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209

Ebsteins Anomaly in Adults: Doppler-Echocardiographic Evaluation

E. Oechslin, S. Buchholz, and R. Jenni
Echocardiography Laboratory, University Hospital, Zurich, Switzerland

A systematic approach and segmental analysis are required for comprehensive assessment including both morphologic and functional abnormalities associated with Ebsteins anomaly. The essence of the disease is an apical displacement of both the septal and the posterior tricuspid leaflets, exceeding 20 mm or 8 mm/m2 in adults. As a consequence, the right heart consists of three components including the true right atrium, the functional right ventricle (RV) and an intervening zone that is anatomically ventricular but functionally right atrial (atrialized RV). The thin wall of the atrialized RV may result in an aneurysm between the anatomic tricuspid annulus and the apically displaced posterior leaflet. The annular attachment of the anterior leaflet is normal, which may be dysplastic and adherent to the RV wall. Tricuspid regurgitation is usually moderate to severe. Size, shape and function of the functional RV must be described. The paradoxical motion of the interventricular septum causes alterations in left ventricular geometry and function. An interatrial communication is frequently present. Echocardiography is the method of choice to diagnose Ebsteins anomaly on its own or in association with other heart defects. Key words: Ebsteins anomaly Doppler-echocardiography evaluation

Introduction
In 1866, Wilhelm Ebstein described beautifully and exactly the pathological anatomical characteristics of a previously unrecognized congenital anomaly in a 19-year-old man who had suffered from dyspnea, palpitations and cyanosis for many years, and was found to have a markedly abnormal tricuspid valve apparatus at postmortem examination [1]. The anterior leaflet of the tricuspid valve arose from the appropriate position at the tricuspid annulus, the other leaflets, however, originated from the right ventricular myocardium below the valve annulus [1]. Since that first description, it has been recognized that Ebsteins anomaly comprises a wide spectrum of both clinical and pathologic features, with certain features being common and essential to the diagnosis, and that it affects not only the

tricuspid valve apparatus but also the structure of the right and left myocardial wall [2 9]. This very rare congenital malformation occurs in approximately one in 20,000 live births, and its prevalence accounts for 0.3 to 0.7 % of all cases of congenital heart disease [10,11]. However, this uncommon anomaly is the most frequent malformation of the tricuspid valve and represents 40 % of all congenital malformations of the right sided atrioventricular valve [12]. Angiography used to be the method of choice for the diagnosis of Ebsteins anomaly, but has been replaced by 2-dimensional echocardiography due to technical advances in recent years. A systematic approach is crucial to describe the various morphologic features and to identify associated lesions in patients with Ebsteins anomaly. A comprehensive echocardiographic evaluation includes not only anatomic and functional assessment of the tricuspid valve apparatus, but also the architecture and function of both ventricles, of the atrioventricular and semilunar valves and identification of associated lesions (Table 1). This overview focuses on Doppler-echocardiographic characteristics seen in adults with isolated Ebsteins anomaly, and does not apply to cases with complex congenital malformations associated with Ebstein-like malformation of the tricuspid valve, such as pulmonary atresia, tetralogy of Fallot or congenitally corrected transposition of the great arteries as one should add Ebsteinlike anomaly of the tricuspid valve in these cases to avoid any potential confusion with the index case. Some of the pathological features are less pronounced in adults than in children, as severe forms of Ebsteins anomaly have a poor prognosis and are less frequently seen in adults.

Anatomic Criteria
Normally, the basal attachment of the septal tricuspid valve leaflet is positioned slightly more apically than the corresponding mitral valve leaflet, which is a landmark for identifying the morphologic right ventricle (Fig. 1). In Ebsteins anomaly, however, excessive apical displacement of both the septal and the posterior tricuspid valve leaflets is the essence of this congenital malformation. The attachment of the septal leaflet is best visualized in the apical 4-chamber view and the posterior tricuspid leaflet in a modified parasternal long-axis view,

Thorac Cardiov Surg 2000; 48: 209 213  Georg Thieme Verlag Stuttgart New York ISSN 0171-6425

Received for Publication: March 27, 2000

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Table 1 Anatomic and functional assessment of patients with Ebsteins anomaly Anatomic assessment Tricuspid valve leaflets (septal, anterior, posterior) Apical displacement of septal/ posterior leaflet (>8 mm/m2 ) Tethering, elongation, absence of the leaflets Leaflet fenestrations Accessory leaflet tissue (muscular shelf) Atrialized right ventricle Right ventricular dilatation Functional assessment Tricuspid regurgitation (or stenosis?) Pressure gradient across the tricuspid valve Restricted motion/tricuspid valve stenosis Tricuspid regurgitation Right ventricular inflow tract obstruction Progression of chamber enlargement Right ventricular function Left ventricular function Mitral regurgitation (severity) Severity of shunt at the atrial level RVOT gradient

E. Oechslin, et al.
Fig.1 Apical 4chamber view of a normally structured heart. The basal attachment of the tricuspid valve exhibits slight apical displacement (arrowheads) compared to the mitral valve leaflet. LA: left atrium. LV: left ventricle. RA: right atrium. RV: right ventricle.

Posterior aneurysm/RVOT aneurysm Size and shape of the left ventricle Mitral valve prolapse Associated anomalies Patent foramen ovale/atrial septal defect RVOT obstruction
RVOT: right ventricular outflow tract

respectively. Using the apical 4-chamber view, apical displacement of the septal leaflet describes the distance between the tricuspid annulus and the distal point of septal leaflet attachment. There is a wide variability in this most diagnostically anatomical abnormality. Apical displacement must exceed 20 mm or 8 mm/m2 in adults (Fig. 2) [13,14]. As a consequence of this apical displacement, the right heart consists of three components including the true right atrium, the functional right ventricle and an intervening zone that is anatomically ventricular but functionally right atrial (atrialized right ventricle).

Tricuspid Annulus and Valve Abnormality

Ebsteins anomaly includes both tricuspid valve dysplasia and apical displacement of the septal and posterior leaflets of various degree (Table 1). This apical leaflet displacement results in location of some part of the hinge point of the tricuspid valve within the inlet portion of the right ventricle rather than at the atrioventricular junction [15]. The leaflets, however, are never displaced beyond the junction at the inlet and trabecular portion of the right ventricle. Tricuspid annular dilatation is an important feature and may be severe. The diameter of the tricuspid annulus must be measured, especially if surgery is considered [15]. The tricuspid annular diameter was significantly larger (p < 0.001) in patients with Ebsteins anomaly (median 30.5 mm/m2, range 20 63 mm/m2) than in normal controls (median 18 mm/m2, range 14 22 mm/m2), in patients with atrial septal defect (median 20.9 mm/m2, range 14 38 mm/m2) and tricuspid regurgitation (median 22.5 mm/m2, range 17 33 mm/m2) [13].

Fig. 2 Apical 4chamber view best visualizes apical displacement of the septal tricuspid valve leaflet delineated by the arrows and exceeding 40 mm in a 47 year old patient. Note leftward bulging of the atrialized interventricular septum (between the two arrows) and chordal attachment (tethering, arrowheads) of the elongated anterior leaflet.LA: left atrium. LV: left ventricle. RA: right atrium. RV: right ventricle.

Dysplasia Alterations in size, shape and structure of a valve described as dysplasia are an integral part in Ebsteins anomaly, involving all tricuspid valve leaflets and depending on the severity of this malformation. Valve thickening is the most frequent, but nonspecific feature. Poor development of the septal and posterior leaflets, however, is common, and their mobility is impaired due to short chordae tethering the leaflets to the underlying myocardium. The septal leaflet and its chordae may be absent in cases with severe form of Ebsteins anomaly [4]. Chordal attachments from the body or free edge of the tricuspid valve to the subjacent ventricular myocardium are a common

Ebsteins Anomaly in Adults: Doppler-Echocardiographic Evaluation

feature in Ebsteins anomaly. These attachments are called tethering, may be of a variable degree and affect most frequently the septal and anterior leaflets (Fig. 2). The tethering between the septal leaflet and the ventricular septum and between the anterior leaflet and the ventricular wall results in restricted leaflet motion. In addition, valve dysplasia and papillary muscle malformation may also contribute to restricted motion of the leaflets [4, 6,15]. Tethering can also lead to diastolic doming of the septal or anterior leaflet [13]. Anterior tricuspid leaflet Morphologic presentation of the anterior leaflet is wide and depends on the severity of the Ebsteins anomaly. Its basal attachment is normal at the atrioventricular level, but it may be, with very rare exception, apically displaced [13]. The large anterior leaflet is frequently redundant and sail-like. Echocardiography may identify fenestrations in the frequently thikkened and elongated anterior leaflet, which presents with multiple regurgitant jets visualized by color Doppler imaging [16]. Prolapse of the anterior leaflet is uncommon, but may be present [13]. An anomalous tongue of tissue or shelf may be present between the septal and anterior leaflets. This tongue is inserted distally at the junction of the inlet and apical trabecular components of the right ventricle and results in right ventricular inflow obstruction [3,15].

Thorac Cardiov Surg 2000; 48

Fig. 3 Modified parasternal long-axis view showing apical displacement of the posterior leaflet and aneurysmatic dilatation (arrow) of the atrialized portion of the right ventricle localized between the coronary sinus (CS) and the posterior tricuspid leaflet (T). RA: right atrium. RV: right ventricle.

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Ventricular Size, Shape and Function

Size, shape and function of both the functional right ventricle and the left ventricle are altered, and must be visualized and described in all echocardiographic views (Table 1). The functional right ventricle is smaller than normal because of the apical displacement of the septal and posterior leaflets. As the wall of the functional right ventricle is usually thinner and contains fewer muscle fibers and more fibrous tissue than normal, the right ventricular outflow tract, best assessed in the subcostal view, may be aneurysmal and not act normally [19, 22]. Thus, the aneurysmal right ventricular outflow tract is thought to be a morphologic feature of a dysplastic right ventricle [23]. Aneurysmal dilatation of the right ventricular outflow tract, defined as the right ventricular diameter being equal to or greater than twice the aortic root diameter in the parasternal short-axis view, was found in 20 % of patients with Ebsteins anomaly [13]. Right ventricular outflow tract obstruction can be a result of a redundant anterior tricuspid valve leaflet. The paradoxical motion of the interventricular septum functions as part of both the true and the atrialized right ventricle. It causes alterations in the left ventricular geometry and results in a decrease in left ventricular end-diastolic volume in severe forms of Ebsteins anomaly. The shape of the left ventricular chamber may be a crescent because of the bulging of the interventricular septum to the left. In addition, reduced left ventricular end-diastolic volume is caused by volume off-load due to the low output state. As a consequence of this altered geometry and paradoxical septal motion, left ventricular function is difficult to quantify, and the area-length method should not be used to calculate left ventricular systolic function. Frequently, it is semi-quantitatively described by using fractional shortening or visual

Atrialized Right Ventricle

Apical displacement of the septal and posterior leaflets results in atrialization of the right ventricle, which describes the area between the anatomic (true) and the functional tricuspid annulus. Thus, the landmarks of the atrialized right ventricle are the atrioventricular junction and the displaced hinge point of both the septal and posterior leaflets [15]. With increasingly severe apical leaflet displacement, the atrialized right ventricle increases and the functional right ventricle decreases in size. The severity of Ebsteins anomaly is described as the ratio between the area of the functional right ventricle and the combined area of both the right atrium and the atrialized right ventricle. The larger the atrialized right ventricle or the smaller the ratio (<35 %), the poorer the prognosis is [17,18]. Malformation in Ebsteins anomaly involves both the tricuspid valve and the subjacent myocardial wall as being thinner than normal [19]. This may frequently result in a dilatation or even in an aneurysm, which would be located between the anatomic tricuspid annulus and the apically displaced posterior leaflet, and is best visualized in the modified parasternal long-axis view (Fig. 3). Paradoxical motion of the thin-walled atrialized right ventricle during ventricular systole is a well known phenomenon and influences geometry and function of the left ventricle [20]. According to the severity of Ebsteins anomaly, four anatomic types were described by Carpentier in order to plan surgical management and to assess the surgical risk [21].

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assessment [17]. Left ventricular systolic function may be decreased at rest and during exercise [16, 20, 24]. Increase in left ventricular ejection fraction during exercise is the result of a reduced end-systolic volume rather than an increased enddiastolic volume. Regional wall motion abnormality can be observed and may be the result of an increased content of fibrous tissue in the left ventricular myocardium [2, 22, 24 26]. Generally, the left ventricle was found to be of normal size in absolute dimension and small relative to the dilated right heart [13]. In order to plan surgery, measurement of left ventricular dimensions is important, as its size may be congenitally small or undersized due to a shunt at the atrial level [15, 20]. As a consequence of the reduced left ventricular size and altered geometry caused by the abnormal position of the interventricular septum in more severe forms of Ebsteins anomaly, the chordae of the normal mitral valve apparatus appear to be too long in relation to the left ventricular long axis which may result in mitral valve prolapse [13, 25, 27 30].

E. Oechslin, et al.
malformation should be described as an Ebstein-like anomaly of the tricuspid valve, as this term seems to be more appropriate in patients with complex congenital heart defects associated with Ebsteins anomaly. Confusion is therefore avoided with the index case described by Ebstein [1].

Differential Diagnosis
Differentiation between Ebsteins anomaly and congenital tricuspid valve dysplasia in the normal right heart can be easily made by echocardiography. The latter is characterized by tricuspid leaflet, chordae and papillary muscle malformations and by the absence of any apical displacement of the septal and posterior leaflets [32]. Congenital cleft of the anterior tricuspid leaflet is another rare dysplasia [33]. Idiopathic dilatation of the right ventricle, arrhythmogenic right ventricular cardiomyopathy or Uhls disease are other anomalies which can be easily diagnosed by echocardiography and differentiated from Ebsteins anomaly. In contrast to Ebsteins anomaly, these two anomalies are characterized by an altered structure of the myocardium in the presence of a normally structured tricuspid valve.

Tricuspid Valve Function

Tricuspid regurgitation emerging from the apically displaced septal and posterior leaflets is caused by several mechanisms and is usually moderate to severe (Table 1). Eccentric coaptation of the tricuspid leaflets, exaggerated motion of the anterior leaflet, restricted leaflet mobility and/or leaflet fenestrations visualized by several jets on color Doppler imaging may lead to hemodynamically important tricuspid regurgitation which usually does not correlate with the anatomic abnormalities. The gradient across the regurgitant tricuspid valve estimated by continuous wave Doppler imaging is usually low. Tricuspid valve stenosis may occur due to accessory leaflet tissue, severely restricted leaflet motion and/or hypertrophy of the abnormal apical muscular shelf, or may be a result of an imperforate tricuspid valve [15, 31]. An anomalous tongue of tissue may be present between the septal and anterior leaflets [15]. This curtain may act as obstruction between the inlet chamber and the trabecular and outflow segments of the right heart. These features leading to a right ventricular inflow tract obstruction are very rare in adults and have been never seen in our laboratory.

Conclusions
Doppler echocardiography has become the contemporary method of choice for the diagnosis of Ebsteins anomaly. It allows the description of the wide spectrum of morphologic features as it delineates detailed intracardiac anatomy and provides excellent anatomic and functional assessment of the heart. Knowledge and experience in both morphologic and functional characteristics, however, are crucial for sophisticated Doppler echocardiographic evaluation of patients with Ebsteins anomaly, which should be performed by an experienced and skilled echocardiographer. A systematic approach and strictly performed segmental analysis are required for comprehensive assessment and accurate characterization of both morphologic and functional abnormalities. Although Ebsteins anomaly, characterized by both excessive apical displacement and dysplasia of the tricuspid valve, presents with a variability of anatomic abnormalities, certain features are common and are integral aspects of this anomaly: excessive elongation of the anterior leaflet, the presence of chordal attachment (tethering) to the adjacent myocardium, moderate to severe tricuspid regurgitation, aneurysmatic dilatation of the thin posterior wall or right ventricular outflow tract, the presence of right ventricular outflow tract obstruction or shunt at the atrial level.

Associated Anomalies
Ebsteins anomaly can be either isolated or associated with a variety of congenital cardiac lesions (Table 1). An interatrial communication is frequently present in Ebsteins anomaly, and is best visualized by color flow imaging or agitated saline contrast echocardiography [8, 9,19]. Ebsteins anomaly can be associated with other congenital heart defects, for example right ventricular inflow and outflow tract obstruction, restrictive ventricular septal defect or patent ductus arteriosus. Tetralogy of Fallot, pulmonary atresia with intact ventricular septum, divided right ventricle, atrioventricular septal defect, aortic coarctation, complete transposition of the great arteries or both atrioventricular and ventriculoarterial discordance left-sided Ebsteins anomaly in congenitally corrected transposition of the great arteries are less frequent [10]. In the latter congenital anomalies, however, the atrioventricular valve

References
1

Ebstein W. ber einen sehr seltenen Fall von Insuffizienz der Valvula tricuspidalis, bedingt durch eine angeborene hochgradige Missbildung derselben. Arch Anat Physiol Wissensch Med 1866: 238 254 2 Celermajer DS, Dodd SM, Greenwald SE, Wyse RK, Deanfield JE. Morbid anatomy in neonates with Ebsteins anomaly of the tricuspid valve: pathophysiologic and clinical implications. J Am Coll Cardiol 1992; 19: 1049 1053 3 Leung MP, Baker EJ, Anderson RH, Zuberbuhler JR. Cineangiographic spectrum of Ebsteins malformation: its relevance to clinical presentation and outcome. J Am Coll Cardiol 1988; 11: 154 161

Ebsteins Anomaly in Adults: Doppler-Echocardiographic Evaluation

Rusconi PG, Zuberbuhler JR, Anderson RH, Rigby ML. Morphologic-echocardiographic correlates of Ebsteins malformation. Eur Heart J 1991; 12: 784 790 5 Zuberbuhler JR, Becker AE, Anderson RH, Lenox CC. Ebsteins malformation and the embryological development of the tricuspid valve. With a note on the nature of clefts in the atrioventricular valves. Pediatr Cardiol 1984; 5: 289 295 6 Roberson DA, Silverman NH. Ebsteins anomaly: echocardiographic and clinical features in the fetus and neonate. J Am Coll Cardiol 1989; 14: 1300 1307 7 Zuberbuhler JR, Allwork SP, Anderson RH. The spectrum of Ebsteins anomaly of the tricuspid valve. J Thorac Cardiovasc Surg 1979; 77: 202 211 8 Anderson KR, Lie JT. Pathologic anatomy of Ebsteins anomaly of the heart revisited. Am J Cardiol 1978; 41: 739 745 9 Anderson KR, Zuberbuhler JR, Anderson RH, Becker AE, Lie JT. Morphologic spectrum of Ebsteins anomaly of the heart: a review. Mayo Clin Proc 1979; 54: 174 180 10 Freedom RM, Mawson JB, Yoo SJ, Benson LN. Ebsteins malformation of the tricuspid valve. In: Freedom RM, Mawson JB, Yoo SJ, Benson LN, eds. Congenital Heart Disease: Textbook of Angiocardiography, First ed. Armonk, NY: Futura Publishing Company, Inc. 1997: 349 366 11 Perloff JK. Ebsteins anomaly of the tricuspid valve. In: Perloff JK, ed. The clinical recognition of congenital heart disease. Philadelphia: W. B. Saunders Company 1994: 247 272 12 Hauck AJ, Freeman DP, Ackermann DM, Danielson GK, Edwards WD. Surgical pathology of the tricuspid valve: a study of 363 cases spanning 25 years. Mayo Clin Proc 1988; 63: 851 863 13 Shiina A, Seward JB, Edwards WD, Hagler DJ, Tajik AJ. Twodimensional echocardiographic spectrum of Ebsteins anomaly: detailed anatomic assessment. J Am Coll Cardiol 1984; 3: 356 370 14 Gussenhoven EJ, Stewart PA, Becker AE, Essed CE, Ligtvoet KM, De VV. Offsetting of the septal tricuspid leaflet in normal hearts and in hearts with Ebsteins anomaly. Anatomic and echographic correlation. Am J Cardiol 1984; 54: 172 176 15 Chauvaud SM, Mihaileanu SA, Gaer JAR, Carpentier AC. Surgical treatment of Ebsteins malformation the Hpital Broussais experience. Cardiol Young 1996; 6: 4 11 16 Seward JB. Ebsteins anomaly: ultrasound imaging and hemodynamic evaluation. Echocardiography 1993; 1: 641 17 Celermajer DS, Bull C, Till JA, et al. Ebsteins anomaly: presentation and outcome from fetus to adult. J Am Coll Cardiol 1994; 23: 170 176 18 Shiina A, Seward JB, Tajik AJ, Hagler DJ, Danielson GK. Twodimensional echocardiographic surgical correlation in Ebsteins anomaly: preoperative determination of patients requiring tricuspid valve plication vs replacement. Circulation 1983; 68: 534 544 19 Anderson KR, Lie JT. The right ventricular myocardium in Ebsteins anomaly: a morphometric histopathologic study. Mayo Clin Proc 1979; 54: 181 184 20 Benson LN, Child JS, Schwaiger M, Perloff JK, Schelbert HR. Left ventricular geometry and function in adults with Ebsteins anomaly of the tricuspid valve. Circulation 1987; 75: 353 359 21 Carpentier A, Chauvaud S, Mace L, et al. A new reconstructive operation for Ebsteins anomaly of the tricuspid valve. J Thorac Cardiovasc Surg 1988; 96: 92 101 22 Celermajer DS, Cullen S, Sullivan ID, Spiegelhalter DJ, Wyse RK, Deanfield JE. Outcome in neonates with Ebsteins anomaly. J Am Coll Cardiol 1992; 19: 1041 1046 23 Takayasu S, Obunai Y, Konno S. Clinical classification of Ebsteins anomaly. Am Heart J 1978; 95: 154 162
4 24

Thorac Cardiov Surg 2000; 48

213

Saxena A, Fong LV, Tristam M, Ackery DM, Keeton BR. Late noninvasive evaluation of cardiac performance in mildly symptomatic older patients with Ebsteins anomaly of tricuspid valve: role of radionuclide imaging. J Am Coll Cardiol 1991; 17: 182 186 25 Monibi AA, Neches WH, Lenox CC, Park SC, Mathews RA, Zuberbuhler JR. Left ventricular anomalies associated with Ebsteins malformation of the tricuspid valve. Circulation 1978; 57: 303 306 26 Saxena A, Fong LV, Tristam M, Ackery DM, Keeton BR. Left ventricular function in patients greater than 20 years of age with Ebsteins anomaly of the tricuspid valve. Am J Cardiol 1991; 67: 217 219 27 Cabin HS, Roberts WC. Ebsteins anomaly of the tricuspid valve and prolapse of the mitral valve. Am Heart J 1981; 101: 177 180 28 Castaneda ZW, Nath HP, Moller JH, Edwards JE. Left-sided anomalies in Ebsteins malformation of the tricuspid valve. Pediatr Cardiol 1982; 3: 181 185 29 Roberts WC, Glancy DL, Seningen RP, Maron BJ, Epstein SE. Prolapse of the mitral valve is described in two patients with the Ebsteins anomaly of the tricuspid. Am J Cardiol 1976; 38: 377 382 30 Sharma S, Rajani M, Mukhopadhyay S, Aggarwal S, Shrivastava S, Tandon R. Angiographic abnormalities of the morphologically left ventricle in the presence of Ebsteins malformation. Int J Cardiol 1989; 22: 109 113 31 Gerlis LM, Anderson RH. Cor triatriatum dexter with imperforate Ebsteins anomaly. Br Heart J 1976; 38: 108 111 32 Lang D, Oberhoffer R, Cook A, et al. Pathologic spectrum of malformations of the tricuspid valve in prenatal and neonatal life. J Am Coll Cardiol 1991; 17: 1161 1167 33 Eichhorn P, Ritter M, Suetsch G, von SL, Turina M, Jenni R. Congenital cleft of the anterior tricuspid leaflet with severe tricuspid regurgitation in adults. J Am Coll Cardiol 1992; 2: 1175 1179

Rolf Jenni, MD, MSEE

Echocardiography Laboratory University Hospital Raemistrasse 100 8091 Zrich Switzerland Tel. ++ 41 1 255 3447 Fax ++ 41 255 4401 E-mail: karjer@usz.unizh.ch