently high cTnT concentrations (>0.02 ng/ml; group 3). While group 1 and group 2 patients presented an improvement in left ventricular dimensions and function, group 3 patients experienced a progressive worsening of left ventricular function and more events (cardiac death and hospitalisation for heart failure), despite optimal medical treatment. Similarly, Miller et al.51 collected plasma cTnT and BNP samples in 190 stable NYHA III–IV heart failure outpatients (45 % of which were of non-ischaemic origin) every three months during a two-year clinical follow-up: elevations of both cTnT (>0.01 ng/ml) and BNP were highly associated with an increased risk for events (death, heart transplant, or hospitalisation). In particular, further increases in cTnT (>20 %) from an elevated level contribute to additional risk, changes in BNP (increase or decrease) remained associated with the same risk and combined elevation of cTnT and BNP contributed to the highest risk.

Nellessen et al.52 assessed the prognostic value of cTnI in 58 patients with chronic heart failure (57 % non-ischaemic origin). The mean serum concentration of cTnI in patients with congestive heart failure was higher (0.66±1.8 ng/ml) than that of healthy volunteers (0.11±0.48 ng/ml). There was no significant difference between patients with and without coronary artery disease, but following hospital discharge troponin release was significantly lower in survivors than in non-survivors at a three-year follow-up (0.56 versus 0.84 ng/ml); this indicates that permanent cTnI release is a common finding in patients with chronic heart failure and is a strong prognosticator, while coronary morphology seems to play a minor role in disease progression. Miettinen et al.43 demonstrated in 95 DCM patients that increased levels of cTnI were associated with worse left ventricular function, increased neurohormonal activation, and worse prognosis during a median follow-up of 4.1 years (cardiovascular death, heart transplantation, or clinical need for an implantable cardioverter–defibrillator). On the other hand, the presence of circulating cardiac troponin autoantibodies was not associated with the clinical status or outcome of patients. Similarly, Sugiura et al.53 demonstrated that cTnT, myosin light chain-I, heart fatty-acid-binding protein, and creatine kinase isoenzyme MB were all predictors of acute decompensation in 78 stable DCM patients during a 30-month follow-up.

A recent study54 evaluated 238 heart failure patients (50 % non-ischaemic origin) referred for cardiac transplantation. Detectable cTnI plasma levels were associated with higher pulmonary wedge pressure, lower cardiac index, higher BNP levels, a progressive decline in ejection fraction and increased mortality at six-month follow-up. Notably, patients with ischaemic and non-ischaemic causes of heart failure had similar cTnI concentrations. Latini et al.55 evaluated plasma cTnT in 4,053 heart failure patients (42 % non-ischaemic origin) enrolled in the Valsartan heart failure trial (Val-HeFT). Troponin T was detectable in 10.4 % of the population using the cTnT assay (detection limit 0.01 ng/ml) compared with 92.0 % using the new highly sensitive cTnT assay (detection limit 0.001ng/ml). Patients with cTnT elevations had more severe heart failure and worse outcome (death or hospitalisation). The high-sensitivity cTnT assay confirmed that troponin retains a significant predictive value even at concentrations lower than the detection limit of traditional assays (0.01 ng/ml) and has an incremental prognostic role even over BNP, which is the best current biomarker in heart failure.

While BNP is known to have elevated biological variability in patients with stable chronic heart failure, Latini et al.55 demonstrated a minimal difference in the plasma concentration of high-sensitivity cTnT over a four-month observation period. This might explain why a further cardiac troponin increase from baseline values during follow-up may better discriminate a real clinical worsening compared with BNP, which presents higher biological variability but lower specificity.51

Novel Markers of Cardiac Injury

Beside cardiac troponins, several novel biohumoral markers of cardiac damage have recently been studied,56 such as heart-type fatty-acid-binding protein (H-FABP), a cytoplasmic protein involved in lipid homeostasis, and myosin light chain 1 (MLC-1), a structural protein of the sarcomere. Concentrations of these biochemical markers increase not only in ischaemic cardiomyopathy but also in non-ischaemic heart failure patients, predicting adverse outcome.57,58 In particular, while cardiac troponin is a marker of myofibril damage, H-FABP is a cytosolic protein that is released immediately after sarcolemmal damage and cleared from the circulation in a few hours.

Conclusions and Perspectives

While BNP is currently the best biohumoral marker of myocardial overload, cardiac troponins are the most sensitive and specific markers of cardiac injury. At present, troponins represent a marker of staging and prognosis in DCM, in addition to BNP levels. Highly sensitive assays for cTnT make it possible to measure concentrations 10-fold lower than the lower limit of traditional assays, allowing an even more accurate biohumoral assessment of ischaemic and non-ischaemic heart failure.55 Unfortunately, the high sensitivity of cardiac troponins for myocyte injury is counterbalanced by their lack of specificity for the cause of the injury, limiting their role in the aetiological diagnosis of cardiac diseases.

In the near future, cardiac troponins may also acquire a role in the therapeutic management of non-ischaemic cardiomyopathies: tailoring treatment options and assessing treatment response. Moreover, the interest in surrogate end-points has recently increased since their use may allow successful completion of controlled clinical trials with smaller patient populations within shorter observation periods.

Troponins, alone or in combination with other cardiac biochemical markers, may represent surrogate end-points suitable for the design of such trials.56 Optimal treatment might seek to normalise cardiac troponin levels in patients with increased baseline values; future studies will be necessary to determine whether normalisation is associated with better compensation of heart failure and/or a better prognosis. Troponin levels may also act as a marker of ventricular function in the donor heart, guiding heart selection before transplantation. The process of brain death leads to intensive sympathetic nervous system activity followed by vasoparesis, causing at least transient myocardial ischaemia and injury, further exacerbated by changes in endocrine homeostasis, metabolism, and a pro-inflammatory state. For this reason, troponin appears to be almost always elevated in donor hearts, yet its prognostic relevance has not been completely investigated. Some studies have reported that higher troponin levels are associated with an increased need for inotropes and early graft failure in the recipient, but a discriminatory cut-off of troponin levels suggesting that an individual donor heart should not be used remains undefined.59

Besides cardiac troponins, several other novel biohumoral markers of myocyte injury have recently been studied.56 Their different half-lives, molecular sizes, and intracellular distribution may provide detailed information about the process of myocyte injury by monitoring the markers in combination. Combinations of markers of myocyte injury and markers of interstitial matrix collagen turnover may also add new information about the process of cardiac remodelling in patients with chronic heart failure; this is a topic that deserves further research.

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