Academic Center for Pulmonary Hypertension

Last updated: 365 days ago.

To provide excellent patient care for patients with pulmonary hypertension (PH), improve prognosis and quality of life through understanding mechanisms of PH development and progression, identification of biomarkers for early recognition and disease progression and testing of novel therapy.

Academic Center of Excellence

Research Activities

Basic scientists and clinicians with strong interest in research participate in our ACE. We aim to identify novel mechanisms that contribute to development and progression of PH, as well as biomarkers for diagnosis and prognosis and to translate those into drugable targets and/or personalized treatment strategies. Our research therefore needs to bridge fundamental, translational and clinical research.

From bench-to bedside:

1. Study of the role of (auto-)immunity in PAH: different mouse models were developed to understand basic mechanisms, clinically relevant for auto-immune-related PH as well as idiopathic PAH.

2. Study of mechanisms of pulmonary vascular disease resulting in PH and ensuing right ventricular dysfunction. Unique swine models allow correlation of potential biomarkers to well-defined hemodynamics and tissue specimens.

3. Studying (immune) cell proportions, activation and function in donated biological material, such as blood from patients suffering from different forms of P(A)H and healthy donors;

4. Studying the developmental origins of pulmonary hypertension of the newborn, particularly in diseases like congenital diaphragmatic hernia (CDH), bronchopulmonary dysplasia (BPD) and alveolar capillary dysplasia (ACD).

From bedside-to bench:

Identify mechanisms of disease as well as biomarkers for diagnosis and prognosis through:

1. Biobanking of patient samples of patients with various forms of pulmonary hypertension (blood, surgical material of CTEPH endarteriectomy, lung explants) in collaboration with UMCG and Antonius Hospital, Nieuwegein.

2. Identification of risk factors for PH development in our unique cohort of patients that had surgery for congenital heart disease.

3. Identification of risk factors for PH development in patients suffering from systemic sclerosis in collaboration with the ACE-ILD-sarcoidosis

4. Identifying risk factors for the development of PH in young adults who were born prematurely. Besides a research project on this topic a specialized out-patient clinic will be set up to follow these patients in collaboration with the ACE ILD.

5. Participation in international medication trials

6. Research on the topic of improving Quality of Life, prospectively validation of the Health Related Quality of Life Questionnaire (CAMPHOR) and by means of an integrated multidisciplinary rehabilitation program (collaboration with tertiary rehabilitation center Revant, Breda)

7. Research on the topic of the role of nutrition and physical status and quality of life in patients with PH (collaboration with University of Wageningen and University of Leipzig)

Our participation in the national and international PH database and participation in the ERN-network allows further translation of our findings in a broader worldwide context. It also allows us to compare our clinical outcome parameters with the of other centers nationally and internationally.

The different PIs in our ACE collaborate with various clinical and research partners from both national (Amsterdam, Groningen, Nieuwegein, Wageningen) and international top PH centers (e.g. Cambridge, Giessen, Paris, Toronto, Minneapolis).

Type of

Collaborations

The different PIs in our ACE collaborate with various clinical and research partners from both national (Amsterdam, Groningen, Nieuwegein, Wageningen) and international top PH centers (e.g. Cambridge, Giessen, Paris, Toronto, Minneapolis).

The ACE pulmonary hypertension has collaboration with several other ACE in the ErasmusMC as pointed out before: ACE -ILD -sarcoidosis, ACE congenital heart disease, ACE Rare Immunological Diseases, ACE Heart Failure. These collaborations concern patient care, research as well as education.

Educational

Contributions

Educational programs of the departments of Pulmonary Medicine and Cardiology are evaluated regularly (and with excellent results) based on SETQ, D-RECT guidelines and visitation reports are available.

Within our ACE, we emphasize that continuous education is an important tool to decrease the doctor's delay in diagnosis of PH. This education involves all levels, from medical students to fellow specialists, and also involves education of our specialized PH nurses and nursing staff in our departments, which is essential to ensure excellent patient care.

Our ACE therefore:

• provides education to Bachelor's and Master's students

• provides education to PhD students, by participating in two research schools for PhD students at Erasmus MC; Molecular Medicine and COEUR, both of which have been audited recently. An educational program on PH has been scheduled for April 18th 2019.

• provides the opportunity for an official internship in pulmonary hypertension for residents in pulmonology and cardiology

• provides the opportunity for a fellowship in pulmonary hypertension for clinical fellows in pulmonary medicine and cardiology

• actively involves our specialized PH nurses in the Dutch and the European network of PH nurses. Participating in international conferences is part of their education.

• participates in an international writing committee for clinical care guidelines

• accommodates 2 international students/ fellows from China and Finland

Patient

Care Activities

PH is a progressive, devastating but rare disease. Diagnostic work-up and treatment of PH is labelled as 100% academic care by the ROBIJN model.

We provide a multidisciplinary approach to ascertain proper diagnosis and treatment, involving a clinical diagnostic work path to guarantee a short diagnostic track and a weekly, multidisciplinary, meeting to discuss patient cases. Patients are treated according to international guidelines, including a rehabilitation program and (screening for) lung transplantation.

Patients with PH are referred relatively late during their disease course, which has negative implications on clinical outcome. This underlines the need for strong collaboration with our referral centers, as implemented through multidisciplinary team meetings with referring centers. Also, a short screening-track for PH is well-established for patients with systemic sclerosis and porto-pulmonary hypertension.

A prospective study that follows all newly referred patients with PH according to a standardized protocol has been implemented since 2011. This program allows us to study new biomarkers, imaging technics and hemodynamic data, and correlate those with diagnosis and prognosis.

Our PH center is recognized as expert center by the NFU (Dutch Federation of Universities) and the Dutch PH patient association and has been audited by "expertise in kaart".

In addition, we participate in the European Reference Network of Rare Diseases-PH.

Finally, we joined the international database of PH patients, which allows comparison of our outcome parameters with those of other PH centers.

Societal Relevance to Research, Education and Patient Care

Besides patient care, research and education are essential priorities of the ACE Pulmonary Hypertension. We remain on the forefront of clinical research in the field of PH, as our center participated in most of the clinical research drug trials to date for the development of new medical treatments.

Currently, we participate in several scientific trials to study novel mechanisms and medications for the treatment of PAH. Thus, our patients have access to clinical trials of new medications, allowing our physicians to provide novel treatments when appropriate, to patients not responsive to currently available treatment options.

We closely collaborate with the Dutch PH patient association in education of patients and their families as well as in ensuring that patients with PH receive the best possible care. We believe that close relationships with referring physicians are critical for optimizing the management of PH-patients.

Our doctors and nurses are readily available to educate and support our patients and their needs. Furthermore, our team is highly committed to the local, national, and international PH community to provide education and awareness about the condition. Our active involvement in the scientific community allows us to advocate for more support, education and research that directly impacts our patients.

Viability of Research, Education and Patient Care

The field of PH is dynamic and has developed greatly over the past decade. This dynamic environment is reflected within our ACE, that is comprised of experienced clinicians, in combination with researchers with a diverse background that actively recognize the need to combine and share their knowledge to advance understanding and treatment of PH through:

· Organizing seminars and symposia around different topics of PH that are open for both researchers and clinicians (e.g. International symposium on PH (March 2018) and symposium on RV failure, June 2018)

· Organizing a monthly meeting for all participants of the ACE; two members of the ACE give a presentation of their recent research. Future objectives of the ACE are also discussed at this meeting.

· Organizing a PH-course for PhD students.

· Actively scouting students interested in the pulmonary circulation during their Bachelor and Master phase to participate in our ACE during their study or later-on in their career.

· One of our PIs is the chair of the national multidisciplinary PH working group. We know from experience that international exposure is an important tool to grow to into independence.

· We therefor aim for each PhD student to participate in at least 3 international conferences during his/her PhD

· We actively promote our PhD students as speakers on international conferences

· We stimulate our PhD students to participate in international courses

Our participation in multicenter grants that have talent development work packages and collaboration in our (inter)national network further facilitate international career development. At least 2 former PhD students have started an international career. In addition, a Chinese CSC-recipient has joined our ACE at the end of 2016. We publish in international top journals and are active members of the editorial board of international top journals.

Key and relevant publications of the last five years

  • Clinical symptoms of right ventricular failure in experimental chronic pressure load are associated with progressive diastolic dysfunction. Borgdorff MA, Koop AM, Bloks VW, Dickinson MG, Steendijk P, Sillje HH, van Wiechen MP, Berger RM, Bartelds B. J Mol Cell Cardiol. 2015 Feb;79:244-53.
  • Cardiac magnetic resonance findings predicting mortality in patients with pulmonary arterial hypertension: a systematic review and meta-analysis.Baggen VJM, Leiner T, Post MC, van Dijk AP, Roos-Hesselink JW, Boersma E, Habets J, Sieswerda GTj. Eur Radiol 2016, e-pub ahead of publication
  • Egr-1 identifies neointimal remodeling and relates to progression in human pulmonary arterial hypertension. van der Feen DE, Dickinson MG, Bartelds B, Borgdorff MA, Sietsma H, Lévy M, Berger RM. J Heart Lung Transplant. 2016 Apr;35(4):481-90
  • Adaptation and validation of the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) for the Netherlands. Wapenaar M, Twiss J, Wagenaar M, Seijkens P, van den Toorn L, Stepanous J, Heaney A, den Bosch AE , Boomars KA. Neth Heart J 2016;24:417- 424
  • Pulmonary vasoconstrictor influence of endothelin in exercising swine depends critically on phosphodiesterase 5 activity. Zhou Z, de Beer VJ, de Wijs-Meijler D, Bender SB, Hoekstra M, Laughlin MH, Duncker DJ, Merkus D: Am J Physiol Lung Cell Mol Physiol 2014; 306: L442-52
  • Echocardiography in pediatric pulmonary arterial hypertension: early study on assessing disease severity and predicting outcome. Ploegstra MJ, Roofthooft MT, Douwes JM, Bartelds B, Elzenga NJ, van de Weerd D, Hillege HL, Berger RM. Circ Cardiovasc Imaging. 2014 Dec 31;8(1). pii: e000878.
  • PulmoCor: national registry for pulmonary hypertension. Post MC, Van Dijk AP, Hoendermis ES, Bogaard HJ, Van Empel V, Boomars KA. Neth Heart J 2016, 425-30.
  • Exercise facilitates early recognition of cardiac and vascular remodeling in chronic thromboembolic pulmonary hypertension in swine. Stam K, van Duin RWB, Uitterdijk A, Cai Z, Duncker DJ, Merkus D. Am J Physiol Heart Circ Physiol. 2018 Mar 1;314(3):H627-H642.
  • Immunoglobulin G anti-endothelial cell antibodies; inducers of endothelial cell apoptosis in pulmonary hypertension ? Arends SJ, Damasoieaux J, Duijvenstijn A, Debrus-Palmans L, Vroomen M, Boomars KA, Brunner-La Rocca HP, Reutelingsberger CP,Tervaert JW, van Paassen P. Clin Exp Immunol. 2013;174:433-440
  • Pulmonary arterial stiffness indices assessed by intravascular ultrasound in children with early pulmonary vascular disease: prediction of advanced disease and mortality during 20-year follow-up. Ploegstra MJ, Brokelman JGM, Roos-Hesselink JW, Douwes JM, van Osch-Gevers LM, Hoendermis ES, van den Bosch AE, Witsenburg M, Bartelds B, Hillege HL, Berger RMF. Eur Heart J Cardiovasc Imaging. 2018 Feb 1;19(2):216-224. doi: 10.1093/ehjci/jex015. PubMed PMID: 28329155.
  • Physical Activity in Pediatric Pulmonary Arterial Hypertension Measured by Accelerometry. A Candidate Clinical Endpoint. Zijlstra WMH, Ploegstra MJ, Vissia-Kazemier T, Roofthooft MTR, Sarvaas GDM, Bartelds B, Rackowitz A, van den Heuvel F, Hillege HL, Plasqui G, Berger RMF.Am J Respir Crit Care Med. 2017 Jul 15;196(2):220-227. doi: 10.1164/rccm.201608-1576OC. PubMed PMID: 28178426.
  • Transition from post-capillary to combined pre- and post-capillary pulmonary hypertension in swine: A key role for endothelin. van Duin RWB, K Stam, Cai Z, Uitterdijk A, Garcia-Alvarez A, Ibanez B, Danser AHJ, Reiss IKM, Duncker DJ, and Merkus D. J Physiol 2018 ,in press
  • Changes in vasoactive pathways in congenital diaphragmatic hernia associated pulmonary hypertension explain unresponsiveness to pharmacotherapy. Mous DS, Buscop-van Kempen MJ, Wijnen RMH, Tibboel D, Rottier RJ. Respir Res. 2017 Nov 7;18(1):187.
  • Impaired Angiogenic Supportive Capacity and Altered Gene Expression Profile of Resident CD146+ Mesenchymal Stromal Cells Isolated from Hyperoxia-Injured Neonatal Rat Lungs. Collins JJP, Lithopoulos MA, Dos Santos CC, Issa N, Möbius MA, Ito C, Zhong S, Vadivel A, Thébaud B. Stem Cells Dev. 2018 Jun 29.
  • Hypoxia inducible factor 2α (HIF2α/EPAS1) is associated with development of pulmonary hypertension in severe congenital diaphragmatic hernia patients. Huang Y, Boerema-de Munck A, Buscop-van Kempen M, Sluiter I, de Krijger R, Tibboel D, Rottier RJ. Pulm Circ. 2018 Jul-Sep;8(3):

PhD theses of the last five years

  • Zhichao Zhou (2013): The Dual Face of Endothelial Control of Vascular Tone
  • Janet van Eindhoven (2015): Cardiac Biomarkers in Adult Congenital Heart Disease.
  • Marinus Borgdorff (2014): The elusive heart: the right ventricle under abnormal loading conditions.
  • Vincent de Beer (2011): Vasoconstrictors: a Tale of two Circulations
  • Heleen Kool (2018): The Cellular Origin of Congenital Diaphragmatic Hernia and Potential Translational Approaches
  • Vivan Baggen (2018): Risk prediction in adult congenital heart disease
  • Daphne Mous (2017): Pulmonary Vascular Defects in Congenital Diaphragmatic Hernia: The quest for early factors and intervention

Non-scientific publications related to the ACE

  • Papillon (publicatie PH patiënten vereniging): Revalidation study in PAH patients (Boomars)
  • Papillon (publicatie PH patiënten vereniging): Inflammation and PAH, (Koudstaal)
  • Papillon (publicatie PH patiënten vereniging): Autoimmunity in PAH, (Kool)
  • Papillon (publicatie PH patiënten vereniging): Revie: Biopulse study and congenital heart defect in PAH (vd Bosch)
  • Pulse media Treatment options in patients with systemic sclerosis and PAH 2017
  • Involvement in Patient days Chair National PH Patientday 2016 Amsterdam, (van den Toorn)
  • Involvement in Patient days Chair National PH Patientday 2017 Amsterdam, (Boomers)
  • Regional Patientday in Roermond: Presentation: New developments in PH, ( Boomars)

Principal coordinator(s)