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Editorial Board...... CHIEF EDITOR Harikrishnan S. Additional Professor in Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India - 695011
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EDITORIAL BOARD/ REVIEWERS PVRI Faculty
PVRI Review
January - March 2010 | Volume 2 | Issue 1
Contents..... From the Editor’s Desk
S. Harikrishnan......................................................................................................................................................................................1
Review Articles Role of Inflammation in Pulmonary Arterial Hypertension Paul M. Hassoun..................................................................................................................................................................................2
The Diseased Endothelium: Would It Explain It All? Rubin M. Tuder, Brian B. Graham.......................................................................................................................................................5
Biomarkers in Pulmonary Hypertension Gustavo A. Heresi, Raed A. Dweik....................................................................................................................................................12
Utility of Tricuspid Annular Plane Systolic Excursion in the Assessment of Right Ventricular Function Nabil S. Zeineh, Hunter C. Champion...............................................................................................................................................17
Journal Scan Commentary- Wnt Signaling Regulates Smooth Muscle Precursor Development in the Mouse Lung via A Tenascin C/PDGFR Pathway Swapna Menon...................................................................................................................................................................................22
PVRI 2009 Annual Reports Images from the 3rd PVRI Annual General Meeting in Mexico City, 25-28 January 2009.....................................24
Regional Reports 2009 Annual Report of the PVRI Eastern Mediterranean Region Majdy Idrees........................................................................................................................................................................................25
PVRI Sub-Saharan Africa Region Taskforce Ana Olga H. Mocumbi, Karen Sliwa-Hahnle.....................................................................................................................................29
PVRI Western Pacific Region (China Center) Chen Wang, Martin Wilkins................................................................................................................................................................30
Annual Report of PVRI South East Asia R. Krishna Kumar, Sheila G. Haworth...............................................................................................................................................32
Diseases Taskforces Taskforce: Pulmonary Hypertension Associated with High Altitude and Hypoxia - Annual Report 2009 Qadar Pasha, Max Gassmann...........................................................................................................................................................36
Pulmonary Hypertension Associated with HIV‑Taskforce Nicola Petrosillo, Sonia C. Flores, Sharilyn Almodovar, Norbert Voelkel.........................................................................................42
PVD in Schistosomiasis Task Force Ghazwan Butrous, Nicholas Morrell...................................................................................................................................................44
Contents..... Pulmonary Hypertension Associated with Congenital Heart Disease Task Force Antonio A. Lopes, Marlene Rabinovitch.............................................................................................................................................47
Educational and Functional Taskforces Progress Report on the Textbook of Pulmonary Vascular Disease Jason XJ Yuan, Stephen L. Archer....................................................................................................................................................50
The Story of the Journal of PVRI Review S. Harikrishnan....................................................................................................................................................................................51
PVRI Open Webcasts (PVRI Webinars) http://www.pahforum.com (2008-2009) Antonio Augusto Lopes.......................................................................................................................................................................53
Pvri Activities 2009 - In Pictures................................................................................................................4,21,23,35 Instructions
for
Authors.................................................................................................................................................59
PVRI Review
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From the Editor’s Desk Dear fellows, PVRI Review is into its second year. We had a successful initial year and succeeded in delivering at least partially, what we envisaged when we started this endeavor in late 2008. We had good feedback and our access statistics are quite gratifying (Google Analytics). I have written a small write-up about the story of PVRI Review in this issue (The Story of the Journal of PVRI REVIEW, pg. 51). This issue, in addition to our usual sections, will have reports about the activities of PVRI happening in different regions of the world. They are either in the form of reports of regional task forces or disease specific taskforces. In the October issue of PVRI we started a new section- Journal Scan, which got a good feedback. The efforts by PVRI India continue. The section headings were published in the October issue and the citations are available online. This time we plan to publish a commentary and the citation list will be available online as usual. Each issue of PVRI REVIEW carry mini-reviews on various aspects of pulmonary vascular diseases. This issue carries a mini-review on pulmonary vascular endothelium by Rubin M. Tuder and Brian B. Graham. They analyze the data in support of the endothelium as a central element in the pathogenesis of pulmonary hypertension; provide evidence about the similarity in metabolic features between pulmonary endothelial cells and neoplastic cells. (“Cancer hypothesis”) They also discuss the evidence on potentially shared pathobiological processes that can be therapeutically aimed at smooth muscle and endothelial cells like metabolic shift or apoptosis.
various aspects of Tricuspid Annular Plane Systolic Excursion (TAPSE). They describe TAPSE as a simple and reliable index of RV function. Gustavo A. Heresi, Raed A. Dweik discuss the utility of Biomarkers in PH in another review article. For patients with PH, follow-up and assessment of the impact of therapy may necessitate repeated invasive testing. Biomarkers will be helpful in this scenario and also it can be used to aid in the screening, diagnosis and evaluate prognosis of patients with PH. They conclude by saying that there is enough evidence to support the clinical use of BNP and uric acid as biomarkers for patients with PH. The search for the ideal biomarker is on. Another article by Paul M. Hassoun, from the Johns Hopkins, describes the role of inflammation in PH. He describes the specific components of inflammation in the development of PH as well as potential targets for therapy. The role of growth factors like VEGF and the potential clinical uses of its inhibitors are really promising. Dear readers, PVRI REVIEW will undergo some form of transformation in the coming year. The details will be reaching you after the Annual General Meeting in Lisbon. Please keep contributing to PVRI REVIEW in the form of review articles, case reports and commentaries.
Right ventricular (RV) function is an important determinant of prognosis in PH. A reliable index of right ventricular systolic function is difficult to find because of the complex geometry and pattern of contraction of the right ventricle. In the commentary section, Nabil S. Zeineh and Hunter C. Champion analyze the
Jan - Mar 2010 • Volume 2 • Issue 1
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S. Harikrishnan Editor in Chief, PVRI Review, Fellow, Pulmonary Vascular Research Institute, Co-leader, PVRI Publication Taskforce. E-mail: drharikrishnan@hotmail.com DOI: 10.4103/0974-6013.58618
PVRI REVIEW
Review Article
Role of Inflammation in Pulmonary Arterial Hypertension Paul M. Hassoun Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, 21224 USA
INTRODUCTION
human PAH are also prominent in PAH.
Pulmonary arterial hypertension (PAH) constitutes a heterogeneous group of clinical entities sharing similar pathologies that have been subcategorized as idiopathic PAH (IPAH), familial PAH, pulmonary hypertension (PH) associated with other diseases such as connective tissue diseases (e.g., systemic sclerosis (SSc)), portopulmonary hypertension and PH related to human immunodeficiency virus (HIV) infection, drugs and toxins.[1]
CYTOKINES AND CHEMOKINES IN PULMONARY ARTERIAL HYPERTENSION
This brief review focuses on inflammatory processes in PAH, highlighting specific components of inflammation in the development of PH, as well as potential targets for therapy.
ROLE OF INFLAMMATION IN PULMONARY ARTERIAL HYPERTENSION Inflammation plays a significant role in various types of human PH such as IPAH and PAH associated with connective tissue diseases and HIV infection, and in experimental animal models (e.g., monocrotaline (MCT)induced PH). A subset of PAH patients have circulating autoantibodies, including antinuclear antibodies [2] and elevated circulating levels of the proinflammatory cytokines interleukin-1 (IL-1) and IL-6.[3] While there are serologic and pathologic features suggestive of inflammation in both IPAH and PAH related to connective tissue diseases, it is likely that inflammatory pathways and autoimmunity are more pronounced in connective tissue diseases and may explain survival discrepancies and differential response to therapy between the two syndromes. [4,5] A role for inflammation in PAH is suggested by the presence of inflammatory cells, including macrophages and T and B lymphocytes, and dendritic cells around the plexiform lesions of PAH. [6] Levels of macrophage inflammatory protein-1 alpha, interleukin-1b and interleukin-6[3,7] and P-selectin[8] are increased in severe IPAH. Involvement of leukocytes, macrophages, and lymphocytes in the complex vascular lesions of IPAH was initially described by several investigators. [9,10] Cytokine and chemokine-dependent mechanisms leading to inflammatory cell recruitment in Address for correspondence: Dr. Paul M. Hassoun, Division of Pulmonary and Critical Care Medicine, 1830 East Monument Street, Baltimore, MD 21287 USA. E-mail: phassoun@jhmi.edu DOI: 10.4103/0974-6013.58620
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Fractalkine (CX3CL1) promotes the chemokine (C-X3-C motif) receptor 1 (CX3CR1)-expressing leukocyte recruitment and is upregulated in circulating CD41 and CD81 T lymphocytes from PAH patients as compared with controls. These patients also have elevated soluble CX3CL1 plasma concentrations; their lung tissue samples demonstrate increased CX3CL1 mRNA expression as compared with controls, and pulmonary artery endothelial cells (EC) from these lungs express CX3CL1 protein.[11] RANTES (Regulated upon Activation, Normal T cell expressed and secreted: CCL5) is an important chemoattractant for monocytes and T-cells and plays a key role in several vascular inflammatory processes, particularly vasculitides. CCL5 may also play an indirect role in PAH through the induction of endothelin-converting enzyme-1 and endothelin-1, a potent endothelium-derived factor with strong vasoconstrictive and mitogenic action. CCL5 mRNA expression is increased in lung samples from PAH patients as compared to controls, and probably originates from EC as demonstrated by in situ hybridization and immunohistochemistry studies.[12] The exact relevance of these findings to the pathophysiology of PAH requires further investigation. Recent studies further suggest that chemokines produced from small pulmonary arteries (PA) of PAH patients may contribute to inflammatory cell recruitment and PA smooth muscle cell (SMC) proliferation.[13]
GROWTH FACTORS AND INFLAMMATION IN PULMONARY ARTERIAL HYPERTENSION Several growth factors, including platelet-derived growth factor (PDGF),[14,15] epidermal growth factor (EGF)[16] and vascular endothelial growth factor (VEGF),[17] have been implicated in the abnormal proliferation and migration of PA vascular cells. They act as potent mitogens and chemoattractants for SMCs, fibroblasts and EC and cause resistance to apoptosis. These factors, like VEGF, play important roles in PAH and may mediate angiogenesis but are also involved in the permeability and inflammatory processes of the vascular endothelium. They have been the targets of novel therapeutic agents such as tyrosine kinase inhibitors and have been tested in experimental models of PH[ 15] and more recently in clinical trials. Jan - Mar 2010 • Volume 2 • Issue 1
Hassoun: Inflammation and PAH
VIRAL AND OTHER INFECTIOUS ETIOLOGIES IN PULMONARY ARTERIAL HYPERTENSION Hypothetically, PH may be caused by latent viral infections as suggested by associations between Epstein Barr virus (EBV) infection and Hodgkin’s disease and parvovirus and cytomegalovirus (CMV) infection and SSc;[18] both diseases have also been associated with PH. Infectious organisms can affect the lung circulation directly by obliterating lung vessels or indirectly by causing and maintaining inflammation. IPAH has a prevalence of 0.0002% in the general population, but in HIV-infected individuals the prevalence is 0.46% in France.[19] The clinical features of HIV-related PAH (HRPAH) are similar to those of different etiologies. This disease remains a significant clinical complication in the HIV-1-infected population. In the lung, HIV-1 infects primarily macrophages providing a potential reservoir for the transmission of the virus to circulating T-cells and a source for localized viral proteins which may have direct or indirect effects. Chronic exposure to these viral products as well as deficiency in regulatory T cells and altered production of chemokines/cytokines may contribute to pulmonary vascular dysfunction. HHV8, also known as Kaposi’s sarcoma-associated herpes virus, has been associated with angioproliferation disorders[20] including multicentric Castleman’s disease and Kaposi’s sarcoma. Evidence of HHV8 is found in a large percentage of plexiform lesions of one cohort of PH patients, suggesting for the first time that this virus was a contributing factor,[21] a concept that has, however, been challenged by other investigators.[22-25] Schistosomiasis is a prototypical example of a parasitic disease causing significant inflammation and pulmonary vascular disease. Schistosoma eggs modulate regulatory T cell activity and express a novel TGF-b superfamily member: Schistosoma mansoni inhibin/activin (SmInAct).[26] Infiltration of T and B cells have been reported in the pulmonary vascular lesions, and serum levels of IL-1, IL-6, CX36, fractalkine and RANTES are elevated, in patients with scistosoma-related PH.[27] In brief, very little is known about the natural history of any form of virus or other infectious organism-related PH or the molecular mechanisms that account for the pathogenesis. Cell biological studies with recombinant viral proteins or with cloned virions may shed some light as to potential molecular mechanisms whereby viral proteins induce angioproliferation.
CONCLUSION In summary, inflammatory processes involving cellular effectors, chemokines, cytokines and growth factors play a preponderant role in the vascular remodeling characteristic of PAH. A better understanding of these specific inflammatory pathways might allow development of targeted therapy for PAH.
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REFERENCES 1. Simonneau G, Galie N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43:5S-12S. 2. Isern RA, Yaneva M, Weiner E, Parke A, Rothfield N, Dantzker D, Jan - Mar 2010 • Volume 2 • Issue 1
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19.
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et al. Autoantibodies in patients with primary pulmonary hypertension: Association with anti-Ku. Am J Med 1992;93:307-12. Humbert M, Monti G, Brenot F, Sitbon O, Portier A, GrangeotKeros L, et al. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med 1995;151:1628-31. Condliffe R, Kiely DG, Peacock AJ, Corris PA, Gibbs JS, Vrapi F, et al. Connective tissue disease associated pulmonary arterial hypertension in the modern treatment era. Am J Respir Crit Care Med 2009;179:151-7. Fisher MR, Mathai SC, Champion HC, Girgis RE, HoustenHarris T, Hummers L, et al. Clinical differences between idiopathic and scleroderma-related pulmonary hypertension. Arthritis Rheum 2006;54:3043-50. Nicolls MR, Taraseviciene-Stewart L, Rai PR, Badesch DB, Voelkel NF. Autoimmunity and pulmonary hypertension: A perspective. Eur Respir J 2005;26:1110-8. Fartoukh M, Emilie D, Le Gall C, Monti G, Simonneau G, Humbert M. Chemokine macrophage inflammatory protein-1a mRNA expression in lung biopsy specimens of primary pulmonary hypertension. Chest 1998;114:50S-1S. Sakamaki F, Kyotani S, Nagaya N, Sato N, Oya H, Satoh T, et al. Increased plasma P-selectin and decreased thrombomodulin in pulmonary arterial hypertension were improved by continuous prostacyclin therapy. Circulation 2000;102:2720-5. 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. Dorfmuller P, Humbert M, Perros F, Sanchez O, Simonneau G, Müller KM, et al. Fibrous remodeling of the pulmonary venous system in pulmonary arterial hypertension associated with connective tissue diseases. Hum Pathol 2007;38:893-902. Balabanian K, Foussat A, Dorfmuller P, Durand-Gasselin I, Capel F, Bouchet-Delbos L, et al. CX(3)C chemokine fractalkine in pulmonary arterial hypertension. Am J Respir Crit Care Med 2002;165:1419-25. Dorfmuller P, Zarka V, Durand-Gasselin I, Monti G, Balabanian K, Garcia G, et al. Chemokine RANTES in severe pulmonary arterial hypertension. Am J Respir Crit Care Med 2002;165:534-9. Sanchez O, Marcos E, Perros F, Fadel E, Tu L, Humbert M, et al. Role of endothelium-derived CC chemokine ligand 2 in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2007;176:1041-7. Humbert M, Monti G, Fartoukh M, Magnan A, Brenot F, Rain B, et al. Platelet-derived growth factor expression in primary pulmonary hypertension: Comparison of HIV seropositive and HIV seronegative patients. Eur Respir J 1998;11:554-9. Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, Roth M, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 2005;115:2811-21. Merklinger SL, Jones PL, Martinez EC, Rabinovitch M. Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertension. Circulation 2005;112:423-31. Sakao S, Taraseviciene-Stewart L, Cool CD, Tada Y, Kasahara Y, Kurosu K, et al. VEGF-R blockade causes endothelial cell apoptosis, expansion of surviving CD341 precursor cells and trans-differentiation to smooth muscle-like and neuronal-like cells. FASEB J 2007;21:3640-52. Hamamdzic D, Kasman LM, LeRoy EC. The role of infectious agents in the pathogenesis of systemic sclerosis. Curr Opin Rheumatol 2002;14:694-8. Sitbon O, Lascoux-Combe C, Delfraissy JF, Yeni PG, Raffi F, De PVRI REVIEW
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21.
22.
PVRI Activities 2009 - In Pictures
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Zuttere D, et al. Prevalence of HIV-related pulmonary arterial hypertension in the current antiretroviral therapy era. Am J Respir Crit Care Med 2008;177:108-13. Desrosiers RC, Sasseville VG, Czajak SC, Zhang X, Mansfield KG, Kaur A, et al. A herpesvirus of rhesus monkeys related to the human Kaposi’s sarcoma-associated herpesvirus. J Virol 1997;71:9764-9. Cool CD, Rai PR, Yeager ME, Hernandez-Saavedra D, Serls AE, Bull TM, et al. Expression of human herpesvirus 8 in primary pulmonary hypertension. N Engl J Med 2003;349:1113-22. Henke-Gendo C, Mengel M, Hoeper MM, Alkharsah K, Schulz TF. Absence of Kaposi’s sarcoma-associated herpesvirus in patients with pulmonary arterial hypertension. Am J Respir Crit Care Med 2005;172:1581-5. Katano H, Ito K, Shibuya K, Saji T, Sato Y, Sata T. Lack of human herpesvirus 8 infection in lungs of Japanese patients with primary
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pulmonary hypertension. J Infect Dis 2005;191:743-5. 24. Laney AS, De Marco T, Peters JS, Malloy M, Teehankee C, Moore PS, et al. Kaposi sarcoma-associated herpesvirus and primary and secondary pulmonary hypertension. Chest 2005;127:762-7. 25. Bendayan D, Sarid R, Cohen A, Shitrit D, Shechtman I, Kramer MR. Absence of human herpesvirus 8 DNA sequences in lung biopsies from Israeli patients with pulmonary arterial hypertension. Respiration 2008;75:155-7. 26. Freitas TC, Jung E, Pearce EJ. TGF-beta signaling controls embryo development in the parasitic flatworm Schistosoma mansoni. PLoS Pathog 2007;3: E52. 27. Butrous G, Ghofrani HA, Grimminger F. Pulmonary vascular disease in the developing world. Circulation 2008;118:1758-66. Source of Support: Nil, Conflict of Interest: None declared.
The 2nd PVRI Clinical Trial Debates 2009 Mexico city
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Jan - Mar 2010 • Volume 2 • Issue 1
Review Article
The Diseased Endothelium: Would It Explain It All? Rubin M. Tuder, Brian B. Graham Program in Translational Lung Research, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, School of Medicine, Colorado, United States
The field of pulmonary hypertension pathogenesis has struggled with the pseudo-dichotomy of the causal role of pulmonary vascular endothelium vis-à-vis smooth muscle cells as the central element of the disease. Medial hypertrophy and intima thickening due to migration or proliferation of vascular smooth muscle cells is seen in all forms of pulmonary hypertension, while endothelial cell lesions, particularly plexiform and concentric lesions, predominate in cases of severe pulmonary hypertension. Growing insight that the pathogenesis of pulmonary hypertension involves metabolic alterations of pulmonary vascular cells, including vascular smooth muscle and endothelial cells, opens new venues for therapies and diagnoses.
INTRODUCTION
combination of chronic hypoxia and vascular endothelial growth factor inhibition with the receptor blocker SU5416.[12]
Investigations in the pathogenesis of pulmonary hypertension have yielded seminal insights, which have translated into a growing number of novel therapies, largely unmatched elsewhere in the pulmonary field.[1] These insights developed from research centered on mechanisms of excessive pulmonary vascular reactivity, dating back to the early 1950s.[1,2] The central element of this early revolution was the advent of tools to assess real-time pulmonary vascular hemodynamics.[3] Indeed, the realization that pulmonary arteries constrict with alveolar hypoxia[4,5] implied that the severity of pulmonary hypertension would follow excessive vasoconstrictive mechanisms, which, teleologically has been postulated to work in hypoxic vasoconstriction,[4,5] including abnormal sensitivity to intracellular calcium in vascular smooth muscle cells, decreased potassium channel expression with ensuing membrane depolarization[6] and, more recently, abnormal RhoA/Rho kinase activity. These collective data point toward a central role of vascular smooth muscle cells in the pathogenesis of pulmonary hypertension. However, it has become apparent that the altered function of vascular smooth muscle cells in pulmonary hypertension follows the signaling miscues emanated from an abnormal endothelium.[7,8] This compelling evidence has shifted the focus to the pulmonary endothelium as the critical element underlying pulmonary hypertension. [9] Indeed, current therapies target the supplementation of the deficiency of prostacyclin or nitric oxide (NO), or block the excessive production/action of endothelin.[10] Experiments targeting the pulmonary endothelium revealed the potential for concepts not previously recognized in the investigation of the pathogenesis of pulmonary hypertension.[9,11] One of these novel concepts is that the initiation and progression of the disease involves vascular cell death superseded by proliferation of apoptosis-resistant vascular cells.[11] This concept was developed based on the experimental observations of severe pulmonary hypertension due to the Address for correspondence: Dr. Rubin M. Tuder, 12700 19th Avenue, Campus Box C272, Aurora, CO 80045, Colorado, United States. E-mail: rubin.tuder@ucdenver.edu DOI: 10.4103/0974-6013.58622
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In spite of these conceptual and experimental advances in the field on pulmonary hypertension, only recent evidence has converged on alterations of metabolism of pulmonary vascular cells, a potential common denominator for both endothelial and smooth muscle cell dysfunction. These alterations are critical for the proliferative phenotype of pulmonary vascular cells and provide a common platform for drug development. The scope of the present article is to highlight some of these concepts, particularly data in support of the endothelium as a central element in the pathogenesis of pulmonary hypertension. Furthermore, we also provide evidence that pulmonary endothelial cells present metabolic features akin to neoplastic cells in that they are predominantly glycolytic with decreased numbers of mitochondria. These data are similar to observations made in hypertensive pulmonary vascular smooth muscle cells, thus providing a common pathogenetic platform for novel therapies.[13]
E X T E N T O F P U L M O N A RY VA S C U L A R PATHOLOGY AND PULMONARY HYPERTENSION There is a limited understanding of the distribution and extent of involvement of pulmonary vascular lesions in the lungs of patients with pulmonary hypertension. The lung can accommodate increases in cardiac output of about four- to fivefold without significant increase in pulmonary artery pressures. It is, therefore, anticipated that the development of pulmonary hypertension would occur when approximately 80% of the overall luminal surface area becomes compromised. We assume that this reduction translates in the compromise an equivalent (i.e., 80%) of the overall relevant vascular segments. The pulmonary circulation is predicted to contain approximately 100 million segments distributed along approximately 17 branching orders prior to draining into a rich network of alveolar capillaries. Precapillaries represent the first to fourth orders of branching and account for 70 million vascular segments. Muscular arteries, that is, those with a well-defined medial muscular layer ranging in diameter between 500 and 70 mm, represent orders 5 to 9 and account PVRI REVIEW
Tuder and Graham: Diseased endothelium
for 800 000 segments. Elastic arteries are distributed along orders 10 to 7 and correspond to approximately 3000 segments.[14,15] It is conceivable that pulmonary hypertension is a pan vascular disease compromising different segments of pulmonary arteries, ultimately accounting for the predicted 80% reduction in overall pulmonary vascular luminal area. Given that the impact of luminal reduction would be more pronounced in muscular or precapillary arteries vis-a-vis elastic arteries, it has been postulated that pulmonary hypertension occurs due to the obliteration primarily of precapillary muscular pulmonary arteries. However, this hypothesis requires a larger number of independent lesions (i.e., about 640 000 single vascular lesions in muscular arteries or 56 million lesions in precapillary arteries), since the vascular site of occlusion is preferentially located in the periphery of the lung. This interpretation is supported by data from vascular casts or angiograms or NMR imaging, revealing decreased filling in the lung periphery in pulmonary hypertension—often interpreted as vascular pruning. Furthermore, which vascular lesion contributes to most of the vascular occlusion remains undetermined. More detailed mapping of the vascular lesions in pulmonary hypertension revealed that many lesions occur in branching points.[16,17] However, these studies were based on a relatively restricted lung sampling,[16] thus limiting extrapolation of the data to the entire pulmonary vascular bed. Moreover, these studies concerned idiopathic pulmonary arterial hypertension (IPAH), with no attempt to extend the relevance of these findings to pulmonary hypertension with underlying clinical conditions, including collagen vascular disease. The sole attempt to map significant pulmonary vascular lesions in IPAH showed that a single lesion obliterative (intima obliteration or plexiform lesion) was found to be located in reconstructed pulmonary arteries.[18] This study was significantly limited by the restricted sampling performed to quantify the pulmonary vascular lesions.
SMOOTH MUSCLE CELL BASED PULMONARY VASCULAR REMODELING In prior reviews, we have outlined the pulmonary vascular pathology according to different grades of severity of pulmonary hypertension.[19,20] Eccentric intimal thickening and medial hypertrophy has been recognized as a central component of pulmonary vascular pathology in IPAH.[21] However, this form of remodeling is also seen in postcapillary forms of pulmonary hypertension, in mild forms of pulmonary hypertension complicating chronic obstructive pulmonary vascular disease, or a localized finding in smokers’ lungs [Figure 1]. Unfortunately, there is lack of cellular markers indicative of smooth muscle cell dysfunction distinguishing mild versus severe pulmonary hypertension or to particular etiologies of pulmonary hypertension. Even the commonly investigated aspect of abnormal smooth muscle cell proliferation is of unclear relevance in more severe forms of pulmonary hypertension. We have outlined that mitotic Figures or expression of cell proliferation markers (i.e., MIB1 or PCNA) are infrequent in lungs of patients with severe pulmonary hypertension.[22] These observations do not preclude, however, that cell proliferation may be indeed a central element in the early stages of pulmonary hypertension. Severe luminal obliteration with smooth muscle cells or myofibroblasts is characteristically observed in severe pulmonary PVRI REVIEW
hypertension,[20] with the pathologic finding of luminal fibrosis with large amounts of extracellular matrix deposition and of concentric lesions.
ENDOTHELIAL CELL PATHOLOGY IN PULMONARY HYPERTENSION The evidence of endothelial cell dysfunction in IPAH or in mild forms of pulmonary hypertension in smokers’ lungs,[23] derives from significant pathological lesions found in lungs of patients with severe pulmonary hypertension. These intima lesions include plexiform, concentric, and dilated lesions [Figure 2].[24] Immunohistochemical markers of endothelial cells including Factor VIII related antigen, CD31, or even CD34 highlights the endothelial cell contribution to these lesions.[20] In fact, we have proposed that endothelial cell clustering leading to a loss of the single layer pattern of the pulmonary artery endothelium can be used for relatively early diagnosis of plexiform lesions and, therefore, of severe pulmonary hypertension.[20,25] However, no detailed study has documented the potential link between these clusters and fully developed plexiform lesions. Endothelial cell proliferation is a central finding in all forms of severe pulmonary hypertension, including IPAH, or PAH associated with HIV infection, collagen vascular disease,[26] liver cirrhosis, schistosomiasis, or congenital heart malformations with increased left to right shunt.[9] Endothelial cell proliferation is exemplified by plexiform and concentric lesions; dilated lesions may represent a similar pathogenetic process with formation of localized shunts or genesis of new but dilated vessels.[27] The contribution of endothelial cell-based lesions to the overall increase in pulmonary vascular resistance is unknown. Since these lesions are encountered at autopsy or explanted lungs, some reviews have authoritatively postulated that these lesions are “hemodynamically not relevant”—an argument similar to saying that colonic adenocarcinoma is “irrelevant” since it is found at autopsy! A limited mapping study revealed occlusive lesions in every vascular segment, usually at the vessels’ takeoff immediately after the branching site.[16] The contribution of plexiform and other pulmonary vascular lesions characterized by proliferation of endothelial cells to the overall increase in pulmonary vascular resistance in severe PAH remains unclear. [28] Generalizations that endothelial cell proliferation is a unifying finding in PAH are probably inaccurate;[29,30] PAH and pulmonary hypertension in general is probably heterogeneous based on the underlying etiology, both pathologically and pathobiologically. Some forms may be indeed angioproliferative; however, it is unclear whether the smooth muscle cell based remodeling initiates with angioproliferation or is reactive to distinct processes, and shares the extensive luminal obliteration and restriction to blood flow. Notwithstanding these considerations, the study addressing the molecular features of plexiform lesions revealed critical pathogenetic elements that at present are being extended to different forms of pulmonary hypertension and to the varied spectrum of lesions seen in the disease. Endothelial cell proliferative lesions have been attributed as consequence to the high transluminal pressures in severe pulmonary hypertension[24] or vascular wall necrosis.[31] We undertook the alternative hypothesis that important insights could be gained into the pathogenesis of severe pulmonary
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a
b
g
c
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Figure 1: Examples of smooth muscle cell based remodeling in veno-occlusive (a-c), cigarette smoke induced respiratory bronchiolitis (d-f), and IPAH (g, h). The overall pulmonary artery thickening due to increase in vascular smooth muscle cells is similar in all conditions, exemplified in hematoxylin and eosin-stained sections (a, e), smooth muscle actin immunohistochemistry (b, d, h), Factor VIII related antigen immunohistochemistry (c), and elastic stain (f,g), either arterial or venous pulmonary hypertension cause similar smooth muscle based remodeling. The difficulty of predicting the presence or severity of pulmonary hypertension based on smooth muscle cell based remodeling is illustrated by the extensive remodeling in cigarette smoke induced pulmonary vascular changes with mild or no pulmonary hypertension
Figure 2: Plexiform and intima lesions in IPAH. Two cellular plexiform lesion are seen in a branching point of a muscular pulmonary artery (a, highlighted by arrows). Another pulmonary artery shows overall intima thickening with predominance of extracellular matrix (b). However, the cells have a more concentric arrangement at the branching point (arrows), reminiscent of the process seen in panel (a). Indeed, a close up of a lesion in the same pulmonary artery shows increased numbers of endothelial cells immersed in an extracellular rich background (c, highlighted in yellow circle)
hypertension by studying the molecular profile of the proliferating cells within these lesions. As there are no cell culture systems that allow expansion of these cells, we employed microdissection of paraffin-embedded lungs to selectively enrich for DNA of these abnormal cells. This approach allowed us to document that the proliferative endothelial cells in plexiform lesions in IPAH are clonal.[32,33] The importance of these findings was that they Jan - Mar 2010 • Volume 2 • Issue 1
indicated for the first time that mutations in tumor suppressor genes might underlie the molecular pathogenesis of the disease. [34] This hypothesis was largely supported by the identifications of germline mutations in bone morphogenetic protein receptor 2 in families with IPAH[35,36] and somatic mutations in transforming growth factor-b receptor 2 in sporadic cases of IPAH.[37] The most important insights derived from these observations were
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threefold. First, pulmonary hypertension might involve cellular processes akin to neoplasia (discussed as follows),[38] including imbalance of cell proliferation versus cell apoptosis,[17] abnormal intravascular angiogenesis,[39] and potential genetic mutations.[40] Second, several studies compared the metabolic adaptations seen in cancer cells that underlie the shift toward a more glycolytic metabolism to vascular cells in pulmonary hypertension. Finally, vascular progenitor cells were predicted to exist in the pulmonary circulation,[34] capable of modulating gene expression due to mutations or epigenetically, in line with the investigations by the group of Yoder et al. showing that “true” circulating progenitor endothelial cells might derive from preexisting progenitor cells located in vascular walls rather than the bone marrow.[41]
The switch to energy derived from primarily glycolytic metabolism in human pulmonary hypertension parallels the metabolic findings identified in avian and rodent pulmonary hypertension[13,67-70] and are analogous to the alterations in cancer cell metabolism. Tumor cells often exhibit this combination of alterations in cellular energy production, a phenomenon first described over 80 years ago and known as the Warburg effect. [71] The condition of aerobic glycolysis is not a unique feature of tumor cells, but is also found in nontransformed rapidly proliferating cells when sufficient glucose is available. [72] Thus, the occurrence of aerobic glycolysis, or the Warburg effect, in IPAH endothelial cells is consistent with the increased proliferative capacity of these cells.[73]
METABOLIC SHIFT OF PULMONARY VASCULAR CELLS IN PULMONARY HYPERTENSION
Despite many years of investigation, the regulatory mechanisms for the transition of proliferating cells from oxidative glucose metabolism to anaerobic glycolysis are yet unclear. However, in IPAH pulmonary artery endothelial cells, decreased cellular respiration and increased glycolysis are mainly due to low mitochondrial numbers, which is related to reduced NO/cGMPdependent mitochondrial numbers.[59] In contrast, studies of pulmonary hypertension in avian and rodent species identified intrinsic deficiencies in mitochondrial function, rather than alteration in mitochondria abundance.[13,67] Nevertheless, the cumulative data indicate that decreased mitochondrial function, whether related to lower numbers of mitochondria and/or an intrinsic impairment of function, is a pathologic hallmark of pulmonary hypertension.
The earlier observations of expression of angiogenic molecules, including HIF-1a in plexiform lesions in IPAH lungs,[39] have been significantly expanded by a series of elegant animal models of pulmonary hypertension by the groups of Michelakis and Archer.[42] These studies and those of Yuan et al.[43] linked the downregulation of voltage-dependent potassium channels (Kv channels) in pulmonary artery smooth muscle cells from IPAH lungs[44] with the resistance to apoptosis and mitochondrial hyperpolarization in hypertensive smooth muscle cells.[45] They showed that the altered phenotype of cells is related to abnormal expression and localization of the inhibitor of apoptosis survivin[46] and a metabolic shift toward a more anaerobic metabolism. The pathogenetic importance of these properties was highlighted by the observation that they were amenable to inhibition by dichloroacetate (an inhibitor of pyruvate dehydrogenase kinase).[47] More recently, this paradigm came full circle with the experimental observation that HIF-1a expression results in a cascade of events including ion channel abnormalities and alterations in mitochondrial redox, metabolic regulation, and apoptotic machinery, which dictate a growth prone, apoptosisresistant pulmonary smooth muscle cell.[13] Deficiency in the vasodilator NO has been identified in the pathogenesis of pulmonary hypertension.[48-55] Pulmonary and total body NO are lower in IPAH patients as compared to healthy controls,[50,56-58] NO production by endothelial NO synthase is lower than normal in IPAH endothelial cells in vitro[56,59] and IPAH lungs have decreased expression of eNOS[60] (despite localized increase in eNOS expression in plexiform lesions). [61,62] In addition to effects on vascular tone, NO regulates cellular bioenergetics through effects on glycolysis, oxygen consumption by mitochondria, and mitochondrial biogenesis.[63-65] eNOSdeficient mice, which develop more pronounced pulmonary hypertension under hypoxia,[66] have reduced mitochondria content in a wide range of tissues associated with significantly lower oxygen consumption and ATP content.[63-65] Similarly, in human IPAH cells with reduced NO production, cellular metabolic energy pathways are characterized by lower oxygen consumption of mitochondria and a significantly higher glycolytic rate.[59] Greater than normal glucose uptake in the lungs of IPAH patients is detectable by nuclear imaging using (18F) fluoro-deoxyd-glucose-positron emission tomography, which indicates that the proliferative endothelial cells in the pulmonary vasculature also have greater reliance on the glycolytic pathway in vivo.[59] PVRI REVIEW
The metabolic shift in pulmonary vascular cells has been linked to HIF-1a,[13] which has been localized to plexiform lesions and muscular artery endothelial cells in IPAH lungs.[39] We have recently also documented that HIF-1a expression correlates with expression of its transcriptional target carbonic anhydrase IX (Fijalkowska, Xu, et al. Submitted, 2009). Furthermore, HIF- 1a and HIF-2a heterozygous deleted mice are protected against hypoxic-induced pulmonary hypertension.[74,75] Our recent findings have linked increased oxidative stress due to decreased expression of manganese superoxide dismutase in IPAH lungs[76] and endothelial cell cultures (also been documented in animal models[13]), decreased NO levels in IPAH patients,[77] upregulation of HIF-1a in IPAH cells, and decreased mitochondria numbers in IPAH cells.[59]
PULMONARY HYPERTENSION AND THE “CANCER” HYPOTHESIS As outlined earlier, there is growing evidence linking the hypertensive vascular phenotype to the cellular and molecular features seen in neoplastic cells. [30,38] Historically, this hypothesis originated from the realization of excessive growth of pulmonary vascular cells observed in plexiform lesions that were reconstructed three-dimensionally[17] and, most importantly, the finding that the growth of endothelial cells in plexiform lesions was clonal.[32] The coexpression of VEGF and its type 2 receptor in these lesions,[39] a finding also seen in neoplastic endothelial cells, further strengthened this concept.[38] Finally, compilation of expression patterns of several markers detected in IPAH lung tissue and characteristically described in cancers, including reduced expression of caveolin-1,[78] hemoygenase-1,[78] p27/ Kip1,[17] peroxisome proliferator-activated protein (PPAR)-g,[79]
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and increased expression of surviving,[46] VEGF and VEGF receptors,[39] PDGF receptors,[80] and FGF2.[81] HIF-1a, discussed earlier, may entail several of the abnormal growth and migratory properties of cancer cells.[82] Fundamental concepts of vascular cell growth triggered by the selection of apoptosis-resistant endothelial cells, originated from studies in animal models,[12] appear to be validated in different experimental settings.[83,84] Importantly, this hypothesis also aligns with the origin of cancer processes in the setting of normal organ or cell dysfunction or injury. A central element in the process of pulmonary vascular cell proliferation in PAH has been ascribed to early endothelial cell apoptosis.[11] In fact, there is no documentation that this early vascular (particularly endothelial) cell death occurs in patients with severe PH. However, experimental evidence from a model of severe PH have provided the initial documentation of endothelial cell apoptosis in the pathogenesis of the disease,[12] which was followed by subsequent documentation in the monocrotaline model[85] and in culture model system, in which cell survival can be protected by treatment with bone morphogenetic protein. [83] The latter data highlighted that bone morphogenetic protein receptor mutations might be involved in the disease process by decreasing the anti-apoptotic effects of the pathway. These processes may impose the progressive expansion of growth factor driven, predominantly glycolytic, apoptosis-resistant endothelial cells in severe PAH. Modulation of vascular cell apoptosis represents a promising venue for reversing the pathologic remodeling. This potential therapy was first demonstrated in the monocrotaline model in rats treated with elafin or serine protease inhibitors.[86,87] Furthermore, imatinib (Gleevec™) reverses monocrotaline-induced PH with evidence of vascular smooth muscle cell apoptosis.[80] Increasing membrane K1 channels is linked to hyperpolarization of mitochondria, decrease in survivin, and reversal of monocrotaline-induced PH.[46]
CONCLUSIONS There is compelling evidence linking dysfunctional pulmonary vascular endothelial cells in the pathobiology of severe PH. Whether all forms of severe PAH carry a similar spectrum of endothelial cell abnormalities remains unknown; however, the combined human and experimental evidence provides potentially shared pathobiological processes that can be therapeutically aimed at smooth muscle and endothelial cells (i.e., metabolic shift, apoptosis, etc.). The studies reviewed herein are clinically relevant as they provide the translational framework to understand the recent successes of pharmacologic strategies that target cellular utilization of mitochondria respiration vis-a-vis glycolysis, including imatinib,[88] which inhibits not only PDGF and c-kit receptors but also hexokinases,[89] 2-metoxyestradiol[90] or cyclosporine-A,[91] nonspecific inhibitors of HIF-1a, and the pyruvate kinase inhibitor dichloroacetate. [70] The inclusion of schistosomiasis as a cause of PAH opens new venues of investigation of the interplay of inflammation with pulmonary vascular disease.[92] In the setting of schistosomiasis-associated PAH, Th-2-driven inflammation may alter genetic programs that control cell proliferation and apoptosis in pulmonary vascular cells.[93] These investigations may provide important insights into how the pulmonary vascular lesions develop in the setting of pulmonary vascular inflammation and reveal novel therapies Jan - Mar 2010 • Volume 2 • Issue 1
that modify or prevent the consequences of severe PH.
REFERENCES 1. Zaiman A, Fijalkowska I, Hassoun PM, Tuder RM. One hundred years of research in the pathogenesis of pulmonary hypertension. Am J Respir Cell Mol Biol 2005;33:425-31. 2. Fishman AP. A century of primary pulmonary hypertension. In: Rubin LJ, Rich S, editors. Primary pulmonary hypertension. 1st ed. New York: Macel Decker; 1997. p. 1-17. 3. Cournand A, Ranges HA. Catheterization of the right auricle in man. Proc Soc Exp Biol Med 1941;46:462. 4. Euler US, Liljsjestrand G. Observations of the pulmonary arterial blood pressure on the cat. Acta Physiol Scand 1946;12:301-20. 5. Hales CA. Physiological function of hypoxic pulmonary hypertension. In: Yuan JX, editor. Hypoxic pulmonary vasoconstriction: Cellular and molecular mechanisms. Norwell, MA: Kluwer Academic Publishers; 2002. p. 3-32. 6. Yuan XJ, Wang J, Juhaszova M, Gaine SP, Rubin LJ. Attenuated K1 channel gene transcription in primary pulmonary hypertension. Lancet 1998;351:726-7. 7. Loscalzo J. Endothelial dysfunction in pulmonary hypertension. N Engl J Med 1992;327:70-5. 8. Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation 2004;109:159-65. 9. Tuder RM, Cool CD, Yeager ME, Taraseviciene-Stewart L, Bull TM, Voelkel NF. The pathobiology of pulmonary hypertension: Endothelium. Chest Clin North Am 2001;22:405-18. 10. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004;351:1425-36. 11. Tuder RM, Yeager ME, Geraci M, Golpon HA, Voelkel NF. Severe pulmonary hypertension after the discovery of the familial primary pulmonary hypertension gene. Eur Respir J 2001;17:1065-69. 12. Taraseviciene-Stewart L, Kasahara Y, Alger L, Alger L, Hirth P, McMahon G, et al. Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. FASEB J 2001;15:427-38. 13. Bonnet S, Michelakis ED, Porter CJ, Andrade-Navarro MA, Thébaud B, Bonnet S, et al. An abnormal mitochondrial-hypoxia inducible factor-1 alpha-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. 14. Horsfield K. Morphometry of the small pulmonary arteries in man. Circ Res 1978;42:593-7. 15. Singhal S, Henderson R, Horsfield K, Harding K, Cumming G. Morphometry of the human pulmonary arterial tree. Circ Res 1973;33:190-7. 16. Yaginuma G, Mohri H, Takahashi T. Distribution of arterial lesions and collateral pathways in the pulmonary hypertension of congenital heart disease: A computer aided reconstruction study. Thorax 1990;45:586-90. 17. Cool CD, Stewart JS, Werahera P, Miller GJ, Williams RL, Voelkel NF, et al. Three-dimensional reconstruction of pulmonary arteries in plexiform pulmonary hypertension using cell specific markers: Evidence for a dynamic and heterogeneous process of pulmonary endothelial cell growth. Am J Pathol 1999;155:411-9. 18. Yaginuma GY, Mohri H, Takahashi T. Distribution of arterial lesions and collateral pathways in the pulmonary hypertension of congenital heart disease: A computer aided reconstruction study. Thorax 1990;45:586-90. 19. Tuder RM, Marecki JC, Richter A, Fijalkowska I, Flores S. Pathology
9
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Tuder and Graham: Diseased endothelium of pulmonary hypertension. Clin Chest Med 2007;28:23-42, vii. 20. Tuder RM, Zaiman AL. Pathology of pulmonary vascular disease. In: Peacock A, Rubin LJ, editors. Pulmonary circulation. 2nd ed. London: Arnold; 2003. 21. Chazova I, Loyd JE, Newman JH, Belenkov Y, Meyrick B. Pulmonary artery adventitial changes and venous involvement in primary pulmonary hypertension. Am J Pathol 1995;146:389-97. 22. Tuder RM, Zaiman AL. Prostacyclin analogs as the brakes for pulmonary artery smooth muscle cell proliferation: Is it sufficient to treat severe pulmonary hypertension? Am J Respir Cell Mol Biol 2002;26:171-4. 23. Santos S, Peinado VI, Ramirez J, Melgosa T, Roca J, RodriguezRoisin R, et al. Characterization of pulmonary vascular remodelling in smokers and patients with mild COPD. Eur Respir J 2002;19:632-8. 24. Heath D, Edwards JE. The pathology of pulmonary hypertensive disease: A description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal changes. Circulation 1958;18:533-47. 25. Horton MR, Tuder RM. Primary pulmonary arterial hypertension presenting as diffuse micronodules on CT. Crit Rev Comput Tomogr 2004;45:335-41. 26. Cool CD, Kennedy D, Voelkel NF, Tuder RM. Pathogenesis and evolution of plexiform lesions in pulmonary hypertension associated with scleroderma and human immunodeficiency virus infection. Hum Pathol 1997;28:434-42. 27. Tuder RM, Groves BM, 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. 28. Eddahibi S, Morrell N, d’Ortho MP, Naeije R, Adnot S. Pathobiology of pulmonary arterial hypertension. Eur Resp J 2002;20:1559-72. 29. Nicolls MR, Taraseviciene-Stewart L, Rai PR, Badesch DB, Voelkel NF. Autoimmunity and pulmonary hypertension: A perspective. Eur Respir J 2005;26:1110-8. 30. Rai PR, Cool CD, King JA, Stevens T, Burns N, Winn RA, et al. The cancer paradigm of severe pulmonary arterial hypertension. Am J Respir Crit Care Med 2008;178:558-64. 31. Wagenvoort CA, Wagenvoort N. Unexplained plexogenic pulmonary arteriopathy: Primary pulmonary hypertension. In: Wagenvoort CA, Wagenvoort N, editors. Pathology of pulmonary hypertension. 1st ed. New York: John Wiley and Sons; 1977. p. 119-42. 32. Lee SD, Shroyer KR, Markham NE, Cool CD, Voelkel NF, Tuder RM. Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. J Clin Invest 1998;101:927-34. 33. Tuder RM, Radisavljevic Z, Shroyer KR, Polak JM, Voelkel NF. Monoclonal endothelial cells in appetite suppressant-associated pulmonary hypertension. Am J Respir Crit Care Med 1998;158:19992001. 34. Tuder RM, Lee SD, Cool CD. Histopathology of pulmonary hypertension. Chest 1998;114:1S-6S. 35. Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, et al. Familial primary pulmonary hypertension (gene PPH1) Is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 2000;67:737-44. 36. The International PPH Consortium; Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA 3rd, et al. Heterozygous germline mutations in BMPR2 encoding a TGF-B receptor cause familiar pulmonary hypertension. Nat Genet 2000;26:81-4. 37. Yeager ME, Halley GR, Golpon HA, Voelkel NF, Tuder RM. Microsatellite instability of endothelial cell growth and apoptosis genes within plexiform lesions in primary pulmonary hypertension. Circ Res 2001;88: E8-11. 38. Voelkel NF, Cool CD, Lee SD, Wright L, Geraci MW, Tuder RM. PVRI REVIEW
39.
40. 41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52. 53. 54. 55.
56.
10
Primary pulmonary hypertension between inflammation and cancer. Chest 1999;114:225S-30S. Tuder RM, Chacon M, Alger LA, Wang J, Taraseviciene-Stewart L, Kasahara Y, et al. Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: Evidence for a process of disordered angiogenesis. J Pathol 2001;195:367-74. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57-70. Yoder MC, Mead LE, Prater D, Krier TR, Mroueh KN, Li F, et al. Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood 2007;109:1801-9. Archer SL, Gomberg-Maitland M, Maitland ML, Rich S, Garcia JGN, Weir EK. Mitochondrial metabolism, redox signaling, and fusion: A mitochondria-ROS-HIF-1{alpha}-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer. Am J Physiol Heart Circ Physiol 2008;294: H570-8. Remillard CV, Yuan JX. Activation of K 1 channels: An essential pathway in programmed cell death. Am J Physiol -Lung Cell M PH 2004;286: L49-67. Yuan JX, Aldinger AM, Juhaszova M, Wang J, Conte JV Jr, Gaine SP, et al. Dysfunctional voltage-gated K 1 channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation 1998;98:1400-6. Krick S, Platoshyn O, McDaniel SS, Rubin LJ, Yuan JX. Augmented K(1) currents and mitochondrial membrane depolarization in pulmonary artery myocyte apoptosis. Am J Physiol Lung Cell Mol Physiol 2001;281: L887-94. McMurtry MS, Archer SL, Altieri DC, Bonnet S, Haromy A, Harry G, et al. Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J Clin Invest 2005;115:1479-91. McMurtry MS, Bonnet S, Wu X, Dyck JR, Haromy A, Hashimoto K, et al. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res 2004;95:830-40. Jeffery TK, Morrell NW. Molecular and cellular basis of pulmonary vascular remodeling in pulmonary hypertension. Prog Cardiovasc Dis 2002;45:173-202. Archer S, Rich S. Primary pulmonary hypertension: A vascular biology and translational research “Work in progress”. Circulation 2000;102:2781-91. Kaneko FT, Arroliga AC, Dweik RA, Comhair SA, Laskowski D, Oppedisano R, et al. Biochemical reaction products of nitric oxide as quantitative markers of primary pulmonary hypertension. Am J Respir Crit Care Med 1998;158:917-23. Azeka E, Costa AJ Jr, Kajita L, Alliman AC, Franchini Ramires JA, Ebaid M. Effects of low doses of inhaled nitric oxide combined with oxygen for the evaluation of pulmonary vascular reactivity in patients with pulmonary hypertension. Pediatr Cardiol 2002;23:20-6. Cooke JP, Dzau VJ. Nitric oxide synthase: Role in the genesis of vascular disease. Annu Rev Med 1997;48:489-509. Ignarro LJ. Nitric oxide-mediated vasorelaxation. Thromb Haemost 1993;70:148-51. Moncada S. Nitric oxide: Discovery and impact on clinical medicine. J R Soc Med 1999;92:164-9. Champion HC, Bivalacqua TJ, Greenberg SS, Giles TD, Hyman AL, Kadowitz PJ. Adenoviral gene transfer of endothelial nitricoxide synthase (eNOS) partially restores normal pulmonary arterial pressure in eNOS-deficient mice. Proc Natl Acad Sci USA 2002;99:13248-53. Xu W, Kaneko FT, Zheng S, Comhair SA, Janocha AJ, Goggans T, et al. Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension. Jan - Mar 2010 • Volume 2 • Issue 1
Tuder and Graham: Diseased endothelium FASEB J 2004;18:1746-8. 57. Ozkan M, Dweik RA, Laskowski D, Arroliga AC, Erzurum SC. High levels of nitric oxide in individuals with pulmonary hypertension receiving epoprostenol therapy. Lung 2001;179:233-43. 58. Girgis RE, Champion HC, Diette GB, Johns RA, Permutt S, Sylvester JT. Decreased exhaled nitric oxide in pulmonary arterial hypertension: Response to bosentan therapy. Am J Respir Crit Care Med 2005;172:352-7. 59. Xu W, Koeck T, Lara AR, Neumann D, DiFilippo FP, Koo M, et al. Alterations of cellular bioenergetics in pulmonary artery endothelial cells. Proc Natl Acad Sci USA 2007;104:1342-7. 60. Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995;333:214-21. 61. Mason NA, Springall DR, Burke M, Pollock J, Mikhail G, Yacoub MH, et al. High expression of endothelial nitric oxide synthase in plexiform lesions of pulmonary hypertension. J Pathol 1998;185:313-8. 62. Xue C, Johns RA. Endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995;333:1642-4. 63. Nisoli E, Clementi E, Paolucci C, Cozzi V, Tonello C, Sciorati C, et al. Mitochondrial biogenesis in mammals: The role of endogenous nitric oxide. Science 2003;299:896-9. 64. Nisoli E, Falcone S, Tonello C, Cozzi V, Palomba L, Fiorani M, et al. Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals. Proc Natl Acad Sci USA 2004;101:16507- 12. 65. Momken I, Fortin D, Serrurier B, Bigard X, Ventura-Clapier R, Veksler V. Endothelial nitric oxide synthase (NOS) deficiency affects energy metabolism pattern in murine oxidative skeletal muscle. Biochem J 2002;368:341-7. 66. Fagan KA, Fouty BW, Tyler RC, Morris KG Jr, Hepler LK, Sato K, et al. The pulmonary circulation of mice with either homozygous or heterozygous disruption of endothelial nitric oxide synthase is hyperresponsive to chronic mild hypoxia. J Clin Invest 1998;1- 3:291-9. 67. Tang Z, Iqbal M, Cawthon D, Bottje WG. Heart and breast muscle mitochondrial dysfunction in pulmonary hypertension syndrome in broilers (Gallus domesticus). Comp Biochem Physiol A Mol Integr Physiol 2002;132:527-40. 68. Iqbal M, Cawthon D, Wideman RF Jr, Bottje WG. Lung mitochondrial dysfunction in pulmonary hypertension syndrome: I: Site-specific defects in the electron transport chain. Poult Sci 2001;80:485-95. 69. Cawthon D, Iqbal M, Brand J, McNew R, Bottje WG. Investigation of proton conductance in liver mitochondria of broilers with pulmonary hypertension syndrome. Poult Sci 2004;83:259-65. 70. Michelakis ED, McMurtry MS, Wu XC, Dyck JR, Moudgil R, Hopkins TA, et al. Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: Role of increased expression and activity of voltage-gated potassium channels. Circulation 2002;105:244-50. 71. Warburg O, Posener K, Negelein E. Ueber den Stoffwechsel der Carcinomzelle. Biochem Z 1924;152:319-44. 72. Wang T, Marquardt C, Foker J. Aerobic glycolysis during lymphocyte proliferation. Nature 1976;261:702-5. 73. Masri FA, Xu W, Comhair SA, Asosingh K, Koo M, Vasanji A, et al. Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 2007;293: L548-54. 74. 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 1 alpha. J Clin Invest Jan - Mar 2010 • Volume 2 • Issue 1
1999;103:691-6. 75. Brusselmans K, Compernolle V, Tjwa M, Wiesener MS, Maxwell PH, Collen D, et al. Heterozygous deficiency of hypoxiainducible factor-2a protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia. J Clin Invest 2003;111:1519-27. 76. Bowers R, Cool C, Murphy RC, Tuder RM, Hopken MW, Flores SC, et al. Oxidative stress in severe pulmonary hypertension. Am J Respir Crit Care Med 2004;169:764-9. 77. Machado RF, Londhe Nerkar MV, Dweik RA, Hammel J, Janocha A, Pyle J, et al. Nitric oxide and pulmonary arterial pressures in pulmonary hypertension. Free Radic Biol Med 2004;37:1010-7. 78. Achcar RO, Demura Y, Rai PR, Taraseviciene-Stewart L, Kasper M, Voelkel NF, et al. Loss of caveolin and heme oxygenase expression in severe pulmonary hypertension. Chest 2006;129:696-705. 79. Ameshima S, Golpon H, Cool CD, Chan D, Vandivier RW, Gardai SJ, et al. Peroxisome proliferator-activated receptor gamma (PPARgamma) expression is decreased in pulmonary hypertension and affects endothelial cell growth. Circ Res 2003;92:1162-9. 80. Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, Roth M, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 2005;115:2811-21. 81. Zikki M, Guignabert C, Fadel E, Humbert M, Tu L, Zadigue P, et al. Endothelial-derived FGF2 contributes to the progression of pulmonary hypertension in humans and rodents. J Clin Invest 2009;119:512-23. 82. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003;3:721-32. 83. Teichert-Kuliszewska K, Kutryk MJ, Kuliszewski MA, Karoubi G, Courtman DW, Zucco L, et al. Bone morphogenetic protein receptor-2 signaling promotes pulmonary arterial endothelial cell survival: Implications for loss-of-function mutations in the pathogenesis of pulmonary hypertension. Circ Res 2006;98:209-17. 84. 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. 85. Zaiman AL, Podowski M, Medicherla S, Gordy K, Xu F, Zhen L, et al. Role of TGF-b/ALK5 Kinase in monocrotaline-induced pulmonary hypertension. Am J Respir Crit Care Med 2008;177:896-905. 86. Cowan KN, Heilbut A, Humpl T, Lam C, Ito S, Rabinovitch M. Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nat Med 2000;6:698-702. 87. Zaidi SH, You XM, Ciura S, O’Blenes S, Husain M, Rabinovitch M. Suppressed smooth muscle proliferation and inflammatory cell invasion after arterial injury in elafin-overexpressing mice. J Clin Invest 2000;105:1687-95. 88. Ghofrani HA, Seeger W, Grimminger F. Imatinib for the treatment of pulmonary arterial hypertension. N Engl J Med 2005;353:1412-3. 89. Pelicano H, Martin DS, Xu RH, Huang P. Glycolysis inhibition for anticancer treatment. Oncogene 2006;25:4633-46. 90. Tofovic SP, Salah EM, Mady HH, Jackson EK, Melhem MF. Estradiol metabolites attenuate monocrotaline-induced pulmonary hypertension in rats. J Cardiovasc Pharmacol 2005;46:430-7. 91. Koulmann N, Novel-Chate V, Peinnequin A, Chapot R, Serrurier B, Simler N, et al. Cyclosporin A inhibits hypoxia-induced pulmonary hypertension and right ventricle hypertrophy. Am J Respir Crit Care Med 2006;174:699-705. 92. Dorfmuller P, Perros F, Balabanian K, Humbert M. Inflammation in pulmonary arterial hypertension. Eur Respir J 2003;22:358-63. 93. Butrous G, Ghofrani HA, Grimminger F. Pulmonary vascular disease in the developing world. Circulation 2008;118:1758-66.
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Source of Support: Nil, Conflict of Interest: None declared. PVRI REVIEW
Review Article
Biomarkers in Pulmonary Hypertension Gustavo A. Heresi, Raed A. Dweik1 Departments of Pathobiology/Lerner Research Institute and 1Pulmonary and Critical Care Medicine Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, 44195 USA
INTRODUCTION
high follow-up BNP levels in the face of vasodilator therapy may reflect progressive RV dysfunction.[4]
Pulmonary arterial hypertension (PAH), albeit a rare disease in its idiopathic form, is associated with significant morbidity and markedly reduced life expectancy. Its clinical presentation is particularly non-specific and PH is often confused with more common disorders.[1-3] The diagnostic process typically begins with an echocardiographic estimate of the pulmonary artery systolic pressure. Right heart catheterization is required to confirm the diagnosis and asses its severity, in conjunction with clinical tools like the six-minute walk distance (6MWD) and the New York Heart Association (NYHA) or World Health Organization (WHO) classification systems. Prognosis correlates with mean right atrium pressure, cardiac index and mean pulmonary artery pressure. Patient follow-up and assessment of the impact of therapy is sometimes problematic, and often repeated invasive testing, i.e. right heart catheterization is necessary. Thus, non-invasive markers of the disease are highly desirable to aid in the screening, diagnosis, prognosis and follow-up of PAH patients. An ideal marker should be sensitive, reproducible and easy to perform. It should also correlate reasonably well with hemodynamic parameters and reflect the impact of therapy. In this review, we summarize the literature on non-invasive biomarkers of PAH in adult human subjects.
BRAIN NATRIURETIC PEPTIDE Nagaya et al. found that high levels of baseline brain natriuretic peptide (BNP) ($150 pg/ml) and especially high follow-up levels ($180 pg/ml) were associated with decreased survival in 60 patients with idiopathic PAH (iPAH).[4] Baseline plasma BNP was increased and correlated positively with NYHA functional class, mean pulmonary artery pressure (mPAP), mean right atrial pressure (mRAP), and pulmonary vascular resistance (PVR), and correlated negatively with cardiac output (CO). During a mean follow-up of 24 months, plasma BNP was an independent predictor of mortality. There was a marked increase in survival in patients with a follow-up BNP below the median level of 180 pg/ml. The receiver operating characteristic analysis showed that baseline BNP was at least equal to mPAP and superior to CO in predicting mortality. Further, the prognostic accuracy of follow-up plasma BNP was superior to that of baseline plasma BNP. During prostacyclin therapy, plasma BNP significantly decreased in survivors but increased in nonsurvivors, despite treatment, suggesting that Address for correspondence: Dr. Raed A. Dweik, Pulmonary Vascular Program, Department of Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, 9500 Euclid Avenue A90, Cleveland, OH 44122 USA. E-mail: dweikr@ccf.org
In a study by Leuchte et al. BNP levels were inversely correlated with the 6MWD, peak oxygen consumption and cardiac index, and positively correlated with WHO-class, PVR, PAP and RAP in 24 patients with iPAH.[6] The same authors reported on a group of 30 patients with iPAH in whom BNP levels paralled 6MWD, as well as a PAP and PVR during 12 months of follow-up.[7] BNP elevations have been also described in patients with atrial septal defects,[8] chronic thromboembolic pulmonary hypertension (CTEPH) [9] and pulmonary hypertension associated with interstitial lung disease.[10] In the Sildenafil vs. Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) study, plasma BNP levels ‑ a secondary endpoint - were elevated at baseline in both treatment groups, and sildenafil therapy was associated with a significant decline in plasma BNP as well as a reduction in RV mass by cardiovascular magnetic resonance imaging.[11] Thus there is a significant body of evidence suggesting that BNP measurement can aid in the management of PH patients, especially in terms of prognosis and follow up of therapy.
N-TERMINAL PRO-BRAIN NATRIURETIC PEPTIDE High N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) concentrations identified systemic sclerosis patients with PAH with a sensitivity of 90%, specificity of 90%, positive predictive value of 69%, and negative predictive value of 96% in a study by Allanore et al.[12] This analysis was limited by the fact that NT-proBNP was not compared with right heart catheterization values, but with right ventricular systolic pressure estimated by Doppler echocardiography. Also, heart failure was excluded by nuclear ventriculography. In a study of various terminal chronic pulmonary diseases, NT-proBNP was found to be elevated only in patients with iPAH, and not in patients with chronic obstructive pulmonary disease (COPD), emphysema or lung fibrosis.[13] Further studies are needed to establish a role or not for NT-pro-BNP.
TROPONIN T Torbicki et al. found that cardiac troponin T (cTnT) was
DOI: 10.4103/0974-6013.58623
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Park and colleagues studied 20 patients with PAH on epoprostenol and found that BNP may help predict those who are refractory to treatment.[5]
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detectable in eight of the 56 patients with stable pulmonary hypertension, 51 with PAH and five with CTEPH.[14] These patients had significantly worse survival after 24 months of follow-up. In a multivariate analysis, troponin T was an independent predictor of mortality, with the highest hazard ratio, along with the 6MWD and PVR. Furthermore, among these eight patients, seven had a repeat cTnT measurement. All four patients in whom cTnT remained detectable died. On the other hand, the three patients in whom cTnT became undetectable survived. Thus, cardiac troponin T, although not too sensitive, appears to correlate well with disease prognosis and effectiveness of therapy. This single center results, albeit promising, require further confirmation.
ENDOTHELIN-1 Stewart and coworkers reported that venous plasma endothelin-1 (ET-1) was significantly higher in 27 patients with pulmonary hypertension (seven idiopathic, 20 associated with several different conditions) than in normal subjects or patients with coronary disease.[15] In another study, a strong correlation was shown between PVR, mPAP, CO, cardiac index (CI), 6MWD, and elevated venous plasma levels of big ET-1 and mature ET-1 in 16 patients with severe iPAH.[16] In COPD patients with PAH, ET-1 was elevated in pulmonary artery samples as compared to controls, but not in peripheral arterial nor venous blood.[17] None of the studies assessed the prognostic significance of ET-1 or the impact of therapy on its levels. Furthermore, ET-1 is cleared by the pulmonary vascular bed, making peripheral venous sample somewhat unreliable. Thus, ET-1 does not appear to be a noninvasive marker suitable for clinical use.
Kereveur and colleagues measured serotonin levels in 16 patients with severe iPAH and compared them with controls. [21] At the same time, they measured platelet membrane epitopes as markers of platelet activation. Mean plasma serotonin levels were elevated in iPAH patients and correlated positively with PVR. Epoprostenol therapy did not modify these levels in spite of hemodynamic improvement. When compared with control platelets, membrane epitopes were not significantly elevated, suggesting that platelet activation is not the origin of the increased serotonin levels. Further studies are needed, especially to clarify if the lack of response of serotonin levels to prostacyclin therapy correlates with a worse clinical outcome as well.
VON WILLEBRAND FACTOR Eighteen iPAH patients showed a higher content of von Willebrand factor (vWF) antigen in venous and arterial blood samples than 12 controls in a study by Collados et al.[22] In two studies by Lopes et al. high plasma vWF antigenic activity was strongly associated with decreased survival at one-year of follow-up in patients with PAH, both idiopathic and associated with other conditions.[23,24] More recently, Kawut et al., reported that 30 out of 66 patients with PAH, most of them idiopathic, had elevated vWF levels, and that vWF levels at baseline and follow-up were associated with the risk of death after a median follow-up of 833 days. [25] Baseline vWF levels . 220% had a dramatically increased risk of death, as previously shown by Lopes et al. as well.[24] Previously, prostacyclin therapy was shown to be associated with a decreased in vWF levels.[26] Thus, there is evidence supporting a possible role of vWF measurements to aid in the prognosis and follow up of patients with PAH.
NITRIC OXIDE AND ITS METABOLITES Nitric oxide (NO) is too labile to be measured in plasma. However, NO in exhaled breath of individuals with iPAH was lower than associated pulmonary hypertension (aPAH) or controls, while it was strikingly higher in individuals with iPAH or aPAH receiving IV epoprostenol.[18] Similarly, exhaled NO and 24-hour-urine NO metabolites (nitrate) were decreased in 10 patients with PAH as compared with healthy controls. With three months of bosentan therapy, both values normalized.[19] Cyclic guanosine monophosphate (cGMP) is an indicator of the action of natriuretic peptides and nitric oxide on target cells. Bogdan et al. reported that patients with iPAH had higher urinary cGMP concentrations than asthmatic patients or normal healthy controls; also, urinary cGMP concentrations were inversely correlated with CI and venous oxygen saturation.[20] The evidence supports the measurement of exhaled-breath NO in the monitoring of response to therapy in patients with PAH, recognizing that exhaled-gas analysis is not widely available. Urine nitrate seems appealing as well. However, its accurate measurement requires strict dietary nitrate restrictions, which makes it somewhat unpractical. Jan - Mar 2010 • Volume 2 • Issue 1
SEROTONIN
THROMBOMODULIN Sakamaki and coworkers showed that plasma thrombomodulin (TM) level was significantly lower in 32 patients with iPAH as compared to patients with aPAH, pulmonary venous hypertension (PVH) and healthy controls. After prostacyclin therapy, the lower TM levels increased.[27] Cella and colleagues found decreased TM levels in 15 pulmonary hypertension patients, seven with iPAH, six aPAH and two pulmonary venous hypertension, vs. 20 controls. There was a weak correlation between TM plasma levels and the magnitude of systolic pulmonary artery pressure.[28] In another study, mean TM was raised in scleroderma associated pulmonary hypertension when compared with scleroderma controls and when compared with healthy controls.[29] Thus, TM seems to be low in iPAH, but it is unclear in patients with secondary causes. Mean TM concentration was significantly lower in 44 patients with CTEPH than in 22 healthy controls, while it was similar to controls in 22 patients with acute pulmonary embolism. After the CTEPH patients underwent pulmonary thromboendarterectomy,
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the mean TM concentration increased significantly. In the CTEPH group, the plasma TM concentration was negatively correlated with mPAP and PVR.[30] This single center study requires further confirmation.
SELECTINS In the previously quoted study by Sakamaki et al., P-selectin levels in both the aPAH and iPAH groups were significantly higher than those in the control and PVH groups, and they decreased with prostacyclin therapy. In the study by Cella et al.,[28] P-selectin was also elevated in pulmonary hypertension patients versus controls, but the difference did not reach statistical significance; L-selectin was significantly lower though and E-selectin was significantly higher. None of these studies evaluated the prognostic value of any of these markers. [27]
More recently, Kato et al. reported median plasma levels of soluble vascular cell adhesion molecule-1, E-selectin, and P-selectin significantly higher in patients with sickle cell disease (SCD) and pulmonary hypertension compared with SCD patients without PH.[31] No definitive evidence supports the use of these markers in the management of PAH patients yet.
OTHER MARKERS OF ENDOTHELIAL DYSFUNCTION Mean lipoprotein (a) levels were significantly higher in PAH patients compared to age- and sex-matched controls. Younger age, higher functional class, more severe congestive heart failure, shorter duration of symptoms, and more cases of hemoptysis were observed in the group with lipoprotein (a) levels . 30 mg/dl.[32] Systemic sclerosis patients with elevated plasmin-alpha(2)-plasmin inhibitor complex levels had pulmonary hypertension (PH) at a significantly higher incidence than those with normal levels.[33] Clearly, further investigations are needed for these and other potential markers of endothelial dysfunction, as it is a major contributor to the pathogenesis of pulmonary hypertension.
D-DIMER Shitrit and coworkers reported that mean ELISA D-dimer levels were significantly higher in 12 iPAH patients than in matched controls.[34] The same group showed that D-dimer levels were positively correlated with NYHA classification and PAP and were negatively correlated with oxygen saturation and 6MWD. A higher d-dimer value was also associated with poorer one-year survival.[35] So far, data on D-dimer seem preliminary and further confirmation is required.
ISOPROSTANES Isoprostanes are chemically stable lipid peroxidation products of arachidonic acid. Their quantification provides an approach to the assessment of oxidative stress in vivo. Urinary isoprostaglandin F (2alpha) type III (iPF(2alpha)-III) levels were measured by gas PVRI REVIEW
chromatography-mass spectrometry in 25 patients with PAH, both idiopathic and associated with different conditions. Urinary iPF(2alpha)-III levels in PAH patients were 2.3 times as high as in controls and correlated with the mPAP variation and the PVR variation in response to inhaled NO.[36] In another study, 2, 3-dinor-5,6-dihydro-8- isoprostaglandin F2a (F2-IsoP-M), the major urinary metabolite of the isoprostane 8-iso-PGF2a, was elevated at baseline in 19 patients with iPAH. During treatment with epoprostenol, values decreased and there was a strong correlation between the change in F2- IsoP-M and follow-up PVR; thromboxane A2 levels were markedly elevated at baseline as well, but were unchanged with therapy.[37] Thus, urinary isoprostanes appear to be promising markers in pulmonary hypertension, recognizing that their measurement requires gas chromatography-mass spectrometry, which is not widely available.
INTERLEUKINS Elevated levels of interleukin-1 beta (IL-1 beta) and IL-6 were found in 29 patients with severe iPAH as compared to 15 healthy controls and nine patients with PAH-associated with COPD.[38] Lesprit and coworkers found elevated levels of IL-1 beta, IL-6, tumor necrosis factor-alpha (TNF-alpha) and vascular endothelial growth factor in five patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome (POEMS) compared to 15 others who did not develop PAH over a 10-year period of follow-up.[39] Kimura et al. measured circulating levels of monocyte chemoattractant protein-1 (MCP‑1), IL-1 beta and TNFalpha in peripheral venous samples of 14 patients with CTEPH. The plasma level of MCP-1 was significantly correlated with PVR; there was no correlation between IL-1 beta and TNF-alpha and pulmonary hemodynamics.[40] Measurement of interleukins provides further insight into the pathogenesis of different types of pulmonary hypertension. They are not, however, suitable as markers to aid in the management of patients yet.
SOLUBLE CD40 LIGAND Damås et al., found increased mixed venous plasma levels of soluble (s) CD40 Ligand (sCD40L) in 13 patients with idiopathic and 11 with associated PAH compared with 8 control subjects, but not in 8 patients with CTEPH.[41] Patients using warfarin had markedly lower sCD40L levels than those without such therapy, possibly accounting for the lower levels in CTEPH patients. sCD40L levels were higher in arterial compared with mixed venous blood, suggesting enhanced release or reduced clearance in the pulmonary vasculature. No peripheral venous sampling was done. MCP-1 and IL-8 were significantly increased in all PAH groups compared with control subjects, and both significantly correlated with PVR. Of note, in eight out of nine PAH subjects treated with prostacyclin therapy, MCP-1 levels increased despite hemodynamic and functional class improvements. In another study of 50 patients with systemic sclerosis, median sCD40L was higher in the 10 patients with PAH, than in those without PAH; CD40L correlated with systolic PAP estimated by
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Doppler echocardiography.[42] More investigations are needed to further define the role of sCD40L in PAH, and whether or not it could become a marker of the disease.
2.
3.
C-REACTIVE PROTEIN An elevated C-reactive protein (CRP) level (.0.5 mg/dl) was a risk factor for pulmonary hypertension with an odds ratio of 8.47 in a group of 45 patients with Gaucher disease. The area under the receiving operator characteristic curve for diagnosis of pulmonary hypertension was 0.93 for CRP, much better that that for NT-proBNP (0.7).[43] There are no data for CRP in other populations of pulmonary hypertension.
4.
5.
6.
URIC ACID Serum uric acid (UA) was significantly elevated in 90 patients with iPAH compared with age-matched control subjects (7.5 6 2.5 versus 4.9 6 1.2 mg/ml, P , 0.001) and increased in proportion to the severity of NYHA functional class. Serum UA correlated negatively with CO and positively with PVR. These findings remained the same across both male and female subjects. Serum UA significantly decreased with vasodilator therapy, and its reduction correlated with a reduction in total PVR. During a mean follow-up period of 31 months, 53 patients died of cardiopulmonary causes. Among noninvasive variables, serum UA was independently related to mortality. Patients with high serum UA ($ 8.9 mg/dl in men and $ 6.4 mg/dl in women) had a significantly higher mortality rate than did those with low serum UA.[44] Subsequently, other investigators have found an association between serum UA levels and right atrial pressure[45,46] and confirmed its association with NYHA and 6MWD,[47] CI[45] and survival.[47,48] Thus, uric acid appears to be a simple test that correlates well with some hemodynamic parameters and, more importantly, with survival. Of note, uric acid remained a good marker when accounted for diuretic use by PH patients. This does not apply to patients with renal failure, as they were excluded from most trials.
7.
8.
9.
10.
11.
12.
13.
CONCLUSION A variety of markers have been studied in patients with pulmonary arterial hypertension. These studies bring further insight into the pathogenesis of the disease. There seems to be enough evidence to support the clinical use of BNP and uric acid to aid in the prognosis and, for BNP, follow up of patients with PAH. Markers that appear promising but require further confirmation include troponin T and von Willebrand factor. When available, exhaled nitric oxide should be considered as well. However, the search for the ideal marker[49] continues and clinicians should stay tuned.
14.
15.
16.
REFERENCES
17.
1. D’Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, et al. Survival in patients with primary pulmonary
18.
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hypertension: Results from a national prospective registry. Ann Intern Med 1991;115:343-9. Barst RJ, McGoon M, Torbicki A, Sitbon O, Krowka M, Olschewski H, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:40-7. Sandoval J, Bauerle O, Palomar A, Gómez A, Martínez-Guerra ML, Beltrán M, et al. Survival in primary pulmonary hypertension: Validation of a prognostic equation. Circulation 1994;89:1733-44. Nagaya N, Nishikimi T, Uematsu M, Satoh T, Kyotani S, Sakamaki F, et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation 2000;102:865-70. Park MH, Scott RL, Uber PA, Ventura HO, Mehra MR. Usefulness of B-type natriuretic peptide as a predictor of treatment outcome in pulmonary arterial hypertension. Congest Heart Fail 2004;10:221-5. Leuchte H, Holzapfel M, Baumgartner R, Ding I, Neurohr C, Vogeser M, et al. Clinical significance of brain natriuretic peptide in primary pulmonary hypertension. J Am Coll Cardiol 2004;43:764‑70. Leuchte H, Holzapfel M, Baumgartner R, Neurohr C, Vogeser M, Behr J. Characterization of brain natriuretic peptide in longterm follow-up of pulmonary arterial hypertension. Chest 2005;128:2368-74. Nagaya N, Nishikimi T, Uematsu M, Kyotani S, Satoh T, Nakanishi N, et al. Secretion patterns of brain natriuretic peptide and atrial natriuretic peptide in patients with or without pulmonary hypertension complicating atrial septal defect. Am Heart J 1998;136:297-301. Nagaya N, Ando M, Oya H, Ohkita Y, Kyotani S, Sakamaki F, et al. Plasma brain natriuretic peptide as a noninvasive marker for efficacy of pulmonary thromboendarterectomy. Ann Thorac Surg 2003;74:180-4. Leuchte H, Neurohr C, Baumgartner R, Holzapfel M, Gierhl W, Vogeser M, et al. Brain natriuretic peptide and exercise capacity in lung fibrosis and pulmonary hypertension. Am J Respir Crit Care Med 2004;170:360-5. Wilkins MR, Paul GA, Strange JW, Tunariu N, Gin-Sing W, Banya WA, et al. Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) Study. Am J Respir Crit Care Med 2005;171:1292-7. Allanore Y, Borderie D, Meune C, Cabanes L, Weber S, Ekindjian OG, et al. N-terminal probrain natriuretic peptide as a diagnostic marker of early pulmonary artery hypertension in patients with systemic sclerosis and effects of calcium-channel blockers. Arthritis Rheum 2003;48:3503-8. Goetze JP, Videbaek R, Boesgaards S, Aldershvile J, Rehfeld JF, Carlsen J. Pro-brain natriuretic peptide as marker of cardiovascular or pulmonary causes of dyspnea in patients with terminal parenchymal lung disease. J Heart Lung Transplant 2004;23:80-7. Torbicki A, Kurzyna M, Kuca P, Fijałkowska A, Sikora J, Florczyk M, et al. Detectable serum cardiac troponin T as a marker of poor prognosis among patients with chronic precapillary pulmonary hypertension. Circulation 2003;108:844-8. Stewart DJ, Levy RD, Cernacek P, Langleben D. Increased plasma endothelin-1 in pulmonary hypertension: Marker or mediator of disease? Ann Intern Med 1991;114:464-9. Rubens C, Ewert R, Halank M, Wensel R, Orzechowski HD, Schultheiss HP, et al. Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension. Chest 2001;120:1562-9. Celik G, Karabiyikoglu G. Local and peripheral plasma endothelin-1 in pulmonary hypertension secondary to chronic obstructive pulmonary disease. Respiration 1998;65:289-94. Ozkan M, Dweik RA, Laskowski D, Arroliga AC, Erzurum SC. High PVRI REVIEW
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19.
20.
21.
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23.
24.
25.
26.
27.
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levels of nitric oxide in individuals with pulmonary hypertension receiving epoprostenol therapy. Lung 2001;179:233‑43. Girgis RE, Champion HC, Diette GB, Johns RA, Permutt S, Sylvester JT. Decreased exhaled nitric oxide in pulmonary arterial hypertension: Response to Bosentan therapy. Am J Respir Crit Care Med 2005;172:352-7. Bogdan M, Humbert M, Francoual J, Claise C, Duroux P, Simonneau G, et al. Urinary cGMP concentrations in severe primary pulmonary hypertension. Thorax 1998;53:1059-62. Kereveur A, Callebert J, Humbert M, Herve P, Simonneau G, Launay JM, et al. High plasma serotonin levels in primary pulmonary hypertension: Effect of long-term epoprostenol prostacyclin therapy. Arterioscler Thromb Vasc Biol 2000;20:2233-9. Collados MT, Sandoval J, Lopez S, Masso FA, Paez A, Borbolla JR, et al. Characterization of von Willebrand factor in primary pulmonary hypertension. Heart Vessels 1999;14:246-52. Lopes AA, Maeda NY. Circulating von Willebrand factor antigen as a predictor of short-term prognosis in pulmonary hypertension. Chest 1998;114:1276-82. Lopes AA, Maeda NY, Bydlowski SP. Abnormalities in circulating von Willebrand factor and survival in pulmonary hypertension. Am J Med 1998;105:21-6. Kawut SM, Horn EM, Berekashvili KK, Widlitz AC, Rosenzweig EB, Barst RJ. von Willebrand factor independently predicts long-term survival in patients with pulmonary arterial hypertension. Chest 2005;128:2355-62. Friedman R, Mears G, Barst RJ. Continuous infusion of prostacyclin normalizes plasma markers of endothelial cell injury and platelet aggregation in primary pulmonary hypertension. Circulation 1997;96:2782-4. Sakamaki F, Kyotani S, Nagaya N, Sato N, Oya H, Satoh T, et al. Increased plasma P-selectin and decreased thrombomodulin in pulmonary arterial hypertension were improved by continuous prostacyclin therapy. Circulation 2000;102:2720-5. Cella G, Bellotto F, Tona F, Sbarai A, Mazzaro G, Motta G, et al. Plasma markers of endothelial dysfunction in pulmonary hypertension. Chest 2001;120:1226-30. Stratton RJ, Pompon L, Coghlan JG, Pearson JD, Black CM. Soluble thrombomodulin concentration is raised in scleroderma associated pulmonary hypertension. Ann Rheum Dis 2000;59:132-4. Sakamaki F, Kyotani S, Nagaya N, Sato N, Oya H, Nakanishi N. Increase in thrombomodulin concentrations after pulmonary thromboend arterectomy in chronic thromboembolic pulmonary hypertension. Chest 2003;124:1305-11. Kato GJ, Martyr S, Blackwelder WC, Nichols JS, Coles WA, Hunter LA, et al. Levels of soluble endothelium-derived adhesion molecules in patients with sickle cell disease are associated with pulmonary hypertension, organ dysfunction, and mortality. Br J Haematol 2005;130:943-53. Tewari S, Gupta D, Kumar S, Garg N, Godbole MM, Sinha N. Plasma lipoprotein a levels in patients with pulmonary arterial hypertension. Indian Heart J 2001;53:56-60. Jinnin M, Ihn H, Yamane K, Asano Y, Yazawa N, Tamaki K. Plasma plasmin-alpha2-plasmin inhibitor complex levels are increased in systemic sclerosis patients with pulmonary hypertension. Rheumatol Oxford 2003;42:240-3. Shitrit D, Bendayan D, Rudensky B, Izbicki G, Huerta M, Fink G, et al. Elevation of ELISA d-dimer levels in patients with primary
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pulmonary hypertension. Respiration 2002;69:327-9. 35. Shitrit D, Bendayan D, Bar-Gil-Shitrit A, Huerta M, Rudensky B, Fink G, et al. Significance of a plasma D-dimer test in patients with primary pulmonary hypertension. Chest 2002;122:1674-8. 36. Cracowski JL, Cracowski C, Bessard G, Pepin JL, Bessard J, Schwebel C, et al. Increased lipid peroxidation in patients with pulmonary hypertension. Am J Respir Crit Care Med 2001;164:1038-42. 37. Robbins IM, Morrow JD, Christman BW. Oxidant stress but not thromboxane decreases with epoprostenol therapy. Free Radic Biol Med 2005;38:568-74. 38. Humbert M, Monti G, Brenot F, Sitbon O, Portier A, Grangeot‑Keros L, et al. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med 1995;151:1628-31. 39. Lesprit P, Godeau B, Authier FJ, Soubrier M, Zuber M, Larroche C, et al. Pulmonary hypertension in POEMS syndrome: A new feature mediated by cytokines. Am J Respir Crit Care Med 1998;157:907-11. 40. Kimura H, Okada O, Tanabe N, Tanaka Y, Terai M, Takiguchi Y, et al. Plasma monocyte chemoattractant protein-1 and pulmonary vascular resistance in chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2001;164:319 24. 41. Damas JK, Otterdal K, Yndestad A, Aass H, Solum NO, Froland SS, et al. Soluble CD40 ligand in pulmonary arterial hypertension: Possible pathogenic role of the interaction between platelets and endothelial cells. Circulation 2004;110:999-1005. 42. Allanore Y, Borderie D, Meune C, Lemarechal H, Weber S, Ekindjian OG, et al. Increased plasma soluble CD40 ligand concentrations in systemic sclerosis and association with pulmonary arterial hypertension and digital ulcers. Ann Rheum Dis 2005;64:481-3. 43. Elstein D, Nir A, Klutstein M, Rudensky B, Zimran A. C-reactive protein and NT-proBNP as surrogate markers for pulmonary hypertension in Gaucher disease. Blood Cells Mol Dis 2005;34:201‑5. 44. Nagaya N, Uematsu M, Satoh T, Kyotani S, Sakamaki F, Nakanishi N, et al. Serum uric acid levels correlate with the severity and the mortality of primary pulmonary hypertension. Am J Respir Crit Care Med 1999;160:487-92. 45. Hoeper MM, Hohlfeld JM, Fabel H. Hyperuricaemia in patients with right or left heart failure. Eur Respir J 1999;13:682-5. 46. Voelkel MA, Wynne KM, Badesch DB, Groves BM, Voelkel NF. Hyperuricemia in severe pulmonary hypertension. Chest 2000;117:19-24. 47. Bendayan D, Shitrit D, Ygla M, Huerta M, Fink G, Kramer MR. Hyperuricemia as a prognostic factor in pulmonary arterial hypertension. Respir Med 2003;97:130-3. 48. Wensel R, Opitz CF, Anker SD, Winkler J, Hoffken G, Kleber FX, et al. Assessment of survival in patients with primary pulmonary hypertension: Importance of cardiopulmonary exercise testing. Circulation 2002;106:319-24. 49. Cracowski JL, Yaici A, Sitbon O, Reynaud-Gaubert M, Renversez JC, Pison C, et al. Biomarkers as prognostic factors in pulmonary arterial hypertension: Rationale and study design. Rev Mal Respir 2004;21:1137-43.
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Source of Support: Nil, Conflict of Interest: None declared.
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Utility of Tricuspid Annular Plane Systolic Excursion in the Assessment of Right Ventricular Function Nabil S. Zeineh, Hunter C. Champion Department of Medicine and the Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
Right ventricular (RV) function is an important determinant of prognosis in a large number of cardiopulmonary disease conditions and its assessment is a challenge in day-to-day clinical practice, mostly because of the complex geometry of the chamber. The search for, and validation of reliable indexes of RV function are ongoing. In particular, a large body of evidence has accumulated regarding the use of the tricuspid annular plane systolic excursion (TAPSE) as an index of RV systolic function in a variety of pathologic conditions. We will review the different areas of application of TAPSE to date.
INTRODUCTION Over the past two decades, there has been a revived interest in the role of right ventricular function in cardiovascular health. While majority of the published data on heart failure has focused on left ventricular structure and function, the appreciation of the importance of RV function has, nevertheless, been steadily increasing. The advent of echocardiography and its subsequent widespread use since the 1980’s has had an immeasurable impact on the care of patients with heart disease. Quantization of heart function has become readily available, reliable, and noninvasive. The evaluation of left ventricular systolic function routinely and mainly depends on a simple measurement of stroke volume, indirectly reported as ejection fraction. The search for similarly reliable index of right ventricular systolic function has been challenging, mostly because of its complex geometry and pattern of contraction (base to apex as opposed to LV concentric contraction).[1] Tricuspid Annular Plane Systolic Excursion, described in the 1980’s[2] has been proposed as a reliable objective index of RV function. Since then, a number of studies have validated its diagnostic and prognostic value in a number of pathologic conditions. We will review the accumulated evidence regarding the clinical utility of TAPSE in various disease states.
DEFINITION OF TRICUSPID ANNULAR PLANE SYSTOLIC EXCURSION The rationale of using TAPSE as indicator of RV systolic performance comes from the fact that in contradistinction to the LV the RV contraction is characterized by predominant longitudinal shortening[1] [Figure 1]. The value of TAPSE is obtained using M-mode echocardiography. It is the difference between end systolic and end diastolic distance from the tricuspid annulus to the apex. This is obtained by placing the cursor on the lateral aspect of the tricuspid Address for correspondence: Dr. Hunter C. Champion, Pulmonary Vascular Disease Center, Translational Research for the Vascular Medicine, Institute of the University of Pittsburgh, University of Pittsburgh, NW 628 Montefiore Hospital, 3459 Fifth Avenue, Pittsburgh, PA 15213 USA. E-mail: championhc@upmc.edu DOI: 10.4103/0974-6013.58625
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Figure 1: Changes in ventricular dimensions during systole in dogs. Dashed line: Right ventricle, solid line left ventricle. Arrows indicate temporal changes during systole (Adapted from Rushmer et al.[1])
annulus [Figure 2]. The normal values are between 2.4 and 2.6 cm.[3,4] Decreases in TAPSE correlate with progressive decrease in RV function. The TAPSE was first shown to correlate with RV ejection fraction in 1984.[2] Since then, this has been reconfirmed in studies using comparisons with MRI[5] and radionuclide angiography.[6]
ADVANTAGES OF THE TECHNIQUE Advantages of TAPSE include: Its relative ease of acquisition, low inter- and intraobserver variability[7] and the objective nature of data obtained. In addition, the technique now has a long track record as a large number of studies have evaluated its role in several disease processes involving RV dysfunction. In addition, the TAPSE can be measured irrespective of heart rhythm, such as atrial fibrillation.[8] Finally like any echocardiographic technique, the method is non-invasive, safe, and inexpensive.
DISADVANTAGES There are some shortcomings to TAPSE as a measure of RV function. It may not always be feasible to obtain adequate PVRI REVIEW
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visualization of the tricuspid annulus, such as in obesity and chronic obstructive pulmonary disease. Left ventricular systolic dysfunction may by itself induce changes in TAPSE independently of RV function. [9] Apical akinesis may impair RV systolic function while maintaining a relatively normal TAPSE, thereby underestimating the degree of RV dysfunction. Severe tricuspid regurgitation may also cause TAPSE to underestimate the degree of RV dysfunction and correlation with RVEF[10] [Figure 3].
AREAS OF USE Right ventricular dysfunction in left ventricular failure It is now well established that the prognosis of patients with LV dysfunction and heart failure of various severity is adversely affected by concomitant dysfunction/failure of the RV.[11-13] In addition, the risk of death and new onset heart failure is increased in the presence of signs of RV dysfunction. [14] Although not included in the current guidelines,[15] the assessment of RV function provides complementary information that can further refine risk stratification in patients with heart failure due to LV dysfunction of ischemic or non-ischemic etiology. Several prospective studies have investigated the use of TAPSE to this end. A value for TAPSE , 1.4 cm has been shown to be an independent predictor of all cause mortality in several cohorts
of patients with systolic LV failure.[8,16] The cutoff value of 1.4 cm was first evaluated in 140 patients admitted with decompensated LV failure[8] and subsequently followed for a median of two years. This finding has thereafter been reproduced in a larger cohort of Danish patients admitted for the same syndrome of acute decompensated LV failure not due to acute myocardial infarction (817 patients with NYHA class II-IV heart failure). A TAPSE of less than 1.4 cm was independently associated with increasing mortality over a follow up period of roughly four years.[16] The prognostic value of this index of RV function is additive to the information obtained from well established markers of prognosis such as heart rate on admission, severity of functional mitral regurgitation[17] and NYHA functional class. Finally, higher levels of ventricular dyssynchrony have been correlated with lower TAPSE values,[18] raising the question of whether TAPSE could be used to refine patient selection for cardiac resynchronization therapy (CRT).
Cardiac resynchronization therapy CRT is an established therapeutic modality in advanced LV failure of ischemic and non-ischemic etiologies.[19,20] It has a positive effect on survival as well as on quality of life, but unfortunately a significant minority of patients (around 40%) gets no benefit from
Figure 2: Representative M-mode recordings through the lateral tricuspid valve annulus for the purpose of measuring the tricuspid annular plane systolic excursion. Tracings were taken from two separate patients: (a) one with relative preservation of right ventricular function and the other (b) from a patient with significant right ventricular dysfunction. Below each panel - respective hemodynamics for each patient. CI - Cardiac index; mPAP - Mean pulmonary arterial pressure; PVR - Pulmonary vascular resistance; RAP - Right atrial pressure; SVI - Stroke volume index (Reprinted from Forfia et al.,[7] with permission)
Figure 3: Relationship of tricuspid annular plane systolic excursion and right ventricular ejection fraction in patients with mild (a), moderate (b), and severe (c) tricuspid regurgitation (TR) (Reprinted from Hsiao et al.,[10] with permission)
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it.[19,21] Identifying patients who will respond to biventricular pacing, therefore, becomes an important aspect of clinical care. Among others, it seems that markers of RV dysfunction portend therapeutic failure as seen with RVSP elevations pre-implantation. [22-24] A recent study showed provoking results regarding the use of TAPSE along with other markers of RV function such as right ventricular fractional area change (RVFAC) in discerning responders from non-responders.[25] Although conducted in only 44 patients and over a limited time period of six months, a TAPSE of less than 1.4 cm was strongly associated with failure of CRT to improve clinical status and LV remodeling. Larger studies will need to be conducted to evaluate this important finding, especially in view of the practicality of this simple index of RV function.
ACUTE PULMONARY EMBOLISM Acute pulmonary embolism (PE) is potentially a fatal condition with a reported mortality rate of nearly 15% after three months. [26] The prognosis of acute PE is directly correlated to the degree of hemodynamic derangement. Most of the controversy in the treatment of acute PE lies within the group of patients with submassive embolic burden, defined as impairment in RV function in the face of hemodynamic stability. Echocardiographic assessment of RV function has traditionally relied upon subjective measures such as dilatation as well as RVSP determination. [27] In addition, various clinical and laboratory[28-32] parameters have been evaluated in addition to echocardiography for risk stratification. The value of TAPSE in this context has recently been looked at in a small study involving patients with nonmassive PE followed up over a short term.[33] A lower value for TAPSE (, 1.8 cm) was significantly correlated with clinical and laboratory markers of poor prognosis. This thought-provoking study called for larger scale investigations to be conducted for a better definition of the value of TAPSE in acute PE over and above other subjective measures of RV function.
IDIOPATHIC PULMONARY ARTERIAL HYPERTENSION Idiopathic pulmonary arterial hypertension (IPAH), formerly
known as primary pulmonary hypertension is a disorder of unclear etiology that results in pulmonary vascular remodeling thereby causing elevation in pulmonary vascular resistance and an increase in RV afterload. The mortality of this disease is high, with about half of the patients dying after a median of 5 years from initial diagnosis.[34] Fortunately, a number of therapies (including lung transplantation) are now available that have significantly improved this grim prognosis. It is now clear that the state of RV function (and its phenotypic response to chronically elevated afterload) is an important determinant of patient outcome.[35-37] Although a formal invasive hemodynamic assessment through right heart catheterization is essential for the diagnosis, and staging of IPAH,[38] several echocardiographic parameters have been shown to provide very useful prognostic information. The presence of a pericardial effusion, a high LV eccentricity index, and an enlarged right atrium, have all been found to correlate with adverse outcomes.[39] TAPSE has recently emerged as an important predictor of prognosis. In a large cohort of patients with pulmonary hypertension (the majority being in the WHO class 1 of pulmonary hypertension), a TAPSE of , 1.8 cm was strongly associated with a lower cardiac index as well as a much higher mortality rate over a median follow-up of 19 months[7] [Figure 4]. This important finding has been reproduced by other investigators[40] in conjunction with using correlations with signs of increased right sided filling pressures in a similarly large patient cohort. It remains to be seen whether serial TAPSE measurements will be of help in the follow-up of patients with IPAH and perhaps obviate the need for repeated catheterizations.
CONCLUSION There are only rare instances of single isolated laboratory tests results, clinical or radiologic findings altering the course of a patient’s care. It is only when these are placed in the context of a given patient alongside the rest of the data that their importance can be appreciated. TAPSE is not a perfect tool to evaluate global RV function, and obtaining its value in isolation is unlikely to affect patient care. However, as detailed above, there are many
Figure 4: Kaplan and Meier estimates of survival (primary endpoint, all-cause mortality) in patients stratified by TAPSE values. (a) represents the overall cohort; (b) represents the pulmonary arterial hypertension population only. Numbers below each Figure represent the number of patients at risk for death at each time point (Reprinted from Forfia et al.,[7] with permission)
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instances where it can provide the physician with more insight as to the clinical status of the patient and potentially guide therapy, or at least trigger more vigilance. It is relatively easy to obtain, is versatile with regards to areas of application, and most likely underutilized. As such, whenever possible, it should be a part of echocardiographic studies obtained for several indications including the ones discussed at present. Future research will better define the role of TAPSE in the care of patients with various forms of cardiopulmonary disease.
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REFERENCES 1. Rushmer RF, Crystal DK, Wagner C. The functional anatomy of ventricular contraction. Circ Res 1953;1:162-70. 2. Kaul S, Tei C, Hopkins JM, Shah PM. Assessment of right ventricular function using two-dimensional echocardiography. Am Heart J 1984;107:526-31. 3. Hemnes AR, Forfia PR, Champion HC. Assessment of pulmonary vasculature and right heart by invasive haemodynamics and echocardiography. Int J Clin Pract Suppl 2009;162:4-19. 4. Hammarstrom E, Wranne B, Pinto FJ, Puryear J, Popp RL. Tricuspid annular motion. J Am Soc Echocardiogr 1991;4:131-9. 5. Kjaergaard J, Petersen CL, Kjaer A, Schaadt BK, Oh JK, Hassager C. Evaluation of right ventricular volume and function by 2D and 3D echocardiography compared to MRI. Eur J Echocardiogr 2006;7:430-8. 6. Ueti OM, Camargo EE, Ueti Ade A, de Lima-Filho EC, Nogueira EA. Assessment of right ventricular function with Doppler echocardiographic indices derived from tricuspid annular motion: Comparison with radionuclide angiography. Heart 2002;88:244-8. 7. Forfia PR, Fisher MR, Mathai SC, Housten-Harris T, Hemnes AR, Borlaug BA, et al. Tricuspid annular displacement predicts survival in pulmonary hypertension. Am J Respir Crit Care Med 2006;174:1034-41. 8. Ghio S, Recusani F, Klersy C, Sebastiani R, Laudisa ML, Campana C, et al. Prognostic usefulness of the tricuspid annular plane systolic excursion in patients with congestive heart failure secondary to idiopathic or ischemic dilated cardiomyopathy. Am J Cardiol 2000;85:837-42. 9. Lopez-Candales A, Rajagopalan N, Saxena N, Gulyasy B, Edelman K, Bazaz R. Right ventricular systolic function is not the sole determinant of tricuspid annular motion. Am J Cardiol 2006;98:973-7. 10. Hsiao SH, Lin SK, Wang WC, Yang SH, Gin PL, Liu CP. Severe tricuspid regurgitation shows significant impact in the relationship among peak systolic tricuspid annular velocity, tricuspid annular plane systolic excursion, and right ventricular ejection fraction. J Am Soc Echocardiogr 2006;19:902-10. 11. Di Salvo TG, Mathier M, Semigran MJ, Dec GW. Preserved right ventricular ejection fraction predicts exercise capacity and survival in advanced heart failure. J Am Coll Cardiol 1995;25:1143-53. 12. de Groote P, Millaire A, Foucher-Hossein C, Nugue O, Marchandise X, Ducloux G, et al. Right ventricular ejection fraction is an independent predictor of survival in patients with moderate heart failure. J Am Coll Cardiol 1998;32:948-54. 13. Ghio S, Gavazzi A, Campana C, Inserra C, Klersy C, Sebastiani R, et al. Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure. J Am Coll Cardiol 2001;37:183-8. 14. Zornoff LA, Skali H, Pfeffer MA, St John Sutton M, Rouleau JL, Lamas GA, et al. Right ventricular dysfunction and risk of heart failure and mortality after myocardial infarction. J Am Coll Cardiol 2002;39:1450-5. 15. Jessup M, Abraham WT, Casey DE, Feldman AM, Francis GS, Ganiats TG, et al. 2009 focused update: ACCF/AHA Guidelines for PVRI REVIEW
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
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the Diagnosis and Management of Heart Failure in Adults: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: Developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009;119:1977-2016. Kjaergaard J, Akkan D, Iversen KK, Kober L, Torp-Pedersen C, Hassager C. Right ventricular dysfunction as an independent predictor of short- and long-term mortality in patients with heart failure. Eur J Heart Fail 2007;9:610-6. Dini FL, Conti U, Fontanive P, Andreini D, Banti S, Braccini L, et al. Right ventricular dysfunction is a major predictor of outcome in patients with moderate to severe mitral regurgitation and left ventricular dysfunction. Am Heart J 2007;154:172-9. Gupta S, Khan F, Shapiro M, Weeks SG, Litwin SE, Michaels AD. The associations between tricuspid annular plane systolic excursion (TAPSE), ventricular dyssynchrony, and ventricular interaction in heart failure patients. Eur J Echocardiogr 2008;9:766‑71. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, et al. MIRACLE Study Group. Multicenter InSync Randomized Clinical Evaluation. N Engl J Med. 2002 Jun 13;346:1845-53. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539-49. Yu CM, Wing-Hong Fung J, Zhang Q, Sanderson JE. Understanding nonresponders of cardiac resynchronization therapy-current and future perspectives. J Cardiovasc Electrophysiol 2005;16:1117-24. Field ME, Solomon SD, Lewis EF, Kramer DB, Baughman KL, Stevenson LW, et al. Right ventricular dysfunction and adverse outcome in patients with advanced heart failure. J Card Fail 2006;12:616-20. Stern J, Heist EK, Murray L, Alabiad C, Chung J, Picard MH, et al. Elevated estimated pulmonary artery systolic pressure is associated with an adverse clinical outcome in patients receiving cardiac resynchronization therapy. Pacing Clin Electrophysiol 2007;30:603-7. Tedrow UB, Kramer DB, Stevenson LW, Stevenson WG, Baughman KL, Epstein LM, et al. Relation of right ventricular peak systolic pressure to major adverse events in patients undergoing cardiac resynchronization therapy. Am J Cardiol 2006;97:1737-40. Scuteri L, Rordorf R, Marsan NA, Landolina M, Magrini G, Klersy C, et al. Relevance of echocardiographic evaluation of right ventricular function in patients undergoing cardiac resynchronization therapy. Pacing Clin Electrophysiol 2009;32:1040-9. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: Clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999;353:1386-9. Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002;347:1143-50. Kucher N, Printzen G, Goldhaber SZ. Prognostic role of brain natriuretic peptide in acute pulmonary embolism. Circulation 2003;107:2545-7. Binder L, Pieske B, Olschewski M, Geibel A, Klostermann B, Reiner C, et al. N-terminal pro-brain natriuretic peptide or troponin testing followed by echocardiography for risk stratification of acute pulmonary embolism. Circulation 2005;112:1573-9. B MP, J MD, M PG. Mimotopes and proteome analyses using human genomic and cDNA epitope phage display. Comp Funct Genomics 2002;3:254-63. Kucher N, Printzen G, Doernhoefer T, Windecker S, Meier B, Hess OM. Low pro-brain natriuretic peptide levels predict benign clinical outcome in acute pulmonary embolism. Circulation 2003;107:1576-8. Jan - Mar 2010 • Volume 2 • Issue 1
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32. Konstantinides S, Geibel A, Olschewski M, Kasper W, Hruska N, Jäckle S, et al. Importance of cardiac troponins I and T in risk stratification of patients with acute pulmonary embolism. Circulation 2002;106:1263-8. 33. Holley AB, Cheatham JG, Jackson JL, Moores LK, Villines TC. Novel quantitative echocardiographic parameters in acute PE. J Thromb Thrombolysis 2009;28:506-12. 34. Shapiro SM, Oudiz RJ, Cao T, Romano MA, Beckmann XJ, Georgiou D, et al. Primary pulmonary hypertension: Improved long-term effects and survival with continuous intravenous epoprostenol infusion. J Am Coll Cardiol 1997;30:343-9. 35. D’Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, et al. Survival in patients with primary pulmonary hypertension: Results from a national prospective registry. Ann Intern Med 1991;115:343-9. 36. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: The impact of epoprostenol therapy. Circulation 2002;106:1477-82.
37. Sitbon O, Humbert M, Nunes H, Parent F, Garcia G, Hervé P, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: Prognostic factors and survival. J Am Coll Cardiol 2002;40:780-8. 38. Badesch DB, Champion HC, Sanchez MA, Hoeper MM, Loyd JE, Manes A, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2009;54: S55-66. 39. Raymond RJ, Hinderliter AL, Willis PW, Ralph D, Caldwell EJ, Williams W, et al. Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol 2002;39:1214-9. 40. Ghio S, Klersy C, Magrini G, D’Armini AM, Scelsi L, Raineri C, et al. Prognostic relevance of the echocardiographic assessment of right ventricular function in patients with idiopathic pulmonary arterial hypertension. Int J Cardiol 2008 in press. Source of Support: Nil, Conflict of Interest: None declared.
PVRI BRAZIL CHAPTER There were three sessions organized by the Brazil Chapter of the PVRI during the 64th annual Brazilian Cardiac Society
Figure 1: Dr. Maria Virginia Tavares Santana during a presentation in the special PVRI session of the 64th Annual Brazilian Cardiac Society meeting in Salvador Bahia, Brazil. She is the Director of Paediatric Cardiology, “Dante Pazzanese” Institute, São Paulo-Brazil. She is President of Pulmonary Circulation Study Group of Brazilian Society of Cardiology and a PVRI Fellow. She is also the Chief Editor of the PVRI REVIEW Portuguese edition
Figure 3: The special PVRI sessions during the 64th Annual Brazilian Cardiac Society meeting in Salvador Bahia Brazil
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meeting in Salvador, Bahia Brazil [Figures 1 and 2]. The sessions were very well attended [Figure 3]. The PVRI Brazil chapter is part of the PVRI America Region [Figure 4].
Figure 2: Dr. Rubin Tuder from Denver presented two talks (both in Portuguese) during special PVRI session of the 64th Annual Brazilian Cardiac Society meeting in Salvador Bahia Brazil
Figure 4: PVRI Brazil chapter get together during the 64th Annual Brazilian Cardiac Society
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Journal Scan
Commentary- Wnt Signaling Regulates Smooth Muscle Precursor Development in the Mouse Lung via A Tenascin C/PDGFR Pathway Swapna Menon PVRI India Office, Department of Pediatric Cardiology, Amrita Institute of Medical Sciences and Research Center, Kerala, India
A list of citations for the months of August to December 28, 2009 is available at http://www.pvrireview.org/articles/2010/2/1/images/ PVRIReview_2010_2_1_22_58627_sm1.doc The list was obtained using the following search strategy in PubMed: Keywords: “pulmonary hypertension” OR “pulmonary arterial hypertension” Field: Title, Limits: Publication Date from 2009/08 to 2009/12/28.
Ethan David Cohen,Kaori Ihida-Stansbury,Min Min Lu, Reynold A. Panettieri,Peter Lloyd Jones and Edward E. Morrisey. Wnt signaling regulates smooth muscle precursor development in the mouse lung via a tenascin C/PDGFR pathway. J. Clin. Invest. 119:2538-2549 (2009). doi:10.1172/ JCI38079.
BACKGROUND The Wnt pathway is a well conserved, complex signalling pathway, known for its involvement in embryonic development and tumorigenesis. Binding of one of the 19 cysteine rich Wnt family proteins to one of the 7 transmembrane receptors of the Frizzled family, in complex with LRP5/6 coreceptor, initiates the canonical Wnt pathway. This binding event is transduced to the cell interior, resulting in the nuclear translocation of b-catenin and potent activation of the transcription factor TCF/LEF. The downstream effectors of TCF/LEF are genes that promote cellular proliferation, differentiation and tissue development. Wnt7b is a protein expressed in fetal lung, kidney and brain and weakly expressed in the adult. In the lung, it is exclusively expressed in the epithelium. Wnt7b regulates lung airway and vascular development (Wang Z et al., Mol Cell Biol. 2005 Jun;25(12):5022-30; Shu W et al. Development. 2002 Oct;129(20):4831-42). A previous study using Wnt7b null mice embryos showed that Wnt7b promotes coordinated proliferation of lung epithelial and mesenchymal cells (Rajagopal J et al., Development. 2008 May;135(9):1625-34). The embryonic lungs of these null mutants, although hypoplastic, show largely normal differentiation and patterning.
SUMMARY Cohen et al. studied smooth muscle development in the airway and lung vasculature using mice embryos that were null mutants of Wnt7b or b-catenin. Immunohistochemical Address for correspondence: Swapna Menon, PVRI India Office, Department of Pediatric Cardiology, Amrita Institute of Medical Sciences and Research Center, Kerala, India. E-mail: swapna30@gmail.com DOI: 10.4103/0974-6013.58627
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and quantititative PCR (Q-PCR) assessment of smooth muscle markers, SM22-a , SM-MHC and calponin-h1 suggested defects in early development of smooth muscles in the lung. Further, expression of Pdgfr-b as well as Pdgfr-a receptors was reduced in embryonic lungs from both mutants compared to wild type. On treating wild type embryos with LiCl, expression of Pdgfr-b and Pdgfr-a receptors, as well as, Axin2, a downstream target of canonical Wnt signaling, increased significantly. LiCl is an inhibitor of GSK-b kinase activity; GSK-b, in turn, is an in vivo inhibitor Wnt/bcatenin signaling. Smooth muscle markers, SM-MHC and calponin-h1 also showed increased staining in the LiCl treated embryos, along with thicker airway and vascular smooth muscle layers. Immunostaining for phosphohistone H3 and Pdgfr-b receptor for embryonic lungs of both mutants showed reduction in smooth muscle precursors, partly due to reduced proliferation. Further, in the pulmonary VSMC cell line,Pac1, Wnt7b and b-catenin appear to specifically regulate Pdgfr-b receptor expression. Analysis of embryonic lungs from both mutants and LiCl treated wild type embryo indicated tenascin C, an important extracellular matrix component as an important target of the Wnt7b/ b-catenin signalling. Not only was this signalling pathway required for normal expression of tenascin C (TnC) but the TnC promoter also has TCF binding elements (TBE) in its promoter that could make it a direct target of the pathway. Treating wild type lung explants with TnC antibodies suggests that TnC regulates Pdgfr-a and Pdgfr-b receptor expression, as well as, mesenchymal cell proliferation. Mice with asthma induced by Aspergillus fumigatus,showed increased expression of Axin2, tenascin C and Pdgfr-a and Pdgfr-b receptors, as per immunohistochemistry and Q-PCR. Increased immunohistochemical expression of the same Wnt/TnC/Pdgfr pathway markers was shown in pulmonary hypertension in humans. Thus, this study established a Wnt7b canonical signaling pathway, dependent on b-catenin and GSK-b, which mediates smooth muscle proliferation in the airway and pulmonary vasculature. Importantly, Pdgfr-a and Pdgfr-b receptor expression was upregulated by this pathway via tenascin C. Tenascin C is a direct transcriptional regulation Jan - Mar 2010 • Volume 2 • Issue 1
Menon: Journal scan
target of Wnt signaling. PDGF receptors and tenascin C, an extra cellular matrix component, are among some of the known important mediators of pulmonary vascular disease.
COMMENTARY
PVRI Activities 2009 - In Pictures
Wnt7b appears to be required during ontogeny of other different systems. The canonical Wnt7b/b-catenin pathway is required for establishment of the cortico-medullary axis and normal tissue architecture of the mammalian kidney (Yu J et al., Development. 2009 Jan;136(1):161-71). A number of Wnts, including Wnt7b, have also been shown to be required for limb development and chondrogenesis in the mouse (Witte F et al., Stem Cells. 2008 Nov;26(11):2991-3001). Wnt signaling by osteoblasts has a role in bone development- Wnt7b, Wnt10b and Wnt3a have a role in mesenchymal commitment to the osteogenetic lineage in lieu of the default adipogenetic path (Zhou H et al. J Biol Chem. 2008 Jan 25;283(4):1936-45). Wnt7b also regulates placental development (Parr BA et al., Dev Biol. 2001 Sep 15;237(2):324-32).
A recent study investigating the mechanism of pulmonary fibrosis shows that Wnt/b-catenin from mesenchymal stem cells is required for proliferation of lung fibroblasts in mice (Salazar KD et al., Am J Physiol Lung Cell Mol Physiol. 2009 Nov;297(5):L1002-11). However, this proliferation was not dependent on the PDGF receptors. Wnt7b and Frizzled4 have been implicated in angiogenesis. Secreted Frizzled-related protein-1 (sFRP1), a modulator of the Wnt/ Fz pathway is important for mesenchymal stem cell mediated neoangiogenesis; PDGF-BB, b-catenin and GSK3-b modulate this action of sFRP1 (Dufourcq P et al., Stem Cells. 2008 Nov;26(11):2991-3001). Cohen et al. have shown that Wnt7b signaling via tenascin C and PDGF receptors is involved in proliferation of pulmonary smooth muscle cells. Important clues to pharmacological targets to lung diseases may be derived from future studies revealing the molecular targets specific to the pathway linking Wnt7b signaling to TnC and PDGFRs in bronchial and/or pulmonary vascular smooth muscles.
PVRI INTERNATIONAL ADVISORY BOARD AND BOARD OF DIRECTORS EXTRAORDINARY MEETING On 30th November and 1st December 2009, the PVRI International Advisory Board and Board of Directors met at Halliwells LLP office and then at Royal Society of Medicine in London to assess the works and achievements during the last three years. The plans for the future was discussed in detail [Figures 1-3].
Figure 2: Dr. Ahvie Herskowitz presented plans for the future
Figure 1: Attendees from the left: Prof Rich, Mr. P Raymond Professors Morrell, Butrous, Ghofrani, Haworth, Wilkins, Doogan and Herskowitz
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Figure 3: During one of the extraordinary sessions
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PVRI 2009 Annual Reports
Images from the 3rd PVRI Annual General Meeting in Mexico City, 25-28 January 2009
Figure 1: 3rd PVRI AGM meeting Mexico 2009
Figure 2: 3rd PVRI AGM meeting Mexico 2009
Figure 3: Lunch side meetings - 3rd PVRI AGM meeting Mexico 2009
Figure 4: Relaxing after a long meeting - 3rd PVRI AGM meeting Mexico 2009
Figure 5: Relaxing after a long meeting 3rd PVRI AGM meeting Mexico 2009
Figure 6: PVRI likes to express our gratitude to our hosts in Mexico - Prof. and Mrs Julio Sandowal for the hard work and dedication which made the 3rd PVRI AGM a grand success.
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Regional Reports
PVRI 2009 Annual Reports
2009 Annual Report of the PVRI Eastern Mediterranean Region Majdy Idrees Co-Leader, PVRI EMR Region Address for correspondence: Dr. Majdy Idrees, Co-Leader, PVRI EMR Region. E-mail: majidrees@gmail.com DOI: 10.4103/0974-6013.58632
The Saudi Advisory Group for Pulmonary Hypertension (SAPH), which also represents the Eastern Mediterranean Region (EMR) office of the global Pulmonary Vascular Research Institute (PVRI), has achieved the following during 2009: 1. SAPH has continued to expand in different directions. The board of Directors was expanded with the inclusion of people from different countries in the region. These countries include the following: • • • • • • • • • • •
Saudi Arabia United Arab Emirates Qatar Bahrain Kuwait Oman Lebanon Egypt Libya Sudan International members: Prof Paul Hassoun and Prof H A Ghofrani
The Board of Directors will be responsible for the administrative work of the EMR and will meet on an annual basis. 2. The following task forces are now operating under SAPH/ EMR: • National Registry Task Force: SAPH has officially started the national registry for pulmonary hypertension in the Kingdom of Saudi Arabia since June 2008, after the regulatory authorization. Five centers have been allocated in different regions of the Kingdom for reporting the data, and have hired trained personnel for this project. Unfortunately, the registry is progressing very slowly secondary to the extreme bureaucratic obstacles that SAPH is trying to overcome • Research Task Force: SAPH continues to work on fundraising for this particular issue. Currently, the following research proposals have been started: ♦♦ Prevalence of PAH in Sickle cell disease patients in Saudi Arabia (EMR project) ♦♦ Schistosoma and PAH in Saudi Arabia (EMR project) ♦♦ High altitude PH, Saudi Experience ♦♦ Genetic studies in Saudi patients with congenital heart disease ♦♦ The prevalence of PH in Bronchiectasis in Saudi Jan - Mar 2010 • Volume 2 • Issue 1
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patients ♦♦ R ole of selective therapy in sub-massive pulmonary embolism ♦♦ Iloprost experience in PH patients in a tertiary care Saudi hospital ♦♦ Involvement in Phase IV multinational, multicenter trial (COMPASS 2) • Scientific Task Force: The following scientific activities were undertaken in 2009: ♦♦ The 2nd Annual Scientific Joint Meeting (EMR). This was held in Casablanca (Morocco) in February 2009 [Figures 1 and 2]. It was a two-and-a-half day meeting that covered many topics in pulmonary hypertension, including the basic understanding of the pathobiology of pulmonary hypertension, congenital heart disease, pediatric perspectives, management of pulmonary hypertension, clinical follow up, and special situations (see Appendix 1 for a report) ♦♦ T he 1 st Annual PH-CHD symposium held in Jeddah in Nov 2009. This was an one-day meeting and included topics about pathophysiology, classification, and hemodynamics of PH in CHD, Criteria for operability and perioperative complications, imaging technique in CHD, and management of special situations ♦♦ Awareness days: Six awareness days were conducted, targeting different specialties. These sessions included the epidemiology of the disease, natural history, diagnostic work up, and outlines of management. ♦♦ Master-class sessions: SAPH will start master-class training sessions twice a year. These include an extensive two-day course for theoretical knowledge, echocardiographic and hemodynamic session participations, and follow up of real patients in the outpatient clinical settings. ♦♦ Preparation for the forthcoming 3rd Joint meeting (EMR) in Sharm El Sheik, Egypt in April 2010. • Pediatric and Congenital Heart Disease Task Force: This newly formed task force has managed to conduct the following activities: ♦♦ P ulmonary Hypertension Saudi Guidelines for Pediatric Population (in press) ♦♦ National CHD protocol for pre and postoperative work up in CHD patients ♦♦ The first Annual PH-CHD symposium (please see above) • Cardiac and Rheumatology Task Forces: These newly PVRI REVIEW
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Figure 1: Second Eastern Mediterranean Region meeting at Casablanca
Figure 2: Attendees of the 2nd EMR meeting in Casablanca
created task forces will include specialists from both fields. Their works and tasks will be discussed and planned in 2010.
SAPH PLANS FOR 2010 1. To update the guidelines published in 2008. Fellows from both PVRI and SAPH will be invited to take part in this project. It is not yet determined if the title will be changed to “EMR guidelines”
APPENDIX 1 Report of the 2nd EMR meeting on Casablanca The Casablanca meeting was held as the 2nd East Mediterranean Region Conference of the PVRI in association with the Saudi Group Pulmonary Hypertension, organized as two-and-a-half days symposium on the advances of pulmonary hypertension. On the first session, the Chair of the meeting, Majdy Idrees, presented the highlights of the Saudi guideline. The Saudi guideline has already been published in the Annals of Thoracic Medicine Journal, which is the official journal of Saudi Thoracic Society and is also available online. Ghazwan Butrous later presented the concept of the Pulmonary Vascular Research Institute emphasizing the importance of the incidents of pulmonary hypertension worldwide and that the majority of the said patients are actually in the developing world. Whereby the conditions have not been studied appropriately; cases such as schistosomiasis and high altitude-related pulmonary hypertension, HIV and COPD, etc. He emphasized that the PVRI is a flat organization, whereby experts and fellows from all over the world can work together in equal partnership to achieve increased awareness of pulmonary vascular diseases and enhance research and education as knowledge exchange. The meeting was followed by various scientific sessions discussing the pathophysiology of pulmonary hypertension in general. Rubin Tudor started the discussion on the pathophysiology of pulmonary hypertension. He discussed the severity of pulmonary hypertension and the role of endothelium, the vascular smooth muscle, and inflammatory cell in the pathogenesis of pulmonary hypertension. He described some of the pathological processes which target the pathological sensing of hypoxia, and the importance of the shift to a glycolytic pathway in the pulmonary hypertension endothelial cells as one of the paradigm of pulmonary hypertension pathophysiology. Ghazwan Butrous then discussed the neoplastic nature of pulmonary vascular diseases and emphasized that the dynamic of pulmonary hypertension involves early vascular tone changes, but as the disease progresses the remodeling process takes place. Most of the remodeling processes involve changes in susceptibility to epigenetics, infection, PVRI REVIEW
2. To follow the progress of the National registry 3. To follow the progress in research and work with PVRI for more collaborative works in this field 4. To finalize the scientific and social program for both the 3rd Annual meeting in Sharm El Sheik meeting in April 2010, and the 2nd Annual meeting for PH-CHD in Dammam, Saudi Arabia 5. To further establish Cardiology and Rheumatology task forces:
inflammation, immunity and angiogenesis and genes suppression. The paradigm is more or less similar to what we find including effects on the remodeling process like the migrations, dedifferentiation angiogenesis, thrombosis and abnormal proliferation. Then the discussion went on to show that the hallmark of cancer as described by Henheim and Weinberg in their Cell publication can be implemented in patients in the pathophysiology of pulmonary hypertension. Paul Hassoun discussed the role of inflammation in pulmonary hypertension and reviewed the presence of endothelial injuries and inflammations in various models in particular in the autoimmune model and connective tissues diseases. He showed that autoimmunity and pulmonary hypertension is evidenced from the presence of circulating antibodies; inflammatory cytokines, such as IL1 and IL6, association with auto-immune diseases such as SLE, and association with infection like HIV and HHV8 and parasitic infections like schistosomiasis. He showed that many current genes profiling in pulmonary hypertension is usually associated with genes involving inflammatory mediators and some of the cytokines and chemokines. Antonio Lopes discussed pulmonary hypertension in adults with congenital heart diseases (the Eisenmenger’s syndrome), and showed that various different lesions which represent the characteristic features of pulmonary hypertension can be seen in patients with Eisenmenger’s syndrome. He emphasized the importance of completely different survival curves compared with the other form of pulmonary hypertension whereby a patient with the Eisenmenger’s syndrome could have a slightly better prognosis, particularly in the early years, compared to idiopathic pulmonary arterial hypertension. Dr. Lopes also emphasized the importance of micro-vascular dysfunction and thrombosis in the pathophysiology of pulmonary hypertension in Eisenmenger’s syndrome. Rolf Berger discussed pulmonary hypertension in children with congenital heart diseases. He described the evolution of pulmonary vascular diseases in pulmonary hypertension in congenital heart disease. Children with the pulmonary artery hypertension and congenital heart diseases are a heterogeneous group with different natural history that may change continuously. This was followed by
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PVRI 2009 Annual Reports Robin Barst, who discussed what is special in pulmonary hypertension in children. Raed Dwaik presented a talk on how to achieve optimal goal in the treatment of pulmonary hypertension, emphasizing that the current trials showing that there is an increase of exercise capacity of about 1 30 to 40 meter and improvement in the functional capacity in about 2040% of the patients and with a variable reduction in the time to clinical worsening. Dr. Dwaik discussed the forthcoming targeted therapy and gave an example of the value of PHUTURE study, which stands for Pulmonary Hypertension Universal Tissue Repository. Hunter Champion discussed the role of right ventricle in pulmonary hypertension. He showed that we have to think differently about the diseases and that pulmonary hypertension is not just high pressure and high PVR - patients do not die from high pulmonary pressure, they die from right ventricular decomposition. In addition, he emphasized the importance of pulmonary vascular stiffness in understanding the pathophysiology and the prognosis of patients with pulmonary hypertension, therefore, that the paradigm is that higher ventricle hemodynamic and pulmonary hemodynamics should be considered in the treatment decisions. Ali Al-Azem from Critical Care Medicine in KFMC Riyadh, Saudi Arabia discussed the management of pulmonary hypertension in intensive care units, and emphasized the importance of a comprehensive work-up to determine the cause of hemodynamic consequences of pulmonary hypertension. He discussed various biomarkers as well as echocardiographic parameters and also commented on the common causes of pulmonary hypertension. In the second talk by Dr. Hunter Champion, he discussed the role of right heart catheterization. He showed that normal pulmonary vascular responses to exercise reflects the importance of the exercise testing on the hemodynamic parameters. Steve Archer presented a talk on the role of Pyruvate dehydrogenase kinase inhibitors in the pathophysiology of pulmonary hypertension and discussed the importance of the mitochondria and potassium channel pathways in the pathophysiology of pulmonary vascular diseases. He also touched base on the interaction between hypoxic pulmonary hypertension, pulmonary artery hypertension and cancer. Dr. Dwaik in his second talk reviewed the importance of biomarkers in the diagnosis and follow-up of pulmonary hypertensions. He summarized the NIH definition working group as a biomarker is an objective measurement of normal biological process in response to a therapeutic intervention. This is different from the clinical end-point, which is a characteristic of a variable that reflects how a patient feels, functions, or survives, while the surrogate end-point is a biomarker that is intended to substitute for a clinical end-point. The current outcome measurements, such as New York Heart Association functional class, six-minute walk test, cardiopulmonary exercise testing, and echocardiography are not very ideal. So better end-measurements and end points are needed, including biological markers. He also emphasized the importance of breath analysis as a new frontier in the medical testing and he showed that some studies have shown that exhaled nitric oxide in pulmonary hypertension could be a useful biomarker. Omar Minai discussed the preoperative risk and management of patients with pulmonary hypertension. He showed that healthy pulmonary circulation and adequate right ventricle function are critical for hemodynamic stability and oxygenation. These factors become magnified in situations of added stress such surgical intervention and patients with pulmonary hypertension are felt to be at increasing risk of perioperative complications including hypoxia, right ventricular failure and ischemia. These risks are better appreciated in association with cardiac surgery, but are less well described in patients undergoing Jan - Mar 2010 • Volume 2 • Issue 1
non-cardiac surgery. He showed that the mortality rate of up to 25% has been described; and in his conclusion he mentioned that pulmonary hypertension is a significant risk factor for perioperative complication after cardiac and non-cardiac surgery. Sarfraz Saleemi presented a summary of the current status of the diagnosis and management of chronic thromboembolic pulmonary hypertension (CTEPH) and emphasized that the CTEPH is increasingly being recognized as one of the leading causes of pulmonary hypertension with estimated incidences of 0.1 to 0.5% of patients with pulmonary embolism. He mentioned that three-year mortality is 90% when the mean pulmonary pressure is more than 33 mmHg. The pathophysiological features are similar to the PAH pathology and include misguided angiogenesis, inflammation, auto-immunity, and other remodeling process. He emphasized the importance of cardiac catheterization and ventilation perfusions studies in this patients’ population. The medical therapy could be indicated in the majority of the cases as more than 50% of the cases are inoperable. He also discussed the various observational studies with current CTEPH therapies, which include inhaled iloprost and both ERA and PDE-5 inhibitors. Dr. Omar Minai, in his second talk, reviewed the management of pulmonary hypertension in the interstitial lung diseases (ILD). The prevalence of pulmonary hypertension in the ILD could be reaching 59%, and that not all subclasses of ILD are equal in their prevalence. Pulmonary hypertension in parenchymal lung diseases can occur in a significant proportion of patients and may progress over time. It may limit the functional capacity of the patients and it has a negative impact on prognosis and survival. The pathophysiology could be more than just simple hypoxic, as in many cases an evidence of endothelial dysfunction, active inflammation, abnormal proliferation, and even the role of genetics have been described. He reviewed the limited data available on the effect of current PAH therapies in this condition. Ayman Krayem discussed pulmonary hypertension in the Obstructive Sleep Apnea (OSA). He emphasized that the disease can be severe, but is easily recognizable treatable. OSA can induce both cardiovascular complications and excessive sleeplessness, which will increase morbidity and mortality. He noted that pulmonary hypertension prevalence in the group of patients can range from 10 to 20% and usually it is of a mild degree and strongly associated with other factors like COPD, obesity, and nocturnal desaturation. Continuous positive airway pressure (CPAP) is the treatment of choice for OSA and has the potential of improving pulmonary pressures, but more studies are needed to assess this condition further. Saleh Al-Dammas discussed the portopulmonary hypertensions. He showed that portopulmonary hypertension is associated with volume overload. However, the disease is associated with vascular lesions such as endothelial and small muscles proliferation and other features similar to idiopathic pulmonary hypertension. He reviewed the treatment strategies, which include the use of the pulmonary hypertension drugs such as prostanoid, PED5i and ERA. Liver transplantation, when performed timely, is almost curative. Jean-Paul Richalet discussed pulmonary hypertension in association with Monge’s disease. He started his presentation clarifying that 140 million people live permanently above 2,500 m of altitude; mostly they are in South America, where 36 million inhabitants are living in such environment (in Africa about 25 million, and 7-8 million are in the Tibetan area around the Himalayas). Monge’s disease (or chronic mountain sickness) is associated with excessive polycythemia and some cases are associated with pulmonary hypertension, which is more common in males or post-menopausal women. A clinical presentation is usually headache, insomnia, anorexia, cyanosis and tinnitus. He went on to discuss the various studies and observations, in both clinical and physiological experiments in this condition, particularly emphasizing the observation in using acetazolamide (which is the first
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PVRI 2009 Annual Reports efficient pharmacological treatment of chronic mountain sickness with minimal adverse effects) that works probably by reducing nocturnal hyperventilation. It also reduces pulmonary vascular resistance in rats. Its low cost may allow a further development with considerable positive impact on public health in high altitude regions. However, other drugs such as ACE inhibitor might be considered. Roberto Machado discussed the sickle cell diseases associated with pulmonary hypertension. He showed that some evidence of pulmonary hypertension could be seen in around 33% of the patients with sickle cell anemia and that the severity of pulmonary hypertensions is usually reflected by the measurement of tricuspid regurgitation velocity. He explained that the pulmonary hypertensions may be related to several factors in sickle cell anemia. One of these factors is related to abnormal release of nitric oxide during hemolysis. The impact of pulmonary hypertension on the cardiopulmonary function in patients with sickle cell anemia was also discussed. He said sickle cell diseases in the world showed that about 70,000 people in the Americas may have this condition versus 13 million in Africa, with an estimated prevalence of 4.5% worldwide. Ghazwan Butrous discussed the pulmonary hypertension in schistosomiasis. He emphasized that schistosomiasis is the third leading endemic parasitic disease in the world and more than 300 million individuals are infested with these conditions. Pulmonary hypertension has been recorded in various centers, particularly through various studies in Brazil. He showed that inflammation plays a very important role in pulmonary hypertension and the pulmonary vascular diseases. Nicola Petrosillo discussed pulmonary hypertension secondary to HIV. He showed that 39.5 million can be infected by HIV in both adults and children. Although modern anti-viral treatment has
dramatically reduced the mortality rate, there remain many obstacles to the successful management of HIV patients mainly because of the lack of adherence, drug absorption, metabolism, and resistance. He summarized the cardiac diseases in HIV infection, which include pericarditis, acute myocarditis and endocarditis. The pulmonary hypertension associated with HIV is seen in about 0.5% of the cases and the survival of patients with pulmonary hypertension is much worse than those who do not have it. He explained that the pathogenesis could be due to various factors including the virus itself, although the HIV has never been isolated from the endothelial cells. There is a direct role of the inflammations in the HIV-related pulmonary hypertension. Some genetic factors could also be involved. He concluded that the current interest in this condition is based on the fact that the frequency of pulmonary hypertension in HIV infected patients is 600 times more than the general population. This estimate means that only in North America and Western Europe, with 3.8 million people living with HIV, there are about 8 to 10,000 cases of HIV infected patients with either severe or life-threatening pulmonary hypertension. Finally, he clarified that pulmonary hypertension development in HIV-infected patients is independent of both CD41 cells count and the presence or absence of ant-retro viral treatment. Andrew Peacock gave a detailed talk on the imaging of the right ventricle in pulmonary hypertension, and on the pros and cons of echocardiography in diagnosing and assessing patients with pulmonary hypertension. He also talked about the future role of RV imaging and its potential effect on PH management. H. Ardeschir Ghofrani from Giessen gave a talk on the pharmacological management of pulmonary hypertension. He reviewed the data on current available treatment and emphasized on some new potential drugs, such as the role of Guanylate cyclase activators in pulmonary hypertension.
Announcement
The Eastern Mediterranean Region The 3 Joint Pulmonary Hypertension Assembly (SAPH/PVRI) The 1st Joint Meeting (SAPH/SAVTE) Scientific Program Sharm El-Sheik, Egypt 7-8 April, 2010 rd
For more details please e-mail: Dr Majdy Idrees, majidrees@gmail.com SAVTE is the Saudi Arabian Venous Thrombo-Embolism Advisory Group PVRI REVIEW
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PVRI Sub-Saharan Africa Region Taskforce Ana Olga H. Mocumbi, Karen Sliwa-Hahnle Report of Activities-2009 Address for correspondence: Dr. Ana Olga Mocumbi, Instituto do Coração, Moçambique, Mozambique. E-mail: amocumbi@yahoo.com DOI: 10.4103/0974-6013.58633
The PVRI Sub-Saharan Africa Region was established this year and the Board of Directors nominated Dr. Ana Olga H Mocumbi from Instituto do Coração, Moçambique and Professor Karen Sliwa-Hahnle Director: Soweto Cardiovascular Research Unit, Department of Cardiology, Baragwanath Hospital, University of the Witwatersrand South Africa as co-leaders of the task-force. There were several dicussions and tele-conferences with the executive committee of the PVRI during the inception of the task force. On September 1, 2009, Dr. Ana Olga Mocumbi and Professor Karen Sliwa met in Barcelona, during the Congress of the European Society of Cardiology. The main objective was to identify short terms activities for the Taskforce, following the teleconference we had on August 17 with Professor Ghazwan Butrous. The main activities this year were:
BUILDING UP MEMBERSHIP FOR THE TASKFORCE As of now, 12 colleagues of colleagues have expressed interest in being part of the Taskforce. These colleagues come from several African countries namely: Mozambique, South Africa, Nigeria; some new colleagues from Kenya, Uganda and Tanzania are also under consideration. The following are currently members of PVRI SSA Region taskforce: 1) Adriano Màrio Francisco Tivane Mozambique 2) Albertino Damasceno Mozambique 3) Ana Olga H Mocumbi Mozambique 4) Gulnaze Mahomed Arif Mozambique 5) Janet Ajuluchukwu Nigeria 6) Okechukwu S Ogah Nigeria 7) Karen Sliwa-Hahnle South Africa 8) Antoinette Myrna Cilliers South Africa 9) Bongani Mayosi South Africa 10) Mpiko Ntsekhe South Africa 11) Rosie Burton South Africa
PLAN FOR PVRI SSA TASKFORCE MEETING IN 2010 The meeting has been planned for April 23-24, 2010, as the 1st PVRI Sub-Saharan Africa meet, at Hatter Institute for Cardiovascular Research, Chris Barnard Building, University of Cape Town, Cape Town, South Africa. The meeting will consider the following items in its agenda a) Our vision b) Presentation and discussion of the PVD SSA REGISTRY to establish regional database that can talk to the international database (including all features of the international database to be able to cross information, but also trying to answer the Jan - Mar 2010 • Volume 2 • Issue 1
particular aspects of PHT in Africa). The database should allow capturing demographics, natural history, prognosis and survival. It should be simple and avoid subjectivity but must include data that are relevant to increase awareness and allow advocacy for research and influence policy-making in our region. The need of expertise to design and establish the internet-based database will be evaluated c) Research programs to assess the risk factors to pulmonary vascular diseases in SSA region; for example, HIV/AIDS, chronic hepatitis B and C, Schistosomiasis, and other infectious diseases as well as hemolytic anemia and in particular Sickle Cell Disease. We would also like to consider extent of PVD in congenital heart diseases; the epidemiology of PVD in other cardiac conditions like rheumatic heart diseases, endomyocardial fibrosis, the role of occupational and other risk factors like wood smoke and smoking/tobacco exposure d) Ethical issues (informed consent, consent forms) for any PVD research in SSA.
ESTABLISH A REGISTRY OF P ULMONARY HYPERTENSION This registry would be launched in mid-April 2010 at a meeting to which 15-20 researchers members of the PVRI Taskforce for the SSA would be invited (from at least 5 countries), in Cape Town. We aim at having the survey on the web from mid-April 2010 so that some data would be available for initial discussion in October at the South African Heart Association Congress, where a session/ round table on PHT would be organized. The co-leaders would like to have the support of the PVRI in opening access to any existing questionnaire, which would be adapted to the local conditions for diagnosis and management.
PUBLICATIONS A non-systematic review on “Pulmonary Hypertension in Africa” was published in the PVRI review (PVRI Review 2009;1:227-9, http://www.pvrireview.org/text.asp?2009/1/4/227/57758)
SUMMARY OF THE PLAN FOR 2010 (1) Meeting on April 23-24, 2010 (2) Dedicated session during the South Africa Heart Association Meeting in October (3) Discuss the design of collaborative research projects for the region.
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PVRI Western Pacific Region (China Center) Chen Wang, Martin Wilkins Annual Report of PVRI China Taskforce (2008-2009) Address for correspondence: Prof. Martin Wilkins, Imperial College London. E-mail: m.wilkins@imperial.ac.uk DOI: 10.4103/0974-6013.58636
The Pulmonary Vascular Research Institute (PVRI) China Taskforce was established as a section of PVRI with the aim of exploring collaboration with doctors in China who have an interest in pulmonary vascular disease. Significant progress has been made in 2008-2009 in collaboration with the Chinese Medical Association (CMA) and the Chinese Thoracic Society (CTS). A summary of these include: • The 2nd International Symposium on Pulmonary Circulation Disorders in association with the 4 th National Congress of Pulmonary Embolism and Pulmonary Vascular Diseases in Beijing in August, 2009. • An exploratory collaboration meeting between PVRI China Centre and the Pulmonary Embolism and Pulmonary Vascular Assembly of the Chinese Thoracic Society. • A review of pulmonary hypertension published in the Chinese Medical Journal. • Distribution of a Chinese version of PVRI-Review. • A visit to share the surgical experience of pulmonary thrombo endarteractomy for CTEPH. • Symposium on CTEPH diagnosis and treatment. • Representation at the International Beijing Heart Forum and the Great Wall Heart meeting. • Initiation of research projects in PAH and CTEPH funded by the 11th five year plan. 1. The 2nd International Symposium on Pulmonary Circulation Disorders in association with the 4 th National Congress of Pulmonary Embolism and Pulmonary Vascular Diseases [Figure 1]. The 2nd International Symposium on Pulmonary Circulation Disorders was held in association with the 4th National Congress on Pulmonary Vascular Diseases in Beijing in Aug 21-23, 2009. Members of PVRI worked with the CTS to organize and deliver the program. The conference focused on the latest treatment guidelines based on recent clinical trials in venous thromboembolism (VTE) and pulmonary hypertension, the right ventricle and on-going research programs. The first session of the conference focused on the most updated guidelines of VTE and the on-going clinical research of diagnosis, treatment and prevention of pulmonary embolism and deep venous thrombosis. The second session of the conference described the clinical practice, diagnosis and treatment of PAH based on the recent guidelines and experienced clinical practitioners. The third session gave a brief introduction of translational research, novel targets and clinical trials on pulmonary hypertension. A final session highlighted the most pressing issues facing the diagnosis and management of pulmonary vascular disorders such as right ventricle dysfunction, heart and lung interaction, and related disorders. PVRI REVIEW
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Professors Martin Wilkins, Ghazwan Butrous, Ardi Ghofrani, Ralph Schermuly and Dr. Lan Zhao from PVRI and Professors Xiansheng Cheng, Chen Wang, Weixuan Lu and other colleagues from China took part in the meeting. 2. An exploratory collaboration meeting between PVRI China Centre and the Pulmonary Embolism and Pulmonary Vascular Assembly of the Chinese Thoracic Society [Figure 2]. An exploratory collaboration and strategy meeting between PVRI China Center and the Pulmonary Embolism and Pulmonary Vascular Assembly of the CTS was held in Beijing on Aug 22. An overview of current research projects directed at understanding pulmonary vascular diseases in China was given. Prof Wilkins gave an overview of PVRI. Prof Butrous talked about current research projects involving PVRI and China. Among the topics that arose in the general discussion were: 1) Expansion of membership of the PVRI China centre among Chinese specialists. 2) Collaboration on clinical research for novel target identification for pulmonary hypertension treatments. 3) Collaboration on translational research and basic research. 4) Fellow exchange program. 5) Education of PVD for Chinese physician. The feedback from the meeting was encouraging with the attendees reporting enthusiasm for the future of pulmonary vascular research in China. PVRI China Centre will invite some other experts (PVD assembly membership in CTS) representing all China to join the Center. 3. A review of pulmonary hypertension published in the Chinese Medical Journal. PVRI China Taskforce organized a specific supplement for the Chinese Medical Journal (CMJ, Chinese edition) comprising of a series of editorials, mini-reviews and original articles, including a discussion of the current status and future prospect of pulmonary hypertension in China, the pathogenesis and classification of pulmonary hypertension and the current and future treatment of pulmonary hypertension. The publication was distributed in the national conference of pulmonary circulation disorders. 4. Distribution of a Chinese version of PVRI-Review Jan - Mar 2010 • Volume 2 • Issue 1
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The PVRI-Review (Chinese version) [Figure 3] of the official publication of PVRI, The PVRI Review, was published. An editorial team based on the experts in the clinical and basic research of pulmonary vascular diseases in China was established. Translation of articles for the PVRI Review Chinese Issue was finished by 1st July and printed copies were distributed 22nd August during the PVRI China Symposium in Beijing (August 21-23, 2009). The translated articles are also available on-line on the PVRI review website. The articles include: 1) Issues facing clinical trials in pulmonary hypertension on a global scale. 2) Pulmonary hypertension in congenital heart disease. 3) Peri-operative risk and management of patients with pulmonary hypertension. 4) Receptor tyrosine kinases in pulmonary hypertension. 5) Chronic thrombo embolic pulmonary hypertension. 6) Histopathology images of pulmonary vascular disease: Parts 1. 7) Histopathology images of pulmonary vascular disease: Parts 2. 8) Pulmonary hypertension and COPD. 9) TGF-b-related molecules and pulmonary vascular remodeling in familial and non-familial pulmonary arterial hypertension. 10) Biomarkers in pulmonary hypertension.
5. Professor Madani was invited to China this June to share his experience of pulmonary thromboendarteractomy for CTEPH patients. A symposium on CTEPH diagnosis and treatment was held at the same time [Figure 4]. Prof Michael Madani visited ChaoYang Hospital, Beijing Institute of Respiratory Medicine in June 2009, to perform surgery for a patient with chronic thrombo embolic pulmonary hypertension (CTEPH). A whole day symposium on CTEPH and PAH was held. Prof Michael Madani and other experts from China gave talks covering the diagnosis, image evaluation, medical and surgical management of CTEPH, intensive care of the patients after surgery and future prospects for treatment. Two hundred doctors from around Beijing took part in the symposium. 6. Initiation of research projects in PAH and CTEPH funded by the 11th Five Year Plan A research project entitled ‘Promoting the Research on Diagnosis and Treatment for PH,’ sponsored by the 11th Five Year Plan of Chinese Science and Technology Foundation, is in progress. Different medications will be evaluated during the study, with the aim of providing evidence for the optimum management for PH in China. Another research project, ‘The registry study of pulmonary embolism,’ also sponsored by the 11th Five Year Plan, has started to explore the prevalence, treatment and preventive
Figure 1: The 2nd international symposium on pulmonary circulation disorders
Figure 2: The research meeting between pulmonary vascular research institute and pulmonary vascular assembly of the chinese thoracic society
Figure 3: The cover of the Chinese edition of the PVRI Review
Figure 4: Prof. Michael Madani
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strategies for pulmonary embolism and deep venous thrombosis. 7. Supporting the International Beijing Heart Forum and the Great Wall Heart meeting. Prof Martin Wilkins and Dr. Lan Zhao were invited as speakers in the Pulmonary Circulation section of the International Heart Forum Beijing (September 11-13, 2009). They gave presentations on the investigation of right heart function in pulmonary hypertension and the role of animal models in the development of new drug therapies. They also visited the Pulmonary Vascular Center in Beijing Fuwai Hospital to establish collaborations with this center. Prof Ardi Ghofrani was invited to take part in the The Great Wall International Cardiology meeting, held from Oct 9-13 2009. He gave a presentation on novel targets for the treatment for PAH. 8. Publications We have prepared a manuscript, Pulmonary Hypertension in China, for the upcoming supplement to CHEST, “Pulmonary Vascular Diseases: The Global Perspective”. The paper for this supplement has been uploaded. This article reviews and highlights the current status and future prospects for pulmonary hypertension management in China based on the current literature.
Members
1. Almaz Aldashev 2. Ghazwan Butrous
3. Ardi Ghofrani 4. Friedrich Grimminger 5. Stuart Rich 6. Norbert Voekel 7. Martin Wilkins 8. Jason Yuan 9. Chen Wang 10. Weixuan Lu 11. Xiansheng Cheng 12. Yuanhua Yang 13. Lan Zhao 14. Charles Hales 15. Jun Wang 16. Zhenguo Zhai
New members Yongcheng Du, Zhuang Ma, Zhonghe Zhang, Shi Wang, Zhaozhong Cheng, Nuofu Zhang, Jinming Liu, Shuang Liu, Qi Wu, Baomin Fang, Jianguo He, Liangxing Wang, Yipeng Ding, Hong Wang, Guohua Zhen, Xuejun Guo, Rui Zheng, Juhong Shi, Tuguang Kuang, Wanmu Xie.
Beijing office
PVRI (China Center), Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, 8 Gongtinan Road, Chao Yang District, Beijing 100020, China. E-mails: jun Wang [wang_jun@ccmu.edu.cn]; Zhenguo Zhai [zhaizhenguo@gmail.com]
Annual Report of PVRI South East Asia R. Krishna Kumar, Sheila G. Haworth1 Amrita Institute of Medical Sciences, India, 1Great Ormond Street Hospital for Children, and UCL Institute of Child Health, University College London, UK Address for correspondence: Dr. R Krishna Kumar, Amrita Institute of Medical Sciences, Ponekkara - 682 041, Kochi, India, Great Ormond Street Hospital for Children, London WC1N 3 JH, UK. E-mail: rkrishnakumar@aims.amrita.edu; s.haworth@ich.ucl.ac.uk DOI: 10.4103/0974-6013.58638
REGISTRATION AND NEW ACCOUNT CREATION PVRI India was registered with the official name of “ Pulmonary Vascular Research Institute of India” register number ER 262/09 under the Travancore Cochin Literary Scientific and Charitable Societies Act, 1855, in the state of Kerala in India on 15th of April, 2009. The registration of the society enabled opening of an independent bank account in the name of “PVRI India”. This account can be operated via a center in southern India as well as the North. Funds from abroad may be accepted in this account following set procedures and regulations. Simultaneously, a PAN card, issued by the Income Tax department of the Government of India, was obtained. It is not only essential for tax purposes
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but also the first official proof of address of PVRI in India. The process of registration involved creation of a memorandum of understanding (MoU) where the individual byelaws of the society were listed. The MoU was circulated among all members of the PVRI India executive for approval. A chartered accountant was identified for the purpose of creating and maintaining the PVRI account.
EDUCATIONAL EVENTS Pulmonary hypertension for adult cardiologists A meeting of nearly 50 cardiologists was held in the sidelines of the annual society of Cardiological Society of India (CSI) on
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December 5, 2008. PVRI was introduced to the audience. There were three lectures on the diagnosis and management of PAH in adults. Dr. BKS Sastry, Fellow, PVRI, and one of the executive members of PVRI India organized this meeting.
The high altitude meeting at Leh A meeting on “Recent Trends and Future Perspectives in High-Altitude Research”, was held at Leh Ladakh on September 4-5, 2009. The basic objective of this symposium was to integrate all branches of research on high-altitude and bring them to a common global platform for long term future perspectives. The symposium included talks by experts of the field and was followed by panel discussion mainly focusing on the application of medicine, physiology and basic sciences in life at high-altitude, both native and sojourn. Dr. Qadar Pasha (FPVRI) and the task force leader on Pulmonary Hypertension Associated With High Altitude and Hypoxia organized the event. (for more details see a separate report by Dr. Pasha page 36).
The annual symposium on pulmonary hypertension This was held in PGI Chandigarh [Figure 1] in association with the 11th Annual Conference of the Pediatric Cardiac Society of India. The symposium was organized by Prof. GD Puri (FPVRI). The event was attended by approximately 150 delegates. The meeting specially focused on pathobiology of pulmonary vascular diseases, persistent pulmonary hypertension in the newborn and specific management issues. A special guest lecture on PAH and high altitude was delivered by Prof. Inder Anand from the University of Minneapolis. The late afternoon session included case presentations on post-operative PAH.
Webcast A webcast on pulmonary hypertension in rheumatic and congenital heart disease was organized on the 22nd October, 2009 [Figures 2 and 3 legend preparation before the webcast]. The transmission was from Chandigarh (the full recording of the webcast can be reviewed at www.pahforum.com). Dr. S. G. Haworth (FPVRI). Dr. Harikrishnan (FPVRI), Dr. Krishna Kumar (FPVRI) Dr. Munesh Tomar participated in the webcast. Dr. Ghazwan Butrous (FPVRI), Dr. GD Puri (FPVRI) and Dr. Sivashankaran also attended the event. The webcast was organized by Dr. Puri and Swapna Menon, coordinator PVRI India. The webcast involved the following presentations: • An overview on pulmonary hypertension in RHD by Dr. Harikrishnan • A case presentation on RHD with PAH by Dr. Harikrishnan • CHD and Pulmonary Hypertension in India an overview by Dr. Krishna Kumar • Case presentation on an eight year old with a large PDA and coarctation by Dr. Munesh Tomar from Escorts Heart Institute New Delhi.
REGISTRY Dr. Sastry has accepted the responsibility of developing the PVRI India registry. The registry will initially be done as a pilot project in three centers. A blue print of the project has been prepared together with a case record form and ICF. A consensus agreement on the contents and format was arrived at through a tele-video conference. The registry will be initiated after obtaining permission from the respective ethics committees of the three centers. Participating centers will submit data online. Jan - Mar 2010 • Volume 2 • Issue 1
Figure 1: Rock Garden in Chandigarh
The software required for the registry of PVRI India is being developed. The registry is supported in part by a grant from Pfizer India.
MEMBERSHIP A brochure together with a registration form has been printed for PVRI India and efforts are underway to identify physicians and basic scientists from various disciplines (adult and pediatric cardiology, cardiac anesthesiology, pulmonology, neonatology, rheumatology, internal medicine, vascular biology, genetics, pharmacology and molecular biology) who are interested in pulmonary hypertension. The forms will be distributed at various meetings and at educational events undertaken by PVRI India.
PVRI REVIEW (See separate report from Dr. Harikrishnan page 51.
SPECIFIC RESEARCH INITIATIVES A study of the influence of ongoing inflammation due to subclinical rheumatic activity in the non-regression of pulmonary hypertension and the development of restenosis following balloon mitral valvotomy in Juvenile Mitral stenosis (JMS) has been initiated in August, 2009, at the Sree Chitra Thirunal Institute. Dr. Harikrishnan (FPVRI) is to look after this project. The specific aims and objectives are: 1. To assess the regression pattern of pulmonary hypertension in JMS patients following BMV. 2. To study the influence of non-regression of PAH and its influence in the development of re-stenosis of mitral valve. 3. To study the relation between markers of inflammation and markers of ongoing rheumatic activity to pulmonary artery pressure and non-regression of PAH. a. Pre-procedural levels of serum inflammatory markers ESR, total leukocyte count, differential WBC cell count Fibrinogen and high-sensitive C-reactive protein (hs-CRP) b. Levels of cytokines (interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) c. Markers of ongoing rheumatic activity-ASO, ADNase B, ACHO antibody titre.
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Figure 3: Preparation for the PVRI Webinar
Figure 2: PVRI Webinar 21 October 2009
PVRI RESEARCH MEETING AT CHANDIGARH 22ND OCTOBER 2009
Figure 4: Research meeting, Chandigrah, October 22nd,2009.
The purpose of this first meeting was to: i) Identify current areas of research activity in India ii) Identify important, relevant questions iii) Identify fields of interest in which there is currently no activity iv) Identify workable, relevant studies each with a responsible; for future purposes. The meeting was conceived and planned by Professor Haworth. Professor Kartha coordinated and arranged for scientists in a variety of disciplines from various Indian centers to participate in the meeting. He also liaised with administrative scientists in national research funding agencies. It was attended by all members of the Executive Committee of PVRI India, Professor Butrous, Professor I Anand, basic scientists known to be working on pulmonary vascular diseases or those interested in the subject; representatives of the Government of India Scientific Bodies, Indian Council of Medical Research and the Department of Biotechnology [Figure 4].
disease. Eight studies are planned, each with a named PI. Progress will be monitored throughout the year and at the Second Research Meeting to be held in October, 2010. The meeting was partially supported by the PVRI Central fund and a grant from CIPLA Ltd.
PLANS FOR THE YEAR 2010 The plans for the year 2010 were generated following discussions among members of the executive committee on 22 and 23 October, 2009, at Chandigarh. All members of the PVRI India executive attended the meeting.
Workshop on pulmonary vascular pathology PVRI India will explore the possibility of holding a workshop in Hyderabad in October 2010. Professor Haworth will help.
PVRI India annual symposium on pulmonary hypertension Each of the nine presentations was followed by considerable discussion. There was a consensus on priorities that include: Standardization of echocardiographic and cardiac catheterization protocols and standardization of the interpretation of pulmonary vascular pathology for use by all Indian cardiac centers, developing expertise in animal models of pulmonary vascular PVRI REVIEW
This will be be held in Hyderabad in October 2010. Dr. Sastry has kindly agreed to host and organize this meeting. Special efforts will be made to attract adult cardiologists, pulmonologists and rheumatologists. Abstract submission to encourage participation by young people will be considered. The principle topics that will be included are chronic thrombo-embolic disease, COPD and
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PH in connective tissue disease. It has also been proposed that an hour-long teaching session on grant writing be incorporated as well. The Executive Committee Meeting of PVRI India would be held at Hyderabad, overlapping with these meetings. Also, the Second Research Meeting on Pulmonary Hypertension will be organized. In this meeting the specific action items generated in the first meeting will be reviewed.
enable better attendance.
Regional education meetings A series of educational meetings involving multiple specialties (pulmonologists, CVTS surgeons, adult cardiology, and pediatric cardiology) have been planned with help from the industry in Kerala. Details of the program will provide a template for this to be done in other regions of the country.
Webcasts
PVRI Activities 2009 - In Pictures
Dr. Krishna Kumar and others will explore organizing India-wide webcasts in 2010. Clinicians will be invited to specific local venues accessible to them in the evening after work hours to
The second high altitude meeting Encouraged by the success of the first meeting, Dr. Pasha plans to host a sequel in late September- early October 2010.
PVRI GET TOGETHER IN SAN DIEGO USA DURING ATS 2009 MEETING Traditionally, the get together of PVRI Fellows during meetings like ATS is an informal one. These photos were
taken during a meeting in San Diego during ATS 2009 [Figures 1 and 2].
Figure 1: PVRI get-together during the ATS 2009 meeting in San Diego USA
Figure 2: PVRI get-together during the ATS 2009 meeting in San Diego USA
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Diseases Taskforces
PVRI 2009 Annual Reports
Taskforce: Pulmonary Hypertension Associated with High Altitude and Hypoxia - Annual Report 2009 Qadar Pasha1,2, Max Gassmann Fellows and Co-chairs, HATF, PVRI, 1Co-chair - Pulmonary Hypertension Associated With High Altitude and Hypoxia Taskforce, PVRI, 2 Institute of Genomics and Integrative Biology, Delhi, India Address for correspondence: Dr. Qadar Pasha, Institute of Genomics and Integrative Biology, Delhi, India. E-mail: qpasha@igib.res.in DOI: 10.4103/0974-6013.58637
Taskforce team: Almaz Aldashev, Inder Anand, Serge Adnot, Alexandra Heath, Friedrich Grimminger, Robert Naeije, John Newman, Louise Ostergaard, I Preston, Kurt Stenmark, Patricia Thistlethwaite, Ishizaki, Takeshi, Jun Wang, E. Kenneth Weir, Norbert Weissmann, Martin Wilkins, Jason Yuan, Max Gassmann, Qadar Pasha, Rich Stuart, Butrous Ghazwan. There has been a wide range of activities under this taskforce during the last few months. It may be categorized under the following heads: 1. Interaction among the taskforce members 2. Scientific efforts 3. Organization of a symposium at Leh, India 4. Invited reviews
SCIENTIFIC CONTRIBUTIONS • The taskforce members had a meaningful dialogue with each other during this calendar year. The emphasis has been on collaborations between and among the taskforce members and the funding possibilities to sustain the research activities. Each member was supportive and provided her/his valuable suggestions including through teleconferencing, small group meetings over dinner within conferences and collaborations even without waiting for financial support etc. Max Gassmann and myself (Qadar Pasha) have been actively engaged in designing joint research activities with a consensus to use each one’s expertise, however, the actual research has yet to be initiated by overcoming the technicalities. Max will add supportive evidence through his established animal model to our genetic and biological studies. We intend to focus on two genes. John has been a continuous source of inspiration and a possibility of collaborative research is very much on the cards. Jean-Paul and myself discussed possibilities of collaborations during the 1st APSMM in Delhi. Inder Anand had carried out pioneering work on the Yak, a bovine from the Himalayas and we did some genetic studies. We may work on ‘Hypoxia Ventilatory Response in Yak, Bluntness of Vasoconstrictor ResponseRole of Growth factors’ by adding these markers (growth factors) to our ongoing studies. Alexandra has shown keen interest in interacting and working with the Himalayan pediatricians. Kurt, Ken, Jason and Patricia have offered their expertise and so is the case with all the other members. • Two project proposals were drafted for external funding: PVRI REVIEW
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• First, Max Gassmann and myself (Qadar Pasha) submitted a proposal on high altitude pulmonary edema (HAPE) under the Indo-Swiss Joint Collaboration. Both of us had submitted a proposal to our respective national scientific bodies associated with the collaborations, namely ‘Department of Science and Technology’. We may have to resubmit a modified proposal. • The second effort involved PVRI members Ghazwan Butrous, JP Richalet, A Aldashev, A Heath, Qadar Pasha and Dr. Fabiola Velarde in drafting a joint project proposal that had three sub-projects on altitude diseases, namely a) chronic mountain sickness (CMS), b) high altitude pulmonary hypertension (HAPH), and c) high altitude pulmonary edema’ (HAPE). As a consequence an attempt was made to avail funds from various bodies that also included a philanthropic body. We may have to renew and energize our efforts for funds. • Among the various individual efforts and contributions, Ostergaard and Gassmann have contributed two reports on his ongoing research activities. The first report pertains to the effectiveness of single or combination therapy of sildenafil and erythropoietin on pulmonary hypertension in in vitro and in vivo experiments [Box 1]. The second report focuses on dexamethasone in a hypoxia/HAPE simulated mouse model [Box 2]. The two reports are provided separately but in continuation to this report as Section A and B. John Newman has contributed significantly on Brisket disease in cows and his work can be read in one of the coming issues of Circulation.
CONFERENCE/SYMPOSIUM ORGANIZATION In mid-2009, a proposal was floated to organize a brainstorming symposium at SNM Hospital, Leh, Ladakh, India. It was a successful and a highly satisfactory attempt. The local participation was in strength although due to short notice the PVRI members could not attend. Nevertheless there was international participation. However, our persistence in holding a meeting of PVRI members paid dividends and PVRI leadership consented to holding another meeting in Leh in 2010. A report on the symposium of 2009 is summarized separately (Appendix below).
ACHIEVEMENTS • The journal Chest invited reviews for its Supplement of June 2010. Among others, Qadar Pasha and John Newman submitted one review entitled ‘High altitude diseases’. Jan - Mar 2010 • Volume 2 • Issue 1
PVRI 2009 Annual Reports
• The other highlight of the year has been the successful organization of a brainstorming symposium titled “Recent trends and future perspectives in high-altitude research’ in Leh in September 2009. • Each member of High Altitude Task Force (HATF) has published several high-impact papers during the current year as part of their ongoing research activities.
Lowland Nepalis 24%
Lowland Indians 70%
FUTURE ACTIVITIES
International Tourists 6%
• Efforts will be made for collaborative research activities and to avail funds from Government and private bodies to sustain such activities. • The scientific contribution of individual PVRI faculty shall also be encouraged. • A Conference will be organized in Leh, Ladakh, India in the last week of September 2010. Most of the HATF members are expected to participate. The major focus will be status of joint efforts, furthering the cause by devising newer proposals and sharing the experience with local highaltitude experts. • This taskforce wishes that the support of all the PVRI family members continues in future as well. Like with other members, we interacted so much with Ghazwan, thanks.
THE LEH SYMPOSIUM - A REPORT The Leh 2009 symposium “Recent trends and future perspectives in high-altitude research”: An overview This supplement focuses on the proceedings of a recently concluded symposium that highlighted the acute hypoxiaassociated problems of Asian high-altitude region. The Leh Symposium entitled ‘Recent Trends and Future Perspectives In High-Altitude Research’ was organized jointly by the Institute of Genomics and Integrative Biology, Delhi and SNM Hospital, Leh, Ladakh, Jammu and Kashmir, India with patronage of PVRI. The response of the local faculty of all the hospitals was overwhelming and heartening. During the two day Symposium strategies were designed to bridge the gap between the clinical practitioners and researchers and feasibilities were looked for prospective studies aimed at a better understanding of various high-altitude (HA) associated maladies, with focus on pulmonary hypertension.[1,2] The venue was very appropriate as every year a large number of sojourners from all parts of the world visit Leh for various reasons e.g. adventure, duty-bound and labor. Thus, the SNM Hospital caters to an exceptionally high percentage of patients suffering from various HA diseases [Figure 1] and is among the few centers of the highland world that directly deal with such patients. Several experts read papers on various common diseases of HA; a few of them are discussed here. Dr. Ghulam Mohammad, senior physician specialist, SNM Hospital, highlighted the role of pulmonary artery systolic pressure (PASP) in HAPE and High-altitude cerebral edema (HACE). The significance of elevated pulmonary artery pressure (PAP) and the prophylactic administration of drugs effective in lowering PAP was explained in relation to HAPE.[3] The augmentation of PASP corresponds to a dramatic fall in arterial oxygen saturation (SaO2). Almost one-third of HAPE patients show symptoms of pulmonary Jan - Mar 2010 • Volume 2 • Issue 1
Figure 1: Percentage distribution of the number of HAPE patients admitted at SNM Hospital, Leh
edema with fall of SaO2, doubtful hilar congestion but apical veins being prominent and high PASP. Grading HAPE as per chest radiography reveals that older the age higher the PASP and the latter further intensifies in patients with pulmonary thromboembolism. It was emphasized to grade PASP severity with that of severity of HAPE into three grades. The decrease of PASP at the rate of 10 mmHg in uncomplicated and , 5 mmHg in complicated HAPE cases on subsequent follow-up gave a good parameter for prognostication. He cautioned that although the PASP and severity of edema relate proportionately, the rise of PASP at HA does not necessarily mean that the patient is suffering from HAPE.[4] Further, a severe rise of PASP in HAPE gives rise to chest pain mimicking angina that subsides once the PASP returns to normal. Moreover, radiography, unless taken in consideration with other investigations, can misdiagnose a case of HAPE. Such observations offer a rationale for further studies on the role of PASP in the pathophysiology and even for grading the severity in HAPE. While in case of HACE, PASP was normal, this was in agreement with earlier reports. Exceptionally, a case of HACE does show a fall of SaO2 by more than 50%, yet does not show rise of PASP, which should otherwise happen once SaO2 falls to less than 60%. Based on this observation, two groups were categorized with respect to pulmonary capillary response to hypoxia, the first group showing an acute rise of PASP (28%) while the other group with normal PASP (72%). Dr. Qadar Pasha and his team highlighted the significance of polymorphisms in various genes associated with pertinent pathways in HA physiology. In addition to the genetic setup, data was also presented to emphasize the role of biomarkers, the clinical characteristics and the various correlations for an association with HA disorders, primarily aiming at its application in the predisposition. The genes covered were endothelial nitric oxide synthase (NOS3), b2-Adrenergic Receptor (ADRB2), Angiotensin I-converting enzyme (ACE), Bone morphogenetic protein receptor Type II (BMPR2), activin receptor-like kinase 1 (ALK1), 5-hydroxy-tryptamine transporter (5-HTT) in humans and hypoxia-inducible Factor 1 (HIF-1a) in the yak, a Himalayan animal. The NOS3 and ADRB2 variants and circulating nitrogen oxide (NO) levels were discussed at length. The variants of G894T (Glu298Asp), 4b/4a (a 27-base-pair variable number of tandem
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Figure 2: Influence of genotypes on circulating nitric oxide level. (a) NOS3G984T Genotypes vs NO level, (b) 4B/4A Genotypes versus NO level in the three study groups
repeat in intron 4) polymorphisms of NOS3 contributed to varied NO levels in HAPE [Figure 2].[5] Over-represented Asp and 4a alleles correlated with reduced NO levels, thereby associating with endothelial dysfunction and thus contributing to HAPE (P , 0.01); whereas, Glu and 4b alleles in natives associated with HA adaptation (P , 0.01).[6] However, conflicts do exist.[7,8] The diagnostic and therapeutic significance of NO in HA diseases has since been recognized. It would be of consequence to investigate the NOS3 variants in Andes and other HA populations. The role of ADRB2 in HA acclimatization is correlated to improved oxygen (O2) delivery.[9] The prophylactic administration of salmeterol, a b2-adrenergic agonist, decreases the incidence of HAPE in susceptible individuals.[10] We systematically explored the possible role of SNPs of this gene. The haplotypes of 46A/G and 79C/G single nucleotide polymorphism (SNP) associated with HAPE. Moreover, the multidimensional reduction (MDR) model that depicts disease association through genotypegenotype and genotype-phenotype interaction revealed the 46A/G, 79C/G and 523C/A SNPs as the best disease-predicting combination. These variants have also been investigated in other HA population but without much success. Presentation of the ACE I/D polymorphism among 13 SNPs, was a classical example of the Renin-angiotensin system (RAS). A significant linkage disequilibrium (LD) was observed between SNPs among the native HA population. The LD values were highest among the natives when compared to other lowland Indian population. ACE I/D has been associated with endurance, HA adaptation, O2 saturation and HAPE. Further, the ACE level was reported lower in acclimatized subjects.[11,12] Among other important genes, several studies implicated BMPR2, ALK1 and PVRI REVIEW
5HTT, through receptor and/or transporter signaling in the development of pulmonary hypertension (PH). PH being one of the leading factors in the pathogenesis of HAPE, these genes were screened for association with HAPE. Our preliminary analysis revealed a significant association of a few polymorphisms of BMPR2, ALK1 and 5HTT with HAPE (P , 0.01) like in pulmonary hypertension.[2,13] The yak genome was presented with some interesting findings on HIF1-a and NOS3. Dr. Tsering Norboo, physician specialist shared his five decades of clinical and basic research experience and his findings. He underlined various diseases of the region, however, his significant disclosure, for the first time, was of CMS in the nomads of Ladakh. [14] In his investigation of the population (n 5 91) living at an altitude of 4550 m (Korzok, Leh), the CMS score[15] was 16% mild, 7% moderate and 2% severe. Moreover, blurring of vision and occasional diplopia, symptoms not included in the international consensus scoring were unusual complaints reported by 10% of subjects. With regard to HA adaptation, the natives have physiological adaptation in the form of enlargement of carotid bodies, which augment tachypnea with hypoxia,[16] rise of overall body blood volume and polycythemia and a high FEV1%.[17] Among other rare regional problems, non-occupational silicosis in the Indus belt on the southern side is another important observation; this disease results in a short lifespan and hence its prevalence is a major concern. According to Dr. Tashi Motup, Senior Surgeon, SNM Hospital, Leh the incidence of cancers in natives and specific cases in low-landers are becoming more visible. He noticed that adenocarcinoma of the distal stomach is alarmingly on the rise, the clinical presentation is late and outcome of surgical treatment is dismal. Polyunsaturated fatty acid consumption, lack of
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Figure 3: One of the presenter’s on pulmonary hypertension
Figure 4: Panoramic view of Pangong lake
Figure 5: Khardugla pass, 18300 feet, the highest motorable road in the world:
Figure 6: Shanti stupa: A tourist’s attraction
vasoactive agents seem to be the basis of hypoxic cellular damage, thereby the acute abdominal ailments. Further, surgical management at HA is required frequently for splenic infarct, mesenteric artery thrombosis, appendicular perforation in lowlanders.
Figure 7: The participants of the meeting
protective elements in diet with poor food-stocking methods and Helicobacter pylori infection seem to be the leading causes. Lung cancer in non-smoker females residing in the silicosis belt is significantly high. Skin cancers, surprisingly, are not common in spite of the thin ozone layer and excessive ultraviolet radiation. The low-land middle-aged male laborers at HA showed high incidence of duodenal ulcer perforation as compared to natives, which is attributed to long hours of fasting and irregular meals. Stress responses, microvascular thromboembolic phenomena, Jan - Mar 2010 • Volume 2 • Issue 1
Since the interaction of anesthesia and altitude has not been systematically studied in controlled experiments, very few reports are available on the use of anesthesia at altitude. As reviewed by Firth et al., the exact causes of the many early chloroform deaths have not been clearly established in general.[18] This important issue was adequately covered with a presentation on anesthesia at HA by Prof. G D Puri, PGIMER, Chandigarh, who observed that higher dosages of intravenous anesthetic Propofol was required for anesthetizing HA natives at 11,000 feet. Interestingly the recovery period was faster from these dosages, suggesting that general anesthesia may be performed satisfactorily and safely at any HA under the supervision of trained and experienced anesthetists. Whether this is due to altered pharmacokinetics (disposition of the drug by body) of the drugs at this altitude or due to altered pharmacodynamics (altered response of the body to the drug) in the HA natives needs to be evaluated, on which his group is working. Further, Dr. Morup, SNM Hospital, Leh cautioned about
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the recovery period of anesthesia because a dip in respiration takes place at midnight; as a result higher level of O2 needs to be supplied during this period. The dip he believes is because of respiratory depression and altered sleep patterns after the anesthesia and surgery which complicate the matter due to already low inspired oxygen tension at HA.
THE PENGONG LAKE DECISION In the panoramic scenery of Pangong Lake [Figure 4], away from Leh and the routines, a core group discussed future collaborations and extending the activities at the global level. In this context, the role of PVRI was discussed and it was realized that with the cooperation of PVRI most of the scientific groups at the international level may be brought together for global science. The present team of collaborators, namely Dr. Qadar Pasha, Dr. Ghulam Mohammad and colleagues reiterated full support in such an eventuality. PVRI’s role is crucial in raising the funds for such a project(s). Thus, organizing this symposium at Leh provided some interesting insights and some queries giving an enormous boost to conduct further studies on HA-related diseases. A few activities of the meeting are presented in Figures 3-7.
REFERENCES 1. Maignan M, Rivera-Ch M, Privat C, León-Velarde F, Richalet JP, Pham I. Pulmonary pressure and cardiac function in chronic mountain sickness patients. Chest 2009;135:499-504. 2. Morrell NW, Adnot S, Archer SL, Dupuis J, Jones PL, MacLean MR, et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol 2009. 3. Bartsch P, Maggiorini M, Ritter M, Noti C, Vock P, Oelz O. Prevention of high-altitude pulmonary edema by nifedipine. N Engl J Med 1991;325:1284-9. 4. Sartori C, Allemann Y, Trueb L, Lepori M, Maggiorini M, Nicod P, et al. Exaggerated pulmonary hypertension is not sufficient to trigger high-altitude pulmonary oedema in humans. Schweiz Med Wochenschr 2000;130:385-9. 5. Ahsan A, Mohd G, Norboo T, Baig MA, Pasha MA. Heterozygotes of NOS3 polymorphisms contribute to reduced nitrogen oxides in high-altitude pulmonary edema. Chest 2006;130:1511-9.
6. Ahsan A, Charu R, Pasha MA, Norboo T, Charu R, Afrin F, et al. eNOS allelic variants at the same locus associate with HAPE and adaptation. Thorax 2004;59:1000-2. 7. Droma Y, Hanaoka M, Ota M, Katsuyama Y, Koizumi T, Fujimoto K, et al. Positive association of the endothelial nitric oxide synthase gene polymorphisms with high-altitude pulmonary edema. Circulation 2002;106:826-30. 8. Smith EM, Baillie JK, Thompson AA. Endothelial nitric oxide synthase polymorphisms do not influence pulmonary artery systolic pressure at altitude. High Alt Med Biol 2006;7:221-7. 9. Mazzeo RS, Reeves JT. Adrenergic contribution during acclimatization to high altitude: Perspectives from Pikes Peak. Exerc Sport Sci Rev 2003;31:13-8. 10. Sartori C, Allemann Y, Duplain H, Lepori M, Egli M, Lipp E, et al. Salmeterol for the prevention of high-altitude pulmonary edema. N Engl J Med 2002;346:1631-6. 11. Charu R, Stobdan T, Ram RB, Khan AP, Qadar Pasha MA, Norboo T, et al. Susceptibility to high altitude pulmonary oedema: Role of ACE and ET-1 polymorphisms. Thorax 2006;61:1011-2. 12. Hotta J, Hanaoka M, Droma Y, Katsuyama Y, Ota M, Kobayashi T. Polymorphisms of renin-angiotensin system genes with high-altitude pulmonary edema in Japanese subjects. Chest 2004;126:825‑30. 13. Newman JH, Wheeler L, Lane KB, Loyd E, Gaddipati R, Phillips JA 3rd, et al. Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred. N Engl J Med 2001;345:319-24. 14. Monge CC, Whittembury J. Chronic mountain sickness. Johns Hopkins Med J 1976;139:S87-9. 15. Leon-Velarde F, McCullough RG, McCullough RE, Reeves JT; CMS Consensus Working Group. Proposal for scoring severity in Chronic Mountain Sickness (CMS): Background and conclusions of the CMS Working Group. Adv Exp Med Biol 2003;543:339-54. 16. Prabhakar NR, Peng YJ, Kumar GK, Nanduri J, Di Giulio C, Lahiri S. Long-term regulation of carotid body function: Acclimatization and adaptation—invited article. Adv Exp Med Biol 2009;648:307‑17. 17. Wood S, Norboo T, Lilly M, Yoneda K, Eldridge M. Cardiopulmonary function in high altitude residents of Ladakh. High Alt Med Biol 2003;4:445-54. 18. Firth PG, Pattinson KT. Anaesthesia and high altitude: A history. Anaesthesia 2008;63:662-70. Source of Support: Nil, Conflict of Interest: None declared.
Box 1: Effects of sildenafil, erythropoietin in treatment of pulmonary hypertension The study aimed to characterize the effects of Sildenafil and Erythropoietin (Epo), alone or as a combined therapy, to treat pulmonary hypertension.
Our approach is to use both in vitro methods (cell culture) and in vivo (an animal model).
Figure 8: Induction of angiogenic response of endothelial cells by sildenafil and eryhthropoietin
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PVRI 2009 Annual Reports First we investigated the effects of the drugs on proliferation and survival of rat pulmonary artery endothelial cells, and second on migration and the angiogenic response. We observed that sildenafil and Epo do not have any significant effects on proliferation. However, there is a clear dose-dependent reduction on the hypoxia-induced cell death of both drugs, both alone and in combination. The mechanisms behind this effect are now being investigated in more detail. Moreover, using transwell and 3D collagen assays, we have obtained preliminary evidence that both drugs can also induce an angiogenic response
of the endothelial cells [Figure 8]. We have now obtained the permission to perform animal experimentation. To this end, we will use the hypoxic mouse model to mimic hypoxia-induced pulmonary hypertension. As depicted above, we plan to investigate the effects of both drugs alone and in combination and furthermore, we will also use our transgenic Epo-overexpressing mouse model (tg6). The first panel shows the uniform confluent layer of endothelial cells on top of the collagen gel (control). Whereas the second panel illustrate the beginning of tube-formation of Epo-treated endothelial cells, that are migrating into the gel. The cell nuclei are stained with DAPI.
Box 2: Section B: HAPE and dexamethasone study High altitude induced pulmonary edema (HAPE) is characterized by the accumulation of protein-rich fluid and red blood cells in the interstitium. This can occur during rapid ascent to high altitude. This project aims to, first, validate the development of HAPE in the hypoxic rat and, second, investigate if treatment with dexamethasone, either prior to hypoxic exposure or during, would improve the clinical outcome. Animals were exposed to increasing times of hypoxia; 0, 8, 16, 24 and 48 hours. To verify that the animals were indeed hypoxic we used immunoblotting to confirm the stabilization of HIF-1alpha in liver homogenates. This was proven for all hypoxic time points. We performed histological investigations of the lungs, but were not able to find conclusive evidence of edema. This is also not expected for this type of mild, patchy edema. The lung wet weight to body weight ratio on the other hand revealed a clear and statistically significant increase when comparing hypoxic to normoxic values. There was a further increase from eight to 16 hours, but no additional increase to 24 or 48 hours. Based on these findings the
Figure 9: The arterial partial pressure of O2 and CO2 (in mmHg) and the oxygen saturation (in %)
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16 hour time point was chosen for further experimentation. Blood was drawn for blood gas analysis, which revealed several parameters that confirmed the hypoxic state of the animals, such as low pO2, pCO2 and sO2 [Figure 9] as well as very high lactate and base levels and in addition bicarbonate deficiency [Figure 10]. This, together with a slightly lowering of the pH, indicates metabolic acidosis. Furthermore, we observed a minor increase in hematocrit and hemoglobin, but most likely this is due to a disturbed fluid balance. To further characterize the possible edema formation we collected bronchoalveolar fluid (BALF) and measured total protein concentration as well as albumin. We found that in BALF from hypoxic animals (10% O2, 16 hr) the amount of total protein increased approximately 60%, and for albumin the increase was approximately 80%. To complete the characterization of the hypoxic rat as a model for HAPE, we plan to also measure hemodynamic parameters such as right ventricular systolic pressure and mean pulmonary arterial pressure. Moreover, the cells found in the BALF will be investigated to clarify the influence of inflammation.
Figure 10: Lactate, base and bicarbonate levels (in mM) measured in arterial blood
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Pulmonary Hypertension Associated with HIV‑Taskforce Nicola Petrosillo, Sonia C. Flores, Sharilyn Almodovar, Norbert Voelkel Pulmonary Vascular Diseases associated with HIV taskforce Address for correspondence: Prof. Sonia Flores, Division of Pulmonary Sciences and Critical Care Medicine University of Colorado Denver, USA. E-mail: sonia.flores@ucdenver.edu DOI: 10.4103/0974-6013.58635
After the introduction of highly active antiretroviral therapy (HAART), HIV has become a chronic condition, with clinical manifestations related both to chronicity and antiretroviral side effects. Cardiovascular involvement in HIV infection, thus, represents a new challenge in the management of HIV infected patients. Using the mesh terms “cardiovascular” and “HIV,” we found in PubMed that in the year 2000 there were 132 articles published, while 2008 saw 285 articles published. Articles dealing with pulmonary hypertension and HIV were nine and 27 in the years 2000 and 2008 respectively.
people with well-controlled HIV infection and no symptoms of pulmonary or cardiovascular disease. These patients had undergone transthoracic echocardiography, PAH was defined as pulmonary artery systolic pressures at or above 35 mmHg. In a clinic at the University of California, San Francisco, the prevalence of a cohort longitudinally followed by Dr. Priscilla Hsue is currently as high as eight per cent. These studies suggest that the prevalence may be higher than originally described and that there may be regional differences in the clinical presentation.
Therefore, in recent years, much more attention has been paid to the pathogenic role of HIV and the clinical manifestations of HIVrelated pulmonary arterial hypertension (HIV-PAH) that currently represents one of the most severe events during the course of chronic HIV infection.
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.
To date, about 500 cases of PAH related to HIV infection have been reported in the literature. In 1991; the prevalence of HIVPAH was estimated to be 0.5%, and this figure has not changed in the recent years [62, 67, 69, 72], regardless of the introduction of HAART. Nevertheless, a 2008 study of a Naval Hospital cohort found a 5.5% prevalence of pulmonary arterial hypertension in 91
Patients with HIV-PAH are younger than those with other forms of PAH, and, unlike idiopathic PAH, which is more common in women than in men (ratio of men to women 1:1.7), men are more frequently affected by HIV-PAH, possibly reflecting
Figure 1: Phylogenetic tree of San Francisco nef HIV sequences colored by individual and PH status. Closed symbols represent either borderline of frank PAH as determined by right heart catheterization. Note essentially perfect clustering by individual and by PH status
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the high prevalence of men in the HIV-infected population. 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. Aims of the HIV-pulmonary arterial hypertension taskforce remain:
• To provide educational tools for a better insight into issues of PAH and HIV infection; • To establish a network of centers that care for HIV positive patients with PAH that will provide sound epidemiological data • To carry out research studies on the pathobiology and better therapeutic approaches for the clinical management of HIVPAH patients In the year 2009 the taskforce undertook the following initiatives:
Providing educational and research articles on HIVpulmonary arterial hypertension
• An article, “Treatment and outcome of pulmonary arterial hypertension in HIV-infected patients: A review of the Literature” has been written by the Italian members of the taskforce and has been accepted for publication by Current HIV Research. • An article titled “Pulmonary hypertension associated with HIV Infection” has been written jointly by the Denver, US and Rome, Italy groups and will be published in Chest. • The journal Clinical Microbiology and Infection, official journal of the European Society of Clinical Microbiology and Infectious Diseases, accepted to publish, in a regular issue, an editorial on infectious diseases and pulmonary hypertension and three full articles (reviews) on related issues. All the articles will be written by PVRI members.
Research studies Figure 2: H and E stained lung sections from an HIV-infected Italian patient diagnosed with PAH
As part of our efforts to understand the pathogenesis of HIV-related PAH, we seek to define the contribution of the adaptor protein nef to the etiology of the disease. We have demonstrated that
Figure 3: Immunofluorescence images from the lungs of the same patient shown in Figure 2. Note patchy nef-positive cells that do not colocalize with Factor VIII
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allelic variations in nef are associated with HRPAH in a French patient cohort. We have now processed and analyzed plasma samples from HIV-infected normotensive and hypertensive patients from a University of California San Francisco cohort. Nef sequences were amplified, cloned and molecular clone sequences analyzed. A total of 15 patients, 10-20 clones/patient were analyzed. The patient mean pulmonary artery pressures measured by right heart catheterization ranged from ,25 mmHg for normotensive, 25-29 mmHg for borderline and .30 mmHg for bona fide PAH. Sequence analyses revealed similar patterns of functional domain mutations as found in the French cohort only in the frank hypertensive group. Phylogenetic analyses revealed that the sequences per patient cluster individually, suggesting no
cross-contamination [Figure 1]. We also analyzed archived lung samples from an HIV-infected Italian patient with pulmonary hypertension diagnosed by echocardiography. Figure 2 shows some vascular remodeling and medial hypertrophy, but we could not find evidence of plexiform lesions. We find nef in uninfected cells as shown by immunofluorescence but not in the pulmonary artery intimal layers [Figure 3]. We will continue the longitudinal studies of nef evolution in the San Francisco cohort of patients and examine sequences from a larger cohort of HIV-infected patients enrolled in the Longitudinal Studies of Pulmonary Complications of HIV infection studies.
PVD in Schistosomiasis Task Force Ghazwan Butrous, Nicholas Morrell
Professor of Cardiopulmonary Sciences, University of Kent, Canterbury, UK Address for correspondence: Prof. G. Butrous, Professor of Cardiopulmonary Sciences, University of Kent, Canterbury, UK. E-mail: g.butrous@kent.ac.uk DOI: 10.4103/0974-6013.58634
We continue our plan to enhance awareness of the role of infectious diseases and in particular, schistosomiasis. In 2009 the taskforce had the following activities: 1. Lecture on Pulmonary Hypertension secondary to schistosomiasis by Prof Ghazwan Butrous in during the 2nd PVRI EMR meeting in Casablanca February 18-20, 2009. 2. Dr. Alexi Crosby presented an abstract on Pulmonary Vascular Remodeling in a Mouse Model of schistosomiasis, during the ATS 2009 in San Diego (17-20 May 2009) (see Appendix-1 below). Dr. Alexi Crosby received the highest graded abstract, as scored by the Pulmonary Circulation assembly of the ATS 2009 [Figures 1,2]. 3. Dr. Brian Graham presented an abstract on Physiologic and Pathologic Analysis of a Murine Model of schistosomiasis Pulmonary Vascular Remodeling during the ATS 2009 in San
Figure 1: Professor Nicholas Morrell and Research Fellow, Dr. Alexi Crosby recieved the highest graded abstract for her abstract on schistosomiasis as scored by the Pulmonary Circulation assembly of the ATS.
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Diego (17-20 May 2009) (see Appendix-1 below) [Figure 3]. 4. Prof Ghazwan Butrous presented the key note talk on pulmonary hypertension associated with schistosomiasis: A world wide challenge on Tuesday, September 15, 2009, during the 64th Brazilian Congress of Cardiology in Salvador Bahia, Brazil. 5. A Webinar on pulmonary hypertension associated with schistosomiasis on 26 August 2009. The participants were Prof. Antonio Augusto Lopes-Brazil, Prof. Ghazwan Butrous Professor of Cardiopulmonary Sciences UK, and Dr. Angela Pontes Bandeira - from Recife-Pe-Brazil [Figure 4]. 6. A manuscript on “The global perspective of schistosomiasisassociated PH by Brian Graham, Angela Machado, Nicholas Morrell, Ghazwan Butrous, and Rubin Tuder has been accepted for publication in Chest. 7. Planning for the global epidemiological studies as described in our 2008 report published in PVRI Review 2009;1:53-8 (http://www.pvrireview.org/text.asp?2009/1/1/53/44877);
Figure 2: Dr. A Crosby and Prof N Morrell at their poster during the ATS 2009
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Figure 4: Webinar on pulmonary hypertension associated with schistosomiasis on 26 August 2009
Figure 3: Dr. G.B. Graham with his Poster at the ATS 2009
Figure 5: PVRI Immunohistology and Molecular Biology Lab at University of Kent, Medway campus Figure 6: Dr. Ewa Kolosionek a Postdoc research fellow at the University of Kent
Figure 7: B. glabrata snails infected with S. mansoni in Denver laboratory
Figure 8: Vascular remodeling in response to schistosomiasis infection. Compared to an uninfected mouse (left), a mouse infected with schistosomiasis develops significant vascular medial and intimal hypertrophy (right)
Institute of Allergy and Infectious Disease - National Institutes of Health and John Hopkins Medical center. Short descriptions are given below: Figure 9: Human pulmonary vascular pathology form an autopsy of a patient who died of schistosomiasis-associated ph. Histologic examination reveals medial hypertrophy (left) and centric intimal remodeling (right; marked with an arrow)
is ongoing - to establish the appropriate methodology and grants application. This year’s main activities of taskforce include collaborative research activities between three research laboratories of Cambridge University, Kent University in UK and University of Colorado Denver in USA with close collaboration National Jan - Mar 2010 • Volume 2 • Issue 1
CAMBRIDGE UNIVERSITY LABORATORY The laboratory is under the supervision of Professor Nicholas Morrell and Research Fellow, Dr. Alexi Crosby [Figure 1]. The work is in collaboration with Professor David Dunne, Department of Parasitology (a Fellow of the PVRI). Mouse model of chronic schistosomiasis is used to study the pathobiology of pulmonary vascular. Their initial results (accepted for publication in the American journal of Respiratory and Critical Care Medicine) demonstrate that the extent of lung vascular remodeling correlates with the number of eggs deposited in the lung and
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with serum cytokines in infected animals. They reported that infected animals manifest exuberant but heterogeneous vascular remodeling, often accompanied by perivascular inflammation. They also provide evidence that chronic infection leads to the development of angiomatoid lesions reminiscent of plexiform lesions. This was particularly interesting since the animals had no significant pulmonary arterial hypertension at right heart catheterization, implying that inflammation may be responsible for the appearance of these lesions rather than severe PAH. Their latest studies do indicate that animals develop significant PAH at later time points after infection. Further studies are planned to study the pulmonary pathology in response to schistosomal infection in BMPR-II knock out animals, and to determine whether the vascular changes are reversible following eradication of the adult worms. Studies are also ongoing to determine the specific mechanisms underlying the vascular remodeling observed.
PVRI IMMUNOHISTOLOGY AND MOLECULAR BIOLOGY LAB AT UNIVERSITY OF KENT, MEDWAY CAMPUS We have established and developed an Immunohistology and Molecular Biology Lab at University of Kent at Medway [Figure 5]. The lab is a collaborative work between University of Giessen and University of Kent under supervision of Prof Ghazwan Butrous, Prof. Ralph Schermuly and Dr. Soni Savai Pullamsetti. The Postdoc research fellow is Dr. Ewa Kolosionek [Figure 6]. The task of this lab is identify pulmonary vascular changes after schistosoma infection in lungs (study the pulmonary vascular changes secondary to schistosomiasis and to focus on inflammatory response caused by schistosoma infection by identifying inflammatory cells present in the lungs as well as identifying cytokines which play role in this inflammatory response). The animal models are prepared at the Department of Zoology of the Natural History Museum, London, under the supervision of Dr. David Rollinson (a Fellow of the PVRI) with the technical assistance of Ms. Jayne King. David Rollinson’s group has experience in the maintenance of the schistosoma life cycle as well as mice infection since their main interests concern the taxonomy, molecular diversity, distribution and ecology of parasitic
APPENDIX 1: ABSTRACTS PRESENTED AT THE ATS 2009 FROM THE TASKFORCE A Crosby, FMJ, M Southwood, D Dunne, NW Morrell. Pulmonary Vascular Remodeling in a Mouse Model of Schistosomiasis. Am J Respir Crit Care Med 2009;179: A1799 Introduction: Schistosomiasis is the most common world-wide cause of pulmonary hypertension. There is currently no established animal model to study the pathobiology of this important condition. We sought to develop and characterize a mouse model that recapitulates the pulmonary vascular pathology seen in patients with schistosomiasis. Methods: We infected mice percutaneously with a high dose or low dose of Schistosoma mansoni and studied the development of lung and liver pathology in the sub-acute (high dose) and chronic
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organizms, especially schistosome and their molluscan hosts. Ms. Jane King undertook special training visit in the University of Giessen laboratory (October 2009) sponsored by the taskforce.
UNIVERSITY OF COLORADO DENVER, USA The research activities in this lab are conducted under the supervision of Professor Rubin Tuder and Research Fellow Dr. Brain Graham; with collaborators from Dr. Thomas Wynn’s lab in immunopathogenesis at the National Institutes of Health and Dr. Hunter Champion’s lab in cardiology at Johns Hopkins (now at the University of Pittsburgh) (all Fellows of the PVRI). They have developed a mouse model of schistosomiasisassociated PH using percutaneous infection with S. mansoni cercariae followed by intravenous augmentation with S. mansoni ova. The lab has a colony of B. glabrata snails infected with S. mansoni [Figure 7], originally derived from a Puerto Rican strain, and supplied by the Biomedical Research Institute. The infected mice develop elevated pulmonary artery pressures and pulmonary vascular remodeling [Figure 8], similar to the pathology seen in human disease. They investigated the role of IL-13 signaling by applying our model to transgenic mice lacking IL-13 receptors. They intend to further explore the role of RELM-a, a downstream signaling molecule in the IL-13 pathway, in the pathogenesis of schistosomiasisassociated PH and also plan to investigate vascular remodeling using CT angiography of the mouse lungs. The lab has received several specimens of lung tissue from patients who died of schistosomiasis-associated PH from Dr. Angela Bandera at the Universidade de Pernambuco in Recife, Brazil (a Fellow of the PVRI), and Dr. Luciano Espinheira at the Hospital das Clinicas in Salvador, Brazil. Examples of pulmonary vascular pathology from one of the specimens are shown in Figure 9. The Denver Lab plans to perform further analysis of the human tissue including immunostaining for markers of schistosomiasisinduced inflammation and inflammatory sign.
(low dose) settings. We determined the degree of right ventricular (RV) hypertrophy. Liver and lung egg counts were measured at specified time points. Pulmonary vascular remodeling was assessed by morphometry, following immunohistochemistry with antibodies for smooth muscle actin alpha and von Willebrand factor. A cytokine array was performed and the migration of pulmonary arterial smooth muscle cells (PASMC) to cytokines was assessed. Results: In the sub-acute, high dose setting mice had few eggs in the lungs and no evidence of pulmonary vascular remodeling. Chronically infected animals had a greater lung egg burden with marked pulmonary vascular remodeling and perivascular inflammation. In addition, we observed the presence of plexiform-like lesions in these mice. Lung egg burden positively correlated with liver egg burden and the degree of RV hypertrophy in the chronic group. Plasma cytokines increased with time in the chronic group and correlated with the degree of pulmonary
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PVRI 2009 Annual Reports vascular remodeling. Mouse PASMC showed an increase in migration to IL-13. Conclusions: This study provides evidence for extensive pulmonary vascular remodelling in a mouse model of pulmonary schistosomiasis, including the formation of plexiform-like lesions. The degree of remodeling and RV hypertrophy was related to the lung egg burden. This experimental model will be of use to study the pathobiology and treatment of pulmonary hypertension associated with schistosomiasis. G.B. Graham, L. Zhang, M.M. Mentink-Kane, H. El- Haddad, H. Champion, T.A. Wynn, G. Butrous, R.M. Tuder. Physiologic and Pathologic Analysis of a Murine Model of Schistosomiasis Pulmonary Vascular Remodeling. Am J Respir Crit Care Med 2009;179: A1796 Introduction: Schistosomiasis infects approximately 200 million people worldwide, and five to 20% of those chronically infected develop various degrees of pulmonary vascular disease. Pulmonary pathology is characterized by inflammatory cell infiltration, increased media thickness, and plexiform lesions in association with occasional schistosoma ova. The pathogenesis of these lesions is unclear.
Methods: C57BL/6 wild-type, IL-13Ra1 knockout, and IL- 13Ra2 knockout mice were injected with intravenous S mansoni ova after intraperitoneal sensitization, or percutaneously exposed to cercariae (wild-type only). Pulmonary artery catheterization was performed and the lung tissue analyzed. Results: Compared to wild-type infected mice, pulmonary perivascular granulomas were smaller in IL13Ra 1knockout and larger in IL13Ra2 knockout mice. Media thickness by smooth muscle actin staining was increased in vessels in infected wild-type and IL13Ra2 knockout, but not IL13Ra1 knockout mice. PCNA staining revealed significant cellular proliferation in granulomas in all mice. Some smooth muscle cells double stained positive for PCNA. Other PCNA-positive cells expressed CD45 but not thrombomodulin or MAC3. There was little evidence of apoptosis by TUNEL staining. Significant phosphorylated SMAD 2/3 staining was present in the granulomas in all mice. Conclusions: Our findings indicate that schistosoma eggs cause a marked pulmonary vascular remodeling, with partial destruction of pulmonary vessels. Inflammatory cell responses are related to the remodeling process and both processes may be related to IL-13 signaling.
Pulmonary Hypertension Associated with Congenital Heart Disease Task Force Antonio A. Lopes, Marlene Rabinovitch Co-chairs, PAH-CHD Task Force Address for correspondence: Prof. Antonio Augusto 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 DOI: 10.4103/0974-6013.58631
After the initial recognition that advanced pulmonary vasculopathy associated with congenital cardiac shunts should have a place in the first diagnostic category of pulmonary hypertension, namely pulmonary arterial hypertension (PAH), it is now becoming clearer that the so called Eisenmenger syndrome (marked heightening of pulmonary arterial pressure and vascular resistance causing right-to-left shunting, systemic oxygen desaturation and chronic erythrocytosis) is only part of the problem, not the whole scenario. Actually, PAH-CHD corresponds to a wide range of conditions, each requiring specific diagnostic and therapeutic approaches. Young infants/children who have complete normalization of pulmonary hemodynamics after repair of shunts correspond to one side of this range. The Eisenmenger syndrome is to the other. In the middle, there are several conditions that have not been specifically addressed in terms of diagnosis and treatment. Postoperative pulmonary hypertensive crises, persistent pulmonary hypertension in operable cases, the possibility of changing “inoperable” into “operable” and inappropriately elevated pulmonary artery pressure and vascular resistance in subjects without a sub pulmonary ventricle are examples of problems that have not been solved yet. The PAH-CHD task force has been involved with some of these issues in the last three years. From the educational point of Jan - Mar 2010 • Volume 2 • Issue 1
view, the most important steps were the development of general policies to achieve higher standards of medical practice, and the implementation of a case discussion program via internet. The policies have been recently published as Statements on the Management of Pulmonary Hypertension Associated With Congenital Heart Disease (on-line supplement to Cardiology in the Young, May 2009, sponsored by the Pulmonary Vascular Research Institute-PVRI see Apendix 1)). The case presentation and discussion sessions have been prepared on a web basis, involving several guests of the PVRI staff. These sessions are permanently open to everyone who might be interested on pulmonary hypertension in general, and PAH-CHD in particular (www.pahforum.com). (Please see separate report) The PAH-CHD task force has important problems to deal with in the months and years to come. One of the objectives is to address the issue of operability in patients with PAH-CHD, and the possible impact of currently available therapies on pulmonary vascular remodeling on a long-term basis. This involves the definition of predictors of outcome, at clinical, molecular and genetic levels. There has been general agreement that these predictors must be defined not only as a general rule, but also for specific patient populations, e.g. those with particular genetic backgrounds and/or naturally acclimatized to different altitudes around the world. Defining operability and reversibility of
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Balloon occlusion pulmonary wedge angiography and lung biopsy assessment in the child with a congenital cardiac defect Marlene Rabinovitch and Sheila G. Haworth Cardiology in the Young, Volume 19, Issue S1, May 2009, pp 13-15. Use of magnetic resonance imaging and computed tomography Jeffrey A. Feinstein and Michael A. Gatzoulis Cardiology in the Young, Volume 19, Issue S1, May 2009, pp 16-22. Immediate postoperative care Ian Adatia and Maurice Beghetti Cardiology in the Young, Volume 19, Issue S1, May 2009, pp 23-27. Figure: Cardiology in the Young Supplement (Volume 19, Issue S1, May 2009)
pulmonary vascular lesions for these populations is crucial in the era of the so called new drugs. In particular, there is much to be learned in terms of the difference between treating operable patients who are at a risk of persistent pulmonary hypertension following repair of cardiac shunts, and making inoperable patients become operable. This second issue is considerably more difficult to be addressed. Controlled studies and increasing knowledge on vascular biology and specific signaling pathways will be required.
THE CONTENTS Can we start to think about consensus-oriented clinical practices? Antonio Augusto Lopes and Marlene Rabinovitch Cardiology in the Young, Volume 19, Issue S1, May 2009, pp 1-3. Neonates with congenital cardiac defects and pulmonary hypertension Anthony C. Chang and Duncan Macrae Cardiology in the Young, Volume 19, Issue S1, May 2009, pp 4-7. Measurement, interpretation and use of hemodynamic parameters Antonio A. Lopes and Patrick W. O’Leary Cardiology in the Young, Volume 19, Issue S1, May 2009, pp 8-12.
APPENDIX -1 From the introductory article by Antonio Augusto Lopes and Marlene Rabinovitch (Cardiology in the Young, Volume 19, Issue S1, May 2009, pp 1-3. Pulmonary vascular disease is a major complicating factor in patients with congenital cardiac defects and left-to-right shunts. Unoperated patients have a prevalence of severe pulmonary vasculopathy ranging from 3% to nearly 100% depending on the defect. Even successful correction of the anomalies may be followed by residual pulmonary arterial hypertension depending on the magnitude of preoperative hemodynamic abnormalities and the severity of vascular lesions. This is usual in patients operated after nine months of age, and inevitable above the age of two years. PVRI REVIEW
Conventional and targeted medical therapies Robyn J. Barst and Duncan Stewart Cardiology in the Young, Volume 19, Issue S1, May 2009, pp 28-34. Assessment of the pulmonary circulation in patients with functionally univentricular physiology Maria A. Binotto and Andrew N. Redington Cardiology in the Young, Volume 19, Issue S1, May 2009, pp 35-38. Advanced pulmonary vascular disease: The Eisenmenger syndrome R. Krishna Kumar and Julio Sandoval Cardiology in the Young, Volume 19, Issue S1, May 2009, pp 39-44. Lung and heart-lung transplantation Hiroshi Date and Stuart C. Sweet Cardiology in the Young, Volume 19, Issue S1, May 2009, pp 45-48. Pulmonary hypertension associated with congenital diaphragmatic hernia Bernard Thébaud and Dick Tibboel Cardiology in the Young, Volume 19, Issue S1, May 2009, pp 49-53.
The consensus was proposed in January 28-30, 2007, in Valetta, Malta, during the 1st Annual Meeting of the Pulmonary Vascular Research Institute (www.pvri.info). During the first semester of 2007, the board of authors was established, with inclusion of additional physicians and scientists according to the mentioned criteria. The literature searching was started in July. On the 11th of October, 2007, the taskforce had a videoconference for discussion of the ongoing process of consensus preparation. The second discussion was in Marbella, Spain, January 20-22, 2008, during the 2nd Annual Meeting of the Institute. At that time, all the chapter drafts were available for discussion. Each of the chapters was prepared by two authors. As a general rule, the first author prepared the text, which was reviewed by the second one. Subsequently, the text was analyzed by at least two other members of the taskforce, for critical comments and suggestions. Finally, the original authors expressed their opinion about the points
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PVRI 2009 Annual Reports and suggestions that were raised. Whenever necessary, quick withintaskforce surveys were implemented in order to solve problems that depended on expert opinion. The issues addressed in the consensus are of potential interest for all professionals involved in the management of patients with congenital cardiac disease associated with pulmonary hypertension, including: • Pediatric cardiologists involved in invasive and noninvasive diagnostic procedures • Cardiologists who assist adults with congenital cardiac disease • Cardiac and cardiothoracic surgeons • Pathologists who are interested in congenital cardiac disease in
general, and pulmonary hypertension in particular • Preoperative and postoperative intensive care specialists involved in the management of patients with congenital cardiac disease • Anesthesiologists involved in diagnostic and therapeutic procedures • Nurses, physiotherapists and other professionals involved in the management of patients with congenital cardiac disease, particularly neonates, infants and children. The present work is an initiative of the Pulmonary Vascular Research Institute, as an educational activity of the Pulmonary Hypertension Associated with Congenital Heart Disease Taskforce. The project was entirely supported by the Institute, with no direct involvement of any other institutions. Thus, there are no conflicts of interest involved.
Appreciation Note The Pulmonary Vascular Research Institute (PVRI) appreciates the administrative support of the University of Kent (http://www.kent.ac.uk/), The University of Giessen Lung Centre (http://uglc.de/) and The Excellence Cluster Cardio-Pulmonary System (http://eccps.de/).
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Educational
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Progress Report on the Textbook of Pulmonary Vascular Disease Jason XJ Yuan, Stephen L. Archer PVRI Publication Taskforce Address for correspondence: Prof. Jason Yuan, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. E-mail: xiyuan@ucsd.edu DOI: 10.4103/0974-6013.58630
It has been almost two years since the taskforce started to work on the Textbook of Pulmonary Vascular Disease. On behalf of the taskforce members and editors (Yuan JX-J, Garcia JGN, Hales CA, Rich S, Archer SL and West JB), we are pleased to report that Textbook of Pulmonary Vascular Disease will soon be published by Springer. Textbook of Pulmonary Vascular Disease (including 116 chapters) is divided into five parts: Part 1 (Structure, Function and Regulation), consisting nine sections and 29 chapters, is designated for basic knowledge and recent findings related to pulmonary vascular structure, function, and regulation at levels of molecule, cell, tissue, organ and system. 1. The Human Pulmonary Circulation (1 chapter) 2. Structure and Function of the Pulmonary Circulation (6 chapters) 3. Pulmonary Vasomotor Tone, Vascular Reactivity, and Vascular Permeability (5 chapters) 4. Signal Transduction (4 chapters) 5. Oxygen Sensing and Reactive Oxygen Specials in the Lung (3 chapters) 6. Cell Proliferation and Apoptosis (3 chapters) 7. Coagulation, Thrombosis, and Fibrinolysis (3 chapters) 8. Interactions of Pulmonary Vascular Cells with Circulating Blood Cells (3 chapters) 9. The Systemic Circulation in the Lung (1 chapter) Part 2 (Methodological Approaches for Research) is composed of six sections and 16 chapters that are exclusively designed to provide a basic knowledge and spectrum on the techniques and technology that are commonly used to study genetic, molecular, cellular, systemic and pathophysiological aspects of the pulmonary vasculature. 1. In vivo and Genetic Animal Models (3 chapters) 2. Morphological, Functional, and Regulatory Approaches (3 chapters) 3. Molecular Biological Techniques (3 chapters) 4. Genomic, Proteomic and Bioinformatical Approaches (3 chapters) 5. Stem Cells (3 chapters) 6. Clinical Research Approaches (1 chapter) Part 3 (Pathology and Pathobiology) includes four sections and 19 chapters that discuss the potential mechanisms or sequence of events involved in the initiation and progression of abnormalities in the pulmonary vasculature in patients with pulmonary vascular disease.
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1. Hypoxia and Hyperoxia in the Development of Pulmonary Hypertension (6 chapters) 2. Pulmonary Vasoconstriction and Vascular Remodeling in Pulmonary Hypertension (6 chapters) 3. Endothelium and Thrombosis in the Development of Pulmonary Hypertension (2 chapters) 4. Pulmonary Edema and Acute Lung Injury (5 chapters). Part 4 (Pulmonary Vascular Diseases) consists of nine sections and 32 chapters devoted to describe pathogenesis, epidemiology and pathophysiology of almost all of the pulmonary vascular diseases identified so far by the World Health Organization (WHO). One of the sections is specifically designated to describe pulmonary vascular disease in pediatric patients. 1. Nomenclature, Classification and Epidemiology of Pulmonary Hypertension (3 chapters) 2. Pulmonary Arterial Hypertension (7 chapters) 3. Pulmonary Arterial Hypertension in Pediatric Patients (5 chapters) 4. Pulmonary Venous Hypertension (2 chapters) 5. Pulmonary Hypertension Associated with Hypoxia and Hypoxemia (3 chapters) 6. Pulmonary Hypertension due to Chronic Thrombotic and/or Embolic Disease (5 chapters) 7. Pulmonary Hypertension due to Disorders Directly Affecting the Pulmonary Vasculature (2 chapters) 8. Right Heart Dysfunction and Pulmonary Hypertension (1 chapter) 9. Other Disorders of the Pulmonary Circulation (4 chapters) Part 5 (Diagnosis and Treatment) includes three sections and 20 chapters designed to illustrate, in details, the diagnostic and therapeutic procedures currently used for patients with pulmonary vascular disease. 1. Diagnostic Approaches for Pulmonary Vascular Diseases (4 chapters) 2. Therapeutic Interventions for Pulmonary Vascular Diseases (9 chapters) 3. Interventional and Surgical Approaches to Treatment of Pulmonary Vascular Diseases (7 chapters) Textbook of Pulmonary Vascular Disease is written by more than 220 experts in the field including clinicians, physician scientists and investigators. All the contributors are actively involved in clinical, physiological, and pathophysiological studies on the pulmonary circulation and pulmonary vascular diseases; most of them are renowned and eminent experts in the research area of the topic on which the chapter is based. Jan - Mar 2010 • Volume 2 • Issue 1
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Many of the contributors are Fellows of the Pulmonary Vascular Research Institute (PVRI). Textbook of Pulmonary Vascular Disease is designed for and is of special interest to a) clinicians (pulmonologists, cardiologists, intensive care physicians, cardiothoracic and vascular surgeons, and emergency physicians), b) physician-scientists and basicscience researchers in the fields of cardiopulmonary and critical care medicine, vascular physiology and pathophysiology, translational medical research, and bioengineering, c) healthcare workers in cardiopulmonary and critical care medicine, and d) clinical and research fellows as well as residents, medical and graduate students. Textbook of Pulmonary Vascular Disease intends to combine basic scientific concepts and knowledge on the pulmonary circulation with clinical diagnosis and treatment on pulmonary vascular diseases. No similar book is currently available that i) focuses on elucidating the cellular and molecular regulation of normal pulmonary vasculature and the pathogenic mechanisms of pulmonary vascular diseases, ii) includes advanced techniques and technology for basic and clinical research, and
iii) includes conventional and molecular approaches currently available for diagnosis and treatment of patients with pulmonary vascular diseases. Another feature of the book is the inclusion of surgical approaches for treatment of pulmonary vascular diseases, which have not been well described in previously published books. Textbook of Pulmonary Vascular Disease will not only serve as a reference book for physicians, surgeons, private practitioners, translational medical researchers, clinical and research fellows, and medical and graduate students, but can also be used as a guidance manual for technical and marketing personnel in pharmaceutical and biotechnological companies, who are interested in clinical and basic science research in cardiopulmonary diseases, pulmonary vascular diseases, vascular biology, and lung/heart transplantation. The book could not have been completed without the support from the members and fellows of PVRI. We would like to take this opportunity to thank all the contributors for their patience and conscientiousness in writing the manuscripts.
The Story of the Journal of PVRI Review S. Harikrishnan Editor in Chief, PVRI Review, Fellow, Pulmonary Vascular Research Institute, Co-leader, PVRI Publication Taskforce Address for correspondence: Dr. S. Harikrishnan, Additional Professor in Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum - 695 011, India. E-mail: drharikrishnan@hotmail.com DOI: 10.4103/0974-6013.58624
After the formation of the Pulmonary Vascular Research Institute (PVRI), many of PVRI fellows felt that journals specifically aimed at disciplines like pulmonary circulation, pulmonary vascular physiology and pathophysiology and pulmonary vascular disease were not available. It was also felt that the physician and research community dealing with this disease entity is increasing in size and research output on the rise, which was evidenced by the number of abstracts presented at different meetings. (e.g. 450 abstracts were presented at the ATS meeting in 2009). Hence, it was agreed in principle to start a new and specialized journal aimed at practicing physicians, surgeons, basic science investigators and trainees. We realized that it will be difficult to attract original articles to the journal in its initial stages. So it was decided to publish review articles and regular educational features like case reports, images and guidelines. The journal was planned to be published by PVRI with the help of a well-known experienced publisher. PVRI wanted the journal to be in full color and open access. We also wanted it published in English and other languages like-Portuguese, Chinese, Spanish and Arabic. We did a global search and we could identify, Medknow Publishers, Mumbai, India as a potential publisher partner. In the AGM of PVRI India held at New Delhi in 2008, PVRI India was endowed with the responsibility of co-ordinating with Medknow publishers in bringing out the journal. Jan - Mar 2010 • Volume 2 • Issue 1
The journal was intended to publish educational materials and also news about activities of PVRI. So it was decided to name the journal “PVRI REVIEW”. I was entitled the job of editing this journal by the PVRI South East Asia Region (India Chapter). We had to do a lot of hard work from developing a format for the journal, inviting articles, editing it and finally going for the print. We aimed at distributing the first issue in print at the AGM at Mexico in January 2009. With the hard work of Prof. Ghazwan Butrous and the experience and co-operation of Medknow chief executive Dr. DK Sahu and all the staff at Medknow, we could bringout a reasonably good first issue on-time. In the first issue we translated two articles each into Arabic, Portuguese and Spanish. Since then PVRI REVIEW published all its four issues on time.
Issue statistics Volume 1 Issue 1 Issue 2 Issue 3 Issue 4
Pages Jan - March 1-92 April - June 93-146 July - Sep 147-194 Oct- Dec 195-245
Hits (as on Oct 20th) 21700 9022 5346
Online 1 Print Online 1 Print Online in July Online on Nov 11
Feed-back was good and we feel the journal is of reasonably good quality in content, format and print. We had authors from
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Figure 1: Author institution mapping - City wise distribution (Medknow)
Figure 2: Journal site hits from different regions (30 days)–Google analytics - Citywise
almost all regions in the world [Figure 1]. A good number of people had accessed the journal from almost all regions of the world as evidenced in the Google analytics map [Figures 2 and 3]. We brought out two more editions - The Portuguese edition - Supplement S1-S47 was published by medknow and was distributed at the PVRI meeting in Brazil. The Chinese edition was printed in China and was distributed at the China PVRI meeting [Figure 4]
FUTURE PLANS
Figure 3: Journal site hits from different regions (30 days)– Google analytics - Countrywise
PVRI REVIEW will continue to be published, in a different format and perspective. The details of the transformation will be informed to all the fellows in the coming weeks The PVRI will publish another Journal (Pulmonary Circulation) which will be a fully peer-reviewed journal. Pulmonary Circulation will accept original research articles and also review articles. The
Figure 4: The cover of the three editions of PVRI REVIEW
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plan is to come out with the first issue of Pulmonary Circulation in July 2010.
TIME LINE
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2011-30% Original Articles
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2012-50% Original Articles
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2009-PVRI REVIEW
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2013-Indexed in Pubmed
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2010-Pulmonary Circulation
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2015-Impact Factor of 2-4
P V R I O p e n We b c a s t s ( P V R I We b i n a r s ) http://www.pahforum.com (2008-2009) Antonio Augusto Lopes Department of Pediatric Cardiology and Adult Congenital Heart Disease, The Heart Institute (InCor), University of São Paulo Medical School Brazil Address for correspondence: Prof. Antonio Augusto 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 DOI: 10.4103/0974-6013.58619
27/Jun/08-16h00 (GMT): To Operate or Not to Operate: That is the Question
3. Professor of Pediatrics, University of Alberta, Edmonton, Canada.
LECTURERS 1. Dr. Antonio Augusto Lopes - Professor of Medicine (Cardiology), Director, Department of Pediatric Cardiology and Adult Congenital Heart Disease, The Heart Institute (InCor), University of São Paulo Medical School. 2. Shyam Sunder Kothari, Professor (Cardiology), All India Institute of Medical Sciences, New Delhi, India. 3. Marlene Rabinovitch - Dwight and Vera Dunlevie, Professor of Pediatrics, Professor (by courtesy) Developmental Biology Research, Director of the Wall Center for Pulmonary Vascular Diseases Stanford University School of Medicine.
19/Nov/08-16h00 (GMT): From Diagnosis to Outcome: Assessment of Pulmonary Vascular Abnormalities: Pre and Postoperative Management
4. Marlene Rabinovitch - Dwight and Vera Dunlevie, Professor of Pediatrics, Professor (by courtesy) Developmental Biology Research, Director of the Wall Center for Pulmonary Vascular Diseases Stanford University School of Medicine.
22/Apr/09-16h00 (GMT): Pulmonary Hypertension with Chronic Obstructive Pulmonary Disease (COPD) LECTURERS 1. Dr. Antonio Augusto Lopes - Professor of Medicine (Cardiology) Director, Department of Pediatric Cardiology and Adult Congenital Heart Disease, The Heart Institute (InCor), University of São Paulo Medical School. 2. Ari Chaouat - Service des Maladies Respiratoires et Réanimation Respiratoire. 3. Serge Adnot - Professor of Physiology Service de Physiologie Explorations Fonctionnelles Head.
LECTURERS 1. Dr. Antonio Augusto Lopes - Professor of Medicine (Cardiology), Director, Department of Pediatric Cardiology and Adult Congenital Heart Disease, The Heart Institute (InCor), University of São Paulo Medical School. 2. Ian Adatia - Director, Pediatric Cardiac Critical Care and Pulmonary Hypertension Program, Stollery Children’s Hospital, Edmonton, Alberta, Canada. Jan - Mar 2010 • Volume 2 • Issue 1
27/May/09-16h00 (GMT): Congenital Heart Disease and PAH in High Altitudes LECTURERS 1. Dr. Antonio Augusto Lopes - Professor of Medicine (Cardiology), Director, Department of Pediatric Cardiology
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and Adult Congenital Heart Disease, The Heart Institute (InCor), University of São Paulo Medical School 2. Alexandra Heath Freudenthal - Pediatric cardiologist in La Paz Bolivia at “Kardiozentrum” Felowship in RWTH-aachen - Germany 3. Patricia Cortez - Professor of Pediatric Cardiology Director Department of Pediatric Cardiology, Metropolitano Hospital.
26/Aug/09-16h00 (GMT): Pulmonary Hypertension Associated with Schistosomiasis
LECTURERS 1. Dr. Antonio Augusto Lopes - Diretor da Equipe de cardiopatias Congênitas - InCor - FMUSP 2. Dr. Ghazwan Butrous - Professor of Cardiopulmonary Sciences University of Kent, Canterbury 3. Dra. Angela Pontes Bandeira - Memorial S. Jose Hospital - Recife-pe PROCAPE - Pernambuco’s University Recife-PeBrazil
23/Sep/09-14h00 (GMT): The Right Ventricle in Pulmonary Hypertension LECTURERS 1. Dr. Antonio Augusto Lopes - Diretor da Equipe de cardiopatias Congênitas - InCor - FMUSP 2. Herman J Bogaard - Assistant Professor of Medicine and his main research interest is translational models of pulmonary hypertension and associated right heart failure 3. Norbert Voelkel - Director, Virginia Johnson Center for Pulmonary Research 4. Ramesh Natarajan - Molecular Biologist investigating
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mechanisms of left ventricular failure following ischemiareperfusion and right ventricular failure following pulmonary artery hypertension
Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India Member of the Executive Board of the PVRI India 3. Dr. Munesh Tomar - Consultant Dept. of Pediatric Cardiology and Congenital Heart Surgery Escorts Heart Institute and Research Centre, New Delhi, India
21/Oct/09-16 h00 (GMT): Pulmonary Vascular Diseases in Rheumatic and Congenital Heart Diseases
4. Dr. R. Krishna Kumar - Head of the Department, Department of Pediatric Cardiology, Amrita Institute of Medical Sciences and Research Center, Kochi, Kerala, India
LECTURERS 1. Dr. Antonio Augusto Lopes - Professor of Medicine (Cardiology), Director, Department of Pediatric Cardiology and Adult Congenital Heart Disease, The Heart Institute (InCor), University of São Paulo Medical School 2. Dr. Harikrishnan S - Additional Professor in Cardiology, Sree
5. Dr. Sheila Haworth - Professor of Developmental Cardiology, Great Ormond Street Hospital for Children, London, UK. Lead Clinician of the National Pulmonary Hypertension Service for Children in the UK 6. Dr. Vera Demarchi Aiello - Pathologist-in-chief, Surgical Pathology Section, Laboratory of Pathology at the Heart Institute (InCor), University of Sao Paulo Medical School.
Author Help: Online submission of the manuscripts Articles can be submitted online from http://www.journalonweb.com. For online submission, the articles should be prepared in two files (first page file and article file). Images should be submitted separately. 1) 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. 2) 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. 3) Images: Submit good quality color images. Each image should be less than 2048 kb (2 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. 4) Legends: Legends for the figures/images should be included at the end of the article file.
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The 4th Annual General Meeting of the Pulmonary Vascular Research Institute PVRI Annual General Meeting Agenda, at Hotel Real Palacio, Lisbon, Portugal. Sunday 10th January 2010 (Fellows only) 8:30-10:30 Executives reports 1. Summary Report of the Past 3 Years Activities 2. Detailed PVRI Activities 2009 3. Report on IAB/BOD meeting 30 Nov 2009 • Restructuring of PVRI 1. Establishment of New Executive Officers 2. Reformatting the Board of Directors 3. PVRI Patrons 4. Hiring of a Full Time Chief Operational Officer 4. PVRI Communications: New PVRI Website 5. Financial Report
Workshops for Industry
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2010 PVRI workshop sand Debates
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Other Conferences (with Regulatory Agencies, Grover Conference, etc)
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14:00-15:00 Publication taskforce activities •
Textbook Report
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PVRI Review
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Pulmonary Circulation
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Publication Logistics
15:00-15:30 Coffee break 1. Report of the India Research Day 2. Other On-going Research (one slide each) a. Schistosomiasis Research Activities b. Congenital Heart Diseases Research Program c. MV Valvuloplasty Research Program 3. Developing a Screening Device 4. PVRI Funded Research (PVRI Research Grants) 5. Clinical Trial 19:00 Dinner at Restaurant Velho Pateo de Santana Monday 11th January 2010 8:30-12:30 PVRI Annual General Meeting at Hotel Real Palacio (Fellows only) 8:30-10:30 Approval of Actions Plan (Follow up of previous day discussion) 1. Administration and Logistics 2. Knowledge Exchange 3. Educational 4. Research Plans
12:30-1:30 Lunch 1:30-15:30 PVRI educational and publication activities
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PVRU Video Channels
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15:30-17:30 PVRI research activities
10:30-11:00 Coffee break 1100-12:30 Task force activities Regions 1. Western Pacific (China centre) 2. South East Asia / Indian Subcontinent 3. Eastern Mediterranean Region 4. America and Brazil Chapter 5. Europe 6. Sub-Saharan Africa Diseases Taskforces 1. Pulmonary Hypertension Associated with Schistosomiasis 2. Database Taskforce Creation of an International Database Summary report of other taskforces 1. Pulmonary Hypertension Associated with Congenital Heart Disease 2. Pulmonary Hypertension Associated with COPD 3. Pulmonary Hypertension Associated with High Altitude and Hypoxia 4. Pulmonary Hypertension Associated with HIV 5. Pulmonary Venous Hypertension 6. Pulmonary Hypertension Associated with Connective Tissue Diseases 7. Pulmonary Hypertension Associated with Haemolytic Anaemia
13:30-14:00 Educational activities • Summary (15 min presentation one slide each item followed by 15 min discussion) • PVRI Webinars
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10:30-11:00 Coffee break 11:00-12:30 Final approvals
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Revision of the Constitution and Charters
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Election of Officers Jan - Mar 2010 • Volume 2 • Issue 1
The 3rd PVRI Workshops and Debates (Open to PVRI Fellows and Registered Guests)
Monday 11th January 2010 Session 1 (13.30-17.30) ‘Hot Topics’: Novel observations and concepts in pulmonary vascular disease Chairmen: Nicola Petrosillo and Nick Morrell Format: Presentation and general discussion (20 min presentation and 10 min discussion) 1. The effects of chronic prostacyclin on pulmonary vascular pathology in IPAH Stuart Rich 2. Apelin and pulmonary arterial hypertension Marlene Rabinovitch 3. Observations on the physiology of the pulmonary circulation David Kilpatrick Coffee and tea break (15.00-15.30) 4. Cyclosporine and atrial septostomy in patients with acute/ severe/catastrophic PAH Marc Pritzker 5. Multikinase inhibition in pulmonary arterial hypertension Ralph Schermuly 6. The pathophysiology of pulmonary vascular disease associated with schistosomiasis Alexi Crosby and Brian Graham Free time in the evening Tuesday 12th January 2010 Session 2 (08:30-13:00) PVRI workshops Chairman: John Newman Format: One hour for each workshop, which includes presentations by the discussants, questions, and comments from the audience (the audience may show personal data; please provide it on a memory stick with PowerPoint format, maximum 3 slides per audience member) Workshop 1: The cellular pathology of pulmonary arterial hypertension Moderator: Rubin Tuder Discussants: Kurt Stenmark, Duncan Stewart and Ralph Schermuly Discussion topics: 1. What can animal models teach us about the cellular pathology of PAH? Ralph Schermuly 2. The role of smooth muscle/adventitial fibroblast/ inflammatory cells in PH Kurt Stenmark 3. The role of endothelial cell precursors in PH Duncan Stewart Workshop 2: The clinical importance of right ventricular hypertrophy in pulmonary arterial hypertension Jan - Mar 2010 • Volume 2 • Issue 1
Moderator: Stuart Rich Discussants: Paul Hassoun, Hunter Champion and Evangelos Michelakis Discussion topics: 1. Is right ventricular hypertrophy beneficial in pulmonary arterial hypertension? Paul Hassoun 2. What biologic pathways are deranged in right ventricular hypertrophy? Hunter Champion 3. How do current PH drugs affect the right ventricle? Evangelos Michelakis Coffee and tea break (10:30-11:00) Workshop 3: Pulmonary vascular disease associated with connective tissue diseases needs a specific focus Moderator: Virginia Steen Discussants: Steve Mathai and Gerry Coghlan Discussion topics: 1. The outcome of SSc -PAH is different than PAH Steve Mathai 2. Why does PAH in scleroderma have a worse outcome than PAH? Virginia Steen 3. Early diagnosis and treatment can improve the long term outcome of PAH in scleroderma Gerry Coghlan Workshop 4: Pulmonary venous hypertension (PVH) The forgotten pulmonary hypertension? Moderator: S. Ghio Discussants: Evelyn Horn and S. Harikrishnan Discussion topics: 1. PVH in patients with systolic LV dysfunction S. Ghio PVH in patients with diastolic LV dysfunction Evelyn Horn 2. PVH in rheumatic heart disease (the role of mitral valvuloplasty) S. Harikrishnan Free time in the afternoon 19:30-22:00: Gala dinner (By invitation restaurant, Eleven) Wednesday 13th January (08:30-13:00) Session 3 (08:30-10:30) Case presentations and discussion Chairmen: Magdy Idress, Chen Wang and Darren Taichman Format: 15 minutes presentation and 15 minute general discussion per case Discussion topics: 1. PAH in Congenital heart diseases 2. 3. 57
PAH in HIV patient Nicola Petrosillo PHT in COPD patients PVRI REVIEW
Ari Chaouat 4. Clinical dilemma diastolic heart failure and PHT Pilar Escribano Coffee and tea break (10:30-11:00) Session 4 (11:00-12:30) Paediatric pulmonary vascular disease Moderator: Ian Adatia Discussants: Jeffrey Feinstein, Antonio Augusto, Krishna Kumar, Steve Abman, Sheila G Haworth and Rainer Zimmermann Format: Presentations followed by general discussion Discussion topics: 1. The Evian, Venice, and Dana point classifications of PH can/cannot be applied to the paediatric age group Ian Adatia and Sheila G Haworth 2. The principles of trialling pulmonary hypertension therapies in children Sheila G Haworth Lunch break (12:30-13:30) Session 5 (13:30-17:00) The current treatment of pulmonary arterial hypertension Chairman: Julio Sandoval Debate 1: What is the best therapeutic strategy for PAH? Moderator: David Langleben Discussants: Ardi Ghofrani, Ioana Preston and Paul Corris Format: Debates followed by general discussion – total 1 hour The optimum strategy for initiating treatment to achieve the greatest benefit for patients with pulmonary arterial hypertension is controversial. Views range from starting with one drug and adding or switching therapy to starting with a drug combination or even initiating treatment with epoprostenol. This session will discuss these issues. Discussion topics: 1. Monotherapy with substitution for failure is the preferable choice for PAH Paul Corris 2. Combination therapy is preferable for PAH Ardeschir H Ghofrani 3. Hit it hard and fast - PAH therapy should start with intravenous prostacyclin Ioana Preston
Debate 2: Tyrosine kinase inhibitors have a place in the management of pulmonary arterial hypertension Moderator: Ardeschir H. Ghofrani Discussants: Kurt Stenmark, Marlene Rabinovitch, Ioana Preston, Martin Wilkins and Nicholas Morrell Format: Presentation followed by general discussion – total 1 hour Tyrosine kinase inhibitors have been proposed as a treatment for PAH. The subject remains controversial. This session will address the potential role and clinical benefits/side effects of tyrosine kinase inhibitors, by addressing the following questions: 1. Does the early experience with tyrosine kinase inhibitors suggest promise as a treatment for PAH? Martin Wilkins 2. Do we know the right target? More research needs to be done before progressing any one drug for PAH? Marlene Rabinovitch Debate 3: The cyclic GMP signaling pathway has served us well but is now exhausted as a therapeutic target for the treatment of PAH Moderator Jim Klinger Discussants: Raed Dweik, Roger Johns, Martin Wilkins and Ardeschir H. Ghofrani Format: Presentation followed by general discussion - 1 hour The precise role played by cGMP-PKG signaling pathway in the pathophysiology pulmonary hypertension is still controversial but many studies have demonstrated that pulmonary hemodynamics and functional capacity can be improved in affected patients by slowing the metabolism or increasing the production of cGMP. Pharmacologic therapies that target the GMP/PKG pathway now represent one of the major approaches to the medical management of patients with PAH. This session will consider whether there is more to be gained from targeting this pathway: 1. Cyclic GMP has a pivotal role in modulating pulmonary vascular tone but a limited role in vascular remodeling Roger Johns 2. PAH is more than a nitric oxide deficiency state and there is impairment of cGMP synthesis in PAH Raed Dweik 3. Increased cGMP synthesis via direct pharmacological manipulation of sGC is the next therapeutic development in the management of pulmonary hypertension Ardeschir H Ghofrani
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. 2) 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. PVRI REVIEW
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Jan - Mar 2010 • Volume 2 • Issue 1
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 found suitable for 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.
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. Jan - Mar 2010 • Volume 2 • Issue 1
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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. 3. Colour figures,charts and tables are welcome. 4. Article length (1000-5000 words). 5. Extensive referencing is encouraged, but has to be cited in the text. 6. Please use the SI units of measure. 7. Abbreviations and acronyms are acceptable if quoted more than 3 times in the text. 8. Please conform to the “Uniform Requirements for Manuscripts Submitted to Biomedical Journals” http:// www.icmje.org/. 9. Assemble the manuscript in this order: Title Page, Abstract, Text, Acknowledgments, Funding Sources, Disclosures, References, Figure Legends, Tables, and Figures.
References
1. Cite references in numeric order according to first mention in the text. 2. 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. 3. 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 4. References must be from a full length publication in a peer reviewed journal. 5. 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
Figures
1. Colour figures (GIF, TIFF, EPS or JPEG format only) and tables are welcomed 2. Full comprehensive legend to each figure is essential PVRI REVIEW
Instructions for Authors
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
Tables
in a footnote to the table.
Special Notes:
1. Each table should be submitted on a separate page, 2. The table number should be Arabic (example Table -1 Table -2 etc) 3. Abbreviations and symbols used in the table must be defined
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
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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Jan - Mar 2010 • Volume 2 • Issue 1
Announcement
Edited by Dr. S. Harikrishnan, from Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India - 695011, on behalf of Pulmonary Vascular Research Institute. Printed and published by Medknow Publications & Media Pvt. Ltd. from B5-12, Kanara Business Centre, Ghatkopar (E), Mumbai, India.