SPECIAL ARTICLE
Congenital cardsiology: recent advances s
emphasise the need for collaboration
B.J.M. Mulder
The population of adult patients with congenital heart disease is steadily growing, due to the deveopmnats in ardiac surgey and thaerby decreased mortality. However, morbidity in these patients is substantial. Patients with repaired lesions often need ations later in life. Most congenital heart defects, operated or not, have the potential to lead to dlinical heart fiilure. Arrhytbmias affect up to 50% of patients th congenital heart disease. The prevaience ofpulmonary hypertension due to a leftto-right shunt among patients with a congenital heart defect is estimated at 4 to 10%. Advances in diagnostics, interventional and surgical therapy will result in new populations of adult survivors with even more complex disease. Collaboration of cardiologists with expertise in different areas of modern cardiology, such as electrophysiology, imagng and percutaneous interventions, is necessary for optimal care and management of these patients. (Neth HeartJ2006;14:339-42.)
Keywords: congenital cardiology, advances, diagnostics, surgery, intervention, genetics ongenital heart defects occur in approximately W eight of 1000 newborns. The improvements in diagnostic, interventional, and critical care skills have resulted in survival of approximately 90% of these children to adulthood. In 2006, it is estimated that there are more than 25,000 adults with congenital heart disease in the Netherlands. Around 11,000 adults have simple congenital heart disease, 10,000 adults have conditions of moderate complexity and 4000 have conditions of great complexity.' The number of BJ.M. Muldr Department of CardioloV, Academic Medical Centre, Amsterdam, the Netherlands Correspondence to: B.J.M. Mulder Academic Medical Centre, Department of Cardiology, P0 Box 22660, 1100 DD Amsterdam, the Netherlands E-mail: [email protected]
Netherlands Heart Journal, Volume 14, Number 10, October 2006
adults now probably exceeds the number ofchildren and is still growing at a rate of5% per year. The growth rate predicts that the total number of patients with congenital heart disease in the Netherlands is likely to have reached 100,000 within the next few decades. As the past has shown, continuing breakthroughs will result in new populations of adult survivors with ever more complex disease. Insufficient knowledge is available on the long-term outcome ofthe various heart defects. To facilitate research on long-term outcome, the national CONCOR (CONgenital CORvitia) registry was instigated in the Netherlands several years ago. The aim of this registry is to include all patients with a congenital heart defect, also those who are lost to appropriate medical follow-up. Many of these individuals may not realise that they should receive regular care, for early diagnosis and timely treatment oflate cardiovascular complications. The heterogeneity ofthe congenital lesions hampers large population studies and management of congenital heart disease has mostly evolved from trial and error over the past 60 years. On the other hand, the heterogeneity ofthe lesions provides important models for the understanding of basic embryology, genetics, and physiology with clear extrapolations to acquired cardiac and noncardiac pathology. To advance research on the underlying genetic mechanisms of congenital heart defects, a national DNA bank has been connected to the CONCOR registry.2
Genetics Congenital heart disease is thought to be multifactorial in origin. Significant and rapidly advancing discoveries in genetics and cardiovascular development are deciphering the molecular causes of congenital heart disease. Specific genetic malformations may affect outcome, for example the finding that mutations in the transcription factor NkX2.5 are not only associated with structural cardiac malformations, such as atrial septal defects, but may also predispose individuals to arrhythmias. It is reasonable to speculate that individuals with congenital heart disease and this mutation may experience more morbidity than unaffected individuals. 339
Congenital cardiology: recent advances emphasise the need for collaboration
Further understanding of molecular cascades that are active during cardiac formation is proving useful for the identification and manipulation ofembryonic and adult cardiac stem cells thatoffer dramatic opportunities for the treatment of adult and congenital disease. Recent studies in mice with Marfan syndrome have established the critical contribution of flbrillin-l deficiency to disease progression through altered cellmatrix interactions and dysregulated TGF- signalling.3 This new model of pathogenesis in Marfan syndrome has important practical consequences and identifies TGF-, as a potential target to counteract aneurysm progression in Marfan syndrome using for example angiotensin II receptor blockers, such as losartan, which both lower blood pressure and lead to a clinically relevant attenuation of TGF-, signalling.
Diagnstics
Doppler echocardiography plays an essential role for diagnosis and imaging of the structural defects and haemodynamic consequences in congenital heart disease. Advances in diagnostic imaging of congenital heart defects include the development of threedimensional (3D) echocardiography, tissue Doppler echocardiography (TDI) and intracardiac echocardiography (ICE), which improve the insight in anatomic and haemodynamic abnormalities in congenital heart disease. With the use of 3D echocardiography techniques surgery or intervention can better be planned, TDI has become a complementary technique to investigate systolic and diastolic ventricular function. The use of ICE for assessment of and monitoring device closure of atrial septal defects has recently started.4 Cardiovascular magnetic resonance (CMR) imaging allows for better visualisation of extracardiac structures. MR angiography (MRA) involves the use of an intravenous contrast agent, gadolinium, to evaluate vascular anatomy (figure 1). Three-dimensional images are acquired which show excellent spatial resolution. Cine MRI allows for accurate quantitative assessment ofleft and right ventricular volume. This is of importance because many congenital heart defects have right ventricular abnormalities and echocardiography is limited in accurately quantifying right ventricular volume or function. Pulmonary hypertension The prevalence of pulmonary arterial hypertension (PAH) due to a left-to-right shunt among patients with a congenital heart defect is estimated at between 4 and 10%. Patients with the Eisenmenger syndrome represent the extreme end ofthe spectrum and account for 1% ofthe total population in the national CONCOR registry (figure 2).5 Recently, several medical treatment modalities have become available for these patients. Intravenous prostacyclin (Flolan) has been shown to reduce the pulmonary vascular resistance by 50%. The favourable effect ofthe oral endothelin receptor blocker 340
Figure 1. Magnetic resonance angiography showing normal extracardiac structures.
bosentan has been shown in the BREATH-V study. Sildenafil is a selective phosphodiesterase inhibitor (Viagra) and pulmonary vasodilator, but no outcome data for patients with congenital heart defects are available yet. Arrhythmias Arrhythmias affect up to 50% of patients with congenital heart disease. The availability of internal cardioverter-defibrillator (ICD) has changed the outlook for patients with life-threatening arrhythmias. The develop-
Figure 2. Echocardiographic image ofa patientwithEisenmenger syndrome due to a large ventricular septal defrct (arrow). LV=lkft ventricle, RV=right ventricle, AO-Aorta.
Netherlands Heart Journal, Volume 14, Number 10, October 2006
fiC
Congenital cardiology: recent advances emphasise the need for collaboration
has evolved as a viable alternative to surgery in a large number ofpatients (figure 4). Valved stents are a recent innovation for the treatment ofregurgitant pulmonary valves. Bonhoeffer reported his promising results with percutaneous implantation of a bovine jugular vein valve-fitted vascular stent, with currently still limitations for its use in size and shape of the right ventricular outflow tract.6 First preliminary results of aortic valve implantation have been reported and are promising,7 although current application ofthis procedure should be limited to patients who are poor candidates for surgical valve replacement. Recent advances in the transcatheter modes oftherapy have added a new dimension to the management of patients with congenital heart disease. They should now be added to the armamentarium available in centres for congenital cardiology.
Figure 3. Tbree-dimensional ekectroanatomical mapping ofan atrialflutter. Courtesy Dr. TA Simmers.
ment of 3D electroanatomical mapping has led to a tremendous leap in the understanding ofarrhythmias and precise mapping for the purpose of ablation in patients with complex anatomy (figure 3). Also cardiac surgery in these patients is sometimes accompanied by a modified MAZE procedure. Percutaneous Interventions Surgery has been the traditional treatment option for palliation and correction of congenital heart defects. During the last decade a remarkable number of transcatheter methods have been developed and refined. They include balloon dilatation of pulmonary valve stenosis and native or recurrent aortic coarctation. Intravascular stents are used for obstructive lesions in branch pulmonary arteries, systemic and pulmonary veins, right ventricular outflow conduits and aortic coarctation. Device closure of atrial septal defects, patent foramen ovale, ventricular septal defects and patent ductus arteriosus is increasingly being used and
Figure 4. Amplatzerdevicefor closure ofatrialseptal deftets.
Cardiac surgery Surgical methods and concepts have been greatly refined such that surgery can be undertaken even in the sickest and most complex patient. The Norwood correction is performed in children with hypoplastic left heart syndrome, previously considered inoperable. Balloon atrial septostomy followed by venous switch procedures (Senning and Mustard) between three and 12 months of age has now been completely replaced by arterial switch (Jatene) procedure at one to two weeks of age. Aortic valve sparing operations can often be performed in patients with Marfan syndrome and aortic root aneurysm. Many patients with repaired lesions need reoperations in later life. Surgeons are therefore increasingly being confronted with adult patients who need a fourth, fifth or sixth reoperation. Heart failure Most congenital heart defects, operated or not, have the potential to lead to clinical heart failure. There is indirect evidence to suggest that dietary and medical therapy proven in acquired left ventricular dysfunction may be beneficial in heart failure associated with congenital heart disease. Anatomic residua, surgical sequelae, and valvular dysfunction may complicate medical therapy. Right heart failure is particularly common in a number ofcongenital heart defects (figure 5). Increased neurohormonal activation has been demonstrated in several small studies in a wide variety of patients with right ventricular pressure and/or volume overload.8 Very little is known about the use of 3-adrenergic blockade or ACE inhibitors in right ventricular failure. Large-scale, randomised placebo-controlled studies are hampered by anatomic variability and difficulty in defining abnormal ventricular function. It is hoped that the impressive reductions in morbidity and mortality achieved with ACE inhibitors and ,-blockers in
#C
Netherlands Heart Journal, Volume 14, Number 10, October 2006
341
Congenital cardiology: recent advances emphasise the need for collaboration
Figure 5. Magnetic resonance image ofA) a normal kft and ventrick and B) a dilated *r1ht _Iqhttventricle in apatientwith Tetralogy of Fallot. LV=left
ventrick, RV=right ventrick. L_
LV
RV
rnx-u
-_ s S S _ 1S_
heart failure will translate into similar benefit for adults with congenital heart disease. Conclusion Advances in the diagnosis and management of patients with congenital heart disease comprise a broad area of cardiology: interventions, imaging, electrophysiology, genetics, surgery and heart failure. Collaboration of the cardiologists involved is necessary for optimal care and management of adult patients with congenital cardiology. However, knowledge obtained from patients with acquired heart disease, which often concerns the left ventricle, cannot simply be extrapolated to patients with right ventricular abnormalities in congenital heart disease. -
RV-
2
3
4 5
6
7
References 1
Williams RG, Pearson GD, Barst RJ, Child JS, del Nido P, Gersony WM, et al. National Heart, Lung, and Blood Institute Working Group on research in adult congenital heart disease Report of the National Heart, Lung, and Blood Institute Working Group on research in adult congenital heart disease.JAm Coil Cardiol2006; 21:701-7.
342
8
Van der Velde ET, Vriend JW, Mannens MM, Uiterwaal CS, Brand R, Mulder BJ. CONCOR, an initiative towards a national registry and DNA-bank ofpatients with congenital heart disease in the Netherlands: rationale, design, and first results. EurfEpidemiol 2005;20:549-57. Dietz HC, Loeys B, Carta L, Ramirez F. Recent progress towards a molecular understanding of Marfan syndrome. AmJMed Genet CSemin Med Genet2005;15:4-9. Friedberg MK, Rosenthal DN. New developments in echocardiographic methods to assess right ventricular function in congenital heart disease. Curr Opin Cardiol 2005;20:84-8. Duffels MGJ, Engelfried PM, Berger RMF, Loon RLE van, Hoendermis E, Vriend JWJ, et al. Pulmonary arterial hypertension in congenital heart disease: an epidemiologic perspective from a Dutch registry. IntJCardiol [in press 2006]. Khambadkone S, Coats L, Taylor A, Boudjemline Y, Derrick G, Tsang V, et al. Percutaneous pulmonary valve implantation in humans: results in 59 consecutive patients. Circulation 2005;23: 1189-97. Webb JG, Chandavimol M, Thompson CR, Ricci DR, Carere RG, Munt BI, et al. Percutaneous aortic valve implantation retrograde from the femoral artery.Circulation 2006;113:842-50. Vonder Muhil I, Liu P, Webb G. Applying standard therapies to new targets: the use of ACE inhibitors and B-blockers for heart failure in adults with congenital heart disease. IntJ Cardiol 2004; 97(Suppl 1):25-33.
Netherlands Heart Journal, Volume 14, Number 10, October 2006
l
Congenital cardsiology: recent advances s
emphasise the need for collaboration
B.J.M. Mulder
The population of adult patients with congenital heart disease is steadily growing, due to the deveopmnats in ardiac surgey and thaerby decreased mortality. However, morbidity in these patients is substantial. Patients with repaired lesions often need ations later in life. Most congenital heart defects, operated or not, have the potential to lead to dlinical heart fiilure. Arrhytbmias affect up to 50% of patients th congenital heart disease. The prevaience ofpulmonary hypertension due to a leftto-right shunt among patients with a congenital heart defect is estimated at 4 to 10%. Advances in diagnostics, interventional and surgical therapy will result in new populations of adult survivors with even more complex disease. Collaboration of cardiologists with expertise in different areas of modern cardiology, such as electrophysiology, imagng and percutaneous interventions, is necessary for optimal care and management of these patients. (Neth HeartJ2006;14:339-42.)
Keywords: congenital cardiology, advances, diagnostics, surgery, intervention, genetics ongenital heart defects occur in approximately W eight of 1000 newborns. The improvements in diagnostic, interventional, and critical care skills have resulted in survival of approximately 90% of these children to adulthood. In 2006, it is estimated that there are more than 25,000 adults with congenital heart disease in the Netherlands. Around 11,000 adults have simple congenital heart disease, 10,000 adults have conditions of moderate complexity and 4000 have conditions of great complexity.' The number of BJ.M. Muldr Department of CardioloV, Academic Medical Centre, Amsterdam, the Netherlands Correspondence to: B.J.M. Mulder Academic Medical Centre, Department of Cardiology, P0 Box 22660, 1100 DD Amsterdam, the Netherlands E-mail: [email protected]
Netherlands Heart Journal, Volume 14, Number 10, October 2006
adults now probably exceeds the number ofchildren and is still growing at a rate of5% per year. The growth rate predicts that the total number of patients with congenital heart disease in the Netherlands is likely to have reached 100,000 within the next few decades. As the past has shown, continuing breakthroughs will result in new populations of adult survivors with ever more complex disease. Insufficient knowledge is available on the long-term outcome ofthe various heart defects. To facilitate research on long-term outcome, the national CONCOR (CONgenital CORvitia) registry was instigated in the Netherlands several years ago. The aim of this registry is to include all patients with a congenital heart defect, also those who are lost to appropriate medical follow-up. Many of these individuals may not realise that they should receive regular care, for early diagnosis and timely treatment oflate cardiovascular complications. The heterogeneity ofthe congenital lesions hampers large population studies and management of congenital heart disease has mostly evolved from trial and error over the past 60 years. On the other hand, the heterogeneity ofthe lesions provides important models for the understanding of basic embryology, genetics, and physiology with clear extrapolations to acquired cardiac and noncardiac pathology. To advance research on the underlying genetic mechanisms of congenital heart defects, a national DNA bank has been connected to the CONCOR registry.2
Genetics Congenital heart disease is thought to be multifactorial in origin. Significant and rapidly advancing discoveries in genetics and cardiovascular development are deciphering the molecular causes of congenital heart disease. Specific genetic malformations may affect outcome, for example the finding that mutations in the transcription factor NkX2.5 are not only associated with structural cardiac malformations, such as atrial septal defects, but may also predispose individuals to arrhythmias. It is reasonable to speculate that individuals with congenital heart disease and this mutation may experience more morbidity than unaffected individuals. 339
Congenital cardiology: recent advances emphasise the need for collaboration
Further understanding of molecular cascades that are active during cardiac formation is proving useful for the identification and manipulation ofembryonic and adult cardiac stem cells thatoffer dramatic opportunities for the treatment of adult and congenital disease. Recent studies in mice with Marfan syndrome have established the critical contribution of flbrillin-l deficiency to disease progression through altered cellmatrix interactions and dysregulated TGF- signalling.3 This new model of pathogenesis in Marfan syndrome has important practical consequences and identifies TGF-, as a potential target to counteract aneurysm progression in Marfan syndrome using for example angiotensin II receptor blockers, such as losartan, which both lower blood pressure and lead to a clinically relevant attenuation of TGF-, signalling.
Diagnstics
Doppler echocardiography plays an essential role for diagnosis and imaging of the structural defects and haemodynamic consequences in congenital heart disease. Advances in diagnostic imaging of congenital heart defects include the development of threedimensional (3D) echocardiography, tissue Doppler echocardiography (TDI) and intracardiac echocardiography (ICE), which improve the insight in anatomic and haemodynamic abnormalities in congenital heart disease. With the use of 3D echocardiography techniques surgery or intervention can better be planned, TDI has become a complementary technique to investigate systolic and diastolic ventricular function. The use of ICE for assessment of and monitoring device closure of atrial septal defects has recently started.4 Cardiovascular magnetic resonance (CMR) imaging allows for better visualisation of extracardiac structures. MR angiography (MRA) involves the use of an intravenous contrast agent, gadolinium, to evaluate vascular anatomy (figure 1). Three-dimensional images are acquired which show excellent spatial resolution. Cine MRI allows for accurate quantitative assessment ofleft and right ventricular volume. This is of importance because many congenital heart defects have right ventricular abnormalities and echocardiography is limited in accurately quantifying right ventricular volume or function. Pulmonary hypertension The prevalence of pulmonary arterial hypertension (PAH) due to a left-to-right shunt among patients with a congenital heart defect is estimated at between 4 and 10%. Patients with the Eisenmenger syndrome represent the extreme end ofthe spectrum and account for 1% ofthe total population in the national CONCOR registry (figure 2).5 Recently, several medical treatment modalities have become available for these patients. Intravenous prostacyclin (Flolan) has been shown to reduce the pulmonary vascular resistance by 50%. The favourable effect ofthe oral endothelin receptor blocker 340
Figure 1. Magnetic resonance angiography showing normal extracardiac structures.
bosentan has been shown in the BREATH-V study. Sildenafil is a selective phosphodiesterase inhibitor (Viagra) and pulmonary vasodilator, but no outcome data for patients with congenital heart defects are available yet. Arrhythmias Arrhythmias affect up to 50% of patients with congenital heart disease. The availability of internal cardioverter-defibrillator (ICD) has changed the outlook for patients with life-threatening arrhythmias. The develop-
Figure 2. Echocardiographic image ofa patientwithEisenmenger syndrome due to a large ventricular septal defrct (arrow). LV=lkft ventricle, RV=right ventricle, AO-Aorta.
Netherlands Heart Journal, Volume 14, Number 10, October 2006
fiC
Congenital cardiology: recent advances emphasise the need for collaboration
has evolved as a viable alternative to surgery in a large number ofpatients (figure 4). Valved stents are a recent innovation for the treatment ofregurgitant pulmonary valves. Bonhoeffer reported his promising results with percutaneous implantation of a bovine jugular vein valve-fitted vascular stent, with currently still limitations for its use in size and shape of the right ventricular outflow tract.6 First preliminary results of aortic valve implantation have been reported and are promising,7 although current application ofthis procedure should be limited to patients who are poor candidates for surgical valve replacement. Recent advances in the transcatheter modes oftherapy have added a new dimension to the management of patients with congenital heart disease. They should now be added to the armamentarium available in centres for congenital cardiology.
Figure 3. Tbree-dimensional ekectroanatomical mapping ofan atrialflutter. Courtesy Dr. TA Simmers.
ment of 3D electroanatomical mapping has led to a tremendous leap in the understanding ofarrhythmias and precise mapping for the purpose of ablation in patients with complex anatomy (figure 3). Also cardiac surgery in these patients is sometimes accompanied by a modified MAZE procedure. Percutaneous Interventions Surgery has been the traditional treatment option for palliation and correction of congenital heart defects. During the last decade a remarkable number of transcatheter methods have been developed and refined. They include balloon dilatation of pulmonary valve stenosis and native or recurrent aortic coarctation. Intravascular stents are used for obstructive lesions in branch pulmonary arteries, systemic and pulmonary veins, right ventricular outflow conduits and aortic coarctation. Device closure of atrial septal defects, patent foramen ovale, ventricular septal defects and patent ductus arteriosus is increasingly being used and
Figure 4. Amplatzerdevicefor closure ofatrialseptal deftets.
Cardiac surgery Surgical methods and concepts have been greatly refined such that surgery can be undertaken even in the sickest and most complex patient. The Norwood correction is performed in children with hypoplastic left heart syndrome, previously considered inoperable. Balloon atrial septostomy followed by venous switch procedures (Senning and Mustard) between three and 12 months of age has now been completely replaced by arterial switch (Jatene) procedure at one to two weeks of age. Aortic valve sparing operations can often be performed in patients with Marfan syndrome and aortic root aneurysm. Many patients with repaired lesions need reoperations in later life. Surgeons are therefore increasingly being confronted with adult patients who need a fourth, fifth or sixth reoperation. Heart failure Most congenital heart defects, operated or not, have the potential to lead to clinical heart failure. There is indirect evidence to suggest that dietary and medical therapy proven in acquired left ventricular dysfunction may be beneficial in heart failure associated with congenital heart disease. Anatomic residua, surgical sequelae, and valvular dysfunction may complicate medical therapy. Right heart failure is particularly common in a number ofcongenital heart defects (figure 5). Increased neurohormonal activation has been demonstrated in several small studies in a wide variety of patients with right ventricular pressure and/or volume overload.8 Very little is known about the use of 3-adrenergic blockade or ACE inhibitors in right ventricular failure. Large-scale, randomised placebo-controlled studies are hampered by anatomic variability and difficulty in defining abnormal ventricular function. It is hoped that the impressive reductions in morbidity and mortality achieved with ACE inhibitors and ,-blockers in
#C
Netherlands Heart Journal, Volume 14, Number 10, October 2006
341
Congenital cardiology: recent advances emphasise the need for collaboration
Figure 5. Magnetic resonance image ofA) a normal kft and ventrick and B) a dilated *r1ht _Iqhttventricle in apatientwith Tetralogy of Fallot. LV=left
ventrick, RV=right ventrick. L_
LV
RV
rnx-u
-_ s S S _ 1S_
heart failure will translate into similar benefit for adults with congenital heart disease. Conclusion Advances in the diagnosis and management of patients with congenital heart disease comprise a broad area of cardiology: interventions, imaging, electrophysiology, genetics, surgery and heart failure. Collaboration of the cardiologists involved is necessary for optimal care and management of adult patients with congenital cardiology. However, knowledge obtained from patients with acquired heart disease, which often concerns the left ventricle, cannot simply be extrapolated to patients with right ventricular abnormalities in congenital heart disease. -
RV-
2
3
4 5
6
7
References 1
Williams RG, Pearson GD, Barst RJ, Child JS, del Nido P, Gersony WM, et al. National Heart, Lung, and Blood Institute Working Group on research in adult congenital heart disease Report of the National Heart, Lung, and Blood Institute Working Group on research in adult congenital heart disease.JAm Coil Cardiol2006; 21:701-7.
342
8
Van der Velde ET, Vriend JW, Mannens MM, Uiterwaal CS, Brand R, Mulder BJ. CONCOR, an initiative towards a national registry and DNA-bank ofpatients with congenital heart disease in the Netherlands: rationale, design, and first results. EurfEpidemiol 2005;20:549-57. Dietz HC, Loeys B, Carta L, Ramirez F. Recent progress towards a molecular understanding of Marfan syndrome. AmJMed Genet CSemin Med Genet2005;15:4-9. Friedberg MK, Rosenthal DN. New developments in echocardiographic methods to assess right ventricular function in congenital heart disease. Curr Opin Cardiol 2005;20:84-8. Duffels MGJ, Engelfried PM, Berger RMF, Loon RLE van, Hoendermis E, Vriend JWJ, et al. Pulmonary arterial hypertension in congenital heart disease: an epidemiologic perspective from a Dutch registry. IntJCardiol [in press 2006]. Khambadkone S, Coats L, Taylor A, Boudjemline Y, Derrick G, Tsang V, et al. Percutaneous pulmonary valve implantation in humans: results in 59 consecutive patients. Circulation 2005;23: 1189-97. Webb JG, Chandavimol M, Thompson CR, Ricci DR, Carere RG, Munt BI, et al. Percutaneous aortic valve implantation retrograde from the femoral artery.Circulation 2006;113:842-50. Vonder Muhil I, Liu P, Webb G. Applying standard therapies to new targets: the use of ACE inhibitors and B-blockers for heart failure in adults with congenital heart disease. IntJ Cardiol 2004; 97(Suppl 1):25-33.
Netherlands Heart Journal, Volume 14, Number 10, October 2006
l
