Number 43, 2009
Biomarkers: past, present and future

Troponin compared with late enhancement in the assessment of myocardial injury

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Evangelos Giannitsis, Hugo A. Katus
Medizinische Universitätsklinik Heidelberg, Department of Cardiology, Heidelberg, Germany
Correspondence: Prof. Dr Evangelos Giannitsis, Medizinische Universitätsklinik Heidelberg, Abteilung für Innere Medizin III, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
Tel: +49 6221 56 8670; e-mail: evangelos_giannitsis@med.uni-heidelberg.de

Introduction
Prognosis after acute myocardial infarction is strongly determined by the extent of myocardial injury [1]. Assessment of left ventricular function after myocardial infarction is helpful for risk stratification and selection of patients requiring an implantable cardioverter defibrillator for prevention of sudden cardiac death [2], and the presence and extent of “late hyperenhancement” on contrast-enhanced cardiac magnetic resonance imaging (CE-MRI) has been shown to give information on the ability of the myocardium to resume contractility after revascularization procedures [3,4].
Echocardiography has emerged as the most convenient method for the quantification of left ventricular function, but this technique does not allow direct quantification of infarct size, and gives only limited information on the presence of viable myocardium and the potential for functional recovery after revascularization procedures. Currently, several imaging techniques, including thallium sestamibi and positron emission tomography, are used for quantification of infarct size [5]. Among the novel techniques, CE-MRI is noninvasive and does not involve exposure of the patient to radiation or potentially toxic contrast material. It has been shown to provide a good approximation of histological infarct size as assessed by triphenyltetrazolium chloride staining [6]. This technique is therefore preferred by some, because it allows noninvasive assessment of myocardial function and viability in vivo. It has a high spatial resolution, and is superior to single-photon emission computed tomography (SPECT) for the identification of subendocardial myocardial infarction [6,7]. Furthermore, CE-MRI is highly sensitive and permits quantification of small areas of myocardial injury attributable to native coronary artery disease or percutaneous coronary interventions, or both [8,9]. However, the use of cardiac MRI for quantification of infarct size is limited by availability and high cost. A convenient alternative, therefore, is to estimate infarct size from concentrations or activities of cardiac proteins in peripheral blood – as has been practiced for some years [5]. Today, cardiac troponins are established as the preferred biochemical markers for the diagnosis of myocardial infarction [10]. Moreover, there is increasing evidence that measurement of cardiac troponins may also allow estimation of infarct size and detection of the presence of microvascular obstruction.

Cardiac troponin and MRI infarct size
The cardiac troponins C, T, and I (cTnC, cTnT, and cTnI) are structural proteins of the myofilament that are exclusively expressed in cardiomyocytes. Upon irreversible cardiac injury, serum concentrations of cTnT show a biphasic curve, with an early peak within 24 h, resulting from the release of a small cytoplasmic pool, and a “plateau phase” 72–96 h after the onset of symptoms, resulting from continuous proteolytic degradation of the contractile apparatus [11,12].
Animal and human studies using thallium SPECT and MRI have demonstrated an excellent correlation between infarct size and cTn concentrations [13–17]. Using cardiac MRI, the pattern of late hyperenhancement is distinctive for myocardial infarction, with a compact area of subendocardial late hyperenhancement visible after the administration of gadolinium [18]. In patients with myocardial infarction, this area typically starts from the endocardial border of the myocardium, with a variable extent towards the epicardial border (Figure 1). The areas of late hyperenhancement correspond to the territory of the infarct-related coronary artery; the extent of late hyperenhancement is usually given as percent transmurality and is reported either semiquantitatively, or quantitatively as absolute or relative infarct size. The transmurality of hyperenhancement has been shown to correlate with the ability of myocardial contractility to recover after revascularization [3,4]. In contrast, several other nonischemic patterns of late hyperenhancement have been reported in patients with myocarditis, cardiomyopathies, cardiac amyloidosis, and other systemic diseases with cardiac involvement [18].

Cardiac troponin for prediction of the presence and magnitude of microvascular obstruction
Microvascular obstruction (MVO) is believed to be related to peripheral embolization of platelet microaggregates, intimal edema, vasoconstriction, or leukocyte sticking [22,23]. The findings of experimental and clinical studies clearly demonstrated that, irrespective of cause, MVO is associated with a greater degree of myocardial damage, more severely depressed left ventricular function, and a higher mortality [24–27]. Therefore, identification of patients with MVO would be useful for risk stratification at minimum, and might be helpful also in eventually elucidating both its pathophysiology, and possible therapeutic approaches.
Sophisticated techniques such as contrast echocardiography, delayed radionuclide imaging, and CE-MRI have been shown to be capable of identifying this lack of small-vessel perfusion [28–31]. Data have also confirmed that the presence and maximal extent of MVO are best evaluated by early post-contrast MRI [32]. With CE-MRI, zones of hypoenhancement surrounded by areas of hyperenhancement are believed to represent areas of microvascular obstruction in patients after acute myocardial infarction (Figure 2). These areas correspond well to anatomically defined no-reflow zones determined by histological thioflavin S staining [33]. Several studies have clearly demonstrated that patients with MVO have suffered larger infarcts (as determined by CE-MRI, maximal creatine kinase, and cTnI) than those without MVO [24,34]. It is noteworthy that the extent of MVO also correlated positively (r = 0.754, P < 0.0001) with infarct size [24]. In agreement with this, Tarantini et al [30] reported a progressive increase in peak cTnI concentrations, with the lowest values in those patients without transmural necrosis or severe MVO, intermediate values in those with transmural necrosis without MVO, and highest values in patients with transmural necrosis and MVO. Our own (as yet unpublished) findings suggest that cTnT values between 24 and 96 h after AMI are significantly greater in the presence of MVO. The best single value for the prediction of MVO is a cTnT concentration greater than 2.52 μg/L at 24 h after the patient's admission to hospital, and the ability of cTnT to predict MVO persists after adjustment for potential confounders such as duration of ischemia and success of epicardial reperfusion.

Cardiac troponin and nonischemic patterns of late enhancement

Myocarditis
Several cardiac MRI studies have demonstrated that hyperenhancement can be found in at least 85% of patients with acute myocarditis evolving within the first 2 weeks after the onset of symptoms [39]. The two relevant CE-MRI approaches described so far depend on the measurement of myocardial global (early) relative enhancement [39] or the visualization of late gadolinium enhancement. Early enhancement probably reflects myocardial hyperemia and increased capillary permeability as features of present inflammation, whereas late enhancement mostly indicates irreversible myocardial injury (Figure 3). More recently, T2-weighted imaging was found to be useful in a combined imaging approach [40]. The incidence of late hyperenhancement in myocarditis is a controversial issue. Reported incidences vary between 44% and 55% using antimyosin scintigraphy [41,42], and the 88% incidence reported by Mahrholdt et al [43]. The reason for such discrepancies may be related to differences in patient populations or study designs.

Cardiomyopathies

Dilated cardiomyopathy
Increased concentration of cTnT have been reported in dilated cardiomyopathy in the absence of coronary stenoses, and were related to an adverse prognosis [44]. There are substantial differences between concentrations of biomarkers in patients who present with acute decompensated chronic heart failure, depending on the underlying etiology of the heart failure syndrome [45]. Hyperenhancement in ischemic cardiomyopathy characteristically spreads from the subendocardium up to the epicardium, and is confined to the perfusion territories of the coronary arteries [46]. In contrast, several patterns of infarct-atypical, nonischemic late hyperenhancement have been reported in dilated cardiomyopathy, including a pattern in the midventricular rim of hyperenhancement that predominantly involves the septum and is found in 9–28% of patients (Figure 4). This hyperenhancement is presumed to reflect patchy areas of replacement fibrosis [47]. The presence of this particular pattern of hyperenhancement has been shown to be an independent predictor of all-cause mortality and the onset of potentially life-threatening ventricular arrhythmias.

Hypertrophic cardiomyopathy
Increased concentrations of cTn may be encountered in hypertrophic cardiomyopathy, may be prognostically important, and correlate with worsening of left ventricular function [48]. The exact reason for this is unclear, but it may include relative myocardial ischemia resulting from an imbalance between inappropriate hypertrophy of the myocardium and insufficient coronary arterial supply, and myocyte abnormalities determined by gene mutations causing myocyte injury [48].
Myocardial scarring is a common finding in patients with hypertrophic cardiomyopathy; it occurs mostly in hypertrophied regions and is usually patchy with several foci, predominantly affecting the midventricular wall, the junctions of the interventricular septum, and the right ventricular walls (Figure 5) [49–51]. The extent of hyperenhancement measured by CE-MRI correlates with conventional risk markers, and has also been related to the occurrence of ventricular arrhythmias and an increased number of clinical risk factors for sudden death [51–53]. However, the prognostic value of the presence and extent of hyperenhancement in patients with hypertrophic cardiomyopathy remains unknown, and the results of current studies are awaited [51].

Amyloidosis
Cardiac involvement is common in systemic amyloidosis. Usually, it is either diagnosed by a positive heart biopsy, or suspected from left ventricular hypertrophy (interventricular septal thickness 12 mm or more) in the absence of hypertension or other potential causes of the hypertrophy [54]. In conjunction with N-terminal pro brain natriuretic peptide, cardiac troponin T has been found to represent a powerful staging system for patients with immunoglobulin light-chain amyloidosis, with the objective of providing an easily available tool allowing comparison between outcomes of therapeutic interventions in the absence of randomized trials [55,56]. Cardiac amyloidosis typically shows an ill-defined global subendocardial pattern of hyperenhancement, matching the distribution of the amyloid deposition. This pattern of hyperenhancement is very characteristic for cardiac involvement of amyloidosis, and can therefore be used to discriminate this disease from other forms of restrictive or hypertrophic cardiomyopathies. Although most profound in the subendocardial layer of myocardium, amyloid deposition occurs throughout the entire myocardium, causing the entire myocardium to have a higher signal on CE-MRI images than normal myocardium. Therefore, “nulling” of myocardium can be extremely difficult when amyloidosis is present. The typical pattern of hyperenhancement, together with the increased T1 signal of myocardium, yields a diagnostic accuracy of 97% in patients with biopsy-proven amyloidosis (Figure 6).

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