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Evaluation of Macitentan in Patients With Eisenmenger Syndrome:

Results From the Randomized, Controlled MAESTRO Study

GATZOULIS, Michael A, et al. & MAESTRO Study Investigators

Abstract

Eisenmenger syndrome describes congenital heart disease-associated severe pulmonary hypertension accompanied by right-to-left shunting. The multicenter, double-blind, randomized, placebo-controlled, 16-week, phase III MAESTRO study (Macitentan in Eisenmenger Syndrome to Restore Exercise Capacity) evaluated the efficacy and safety of the endothelin receptor antagonist macitentan in patients with Eisenmenger syndrome.

GATZOULIS, Michael A,

et al

. & MAESTRO Study Investigators. Evaluation of Macitentan in Patients With Eisenmenger Syndrome: Results From the Randomized, Controlled MAESTRO Study.

Circulation

, 2019, vol. 139, no. 1, p. 51-63

DOI : 10.1161/CIRCULATIONAHA.118.033575 PMID : 30586694

Available at:

http://archive-ouverte.unige.ch/unige:134639

Disclaimer: layout of this document may differ from the published version.

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SUPPLEMENTAL MATERIAL

This online supplement has been provided by the authors to give readers additional information about their work.

Supplement to: Gatzoulis M, Landzberg M, Beghetti M, et al. Evaluation of macitentan in

patients with Eisenmenger syndrome: Results from the randomized, controlled MAESTRO study

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SUPPLEMENTAL METHODS

Supplemental Methods I. List of investigators in the hemodynamic substudy

Austria – Medical University of Vienna and AKH Cardiology, Vienna: Prof. Irene Lang. Bulgaria – Multi-profile Hospital for Active treatment National Cardiology Hospital, Sofia: Associate Prof.

Borislav Georgiev. China – Fuwai Hospital, Beijing: Prof. Jian’guo He; Beijing Anzhen Hospital of the Capital University of Medical Sciences, Beijing: Prof. Hong Gu. Mexico – Instituto Nacional de Cardiologia (INC) Ignacio Chavez, Mexico City: Dr. Tomas Rene Pulido Zamudio, Dr. Nayeli Zayas; Centro de Estudios Clinicos de Querétaro S. C., Querétaro: Dr. Marco

Alcocer. Portugal – Hospital de Santa Marta, Centro Hospitalar de Lisboa Central, Lisbon: Ana María Figueiredo Agapito; Hospital da Universidade de Coimbra Serviço de Cardiologia,

Coimbra: Maria da Graça Calado de Oliveira Castro. Russian Federation – Almazov Federal North-West Medical Research Centre of Department of Health of Russian Federation, St.

Petersburg: Prof. Olga M. Moiseeva. Spain – Hospital Universitario Virgen Macarena Servicio de Cardiología, Seville: Pastora Gallego. USA – Ahmanson Adult Congenital Heart Disease Center, Los Angeles, California: Dr. Jamil Aboulhosn.

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Supplemental Methods II. List of Steering Committee members

Italy – Institute of Cardiology University of Bologna, Bologna: Nazzareno Galié. Netherlands – Center for Congenital Heart Diseases, University of Groningen, University Medical Center Groningen: Prof. Rolf Berger. Switzerland – Children’s Hospital University of Geneva, Geneva:

Maurice Beghetti. United Kingdom – Adult Congenital Heart Centre and Centre for Pulmonary Hypertension Royal Brompton Hospital: Michael Gatzoulis. USA – Boston Adult Congenital Heart (BACH) and Pulmonary Hypertension Service, Departments of Cardiology, Brigham and Women’s Hospital and Boston Children’s Hospital, Boston, Massachusetts: Michael Landzberg.

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Supplemental Methods III. List of Institutional Review Boards and Independent Ethics Committees

Austria – Ethikkommission der Medizinischen Universität Wien und des Allgemeinen

Krankenhauses der Stadt Wien, Vienna. Belgium – Faculteit Geneeskunde Commissie voor Medische Ethiek/Klinisch Onderzoek, Leuven. Bulgaria – Ethics Committee for Multi-centric trials, Sofia; Ethics Committee to Multi-profile Hospital for Active Treatment National Cardiology Hospital, EAD, Sofia; Ethics Committee to Multi-profile Hospital for Active Treatment Sveta Anna, Sofia, AD; LEC at Multiprofile Hospital for Active Treatment ‘Sveta Marina’ Ltd, Varna.

Canada – IRB – UBC-PHC (Providence Health Care) Office of Research Services, Vancouver;

IRB- Health Research Ethics Board University of Alberta, Edmonton; University of Alberta Health Research Ethics Board – PAH/PULM, Edmonton. Chile – Comité De Etica Cientifico del Servicio de Salud Metropolitano Oriente, Santiago de Chile. China – Ethics Committee of Cardiovascular Institute and Fuwai Hospital for Clinical Trials, Beijing; Ethics Committee of Shanghai Pulmonary Hospital, Shanghai; Ethics Committee of Guangdong General Hospital, Guangzhou; IEC of Beijing Anzhen Hospital of the Capital University of Medical Sciences, Beijing; EC of Wuhan Asia Heart Hospital, Wuhan; EC of The General Hospital of Shenyang Military Region, Liaoning. Czech Republic – Ethics Committee of General Faculty Hospital in Praze, Prague; Etická komise Nemocnice Na Homolce, Prague; Multicentrická etická komise FN Brno, Brno. France – CPP Ile de France VI, Paris; CPP Sud Méditeranée II, Marseille.

Germany – Ethik-Kommission der Ärztekammer Westfalen-Lippe und der Medizinischen Fakultät der Westfälischen Wilhelms-Universität Münster, Münster. Greece – National Ethics Committee, Cholargos. Hungary – Egészégügyi Tudomànyos Tanàcs Klinikai Farmakólogiai Etikai Bizottsàg (Medical Research Council Ethics Committee for Clinical Pharmacology), Budapest. Israel – Helsinki Committee Rabin Medical Center, Petach Tikvah; Helsinki Committee Carmel Medical Center, Haifa. Italy – Comitato Etico dell’ Azienda Ospedaliero-

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Universitaria Policlinico S. Orsola-Malpighi di Bologna Padiglione 3, Bologna; Comitato di Bioetica della Fondazione IRCCS Policlinico S. Matteo di Pavia, Pavia. Malaysia – Ethics Committee Institut Jantung Negara, Kuala Lumpur. Mexico – Comité de Ética del Instituto Nacional de Cardiologia (INC) Ignacio Chavez, Mexico City; Comité de Investigacion Clinica del Instituto de Corazon de Querétaro, Querétaro; Comité de Bioética en Investigacíon del Instituto de Corazón de Querétaro, Querétaro; Comité de Ética del Hospital General de Puebla “Dr.

Eduardo Vazquez Navarro”, Puebla; Comité de Ética en Investigaciόn del Hospital Infantil de Mexico “Dr. Federico Gómez”, Mexico City. Netherlands – Universitair Medisch Centrum Groningen Medisch Ethische Toetsingscommissie umcg.nl, Groningen. Philippines – Institutional Ethics Review Board, Philippine Heart Center, Manila. Poland – Komisja

Bioetyczna przy Okręgowej Izbie Lekarskiej w Krakowie, Kraków. Portugal – CEIC- Comissão de Ética para a Investigação Clinica, Lisbon. Romania – National Bioethics Committee for Medicines and Medical Devices, Bucharest. Russian Federation – Ethics Council of the Ministry of Health of Russia, Moscow; Ethics Committee of the Almazov Federal North-West Medical Research Centre of Department of Health of Russian Federation, St. Petersburg;

Biomedical Ethics Committee of Tomsk Research Institute of Cardiology, Tomsk; Local Ethics Committee of Federal State Budgetary Institution “Scientific Research Institute of Systemic Problems of Cardiovascular Diseases”, Kemerovo. Serbia – Kliničko Bolnički Centar Zemun, Etički Komitet, Belgrade; Institut za kardiovaskularne bolesti Dedinje, Etički odbor, Belgrade;

Institut za zdravstvenu zaštitu majke i deteta Srbije “Dr. Vukan Čupić”, Belgrade. South Africa – University of Stellenbosch Committee for Clinical Trials, Cape Town; University of the

Witwatersrand Human Research Ethics Committee, Johannesburg; University of the Free State Research Ethics Committee, Bloemfontein. Spain – Área de Investigación Clinica y Epas Subdirección General de Evaluación y Control Dirección General de Ordenación e Inspección, Madrid; Hospital Vall d’Hebrón, Fundacio per la Recerca, Barcelona; Comité Coordinador de

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Ética de la Investigación Biomédica de Andalucia, Seville; Departament de Salut- Generalitat de Catalunya Cap de secció de Control de la Recerca i la Farmacovigilància, Barcelona; Agencia Valenciana de Salud Dirección General de Farmacia y Productos Sanitarios, Valencia. Taiwan – Research Ethics Committee National Taiwan University Hospital, Taipei; The Institutional Review Board of Taichung Veterans General Hospital, Taichung; IRB Kaohsiung Veterans General Hospital, Kaohsiung. Turkey – Malatya İnönü Üniversitesi Klinik Araştırmalar Etik Kurulu, Malatya. United Kingdom – NRES Committee London- Fulham, Manchester. USA – IRB – Baylor College of Medicine, Houston, Texas; IRB – Cleveland Clinic, Cleveland, Ohio;

IRB- Children’s Hospital Boston, Boston, Massachusetts; IRB – Columbia University Medical Center, New York, New York; Office of Human Research Protection Program, Los Angeles, California; IRB – Western, Puyallup, Washington; IRB – Nationwide Children’s Hospital, Columbus, Ohio; IRB – Washington University School of Medicine – Human Research Protect.

Office, St. Louis, Missouri; Sunrise Health Institutional Review Board, Las Vegas, Nevada; IRB – University of Maryland School of Medicine - Human Research Protection Office, Baltimore, Maryland. Vietnam – Hanoi Medical University Review Board (HMURB) in Bio-Medical

Research, Hanoi; Local Ethics Committee in Bio-Medical Research of Children’s No. 1 Hospital, Ho Chi Minh; Local Ethics Committee in Bio-Medical Research of Tam Duc Cardiology Hospital, Ho Chi Minh.

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Supplemental Methods IV. Imputation rules

The following imputation rules, pre-specified in the statistical analysis plan, were applied.

6MWD

Missing 6MWD data at Week 16:

 For patients with missing data due to death, a distance of 0 m was imputed (one patient in the macitentan group).

 If the above did not apply, the predicted probability of missing data at Week 8, 12 and 16 was estimated. Imputation of the missing Week 16 value took into account the availability of the 6MWD values at prior visits and incorporated the estimated predicted probability of missing data (two patients both in the macitentan group - the imputed values were 466E-13 and 0.02386).

There were no patients with missing 6MWD data at Week 16 in the hemodynamic substudy.

WHO FC

Missing WHO FC data at Week 16:

 For patients with missing data due to death, heart or lung transplant or disease progression, who had no WHO FC data on or after the day of occurrence of the event and up to the end of study, WHO FC IV was imputed (one patient in the macitentan group).

 If the above did not apply, the last observation carried forward up to the end of study, including baseline, was imputed (one patient in the macitentan group).

PVRi

Missing PVRi data at Week 16:

 For patients with missing data due to death, heart or lung transplant or disease

progression who had no PVRi data on or after the day of occurrence of the event and up to the end of study, the worst value was imputed (no patients).

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 If the above did not apply, the baseline carried forward was imputed (two patients in the macitentan group and two patients in the placebo group).

Other exploratory endpoints

 Analyses for NT-proBNP, SpO2 and other cardiac hemodynamic parameters were performed based on observed data only, with no imputation for missing data.

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Supplemental Figures

Supplemental Figure I. Patient disposition in the hemodynamic substudy

Patients were considered to have completed the study if they completed the 30-day safety follow-up period and Week 16 assessments, regardless of premature study treatment discontinuation. All patients completed the hemodynamic substudy.

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Supplemental Figure II: Effect of macitentan on the primary endpoint by pre-specified subgroups

PDE-5i indicates phosphodiesterase-type 5 inhibitor; WHO, World Health Organization; and CL, confidence limit.

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Shown is the forest plot for the treatment effect (macitentan minus placebo) on the primary endpoint of change from baseline to Week 16 in 6-minute walk distance, according to pre-specified subgroups. The difference in exercise capacity between groups was consistent across the following prespecified subgroups: location of cardiac defect, WHO functional class, geographical region, PDE-5 inhibitors at baseline and Down syndrome status. The vertical solid line references the overall treatment effect adjusted for treatment and baseline 6MWD. 

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Supplemental Figure III: Post-hoc subgroup analysis of the effect of macitentan on the primary endpoint by gender

CL indicates confidence limit.

Shown is the forest plot for the treatment effect (macitentan minus placebo) on the primary endpoint of change from baseline to Week 16 in 6-minute walk distance, according to gender. The difference in exercise capacity between groups was consistent across the gender subcategories. The vertical solid line references the overall treatment effect adjusted for treatment and baseline 6MWD.

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Supplemental Tables

Supplemental Table I. Number of patients randomized in each study center Region

COUNTRY Site identifier

Macitentan n=114

n (%)

Placebo n=112

n (%)

Total n=226

n (%) Asia-Pacific 47 (41.2) 44 (39.3) 91 (40.3)

CHINA 36 (31.6) 34 (30.4) 70 (31.0)

1501 12 (10.5) 9 (8.0) 21 (9.3)

1502 3 (2.6) 5 (4.5) 8 (3.5)

1503 0 2 (1.8) 2 (0.9)

1505 6 (5.3) 2 (1.8) 8 (3.5)

1506 8 (7.0) 7 (6.3) 15 (6.6)

1507 7 (6.1) 9 (8.0) 16 (7.1)

MALAYSIA 3 (2.6) 0 3 (1.3)

2501 3 (2.6) 0 3 (1.3)

PHILIPPINES 2 (1.8) 0 2 (0.9)

4702 2 (1.8) 0 2 (0.9)

VIETNAM 6 (5.3) 10 (8.9) 16 (7.1)

4801 4 (3.5) 6 (5.4) 10 (4.4)

4802 0 1 (0.9) 1 (0.4)

4803 2 (1.8) 3 (2.7) 5 (2.2)

Eastern Europe 25 (21.9) 27 (24.1) 52 (23.0)

BULGARIA 2 (1.8) 4 (3.6) 6 (2.7)

1201 0 1 (0.9) 1 (0.4)

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1202 1 (0.9) 1 (0.9) 2 (0.9)

1203 1 (0.9) 2 (1.8) 3 (1.3)

POLAND 7 (6.1) 3 (2.7) 10 (4.4)

2702 2 (1.8) 0 2 (0.9)

2704 1 (0.9) 1 (0.9) 2 (0.9)

2707 4 (3.5) 2 (1.8) 6 (2.7)

ROMANIA 4 (3.5) 4 (3.6) 8 (3.5)

2903 2 (1.8) 4 (3.6) 6 (2.7)

2904 1 (0.9) 0 1 (0.4)

2905 1 (0.9) 0 1 (0.4)

RUSSIAN FEDERATION

9 (7.9) 10 (8.9) 19 (8.4)

4501 4 (3.5) 6 (5.4) 10 (4.4)

4503 3 (2.6) 2 (1.8) 5 (2.2)

4504 2 (1.8) 2 (1.8) 4 (1.8)

SERBIA 3 (2.6) 6 (5.4) 9 (4.0)

3002 1 (0.9) 3 (2.7) 4 (1.8)

3003 1 (0.9) 1 (0.9) 2 (0.9)

3004 1 (0.9) 2 (1.8) 3 (1.3)

Latin America 19 (16.7) 18 (16.1) 37 (16.4)

CHILE 4 (3.5) 3 (2.7) 7 (3.1)

1401 2 (1.8) 1 (0.9) 3 (1.3)

1407 2 (1.8) 2 (1.8) 4 (1.8)

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MEXICO 15 (13.2) 15 (13.4) 30 (13.3)

2601 11 (9.6) 8 (7.1) 19 (8.4)

2608 0 2 (1.8) 2 (0.9)

2610 4 (3.5) 5 (4.5) 9 (4.0)

North America 2 (1.8) 5 (4.5) 7 (3.1) UNITED STATES 2 (1.8) 5 (4.5) 7 (3.1)

3802 0 1 (0.9) 1 (0.4)

3808 0 1 (0.9) 1 (0.4)

3810 0 1 (0.9) 1 (0.4)

3815 0 1 (0.9) 1 (0.4)

3822 0 1 (0.9) 1 (0.4)

3825 1 (0.9) 0 1 (0.4)

3839 1 (0.9) 0 1 (0.4)

Western Europe-

Israel 21 (18.4) 18 (16.1) 39 (17.3)

AUSTRIA 2 (1.8) 1 (0.9) 3 (1.3)

1101 2 (1.8) 1 (0.9) 3 (1.3)

FRANCE 10 (8.8) 7 (6.3) 17 (7.5)

1901 2 (1.8) 0 2 (0.9)

1903 4 (3.5) 4 (3.6) 8 (3.5)

1904 2 (1.8) 2 (1.8) 4 (1.8)

1905 2 (1.8) 1 (0.9) 3 (1.3)

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GERMANY 2 (1.8) 1 (0.9) 3 (1.3)

2002 1 (0.9) 0 1 (0.4)

2005 0 1 (0.9) 1 (0.4)

2006 1 (0.9) 0 1 (0.4)

GREECE 3 (2.6) 0 3 (1.3)

5302 3 (2.6) 0 3 (1.3)

ISRAEL 0 1 (0.9) 1 (0.4)

2301 0 1 (0.9) 1 (0.4)

PORTUGAL 2 (1.8) 5 (4.5) 7 (3.1)

2801 2 (1.8) 3 (2.7) 5 (2.2)

2802 0 2 (1.8) 2 (0.9)

SPAIN 2 (1.8) 1 (0.9) 3 (1.3)

3504 1 (0.9) 0 1 (0.4)

3505 0 1 (0.9) 1 (0.4)

3508 1 (0.9) 0 1 (0.4)

TURKEY 0 1 (0.9) 1 (0.4)

3706 0 1 (0.9) 1 (0.4)

UNITED KINGDOM 0 1 (0.9) 1 (0.4)

3901 0 1 (0.9) 1 (0.4)

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Supplemental Table II. Patient characteristics at baseline for the hemodynamic substudy*

Macitentan n=20

Placebo n=19

All patients N=39

Female, n (%) 16 (80.0) 10 (52.6) 26 (66.7)

Age, years

Median (range) 37.0 (18.0, 58.0) 32.0 (18.0, 56.0) 35.0 (18.0, 58.0) Distribution, n (%)

18-55 18 (90.0) 18 (94.7) 36 (92.3)

≥56 2 (10.0) 1 (5.3) 3 (7.7)

Geographic region, n (%)

Asia-Pacific 7 (35.0) 6 (31.6) 13 (33.3)

Eastern Europe 1 (5.0) 2 (10.5) 3 (7.7)

Western Europe-Israel 3 (15.0) 2 (10.5) 5 (12.8)

Latin America 9 (45.0) 8 (42.1) 17 (43.6)

North America 0 1 (5.3) 1 (2.6)

Time from ES diagnosis, years, median (range)

6.81 (0.0, 31.7) 4.99 (0.0, 33.4) 6.53 (0.0, 33.4)

WHO functional class, n (%)†

II 14 (70.0) 12 (63.2) 26 (66.7)

III 6 (30.0) 7 (36.8) 13 (33.3)

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6-minute walk distance, meters 359.0±69.8 382.9±91.5 370.6±80.9

SpO2 at rest, % 83±6.8 85±5.3 84±6.1

PDE-5 inhibitors

n (%) 6 (30.0) 4 (21.1) 10 (25.6)

Time from initiation, months, median (range)

10.43 (1.1, 79.1) 3.12 (1.0, 8.2) 3.33 (1.0, 79.1)

Location of cardiac defect, n (%)

Pre-tricuspid 7 (35.0) 5 (26.3) 12 (30.8)

Post-tricuspid 13 (65.0) 14 (73.7) 27 (69.2)

Simple cardiac defect, n (%) 19 (95.0) 17 (89.5) 36 (92.3) Complex cardiac defect, n (%) 1 (5.0) 2 (10.5) 3 (7.7) Right heart catheterization

Mean PAP, mmHg 77.6±11.3 79.7±15.1 78.6±13.1

Mean RAP, mmHg* 6.2±3.8 6.4±3.7 6.3±3.7

Mean PVR, dyn·sec/cm5 1868±958.8 1703±840.8 1788±895.3 Mean LAP, LVEDP or mean

PAWP, mmHg‡

9.8±4.0 9.5±3.4 9.6±3.7

Hemoglobin, g/dL 18.3±2.72 19.0±2.70 18.7±2.70

ES indicates Eisenmenger syndrome; LAP, left atrial pressure; LVEDP, left ventricular end diastolic pressure; PAWP, pulmonary artery wedge pressure; PAP, mean pulmonary arterial

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pressure; PDE-5, phosphodiesterase-type 5; PVR, pulmonary vascular resistance; RAP, right atrial pressure; SpO2, oxygen saturation; and WHO, World Health Organization.

*Plus-minus values are mean ± standard deviation. For mRAP, data were missing for one patient in the placebo group (a total of one patient with missing data).

†The WHO functional class ranges from I to IV, with higher numbers indicating greater functional limitations. There were no patients in WHO functional class I or IV enrolled in the study.

‡If more than one parameter was measured in the same patient, only one is displayed using the following order: mean LAP > LVEDP > mean PAWP.

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Supplemental Table III. Change from baseline to Week 16 in 6-minute walk distance for patient subgroups according to hemoglobin decrease from baseline to end of treatment (observed data only)

Hemoglobin decrease from baseline up to end of treatment

Macitentan Placebo Mean

treatment effect (95% CL) n

Baseline 6MWD, m

Week 16 6MWD, m

Change in 6MWD, m

n

Baseline 6MWD, m

Week 16 6MWD, m

Change in 6MWD, m

≥ 2 g/dL 40 365.7±88.3 396.5±91.2 30.8±55.3 10 397.0±93.5 412.9±89.7 15.9±43.5 14.9 (-22.9, 52.8)

< 2 g/dL 71 369.7±65.6 398.1±74.1 28.3±48.3 102 378.6±74.8 398.7±78.9 20.0±54.0 8.3 (-7.5, 24.1)

6MWD indicates 6-minute walk distance; CL, confidence limit. Plus-minus values are means ± standard deviation. Post-hoc analyses.

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APPENDIX

List of investigators

The MAcitentan in Eisenmenger Syndrome To RestOre exercise capacity (MAESTRO) investigators are as follows (this includes all sites that were initiated, regardless of screening or enrollment): Austria – Medical University of Vienna and AKH Cardiology, Vienna: Prof.

Irene Lang. Belgium – University Hospital Gasthuisberg, Leuven: Prof. Marion Delcroix;

Hôpital Erasme, Brussels: Prof. Jean-Luc Vachiéry. Bulgaria – Multi-profile Hospital for Active treatment National Cardiology Hospital, Sofia: Prof. Margarita Tzonzarova and Associate Prof. Borislav Georgiev; Multi-profile Hospital for Active Treatment Sveta Anna, Sofia: MD Vasil Velchev; Multi-profile Hospital for Active Treatment Sveta Marina, Varna:

Associate Prof. Yoto Yotov. Canada – University of British Columbia- St. Paul’s Hospital Providence Health, Vancouver: Dr. Jasmine Grewal; University of Alberta Hospital,

Edmonton: Dr. Dale Lien. Chile – Hospital San Juan de Dios, Santiago de Chile: Dr. Pablo Sepulveda Varela; Instiuto Nacional del Tórax, Santiago: Polentzi Uriarte. China – Fuwai Hospital, Beijing: Prof. Jian’guo He; Shanghai Pulmonary Hospital, Shanghai: Prof. Jinming Liu; Guangdong General Hospital, Guangdong: Prof. Hua Yao; Beijing Anzhen Hospital of the Capital University of Medical Sciences, Beijing: Prof. Hong Gu; Wuhan Asia Heart Hospital, Hubei: Dr. Gangcheng Zhang; The General Hospital of Shenyang, Liaoning: Dr.

Xianyang Zhu. Czech Republic – Nemocnice Na Homolce, Prague: Associate Prof. Jana Popelová; General Faculty Hospital, Prague: Associate Prof. Pavel Jansa; FN U Sv Anny Brno, Brno: Prof. Jindřich Špinar. France – Hôpital de la Timone enfants, Marseille: Dr.

Philippe Aldebert; Hôpital Laennec, Nantes: Prof. Patrice Guérin; Hôpital Cardiologique du Haut Lévêque, Pessac: Prof. Jean-Benoit Thambo; Hôpital Europeén Georges Pompidou Cardiologie, Paris: Dr. Laurence Iserin. Germany – Justus-Liebig-Universität gieβen, Giessen: Prof. Markus Khalil; Universitätsklinikum Münster, Münster: Prof. Gerhard-Paul Diller; Deutsches Herzzentrum München, München: Prof. Harald Kaemmerer;

Universtiätsklinikum Heidelberg, Heidelberg: Prof. Matthias Gorenflo; Deutsches

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Herzzentrum Berlin, Berlin: Dr. Oliver Miera. Greece – Onaassis Cardiac Surgery Center, Athens: Dr. Spyridon Rammos; Ahepa University General Hospital of Thessaloniki, Thessaloniki: Prof. Haralampos Karvounis. Hungary – Gottsegen György Orszàgos Kardiológiai Intézet, Budapest: Dr. András Temesvári; Szegedi Tudományagetem ÁOK Szent-Györgyi Albert Klinikai Központ, Szeged: Prof. Tamás Forster. Israel – Rabin Medical Centre, Petach Tikvah: Prof. Mordechai Kramer; Carmel Medical Center, Haifa: Prof. Yochai Adir. Italy – Istituto di Malattie dell'Apparato Cardiovascolare, Università di Bologna,

Bologna, Italy: Prof. Nazzareno Galiè; Fondazione IRCCS Policlinico San Matteo, Pavia: Dr.

Stefano Ghio. Malaysia – Institut Jantung Negara, Kuala Lumpur: Dr. David Soon Ping Chew. Mexico – Instituto Nacional de Cardiologia (INC) Ignacio Chavez, Mexico City: Dr.

Tomas Rene Pulido Zamudio, Dr. Daniela Xilonem Ruiz-Juarez; Centro de Estudios Clinicos de Querétaro S. C., Querétaro: Dr. Marco Alcocer; Hospital General de Puebla, Puebla: Dr.

Juan Carlos Perez Alva; Unidad de Investigacion Clinica en Medicina, Nuevo Leon: Dr.

Carlos Jerjes Sanchez; Hospital Infantil de Mexico, Mexico City: Dr. Julio Erdmenger Orellana. Netherlands – Universitair Medish Centrum, Groningen: Prof. Rolf M. F. Berger.

Philippines – Philippine Heart Centre, Manila: Ma Paz B. Mateo. Poland – Klinika Wad Wrodznych Serca Instytut Kardiologii im. Kardynała Wyszyńskiego, Warsaw: Prof. Piotr Hoffman; Krakowski Szpital Specjalistyczny im. Jana Pawła II, Krakow: Prof. Piotr Podolec;

Wojewódzki Szpital Specjalistyczny we Wrocławiu, Wrocław: Prof. Jerzy Lewczuk; SPSK nr 7 Ślaskiego Uniwersytetu Medycznego w Katowicach Górnoślaskie Centrum Medyczne im prof. Lezka Gieca II Oddzial Kardiologii, Katowice: Prof. Zbigniew Gąsior; Uniwersyteckie Centrum Kliniczne, Gdańsk: Prof Grzegorz Raczak; I Klinika Kardiologii Uniwersytetu Medycznego im Karola Marcinkowskiego w Poznaniu, Poznań: Prof. Tatiana Mularek-

Kubzdela. Portugal – Hospital de Santa Marta- Centro Hospitalar de Lisboa Central, Lisbon:

Ana María Figueiredo Agapito; Hospital da Universidade de Coimbra Serviço de Cardiologia, Coimbra: Maria da Graça Calado de Oliveira Castro. Romania – Institutul de Urgenta pentru Boli Cardiovasculare “Prof. Dr. C.C. Iliescu”, Bucharest: Conf. Dr. Ioan Mircea Coman;

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Spitalul Clinic de Boli Infectioase si Pneumoftiziologie “Dr. Victor Babes”, Timisoara: Dr.

Nicoleta Sorina Bertici; Cardio Med SRL, Targu Mures: Dr. Theodora Mariana Nicoleta Benedek. Russian Federation – Almazov Federal North-West Medical Research Centre of Department of Health of Russian Federation, St. Petersburg: Prof. Olga M. Moiseeva;

Organization Department “Scientific Research Institute of Cardiology” of the Federal State Budgetary Scientific Institution “Tomsk National Research Medical Center of Russian Academy of Sciences”, Tomsk: Prof. Sergey Popov; Federal State Budgetary Institution

“Scientific Research Institute of Systemic Problems of Cardiovascular Diseases” ,

Kemerovo: Prof Olga Barbarash; Federal State Budgetary Institution “Russian Cardiology Scientific and Production Complex” of the Ministry of Health Care of the Russian Federation, Moscow: Dr Tamila Martynyuk. Serbia – Kliničko-bolnički centar Zemun, Belgrade: Prof.

Biljana Putniković Tošić; Institut za kardiovaskularne bolesti Dedinje, Belgrade: Dr. Natasa Stokuca Korac; Institut za zdravstvenu zaštitu majke i deteta Srbije “Dr Vukan Čupić”,

Belgrade: Prof. Jovan Kosutic. South Africa – Tread Research/Cardiology Unit, Cape Town:

Dr. Phillipus Herbst; Chris Hani Baragwanath Hospital/Soweto Cardiovascular Research Unit, Johannesburg: Prof. Mohammed Rafique Essop; Department of Paediatric Cardiology University of the Free State, Bloemfontain: Prof. Stephen Brown. Spain – Hospital

Universitario 12 Octubre Servicio de Cardiología, Madrid: Dr. Pilar Escribano; Hospital Universitario Puerta de Hierro- Majadahonda Unidad de Insuficiencia Cardiaca, Madrid:

Javier Segovia Cubero; Hospital Universitario Virgen Macarena Servicio de Cardiología, Seville: Pastora Gallego; Hospital Universitario Vall d’Hebron Servicio de Cardiopatías Congénitas del Adulto y Cardiología Pediátrica, Barcelona: Laura Dos Subira; Hospital General Universitario Gregorio Marañón, Madrid: Francisco Fernández-Avilés Díaz; Hospital Universitario La Fe- Cardiology Department, Valencia: Joaquín Rueda Soriano. Taiwan – National Taiwan Hospital- Department of Pediatrics, Taipei: Dr. Hsao-Hsun Hsu; Taichung Veterans General Hospital/General Cardiology Department, Taichung: Chief Kuo-Yang Wang; Kaohsiung Veterans General Hospital/Intensive Care Unit, Kaohsiung: Director Kai-

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Sheng Hsieh. Turkey – Hacettepe Üniversitesi Tip Fakültesi Çocuk Sağliği Ve Hastaliklari Anabilim Dali Kardiyoloji Bilim Dali, Ankara: Prof. Dursun Alehan; Istanbul Üniversitesi Kardiyoloji Enstitisü Kardyoloji Kliğini, Istanbul: Prof. Serdar Kucukoglu; Gazi University School of Medicine Department of Pediatric Cardiology, Ankara: Prof. Sedef Tunaoğlu;

Ondokuz Mayis University Pediatric Cardiology Department, Samsun: Prof. Kemal Baysal.

United Kingdom – University Hospitals Bristol NHS Foundation Trust Department of

Congenital Heart Disease, Bristol: Prof. Robert M. R. Tulloh; Royal Brompton Hospital Heart Centre and Centre for Pulmonary Hypertension, London; Prof. Michael A. Gatzoulis;

Manchester Heart Centre Manchester Royal Infirmary, Manchester: Dr. Vaikon Mahadevan.

USA – Texas Children’s Hospital Department of Cardiology, Houston, Texas: Dr. Wayne J.

Franklin; Cleveland Clinic - Department of Cardiovascular Medicine, Cleveland, Ohio: Dr.

Richard Krasuski; Boston Children’s Hospital (BCH), Boston, Massachusetts: Dr. Alexander Opotowsky; Columbia University Medical Center Children’s Hospital of New York

Presbytarian, New York, New York: Dr. Erika Rosenzweig; Ahmanson Adult Congenital Heart Disease Center, Los Angeles, California: Dr. Jamil Aboulhosn; Emory University Hospital/The Emory Clinic, Atlanta, Georgia: Dr. Wendy Book; Nationwide Children’s Hospital - Research Institute, Columbus, Ohio: Dr. Curt Daniels; Washington University School of Medicine, St. Louis, Missouri: Dr. Ari Cedars and Dr. Murali Chakinala; Children’s Heart Center Nevada, Las Vegas, Nevada: Dr. Abraham Rothman; University of Maryland, Baltimore, Maryland: Dr. Stacy Fisher; Stanford Hospital and Clinic, Palo Alto, California: Dr.

Anitra W. Romfh; University of Colorado Anschutz Medical Campus, Aurora, Colorado: Dr.

Joseph Kay; LIU Center for Pulmonary Hypertension, Torrance, California: Dr. Ronald Oudiz. Vietnam – Hanoi Medical University Hospital, Hanoi: Associate Prof. Lan Hieu Nguyen; Children’s Hospital No. 1 of Ho Chi Minh City, Ho Chi Minh: Nguyen Tin Do; Tam Duc Cardiology Hospital, Ho Chi Minh: Dr. Nguyen Vinh Pham.

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