PVRI Review 3(1) 2011 by Pulmonary Vascular Research Institute

The Pulmonary Vascular Research Institute proudly presents

The 6th Annual General Meeting & 5th Scientific Workshops & Debates 2012, at the Protea President Hotel in Cape Town, South Africa

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PVRI Review

ISSN 0974-6013 E-ISSN 0975-1602

Editorial Board...... CHIEF EDITOR Harikrishnan S. Additional Professor in Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India - 695011

EXECUTIVE EDITORS Saleh Aldammas (Arabic Edition) Majdy Idrees (Arabic Edition) Jun Wang (Chinese Edition) Maria Virginia Tavares Santana (Portuguese Edition) Katia Stewart (Portuguese Edition) Julio Sandoval (Spanish Edition)

Ghazwan Butrous R. Oudiz Ioana Preston Mardi Gomberg-Maitland Andrew Peacock Alexi Crosby

EDITORIAL TEAM Sheila Glennis Haworth Sastry Bhagavathulla R. Krishna Kumar Shyam Sunder Kothari Goverdhan Dutt Puri Anita Saxena Qadar Pasha Sivasankaran Sivasubramonian Chandrasekharan Cheranellore Kartha

EDITORIAL TEAM FOR PORTUGUESE EDITION Maria Virginia Tavares Santana Antonio Augusto Lopes Ângela Bandeira Vera Demarchi Aiello Maria Angélica Binoto Daniel Waetge Jaquelina Ota Renato Maciel Veronica Amado Frederico Thadeu Campos Maria Ilma Araújo Kátia Stewart

EDITORIAL BOARD/ REVIEWERS PVRI Faculty Jan - Jun 2011 • Volume 3 • Issue 1

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PVRI REVIEW

PVRI Review GENERAL INFORMATION The Journal PVRI Review (ISSN: Print - 0974-6013, Online - 0975-1602) is peerreviewed journal published on behalf of the Pulmonary Vascular Research Institute, supported by the Indian (South-East Asia region) task force. The journal publishes articles on the subject of Pulmonary circulation and pulmonary vascular diseases. The Journal is published quarterly (in the last week of January, April, July and October). Abstracting and Indexing Information The journal is indexed/listed with Caspur, DOAJ, EBSCO Publishing’s Electronic Databases, Expanded Academic ASAP, Genamics JournalSeek, Google Scholar, Health & Wellness Research Center, Health Reference Center Academic, Hinari, Index Copernicus, OpenJGate, PrimoCentral, ProQuest, Scimago Journal Ranking, SCOLOAR, SCOPUS, SIIC databases, Summon by Serial Solutions and Ulrich’s International Periodical Directory. Information for Authors There are page charges for submissions to the journals. Please check http://www.pvrireview.org/contributors.asp for details. All manuscripts must be submitted online at www.journalonweb.com/pvri Subscription Information Copies are provided to the members of PVRI for free of cost. A subscription to PVRI Review comprises 4 issues. Prices include postage. Annual Subscription Rate for non-membersInstitutional: INR 2000.00 for India and USD 200.00 for outside India. Personal: INR 1000.00 for India and USD 100.00 for outside India. For mode of payment and other details, please visit www.medknow. com/subscribe.asp. Claims for missing issues will be serviced at no charge if received within 60 days of the cover date for domestic subscribers, and 3 months for subscribers outside India. Duplicate copies cannot be sent to replace issues not delivered because of failure to notify publisher of change of address. The journal is published and distributed by Medknow Publications and Media Pvt. Ltd. Copies are sent to subscribers directly from the publisher’s address. It is illegal to acquire copies from any other source. If a copy is received for personal use as a member of the association/society, one cannot resale or give-away the copy for commercial or library use. The copies of the journal to the members of the association are sent by ordinary post. The editorial board, association or publisher will not be responsible for non receipt of copies. If any member/subscriber wishes to receive the copies by registered post or courier, kindly contact the publisher’s office. If a copy returns due to incomplete, incorrect or changed address of a member/subscriber on two consecutive occasions, the names of such members will be deleted from the mailing list of the journal. Providing complete, correct and up-to-date address is the responsibility of the member/subscriber. Nonmembers: Please send change of address information to subscriptions@medknow.com. Advertising Policies The journal accepts display and classified advertising. Frequency discounts and special positions are available. Inquiries about advertising should be sent to Medknow Publications, media@ medknow.com. PVRI REVIEW

The journal reserves the right to reject any advertisement considered unsuitable according to the set policies of the journal. The appearance of advertising or product information in the various sections in the journal does not constitute an endorsement or approval by the journal and/or its publisher of the quality or value of the said product or of claims made for it by its manufacturer. Copyright The entire contents of the PVRI Review are protected under Indian and international copyrights. The Journal, however, grants to all users a free, irrevocable, worldwide, perpetual right of access to, and a license to copy, use, distribute, perform and display the work publicly and to make and distribute derivative works in any digital medium for any reasonable non-commercial purpose, subject to proper attribution of authorship and ownership of the rights. The journal also grants the right to make small numbers of printed copies for their personal noncommercial use. Permissions For information on how to request permissions to reproduce articles/ information from this journal, please visit www.pvrireview.org Disclaimer The information and opinions presented in the Journal reflect the views of the authors and not of the Journal or its Editorial Board or the Publisher. Publication does not constitute endorsement by the journal. Neither the PVRI Review nor its publishers nor anyone else involved in creating, producing or delivering the PVRI Review or the materials contained therein, assumes any liability or responsibility for the accuracy, completeness, or usefulness of any information provided in the PVRI Review, nor shall they be liable for any direct, indirect, incidental, special, consequential or punitive damages arising out of the use of the PVRI Review. The PVRI Review, nor its publishers, nor any other party involved in the preparation of material contained in the PVRI Review represents or warrants that the information contained herein is in every respect accurate or complete, and they are not responsible for any errors or omissions or for the results obtained from the use of such material. Readers are encouraged to confirm the information contained herein with other sources. Addresses Editorial Office Dr. S. Harikrishnan Associate Professor in Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum - 695011, India. Tel. 91-471-2551692, FAX- 91-471-2446433 E-mail: drharikrishnan@hotmail.com Web site: www.pvrireview.org Published by Medknow Publications and Media Pvt. Ltd. B5-12, Kanara Business Centre, Off Link Road, Ghatkopar (E), Mumbai – 400075, India. Phone: 91-22-66491818 Website: www.medknow.com Printed at Anitha Art Printers, 29/30, 'OASIS', Opp. Vakola Masjid, Santacruz (E), Mumbai 400 055, India.

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PVRI Review January - June 2011 | Volume 3 | Issue 1

Contents..... EDITORIAL PVRI Review after the Birth of Pulmonary Circulation S. Harikrishnan .....................................................................................................................................................................................1

PVRI NEWS PVRI Achievement Award 2011 Antonio A. Lopes ..................................................................................................................................................................................2

OBITUARY Peter Raymond, MBE Stuart Rich............................................................................................................................................................................................4

REVIEW ARTICLES Hypoxia Inducible Factor and Hypoxia-mediated Pulmonary Hypertension Louise Østergaard, Max Gassmann....................................................................................................................................................5

The Prevalence of Pulmonary Hypertension in Schistosomiasis: A Systematic Review Thomas J. C. Ward, Alan Fenwick, Ghazwan Butrous....................................................................................................................12

COMMENTARY Summary on study of role of Serotonin Transporter, Gender and Hypoxia in mouse models of PAH by White K et al., 2011 Swapna Menon ..................................................................................................................................................................................22

PVRI CONFERENCES AND SYMPOSIA IN 2010 Annual Report of Pulmonary Vascular Research Institute Activities 2010 ................................................................25

TASKFORCE ACTIVITIES The PVRI Publications Taskforce Jason Yuan, S. Harikrishnan .............................................................................................................................................................36

PVRI Schistosomiasis Taskforce Activities for 2010 Ghazwan Butrous, Nicholas Morrell ..................................................................................................................................................38

PVRI High Altitude Taskforce Qadar Pasha, Max Gassmann ..........................................................................................................................................................39

Pulmonary Hypertension Associated with HIV – Taskforce Nicola Petrosillo, Sonia Flores, Sharilyn Almodovar, Norbert Voelkel .............................................................................................40

Pulmonary Hypertension Associated with Congenital Heart Disease Taskforce (PH-CHD TF) Antonio A. Lopes, Marlene Rabinovitch ............................................................................................................................................41

PVRI Hemolytic Anemia Taskforce Kamal Mubarak, Roberto Machado...................................................................................................................................................42 Jan - Jun 2011 • Volume 3 • Issue 1

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Contents..... (Contd..) PVRI China Taskforce 2010 Martin Wilkins, Chen Wang ...............................................................................................................................................................42

PVRI India Taskforce Glennis Haworth, Krishna Kumar ......................................................................................................................................................43

PVRI East Mediterranean Taskforces Majdy Idrees, Paul Hassoun .............................................................................................................................................................44

The PVRI Paediatric Taskforce Maria Jesus del Cerro, Ian Adatia ....................................................................................................................................................45

The PVRI CTEPH Taskforce Nick H. Kim, Eckhard Mayer .............................................................................................................................................................45

PVRI Research Grants .................................................................................................................................................................45 Administrative Activities ............................................................................................................................................................46 PVRI Publication ...........................................................................................................................................................................49

OVERVIEW The 5th PVRI Annual General Meeting and 4th Workshops and Debates, Panama City, 2-5 February 2011 Nikki Krol ............................................................................................................................................................................................51

MEETING REPORT The 4th Annual Joint Pulmonary Hypertension Conference - Dubai Majdy Idrees, Ghazwan Butrous .......................................................................................................................................................57

INSTRUCTIONS FOR AUTHORS .... .............................................................................................................................................62

Author Institution Mapping (AIM)

Please note that not all the institutions may get mapped due to non-availability of the requisite information in the Google Map. For AIM of other issues, please check the Archives/Back Issues page on the journal’s website. PVRI REVIEW

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EDITORIAL

PVRI Review after the Birth of Pulmonary Circulation As you know, Pulmonary Circulation has been available online since mid-March 2011. We at PVRI Review hereby issue a thank you to all those who played an instrumental role in the creation of such a journal, and we are especially grateful to the editors, reviewers and the editorial staff from both PVRI and MedKnow Publications, the Mumbai-based publisher. Now, PVRI Review has taken on a new role as the official newsletter of PVRI. In addition, it will also function as a medium to publish perspectives, hypotheses and more, though these articles will not represent the views and opinions of PVRI and PVRI Review, but rather the sole opinion of the author. As was decided in the AGM in Panama City in 2011, PVRI Review will now be published twice a year, in April and October. In this issue, we have all the annual reports of the various PVRI activities. It is in the form of task force reports-both the reports of the regional task forces and the reports of the disease-specific task forces. In this issue, we have included a tribute to Mr. Peter Raymond, who was one of the members of the PVRI Board of Directors and Advisors. The tribute to Mr. Raymond is contributed by Stuart Rich, the Chairman of the BOD. The Editorial Board of PVRI Review would also like to take this opportunity to pay homage to the great man, whose vision and enthusiasm provided major support for a number of PVRI activities. In the current issue of PVRI Review, Louise Østergaard and Max Gassmann have contributed to a very good review of hypoxia induced factor. It is believed that the hypoxiainducible factor-1 (HIF-1) is the main transcription factor mediating the molecular responses to hypoxia. They describes how HIFs are involved in the numerous pathways that are essential for the progression of PH, and argues that these factors are fundamental for the progression of Pulmonary hypertension. The beneficial effects of drugs like

dehydroepiandrosterone (DHEA), which has been shown to prevent and reverse chronic hypoxic pulmonary artery hypertension in animal studies may be via reduction in HIF-1a and possibly HIF-2a accumulation. Thomas Ward and Ghazwan Butrous attempts to review the prevalence of pulmonary hypertension (PH) in schistosomiasis in another article. But they find that due to poor epidemiological methods employed, none of the available studies met the review’s initial inclusion criteria. After reviewing whatever existing literature - mainly hospital based studies – they conclude that pulmonary hypertension in schistosomiasis is potentially the leading cause of pulmonary hypertension worldwide. They emphasise the need for good quality studies with large community samples from different regions of the world, especially sub-Saharan Africa, in order to accurately estimate the prevalence of PH. Swapna Menon in her usual column, Commentary, has reviewed an article by White et al. on the relation between the transmembrane protein serotonin transporter (SERT) polymorphisms and PAH. The article bases its conclusions on an animal model, and reports that SERT overexpression affects the pulmonary vasculature, as evidenced by vascular remodeling and vasoconstriction in female mice, even at normoxia. The authors state that this animal model displays the converse of the estrogen paradox phenomenon, possibly due to serotonin overexpression. In conclusion, we of the Editorial Board request new submissions of our dear readers, which will fit the new tone and face of PVRI Review.

S. Harikrishnan Access this article online

Editor in Chief, PVRI Review Fellow, Pulmonary Vascular Research Institute Co-leader, PVRI Publication Taskforce E-mail: drharikrishnan@hotmail.com

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How to cite this article: Harikrishnan S. PVRI Review after the Birth of Pulmonary Circulation. PVRI Review 2011;3:1.

DOI: 10.4103/0974-6013.85610

Source of Support: Nil, Conflict of Interest: None declared.

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PVRI NEWS

PVRI Achievement Award 2011 At the 5th Annual General Meeting in Panama this year, Dr. Antonio Augusto Lopes [Figures 1 and 2] was presented with an award in recognition of his efforts and achievements for the Pulmonary Vascular Research Institute. With this gesture, PVRI has begun a tradition whereby an individual Fellow is singled out each year to thank them for their visionary and important accomplishments for the Institute. Dr. Lopes was selected for the 2010 prize in light of his tireless efforts with the webinars, his collaborative efforts with Dr. Marlene Rabinovitch as leaders of the Congenital Heart Disease Taskforce, and many other achievements, big and small. With this award, PVRI wants to thank Dr. Antonio Augusto Lopes for all these and more, and for his positive and tireless presence within the organization. Dr. Antonio Augusto Lopes has prepared a few words in response: It has been a great pleasure and honor for me to participate in the activities of the Pulmonary Vascular Research Institute (PVRI). When PVRI was started, Professor Ghazwan Butrous (Kent, UK) invited me by telephone to become an active participating Fellow. It was late 2006 and PVRI was only just finding direction, but the plans and enthusiasm of its founding members were infectious. I received a formal invitation from Professor Stuart Rich (Chicago, USA) and happily accepted. Since then, I have had wonderful opportunities to interact with a number of professors, scientists and physicians deeply involved with the pathobiology, diagnosis and management of pulmonary vascular disease in their daily practices. Additionally, the last 5 years in the PVRI have awarded me with possibilities to participate in several important activities. I would like to mention to here which have especially had an impact. First, it has been a great honor for me to share the leadership of the Congenital Heart Disease Taskforce with Professor Marlene Rabinovitch (Stanford, USA) who is currently one of the most important scientists in the field. Professor Rabinovitch gave valuable advice on how to implement an ongoing study on the possibility of combining medical (drug) and surgical strategies in the management of moderate to severe pulmonary hypertension associated with congenital cardiac septal defects. Subprojects have emerged from this study, and will probably give us new data on the role of genetics and inflammation in pulmonary vascular remodeling in this particular setting.

The second activity that I have been involved with is a series of videoconferences that have been broadcasted over the internet. These “webinars” have allowed us to reach colleagues all over the world, either in real time or later by recording. The first webinar was held in 2008, and we now have 11 sessions available at www.pahforum.com, or indirectly via the PVRI website, www.pvri.info. At the latest count, the webinars have amassed over 2000 views. Additionally, over a 1000 colleagues from different countries and regions have given their contribution in real time during the sessions. These statistics are fantastic and speak to the interest in these initiatives which transcend borders of state and country. However, I certainly do not believe that I can take credit for these numbers. Without the involvement and contributions of many professors and PVRI members, this educational initiative could not have achieved the success it has. In this regard, may I take this opportunity to express my gratitude to Pfizer Brazil for their unwavering support. Likewise, I am very grateful to all colleagues and professors who have participated in this important initiative and apologize for not mentioning their names individually.

Figure 1: The first PVRI Achievement Award as presented in at the 5th PVRI AGM in Panama City

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Figure 2: Professor Antonio A. Lopes was awarded the PVRI Achievement Award in recognition of his excellent contributions to the Institute

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Lopes: PVRI Achievement Award 2011

In light of this, I am humbled and honored to receive this achievement award, not only for personal reasons, but also for Brazil, my country, and the Heart Institute (InCor) in São Paulo. I am a professor of cardiology and investigator at the Department of Pediatric Cardiology and Adult Congenital Heart Disease for the Heart Institute, and the opportunity to work closely with and for PVRI has made a real difference. My daily practice at the Heart Institute involves the management of different etiologies of pulmonary hypertension in pediatric and adult patients, mainly congenital heart disease-associated pulmonary hypertension. On average, 500 to 700 such patients are operated per year in our department, including complex anomalies and procedures such as hypoplastic left heart, univentricular hearts and transplantation. Since we have genetics and vascular biology laboratories close to us, many opportunities emerge at all times in terms of translational medicine and research. Regarding the years to come, we have developed the idea to put all this in connection with the PVRI and colleagues/laboratories from other institutions and countries, in an attempt to develop research and educational programs. I want to express my gratitude especially to Professor Robin Barst (Columbia, USA) for her kind help in the preparation

of our guidelines (Cardiology in the Young 2009; 19[E-suppl 1):1-53.) and educational subjects that appear in the Congenital Heart Disease Taskforce page, at the PVRI website. I would like to finish by expressing my many thanks to Professors Martin Wilkins, Stuart Rich and Ghazwan Butrous and all colleagues of the PVRI for the opportunities that I have had, and for kindly considering my name for the first Achievement Awards. I truly feel I am only one representative: PVRI is the work of all of us. Antonio A. Lopes Department of Pediatric Cardiology and Adult Congenital Heart Disease, The Heart Institute (InCor), University of São Paulo Medical School, Brazil. E-mail: aablopes@usp.br

How to cite this article: Lopes AA. PVRI Achievement Award 2011. PVRI Review 2011;3:2-3. Source of Support: Nil, Conflict of Interest: None declared.

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First Page File: Prepare the title page, covering letter, acknowledgement etc. using a word processor program. All information related to your identity should be included here. Use text/rtf/doc/pdf files. Do not zip the files. Article File: The main text of the article, beginning with the Abstract to References (including tables) should be in this file. Do not include any information (such as acknowledgement, your names in page headers etc.) in this file. Use text/rtf/doc/pdf files. Do not zip the files. Limit the file size to 1 MB. Do not incorporate images in the file. If file size is large, graphs can be submitted separately as images, without their being incorporated in the article file. This will reduce the size of the file. Images: Submit good quality color images. Each image should be less than 4096 kb (4 MB) in size. The size of the image can be reduced by decreasing the actual height and width of the images (keep up to about 6 inches and up to about 1800 x 1200 pixels). JPEG is the most suitable file format. The image quality should be good enough to judge the scientific value of the image. For the purpose of printing, always retain a good quality, high resolution image. This high resolution image should be sent to the editorial office at the time of sending a revised article. Legends: Legends for the figures/images should be included at the end of the article file.

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OBITUARY

Peter Raymond, MBE Member of the PVRI Board of Directors and Advisors It is with profound sadness that I learnt of the passing away of one of PVRI’s founding board member, Peter Raymond [Figure 1]. As some of you may know, Peter himself had pulmonary hypertension from chronic thromboembolism and underwent successful surgical removal 10 years ago at Papworth Hospital. Unfortunately, his health had declined in recent years and he passed away at home in January. His wife Lis and his family were with him. Peter had a remarkable career. He was responsible for the development and marketing of innovative products at The Dexter Corporation. After serving for 8 years as European Director of Corporate Development for The Dexter Corporation, a Fortune 500 Company, Peter started UMIST Ventures from scratch as the technology transfer company of UMIST. Over a 9-year period, Peter established 20 spin-out companies and floated three on the London Stock Exchange. He was appointed founder

Managing Director of UMIST Ventures Ltd. (UVL), with responsibility for all research grants, technology transfer, and the creation of spin-off companies from the University of Manchester Institute of Science and Technology from 1988 to 1997. Peter then became Chairman of Tepnel Life Sciences (a DNA diagnostic biotech company and spin off of UVL) from 1997 until 2003. During his tenure as Chairman, he was involved with a number of acquisitions and the development of several novel DNA purification instruments. Peter has been involved with over 50 biotechnological start-ups at Sheffield, Manchester and Liverpool Universities. He was a non-executive Director of Contra Vision Ltd. and Chairman of BIONOW (the Steering Group for Biotechnology reporting to the North West Development Authority) for 5 years. As mentioned, Peter was a founding BOD member for PVRI and also a founding Trustee of The Foundation for Science, Technology and Civilisation (FSTC) UK, the parent organization of 1001 Inventions and Curriculum Enrichment (CE4CE). Peter also founded and chaired the Muslim Heritage Awareness Group (MHAG) of FSTC. Most recently, he was Vice-President of the Parliamentary and Scientific Committee comprising members of parliament, members of the House of Lords, academics and industry members of the scientific community, as well as coordinating inter-university research and development in the field of stem cell research. It is clear that over his lifetime, Peter made a vital and sustained contribution to numerous educational initiatives because he was an advocate and guardian of our values. He was an exuberant, larger than life figure with a big heart and powerful intellect. Peter’s contributions, guidance and enthusiasm toward the Pulmonary Vascular Research Institute are immeasurable. He would frequently send me multipage emails about new ideas and opportunities. He will be dearly missed.

Figure 1: Peter Raymond, MBE

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Stuart Rich University of Chicago, PVRI Chairman BOD Website:

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How to cite this article: Rich S. Peter Raymond, MBE. PVRI Review 2011;3:4. Source of Support: Nil, Conflict of Interest: None declared.

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REVIEW ARTICLE

Hypoxia Inducible Factor and Hypoxia-mediated Pulmonary Hypertension Louise Østergaard, Max Gassmann1 Institute of Veterinary Physiology, Vetsuisse Faculty and Zurich Center for Integrative Human Physiology (ZIHP), University of Zürich, Winterthurerstrasse 260, 8057 Zürich, Switzerland, 1Universidad Peruana Cayetano Heredia (UPCH), Lima, Peru

The response to hypoxia of both the systemic and pulmonary circulation is dependent on oxygen sensing and subsequent adaptations. These adaptations are, at least in part, mediated by several oxygen-dependent transcription factors that can initiate changes in gene expression. The hypoxia-inducible factor-1 (HIF-1) is believed to be the main transcription factor responsible for the responses and acclimatization to hypoxia, and certainly in the case of pulmonary hypertension does this transcription factor play an important role. As will be summarized in the present review, this has been demonstrated both on a molecular level, in animal models and in human populations. Key words: Hypoxia, pulmonary hypertension, transcription factors, HIF-1

INTRODUCTION There is no life on earth without oxygen. From prokaryotes to mammals, all aerobic organisms have adapted to maintain an oxygen supply-and-demand homeostasis [Figure 1]. However, the tissues cannot store oxygen and thus rely on an uninterrupted supply at a rate matching the constantly varying metabolic requirements. When this demand is not met, even for a short period of time, tissue hypoxemia develops and anaerobic metabolism with subsequent production of lactate will inevitably follow. Oxygen partial pressure (pO2) alterations, caused either by reduced oxygen delivery or malfunction of cellular utilization, affect either a particular tissue or even the whole body and may result in organ dysfunction and ultimately death. Changes in pO2 constitute a potential signaling mechanism regulation expression and activation of oxygen-responsive transcription factors. Obviously, the reaction to this potentially life-threatening situation requires hypoxia-dependent gene regulation which induces a variety of specific acclimatization mechanisms that ensure survival at cellular and systemic levels alike. Access this article online Quick Response Code:

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DOI: 10.4103/0974-6013.85613

Address for correspondence: Louise Østergaard, Institute of Veterinary Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Winterthurerstrasse 260, 8057 Zürich, Switzerland. E-mail: ost@access.uzh.ch

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Because the pulmonary and systemic vasculature is exposed to hypoxia, a response is activated within seconds, possibly also via the airway chemoreceptors. Oxygen sensing occurs within seconds, whereas changes in gene expression require minutes to hours. To mediate these acclimatizing effects, a range of oxygen-sensitive transcription factors fulfill important roles. The present perception is that an oxygen sensor that responds to changes in pO 2 will relay signals regulating gene expression through activation of specific transcription factors.[1] The hypoxia-inducible factor-1 (HIF-1) is believed to be the main transcription factor mediating these molecular responses, but other transcription factors such as nuclear factor kappa B (NF- B), peroxisome proliferator-activated receptors (PPARs) and early growth response-1 (Egr-1) are also described to be involved. Upon exposure to low pO2, the pulmonary circulation increases its pressure. This is a self-regulatory mechanism to maintain the optimal balance between the lungs’ ventilation and perfusion. As such, the vasoconstriction acts to reduce the lungs’ perfusion of underventilated areas and instead divert blood to well-ventilated regions. When experiencing acute hypoxia, this response is mainly coupled to a transient and reversible change in vascular tone, whereas chronic hypoxia, on the other hand, is associated with sustained pulmonary hypertension (PH) coupled with endothelial dysfunction. This threatening condition is characterized by an elevation in mean pulmonary arterial pressure (mPAP) due to a combination of an increase in vasoconstrictors/decrease in vasodilators on the one hand and hypertrophy of the pulmonary arteries on the other hand. A constant rise in mPAP will lead to right ventricular hypertrophy and eventually right ventricular failure, ultimately leading to death.[2] PVRI REVIEW

Østergaard and Gassmann: HIF and pulmonary hypertension

oxygenation on the endothelium may include changes in the secretion of, for instance, vasodilators and constrictors like nitric oxide (NO), prostacyclin, ET-1, angiotensin II, and serotonin.[4] Often, constrictors and/or their receptors are upregulated, whereas the release of dilators is decreased. Furthermore, persistent structural alterations of the small pulmonary arterioles (i.e. pulmonary vascular remodeling) are believed to be caused by proliferation of endothelial cells. Complex pulmonary vascular lesions, mostly found at sites of bifurcations (the socalled plexiform lesions), are frequently observed in the lungs of patients suffering from severe PH.[5,6] It has been demonstrated that apoptosis of endothelial cells results in the selection of an apoptosis-resistant, proliferating and phenotypically altered endothelial phenotype that can then give rise to plexiform lesions.[7]

HYPOXIA-INDUCIBLE FACTOR Hypoxia-sensitive transcription factors are activated by reduced oxygen supply and can regulate the cellular signaling response. This response is directed at the genetic level by binding to control regions of target genes and thereby influencing their expression. Transcription factors can modulate the initiation, stimulation or termination of the transcriptional process. Changes in the composition of gene expression through regulatory transcription factors are fundamental components in determining the cellular response to oxidative variations. Upon activation, the transcription factor translocates from the cytoplasm to the nucleus. The process from activation to translocation in order to target gene binding and transcription requires multiple steps, and therefore the gene regulation as a result of oxygen reductions involves complex interactions of multiple cellular pathways. Figure 1: Inspired normoxic dry air has a pO2 of 21 kPa or 160 mmHg. Upon entering the lungs this is reduced, first by humidification, to 20 kPa (150 mmHg), and due to the constant removal of oxygen by the pulmonary capillaries, the pO2 in the alveolae is approximately 14 kPa (100 mmHg). In the blood, the oxygen tension is normally between 5 and 13 kPa (40-90 mmHg), venous to arterial side, respectively. Once the oxygen reaches the single cells in the tissue, the pO2 goes down to 0.5-2.5 kPa (4-20 mmHg), being the lowest in the mitochondria. It is therefore obvious that only small changes in oxygen pressure, uptake or delivery can greatly influence the amount of oxygen that can be utilized by the mitochondria for respiration, thereby possibly creating a supply-demand mismatch

PULMONARY HYPERTENSION In most vertebrates, the pulmonary circulation represents a low-pressure, high-flow system. The normal mPAP is below 25 mmHg, and the resistance is approximately one-tenth of that found in the systemic circulation (average 67±30 dynes sec/ cm5).[3] PH is defined as an mPAP above 25 mmHg at rest or 30 mmHg at exercise, with a normal resting mPAP being between 12 and 16 mmHg. A characteristic feature is luminal vascular obstruction caused by cell proliferation of smooth muscle cells, by thrombosis and also to a varying degree by vasoconstriction. Often, these physiological changes reflect a homeostatic imbalance characterized by disproportion between secreted vasodilators and constrictors as well as an increased release of mediators that affect growth and thrombosis. A possible cause of this pathological condition could be endothelial dysfunction. Dysfunctional endothelial cells play a central and critical role in the initiation and progression of severe PH. The effects of reduced PVRI REVIEW

Erythropoietin (EPO) expression was previously used to study hypoxia-responsive transcription factors regulated by oxygen levels.[8] Later, a hypoxia-inducible enhancer 3 to the human EPO gene was discovered (5-RCGTG-3) which contained a hypoxiaresponsive element (HRE) that was required for hypoxia-mediated transcription.[9] This observation subsequently led to the isolation and cloning of a dimeric factor binding to the HRE upon hypoxia, termed the HIF-1.[10-12] HIF-1 turned out to be a ubiquitously expressed heterodimeric basic helix-loop-helix/PER/ARNT/SIM (PAS) domain transcription factor composed of an  subunit, sensitive to oxygen availability, and a constitutively expressed  subunit, the latter being shared with other transcription factors (for reviews, see[13-15]). The  subunit was earlier identified as the heterodimerization partner of the dioxin receptor/aryl hydrocarbon receptor (AhR) and was hence known as the AhR nuclear translocator (ARNT, see[16]). Heterodimerization of the a subunit with ARNT is required for DNA binding and transactivation of target genes,[17-19] but not for translocation into the nucleus.[20,21] The ability of this transcription factor to instantly switch on and off the activity according to changes in pO2 is due to the oxygen-labile HIF- subunit. This very efficient mode of control is illustrated by a half-life of HIF-1 of less than 5 min upon normoxia,[22] and accumulation of HIF-1 in the nucleus already after less than 2 min of hypoxic exposure.[23] Importantly, HIF activity is regulated by the oxygen-dependent degradation domain (ODD), which is responsible for normoxic HIF-1 ubiquitination and subsequent degradation via the proteasome pathway. [24,25] Within the ODD, two proline

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residues (Pro402 and Pro564 in human HIF-1) are the substrates for hydroxylation mediated by specific prolyl hydroxylase enzymes. [26,27] These enzymes belong to a family of ironcontaining hydroxylases (i.e. PHD1, PHD2, and PHD3) that have low affinity for oxygen and can act as oxygen sensors.[27,28] All require oxygen and 2-oxoglutarate as co-substrates and contain iron in coordination with two histidines and one aspartic acid residue. In order to retain iron in its enzymatically active ferrous state, ascorbate is also required.[28,29]

Table 1: HIF-1 targets[37,38,74,75] Angiogenesis Angiopoietin-2 Angiopoietin-4 Autocrine motility factor CXCR4 Endocrine gland VEGF Endoglin Erythroblastosis virus transforming sequence (ETS-1) Fibronectin-1 LDL-receptor-related protein-1

Once the ODD prolyl residues are hydroxylated, the degradation pathway is triggered with the immediate binding of the von Hippel-Lindau tumor suppressor protein (pVHL) to the a subunit.[26,27] pVHL is the recognition component of an E3 ubiquitin-protein ligase, and its binding, in turn, recruits the other involved proteins, namely elongin C, elongin B, cullin 2 and RBX1.[30] The complete ligase complex can then interact with E1 ubiquitin-activating and E2 ubiquitin-conjugating enzymes, thus mediating ubiquitin tagging of the target protein and initiating its subsequent degradation in the 26S proteasome[31-33] [Figure 2].

MIC2/CD99 Plasminogen activator inhibitor-1 Transforming growth factor-3 Vascular endothelial growth factor VEGF receptor-1 (flt-1) Cell proliferation and survival Cyclin G2

During hypoxic conditions and the subsequent stabilization of the HIF- subunit, a heterodimerization with HIF-/ARNT takes place, forming the active transcription factor. This factor can then bind to HREs and recruit co-activators such as p300/CBP for the transactivation of target genes.

Erythropoietin

Insulin-like growth factor-2 (IGF-2) NIP3 NIX p21 Placental growth factor RTP801 IGF-binding protein-1 IGF-binding protein-2 IGF-binding protein-3 Metabolism; glucose, iron, nucleotide, extracellular matrix Aldolase-A Aldolase-C Aminopeptidase-A Adenylate cyclase Ceruloplasmin Collagen type V Cathepsin-D Enolase-1

Close to 200 validated HIF target genes such as glycolytic enzymes, proteins involved in angiogenesis or cell proliferation, transcriptional regulation and others have been identified (for review, see[34-36]). Recent studies even suggest that HIF-1 regulates the expression of hundreds of genes in human cells. [37- 39] Notable is the fact that HIF rarely upregulates just one target gene in a given pathway, but rather coordinates the response of all necessary steps. Table 1 shows a selection of validated HIF targets and their functions. At least three isoforms of HIF exist: HIF-1, -2 and -3, all consisting of an  and a  subunit. HIF-2 is also referred to as endothelial PAS domain protein 1 (EPAS1). HIF-1 and HIF-2 share 48% overall amino acid identity.[40] HIF-1 is the most widely distributed and is believed to be the most important concerning acclimatization and/or pathophysiology, but specialized roles for HIF-2 are now emerging.[41] While HIF-1 is ubiquitously distributed, HIF-2 expression is mainly found in highly vascularized tissues such as the heart, lung, placenta, and liver and its hypoxic protein induction suggests a major role in the regulation of angiogenesis and vasculogenesis.[40-42] Studies in HIF-2 deficient mice have revealed, besides multiple organ damage, increased generation of reactive oxygen species (ROS) probably due to an impaired induction of primary antioxidant enzymes. [43] HIF-2 may thus be a regulator of ROS and mitochondrial homeostasis and, as has been shown before,[44] possibly be subject to redox regulation also. At present, it appears that HIF-1 and HIF-2 not only regulate overlapping, but also separate selections of target genes, indicating independent functions for the two isoforms. As such, HIF-2 has been shown to be involved in the adaptation of Tibetans to high altitude (hypoxia: adapting to high altitude by mutating EPAS-1, the gene encoding HIF-2; Martha C. Tissot Jan - Jun 2011 • Volume 3 • Issue 1

Glucose transporter-1 Glucose transporter-3 Glyceraldehyde-3-Pdehydrogenase Hexokinase-1 Hexokinase-2 Lactate dehydrogenase-A Leptin Matrix metalloproteinase-2 Phosphofructokinase-L 6-Phosphofructokinase-2 kinase/fructose2,6-biphosphatase Phosphoglycerate kinase-1 Prolyl-4-hydoxylase a (I) Pyruvate kinase-M Transferrin Transferrin receptor Transglutaminase-2 Triosephosphate isomerase Urokinase plasminogen activator receptor (uPAR) Vascular tone 1B-adrenergic receptor Adrenomedullin Endothelin-1 Nitric oxide synthase-2 Heme oxygenase-1 Miscellaneous Carbonic anhydrase-9 Carbonic anhydrase-12 DEC1/Stra13 DEC2 Keratin-14 Keratin-18 Keratin-19 p35srj Stanniocalcin-1 Vimentin

van Patot and Max Gassmann; In press). HIF-3 is found in six splice variants and is expressed in a number of tissues,[45,46] and, remarkably, also gives rise to an HIF antagonist. This ODD-lacking (see below), thus stable, splice variant of HIF-3, termed inhibitory PAS protein (IPAS) functions as a hypoxia-induced dominant negative repressor of HIF targets, by, for example, capping the angiogenic stimulus exerted via HIF-1 in tissues where too much vascularization would only lead to functional impairment (e.g. human cornea).[45] The exact function of HIF-3 is not well characterized, but it is suggested that this subunit may constitute a more sensitive and rapidly

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Figure 2: HIF pathway. In the presence of oxygen, PHDs catalyze the post-translational modification of HIF-1α, causing the immediate binding of the von HippelLindau tumor-suppressor protein (pVHL). pVHL binding, in turn, recruits binding of elongin-B, elongin-C, CUL-2,30 and RBX-1. Upon hydroxylation of Pro402 and Pro564 within the ODD of HIF-1α, the VHL/elongin complex, in concert with ubiquitin-activating (E1) and ubiquitin-conjugating (E2) enzymes, mediates the ubiquitination of HIF-1α, leading to subsequent degradation in the proteasome. Under hypoxia, the O2-requiring prolyl hydroxylases cannot modify HIF-1α and the protein remains stable. Stabilized HIF-1α translocates into the nucleus, where it dimerizes with HIF-1β and cofactors such as CBP/p300 and the DNA polymerase II complex to bind to HREs and activate gene transcription

Figure 3: During anaerobic glycolysis, glucose is transformed to pyruvate. As the name indicates, this takes place when O2 is limited, during, for instance, hypoxic exposures or intense exercise. Two ATP molecules per glucose molecule or about 5% of glucose’s energy potential (38 ATP molecules) are produced in this process, making it highly energy inefficient, except that the speed at which ATP is produced is about 100 times that of oxidative phosphorylation. Prolonged anaerobic glycolysis generally leads to lactic acidosis, which is a decrease in the pH. level of the blood

reacting component of the response to tissue hypoxia compared with HIF-1 or HIF-2, and thereby modulates the HIF response even in short and/or moderate hypoxia.[47] PVRI REVIEW

HIF AND PULMONARY HYPERTENSION HIF-2 heterozygous deficient mice exposed to chronic

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hypoxia do not develop PH and right ventricular hypertrophy,[48] indicating a very important role for HIF-2 in the pulmonary response to hypoxia and perhaps explaining the adaption of the Tibetan population to high altitude.[49,50] Furthermore, HIF-1+/- mice did not develop as severe polycythemia, right ventricular hypertrophy, PH, pulmonary vascular remodeling, and weight loss compared to wild-type (wt) mice, when exposed to hypoxia.[51] Also, VHL-/- mice showed increased HIF-2 levels and the spontaneous onset of PH with increasing age.[52] HIF-2 activity was increased in these animals and HIF-2, but not HIF-1, heterozygosity could suppress the induction of PH in the VHL-/- mice. Partial protection against vascular remodeling, hemorrhage, and edema, but not inflammation, was observed, suggesting a selective role for HIF-2 in pulmonary pathology. Recently, Archer and colleagues[53] found that PH is associated with a mitochondrial pseudohypoxic redox state, which favors glycolysis over aerobic metabolism [Figure 3], decreased ROS levels and increased HIF-1 levels, even under near-normoxic conditions. In combination with lower levels of superoxide dismutase (SOD2), this situation will act to further potentiate the development of PH. This metabolic shift is also described in endothelial cells cultured from patients with idiopathic PH.[54] Again, decreased levels of SOD2, and also of NO, are observed, with increased HIF-1 levels. HIF-1 is believed to be directly responsible for the lower number of mitochondria, and if SOD2 is blocked, HIF-1 levels are further augmented. A possible therapeutic treatment for PH utilizing the HIF pathway could be with dehydroepiandrosterone (DHEA), which has been shown to prevent and reverse chronic hypoxic pulmonary artery hypertension in rat via targeting smooth muscle cells. One mechanism of DHEA is to reduce HIF-1 and possibly HIF-2 accumulation, again emphasizing the importance of these transcription factors.[55] As mentioned above, EPO is one of the main targets of HIF, and this hormone contributes to the development of PH by increasing the production of red blood cells during hypoxia[56,57] and possibly by stimulating the release of endothelin-1 by endothelial cells. [58] Another prominent target of HIF, the vascular endothelial growth factor (VEGF), is implicated in vascular remodeling,[59] a well-known characteristic of PH. Other HIF regulated factors implicated in hypoxia-induced pulmonary remodeling are proliferative and vasoactive factors such as endothelin-1, platelet-derived growth factor (PDGF) and angiotensin-converting enzyme (ACE). [60] In addition, the serotonin transporter is regulated by HIF and is linked to augmented smooth muscle cell proliferation.[61] The increase in RhoA expression and concomitant downregulation of the Rho-kinase, at least in fibroblasts, can be mediated by HIF, but a clear role in PH is not yet clarified.[62] The vasodilator NO is produced by the endothelial/inducible nitric oxide synthase, e/iNOS, both of which can be induced by HIF.[63,64] This vasodilator is very important for regulating pulmonary vascular tone and is also implicated in the pathology of PH.[65] Furthermore, NO can attenuate vascular remodeling.[66] This has also been demonstrated in transgenic mice overexpressing EPO. These mice have a hematocrit of approximately 80%, but despite this they do not develop PH, Jan - Jun 2011 • Volume 3 • Issue 1

mainly due to increased NO production.[67,68] Another pathway influenced by HIF is the upregulation of ACE, that can on one side activate angiotensin, a potent vasoconstrictor, and on the other side enhance the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). Both features are important for the pathogenesis of hypoxic PH.[69] Other downstream effectors of HIF can involve, for instance, modulation of ion channels such as the downregulation of Kv+ channels and subsequent membrane depolarization in the PASMCs.[70] This mechanism has been postulated to lead to enhanced vasoconstriction as well as confer resistance to cell death via hyperpolarization of mitochondria and enhanced survivin expression.[71] Cell growth, and in addition increased cellular pH, can also be influenced by the Na+/H+ exchanger, the expression and activity of which are increased by HIF upon chronic hypoxia.[72] The expression of the canonical transient receptor potential channels (TRPC) 1 ad 6 was also observed to be augmented by HIF.[73] These channels act to increase intracellular calcium concentrations in the PASMCs, which contribute to vascular remodeling and reactivity. As described in this short review, HIFs are involved in numerous pathways that are essential for the progression of PH, and therefore HIFs are fundamental for the progression of the disease.

REFERENCES 1.

Weissmann N, Sommer N, Schermuly RT, Ghofrani HA, Seeger W, Grimminger F. Oxygen sensors in hypoxic pulmonary vasoconstriction. Cardiovasc Res 2006;71:620-9. 2. McLaughlin VV, Rich S. Severe pulmonary hypertension: Critical care clinics. Crit Care Clin 2001;17:453-67. 3. Moraes DL, Colucci WS, Givertz MM. Secondary pulmonary hypertension in chronic heart failure: The role of the endothelium in pathophysiology and management. Circulation 2000;102: 1718-23. 4. Dumas JP, Bardou M, Goirand F, Dumas M. Hypoxic pulmonary vasoconstriction. Gen Pharmacol 1999;33:289-97. 5. Tuder RM, Groves B, Badesch DB, Voelkel NF. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol 1994;144:275-85. 6. Hirose S, Hosoda Y, Furuya S, Otsuki T, Ikeda E. Expression of vascular endothelial growth factor and its receptors correlates closely with formation of the plexiform lesion in human pulmonary hypertension. Pathol Int 2000;50:472-9. 7. Sakao S, Taraseviciene-Stewart L, Lee JD, Wood K, Cool CD, Voelkel NF. Initial apoptosis is followed by increased proliferation of apoptosis-resistant endothelial cells. FASEB J 2005;19:1178-80. 8. Goldberg MA, Dunning SP, Bunn HF. Regulation of the erythropoietin gene: Evidence that the oxygen sensor is a heme protein. Science 1988;242:1412-5. 9. Semenza GL, Nejfelt MK, Chi SM, Antonarakis SE. Hypoxiainducible nuclear factors bind to an enhancer element located 3 to the human erythropoietin gene. Proc Natl Acad Sci U S A 1991;88:5680-4. 10. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 1992;12:5447-54. 11. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-pas heterodimer regulated by

9

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Østergaard and Gassmann: HIF and pulmonary hypertension cellular o2 tension. Proc Natl Acad Sci U S A 1995;92:5510-4. 12. Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 1995;270:1230-7. 13. Wenger RH. Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2regulated gene expression. FASEB J 2002;16:1151-62. 14. Fandrey J, Gassmann M. Oxygen sensing and the activation of the hypoxia inducible factor 1 (HIF-1)--invited article. Adv Exp Med Biol 2009;648:197-206. 15. Wenger RH, Gassmann M. Oxygen(ES) and the hypoxia-inducible factor-1. Biol Chem 1997;378:609-16. 16. Hoffman EC, Reyes H, Chu FF, Sander F, Conley LH, Brooks BA, et al. Cloning of a factor required for activity of the AH (Dioxin) receptor. Science 1991;252:954-8. 17. Gradin K, McGuire J, Wenger RH, Kvietikova I, Fhitelaw ML, Toftgard R, et al. Functional interference between hypoxia and dioxin signal transduction pathways: Competition for recruitment of the ARNT transcription factor. Mol Cell Biol 1996;16:5221-31. 18. Salceda S, Beck I, Caro J. Absolute requirement of aryl hydrocarbon receptor nuclear translocator protein for gene activation by hypoxia. Arch Biochem Biophys 1996;334:389-94. 19. Wood SM, Gleadle JM, Pugh CW, Hankinson O, Ratcliffe PJ. The role of the aryl hydrocarbon receptor nuclear translocator (ARNT) in hypoxic induction of gene expression. Studies in arnt-deficient cells. J Biol Chem 1996;271:15117-23. 20. Chilov D, Camenisch G, Kvietikova I, Ziegler U, Gassmann M, Wenger RH. Induction and nuclear translocation of hypoxiainducible factor-1 (HIF-1): Heterodimerization with ARNT is not necessary for nuclear accumulation of hif-1alpha. J Cell Sci 1999;112:1203-12. 21. Kallio PJ, Okamoto K, O’Brien S, Carrero P, Makino Y, Tanaka H, et al. Signal transduction in hypoxic cells: Inducible nuclear translocation and recruitment of the CBP/P300 coactivator by the hypoxia-inducible factor-1alpha. EMBO J 1998;17:6573-86. 22. Huang LE, Arany Z, Livingston DM, Bunn HF. Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its alpha subunit. J Biol Chem 1996;271:32253-9. 23. Jewell UR, Kvietikova I, Scheid A, Bauer C, Wenger RH, Gassmann M. Induction of HIF-1alpha in response to hypoxia is instantaneous. FASEB J 2001;15:1312-4. 24. Huang LE, Gu J, Schau M, Bunn HF. Regulation of hypoxiainducible factor 1alpha is mediated by an o2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci U S A 1998;95:7987-92. 25. Pugh CW, O‘Rourke JF, Nagao M, Gleadle JM, Ratcliffe PJ. Activation of hypoxia-inducible factor-1: Definition of regulatory domains within the alpha subunit. J Biol Chem 1997;272:11205-14. 26. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, et al. Hifalpha targeted for vhl-mediated destruction by proline hydroxylation: Implications for O2 sensing. Science 2001;292:464-8. 27. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, et al. Targeting of HIF-alpha to the von hippel-lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001;292:468-72. 28. Bruick RK, McKnight SL. A conserved family of prolyl-4hydroxylases that modify HIF. Science 2001;294:1337-40. 29. Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O‘Rourke J, Mole DR, et al. C. Elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 2001;107:43-54. 30. Stebbins CE, Kaelin WG Jr, Pavletich NP. Structure of the vhl-elonginc-elonginb complex: Implications for VHL tumor suppressor function. Science 1999;284:455-61. 31. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, PVRI REVIEW

32. 33.

34. 35. 36. 37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

 10 

Cockman ME, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999;399:271-5. Krek W. Vhl takes HIF’s breath away. Nat Cell Biol 2000;2: E121-3. Kamura T, Sato S, Iwai K, Czyzyk-Krzeska M, Conaway RC, Conaway JW. Activation of HIF1ALPHA ubiquitination by a reconstituted von hippel-lindau (VHL) tumor suppressor complex. Proc Natl Acad Sci U S A 2000;97:10430-5. Harris AL. Hypoxia - A key regulatory factor in tumour growth. Nat Rev Cancer 2002;2:38-47. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003;3:721-32. Wenger RH, Stiehl DP, Camenisch G. Integration of oxygen signaling at the consensus HRE. Sci STKE 2005;2005: re12. Elvidge GP, Glenny L, Appelhoff RJ, Ratcliffe PJ, Ragoussis J, Gleadle JM. Concordant regulation of gene expression by hypoxia and 2-oxoglutarate-dependent dioxygenase inhibition: The role of HIF-1alpha, HIF-2alpha, and other pathways. J Biol Chem 2006;281:15215-26. Manalo DJ, Rowan A, Lavoie T, Natarajan L, Kelly BD, Ye SQ, et al. Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood 2005;105:659-69. Ortiz-Barahona A, Villar D, Pescador N, Amigo J, del Peso L. Genome-wide identification of hypoxia-inducible factor binding sites and target genes by a probabilistic model integrating transcription-profiling data and in silico binding site prediction. Nucleic Acids Res 2010;38:2332-45. Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, FujiiKuriyama Y. A novel BHLH-pas factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci U S A 1997;94:4273-8. Wiesener MS, Jurgensen JS, Rosenberger C, Scholze CK, Horstrup JH, Warnecke C, et al. Widespread hypoxia-inducible expression of HIF-2alpha in distinct cell populations of different organs. FASEB J 2003;17:271-3. Tian H, Hammer RE, Matsumoto AM, Russell DW, McKnight SL. The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes Dev 1998;12:3320-4. Scortegagna M, Ding K, Oktay Y, Gaur A, Thurmond F, Yan LJ, et al. Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in EPAS1-/- mice. Nat Genet 2003;35:331-40. Lando D, Pongratz I, Poellinger L, Whitelaw ML. A redox mechanism controls differential DNA binding activities of hypoxia-inducible factor (HIF) 1alpha and the HIF-like factor. J Biol Chem 2000;275:4618-27. Makino Y, Cao R, Svensson K, Bertilsson G, Asman M, Tanaka H, et al. Inhibitory pas domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 2001;414:550-4. Makino Y, Kanopka A, Wilson WJ, Tanaka H, Poellinger L. Inhibitory pas domain protein (IPAS) is a hypoxia-inducible splicing variant of the hypoxia-inducible factor-3alpha locus. J Biol Chem 2002;277:32405-8. Heidbreder M, Frohlich F, Johren O, Dendorfer A, Qadri F, Dominiak P. Hypoxia rapidly activates HIF-3alpha MRNA expression. FASEB J 2003;17:1541-3. Brusselmans K, Compernolle V, Tjwa M, Wiesener MS, Maxwell PH, Collen D, et al. Heterozygous deficiency of hypoxia-inducible factor-2alpha protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia. J Clin Invest 2003;111:1519-27. Beall CM, Cavalleri GL, Deng L, Elston RC, Gao Y, Knight J, et al. Natural selection on epas1 (HIF2ALPHA) associated with low hemoglobin concentration in Tibetan highlanders. Proc Natl Acad Jan - Jun 2011 • Volume 3 • Issue 1

Østergaard and Gassmann: HIF and pulmonary hypertension Sci U S A 2010;107:11459-64. 50. Simonson TS, Yang Y, Huff CD, Yun H, Qin G, Witherspoon DJ, et al. Genetic evidence for high-altitude adaptation in Tibet. Science 2010;329:72-5. 51. Yu AY, Shimoda LA, Iyer NV, Huso DL, Sun X, McWilliams R, et al. Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1alpha. J Clin Invest 1999;103:691-6. 52. Hickey MM, Richardson T, Wang T, Mosqueira M, Arguiri E, Yu H, et al. The von Hippel-Lindau Chuvash mutation promotes pulmonary hypertension and fibrosis in mice. J Clin Invest 2010;120:827-39. 53. Archer SL, Gomberg-Maitland M, Maitland ML, Rich S, Garcia JG, Weir EK. Mitochondrial metabolism, redox signaling, and fusion: A Mitochondria-ROS-HIF-1alpha-KV1.5 o2-sensing pathway at the intersection of pulmonary hypertension and cancer. Am J Physiol Heart Circ Physiol 2008;294: H570-8. 54. Fĳalkowska I, Xu W, Comhair SA, Janocha AJ, Mavrakis LA, Krishnamachary B, et al. Hypoxia inducible-factor1alpha regulates the metabolic shift of pulmonary hypertensive endothelial cells. Am J Pathol 2010;176:1130-8. 55. Dessouroux A, Akwa Y, Baulieu EE. Dhea decreases hif-1alpha accumulation under hypoxia in human pulmonary artery cells: Potential role in the treatment of pulmonary arterial hypertension. J Steroid Biochem Mol Biol 2008;109:81-9. 56. Barer GR, Bee D, Wach RA. Contribution of polycythaemia to pulmonary hypertension in simulated high altitude in rats. J Physiol 1983;336:27-38. 57. Carlini RG, Dusso AS, Obialo CI, Alvarez UM, Rothstein M. Recombinant human erythropoietin (RHUEPO) increases endothelin-1 release by endothelial cells. Kidney Int 1993;43: 1010-4. 58. Vogel V, Kramer HJ, Backer A, Meyer-Lehnert H, Jelkmann W, Fandrey J. Effects of erythropoietin on endothelin-1 synthesis and the cellular calcium messenger system in vascular endothelial cells. Am J Hypertens 1997;10:289-96. 59. Voelkel NF, Hoeper M, Maloney J, Tuder RM. Vascular endothelial growth factor in pulmonary hypertension. Ann N Y Acad Sci 1996;796:186-93. 60. Hanze J, Weissmann N, Grimminger F, Seeger W, Rose F. Cellular and molecular mechanisms of hypoxia-inducible factor driven vascular remodeling. Thromb Haemost 2007;97:774-87. 61. Eddahibi S, Fabre V, Boni C, Martres MP, Raffestin B, Hamon M, et al. Induction of serotonin transporter by hypoxia in pulmonary vascular smooth muscle cells. Relationship with the mitogenic action of serotonin. Circ Res 1999;84:329-36. 62. Greĳer AE, van der Groep P, Kemming D, Shvarts A, Semenza GL, Meĳer GA, et al. Up-regulation of gene expression by hypoxia is mediated predominantly by hypoxia-inducible factor 1 (HIF-1). J Pathol 2005;206:291-304. 63. Coulet F, Nadaud S, Agrapart M, Soubrier F. Identification of hypoxia-response element in the human endothelial nitric-oxide

Jan - Jun 2011 • Volume 3 • Issue 1

synthase gene promoter. J Biol Chem 2003;278:46230-40. 64. Palmer LA, Semenza GL, Stoler MH, Johns RA. Hypoxia induces type II nos gene expression in pulmonary artery endothelial cells via HIF-1. Am J Physiol 1998;274: L212-9. 65. Steudel W, Ichinose F, Huang PL, Hurford WE, Jones RC, Bevan JA, et al. Pulmonary vasoconstriction and hypertension in mice with targeted disruption of the endothelial nitric oxide synthase (NOS 3) Gene. Circ Res 1997;81:34-41. 66. Ozaki M, Kawashima S, Yamashita T, Ohashi Y, Rikitake Y, Inoue N, et al. Reduced hypoxic pulmonary vascular remodeling by nitric oxide from the endothelium. Hypertension 2001;37:322-7. 67. Ruschitzka FT, Wenger RH, Stallmach T, Quaschning T, de Wit C, Wagner K, et al. Nitric oxide prevents cardiovascular disease and determines survival in polyglobulic mice overexpressing erythropoietin. Proc Natl Acad Sci U S A 2000;97:11609-13. 68. Weissmann N, Manz D, Buchspies D, Keller S, Mehling T, Voswinckel R, et al. Congenital erythropoietin over-expression causes “anti-pulmonary hypertensive” structural and functional changes in mice, both in normoxia and hypoxia. Thromb Haemost 2005;94:630-8. 69. Zhang R, Wu Y, Zhao M, Liu C, Zhou L, Shen S, et al. Role of HIF-1alpha in the regulation ace and ACE2 expression in hypoxic human pulmonary artery smooth muscle cells. Am J Physiol 2009;297: L631-40. 70. Shimoda LA, Manalo DJ, Sham JS, Semenza GL, Sylvester JT. Partial HIF-1alpha deficiency impairs pulmonary arterial myocyte electrophysiological responses to hypoxia. Am J Physiol 2001;281: L202-8. 71. Bonnet S, Michelakis ED, Porter CJ, Andrade-Navarro MA, Thebaud B, Bonnet S, et al. An abnormal mitochondrial-hypoxia inducible factor-1alpha-kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: Similarities to human pulmonary arterial hypertension. Circulation 2006;113:2630-41. 72. Shimoda LA, Fallon M, Pisarcik S, Wang J, Semenza GL. HIF-1 regulates hypoxic induction of NHE1 expression and alkalinization of intracellular PH in pulmonary arterial myocytes. Am J Physiol 2006;291: L941-9. 73. Wang J, Weigand L, Lu W, Sylvester JT, Semenza GL, Shimoda LA. Hypoxia inducible factor 1 mediates hypoxia-induced TRPC expression and elevated intracellular CA2+ in pulmonary arterial smooth muscle cells. Circ Res 2006;98:1528-37. 74. Kaluz S, Kaluzova M, Stanbridge EJ. Regulation of gene expression by hypoxia: Integration of the HIF-transduced hypoxic signal at the hypoxia-responsive element. Clin Chim Acta 2008;395:6-13. 75. Rocha S. Gene regulation under low oxygen: Holding your breath for transcription. Trends Biochem Sci 2007;32:389-97.

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How to cite this article: Østergaard L, Gassmann M. Hypoxia Inducible Factor and Hypoxia-mediated Pulmonary Hypertension. PVRI Review 2011;3:5-11. Source of Support: Nil, Conflict of Interest: None declared.

PVRI REVIEW

REVIEW ARTICLE

The Prevalence of Pulmonary Hypertension in Schistosomiasis: A Systematic Review Thomas J. C. Ward, Alan Fenwick1, Ghazwan Butrous2 Imperial College, London Imperial College London, 1Department of Infectious Disease Epidemiology, Imperial College London, 2University of Kent, Kent, United Kingdom

Pulmonary hypertension in schistosomiasis is a topic which has recently attracted renewed attention. Schistosomiasis is endemic in 74 countries, with the greatest burden in sub-Saharan Africa. Pulmonary hypertension is a serious complication of infection for which the prevalence is unclear. Few systematic reviews have attempted to collate and evaluate the evidence behind this issue. A thorough search of the literature was performed and studies assessing prevalence were retrieved and analyzed against a quality assessment score. A total of 38 studies were identified of which 28 were retrieved for assessment. Due to poor epidemiological methods, none of the studies identified met the review’s initial inclusion criteria. There has been an increase in the number of studies over recent years, with better use of invasive methods to detect pulmonary hypertension. However, the majority of these are hospital-based studies, many are from Brazil, most have small sample sizes and there is much variation in the definition of pulmonary vascular disease used. Pulmonary hypertension in schistosomiasis is likely to cause a substantial burden of disease and is potentially the leading cause of pulmonary hypertension worldwide. However, good quality studies with large community samples from sub-Saharan Africa are desperately needed in order to accurately estimate the number of people affected globally.

Key words: Schistosomiasis, Epidemiology, pulmonary hypertension

INTRODUCTION Schistosomiasis is one of the most important neglected tropical diseases worldwide. It is estimated that 200 million people are infected globally, and despite being based on one study from the 1980s, this figure has been enshrined in the literature and adopted by the World Health Organization (WHO). A recent review (Steinman et al.) suggest that the true figure is now over 200 million.[1] The disease is endemic in 74 countries, with a reported 85% of the infected individuals living in sub-Saharan Africa.[1] Pulmonary hypertension is a late consequence of infection, which has benefited from a revival of interest in recent years, driven by the discovery of possible new treatment options. Yet, the prevalence of this condition in association with schistosomiasis is essentially unknown. Schistosomiasis is a parasitic infection caused by flatworms of the Schistosoma spp. There are three major species which cause the disease in man: Schistosoma haematobium, Access this article online Quick Response Code:

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Pulmonary schistosomiasis can either be acute or chronic. Acute pulmonary schistosomiasis is seen shortly after primary infection and is part of the syndrome of Katayama fever; classically seen in travelers from non-endemic areas, although it can be seen in the local population.[4] Acute pulmonary schistosomiasis can have serious consequences,[5] but chronic pulmonary schistosomiasis, the topic of this review, is thought to be the main long term consequence and disease burden to populations in endemic areas, leading to vascular remodeling and pulmonary hypertension. The adult S. mansoni worms reside in the superior mesenteric veins where they can live for up to 20 years though probably for an average of 3-5 years, producing up to 300 ova per day. Many of these ova pass through the blood vessel wall and enter the intestinal lumen to be released into the feces. However, an equal number of ova fail to penetrate the vessel wall and are transported via the hepatic portal

DOI: 10.4103/0974-6013.85614

Address for correspondence: Thomas J. C. Ward, School of Medicine, Imperial College London, UK. E-mail: thomas.ward06@imperial.ac.uk

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Schistosoma mansoni and Schistosoma japonicum. S. mansoni is the main species which is known to cause pulmonary hypertension, but reports of cases caused by S. haematobium[2] and S. japonicum[3] do exist. The life cycle of these worms involves a freshwater snail host, which is penetrated by miracidia released in the urine or feces of infected individuals. These miracidia multiply asexually within the snail before being released as cercariae capable of penetrating the unbroken skin of a human host. The development in the lung is an essential stage in the early life cycle of the schistosome. After entering through the skin, cercariae become schistosomula which migrate to the lungs where they develop further, before moving to the liver and finally taking up residence as an adult pair in the mesenteric or renal veins some six weeks after exposure [Figure 1].

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vein to the liver where they become lodged. When they die, a granulomatous reaction to these ova can result in a pipe-shaped fibrosis around the hepatic vein, which is known as Symmer’s fibrosis. This typically occurs many years after initial infection, and in the absence of liver failure as many hepatocytes remain intact. Periportal fibrosis leads to blockage of hepatic blood flow and portal hypertension. As a result of this increased resistance, portal systemic shunting occurs, forming a direct link from the mesenteric veins to the lungs.[6] Ova therefore have access to the pulmonary circulation and pulmonary hypertension may develop in some individuals. Pulmonary hypertension is rarely seen in S. mansoni infection without the presence of hepatosplenic disease.[7] S. haematobium ova can also be found in the lung; they may indeed migrate there more frequently than S. mansoni ova as the route they take is more direct, but cause damage less frequently.[8] Schistosomal ova were first discovered in the lung by Belleli in 1885.[9] Much of the early work on this subject was done in Egypt where schistosomiasis was reported to affect 60-70% of the population at the time.[10] Cases of cor pulmonale associated with schistosomiasis were first described by Azmy and Effat[11] and Clark and Graef,[12] while Ghreeb and Shaw[10] published the first pathological study where they stressed that vascular lesions only occurred in heavy infections. It was initially thought that disease developed solely due to mechanical obstruction of the ova and focal arteritis.[13] However, current thinking is that schistosomal pulmonary hypertension is probably caused through multiple mechanisms. One of the most important of these is likely to be vascular remodeling caused by the release of Th2 cytokines in response to schistosome ova.[14] A Th2-mediated response occurs late in infection and is necessary for control of the parasite, but also leads to local inflammation and hypertrophy of the blood vessel wall. However, presence of ova in the lungs may not be necessary for the development of pulmonary disease.[15,16] Increased blood flow to the lungs due to portal systemic shunting leads to increased shear stress on the pulmonary arteries and contributes to pulmonary hypertension.[17] Delivery of vasoactive substances, which would usually be broken down in the liver, from the digestive tract to the lung may also play a role, although perhaps not in all cases.[18] This mechanism is thought to explain why pulmonary hypertension is associated with portal hypertension of other etiologies.[19] Similarities to other forms of Pulmonary Arterial Hypertension (PAH) suggest that it is not simply related to mechanical obstruction from eggs or granuloma. The clinical classification of pulmonary hypertension has recently been updated[20] and schistosomal pulmonary hypertension was reclassified under PAH in recognition of its similarity to Idiopathic Pulmonary Arterial Hypertension (IPAH), instead of its previous classification under “chronic thrombotic and/or embolic disease”. The clinical features of schistosomal pulmonary hypertension are indistinguishable from IPAH and the histopathology is also likely to be identical.[21] Histologically, fibrosis and granulomatous tissue are seen in the lung, with plexiform lesions formed by the formation of new blood vessels. Hypertrophy of the intima and media may remain even after the infection has been cleared.[22] The remodeling is heterogenous, with some areas of lung being more affected than others.[23] Jan - Jun 2011 • Volume 3 • Issue 1

Pulmonary hypertension is a serious condition which can lead to cor pulmonale and eventual death due to right heart failure. Schistosomal pulmonary disease is often asymptomatic, but the most common clinical symptoms include dyspnea, weakness, syncope and palpitations.[24] It is unknown whether treatment of schistosomiasis can improve the condition, but it is likely that the damage is irreversible. It is generally thought that the progression is similar to IPAH although there seems to be some evidence that the prognosis is less severe.[25-27] Interestingly, Machado et al. suggested that patients with schistosomal pulmonary hypertension have a better functional capacity than patients whose pulmonary hypertension is caused by other etiologies.[27] The burden of various diseases is calculated by the WHO in terms of disability-adjusted life years (DALYs), defined as the sum of years of life lost (YLL) and years lost to disability (YLD).[28] The figure for YLD is dependent on the disability weight allocated to that condition, reflective of the impairment to the individual affected. Schistosomiasis was estimated to cause 1.7 million DALYs in 2004 which places it relatively far down in the list of infectious diseases. This figure was based on a disability weighting of 0.05 in childhood and 0.06 in adulthood, comparable to decoloration of the face, and many feel that it should be much higher.[29] No mention is made of pulmonary hypertension as an outcome of infection when estimating the burden; however, the WHO Expert Committee suggested that a wider range of sequelae should be included.[30] DALYs for the major helminthiases and other neglected tropical diseases are currently being re-evaluated,[31] providing an opportunity for this to be taken into account. Better estimation of the burden caused by the various complications of infection would allow for a better understanding of the importance of schistosomiasis globally and provision of an appropriate amount of funding for its control. Schistosomiasis is a disease of the developing world and the majority of infected individuals live in sub-Saharan Africa.[1] Approximately 76% of the population of sub-Saharan Africa live near rivers, lakes, and other water bodies contaminated with snails capable of acting as hosts for miracidia.[32] Therefore, much of this population is at risk from schistosomiasis infection, a number that could increase as a result of climate change.[33] Pulmonary hypertension in these areas may be confounded by co-infection with HIV which is thought to cause pulmonary hypertension in 0.5% of sufferers.[34,35] Many other causes of pulmonary hypertension are more common in the developing world and are likely to add to the problem.[36,37] As so many people in these countries are affected, better knowledge of the association and its frequency is essential to aid control programs. The aim of this review is to evaluate the data relating to prevalence of pulmonary hypertension in schistosomiasis with the intention of estimating its prevalence worldwide and understanding its importance in assessing the global burden of disease due to this infection.

MATERIALS AND METHODS A full review of the literature was conducted and the databases searched included MEDLINE, EMBASE and the Cochrane library. The search strategy included all the terms with the prefix “schistosom” or “bilharz” and “pulmonary hypertension” or “cor

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pulmonale” or “pulmonary vascular”. The results were then hand searched for relevant studies. The reference lists of the articles identified were also searched and relevant articles were included.

quite large, ranging from 8 to 682 patients, with a mean of 173. However, many of the more recent studies had smaller samples [Table 1].

Papers were first checked for measures of prevalence of pulmonary hypertension in schistosomiasis and were then checked against inclusion criteria to determine the epidemiological methods used. Only English language papers or papers with an English translation were included. Unpublished studies were not included.

No studies scored more than 3 on the quality assessment score, indicating the lack of robust epidemiological studies on the prevalence of pulmonary hypertension in those infected with schistosomiasis. Studies did not meet the final inclusion criteria for a variety of reasons, but notably none of the articles identified studied a random community-based sample. The studies with the highest quality score differed from the rest of the group as they were more recent and all were from Brazil [Table 2].

The search strategy found a total of 207 articles on the subject, with 38 including measures of prevalence. Two of these were unavailablea and the remaining 36 were retrieved and subject to assessment against inclusion criteria. Studies that did not provide some measure of the prevalence of pulmonary hypertension either a) in infection, b) in hepatosplenic schistosomiasis, or c) as a proportion of all pulmonary hypertension cases were excluded. All studies looking at pulmonary hypertension in S. haematobium or S. japonicum infection were also excluded [Figure 2]. Papers were assessed for the following: (1) Design, with case-control and prevalence studies seen as the most reliable and autopsy studies assumed to overestimate more serious manifestations of disease. Case-control studies were not seen as essential due to the extremely low prevalence of pulmonary hypertension in non-endemic areas (2) Selection of patients, with attention focused on whether there was a random population-based sample as opposed to a hospital-based study which would only see more serious cases (3) How diagnosis of schistosomiasis was assessed? (4) Definition of pulmonary vascular disease including method of measuring pulmonary hypertension and cut-off values used (5) Sample size (6) Exclusion or adjustment for possible confounders Based on these factors, the papers were given a quality score from 1 to 6, with 1 being given to studies which scored highly on each of the above points. It would have been ideal to have included only studies with a quality score of greater than 2 in the final assessment to estimate the prevalence of pulmonary hypertension in schistosomiasis. However, the papers reviewed did not meet these criteria and so only a qualitative evaluation was possible. The subsection of studies with the highest quality score of 3 was separately analyzed in the results to assess the best current evidence.

RESULTS Looking at the studies assessed against the quality score, there was a large spread in the years in which they were published, ranging from 1938 to 2009. There was a relative gap in research from 1978 to 1995 during which only two of the assessed studies were published. From 1995 to 2009, 13 papers (46.4% of the total) were published, suggesting a recent increase in interest in this topic [Figure 3]. The majority of studies were from Brazil which accounted for 57.1% of the assessed articles. 21.4% were from Egypt with the rest coming from Puerto Rico, Uganda, Sudan and Ethiopia. 42.9% of the studies were prevalence studies with another 32.1% being autopsy studies. The study sample sizes were generally PVRI REVIEW

The parameters used to estimate the burden of schistosomal pulmonary hypertension fall into three main categories. Firstly, studies looked at the prevalence of pulmonary hypertension in those infected with schistosomiasis and results ranged from 0 to 28.3% with a mean of 7.4% and a standard deviation of 8.0%. Those studies that estimated the prevalence of pulmonary hypertension in individuals with hepatosplenic schistosomiasis gave prevalences ranging from 0 to 60% with a mean of 18.1% and a standard deviation of 15.9%. Finally, estimates of the proportion of cases of pulmonary hypertension caused by schistosomiasis in areas endemic for S. mansoni ranged from 6.3 to 46.5% with a mean of 20.9% and a standard deviation of 15.9% [Table 1]. If we pool all the results, taking the total number of cases of pulmonary hypertension from the total number of individuals studied in each of the three areas, a method which takes into account the differences in sample sizes, we see a 6.1% prevalence in those having an infection with schistosomiasis, a 15.1% prevalence in those with hepatosplenic schistosomiasis and schistosomiasis as a cause of 30.8% of all cases of pulmonary hypertension. When specifically discussed, methods for detecting schistosomiasis infection were generally acceptable, usually by identifying ova in the stool. However, methods of defining pulmonary vascular disease varied broadly. Some studies, especially earlier studies, defined pulmonary hypertension histologically [46] or used the diagnosis of cor pulmonale to define cardiopulmonary disease, established on the basis of right ventricular wall thickness. [7,38,42,43,47,57] Other studies defined pulmonary hypertension clinically,[39] radiologically[44] or by the presence of schistosomal arterial lesions in the lungs.[10] When pulmonary artery pressure was measured, it was either measured using transthoracic echocardiography[27,49,52,58,60] or invasively through the introduction of a pulmonary artery catheter.[45,51,54-56,59,61] Cutoffs for pulmonary hypertension varied from mean pulmonary artery pressures (mPAP) of 15-35 mmHg, with one study using a cutoff of a pulmonary artery systolic pressure of 40 mmHg.[27] Patients with confounding conditions were excluded or adjusted for in 9 out of the 28 assessed studies, more often in the most recent studies. Exclusion criteria were generally either (1) other conditions which could have caused the patient’s liver disease such as alcohol abuse or hepatitis or (2) other conditions which could have caused the patient’s pulmonary hypertension such as congenital heart disease. Only the study by Ferreira et al. used both the criteria to exclude patients from their study.[60] Few studies compared infected and uninfected individuals and

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Cercariae become schistosomula and migrate to the lungs

Sporocysts in snail produce cercariae

Cercariae penetrate skin Pulmonary hypertension develops

Schistosomula migrate to the liver where they mature to the adult form

S. mansoni ova cause Symmer’s fibrosis and portal hypertension Miracidia penetrate snail host

An adult pair migrate against the blood flow and reside in the mesenteric/ bladder veins

S. mansoni adult worms

S. haematobium

S. mansoni and S. haematobium ova

Ova hatch releasing miracidia

released in faeces and S. japonicum ova released in urine

Figure 1: Life cycle of Schistosoma showing the effects of S. mansoni in the human host

Potentially relevant prevalence studies indentified (n=38)

25 20

Studies unavailable (n=2)

Studies retrieved for more detailed analysis (n=36)

10 5

Studies with incompatible study populations or looking at S japonicum or S haematobium infection (n=8)

0 1930

Studies assessed against quality score (n=28)

1950

1960

1970

1980

1990

2000

2010

2020

considered the prevalence of pulmonary hypertension in the background population, although this was not seen as vital as pulmonary hypertension is extremely rare in populations from non-endemic areas.

Studies with a quality score of 4 or less (n=21) Studies with a quality score of 3 or more

DISCUSSION

Studies which did not meet inclusion criteria (n=7) Studies meeting final inclusion criteria (n=0) Figure 2: Flow diagram of papers identified and those meeting inclusion criteria

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1940

Figure 3: Number of studies (cumulative) assessing prevalence by year, showing a relative gap in research from 1982 to 1995 and an increase since 1995

Schistosomiasis is a global disease for which the burden is likely to have been underestimated. The focus here is on one complication of infection and the literature has been reviewed in an attempt to estimate the proportion of infected individuals with pulmonary disease.

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One conclusion that could be made from this review is that knowledge about the prevalence of pulmonary hypertension in schistosomiasis has not progressed far since the first study in 1938.[10] The majority of studies have been undertaken on S. mansoni infection and it is now known that Symmer’s fibrosis and the resultant portal hypertension is almost always a prerequisite for this complication. The mechanism, although still uncertain, is now better understood. However, despite various attempts made to assess its prevalence throughout the world, figures vary widely and opinion on the subject ranges from the belief that it is a rare and globally insignificant complication of schistosomiasis to the view that it is the most common single cause of pulmonary hypertension worldwide. The latter view certainly seems to be the case from evidence in Brazil where Lapa et al.[58] suggest that 30% of severe pulmonary hypertension cases are as a result of this infection, a figure which is confirmed by Machado et al.,[27] and in the data provided by Butrous et al.[36] However, this is less clear in studies outside of Brazil.[49,57] The most notable finding in this review is the fact that none of the retrieved studies used vigorous epidemiological methods, which is

reflected in their failure to meet the original inclusion criteria. The main reason for this was that none obtained a random community sample from an endemic area and many studied less number of patients. Another important point to note is the methods used to classify patients as having cardiopulmonary disease. These ranged from invasive measurement of mPAP to clinical diagnosis, with some papers failing to state their classification at all. This has a significant effect on the capacity to compare these studies and may partly account for the variation in results. When looking more closely at the studies which had the best quality assessment scores [Table 2], four of these used invasive methods to detect pulmonary hypertension. Lapa et al.[61] showed that pulmonary hypertension in schistosomiasis can be interesting either pre- or post-capillary depending on the pulmonary artery occlusion pressure. This meant that only three of the five patients with elevated mPAP actually had pre-capillary hypertension and could therefore be classified as suffering from PAH, while in the remaining two, post-capillary hypertension was caused by other factors. Invasive measurements are therefore essential to find the true prevalence of PAH. Unfortunately, it is not possible to extrapolate the figures found in this study due to the relatively

Table 1: Prevalence found in all assessed studies Author

Year Estimated prevalence in schistosomiasis (%)

Shaw AFB, Gharebb AA[10]

1938

2.2

Gelfand M[38]

1949

0.0

Kenawy MR[39]

1950

Sami AA[40]

1951

Girgis B[41]

1953

Lopes de Faria J[42]

1954

6.7

Rodriguez et al.[26]

1963

Cheever AW, Andrade ZA[7]

1967

Andrade ZA, Andrade SG[43]

1970

Ongom et al.[44]

1972

Guimarães et al.[45]

1977

Hassan et al.[46]

1977

2.9

15.0

Sudan

102

Cheever et al.[47]

1978

12.9

18.2

Egypt

255

Pittella JEH, Lana-Peixoto MA[48] 1981

39.1

Brazil

Richter et al.[49]

1990

0.0

Sudan

Goncalves et al.[50]

1995

23.5

Brazil

313

Rashwan et al.

1995

0.0

Egypt

Barbosa et al.[52]

1996

28.3

Brazil

177

Lopes et al.[53]

1998

10.0

Brazil

Lopes AA, Maeda NY[54]

1998

7.5

Brazil

de Cleva et al.[55]

1999

60.0

Brazil

de Cleva et al.[56]

2003

11.8

Brazil

Aderaye G[57]

2004

0.0

Ethiopia

Lapa et al.[58]

2006

Brazil

123

de Cleva et al.[59]

2007

5.5

Brazil

Ferreira et al.[60]

2009

10.7

Brazil

Lapa et al.[61]

2009

7.8

Brazil

Machado et al.[27]

2009

Brazil

[51]

Estimated prevalence Estimated proportion of PHT Country in HSS (%) caused by schistosomiasis (%) 6.3

Sample Quality size score

Egypt

232

Zimbabwe

400

Egypt

682

Egypt

520

Egypt

500

13.5

Brazil

180

13.9

35.7

Puerto Rico

3.2

15.2

Brazil

502

26.9

Brazil

4.4

Uganda

13.6

Brazil

165

7.5 0.8 46.5

7.7

30.1

Mean

7.4

18.1

20.9

8.0

15.9

HSS – Hepatosplenic schistosomiasis, PHT – Pulmonary hypertension, SD – Standard deviation

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10.7

Brazil

Country

7.8 (4.7% Pre-capillary PHT)

30.1

Estimated proportion of PHT caused by schistosomiasis (%)

Hospital patients with PHT at a PHT specialized OPC over 2 years

Hospital patients with schistosomal liver fibrosis attending OPC between April and July 2007

Hospital patients with PHT in a 4-year period before the advent of treatment for PHT Hospital patients from non-endemic area

Hospital patients before surgery for esophageal variceal bleeding secondary to HSS

Hospital patients before surgery for HSS

Not mentioned

Patient selection

123

165

Sample size

PASP > 40 mmHg measured using TTE

mPAP > 35 mmHg measured using TTE

mPAP > 25 mmHg. Measured invasively for those with abnormal findings on TTE

mPAP > 25 mmHg presumably measured by TTE

mPAP > 25 mmHg (other cutoffs also taken). Measured invasively

mPAP > 15 mmHg. Measured invasively

mPAP > 20 mmHg. Measured invasively

Definition of pulmonary vascular disease

All patients had BMI less than 30, so reduces the chance of false positives. Cutoff for PH was quite high, so could have missed less severe cases Schistosomiasis patients performed better at the 6 MWT. No difference between the groups regarding frequency of sildenafil therapy

Primarily looking at hypoxia in schistosomiasis patients, but also assesses subjects for pulmonary hypertension Selection of patients before surgery for schistosomal portal hypertension. Cutoff for PHT very low Study of patients before surgery for esophageal variceal bleeding secondary to schistosomal PHT. EGDS found to normalize hyperdynamic circulation in contrast to DSRS Looked at PHT patients from two city hospitals. The functional class of patients with different causes of PHT was similar Large confidence intervals. Invasive measurements only for patients who had abnormal findings on echo – could have missed potential PHT cases

Comments

100% of these studies were from Brazil. 57% used invasive techniques to diagnose pulmonary hypertension. All studies looked at hospital patients except one where recruitment was not mentioned HSS – Hepatosplenic schistosomiasis, EGDS – Esophagogastric devascularization and splenectomy, DSRS – Distal splenorenal shunt surgery, PHT- Pulmonary hypertension, mPAP – mean Pulmonary artery pressure, OPC – Outpatient clinic, TTE – Transthoracic echocardiography, PASP – Pulmonary artery systolic pressure, 6MWT – 6-Minute walk test

Machado et al.[27]

Ferreira et al.[60]

Lapa et al.[61]

Lapa et al.[58]

11.8

de Cleva et al.[56]

Estimated prevalence in HSS (%)

60.0

13.6

Estimated prevalence in schistosomiasis infection (%)

de Cleva et al.[55]

Guimarães et al.[45]

Study

Table 2: Studies with the highest quality assessment score[3] study

Ward, et al.: The prevalence of pulmonary hypertension in schistosomiasis

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Ward, et al.: The prevalence of pulmonary hypertension in schistosomiasis

small sample size, large confidence intervals and selection of hospital patients. For example, one patient in this study refused to be investigated invasively; if this patient was found to have PAH, the prevalence of hepatosplenic schistosomiasis would have increased from 4.6 to 6.2%, a huge difference when applied globally. Invasive measurement is therefore the gold standard for detection of pulmonary hypertension in schistosomiasis; however, this may be a difficult tool to use in endemic areas of Africa and studies may be forced to rely on echocardiography. Yet, the study by Richter et al., in Sudan,[49] which did just that, found no cases of pulmonary hypertension, though only 16 patients were studied. Ideally, invasive methods should be used, but cheaper methods may give reasonable estimates provided large enough samples are taken, although they may overestimate the prevalence.[61] Whichever method is employed, it is vital that standardized cutoffs are used so that studies do not under- or over-exaggerate the proportion of individuals affected whilst allowing comparison of studies. Many of the studies which found very high or low prevalence are those with the smallest sample sizes. However, all but one of these studies had a quality score of 4 or less. Therefore, due to poor epidemiological methods, very little can be established from these figures, but it provides convincing evidence that larger sample sizes are required to provide an accurate prevalence, especially in this relatively uncommon manifestation. As pulmonary disease seems to predominantly occur in those with hepatic disease, many studies focus on this group of patients. It is generally thought that around 5% of untreated patients with schistosomiasis develop hepatosplenic disease,[61,62] although this, like the knowledge of the prevalence of pulmonary hypertension, is also unclear and may be much higher.[63] However, if this figure was verified, then studies of pulmonary hypertension in these select groups may give more reliable results due to the higher risk in these individuals and may be more economical as smaller samples can be used. Methods of detecting schistosomiasis in the studies were generally acceptable. However, stool examination may miss infected patients and the addition of ultrasound looking for liver left lobe enlargement or periportal fibrosis in patients from endemic areas may aid diagnosis. One limitation of measuring pulmonary hypertension in those with productive schistosomiasis infection is that infection may have resolved, yet pulmonary hypertension remains. This may give inaccurate numbers of controls with pulmonary hypertension and may underestimate the burden caused by schistosomiasis. This is a difficult barrier to overcome as prospective studies would be unethical and history of exposure is an unreliable measure of infection.[27] A reliable immunological marker of past infection would be ideal, but perhaps unrealistic. A major limitation of this review is the exclusion of foreign language studies. Much of the research in this area has been done in South America and many of the studies are therefore not published in English. To extend this study and to have a better estimation of the prevalence of this complication, it would be necessary to include these articles. PVRI REVIEW

Suggestions for the future

There has been an increase in the number of studies tackling this issue over the last 15 years and many of these studies have used invasive measurements of mPAP and have eliminated other causes of pulmonary hypertension. However, these studies have mostly been too small to give a reliable estimate of the prevalence of this unusual complication and have been hospital based. Therefore, it would be inaccurate to extrapolate these results to endemic populations. In addition, the majority of studies come from Brazil, a country where only S. mansoni is endemic and where control measures have been implemented over the recent decades, and therefore serious complications of schistosomiasis seem to be decreasing.[64] Many of the studies from Brazil could therefore underestimate the prevalence of pulmonary hypertension in untreated schistosomiasis and present another reason why these results cannot be extrapolated to other parts of the world. The majority of individuals infected with S. mansoni live in subSaharan Africa where studies have not been undertaken, and the prevalence may indeed differ from that in South America due to a variety of factors including the intensity of infection, genetic, environmental and parasite variations,[65] as well as the presence of other infectious diseases and risk factors for pulmonary hypertension. Host immunity `due to previous exposure to animal schistosomes has also been proposed as a mechanism behind different manifestations of disease in different geographic locations.[66] Due to these various factors, it may be necessary to exclude other causes of pulmonary hypertension in Africa in order to estimate the true prevalence or to conduct case-control studies to allow for this increased prevalence in the background population. Historically, it was often thought that the prevalence of schistosomal pulmonary hypertension was much lower in Africa outside of Egypt.[67] These results cannot confirm or disprove this theory, but it is certainly interesting that studies from Sudan,[49] Zimbabwe[38] and Ethiopia[57] found very low levels of pulmonary hypertension. However, there are a number of possible explanations for this result, particularly the fact that two of the studies were very small and all failed to use invasive methods to detect pulmonary hypertension. Indeed, after the initial studies in Egypt, it was thought that this complication was unlikely to occur in Brazil,[68] yet more thorough investigation has disproved this. It is clear that the research in this area is lacking and good quality epidemiological studies are needed in order to understand the true prevalence of this manifestation of infection, especially in sub-Saharan Africa where the majority of S. mansoni infection occurs. It is therefore encouraging that there seems to be an increase in the number of studies in recent years and better understanding of issue may be close at hand. Clear understanding of the prevalence and progression of this complication as well as possible treatments would allow better estimation of the burden of schistosomiasis and would aid in health strategies in endemic countries. Inclusion of a disability weight for pulmonary hypertension to a proportion of schistosomal infected individuals may potentially be a significant addition to the global burden as it is currently calculated and would provide a more accurate representation of the problem. Once pulmonary hypertension has developed, it is unlikely to

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reverse even if the infection resolves. Sami noted that vascular changes persisted even if healing of pulmonary schistosomal lesions occurred. [40] De Almeida and Andrade noted that lesions around ova disappeared with treatment but vascular remodeling remained. [22] Barbosa et al . found that even when treatment causes regression of hepatosplenomegaly, pulmonary hypertension may persist.[52] Therefore, treatment of those with pulmonary hypertension is unlikely to reverse the disease (although a single case has been reported); [69] however, it may prevent progression. No data are available regarding the usefulness of IPAH drugs such as endothelin receptor antagonists, prostanoids or phosphodiesterase inhibitors in schistosomal pulmonary hypertension, although the similar clinical and histological findings make these an attractive option. Oral phosphodiesterase inhibitors are reported to improve cardiopulmonary hemodynamics although this is still unclear. [70] However, even if these drugs were effective, they would doubtlessly be too expensive for developing countries. On a positive note, Andrade and Amaral et al. feel that there is some evidence which suggests that the number of cases of severe complications of schistosomiasis seem to be decreasing relatively quickly in Brazil since the introduction of large-scale treatment regimes.[64,71] Bina[72] found that parasite load directly correlated with the presence of manifestations of disease and serious complications only occurred at high parasite loads. Indeed, in mouse models of infection, lung egg burden correlated with the degree of pulmonary vascular remodeling and the amount of right ventricle hypertrophy. [23] Coura et al.[73] also showed that constant re-infection was required for development of manifestations and that people who moved from endemic areas did not get hepatosplenic disease. Others suggest that rapid, high-intensity infection is required for the development of pulmonary disease and that low-intensity infections fail to produce disease even over a long time period.[8,43,74] Therefore, interruption of transmission in Brazil could explain why morbidity due to schistosomiasis may be decreasing. It may then be possible to eradicate severe forms of schistosomiasis with better use of specific chemotherapy over a relatively short time span,[50] prevalence data would therefore allow the long-term benefits of treatment programmes to be estimated. This review has highlighted the lack of evidence in the field of schistosomiasis, particularly relating to the complication of pulmonary hypertension. There are a number of studies addressing this issue, but more are needed in order to arrive at an accurate conclusion. Resources invested in these studies would allow for a better estimation of the problem and may provide extra evidence of the importance of schistosomiasis control.

4. 5. 6.

9. 10.

11. 12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

REFERENCES 1.

Steinmann P, Keiser J., Bos R., Tanne M., Utzinger J., Schistosomiasis and water resources development: systematic review, metaanalysis, and estimates of people at risk, Lancet Infect Dis 2006, 6:411–425. Sersar SI, Abulmaaty RA, Elnahas HA, Moussa SA, Shiha UA, Ghafar WA, et al. A diagnostic dilemma of right lower lobe collapse caused by pulmonary bilharsiasis. Heart Lung Circ 2006;15:50-2.

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22.

23.

 19 

Watt G, Long GW, Calubaquib C, Ranoa CP. Cardiopulmonary involvement rare in severe Schistosoma japonicum infection. Trop Geogr Med 1986;38:233-9. Lambertucci JR. Pulmonary nodules on CT scan of the lungs in acute schistosomiasis. Br J Radiol 2002;75:491. Pedroso ER. Lung changes associated with schistosomiasis mansoni. Mem Inst Oswaldo Cruz 1989;84:46-57. King CL. Initiation and regulation of disease in schistosomiasis. In: Mahmoud AA, editor. Schistosomiasis London: Imperial College Press; 2001. p. 213-64. Cheever AW, Andrade ZA. Pathological lesions associated with Schistosoma mansoni infection in man. Trans R Soc Trop Med Hyg 1967;61:626-39. Smith JH. A quantitative post mortem analysis of urinary schistosomiasis in Egypt: I. Pathology and pathogenesis. Am J Trop Med Hyg 1974;23:1054. Belleli V. Les œufs de bilharzia haematobia dans les poumons. Unione Med Egypt 1885;1:22-3. Bernard-Shaw AF, Abou-Ghareeb A. The pathogenesis of pulmonary schistosomiasis in Egypt with special reference to Ayerza’s disease. J Pathol Bacteriol 1938;46:401-24. Azmy S, Effat S. Pulmonary atherosclerosis of a Bilharzial nature. J Egypt Med Assoc 1932;15:87. Clark E. Chronic pulmonary arteritis in schistosomiasis mansoni associated with right ventricular hypertrophy: Report of a case. Am J Pathol 1935;11:693. Bedford DE, Aidaros SM, Girgis B. Bilharzial heart disease in Egypt: Cor Pulmonale due to Bilharzial Pulmonary Endarteritis. Br Heart J 1946;8:87-95. Johns RA. Th2 inflammation, hypoxia-induced mitogenic factor/ FIZZ1, and pulmonary hypertension and vascular remodeling in schistosomiasis. Am J Respir Crit Care Med 2010;181:203-5. Pereira GA Jr, Bestetti RB, Leite MP, Santos RB, Ramos SG, Lucchesi FR, et al. Portopulmonary hypertension syndrome in schistosomiasis mansoni. Trans R Soc Trop Med Hyg 2002;96:427-8. Greco DB, Pedroso ER, Lambertucci JR, Rocha MO, Coelho PM, Raso P, et al. Pulmonary involvement in schistosomiasis mansoni. Mem Inst Oswaldo Cruz 1987;82 Suppl 4:221-7. De Cleva R, Pugliese V, Zilberstein B, Saad WA, Pinotti HW, Laudanna AA. Hyperdynamic circulation in Manson’s hepatosplenic schistosomiasis. Rev Hosp Clin Fac Med Sao Paulo 1998;53:6-10. Abdel-Fattah MM, Abou-Zeina A, Nomeir AM, Badawi H, Salah M. Intrapulmonary acetylcholine in bilharzial cor pulmonale. Am Heart J 1978;95:141-5. Hadengue A, Benhayoun MK, Lebrec D, Benhamou JP. Pulmonary hypertension complicating portal hypertension: Prevalence and relation to splanchnic hemodynamics. Gastroenterology 1991;100:520-8. Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54 Suppl 1: S43-54. Pozzan G, Souza R, Jardim C, Dohlnikoff M, Mello G, Canzian M, et al . Histopathological features of pulmonary vascular disease in chronic Schistosoma mansoni infection are not different from those in idiopathic pulmonary hypertension. Presented at: American Thoracic Society International Conference; May 16-21 2008. De Almeida MA, Andrade ZA. Effect of chemotherapy on experimental pulmonary schistosomiasis. Am J Trop Med Hyg 1983;32:1049-54. Crosby A, Jones FM, Southwood M, Stewart S, Schermuly R, Butrous G, et al. Pulmonary vascular remodeling correlates with lung eggs and cytokines in murine schistosomiasis. Am J Respir Crit Care Med 2010;181:279-88. PVRI REVIEW

Ward, et al.: The prevalence of pulmonary hypertension in schistosomiasis 24. De Cavalcanti IL, Tompson G, de Souza, Barbosa FS. Pulmonary hypertension in schistosomiasis. Br Heart J 1962;24:363-71. 25. Fernandes C. Survival in schistosomiasis associated pulmonary arterial hypertension. Am J Respir Crit Care Med 2009;179: A2652. 26. Rodriguez HF, Fernandez-Duran A, Garcia-Moliner L, Rivera E. Cardiopulmonary schistosomiasis. Am Heart J 1963;65:253-60. 27. Machado C, Brito I, Souza D, Correia LC. Etiological frequency of pulmonary hypertension in a reference outpatient clinic in Bahia, Brazil. Arq Bras Cardiol 2009;93:629-36, 679-86. 28. WHO. Metrics: Disability-Adjusted Life Year (DALY). [Online] Available from: http://www.who.int/healthinfo/global_burden_ disease/metrics_daly/en/. [Last accessed on 2010 May 9] 29. King CH. Reassessment of the cost of chronic helmintic infection: A meta-analysis of disability-related outcomes in endemic schistosomiasis. Lancet 2005;365:1561. 30. Michaud CM, Gordon WS, Reich MR. The Global Burden of Disease due to Schistosomiasis. Disease Control Priorities Project Working Paper 19, 2003. 31. Hotez P, Kamath A. Neglected tropical diseases in sub-saharan Africa: Review of their prevalence, distribution, and disease burden. PLoS Negl Trop Dis 2009;3: e412. 32. Steinmann P, Keiser J, Bos R, Tanner M, Utzinger J. Schistosomiasis and water resources development: Systematic review, metaanalysis, and estimates of people at risk. Lancet Infect Dis 2006;6:411-25. 33. Mangal TD, Paterson S, Fenton A. Predicting the impact of longterm temperature changes on the epidemiology and control of schistosomiasis: A mechanistic model. PloS One 2008;3:e1438. 34. Opravil M. HIV-associated primary pulmonary hypertension. A case control study. Swiss HIV Cohort Study. Am J Respir Crit Care Med 1997;155:990. 35. Sitbon O. Prevalence of HIV-related pulmonary arterial hypertension in the current antiretroviral therapy era. Am J Respir Crit Care Med 2008;177:108. 36. Butrous G, Ghofrani HA, Grimminger F. Pulmonary vascular disease in the developing world. Circulation 2008;118:1758-66. 37. Vijayan VK. Parasitic lung infections. Curr Opin Pulm Med 2009;15:274. 38. Gelfand M. The diagnosis and prognosis of schistosomiasis. Am J Trop Med Hyg 1949;1:945. 39. Kenawy MR. The syndrome of cardiopulmonary schistosomiasis (cor pulmonale). Am Heart J 1950;39:678-96. 40. Sami AA. Pulmonary manifestations of schistosomiasis. Dis Chest 1951;19:698-705. 41. Girgis B, Baragan J. The incidence of heart disease and disorders in Egypt. J Egypt Med Assoc 1953;36:601-10. 42. Lopes de Faria J. Cor pulmonale in Manson’s schistosomiasis. I. Frequency in necropsy material; Pulmonary vascular changes caused by schistosome ova. Am J Pathol 1954;30:167-93. 43. Andrade ZA, Andrade SG. Pathogenesis of schistosomal pulmonary arteritis. Am J Trop Med Hyg 1970;19:305-10. 44. Ongom VL, Owor R, Grundy R, Bradley DJ. The epidemiology and consequences of Schistosoma mansoni infection in West Nile, Uganda. II. Hospital investigation of a sample from the Panyagoro community. Trans R Soc Trop Med Hyg 1972;66:852-63. 45. Guimaraes AC, Alves AR Jr, Santos-Filho A, Esteves JP, Vinhaes LS, Abreu WN, et al. Blood gas changes and pulmonary hemodynamics in portal hypertension due to schistosomiasis mansoni. Rev Inst Med Trop Sao Paulo 1977;19:80-93. 46. Hassan AM, Satir AA, Ahmed MA, Omer A. The pathology of schistosomiasis in Sudan. Trop Geogr Med 1977;29:56-64. 47. Cheever AW. Schistosoma mansoni and S. haematobium infections in Egypt: III. Extrahepatic pathology. Am J Trop Med Hyg 1978;27:55. 48. Pittella JE. Brain involvement in hepatosplenic schistosomiasis mansoni. Brain 1981;104:621. PVRI REVIEW

49. Richter J, Dengler A, Mohammed EG, Ali GM, Abdel-Rahim I, Kaiser C, et al. Results of echocardiographic examinations in a regional hospital of central Sudan. Trans R Soc Trop Med Hyg 1990;84:749-52. 50. Goncalves EC, Fonseca AP, Pittella JE. Frequency of schistosomiasis mansoni, of its clinicopathological forms and of the ectopic locations of the parasite in autopsies in Belo Horizonte, Brazil. J Trop Med Hyg 1995;98:289-95. 51. Rashwan MA. Endomyocardial fibrosis in Egypt: An illustrated review. Br Heart J 1995;73:284-9. 52. Barbosa MM, Lamounier JA, Oliveira EC, Souza MV, Marques DS, Silva AA, et al. Pulmonary hypertension in schistosomiasis mansoni. Trans R Soc Trop Med Hyg 1996;90:663-5. 53. Lopes AA, Maeda NY, Bydlowski SP. Abnormalities in circulating von Willebrand factor and survival in pulmonary hypertension. Am J Med 1998;105:21-6. 54. Lopes AA, Maeda NY. Circulating von Willebrand factor antigen as a predictor of short-term prognosis in pulmonary hypertension. Chest 1998;114:1276-82. 55. De Cleva R, Pugliese V, Zilberstein B, Saad WA, Pinotti HW, Laudanna AA. Systemic hemodynamic changes in mansonic schistosomiasis with portal hypertension treated by azygoportal disconnection and splenectomy. Am J Gastroenterol 1999;94:1632-7. 56. De Cleva R, Herman P, Pugliese V, Zilberstein B, Saad WA, Rodrigues JJ, et al . Prevalence of pulmonary hypertension in patients with hepatosplenic Mansonic schistosomiasis-prospective study. Hepatogastroenterology 2003;50:2028-30. 57. Aderaye G. Causes and clinical characteristics of chronic corpulmonale in Ethiopia. East Afr Med J 2004;81:202-6. 58. Lapa MS, Ferreira EV, Jardim C, Martins Bdo C, Arakaki JS, Souza R. Clinical characteristics of pulmonary hypertension patients in two reference centers in the city of Sao Paulo. Rev Assoc Med Bras 2006;52:139-43. 59. De Cleva R, Herman P, D’albuquerque LA, Pugliese V, Santarem OL, Saad WA. Pre- and postoperative systemic hemodynamic evaluation in patients subjected to esophagogastric devascularization plus splenectomy and distal splenorenal shunt: A comparative study in schistomomal portal hypertension. World J Gastroenterol 2007;13:5471-5. 60. Ferreira RC, Domingues AL, Bandeira AP, Markman-Filho B, Albuqerque-Filho ES, Correiade de Araujo AC, et al. Prevalence of pulmonary hypertension in patients with schistosomal liver fibrosis. Ann Trop Med Parasitol 2009;103:129-43. 61. Lapa M, Dias B, Jardim C, Fernandes CJ, Dourado PM, Figueiredo M, et al . Cardiopulmonary manifestations of hepatosplenic schistosomiasis. Circulation 2009;119:1518-23. 62. Conceicao MJ, Borges-Pereira J, Coura JR. A thirty years follow-up study on Schistosomiasis mansoni in a community of Minas Gerais, Brazil. Mem Inst Oswaldo Cruz 2007;102:1007-9. 63. Van der Werf MJ. Quantification of clinical morbidity associated with schistosome infection in sub-Saharan Africa. Acta Trop 2003;86:125. 64. Andrade ZA. The situation of hepatosplenic schistosomiasis in Brazil today. Mem Inst Oswaldo Cruz 1998;93 Suppl 1:313-6. 65. Saoud MF. Comparative studies on the characteristics of some geographical strains of Schistosoma mansoni in mice and hamsters. J Helminthol 1965;39:101-12. 66. Nelson GS, Amin MA, Saoud MF, Teesdale C. Studies on heterologous immunity in schistosomiasis. I. Heterologous schistosome immunity in mice. Bull World Health Organ 1968;38:9-17. 67. Turner PP. Schistosomal pulmonary arterial hypertension in East Africa. Br Heart J 1964;26:821-31.

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Ward, et al.: The prevalence of pulmonary hypertension in schistosomiasis 68. Tidy H. Ayerza’s Disease, Silicosis, and Pulmonary Bilharziasis. Br Med J 1949;1:977. 69. Boure P, Piveteau J, Gerbal JL, Halpen G. Pulmonary arterial hypertension due to bilharziasis. Apropos of a case due to Schistosoma haematobium having been cured by praziquantel. Bull Soc Pathol Exot Filiales 1990;83:66-71. 70. Loureiro R. Oral sildenafil improves functional status and cardiopulmonary hemodynamic in patients with severe pulmonary hypertension secondary to chronic pulmonary schistosomiais: A cardiac magnetic resonance study. Circulation 2004;110:572. 71. Amaral RS, Tauil PL, Lima DD, Engels D. An analysis of the impact of the Schistosomiasis Control Programme in Brazil. Mem Inst Oswaldo Cruz 2006;101 Suppl 1:79-85. 72. Bina JC. Estudo de Variáveis que Podem Influenciar na Evolução da Esquistossomose Mansônica. Efeito da Terapêutica Específica e da Interrupção da Transmissão. PhD Thesis,, Salvador, BA: UFBA;

1995. p. 126. 73. Coura JR. Evolutive pattern of schistosomiasis and life-span of Schistosoma mansoni in patients living in non-endemic area in Brazil. Rev Soc Bras Med Trop 1974;8:193. 74. Cheever AW. Rate of destruction of Schistosoma mansoni eggs in the tissues of mice. Am J Trop Med Hyg 1971;20:62. a. One study published in Arquivos Brasileiros de Cardiologia and the other a thesis paper from the Faculty of Medicine in Bagdad. Neither was archived in Google Scholar or Pubmed and neither was available from either Imperial library or the Wellcome library. How to Cite this article: Ward TJ, Fenwick A, Butrous G. The Prevalence of Pulmonary Hypertension in Schistosomiasis: A Systematic Review. PVRI Review 2011;3:12-21. Source of Support: Nil, Conflict of Interest: None declared.

New features on the journal’s website Optimized content for mobile and hand-held devices HTML pages have been optimized of mobile and other hand-held devices (such as iPad, Kindle, iPod) for faster browsing speed. Click on [Mobile Full text] from Table of Contents page. This is simple HTML version for faster download on mobiles (if viewed on desktop, it will be automatically redirected to full HTML version) E-Pub for hand-held devices EPUB is an open e-book standard recommended by The International Digital Publishing Forum which is designed for reflowable content i.e. the text display can be optimized for a particular display device. Click on [EPub] from Table of Contents page. There are various e-Pub readers such as for Windows: Digital Editions, OS X: Calibre/Bookworm, iPhone/iPod Touch/iPad: Stanza, and Linux: Calibre/Bookworm. E-Book for desktop One can also see the entire issue as printed here in a ‘flip book’ version on desktops. Links are available from Current Issue as well as Archives pages. View as eBook Click on Jan - Jun 2011 • Volume 3 • Issue 1

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COMMENTARY

Summary on study of role of Serotonin Transporter, Gender and Hypoxia in mouse models of PAH by White K et al., 2011 Swapna Menon School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, India White K, Loughlin L, Maqbool Z, Nilsen M, McClure J, Dempsie Y, et al. Serotonin transporter, sex, and hypoxia: Microarray analysis in the pulmonary arteries of mice identifies genes with relevance to human PAH. Physiol Genomics 2011;43:417-37.

BACKGROUND The serotonin transporter is designated as 5-HTT or SERT or Slc6a4. It is a transmembrane protein, which normally functions in serotonin reuptake from the extracellular milieu. This reuptake is coupled with Na+ and Cl- symport and conformational changes in the protein. After release of serotonin and the ions into the cytoplasm, K+ binding is required for return of SERT to its native conformation. SERT is widely expressed in various tissues including the brain, gut and blood platelets. It is highly expressed in lungs and placenta. Polymorphisms of this gene have been associated with increased susceptibility to pulmonary arterial hypertension (PAH), myocardial infarction, sudden infant death syndrome and chronic fatigue syndrome.[1] Larger genome wide association studies (GWAS) showed no association of SERT LL allele with disease among the PAH populations. Nevertheless, increased SERT expression in patient pulmonary arterial smooth muscle cells (PASMCs) and findings from various animal model studies underscore the importance of SERT and serotonin pathway in PAH pathobiology.[2] Animal model studies have attempted to explore the effects of this pathway by overexpressing[3,4] or deleting this gene in mice.[5,6] SERT knockout mice fail to develop PAH even in response to hypoxia.[5] On the other hand, mice overexpressing SERT at the level of that in human Access this article online Quick Response Code:

Website:

www.pvrireview.org

DOI: 10.4103/0974-6013.85615

Address for correspondence: Dr. Swapna Menon, School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Mehrauli Road, New Delhi – 110 067, India. E-mail: swapna30@gmail.com

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PASMCs spontaneously develop PAH.[3] In the latter model, transgene expression was directed to smooth muscle cells using the SM22- promoter.[3] The study showed that mice overexpressing SERT develop progressive disease, with the sampled time points being 8, 20 and 55 weeks (or 2, 5 and 11 months), but the gender of mice used is not reported. The current paper characterizes the phenotype of transgenic mice overexpressing SERT and explores the gene expression in pulmonary arteries of these mice using microarray, followed by validation of select genes by qPCR and Western blotting of the animal model and human samples.

SUMMARY Transgene expression

The protocol for generation of transgenic mice was followed from a previous publication,[4] where SERT transgene is under the control of the short allelic variant of the endogenous promoter. Thus, native-like, constitutive expression pattern is expected.

Phenotypic characterization of model [Table 1]

• Mouse strain used: C57B/6JxCBA • Experimental factors: Normoxia versus hypoxia, male versus female, SERT+ versus WT, 2 months versus 5 months • Method of hypoxia induction: 14 days of hypobaric hypoxia at 10% O2 • Right ventricular (RV) pressure measurement: Transdiaphragmatic right heart catheterization (n = 6-8 per group) • Histopathology: Elastica-Van Gieson stained saggital lung sections to look at arteries <80 μm in external diameter. Remodeled arteries were identified as those with double elastic laminae (n = 5 per group; 150 arteries from each lung section or total of 750 arteries assessed) • RV hypertrophy: Ratio of weights of RV/LV + S (n = 6-8 per group) • Statistics: Comparison of means* between groups: 2-way analysis of variance (ANOVA) with Bonferroni correction • Male and female, WT and SERT+ mice at both ages displayed pulmonary vascular responsiveness to hypoxia, as assessed by Right ventricular systolic pressure (RVSP), Jan - Jun 2011 • Volume 3 • Issue 1

Menon: Commentary

COMMENTARY

Table 1: Effect of SERT+, hypoxia and gender on pulmonary vascular disease of mouse model Group characteristics

Subgroups with differences

Clinical parameters with statistically significant differences

Male and female, WT and SERT+ at 2 months and 5 months Female, normoxic and hypoxic at 5 months Female, chronic hypoxic, 2 months and 5 months

Normoxia versus chronic hypoxia

RVSP, % remodeled vessels, RV/LV + S

WT versus SERT+

RVSP, % remodeled vessels

WT versus SERT+

RV/LV + S

Incidence of idiopathic pulmonary arterial hypertension (IPAH) and familial pulmonary arterial hypertension (FPAH) is roughly three times more common in women than men. No gender bias in genetic associations for SERT allele with incidence or clinical phenotype in PAH cohorts appears;[8-10] one large study affirms that none exists.[11] In these reports, the study population tends to have a 1:1 male to female ratio and the alleles under study are in Hardy–Weinberg equilibrium. A recent report indicates that gender does not influence clinical phenotype of BMPR2 mutation carriers in a French PAH cohort.[12] Thus, women, in general, are at greater risk for developing PAH, but this risk is not associated with increased occurrence of a particular allele of SERT or BMPR2, studied till date. Another point of interest is that estrogen appears to have vasodilatory properties and protective effects in experimental PAH, described as the estrogen paradox in pulmonary hypertension.

remodeling and RV/LV + S weight ratio.[7] • Male SERT+ mice do not show any significant phenotypic differences from wild type (WT) under any of the conditions. • Under normoxia, SERT+ females at 5 months of age were the only group that developed PAH.[7]] • At 5 months of age, under both normoxic and hypoxic conditions, SERT+ female mice display more vascular remodeling and vessel constriction compared to WT[6] but not RV hypertrophy.[7] • At both ages, the hypoxic female SERT+ mice display greater RV hypertrophy compared to WT[7] mice.

Gene expression profile

• Microarray platform: Illumina • Differential expression analysis: Illumina BeadStudio software • Study population: 2-month-old WT (male and female), SERT+ (male and female), normoxia • 2 month old WT (male and female), SERT+ (male and female), hypoxia

Hierarchical clustering analysis

A distinct expression pattern for SERT+ female mice at normoxia, largely the reverse of the control WT female[7], emerged from the clustering analysis. The expression profile of SERT+ female mice was also distinct under hypoxic conditions in contrast to SERT+ male, WT female and male mice[7]. Thus, gene expression pattern at 2 months was predictive of phenotypic differences that emerged at 5 months of age in normoxic, SERT+ female mice. It can also be seen that the expression profiles of male mice showed drastic differences in normoxia versus hypoxia for both WT and SERT[7]. This is consistent with the basal hypoxic responsiveness of all mice. On the other hand, in expression profiles from female mice, the changes appear more subtle between the two conditions [7]. This agrees with the finer modulation of pulmonary response by the interplay of gender, SERT+ and hypoxia as per phenotypic observations. Further, three genes that are modulated by serotonin, namely, CYP1B1, FOS and CEBPB, were identified and validated as differentially expressed, emphasizing the role of the serotonin pathway in this disease model. Jan - Jun 2011 • Volume 3 • Issue 1

This paper has introduced an animal model that demonstrates gender susceptibility. In an accompanying paper, White et al. [13] have shown that ovariectomy protected female SERT+ mice from developing PAH, both under normoxic and hypoxic conditions. Further, it was shown that 17--estradiol in these mice has a proliferative effect on pulmonary smooth muscle cells, that is dependent on serotonin synthesis and 5HT1B receptor stimulation. Thus, this animal model displays the converse of the estrogen paradox phenomenon, possibly due to serotonin overexpression. White et al. have validated the modulation of key targets of serotonin pathway like CYP1B1, FOS and CEBPB in mice and IPAH PASMC samples. The clustering analysis of microarray samples is informative in visualizing the gross differences in expression patterns concordant with phenotype. However, further analysis is restricted to individual genes. More information can be gleaned from this data-rich resource through analyses of pathways, GO annotations, etc. using standard annotation tools like DAVID. All mice used in this study, irrespective of gender, mutation and age, display the expected hypoxic pulmonary vasoresponsiveness. SERT overexpression affects the pulmonary vasculature, as evidenced by vascular remodeling and vasoconstriction (RVSP) in female mice, even at normoxia. As per RV hypertrophy assessment, the additional stimulus of hypoxia influences the right ventricle, worsening the disease in this group.

REFERENCES 1.

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Dempsie Y, MacLean MR. Role of the serotonin transporter in pulmonary arterial hypertension. Expert Rev Clin Pharmacol 2008;1:749-57. Eddahibi S, Adnot S. From functional to genetic studies of a candidate gene for pulmonary hypertension: Any point? Am J Respir Crit Care Med 2006;173:693-4. Guignabert C, Li Z, Hanoune N, Tu L, Raﬀestin B, Rodman D, et al. Mice overexpressing the 5-hydroxytryptamine transporter in smooth muscle cells spontaneously develop pulmonary hypertension. Proc Am Thorac Soc 2005;2:A526. MacLean MR, Deuchar GA, Hicks MN, Morecroft I, Shen S, Sheward J, et al. Overexpression of the 5-hydroxytryptamine transporter gene: Eﬀect on pulmonary hemodynamics and hypoxiaPVRI REVIEW

Menon: Commentary induced pulmonary hypertension. Circulation 2004;109:2150-5. Eddahibi S, Hanoun N, Lanfumey L, Lesch KP, Raffestin B, Hamon M, et al. Attenuated hypoxic pulmonary hypertension in mice lacking the 5-hydroxytryptamine transporter gene. J Clin Invest 2000;105:1555-62. 6. Crona D, Harral J, Adnot S, Eddahibi S, West J. Gene expression in lungs of mice lacking the 5-hydroxytryptamine transporter gene. BMC Pulm Med 2009;9:19. 7. White K, Loughlin L, Maqbool Z, Nilsen M, McClure J, Dempsie Y, et al. Serotonin transporter, sex, and hypoxia: microarray analysis in the pulmonary arteries of mice identifies genes with relevance to human PAH. Physiol Genomics 2011;43:417-37. 8. Eddahibi S, Humbert M, Fadel E, Raffestin B, Darmon M, Capron F, et al. Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J Clin Invest 2001;108:1141-50. 9. Koehler R, Olschewski H, Hoeper M, Janssen B, Grünig E. Serotonin transporter gene polymorphism in a cohort of German patients with idiopathic pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Chest 2005;128 Suppl 6:619S. 10. Willers ED, Newman JH, Loyd JE, Robbins IM, Wheeler LA,

Prince MA, et al. Serotonin transporter polymorphisms in familial and idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2006;173:798-802. 11. Machado RD, Koehler R, Glissmeyer E, Veal C, Suntharalingam J, Kim M, et al. Genetic association of the serotonin transporter in pulmonary arterial hypertension. Am J Respir Crit Care Med 2006;173:793-7. 12. Girerd B, Montani D, Eyries M, Yaici A, Sztrymf B, Coulet F, et al. Absence of influence of gender and BMPR2 mutation type on clinical phenotypes of pulmonary arterial hypertension. Respir Res 2010;11:73. 13. White K, Dempsie Y, Nilsen M, Wright AF, Loughlin L, Maclean MR. The serotonin transporter, gender, and 17{beta} oestradiol in the development of pulmonary arterial hypertension. Cardiovasc Res 2011;90:373-82. How to cite this article: Menon S. Summary on study of role of Serotonin Transporter, Gender and Hypoxia in mouse models of PAH by White K et al., 2011. PVRI Review 2011;3:22-4. Source of Support: Author is supported exclusively by the PVRI Research Award for Microarray Analysis October 2010-2011 Conflict of Interest: None declared.

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2010 IN

SYMPOSIA AND

PVRI CONFERENCES

4th PVRI Annual General Meeting, Lisbon, January 10-11, 2010 The PVRI 4th Annual General Meeting took place in Lisbon and was very well attended by an international array of people, including 46 PVRI Fellows. The Annual General Meeting saw Professor Ghazwan Butrous presenting a review of all the activities of 2009. Fellows were encouraged to participate in the discussion. The AGM topics centered on the restructuring of the PVRI and solidifying plans for taskforce activities, including educational, publication and research projects. After the presentation, the recommendations of the Board of Directors & Advisors meeting in November 2009 were announced. The endorsement of Professor Martin Wilkins as President of the Institute was supported by the Fellows, whilst Professor Sheila Glennis Haworth was named President Elect. Dr. Stuart Rich was thanked for his dedicated contribution as founding President of PVRI and was elected to the post of Chairman of the Board of Directors. The restructuring of the taskforces and the allocation of the new regional vice presidents for the taskforces were presented along with the restructure of said taskforces. The AGM accepted the changes and welcomed the new regional vice presidents.

Figure 1: Scenes from the 4th PVRI Annual General Meeting, Lisbon, January 10-11, 2010

Professor Wilkins then took the chair and discussed future directions and activities. With a view to stimulating research, it was agreed that up to 12 Research Grants would be awarded by competitive assessment in 2010 to fellows of the PVRI. In addition, ideas for the establishment of several new taskforces were discussed. Fellows agreed on the need for a Pediatric Taskforce, with a primary objective of revisiting the classification of pulmonary hypertension in the pediatric population. A second taskforce established at the meeting will focus on chronic thromboembolic pulmonary hypertension. During the meeting, the motion to establish a new PVRI journal was considered and approved. Pulmonary Circulation was the proposed name of the journal, and it is defined as a quarterly peer-reviewed publication. Pulmonary Circulation will be published in addition to the current journal, PVRI Review, and the focus will be on original research articles, review articles, unique case reports and guidelines with regards to pulmonary circulation, pulmonary

Figure 2: Suggested PVRI administrative structure

vascular disease, and lung injury. The initiative for the publication of Pulmonary Circulation was fully supported by all the members. The discussion then turned to the topics for the next annual meeting & workshops. There was overwhelming support to concentrate on thematic issues like translational medicine, molecular targeting and receptors, as well as clinical trials on thromboembolic pulmonary hypertension.

3rd PVRI Workshops & Debates, Lisbon, January 10-12, 2010 The 3rd PVRI Workshops and Debates included topics ranging from the effects of chronic prostacyclin on Jan - Jun 2011 • Volume 3 • Issue 1

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pulmonary vascular pathology in IPAH and the cellular pathology of pulmonary arterial hypertension (Stuart Rich), PVRI REVIEW

PVRI 2010 Annual Report

to the clinical importance of right ventricular hypertrophy in pulmonary arterial hypertension (Paul Hassoun). Among the “Hot Topics” were the role of apelin in pulmonary arterial hypertension (Marlene Rabinovitch); observations on the physiology of the pulmonary circulation (David Kilpatrick); cyclosporine and atrial septostomy in patients with acute/severe/catastrophic PAH (Marc Pritzker); multikinase inhibition in pulmonary arterial hypertension (Ralph Schermuly); the role of smooth muscle/ adventitial fibroblast/inflammatory cells in PH (Kurt Stenmark) and the role of endothelial cell precursors in pulmonary hypertension (Duncan Stewart). An update on PVRI sponsored research on the pathophysiology of pulmonary vascular disease associated with schistosomiasis (Alexi Crosby & Brian Graham) was presented. This was followed by special symposia and debates by various PVRI taskforces, including: • Pulmonary vascular disease associated with connective tissue diseases (from Steve Mathai, Virginia Steen and Gerry Coghlan) • Pulmonary venous hypertension (PVH) in systolic LV dysfunction (S. Ghio) in diastolic dysfunction (Evelyn Horn) and rheumatic heart disease (S. Harikrishnan) The next day started with a series of clinical cases associated with pulmonary hypertension which generated a lot of discussion. These included cases of PAH associated with congenital heart disease presented by Mahesh Kappanayil, HIV by Nicola Petrosillo, COPD by Ari Chaouat and diastolic heart failure by Pilar Escribano. The next session was on pediatric pulmonary vascular disease. The different classifications based on the Evian, Venice and Dana point discussions and their relevance to pediatric population was discussed. This was followed by the presentation of Glennis Haworth on the conduct of clinical trials of pulmonary hypertension therapies in children.

Figure 3: Scenes from the 3rd PVRI Workshops and Debates, Lisbon, January 10-12, 2010

The next session was devoted to debates and focused on the current treatment strategies for pulmonary arterial hypertension Debate 1: What is the best therapeutic strategy for PAH? Paul Corris argued for monotherapy with substitution as the choice for failure of therapy while Ardeschir Ghofrani argued for combination therapy in such a situation. Ioana Preston argued that PAH therapy should start with intravenous prostacyclin as we have to hit as “hard and fast” as possible. Debate 2: The second debate was on the role of tyrosine kinase inhibitors in the management of pulmonary arterial hypertension, debated by Martin Wilkins and Marlene Rabinowitch. Debate 3: The final debate was on the topic on the cyclic GMP pathway and discussed by Roger Johns, Raed Dweik and Ardeschir Ghofrani.

Joint FDA/PVRI Debate on Clinical trials for Pulmonary Arterial Hypertension, Bethesda, March 2-3, 2010 The joint FDA/PVRI meeting was the result of a direct discussion between PVRI and the cardio-renal section of the FDA. It took place in Bethesda, USA under the organization of the Drug Information Agency (DIA). It was structured as an open debate between the regulatory authorities, the clinical community, clinical trial co-ordinators, and the pharmaceutical industry. The overarching theme of the meeting was to evaluate the current conduct of clinical trials, and to understand the value of currently employed endpoints and their acceptability going forward, as new drug targets are assessed with different mechanisms of action on the background of existing licensed treatments. It was well attended with more than 86 members of the pharmaceutical industry as well as academia and regulatory bodies from other countries. The debates focused PVRI REVIEW

on the following questions: • Minimum change in six minute walk (6MW) needs to be established as an indicator of efficacy in future trials vs any significant change in 6MW remains an adequate primary endpoint of efficacy. • Survival needs to be a primary endpoint in future randomized clinical trials (RCTs) until long-term improved survival is demonstrated vs composite endpoints are adequate surrogates for survival. • Future trials need to identify specific etiologies of PAH and to power the trials sufficiently to know in which etiologies the treatment is effective vs Approval of drugs (i.e. WHO group 1) for PAH is appropriate for all patients. • The prescription of PAH therapies should continue to be

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Figure 4: Scenes from FDA/PVRI meeting, March 2-3, 2010

linked to a patient’s functional class vs functional class should not be a determinant of which patients are studied and which patients are treated in RCTs. • Future RCTs with antiproliferative therapies must include both traditional endpoints and endpoints with biomarker/

imaging techniques to demonstrate mechanisms of efficacy vs clinical endpoints are adequate to determine efficacy of newer therapies. The transcript of this meeting will be published in the January 2011 issue of PVRI.

Session on Pulmonary Hypertension in the 3rd National Congress on Infective Cardiopathies and HIV-Related Issues; Naples, March 12, 2010 This special session was organized by the PVRI HIV taskforce and was chaired by Dr. Nicola Petrosillo. The following topics were presented: • Pulmonary hypertension: New guidelines (Stefano Ghio)

• • • •

Pulmonary hypertension: Differential diagnosis (R. Parrella) Pulmonary hypertension: The diagnostic work up (M. D’Alto) Treatment of pulmonary hypertension (Dario C. Vizza) Presentation of the protocol on HIV-related pulmonary hypertension (S. Ferraro)

The Third Joint PVRI and SAPH Symposium, Sham Al Sheik, April 6-8, 2010 The symposium was very well attended by more than 63 members from the Eastern Mediterranean Region (EMR) and saw active participation from the international faculty and PVRI fellows. The meeting dealt with various aspects of pulmonary hypertension, including the clinical challenges and surgical aspects of chronic thromboembolic pulmonary hypertension. Jan - Jun 2011 • Volume 3 • Issue 1

The themes of the meeting covered topics of concern to the EMR. This included talks on • Current status and clinical year in Review (Javid Khan and Majdy Idrees); • The future of Pulmonary Hypertension: New pathways and targets for therapy (Omar Minai);

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• CTEPH: Clinical assessments and updates in management; • Lung transplantation for Pulmonary Hypertension: Timing and technique (Nick H. Kim); Operability of CTEPH patients (Eckhard Mayer); • Intervention in PAH-CHD: Optimal timing (Khalid Najashi); New insights into right ventricular function as a determinant of prognosis for PH patients (Ardeschir Ghofrani); • PH in Sarcoidosis: Local experience (Esam Al Hamad) and a plenary session entitled The Stem Cell: The Future in PH Management (Ghazwan Butrous). There was a debate on whether combination treatment should be started at an early stage in all PAH patients (Pro: Ardeschir Ghofrani, Con: Omar Minai). This very successful meeting will be followed up with a fourth joint PVRI and Saudi Advisory Pulmonary Hypertension (SAPH) symposium in 2011 in Beirut, Lebanon.

Figure 5: Scenes from the third joint PVRI and SAPH (Saudi Advisory Pulmonary Hypertension) symposium, Sham Al Sheik, April 6-8, 2010

Pulmonary Hypertension and Infectious Diseases, special Symposia during the 20th European Congress of Clinical Microbiology and Infectious Diseases, Vienna, April 10-14, 2010 This special symposium organized by the PVRI HIV taskforce allowed for the exchange of knowledge on the current understanding of the role of infectious diseases in the pathobiology of Pulmonary Vascular Disease. The session was chaired by Irene Lang and David Dockrell. The following topics were presented: • Pulmonary arterial hypertension and infections (Serge Adnot) • Pulmonary arterial hypertension related to HIV: update on diagnosis and treatment (Nicola Petrosillo) • Vascular pulmonary hypertension associated with parasitic diseases (Ghazwan Butrous) • Viral infections and pulmonary hypertension (Ardeschir Ghofrani)

Figure 6: Scene from the Pulmonary Hypertension and Infectious Diseases special symposia during the 20th European Congress of Clinical Microbiology and Infectious Diseases, Vienna, April 10-14, 2010

Inaugural Meeting of the Sub Saharan Regional Taskforce, Cape Town, April 23-24, 2010 Professor Karen Sliwa, Dr. Olga Mocumbi and Professor Ghazwan Butrous established the PVRI Sub Saharan Regional Taskforce under the supervision of colleagues from South Africa, Zimbabwe, Mozambique, Nigeria, Kenya, Sudan, Tanzania, Australia and the USA. Participating members included basic scientists, adult and pediatric cardiologists, pulmonologists PVRI REVIEW

and cardiothoracic surgeons. Others, namely Professor Sheila Glennis Haworth (PVRI, UK), Professor Denise Hilfiker-Kleiner (Hannover University, Germany) and Dr. Dirk Otto (BayerSchering, Germany), could not travel to the meeting due to the after-effects of the volcanic ash from Iceland. Professor Haworth participated in the meeting via video conference.

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Friday April 23rd was given to a workshop on pulmonary hypertension. Discussions were held on planning a Pulmonary Vascular Disease (PVD) registry in Africa, under the auspices of the Pulmonary Vascular Research Institute Sub-Saharan Taskforce. The main objective of this research is to describe the epidemiology of pulmonary hypertension among patients attending referral units for cardiovascular and pulmonary diseases in African countries. This information will be crucial to the development of effective and resource-sensitive strategies to tackle PVD in Sub-Saharan Africa. The first step in this direction will be to build a registry of patients with PVD, whom attend a range of hospitals in several countries from this region. Saturday, April 24th, focused on a workshop titled ‘Heart of Africa - post partum cardiomyopathy (PPCM) project’. The main objective of this continuing research is to describe the epidemiology of PPCM in various African centers. This registry will eventually lead to a multi-centre, randomized study, investigating the role of prolactin inhibition with bromocriptine, based on new data from a proof-of-concept pilot study published recently from South Africa (Circulation, 2010). The main topics of discussion were • Overview of the PPCM Heart of Africa Project (Karen Sliwa) • Presentation of clinical findings in PPCM Heart of Africa Project (Lori Blauwet) • Presentation on pathophysiology and treatment options (Karen Sliwa) • Collecting information on cases with newly diagnosed PPCM (n=200) and age matched controls (n=400) (Simon Stewart)

Figure 7: Dr. Ana Olga Mocumbi (Mozambique) and Prof. Karen Sliwa (Cape Town), the leaders of the PVRI Sub-Saharan Africa Region

Figure 8: Prof. Sheila Glennis Haworth presenting to the inaugural meeting of the Sub Saharan Regional Taskforce, Cape Town via Video Conference

Figure 9: Participants in the inaugural meeting of the Sub Saharan Regional Taskforce, Cape Town, April 23-24, 2010

PVRI China Taskforce Strategy Meeting on Pulmonary Vascular Diseases, Chongqing, May 2010 The PVRI China taskforce organized a multi-disciplinary strategy meeting. Sixty physicians and scientists from Jan - Jun 2011 • Volume 3 • Issue 1

Departments of respiratory, cardiovascular, rheumatology and hematology medicine, radiology, and surgery, as well as

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officers from the Chinese Medical Association and Ministry of Health and Science Technology participated in the meeting. The strategy meeting summarized the achievement of the PVRI China task force in the last 4 years and discussed future multicentre research and clinical trial plans in relation to

pulmonary hypertension and pulmonary embolism. A draft consensus statement for the management of pulmonary hypertension and guidelines on the management of pulmonary embolism and deep venous thrombosis were also discussed in this meeting.

Educational Meeting on Pulmonary Embolism, Beijing, June 25, 2010 A continuing medical educational meeting was held in Beijing on June 25, 2010. An overview of current research projects directed at understanding pulmonary embolism and its diagnosis and treatment was presented. The topics included: epidemiology,

diagnostic strategy, anticoagulant and thrombolytic therapy, and imaging of pulmonary embolism and deep vein thrombosis. Over 100 local doctors and health care givers around the Beijing area participated in this educational meeting.

The 5 th PVRI China Centre Annual Meeting & Symposium on Clinical Trials and Translational Medicine of Pulmonary Vascular Diseases, Beijing, August 10, 2010

Figure 10: Participants of the 5th PVRI China centre meeting

The PVRI China center organized the 5th PVRI China center Annual meeting and symposium on pulmonary hypertension, chaired by Chen Wang, Xiansheng Chen and Martin Wilkins. The main theme constituted Clinical Trials and Translational Medicine in Pulmonary Vascular Disease, and was addressed in the following presentations: • Endpoints in Clinical Trials reflections on the FDA and EMA perspectives (Martin Wilkins) • COPD and hypoxic respiratory diseases in China: Potential PVRI REVIEW

Figure 11: Scene from the meeting

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risk factors for pulmonary vascular diseases (Chen Wang) • Pulmonary vascular diseases in the developing world: A global perspective (Ghazwan Butrous) • Animal models of pulmonary hypertension: Potential utility

in translational medicine (Lan Zhao) • Cellular and molecular mechanisms of pulmonary hypertension (Kurt Stenmark) • Current treatment of pulmonary hypertension (Weixuan Lu)

The first PVRI-Chinese Heart Society symposium, Beijing, August 12-15, 2010 The symposium was organized by PVRI in the Beijing Fuwai Hospital on various current issues of pulmonary hypertension in China, with topics ranging from basic science to clinical case studies. The presentations were in English with simultaneous translation to Chinese. The meeting was well attended with around 300 physicians and scientists participating. The scientific program included plenary sessions, symposia, paper presentations, live demonstrations and case discussions. The following topics shaped the discussions: • Pulmonary Arterial Hypertension in 6 Lessons (Martin Wilkins) • Pulmonary Vascular Disease and the Heart (Xiansheng Cheng) • Comparison of American and European Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension (Hong Chen) • Imaging the Pulmonary Hypertensive Lung (Lan Zhao) • Treatment Strategies for Pulmonary Embolism: Comparing Low Molecular Weight Heparin with Unfractionated Heparin, and 2 hours Thrombolysis with 12 hours (Chen Wang) • National ‘Eleventh Five Year Plan’ Major Projects Supporting Science and Technology Issues: Improving

• • • • • • • • • • • •

the Diagnosis and Treatment of Pulmonary Arterial Hypertension (Jianguo He) S t u d i e s f o r t h e E t i o l o g y o f A c q u i r e d Ve n o u s Thromboembolism (Lemin Wang) Neoplastic Nature of Pulmonary Vascular Diseases (Ghazwan Butrous) Diagnosis and Treatment of Right Heart Failure (Hua Yao) Interventional Therapy for Pulmonary Vascular Disease (including case reports) (Zhihong Liu) Management of Chronic Thromboembolic Pulmonary Hypertension (Ardeschir Ghofrani) CPET and Gas Exchange in PAH (Xingguo Sun) Advances in Lung Transplantation for Pulmonary Arterial Hypertension (Jingyu Chen) Inflammation and Progenitor Cells are Critical Regulators of Pulmonary Vascular Remodeling (Kurt Stenmark) Interpretation of the Guidelines for Acute Pulmonary Embolism issued by ESC (Lan Huang) Imaging in the Diagnosis of Pulmonary Vascular Disease (Ruping Dai) Echocardiographic Assessment of the Right Ventricle in Pulmonary Arterial Hypertension (Stefano Ghio) D i a g n o s i s a n d Tr e a t m e n t o f S e v e r e Ve n o u s Thromboembolism (Xihai Ni)

Figure 12: Scenes from the first PVRI-Chinese Heart Society symposium, Beijing, August 12-15, 2010

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The 2nd Leh symposium: Recent Trends and Future Perspectives in High-Altitude Pulmonary Research, Leh, September 27-30, 2010 The meeting was organized in Leh, Ladakh on September 27-30, 2010. The aims of the Leh Symposium were two fold: first, to highlight new discoveries in high-altitude research that will likely have an impact on the future of respiratory medicine. Second, the Leh symposium aimed to bring together established and young scientists from various countries incuding India to encourage debate and interaction. The symposium started with a short inauguration and was followed by scientific presentations. Among the clinical & therapeutic aspects, the following topics were elaborated on: the efficacy of acetazolamide, nitric oxide (NO), nifedipine, phosphodiesterase inhibitors in pulmonary hypertension associated diseases, including sleep apnea, and the benefit of various clinical tests. Other topics which received a platform included: • Opportunities and challenges from the study of geomedicine and high altitude adaptation in Ladakh - A few intriguing observations (Tsering Norboo) • Acute and chronic vascular effects of hypoxia in the pulmonary circulation – NADPH oxidases and TRPC6 channel (Norbert Weissmann) • Risk Factors of Severe Mountain Sickness: A prospective cohort study (Jean Paul Richalet) • High-altitude Adaptation/Mal-adaptation in Indian Population (Qadar Pasha)

• Erythropoietin in the brain enhances ventilation (Max Gassman) • Echocardiography and cardiac output studies at high altitude in different ethnic groups of India (G. Himashree) • Nitric oxide therapy in high-altitude pulmonary edema (B.A. Krishna Prasad) • Introduction to medical problems at high-altitude (Peter Bärtsch, Konrad Bloch, Ghulam Mohammad, Shashi Singh) • Significance of HIF dependent and independent pathways (Patrick Maxwell, Paul T Schumacker, Zahara Ali) • Clinical significance of angiogenesis and vascular remodeling in hypoxia (Ghazwan Butrous, Sridhar Sivasubbu, Ashraf Zahid, Kriti Puri) • Genetics of high-altitude disorders (A.A. Aldashev, Tom Brutsaert, Rahul Kumar, Aastha Mishra) • Pulmonary Hypertension (Oliver Eickelberg, Damian Bailey, T. Govindan Unni, S.K.S. Sarada) • Pulmonary Hypertension (Serge Adnot, G.L. Sharma, L. Ostergaard, Arpana Vibhuti) • Clinical cases: Management (Tashi Motup, V.P. Gopinathan, Norboo Angchuk, Mahesh Kappanayil) • Role of biomolecules in disease control (Santosh Pasha, S. K. Maulik, Kashif Hanif) The evening presentation of the PVRI (Future perspectives of High Altitude research: Possible collaborations) placed

Figure 13: Scenes form the 2nd Leh symposium on Recent Trends and Future Perspectives in High-Altitude Pulmonary Research, September 27-30, 2010

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emphasis on strengthening and fulfilling PVRI goals. It called for possible collaborations among various researchers in order to generate a pool of samples of various high-altitude regions of the world and to collectively solve the puzzle of

hypoxia-induced pulmonary hypertension. The symposium proved a fertile ground for goal setting and achievement, and the delegates affirmed to organize the next symposium at a two-year interval at the same venue.

The 3rd PVRI India Meeting, Hyderabad, October 9-10, 2010 PVRI India held its 3rd annual meeting at the Hotel Marriott in Hyderabad, October 9-10, 2010. An executive committee meeting of PVRI South East Asia was held. The activities of the previous year were reviewed and the agenda for the next meeting discussed. The subsequent symposium on pulmonary hypertension was attended by nearly 100 delegates, comprising physicians, cardiologists, pulmonologists and rheumatologists. Dr. Glennis Haworth and Dr. David Kiely visited Hyderabad from the UK to deliver their lectures, whilst Dr. Butrous and Dr. Ghofrani delivered the lectures through teleconferencing from the UK and Germany respectively. The meeting was successful and PVRI gained many members as a result. Next year a similar meeting is planned for Trivandrum, Kerala and will be organized by Dr. Harikrishnan. It will be held in in October 2011, alongside the annual conference of the Pediatric Cardiology Society of India meeting. The topics discussed in Hyderabad included: • Classification of pulmonary hypertension (Glennis Haworth) • Diagnostic evaluation of pulmonary hypertension (Ghazwan Butrous) • Assessment of exercise tolerance (David Kiely) • Pulmonary hypertension associated with a respiratory disorder chronic obstructive pulmonary disease (Parthasarathy Bhattacharya)

Figure 14: Scene form the 3rd PVRI India meeting, Hyderabad, October 9-10, 2010

• Pulmonary Fibrosis: Pathogenesis, prognosis, treatment (Vijay Kumar ) • Sleep Disorders (J.C. Suri) • Scleroderma: Incidence, diagnosis, management (Aman Sharma) • PAH in other auto-immune diseases (Lisa Rajasekhar) • Diastolic heart failure and PAH (S. Harikrishnan)

PVRI & American College of Chest Physicians joint Symposium: Pulmonary Vascular Disease from a Global Perspective, Vancouver, October 31, 2010 This symposium was chaired by Stuart Rich and Kamal Mubarak. Five seminars were presented

CONGENTIAL HEART DISEASE • Congenital Heart Disease around the World: Incidence, Prevalence, and Challenges of Early Surgical Repair (Ian Adatia) • Pathophysiology of PAH in Congenital Heart Disease (F. Jay Fricker) • Is Eisenmenger Syndrome Still Untreatable? (Antonio Augusto Lopes) Jan - Jun 2011 • Volume 3 • Issue 1

COPD • Pulmonary Hypertension in COPD: What is Out of Proportion and How Common is it? (Omar A. Minai) • Genetic Determinants of Pulmonary Hypertension and COPD: Single Nucleotide Polymorphisms and Alleles (Serge Adnot) • Treatment of Pulmonary Hypertension in COPD: What is the Evidence? (C. Gregory Elliott)

INFECTIOUS DISEASES • Pulmonary Vascular Disease in Schistosomiasis: Magnitude

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of the Problem (G. Butrous) • HIV and the Nef Protein: Pathogenesis of a Deadly Disease (Sonia C. Flores) • Pulmonary Vascular Disease in HIV: Treatment Options (Harrison W. Farber)

HIGH ALTITUDE PULMONARY HYPERTENSION • Acute Mountain Sickness around the World (Michael Koehle) • Cardiopulmonary Consequences of Chronic Hypoxia (David Badesch)

• Pulmonary Vascular Disease with High Altitude and Hypoxia: Do we know enough to treat it? (Nicholas S. Hill)

PULMONARY HYPERTENSION WITH HEMOLYSIS • Pulmonary Vascular Disease With Hemolytic Anemias: H e m o g l o b i n o p a t h i e s A r o u n d t h e Wo r l d ( K a m a l Mubarak) • From Hemolysis to Pulmonary Hypertension: The Nexus of Heart, Lung, and Blood (Roberto Machado) • Pulmonary Vascular Disease With Hemolytic Anemias: Update on Recent Clinical Trial Results (Mark T. Gladwin)

Figure 15: PVRI & American College of Chest Physicians joint Symposium – Pulmonary Vascular Disease from a Global Perspective, Vancouver, October 31, 2010

The PVRI Board of Directors and Advisors Meeting, London, November 20, 2010 The Board of Directors (BOD) of PVRI met in London on November 20, 2010 to discuss the activities and future objectives of the Institute, its finances, its communications and its relationships with other bodies. The BOD recognised that PVRI had made a considerable contribution in its short history on very modest finances. Its highlighted achievements included research into pulmonary hypertension associated with schistosomiasis, a debate with the FDA and the prospective launch of a new journal. PVRI is now a recognised body. The opportunity was taken to discuss the PVRI Constitution and a revised document will be presented at the 5th Annual General Meeting in Panama in February 2011.

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Figure 16: PVRI Board of Directors meeting November 20, 2010. (Sitting from left):- Sheila Haworth Ahvie Herskowitz, Maha Al-Saud. (Standing from the left):Alec Craig, Declan Doogan, Ghazwan Butrous, Stuart Rich, Martin Wilkins and Pascoal Mocumbi (absence Peter Raymond and Magdi Yacoub)

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PVRI Webinars • PVRI Eastern Mediterranean Region and SAPH webcast – PAH associated with connective tissue disease, September 29: Dr. Saleh Al Dammas (Riyadh, KSA), Dr. Maha Al Dabbagh (Jeddah, KSA) and Dr. Antonio Lopes (São Paulo, Brazil) 300

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In 2010, PVRI continued its collaboration with the PAH Forum to allow for live broadcast of webinars via the internet. Under the supervision of Professor Antonio Augusto Lopes, another four webinars were presented this year to a global audience. Since its inception, the webinars have attracted over 2000 views and provide great testament to the PVRI goal of spreading knowledge and awareness of pulmonary vascular disease [Figures 17-19]. • Pathology of pulmonary vascular disease, April 27: Dr. Rubin Tuder (Denver, USA), Dr. Vera D. Aiello (São Paulo, Brazil) and Dr. Antonio Lopes (São Paulo, Brazil) • Oxygen sensing in the ductus arteriosus and the pulmonary circulation, May 12 : Dr. Stephen Archer (Chicago, USA) and Dr. Antonio Lopes (São Paulo, Brazil) • Pulmonary arterial hypertension associated with HIV infection, July 6: Dr. Nicola Petrosillo (Rome, Italy), Dr. Sonia Flores (Denver, USA), Dr. Ghazwan Butrous (Canterbury, UK) and Dr. Antonio Lopes (São Paulo, Brazil)

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Figure 19: Comparison of the attendance during live broadcast vs later views

Staying in touch with the journal 1)

Table of Contents (TOC) email alert Receive an email alert containing the TOC when a new complete issue of the journal is made available online. To register for TOC alerts go to www.pvrireview.org/signup.asp.

RSS feeds Really Simple Syndication (RSS) helps you to get alerts on new publication right on your desktop without going to the journal’s website. You need a software (e.g. RSSReader, Feed Demon, FeedReader, My Yahoo!, NewsGator and NewzCrawler) to get advantage of this tool. RSS feeds can also be read through FireFox or Microsoft Outlook 2007. Once any of these small (and mostly free) software is installed, add www.pvrireview.org/rssfeed.asp as one of the feeds.

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TASKFORCE ACTIVITIES

The PVRI Publications Taskforce Leaders: Jason Yuan, USA and S. Harikrishnan, India

TEXTBOOK PULMONARY VASCULAR DISEASES A textbook on Pulmonary Vascular Disease has recently been published. Over two thirds of the 220 contributors are registered as PVRI members or Fellows, or are actively involved in PVRI activities. PVRI’s contribution and involvement is mentioned in the preface of the textbook.

PULMONARY CIRCULATION The publication taskforce has been working towards the goal of publishing a new peer-reviewed journal dedicated to pulmonary vascular disease, entitled Pulmonary Circulation.

Looking forward, the role of PVRI Review was redefined in Lisbon as follows: PVRI REVIEW becomes the official newsletter of PVRI, publishing all the activities of the regional PVRI taskforces and also reports on various meetings and activities held under the auspices of PVRI. In addition to its function as a newsletter, it will also publish perspectives and points of view, case studies, compilations and commentaries on interesting articles published in major journals. PVRI REVIEW is no longer a peer-reviewed journal, but it will become a forum to express the viewpoints of PVRI fellows. It was also decided in Lisbon that PVRI REVIEW should be published three times a year rather than quarterly, which has been accommodated in 2010.

The journal is open access and available online at www.pulmonarycirculation.org. The journal does not charge for submission, processing or publication of manuscripts nor for color reproduction of photographs. Funding for 3 years has been provided by an educational grant from the Cardiovascular Medical Research and Education Fund (CMREF) (http://www.ipahresearch. org/). Editors-in-Chief are comprised of Jason X.-J. Yuan, MD, PhD (Chicago, USA); Nicholas W. Morrell, MD (Cambridge, UK); Harikrishnan S., MD (Trivandrum, India). The Senior Editor is Ghazwan Butrous, MD (Canterbury, UK) whilst Editorial Staff includes Nikki Krol (London, UK) and Karen Gordon (Chicago, USA). The full editorial board can be found at http://www. pulmonarycirculation.org/EditorialBoard.asp and the Instruction for Authors at http://www.pulmonarycirculation. org/contributors.asp

Figure 20: Pulmonary Circulation

PVRI REVIEW IN 2010 The introduction of Pulmonary Circulation has prompted a rethink about the role of PVRI REVIEW. From its inception, as this was the first publication of a then relatively unknown PVRI, it was decided that the focus would be mostly on review articles and educational features including case reports, images and guidelines, rather than original articles which would have been hard to attract. PVRI REVIEW has proved popular and successful. It remain as an open access journal, in full colour, available in English as well Chinese and Portuguese. In addition, several articles were translated and published in Arabic and Spanish. Authors from all over the world have participated in and contributed to its success. PVRI REVIEW

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Figure 22: Access statistics comparison of site access October 2009 and October 2010 shows 125% increase in page views over one year

Figure 23: Journal site hits from different regions (30days) – Google analytics – Citywise

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Chinese Edition of The PVRI Review – 2010

The second issue of PVRI-Review Chinese edition (Volume 2, Supplement 1) was published in Aug 2010 and distributed in Beijing Heart Forum. Chief Editors - Jianguo He and Lan Zhio.

Portuguese Edition of the PVRI Review – 2010

PVRI Review published a Portuguese edition (Volume 2, Issue Supplement 2, Year 2010) which can be found at http:// www.portuguese.pvrireview.org/. The editor is Dr. Maria Virginia Tavares Santana, leader of the Latin America Taskforce, Brazil.

PVRI Review - Issue statistics 2010 Volume 2

Pages

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Figure 24: Author Institution Mapping - City wise distribution

PVRI Schistosomiasis Taskforce Activities for 2010 Leaders: Ghazwan Butrous and Nicholas Morrell, UK The schistosomiasis taskforce activities included increasing awareness of the problem and collaborative basic research between Cambridge (UK) and Denver (USA). This year Professor Ghazwan Butrous presented a talk at the 20th European Congress of Clinical Microbiology and Infectious Diseases in Vienna on the role of schistosomiasis in pulmonary hypertension (PH in infectious diseases meeting). Likewise, Professor Butrous presented at the Chinese Heart Association meeting in August, and in Vancouver during the ACCP/PVRI session (ref. pp.10-11). Professor Nicolas Morrell presented a talk at the pulmonary hypertension symposium at the British Thoracic Society in December 2010 on “Pulmonary hypertension and inflammation: lessons from schistosomiasis”. Dr. Brian Graham gave an oral presentation at the 2010 ATS conference in New Orleans on “Schistosomiasis-Associated Experimental Pulmonary Hypertension: Role of IL-13 and Th-2 Signalling.

UNIVERSITY OF CAMBRIDGE LABORATORY, UK ACTIVITIES (ALEXI CROSBY, NICK MORRELL, DAVID DUNNE) This year a paper was published in the American Journal of Respiratory and Critical Care Medicine describing a murine model of chronic schistosomal infection associated with lung egg deposition and profound pulmonary vascular remodelling. The model showed plexiform-like lesions and provided evidence for the involvement of cytokines driving the process of remodelling. A project examining the effects of the anthelminthic drug, praziquantel, on schistosomiasis-induced pulmonary vascular remodelling and pulmonary arterial hypertension has been PVRI REVIEW

Figure 25: The taskforce research fellows

completed. Animals developed significant pulmonary hypertension and right ventricular hypertrophy 25 weeks following infection. The presence of pulmonary hypertension was associated with the presence of lung eggs and the local expression of cytokine mRNA in the lung. Treatment with praziquantel at 17 weeks prevented pulmonary hypertension and reversed pulmonary vascular remodelling, suggesting that eradication of the parasite might allow resolution of disease in patients. Some of this work was presented at the ATS and at the BTS. A British Heart Foundation grant was awarded to further study the mechanisms involved in schistosomiasis-induced pulmonary arterial hypertension, with a particular focus on the role of bone-marrow derived progenitor cells in pulmonary vascular remodelling and to investigate the role of individual cytokines in this process. These projects would not have been initiated without the increased awareness and discussion of this important disease area enabled by the PVRI. Collaborators: Nick Morrell, David Dunne, Ghazwan Butrous, Ewa Kolosionek

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UNIVERSITY OF KENT LAB ACTIVITIES (EWA KOLOSIONEK, GHAZWAN BUTROUS, UK) A convenient rodent model for schistosomiasis-associated pulmonary hypertension has been established in collaboration with the Natural History Museum in London. The work has resulted in 2 review articles – one in collaboration with Dr. Brian Graham and Professor Rubin Tuder (Denver, USA), and the other in collaboration with Dr. Alexi Crosby, Dr. Nick Morell (Cambridge, UK) and Michael Harhay (Philadelphia, USA). Additionally, in collaboration with Dr. Brian Graham and Professor Rubin Tuder, an experiment involving whole-genome analysis using different schistosomiasis models of pulmonary hypertension is underway.

UNIVERSITY OF COLORADO DENVER , USA ACTIVITIES (BRIAN GRAHAM, RUBIN TUDER) Research continues into understanding the pathogenesis of

schistosomiasis-associated pulmonary hypertension using a mouse model of the disease and analysis of human autopsy tissue. In the past year, findings have been published in the American Journal of Pathology and two review articles were published through collaboration within the PVRI, namely in CHEST and in Clinical Microbiology and Infection. Several grants support the research, including a research grant from the PVRI to identify schistosomiasis antigens retained in human lung tissue, collected by PVRI collaborator Angela Bandeira using mass spectroscopy and antibodies generated to S. mansoni antigens. Brian Graham received a Parker B. Francis fellowship to perform research in this field. A Pfizer ASPIRE grant to perform RNA-seq on infected mouse tissue to identify signaling hubs for inflammation and cell proliferation was awarded, and in collaboration with Ewa Kolosionek and Ghazwan Butrous, additional whole-genome expression experiments have been performed on several infected and uninfected mouse samples. A Professional Research Assistant, Jacob Chabon, has been hired to assist the research effort.

PUBLICATION OF THE TASKFORCE (Refer PVRI Publications in 2010)

PVRI High Altitude Taskforce Leaders: Qadar Pasha, India and Max Gassmann, Switzerland During the last two years PVRI has greatly encouraged the high altitude taskforce to initiate a scientific program by organizing an international event every two years in Leh, Ladakh (India), a Buddhist city located 3,500 m above sea level. Preparations started months before the Leh meeting occurred in September 2010 by raising funds and convincing colleagues to join the meeting. Support was canvassed at the Peru meeting of the International Society of Mountain Medicine that took place in the City of Arequipa. There, plans were finalised and the prospective audience updated. The Leh meeting entitled ‘Recent trends and future perspectives in high-altitude pulmonary research’ was advertised on several websites, including www.pvri.info. The speakers made this meeting a delightful experience. The participants deliberated on adaptive and nonadaptive phenotypes like the thinner muscle mass in common carotid artery and brachial artery, oxygen saturation, hemoglobin concentration, hypoxic ventilatory rate and pulmonary blood pressure. The significance of increased production of erythropoietin, under low partial pressure of oxygen, on ventilation or cognitive functions was underlined. Likewise, among the various biomolecules, reduced nitric oxide (NO), increased endothelin, aldosterone, asymmetric dimethylarginine, serotonin and isoprostane levels and miRNA-target interactions were highlighted. It was encouraging to note several presentations on the genetic aspects of relevant pathways in Andeans and Ladakhis. In addition to the recent reports, the genetics of HAPH in Kyrgyz highlanders and chronic obstructive pulmonary disease in Caucasians was also Jan - Jun 2011 • Volume 3 • Issue 1

reviewed. Incidentally, the endothelial nitric oxide synthase gene was the focus of attraction. Mouse and rat models have greatly contributed to increasing knowledge in this field. Zebrafish is yet another such model which will provide understanding of the pathophysiology in a much shorter time. The facility at IGIB, the ease of handling and the decoding of zebrafish sequence by the team provided a right platform for collaborations, at least to the Indian participants. The faculty of Sonam Norboo Memorial hospital presented the

Figure 26: Alexandra Heath

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newer trends in disease development with case presentations and the social and geographic contributions. Among the therapeutics, the application of acetazolamide, NO, nifedipine and phosphodiesterase inhibitors in pulmonary hypertension associated diseases, including sleep apnea was elaborated. Equally important was the understanding of the role of newer drug-targets in disease management, such as the emerging science of peptidomimitics as anti-hypertensive therapy and the aqueous extract of Punica granatum in reducing pulmonary hypertension. Finally, the visit to Tangtse hospital at 4600m, and 180km from Leh, provided an insight into the functioning of the hospital under such extreme conditions and its achievements; moreover the visit opened up a new collaboration for IGIB team. The taskforce contributed with presentations in several conferences, such as the Solaci Congress, Buenos Aires, German Congress for Pediatric Cardiology, Weimar and Latin American Congress for pediatric Cardiology, Punta del Este.

Dr. Heath has received a grant from PVRI for investigation of HA-CHD-PH. In the next 2-3 years, collaborative work within this taskforce has to improve. The necessity of collaborations was emphasized in various meetings. Each team member wants it to happen, and efforts have to accelerate. It would be wonderful if the populations from all the high altitude regions become unified for any research investigation; perhaps, a unified source of funding will pave the way. PVRI’s monetary support to such collaborative efforts would certainly be useful. The suggestion was made to begin anew by asking all members to supply their published papers to the High Altitude Taskforce, especially reviews and papers with information on upcoming meeting(s) that might be of interest with regards to pulmonary hypertension. This will identify where common interest lays. Organizing further meetings, such as the one in Leh (which most likely will be repeated in 2012) will provide a forum for bringing the fellows together.

Pulmonary Hypertension Associated with HIV – Taskforce Leaders: Nicola Petrosillo, Italy, Sonia Flores, Sharilyn Almodovar and Norbert Voelkel, USA Pulmonary hypertension as a non-infectious complication of HIV infection continues its insidious course in the era of antiretroviral therapy. In many cases, the disease is under diagnosed or misdiagnosed because of the non-specificity of the symptoms. In recent years, much more attention has been paid to the pathogenic role of HIV and to the clinical manifestations of HIV-related pulmonary arterial hypertension (HIV-PAH). The presence of PAH is an independent risk factor for mortality in patients with HIV infection, and, in most cases, death is causally related to PAH rather than to other complications of HIV infection. The median survival of HIV-PAH patients seems to be significantly lower than that of HIV-infected patients without PAH. HIV-PAH occurs in early and late stages of HIV infection and does not seem to be related to the stage of infection, the degree of immune deficiency or CD4 T-lymphocyte count. No specific risk factor for HIV infection is associated with this disease, although HIV-PAH is reported to be more frequent in intravenous drug users, with patients in this group representing 59% of cases of HIV-PAH in a recent French cohort study.

Aims of the HIV-PAH taskforce remain:

• to provide educational tools for better insights into pathogenesis of PAH and HIV infection; • to establish a network of centers that care for HIV positive patients with PAH and provide sound epidemiological data • to carry out research studies on the pathobiology and better therapeutic approaches for the clinical management of HIVPAH patients PVRI REVIEW

• to expand the number of HIV-infected patients in undeveloped countries who will be screened for the presence of specific nef alleles associated with a high risk of being diagnosed with PAH In the year 2010 the taskforce undertook the following initiatives: a. Providing educational and research articles on HIV-PAH. (Refer publications) b. Meeting/Symposia/Conferences organization: (Refer PVRI conferences and symposia) • Organization of a session on Pulmonary hypertension and infectious diseases at the 20th European Congress of the European Society of Clinical Microbiology and Infectious Diseases April 10-14, 2010 – Vienna, Austria • Session on Pulmonary Hypertension in the III National Congress on Infective • Cardiopathies and HIV-related issues; March 12 - Naples, Italy • Webinar 2010 (in collaboration with Pulmonary Hypertension Associated With Congenital Heart Disease Taskforce) • Session on Pulmonary Arterial Hypertension Association meeting, Garden Grove, CA. June 24-27, 2010. Inflammation in HIV-related pulmonary hypertension: cause or effect? Lessons from animal models; Presenter: Sonia C. Flores • Session at the American Heart Association meeting, Emerging Concepts and New Therapeutic Targets in Pulmonary Arterial Hypertension; Emerging concepts on PAH: HIV and the Nef protein, November 15, 2010, Chicago; Presenter: Sonia C. Flores

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RESEARCH ACTIVITIES Members of the HIV taskforce tested the hypothesis that Nef signature sequences are found at higher frequencies in HIVinfected patients with PH than in HIV-infected normotensives. Indeed, specific nef alleles were present at higher frequencies in pulmonary hypertensive patients from Europe, compared to controls. These results were subsequently validated in a separate cohort of patients from San Francisco, California, USA. The association of nef alleles with the pulmonary hypertensive phenotype was independent of HIV viral load, CD4+ T cell counts, length of infection and antiretroviral drug usage. Although most of the variant amino acids mapped to Nef functional domains, molecularly cloned Nef primary isolates retain the ability to down-regulate CD4. Similar nef mutations were found in lung tissue but not the periphery of an HIV+ pulmonary hypertensive patient. While HIV-1 nef signature sequences may

be used to screen HIV+ individuals and prioritize diagnosis of HIV-associated PH, these results offer new tools to further address mechanistic aspects in the fields of vascular biology and infectious diseases. Through the Lung HIV group, a higher prevalence and incidence of PAH associated with HIV is currently being reported. There are also sporadic reports that incidence may be much higher in sub Saharan Africa. The taskforce contacted Dr. Rosie Burton, the PVRI fellow in charge of developing the infrastructure required to perform echocardiograms and blood draws on the patients in South Africa. Collaborations will grant us access to blood samples from HIV-infected patients and the ability to genotype the nef alleles. The specific genotype can then be used to screen patients who may have PAH but are asymptomatic. This collaboration is currently being developed.

Pulmonary Hypertension Associated with Congenital Heart Disease Taskforce (PH-CHD TF) Leaders: Antonio A. Lopes, Brazil and Marlene Rabinovitch, USA The general objective of this taskforce is to provide education and implement discussion and research on subjects related to the management of PH-CHD in paediatric patients and the adult population.

EDUCATIONAL ACTIVITIES Internet videoconferences (See PVRI Webinars above) In collaboration with the King Faisal Specialist Hospital & Research Centre (PVRI Website, PH-CHD TF page) • Congenital cardiac septal defects associated with pulmonary hypertension (R.C. Gonçalves and A.A. Lopes) • Bedside criteria of severity of the disease before the era of the new drugs for pulmonary arterial hypertension: A historical patient group (R.C. Gonçalves and A.A. Lopes) • A proposed algorithm for management of patients with congenital cardiac defects associated with pulmonary hypertension (A.A. Lopes and R.J. Barst) • Hemodynamic requirements for safely indicating a Fontan procedure (M.A. Binotto and A.A. Lopes) • ECHO-Doppler noninvasive assessment of pulmonary hemodynamics in pulmonary arterial hypertension associated with congenital heart disease (N. Galal, O. Tamimi and M. Dabbagh)

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Daily practice: This is a new educational activity on controversial issues of the daily practices. These controversies and discussions are intended to be part of the CHD page on the PVRI website.

PARTICIPATION IN INTERNATIONAL SCIENTIFIC MEETINGS • ACCP-PVRI Joint Symposium, Vancouver, Canada, October 31, 2010 • Pediatric and Adolescent Pulmonary Arterial Hypertension Workshop, Riyadh, Saudi Arabia, June 15-16, 2010 • Internet videoconference from São Paulo Brazil: Target therapy in pulmonary arterial hypertension: present and future, June 15, 2010 - 11:00AM-GMT • SAPH 2nd Annual Pediatric-Congenital Heart Disease Pulmonary Hypertension Symposium, Jeddah, Saudi Arabia, December 13-14, 2010

ONGOING RESEARCH ACTIVITIES • The “treat-and-repair” strategy in the management of congenital cardiac shunts associated with pulmonary hypertension: pre- and post-operative treatment with specific pulmonary vasodilators. The study (ongoing) includes pre and postoperative catheterization, intraoperative lung biopsy, biomarker determinations and genetics.

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PVRI Hemolytic Anemia Taskforce Leaders: Kamal Mubarak and Roberto Machado, USA Inherited hemoglobin disorders are the most common monogenetic diseases worldwide. For instance, there are 30 million individuals worldwide with sickle cell disease (SCD). Remarkably, virtually every cause of hemolytic anemia, including SCD, thalassemia intermedia and major, hereditary spherocytosis and stomatocytosis, paroxysmal nocturnal hemoglobinuria, hemoglobin-Mainz hemolytic anemia, microangiopathic hemolytic anemia, malaria, hemolysis from mechanical heart valves, left ventricular assist devices, and cardiopulmonary bypass procedures, has been associated with pulmonary hypertension. From a mechanistic standpoint, patients with chronic hemolysis can develop pulmonary vascular disease at least in part due to alterations in nitric oxide bioavailability but other mechanisms such as thrombosis, splenectomy and elevation of serum endothelin have also been implicated. Although significant advances have been made in the understanding of the pathophysiology of pulmonary vascular disease associated with hemolytic disorders, very little is known about its global impact. The etiology of pulmonary hypertension is multifactorial with pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with left heart disease being the most common culprits. It is also apparent that patients with chronic hemolytic disorders tend to poorly tolerate even mild to moderate elevations in pulmonary artery pressure and pulmonary vascular resistance. However, the prevalence of clinically significant pulmonary vascular disease in chronic hemolytic disorders remains controversial.

GOALS AND MISSION 1. Promote awareness of pulmonary hypertension associated with

3. 4. 5.

chronic hemolysis as a subset of World Health Organization (WHO) Classification of Pulmonary Hypertension (Group I), i.e. PAH. Review published literature and emerging evidence to write a consensus paper on global epidemiology, diagnostic workup, and proposed treatment for PAH associated with hemolytic anemias. Define the global impact, in terms of prevalence, morbidity and mortality, of pulmonary vascular disease associated with chronic hemolysis. Identify further areas of research in acute or chronic hemolysis, such as malaria as it relates to vascular disease. Explore the role of treatment of the primary hemolytic disorder in the prevention of the development of pulmonary vascular disease and associated morbidity and mortality.

TASKFORCE ACTIVITIES IN 2010 • Taskforce members published comprehensive reviews on global epidemiology, diagnostic workup, and proposed treatment for PAH associated with hemolytic anemias. Chest, June 2010 137:30S-38S. • Taskforce members helped organize and presented at a symposium on the global impact of pulmonary hypertension at the October 31st American College of Chest Physicians Conference in Vancouver, Canada. • Taskforce members are actively involved in the preparation of the American Thoracic Society’s Consensus-Based Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension of Sickle Cell Disease. The document is in its final stages of preparation and will likely be published early 2011.

PVRI China Taskforce 2010 Leaders: Martin Wilkins, UK and Chen Wang, China The Pulmonary Vascular Research Institute (PVRI) China Taskforce has entered its fourth year. Significant progress has been made in 2010 in collaboration with the Assembly of Pulmonary Embolism & Pulmonary Vascular Diseases in the Chinese Thoracic Society (CTS) and ChaoYang and Fu Wai Hospitals. A summary of these include: • The PVRI China taskforce organized a strategy meeting for pulmonary vascular diseases (PVDs). • Professor Michael Madani visited China to share his experience of pulmonary thromboendarteractomy for CTEPH patients. A symposium on CTEPH and PAH was held at the same time. Prof Michael Madani and his assistants, PVRI REVIEW

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Dr. Ovando and Ms. Morris, visited ChaoYang Hospital, Beijing Institute of Respiratory Medicine from May 28th to June 3rd 2010, to perform surgery on patients with chronic thromboembolic pulmonary hypertension (CTEPH). The utility of cooling jackets for the heart and the head, multiple heart mesh retractors, and multiple pulmonary artery vents were introduced for the operation with Chinese colleagues. A whole day symposium on CTEPH and PAH was held. Prof. Madani and his assistants gave talks covering the diagnosis, medical and surgical management of CTEPH, and intensive care and lung transplantation for pulmonary arterial hypertension (PAH). Two hundred doctors around Beijing took part in the symposium. Jan - Jun 2011 • Volume 3 • Issue 1

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• An educational meeting of pulmonary embolism for the local doctors and health care givers. • The annual meeting of PVRI China taskforce. • An educational supplement of pulmonary hypertension was published in the Chinese Journal of Practical Medicine. (Refer publications). • Supporting the International Beijing Heart Forum. The research projects in PE and PAH funded by the 11th five year plan will be finished by the end of this year. The 12th five year plan will be initiated to push the research of PE, PAH and other forms of PH. • Three PVRI grant applications were awarded: i) China-UK Collaborative Study on the National Registered Patients with Pulmonary Arterial Hypertension; ii) The Role of Fibrinogen AThr312Ala Polymorphism in Chronic Thromboembolic Pulmonary Hypertension; iii) Validation of circulating growth factors as biomarkers in pulmonary arterial hypertension. • Pulmonary Hypertension in China has been published in the supplement of CHEST, 2010 “Pulmonary Vascular Diseases: The Global Perspective”. (Refer publications). • The second issue of (Chinese version) was published in August 2010 and distributed in the Beijing Heart Forum.

Figure 27: Meeting of the PVRI China Centre in Bejing

• Strategy meeting by the committee of PVRI China Taskforce May 2010 in Taiyuan, Shanxi, China to discuss the Consensus statements of pulmonary hypertension and Guidelines of pulmonary embolism and deep venous thrombosis.

PVRI India Taskforce Leaders: Glennis Haworth, UK and Krishna Kumar, India 2010 has been a year of consolidation for PVRI India. The office has moved permanently to Mumbai under the supervision of Prof. K. Kumar, but the organization will retain its charitable status and bank account in Kerala. Clinicians are becoming far more aware of pulmonary vascular disease and the membership of PVRI increases slowly but steadily. In addition to the Annual Pulmonary Hypertension Symposium, smaller meetings are being organized at different centres and these are well attended. In order to facilitate research into problems which relate specifically to the care of Indian people with pulmonary hypertension, GlaxoSmithKline has generously agreed to fund Fellowships to PVRI India. The major events scheduled for 2011 were planned at the Executive Meeting in Hyderabad in October.

Hospital, Mumbai, organised by Professor K. Kumar and the meeting in Trivandrum organized by Prof. Harikrishnan of the Sree Chitra Tirunal Institute for Medical Sciences and Technology. Dr. Kychawla also held a meeting in Baroda, supported by Dr. BKS Sastry. The Mumbai Multidisciplinary Pulmonary Hypertension Meeting, September 5, 2010: This meeting focused on pulmonary hypertension associated with adult and paediatric cardiac disease, and with problems in the intensive care unit and neonatal practice. The Mumbai meeting was beamed to Cochin.

EDUCATIONAL EVENTS Annual Pulmonary Hypertension Symposium

This meeting was held on October 10th in Hyderabad and was organized by Dr. BKS Sastry. For the first time the Annual Symposium was not held in association with a national specialty meeting and there were just over 100 participants. Those targeted were respiratory physicians and rheumatologists. The principal guest speaker was Dr. David Kiely from the UK, an eminent respiratory physician who specializes in pulmonary hypertension.

Local meetings

The two principal local meetings were held at Seven Hills Jan - Jun 2011 • Volume 3 • Issue 1

Figure 28: Mumbai Multidisciplinary Pulmonary Hypertension Meeting, September 5th 2010

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Leh, Ladakh, India, September 27-30 Pulmonary Hypertension Associated with High Altitude This meeting was organised by Prof. BMA Qadar Pasha of the Institute of Genomics and Integrative Biology, Delhi and the Council of Science and Industrial Research of India, on behalf of the High Altitude Taskforce. Discussion topics included the physiology and metabolic adaptation to high altitude, research into mal-adaptation and current understanding of the influence of angiogenesis and genetics.

RESEARCH GSK Fellowships in Pulmonary Hypertension in India

These Fellowships, generously provided by an unrestricted educational grant, will be awarded competitively to young clinical and basic science investigators working to improve the lot of Indian people suffering from pulmonary vascular disease.

Figure 29: PVRI India local meeting at Trivandrum

ongoing inflammation due to subclinical rheumatic activity in the non-regression of pulmonary hypertension and development of restenosis following balloon mitral valvotomy in Juveline Mitral Stenosis.

Current Research Activities

• Dr. Puri and Dr. Bhupesh Kumar, PGI, Chandigarh: Effect of perioperative oral sildenafil on pulmonary hypertension in patients undergoing mitral valve surgery: A prospective double blinded randomized trial. • Dr. Andrew Lynn and Swapna Menon, JNU, Delhi: Bioinformatic analysis of gene expression profiles of pulmonary arterial hypertension. Submitted to the PVRI for funding, June 2010: approved, September 2010 to support Swapna Menon. • Dr. Madhu Dixit and Dr. Kashif Hanif, CDRI, Lucknow: Animal Model of Pulmonary Hypertension for Identification of New Therapeutic Targets. Travel grant submitted to the PVRI for funding, June 2010: approved September 2010 to support Dr. K Hanif. • Dr. Sajal Chakraborti, University of Kalyani: Leukotriene D4 mediated alteration in beta-adrenergic response in pulmonary smooth muscle cells • Dr. Subir Kumar Maulik, AIIMS, Delhi: Evaluation of Novel Pharmacological Agents in Experimental Pulmonary Artery Hypertension in Rats • Dr. S. Harikrishnan, SCTIMST, Trivandrum: Influence of

SUMMARY OF OBJECTIVES FOR 2011 1. Annual Pulmonary Hypertension Symposium, 2011. This will be held in October in Trivandrum. For the first time we will include a Pathology Workshop, to be organised by Professor Kartha. There will also be a Research Meeting which will be open to all those carrying out research into pulmonary hypertension, or interested in doing so. It will give the young Fellows and investigators the opportunity to present their work and meet each other. 2. Intensify the programme of small local meetings and extend our activities to other centres in India, starting with Chennai. 3. Cardiac Imaging: modalities of imaging in pulmonary arterial hypertension, January 6-7th. This meeting was organized by the Association of Physicians of India with the involvement of Dr. Sastry. 4. Award the GSK Fellowships. 5. Extending PVRI Activities to other Regions of South East Asia. This is our most important objective for 2011.

PVRI East Mediterranean Taskforces Leaders: Majdy Idrees, Saudi Arabia, and Paul Hassoun, USA The main activities of the EMR taskforces: • The third joint PVRI and SAPH (Saudi Advisory Pulmonary Hypertension) symposium, Sham Al Sheik, April 6-8, 2010 (see above) • Pulmonary Hypertension in the Young, with the Saudi Association for Pulmonary Hypertension Jeddah, Saudi Arabia, December 13-14, 2010. The 2nd Annual Pediatric – Congenital Heart Disease PVRI REVIEW

Pulmonary Hypertension Symposium was a magnificent and well organized scientific meeting held in Jeddah, Saudi Arabia, in December 2010. Going forward form the First Symposium in Jeddah 2009, the program of 2010 was extended to include not only PAH associated with congenital heart disease, but also important etiologies of pulmonary hypertension in the pediatric population, including PPHN and hemolytic anemias. All subjects of interest for the pediatric population were brought up for discussion, from pathophysiology and classification to diagnosis, pre- and postoperative care, advanced new

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therapies and transplantation. The Symposium was a brilliant scientific initiative of the Saudi Association for Pulmonary Hypertension (SAPH), organized by Prof. Maha Al Dabbagh, Head of the Pediatric-CHD Taskforce, and Prof. Madjy Idrees, Head of SAPH. The National Faculty included Professors Manal Al Asnag, Jameel Al Atta, Saleh Al Dammas, Adel Salem Al Harbi, Ibrahim Al Mogary, Khalid Al Najashi, Abdul Majeed

Al Otay, Howaida Al Qethami, Wafaa Al Suwairi, Omar Al Tamimi, Samer Arar, Haysam Baho, Suhair Balkhi, May Chehab, Manal Hebshi, Mohammad Kabbani, Fawaz Kashlan, Amjad Kouatli, Logambal Kroutz, Dina El Metwally, and Faris Mousily. The International Faculty included Professors Maurice Beghetti from Geneva, Switzerland, and Antonio A. Lopes from São Paulo, Brazil.

The PVRI Paediatric Taskforce Leaders: Maria Jesus del Cerro, Spain, and Ian Adatia, Canada The two most pressing issues for this Taskforce are the Classification of Pulmonary Hypertension in Children and the development of an age–specific Functional Classification. It is generally acknowledged impossible to apply the Adult WHO/

NYHA Functional Classification to children. Both these issues will be discussed at the Panama City PVRI Annual General Meeting in February 2011.

The PVRI CTEPH Taskforce Leaders: Nick H. Kim, USA, and Eckhard Mayer, Germany The main aim of this taskforce is to enhance more understanding of the chronic thromboembolic pulmonary hypertension (CTEPH), by supporting collaborative research, constructing

teaching modules, and writing consensus paper on the operability scoring for patients with CTEPH.

PVRI Research Grants PVRI received 20 grant applications from PVRI Fellows. The geographical distributions are as follows. Region PVRI European Region Taskforces PVRI Western Pacific Taskforces PVRI Sub-Saharan Africa Taskforce PVRI East Mediterranean Region Taskforce PVRI South East Asia Region Taskforce PVRI America Region Taskforce

Number of applications 2 4 3 0 3 8

The Research Committee was comprised of Professors Evangelos Michelakis, Marlene Rabinovitch, Nicholas Morrell, Krishna Kumar and Julio Sandoval. The research applications were scored independently. In discussion with the PVRI Executive Committee it was decided to award the top 11 scores amounting to a total of US $80,000, allocated as follows:

1. The Role of Fibrinogen AThr312Ala Polymorphism in Jan - Jun 2011 • Volume 3 • Issue 1

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Chronic Thromboembolic Pulmonary Hypertension. Ji-Feng Li (PVRI Western Pacific region - PVRI China Centre) under supervision of the PVRI CTEPH taskforce. Bioinformatic analysis of gene expression profiles of pulmonary arterial hypertension. Andrew Lynn (PVRI South East Asia Region - PVRI India Chapter) under supervision of the PVRI International Database and Biobank Taskforce. Validation of circulating growth factors as biomarkers in pulmonary arterial hypertension. L Zhao (PVRI Western Pacific - Fuwai Hospital in collaboration with Imperial College London) under supervision of the PVRI International Database and Biobank Taskforce. The prognostic effects of Pulmonary Hypertension on Hypertensive Heart Failure in a Native African Population. Dike B Ojji (PVRI Sub-Saharan Africa) under supervision of the PVRI Left Heart Failure Taskforce. Does High Altitude Protect against irreversible Pulmonary Hypertension in congenital heart diseases. Alexandra Heath (PVRI America Region) and Pulmonary Hypertension Associated with High Altitude and Hypoxia and Pulmonary PVRI REVIEW

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Hypertension Associated with Congenital Heart Disease. 6. Identification of Schistosoma Mansoni Antigens in the Lungs of Humans with Schistosomiasis-Associated Pulmonary Arterial Hypertension. Brian Graham (PVRI America Region) under supervision of Pulmonary Hypertension Associated with Schistosomiasis. 7. Genetic determinants of Monge’s disease. Jean-Paul Richalet (PVRI European and PVRI America Regions) under supervision of Pulmonary Hypertension Associated With High Altitude and Hypoxia. 8. Travelling grant: Animal Model of Pulmonary Hypertension for Identification of New Therapeutic. Kashif Hanif (PVRI South East Asia Region- PVRI India Chapter) Targets under supervision of PVRI Sponsored International Fellowships and

researches. 9. Pulmonary Hypertension in HIV and sickle cell disease in Dar es Salaam, Tanzania. Kemi Tibazarwa (PVRI SubSaharan Africa) under supervision of Pulmonary Hypertension Associated With HIV. 10. Implementation of an International Registry of Pulmonary Hypertension. Ana Mocumbi (PVRI Sub-Saharan Africa) under supervision of the PVRI International Database and Biobank Taskforce. 11. China-UK Collaborative Study on the National Registered Patients with Pulmonary Arterial Hypertension. J G He (PVRI Western Pacific- Fuwai Hospital and Imperial College London) under supervision of the PVRI International Database and Biobank Taskforce.

Administrative Activities APPOINTMENT OF FULLTIME PVRI ADMINISTRATOR The steady growth of the Pulmonary Vascular Research Institute brings an increased workload for the volunteers. In 2010, it was decided to restructure the workload by hiring a full time employee. Miss Nikki Krol was appointed to the position of PVRI Administrator in July 2010. Miss Krol functions as an assistant to the Managing Director, co-ordinates and organizes meetings, and functions as editorial assistant for both the PVRI Review and Pulmonary Circulation. She is also in charge of the website, the newsletter and serves as a point of contact for all those involved or interested in the PVRI. Miss Krol holds a BA degree in English Literature and an MA in Creative Writing, and has a background in administration. She has worked freelance as a transcriber and proofreader for individuals and industry.

THE PVRI CONSTITUTION During the BOD meeting in November 2010, revisions were made to the PVRI Constitution. The new document will be presented at the 5th Annual General Meeting in Panama City in February 2011.

THE PVRI WEBSITE AND SOCIAL MEDIA The new PVRI website has been live since July 2010. As PVRI is engaging more with social media on a global platform, the website was changed to reflect this and allow for more interaction, knowledge exchange and opportunity. Fellows and members have access to parts of the website and to advantages which are not open to the general public. One such an advantage is the ‘Create Content’ tab. With this tab, one can create their own page, blog post or event. This is a way to keep fellow PVRI members informed of PVRI REVIEW

Figure 30: The new PVRI website

upcoming events, ideas, or theories without being restricted to email addresses. • The website offers information on upcoming events. • Past meetings, upcoming events and general PVRI news can also be found in the newsletter. Current and back issues are viewable on the website. • Blog posts allow PVRI members and Fellows to express ideas and opinions in an informal setting. By using the blog and comment format, a comprehensive discussion of ideas and suggestions can be formed, and it is a viable method of informal communication. It is possible to keep the blog hidden from the general audience so only the Fellows can see it, which allows in depth discussion without immediate concerns regarding (re)presentation. Blogospheres are now

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Figure 31: The PVRI Twitter page

Figure 32: PVRI get-together in New Orleans during the ATS meeting 2010

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Figure 33: PVRI Membership on 24th Dec 2010

very commonly used by many scientists all over the world, and in the future they will become an essential tool for communication. PVRI is now present on several social media networks, such as Facebook, LinkedIn and Twitter. These social networks have created a different way of communicating and allow PVRI to revolutionize her goals of increasing awareness and knowledge of pulmonary vascular diseases. Facebook has over 200 million members who regularly check in on laptops, computer, and mobile phones. This allows for endless possibilities with regards to reaching people who share similar goals and views with regard to PVD. In addition, Twitter allows for PVRI to spread news on events, discoveries and theories in a very broad way and can act as the voice of the organization, whilst LinkedIn provides a platform between members and Fellows who wish to network and create connections and possibilities.

PVRI MEMBERSHIP The total number of registered members in PVRI by end of 2010 was 437. The geographical distribution of the Fellows are in Figure 32. We have added 164 new members in 2010.

PVRI GET-TOGETHERS This year two PVRI get-togethers were organized. The first informal meeting took place during the America Thoracic Society meeting in New Orleans, 17th May 2010. The second PVRI reception was during the American Heart Association meeting in Chicago on 15th Nov 2010. The PVRI get-together is a social informal gathering of all Fellows who attend an international scientific meeting.

“Quick Response Code” link for full text articles The journal issue has a unique new feature for reaching to the journal’s website without typing a single letter. Each article on its first page has a “Quick Response Code”. Using any mobile or other hand-held device with camera and GPRS/other internet source, one can reach to the full text of that particular article on the journal’s website. Start a QR-code reading software (see list of free applications from http://tinyurl.com/ yzlh2tc) and point the camera to the QR-code printed in the journal. It will automatically take you to the HTML full text of that article. One can also use a desktop or laptop with web camera for similar functionality. See http://tinyurl.com/2bw7fn3 or http://tinyurl.com/3ysr3me for the free applications. PVRI REVIEW

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PVRI 2010 Annual Report

PVRI Publication C H E S T S U P P L E M E N T O N P U L M O N A RY HYPERTENSION IN THE DEVELOPING WORLD, ISSUE JUNE 2010 THE URL: HTTP://CHESTJOURNAL.CHESTPUBS.ORG/ CONTENT/137/6_SUPPL 1. Stuart Rich and Ahvie Herskowitz, Targeting Pulmonary Vascular Disease to Improve Global Health. Pulmonary Vascular Disease: The Global Perspective, Chest June 2010 2010 137:1s-5s. 2. Sharilyn Almodovar, Stefania Cicalini, Nicola Petrosillo, and Sonia Flores, Pulmonary Hypertension Associated with HIV infection: Pulmonary Vascular Disease: The Global Perspective, Chest June 2010 137:6s-12s. 3. Qadar Pasha and John Newman, High-Altitude Disorders: Pulmonary Hypertension: Pulmonary Vascular Disease: The Global Perspective, Chest June 2010 137:13s-19s. 4. Brian Graham, Angela Pontes Bandeira, Nicholas Morrell, Ghazwan Butrous, and Rubin Tuder, Schistosomiasisassociated Pulmonary Hypertension: Pulmonary Vascular Disease: The Global Perspective, Chest June 2010 137:20s-29s. 5. Roberto Machado and Mark T. Gladwin, Pulmonary Hypertension in Hemolytic Disorders: Pulmonary Vascular Disease: The Global Perspective, Chest June 2010 137:30s-38s. 6. Omar Minai, Ari Chaouat, and Serge Adnot, Pulmonary Hypertension in COPD: Epidemiology, Significance, and Management: Pulmonary Vascular Disease: The Global Perspective, Chest June 2010 137:39s-51s. 7. Ian Adatia, Shyam Kothari, and Jeffrey Feinstein, Pulmonary Hypertension Associated with Congenital Heart Disease: Pulmonary Vascular Disease: The Global Perspective, Chest June 2010 137:52s-61s. 8. Bhagavathula Sastry, Michael McGoon, and Simon Gibbs, Clinical Trials for Pulmonary Hypertension in the Developing World: Pulmonary Vascular Disease: The Global Perspective, Chest June 2010 137:62s-68s. 9. Zhenguo Zhai, Jun Wang, Lan Zhao, Jason Yuan, and Chen Wang, Pulmonary Hypertension in China: Pulmonary Vascular Disease: The Global Perspective, Chest June 2010 137:69s-77s; 10. Antonio Augusto Lopes, Angela Bandeira, Patricia Cortez Flores, and Maria Virginia Tavares Santana, Pulmonary Hypertension in Latin America: Pulmonary Vascular Disease: The Global Perspective, Chest June 2010 137:78s-84s. 11. C. Gregory Elliott, Robyn Barst, Werner Seeger, Mateo PorresAguilar, Lynette Brown, Roham Zamanian, and Lewis Rubin, Worldwide Physician Education and Training in Pulmonary Hypertension: Pulmonary Vascular Disease: The Global Perspective, Chest June 2010 137:85s-94s. 12. Mardi Gomberg-Maitland and Evangelos Michelakis, A Global Pulmonary Arterial Hypertension Registry: Is It Needed? Is It Feasible? Pulmonary Vascular Disease: The Global Perspective, Chest June 2010 137:95s-101s.Journal of Clinical Microbiology and Infection, issue October 2010 Jan - Jun 2011 • Volume 3 • Issue 1

JOURNAL OF CLINICAL MICROBIOLOGY AND INFECTION, ISSUE, OCTOBER 2010 The Journal of Clinical Microbiology and Infection published a special series on Pulmonary Hypertension due to Infectious Diseases in October 2010. The series included the following: 1. N. Petrosillo, Editorial; Pulmonary Vascular Disease and Infection: A Tale of Two Diseases (pp 5–6). 2. S. Pullamsetti, R. Savai, W. Janssen, B. K. Dahal, W. Seeger, F. Grimminger, A. Ghofrani, N. Weissmann and R. Schermuly; Inflammation, Immunological Reaction and Role of Infection in Pulmonary Hypertension (pp 7–14). 3. E. Kolosionek, B. Graham, R. Tuder and G. Butrous; Pulmonary Vascular Disease Associated with Parasitic Infection—The Role of Schistosomiasis (pp 15–24). 4. S. Cicalini, S. Almodovar, E. Grilli and S. Flores; Pulmonary Hypertension and Human Immunodeficiency Virus Infection: Epidemiology, Pathogenesis, and Clinical Approach (pp 25–33). The full articles can be found at the URL: http://onlinelibrary. wiley.com/doi/10.1111/clm.2010.17.issue-1/issuetoc

SUPPLEMENT FOR THE CHINESE JOURNAL OF PRACTICAL MEDICINE The members of PVRI China Taskforce were invited to organize a specific supplement of PH for the Chinese Journal of Practical Medicine in Chinese. It was comprised of a series of editorials, mini-reviews and original articles, including a discussion of the diagnostic strategy of PH, an update on the management for idiopathic PAH, new perspectives on PH complicated by COPD, alternative treatments for CTEPH, and the clinical use of acute vasoreactivity for PH.

PUBLICATIONS FROM SCHISTOSOMIASIS PHT TASKFORCE 1. Graham BB, Mentink-Kane MM, El-Haddad, Li Zhang SH, Zaiman A, Redente EF, Riches DWH, Hassoun PM, Bandeira A, Champion HC, Butrous G, Wynn TA, Tuder RM; Schistosomiasis-Induced Experimental Pulmonary Hypertension: Role of Interleukin-13 Signaling, Am.J.Pathol 2010. 2. Crosby A, Jones FM, Southwood M, Stewart S, Schermuly R, Butrous G, Dunn DWE, and Morrell NW; Pulmonary Vascular Remodeling Correlates with Lung Eggs and Cytokines in Murine Schistosomiasis, Am J Resp. Crit Care Med. 181: 279-288. 3. Graham BB, Bandeira AP, Morrell NW, Butrous G, Tuder RM; Schistosomiasis-Associated Pulmonary Hypertension: Pulmonary Vascular Disease: The Global Perspective, Chest 2010;137 (6 suppl): 20s-29s.Kolosionek E, Graham B, Tuder R, Butrous G; Pulmonary Vascular Disease Associated with Parasitic Infection – the Role of Schistosomiasis, Clin Microbiol Infect. 2010:15-24.

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4. Kolosionek E, Crosby A, Harhay Mo, Morrell N, Butrous G; Pulmonary Vascular Disease Associated with Schistosomiasis, Expert Rev Anti Infect Ther. 2010;8(12):1467-73.

PVRI REVIEW Please see pp. 36-38 for details on PVRI Review publications

CONCLUSION The past year, 2010, has been a very active year for PVRI, as the list of achievements described in this report bear witness. We have enjoyed increased recognition for our work and goals - to further our understanding of pulmonary vascular disease in all its guises and share that knowledge with the broader community of scientists, physicians and patients. This has been achieved through an enthusiasm for collaborative working that typifies PVRI and has attracted the admiration

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and support of external opinion. The Executive Committee and Board of Directors would like to congratulate and thank all PVRI Fellows and members for the hours invested that led to the meetings hosted, the webinars and discussions held, the papers submitted, the new ideas generated and exchange of information and support that permit and enable research to take place where it would otherwise have struggled. We would also like to thank those organisations that have funded us - for your confidence in us and generosity, we are grateful. We now look forward to 2011 – first to our annual general meeting in Panama City, where we hope to see as many as can attend, but beyond that to the excitement and surprises that this unique community will surely provide.

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How to cite this article: PVRI Conferences and symposia in 2010. PVRI Review 2011;3:25-50. Source of Support: Nil, Conflict of Interest: None declared.

Jan - Jun 2011 • Volume 3 • Issue 1

OVERVIEW

The 5 th PVRI Annual General Meeting and 4 th Workshops and Debates, Panama City, 2-5 February 2011 Nikki Krol PVRI Administrator, Imperial College, London

AN OVERVIEW The 5th PVRI Annual General Meeting and 6th Scientific Workshops and Debates took place in Panama City on 2-5 February 2011. The AGM functions as an opportunity to update all Fellows on the activities and initiatives of the prior year and to set the course for the next term. Typically, Fellows are asked to vote and participate on issues regarding meeting location, taskforces, and positions within the PVRI. The Scientific Workshops and Debates focus on different approaches and activities within the field of pulmonary vascular disease research, and attract members from Pharma, Industry and PVRI alike. It is an excellent opportunity to share and trade ideas and presentations, and discussion and active debate blooms during these days. The Panama meeting was no exception, and in many ways surpassed the previous PVRI conferences. A day-by-day breakdown is provided in the report below.

Wednesday, 2nd February 2011

Day One of the 5th PVRI AGM began with a moment of silence for the late Peter Raymond, a highly respected founding member of the Board of Directors, who sadly passed away the week prior. PVRI President Martin Wilkins recounted Professor Raymond’s support, enthusiasm and many initiatives for the PVRI. The minute of silence ended with a round of applause in his memory. Later, Fellows focused on the PVRI achievements of the past year in order to determine the positives, learn from the negatives and stipulate the course for the coming year. The Annual Report,1 drafted and sent a week in advance of the AGM, holds an overview of all the PVRI meetings and accomplishments in 2010, ranging from taskforce

Board of Directors Chairman Stuart Rich asked all those present to invite two friends or colleagues to join the PVRI in order to grow the membership and strengthen the base of the organization. Managing Director Ghazwan Butrous proposed changes in the Constitution, to be put to a vote during the AGM. Absent Fellows were asked to vote online regarding the location of the 6th PVRI AGM meeting, and to record their opinions regarding the plans for the future course of the Institute. PVRI organizer Andrea Rich estimated that about 40 Fellows attended the first half of the 5th PVRI AGM. Many were deferred and had to send apologies due to the winter weather in parts of America, which shut down flights all over the country. For those unable to attend, PVRI provided a Twitter stream of live updates on the topics and happenings in Panama (www.twitter.com/pvri), images of the slides and attending Fellows at hashalbum.com/pvri and the Facebook page (http://on.fb.me/g8aLWh), as well as on the PVRI website (www.pvri.info/allblogs).

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DOI: 10.4103/0974-6013.85617

Address for correspondence: Nikki Krol Imperial College, London E-mail: nkrol@imperial.ac.uk

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achievements to publications, and educational activities and research to meetings and get-togethers. All these were recounted by PVRI President Martin Wilkins, who placed particular emphasis on the FDA/PVRI meeting, the PVRI Review translation and publication in several languages, and the strong focus on schistosomiasis. Thoughts were also given to the launch of the quarterly peer-reviewed journal Pulmonary Circulation in March 2011 and the ways by which to ensure there are enough material and articles to continue the journal full strength. In order to be eligible for PubMed, Pulmonary Circulation must regularly publish journals of a consistently high quality, which necessitates a steady influx of quality articles. Fellows were encouraged to submit their own work, focusing especially on original research, review articles and case studies. Dr. Harikrishnan S. provided an overview of PVRI Review, which was followed by a discussion regarding its future. One suggestion proposed the relegation of PVRI Review publication to twice a year, to produce issues spanning January-June and July-December. It was briefly suggested that since the journal is available online, there is no need for published copies. However, Managing Director Ghazwan Butrous countered that publication is a minor expense. In addition, the journal is representative of the works of PVRI and helps expand its audience and membership, and the suggestion was not pursued further.

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Krol: PVRI Panama Report

Thursday, 3rd February 2011

Day Two of the 5th PVRI AGM began early in the Panama Room of the hotel. The previous day, attendees nearly filled the room, so extra seating was arranged to accommodate all newly arrived Fellows. As a result, nearly 60 Fellows were present for the second half of the AGM. The discussion addressed the management of the taskforces and relocated roles where necessary. Fellows proposed interesting ideas regarding the PVRI website, which was under scrutiny for future improvement. One such suggestion, by Professor John Newman, will see the creation of “Interest Groups” to allow Fellows to converge and discuss topics close to their interest, so natural collaborations and initiatives can form. Managing Director Ghazwan Butrous also unveiled plans regarding a “PVRI e-learning website”, which will serve as an online course for medical students interested in pulmonary vascular diseases. For this and other initiatives, Professor Butrous requested more

active involvement of key Fellows. In time, roles will be created for the managerial staff to head specific projects and bring fresh ideas and perspectives to the organization. After coffee, Professor Butrous presented the renewed organogram, which showed the proposed changes as discussed the previous day. All Fellows were asked to vote, and in addition to the present Fellows, 25 absentee votes were recorded via the internet poll. The following decisions were the result: • Ghazwan Butrous will serve as the Managing Director for the next 4 years; • establishment of managerial staff to assist the Managing Director and the functioning Vice Presidents for Research, Education and Alliances; • establishment of a PVRI Business Unit for Clinical and Therapeutic Excellence; and • location of AGM 2012: Cape Town. All proposed measures were voted through unanimously or with a clear majority. The PVRI saw a superb turnout at the 4th Annual Workshops and Debates which began in the afternoon with presentations by professors David Systrom, Aaron Waxman, Roger Johns, and Micheala Aldred, chaired by Ken Weir. This was followed by a presentation by Dr. Stuart Rich on the FDA/PVRI meeting in March 2010. All the above sparked interest and lively debate, and the Hot Topics session went slightly over time despite the freezing air-conditioning.

Figure 1: AGM meeting

The number of attendees continued to grow throughout the day as more Fellows and delegates found their way to the hotel, with new arrivals still pouring in during the cocktail hour in the evening.

Figure 2: Scenes from the scientific meeting

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Although many were delayed or forced to cancel due to the weather, organizer Andrea Rich considered this the largest turnout to the PVRI AGM and Workshops and Debates to date. About 90 people were present at the Workshops and Debates on the 3rd of February, a phenomenal number that continued to grow in the next days and was heightened by the enthusiasm and participation of absentee Fellows, who connected via social media.

Friday, 4th February 2011

The morning of the 4th of February, Dr. Ardeschir Ghofrani began the debates with a presentation on “The pharmacological response: The clinical response to a treatment is the best way to dissect PAH Category 1 patients into subtypes and the only

practical strategy to sub-phenotype the disease”. It set the stage for a day of interesting debate, discussion and examination of the existing procedures and proposed alternatives. Many topics, as treated by professors Nicholas Morrell and Ralph Schermuly in Session 3, and Kurt Stenmark, Serge Adnot, Norbert Weissmann and Ralph Schermuly again in Session 4, engaged and inspired the audience and colleagues to questions and serious debate. Professor Hassoun invited Professor Adnot to tell the meeting why he had been wasting his time with serotonin receptors. Professor Adnot obliged with good humor and presented “Abnormalities in serotonin transport have not enlightened discussions on the pathology and management of PAH”. After lunch, the meeting continued as Professor Evangelos Michelakis started the “Dragon’s Den” themed session. Topics included IL-13, Iron, Mitochondrial targets: PDK, PPAR gamma

Figure 3: Scene from the scientific poster discussion

Figure 4: A recording of the Scientific Workshops and Debates is now available online via a link at pvri.info/reflection-panama-scientific-meeting

Figure 5: Pediatric taskforce-discussing proposed classification

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Figure 6: Scenes from the final day including presentations by D. Jenkins, E. Mayer, M. Madani, and D. Gopolan on the operability of CTEPH

research consisted of translating the handwritten original text from Arabic to English, no small task as these texts did not offer images, paragraphs or even punctuation. All in all, the timeline of pulmonary circulation from Galen to Vesalius, through the ages, all the way to PVRI, was well-received. A section of the quarterly peer-reviewed Pulmonary Circulation will be dedicated to similar histories, combining the science and history of medicine in the scientific journal.

Figure 7: Prof. S. Rich’s presentation is available online via a link at pvri.info/ reflection-panama-scientific-meeting

agonists and Key features of an ideal PAH drug and were very well handled by assorted speakers. After a short coffee break, Dr. Andy Grieve sparked debate with his interactive session on alternative clinical trial design and the challenging of dosage protocols. After allowing some time for discussion, Professor Martin Wilkins declared the day’s meeting a success and invited all present to attend the Gala Dinner. The PVRI Gala Dinner took place in the beautifully decorated Barcelona room of the Riu Panama Plaza hotel. A light predinner speech was organized by Professor Ghazwan Butrous, who took meticulous care in preparing an overview of “The Story of Pulmonary Circulation: A 2500 year History”. From the Greeks to the Egyptians, Romans and Arabians, Professor Butrous took those present on a journey through cultures and protocols, and regaled on practises and beliefs that thought the left ventricle “full of air” to leave room for the soul, and told of doctors burned as heretics for proving otherwise. His PVRI REVIEW

During the Gala Dinner, Board of Directors Chairman Stuart Rich, PVRI President Martin Wilkins and Managing Director Ghazwan Butrous took to the stage. Professor Butrous then invited Professor Antonio Augusto Lopes to join them and revealed that he had been chosen to receive the first PVRI Achievement Award. In recognition of his efforts and achievements in education for PVRI, Professor Rich, in name of the Board, presented Professor Lopes with the trophy. Professor Lopes held a brief acceptance speech acknowledging the help and work of those involved with PVRI, and claimed his achievements would not have been possible with said support. He was met with loud applause. Professors Martin Wilkins, Ghazwan Butrous and Miss Nikki Krol were also commended for their work for PVRI, whilst Mrs Andrea Rich received a round of applause for her organizational skills and eye for detail which helped the 5th PVRI AGM and 4th Workshops and Debates see great success.

Saturday, 5th February 2011

The final day began early with an 8 a.m. presentation by Dr. Ian Adatia on the Classification of Pediatric Pulmonary Hypertensive Disease. Dr. Adatia’s talk included previous discussion of the Pediatric Taskforce as held in a parallel meeting on Wednesday, and was met with praise and several questions. Professor Sheila Glennis Haworth subsequently took the stage to expand on

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Figure 8: Scenes from the PVRI Embera Jungle tour

Figure 10: The view from the Panama Canal Visitor Centre Figure 9: PVRI members and Fellows explore Old City

pediatric functional classification. Questions were answered by Dr. Alexandra Heath and assorted members of the Pediatric Taskforce before Professor Brian Graham concluded the first part of the meeting with a presentation on the differences in the pathology of PAH and chronic thromboembolic pulmonary hypertension. Professor Reda Girgis brought up the rear with CTEPH case studies. Each subject provoked significant discussion despite the meeting being in its fourth day. During the mid-morning break, Dr. Deepa Gopolan arrived after having been delayed due to weather-related flight rerouting and promptly presented the next workshop on CTEPH. All week, the audience had been provided with small booklets and posters which detailed symptoms and cardiograms of eight different cases, and were asked to diagnose the patient based on the information provided. Drs Deepa Gopolan, Ardeschir Ghofrani and Ioana Preston went through the booklet on a case by case Jan - Jun 2011 • Volume 3 • Issue 1

Figure 11: Folkloric dancing at one of Old City’s Tinajas restaurants

basis, asking the audience for their initial thoughts and revealing the accurate diagnosis afterward. This method created a very interactive workshop between all those present. The stage was then given to surgeons, David Jenkins, Michael Madani and Eckhard Mayer, whilst Professor Ghazwan Butrous moderated what he predicted would be “much fighting”. Indeed, the session ran overtime as the three engaged the audience in a debate on the “operability of CTEPH patients”.

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As President Martin Wilkins was called away early due to the tempestuous flight weather, Managing Director Ghazwan Butrous closed the meeting with a sincere thank you to all those present who had helped make the meeting a success and a great learning experience. It was agreed that the conference had been a great success and had indeed surpassed the expectations. With that, the 5th PVRI Annual General Meeting and 4th Workshops and Debates came to an end in Panama City.

the PVRI could not have met with this kind of success. Their contributions have not gone unnoticed. In that spirit, the Institute will continue to thrive and grow in the goal to create awareness and education on pulmonary disease in all its guises. This 5th PVRI AGM and 4th Workshops and Debates in Panama City has been another strong step toward these goals, and we look forward to continuing apace in the years to come.

With this article, PVRI would like to express sincere gratitude and pleasure for all those who came together and worked to make this Panama meeting the success it has been. Without their dedication, passion and hard work, the meeting and even

How to cite this article: Krol N. The 5 th PVRI Annual General Meeting and 4 th Workshops and Debates, Panama City, 2-5 February 2011. PVRI Review 2011;3:51-6. Source of Support: Nil, Conflict of Interest: None declared.

Announcement

iPhone App A free application to browse and search the journal’s content is now available for iPhone/iPad. The application provides “Table of Contents” of the latest issues, which are stored on the device for future offline browsing. Internet connection is required to access the back issues and search facility. The application is Compatible with iPhone, iPod touch, and iPad and Requires iOS 3.1 or later. The application can be downloaded from http://itunes.apple.com/us/app/medknow-journals/ id458064375?ls=1&mt=8. For suggestions and comments do write back to us. PVRI REVIEW

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MEETING REPORT

The 4th Annual Joint Pulmonary Hypertension Conference - Dubai Majdy Idrees, Ghazwan Butrous1 Riyadh Military Hospital, Kingdom of Saudi Arabia, 1Cardiopulmonary Sciences, University of Kent, CT2 8HJ, UK

REPORT The 4th annual Joint Pulmonary Hypertension conference in Dubai, held on April 19-22, 2011, was the continuation of a line of annual meetings organized by the Saudi Association of Pulmonary Hypertension (SAPH) and the Eastern Mediterranean Taskforce of the PVRI. The first meeting was held in 2008 in Dubai, followed in 2009 by a meeting in Casablanca, Morocco. In 2010, SAPH hosted the meeting in Shram el Sheik, Egypt, whilst this fourth meeting was planned to take place in Beirut. However, due to the current political instability in the area, the organizer was forced to change the location to the more stable Dubai. This was a positive move as most interested parties were able to attend the meeting as planned. These annual conferences have proved a very successful venture as the topics as well as the attendees have increased each year. At this 4th meeting, over 140 attendees from various parts of the Middle East were in attendance. Similarly, an increase in the level of discussion and general awareness has become noticeable, both of which are strong indicators that the joint SAPH and EMR taskforce goal of enhanced awareness of pulmonary hypertension is being met. For further reflection on this topic, please see Managing Director, Ghazwan Butrous’ blog at http://pvri.info/blogs/butrousg The 4th annual Joint Pulmonary Hypertension conference started with a keynote talk by Professor Ghazwan Butrous on the role of Islamic scientists and physicians in the development of pulmonary hypertension, a topic which is addressed further in the Pulmonary Vascular Medicine History Initiative section of the first issue of the PVRI journal Pulmonary Circulation. The discussion was very lively with 60 people present for the meeting and a similar atmosphere continued during cocktails and dinner. Access this article online Quick Response Code:

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The following morning, the meeting began with a warm welcome from the chair people of the session, Dr. Mohamed Al Hajjaj and Dr. Mirza Al Sayegh from UAE. The word was given to Dr. Majdy Idrees, head of SAPH and organizer and chairman of this meeting. Dr. Idrees initiated this series of meetings and has been very active both within SAPH, and as vice-president of the East Mediterranean region of the PVRI, a role he shares with Dr. Paul Hassoun. Dr. Idrees started the discussion by reminding the attendees of the SAPH mission, which states that “we committed ourselves to be the pilot group to take the lead in the management of pulmonary hypertension in the region, and to serve our patients by providing optimal medical service, support and care”. He reiterated that SAPH is a national not-for-profit organization, and is currently supported by the Saudi Thoracic Society. SAPH’s main goal is to address issues related to the training and education of health care professionals in the area of pulmonary vascular diseases. SAPH is a partner of the PVRI and has in the past worked with the PVRI to enhance its collaboration with other international regional associations, and will continue to do so. In the last 5 years, SAPH has experienced fantastic growth, going from 6 to 74 members including pulmonologists, cardiologists, intensivists, pediatricians and rheumatologists. Dr. Idrees presented the main achievements of SAPH as a summary of three major topics: Firstly, it began and continued the tradition of the Annual Meeting. Secondly, SAPH published the Saudi guidelines for pulmonary hypertension, and thirdly, it achieved increased awareness in the Kingdom of Saudi Arabia through a series of initiatives. Similarly, Dr. Idrees summarized the initial findings from the pulmonary hypertension SAPH registry. Many centers have contributed to this registry and the number of patients is growing. Dr. Idrees presented a small group of patients’ representatives from the Riyadh area, whose analysis was available at the time of presentation. Within this data, two main issues were highlighted: How the diagnosis was performed and when the patient was presented to the specialist centers. Unfortunately, the data were found to represent a trend of an 18 month-or more-delay before diagnosis. Obviously, this is not at all optimal and is in need of evaluation. This is a very important finding that can hopefully help guide the policy for increasing awareness for early diagnosis and treatment.

10.4103/0974-6013.85618

Professor Gerald Simmonneau from France followed this enlightening presentation with his own on the clinical classification of pulmonary hypertension and the recent revision of Dana Point. Dr. Simmonneau stressed the importance of including recent clinical findings and

Address for correspondence: Ghazwan Butrous Cardiopulmonary Sciences, University of Kent, CT2 8HJ, UK E-mail: majidrees@gmail.com

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Idrees and Butrous: PVRI/SAPH Conference 2011

Figure 1: Scenes from the SAPH/PVRI Conference

Figure 2: Dr. Irene Lang

Figure 3: Dr. Saleh al Dammas

advances in clinical classifications and the need to clarify areas of ambiguity. The worldwide community of pulmonary hypertension hopes that this classification will be more comprehensive and more useful to clinicians in the future.

evidence-based treatments of pulmonary hypertension, based on the current guidelines and the findings of clinical observations and discussions from physicians. Dr. Hoeper discussed the importance of supportive therapies like diuretics, oxygen therapies and anticoagulants, and debated the issues of vasoreactivity in pulmonary arterial hypertension and the criteria for respondents and non-respondents. He also stressed the

For the final presentation of the Plenary Session, Professor Marius Hoeper from Germany took the stand. He focused on the PVRI REVIEW

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Idrees and Butrous: PVRI/SAPH Conference 2011

importance of early diagnosis and its impact in the management of pulmonary hypertension. In addition, Dr. Hoeper addressed the combination therapies. He presented some German data which showed that nearly 21% of the patients who have combination therapy are effectively on endothelin receptor and PDE5 inhibitors, whilst only 3% are on a combination of oral therapies including ERA or PDE5i and prostacyclin. The following session focused on updated issues in PH management and was chaired by Dr. Yaseem Samman (KSA) and Dr. Bassam Mahboub (UAE). The first talk was presented by Dr. Qadar Pasha from the Institute of Genomics and Integrative Biology in Delhi, India. He summarized in a very eloquent and clear manner the molecular aspects of pulmonary hypertension, specifically regarding the role of particular genomics in vascular functions and dysfunctions. He presented the recent gene findings and different aspects of recent chromosome genes and their chromosomal localization, and the reflection of function. This was followed by a presentation from Dr. Ghazwan Butrous from the University of Kent on whether post-capillary pulmonary hypertension should be treated with the available vasodilators. Dr. Butrous defined both post-capillary pulmonary hypertension and the available so-called vasodilator treatment for pulmonary hypertension, and discussed its function in the treatment of postcapillary PH. He showed that early studies with prostacyclin and ERA were not encouraging due to various reasons. However, the experimental findings with PDE5i were more encouraging, but there is no current evidence-based medicine, and the recent trial, which was mainly supported by the NIH, has not yet been reported. Therefore, the conclusion so far reads that an early experiment with small trials on pulmonary hypertension vasodilator therapy is encouraging, but the evidence-based medicine larger clinical trials did not show any benefit of prostacyclin and ERA. We are still awaiting the results of PDE5i inhibitors. Based on this, Dr. Butrous argued that in our current knowledge, vasodilators are not considered a standard therapy for post-capillary pulmonary hypertension. Dr. Irene Lang [Figure 2] from Austria followed this presentation by a talk on her experiences in her centre at the AKJ Vienna Hospital regarding the subcutaneous treprostinil. She discussed the value of using this method, as well as its difficulties and practical applications, and the importance of having a proper team that can help with the management of this form of modalities in the treatment of pulmonary hypertension patients. Attendees agreed that Dr. Lang’s presentation was a very enlightening experience with real-life examples, providing a lot of practical implications as well as demonstrating the importance of new developments in the technology of delivering drugs. After a short lunch break, a new session focused on right ventricular pathophysiology secondary to pulmonary hypertension chaired by Dr. Javid Khan and Manal Al Hazmi. The first presenter was Dr. Paul Hassoun from John Hopkins Medical Centre. Dr. Hassoun discussed the right ventricular response to pulmonary vascular load and he compared this to pulmonary hypertension syndrome: The IPAH versus scleroderma associated with pulmonary hypertension of the right ventricle, and described the hemodynamic serum markers and the cardiac factors that may impact on survival. He concluded that scleroderma related to Jan - Jun 2011 • Volume 3 • Issue 1

pulmonary hypertension carries a grave prognosis, and several hemodynamic predictors survivors have been identified from their research group, and accordingly, dysfunction is a prominent factor in the prognosis of this condition. The possible mechanisms for this cardiac involvement could be not only the hemodynamic but also neuro-hormonal myocardial dysfunction, which includes fibrosis inflammation and perfusion defect. For the time being, no medical treatment has been established. This was followed by Dr. Abdulmajeed AlOtay from Saudi Arabia, who discussed the importance of using the new technology of the cardiac MRI in the assessment of right ventricular function and PA reactions in pulmonary hypertension. An interesting presentation, Dr. AlOtay discussed, with a lot of convincing evidence, the importance of the use of the MRI in the diagnosis of pulmonary hypertension and management of patients with pulmonary hypertension. The session on the right ventricle in PH was closed by Dr. Marius Hoeper, who discussed the therapeutic intervention in right heart failure. In this presentation, Dr. Hoeper discussed the importance of accurately identifying the role of the clinical condition of the right heart ventricle when managing a patient with pulmonary hypertension. In his conclusion, he showed that patients who have been treated aggressively with cardiac pumps also might benefit from a transplant which can have vital and successful results. Dr. Hoeper showed encouraging examples of the use of venoarterial ECMO in these patients, via the positive response to the treatment. The attendees agreed that this clinical presentation in the management of severe right ventricle failure in patients with pulmonary hypertension was very illuminating. During the last session, Dr. Saleh al Dammas [Figure 3] presented a well-balanced treatment of the COPD bronchodilators. Dr. al Dammas stated that COPD is the fourth leading cause of death and indicated that the majority of these deaths happen in heavily polluted areas; for example, 50% of these deaths were in China. Dr. al Dammas noted that COPD in the Kingdom of Saudi Arabia is still understudied. This is worrying, as there are many risk factors prevalent in Saudi Arabia. Dr. al Dammas and his group recently published small studies which found that 501 out of 1380 smokers were eligible for some form of analysis. Additionally, they found that 14% had FEV1 of less than 0.7. Almost 44% of these were on stage III COPD. This shows that trials with current PH specific agents like bosentan, sildenafil, iloprost and parentertal prostanoids and even volume reduction surgery were being used. His conclusion was that pulmonary hypertension is common in COPD patients, and a small percentage of COPD patients have severe pulmonary hypertension that behaves like idiopathic pulmonary arterial hypertension. This should be suspected when there is unexplained functional decline, and thus right heart ventricle is a procedure of choice in the diagnosis of PH in patients with COPD. He stressed the importance of more research to evaluate the presence of pulmonary hypertension in groups of patients. Dr. Khalid Al Najashi followed with a presentation on the management of pregnant patients with pulmonary hypertension. He presented three cases on these issues and highlighted the importance of careful clinical management. He concluded that pulmonary hypertension, irrespective of the cause, is an absolute contraindication of pregnancy, and once female pulmonary

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hypertension patients attain childbearing age, they should be counseled in a tertiary center. If a woman with pulmonary hypertension becomes pregnant, this conceives a high alert emergency state whereby a multidisciplinary approach is needed which focuses on aggressive fluid management post-partum and initiation of vasodilators.

The meeting was closed and followed by a very pleasant gala dinner in one of the beach hotels in Dubai. The dinner was kicked off with a welcome speech from Dr. Majdy Idrees who presented a token of appreciation to the guest speakers [Figure 4], the active members of the SAPH and the doctors who participated in enhancing the understanding of PH in the region.

The last presentation of the day was from Dr. Gerald Simmoneau who talked about PH registries: opportunities and difficulties, and focused on the information that may be derived from registries in pulmonary hypertension. He also related the experience of the French PAH registry, which is one of the biggest registries in the world involving 674 patients in 17 medical centers in France. The PAH registry published that idiopathic pulmonary hypertension is the predominant cause of pulmonary arterial hypertension with 39%, followed by connective tissue diseases (15%), congenital heart diseases (11%) and portal hypertension (10%). The majority of the patients (63%) were identified as Class III. In his presentation and the assessment of survival of PAH in the modern era, it became clear that despite our advances in treatment, we still have not achieved our goal, as the majority of the mortality rates is associated with functional flaws. This indicates the importance of early diagnosis in this group of patients. Dr. Simonneau’s summary reiterated that a pulmonary hypertension registry can provide important information in addition to RCTs. However, the methodology for these registries should be particularly rigorous as its subsequent data can generate new hypotheses that form the basis for prospective studies. The design is to be adapted to the questions one wants to answer.

The following day, the final set of meetings began with a presentation of Dr. Ghazwan Butrous on pulmonary hypertension in Clinical Year in Review. Dr. Butrous presented highlights from the important papers and the lessons we have learned. The presentation is available on the PVRI website for download. Next, Dr. M Omar Galal held a very interesting talk on the issues of writing a manuscript and the ethics regarding its proper execution. This was considered a very useful lesson, especially for the younger attendees. Dr. Enas Batubara presented her paper titled “a novel approach to the management of sub-massive pulmonary embolism”, which focused on the targeting of the right ventricle in massive pulmonary hypertension. Dr. Batubara’s paper included a study which was conducted at the Division of Pulmonary Medicine in Riyadh Military Hospital, under the supervision of Dr. Majdy Idrees. The objective of the study was to direct their target of pulmonary vascular resistance rather than eliminate the obstruction, to improve cardiac output, and also to decrease the risk of bleeding. Their conclusion is that in submassive pulmonary embolism, thromboembolic therapy toward decreasing PVRI is effective in improving the hemodynamic management associated with this condition. This strategy might turn out to be the most effective approach for treating this condition and might erase the need for thromboembolic

Figure 4: Dr. Majdy Idrees presented gifts to of appreciations to active participants and organizing committee

Figure 5: Dr. Majdy Idrees

Figure 6: Panoramic view of some of the participants

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Idrees and Butrous: PVRI/SAPH Conference 2011

therapy. This is only the outcome of a small study and needs to be confirmed in a larger randomized placebo-controlled study. This was followed by a presentation of Dr. AlaEldin Ahmed who spoke about pulmonary hypertension patients treated with pulmonary tuberculosis. He presented a series of patients from studies done in Khartoum, whereby pulmonary hypertension was diagnosed by the rigorous criteria of Doppler-echo cardiography which showed that 14 patients were suffering from pulmonary tuberculosis and pulmonary hypertension. He concluded that pulmonary hypertension of different grades occurred even in cured pulmonary TB, but all patients had an abnormal chest radiograph. They were all of a relatively young age, with a mean age of 43 years. This is a small study which obviously needs further evaluation and more work in this area. Dr. Hanaa Banjar presented cases on pediatric pulmonary hypertension and discussed different etiologies. In particular, she is trying to implement the lessons and instruction she learned from the Panama PVRI meeting in February 2011 on the classification of pediatric pulmonary hypertension, and stressed the importance of learning from these cases for the practical aspects of the suggested aspects of the classification. After the coffee break, the focus was on “Pharma-economic and End of Life Issues”, which saw presentations by three participants: Dr. Meshal Al Mutairi, Dr. Maha al Dabbagh (KSA) and Dr. Jameel Al Ata (KSA). Dr. Al Mutairi from Saudi Arabia discussed the pharma-economic models of pulmonary hypertension, in particular, those implemented in Saudi Arabia. There are a lot of good lessons to be learned, particularly in countries that want to establish their pulmonary hypertension service. This was followed by Dr. Maha al Dabbagh with a very exciting talk about the importance of the ethical manner in which to approach patients newly diagnosed with pulmonary hypertension. She spoke of the importance of counseling and her own experience with patients, especially those of the younger generation, and a way to communicate with patients as well as parents and

guardians. This was a very illuminating talk that Dr. al Dabbagh promised to write down for the PVRI Review. The last talk was by Dr. Jameel al Ata who also discussed the ethical issues around the treatment of pulmonary hypertension. He discussed his own experiences with patients in the Kingdom of Saudi Arabia. He also spoke of the implications regarding failure to comply with the guideline, or unnecessarily overusing a drug, and other such issues. In a way, this represents the great awareness and subsequent critical analysis and awareness amongst physicians regarding the way other physicians treat patients with pulmonary hypertension, especially in specialist centers. The session closed with two workshops: one focused on the hemodynamics in pulmonary hypertension, moderated by Paul Hassoun and Majdy Idrees, and a second group saw presentations by Ahmed Ibrahim and Omar Tamimi discussing the echocardiography in the management of PH. Overall, the meeting was very successful, and showed real advances over its previous incarnations. The attendees in particular were very engaged with the discussion and debate, and this was noticeable even during the coffee breaks and lunch periods. In general, this was considered a very successful meeting which has shown that the mission of the SAPH and PVRI is being achieved, both by the increased awareness of pulmonary hypertension worldwide and by the enhancement of the understanding of illness, and its treatment, at even the local level. The 5th SAPH meeting is set for April 2012 and hopes to attract more PVRI members and Fellows; so, the participation and debate between both organizations may continue to grow. How to cite this article: Idrees M, Butrous G. The 4 th Annual Joint Pulmonary Hypertension Conference - Dubai. PVRI Review 2011;3:57-61. Source of Support: Nil, Conflict of Interest: None declared.

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Android App A free application to browse and search the journal’s content is now available for Android based mobiles and devices.. The application provides “Table of Contents” of the latest issues, which are stored on the device for future offline browsing. Internet connection is required to access the back issues and search facility. The application is compatible with all the versions of Android. The application can be downloaded from https://market.android.com/details?id=comm.app.medknow. For suggestions and comments do write back to us. Jan - Jun 2011 • Volume 3 • Issue 1

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AUTHORS FOR

INSTRUCTIONS

Manuscripts must be prepared in accordance with "Uniform requirements for Manuscripts submitted to Biomedical Journals" developed by the International Committee of Medical Journal Editors (Updated October 2007). (http:// www.icmje.org). The uniform requirements and specific requirement of PVRI Review are summarized below. Before sending a manuscript, contributors are requested to check for the latest instructions available. Instructions are also available from the website of the journal (http://www. pvrireview.org) and from the manuscript submission site (http://www.journalonweb.com/PVRI).

The Editorial Process

The manuscripts will be reviewed for possible publication with the understanding that they are being submitted to PVRI Review only and have not been published, simultaneously submitted or already accepted for publication elsewhere. All manuscripts received will be duly acknowledged. The editors will review all the submitted manuscripts initially. Manuscripts, if needs a review, will be sent to two or more expert reviewers without revealing the identity of the contributors. Each manuscript will also be assigned to a member of the editorial team, who based on the comments from the reviewers will take a final decision on the manuscript. The contributors will be informed about the reviewers' comments and acceptance/rejection of manuscript. Articles accepted would be copy-edited for grammar, punctuation, print style, and format. Page proofs will be sent to the corresponding author, which has to be returned within three days.

Conflicts of Interest

All authors who are submitting articles to the journal, must disclose any conflict of interest they may have with an institution or product that is mentioned in the manuscript. Authors should also disclose conflict of interest with products that compete with those mentioned in their manuscript. The Editor will discuss with the authors on an individual basis the method by which any conflicts of interest will be communicated to the readers.

Manuscript Preparation

1. Manuscript should be typed double-spaced. With the following sections in the order. • Title Page • Authors with full affiliation (PVRI fellowship is considered as an affiliation) • Abstract • Main body - text • Acknowledgments. • Funding Sources. • Conflict of interests and full disclosures, • References. • Figure legends and Tables. 2.

Acceptable formats are Word or WordPerfect (but not PDF) 3. All papers has to be submitted electronically to www. pvrireview.org 4. Colour figures,charts and tables are welcome. 5. Article length (1000-5000 words) 6. Extensive referencing is encouraged, but has to be cited in the text 7. Please use the SI units of measure 8. Abbreviations and acronyms are acceptable if quoted more than 3 times in the text 9. Please conform to the "Uniform Requirements for Manuscripts Submitted to Biomedical Journals" http:// www.icmje.org/. 10. Assemble the manuscript in this order: Title Page, Abstract, Text, Acknowledgments, Funding Sources, Disclosures, References, Figure Legends, Tables, and Figures.

References 1. 2.

Copies of Any Permission(s)

To reproduce published material, and to use illustrations or report information about identifiable people a copy of the permission obtained must accompany the manuscript and the source is clearly stated "with permission"

Online Submission of Manuscripts

All manuscripts must be submitted on-line through the website www.journalonweb.com/PVRI . First time users will have to register at this site. Registered authors can keep track of their articles after logging into the site using their user name and password. Authors do not have to pay for submission, processing or publication of articles. The contributor may provide names of two or three qualified reviewers who have had experience in the subject of the submitted manuscript, but who are not affiliated with the same institutes as the contributor/s. However, the selection of these reviewers is at the sole discretion of the editor.

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Cite references in numeric order according to first mention in the text. Use the following format • List all authors (example, Smith J; Li ER, Al-Basi KJ, Jones, JK…etc) • Full title of the articles • Journal (or standard abbreviation) Year, Volume (issue): First page-Last page Eg. Circulation. 2008;118:15981601 Abstracts may be cited only if they are the sole source and must be identified in the reference as "Abstract." Please include the name of the journal,volume, year of publication and if relevant the full URL References must be from a full length publication in a peer reviewed journal. To cite websites/URL or webcasts use full URL and the one used by Google Scholar is preferable; please use the following format • List all authors ( if no authors - use anonymous ) • Full title of the article. • The main source ( example - New York Times - date) • Full URL

Download a PowerPoint presentation on common reference styles and using the reference checking facility on the manuscript submission site.

Jan - Jun 2011 • Volume 3 • Issue 1

Instructions for Authors

Table -2 etc) 3. Abbreviations and symbols used in the table must be defined in a footnote to the table.

Figures

1. Colour figures (GIF, TIFF, EPS or JPEG format only ) and tables are welcomed 2. Full comprehensive legend to each figure is essential 3. Figures should be clearly labelled (As Fig -1, Fig -2 etc). 4. Abbreviations and symbols must be defined in the legend. 5. Limit white space between the panel and panel label

Special notes

1. Clinical Trial Registration Information: Please include the URL and unique identifier. Please conform to the ICMJE policy http://www.icmje.org 2. Authors should obtain written permission from all individuals who are listed in the "Acknowledgments" section or Personal communication

Tables

1. Each table should be submitted on a separate page, 2. The table number should be Arabic (example Table -1

FORM IV Statement about ownership and other particulars about newspaper (PVRI Review) to be published in the first issue every year after the last day of February 1.

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Mumbai

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Semiannually (June and December)

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Address

B5-12, Kanara Business Center, Off Link Rd, Ghatkopar (E), Mumbai - 400075, India. Phone: 91-22-6649 1818

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B5-12, Kanara Business Center, Off Link Rd, Ghatkopar (E), Mumbai - 400075, India. Phone: 91-22-6649 1818

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Address

PVRI Review, Associate Professor in Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum - 695011, India.

Names and addresses of individuals who own the newspaper and partners or shareholders holding More than one per cent of the total capital.

Pulmonary Vascular Research Institute

I, Dr. S. Harikrishnan hereby declare that the particulars given above are true to the best of my knowledge and belief. Date:

Jan - Jun 2011 • Volume 3 • Issue 1

Mr. Hemant R. Manjrekar

 63 

Dr. S. Harikrishnan

PVRI REVIEW

Funded Position Available Clinical Research Fellow What we do:

What: Dedicated Clinical Research Fellow

Our current research interests include non-invasive measurement of pulmonary artery pressure, right ventricular function and pulmonary blood flow, measurement of oxygen consumption in small children and drug therapy and testing in children with pulmonary hypertension.

When: The position would start in July 2012 Where: Pediatric Pulmonary Hypertension and/or Pediatric Cardiac ICU at Stollery Children’s Hospital/University of Alberta in Edmonton, Canada Who:

We will be happy to consider and enable the candidate’s own research proposal. The position will depend on the approval of the candidate by the fellowship training committee.

PVRI REVIEW

 64 

Please contact Professor Ian Adatia at iadatia@ualberta.ca for details on how to apply

Jan - Jun 2011 • Volume 3 • Issue 1

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The Pulmonary Vascular Research Institute is proud to present

The 6th Annual General Meeting & 5th Scientific Workshops & Debates 2012, at the Protea President Hotel in Cape Town, South Africa

The 2012 PVRI Conference program includes the following themes: 3XOPRQDU\ 9DVFXODU 'LVHDVH LQ $IULFD &OLQLFDO 7ULDOV LQ 39' (WKLFDO DQG 0RUDO ,VVXHV 7UDQVODWLRQDO 0HGLFLQH &KDOOHQJHV LQ WKH 'HYHORSPHQW RI 1HZ 'UXJV IRU 3XOPRQDU\ 9DVFXODU 'LVHDVH

TUESDAY, 7 FEBRUARY – FRIDAY, 10 FEBRUARY 2012 FOR THE FULL PROGRAM & MEETING REGISTRATON, PLEASE SEE WWW.PVRI.INFO Edited by Dr. S. Harikrishnan. Printed and published by Medknow Publications and Media Pvt. Ltd., on behalf of Pulmonary Vascular Research Institute, Trivandrum and Printed at Anitha Art Printers, 29/30, 'OASIS', Opp. Vakola Masjid, Santacruz (E), Mumbai 400 055, India. and published at Medknow Publications & Media Pvt. Ltd. from B5-12, Kanara Business Centre, Ghatkopar, Mumbai, India.