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Division of Respiratory Medicine, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
Correspondence and requests for reprints should be addressed to Nicholas W. Morrell, M.A., M.D., F.R.C.P., Department of Medicine, University of Cambridge, Box 157, Level 5, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK. E-mail: nwm23{at}cam.ac.uk
ABSTRACT
Genetic studies in familial pulmonary arterial hypertension (FPAH) have revealed heterozygous germline mutations in the bone morphogenetic protein type II receptor (BMPR-II), a receptor for the transforming growth factor (TGF)-ß/bone morphogenetic protein (BMP) superfamily. PAH is characterized by intense remodeling of small pulmonary arteries by myofibroblast and smooth muscle proliferation. BMPR-II mutation in pulmonary artery smooth muscle cells contributes to abnormal growth responses to BMPs and TGF-ß. Reduced expression or function of BMPR-II signaling leads to exaggerated TGF-ß signaling and altered cellular responses to TGF-ß. The likely mechanism involves an interaction between BMP and TGF-ß–regulated Smad pathways. In endothelial cells, BMPR-II mutation increases the susceptibility of cells to apoptosis. The combination of increased endothelial apoptosis and failure of growth suppression in pulmonary artery smooth muscle cells provides important clues to the cellular pathogenesis of PAH. The reciprocal regulation of TGF-ß and BMP signaling in models of tissue repair may provide new approaches to our understanding of lung disease.
Key Words: genetics • pulmonary arterial hypertension • transforming growth factor-ß
IDIOPATHIC PULMONARY ARTERIAL HYPERTENSION
Severe unexplained idiopathic pulmonary arterial hypertension (IPAH), previously known as primary pulmonary hypertension, is a rare condition with an estimated incidence of 2–3 per million per year (1). Idiopathic PAH is a devastating condition that had a prognosis of less than 3 yr from diagnosis before the advent of modern therapies. The disease typically affects young women (female/male ratio of 2.3:1) with a median age at diagnosis of 36 yr, although the disease may occur at any age (2). Modern targeted therapy with endothelin receptor antagonists, phosphodiesterase inhibition, and prostanoids improves symptoms of breathlessness and, in the case of epoprostenol, survival (3).
GENETICS OF FAMILIAL PAH
The etiology of severe unexplained pulmonary hypertension remained a mystery until a few years ago. Reports of a causal association between appetite-suppressant drugs (4) and the occurrence of severe pulmonary hypertension provided some insight into its pathogenesis. However, the identification of the gene underlying familial PAH (FPAH) in 2000 provided a firm basis for mechanistic studies (5–7). Approximately 10% of cases of IPAH have an affected relative (8). In these families, the disease segregates in an autosomal dominant pattern, with often markedly reduced penetrance. True estimates of penetrance are yet to be reported and will probably vary with the nature of the underlying mutation, but on average penetrance is approximately 20 to 30% (9, 10). Thus, many patients who carry the disease gene do not manifest clinical PAH. After localization of the disease gene to the long arm of chromosome 2 (2q33) (11), two independent groups identified heterozygous germline mutations in the bone morphogenetic protein (BMP) type II receptor (BMPR-II), a receptor for the transforming growth factor (TGF)-ß superfamily, in patients with FPAH (5, 6). Mutations in the BMPR2 gene have been found in approximately 70% of families (12). In addition, up to 25% of patients with apparently sporadic IPAH have been found to harbor similar mutations (13). At least a proportion of these are examples of FPAH in which the condition has not manifested in relatives due to low penetrance (9), whereas others are examples of de novo mutation. Approximately 144 distinct mutations have been identified in 210 independent patients with FPAH (12).
Approximately 30% of mutations are missense mutations occurring in highly conserved amino acids with predictable effects on receptor function. For example, many of these involve the serine-threonine kinase domain of BMPR-II or the extracellular ligand binding domain. However, the majority (
70%) of BMPR2 coding mutations are frame-shift and nonsense mutations, many of which would be expected to produce a transcript susceptible to nonsense-mediated mRNA decay. Thus, haploinsufficiency for BMPR-II represents the predominant molecular mechanism underlying inherited predisposition to FPAH. Further genetic analysis is revealing an increasing number of families in which BMPR-II mutation is implicated, including the identification of gene deletions and rearrangements (14, 15). The genetics of FPAH and BMPR-II mutations has recently been reviewed in detail (12).
NORMAL BMP/TGF-ß SIGNALING
BMPs are the largest group of cytokines within the TGF-ß superfamily and were originally identified as molecules regulating growth and differentiation of bone and cartilage (16). BMPs regulate growth, differentiation, and apoptosis in a diverse number of cell lines, including mesenchymal and epithelial cells, acting as instructive signals during embryogenesis and contributing to the maintenance and repair of adult tissues (16–18). TGF-ß superfamily type II receptors are constitutively active serine–threonine kinases and form homodimers that exist constitutively or are recruited to receptor complexes on ligand stimulation (19). BMPR-II is distinguished from other TGF-ß superfamily type II receptors by a long carboxyl-terminal sequence following the intracellular kinase domain (20). Long and short forms of BMPR-II have been isolated, with the short-form splice variant lacking almost the entire of exon 12 (21). Although the short form of the receptor is widely expressed in human tissues, it is not known whether this form of the receptor serves a differential function compared with the long form. BMPR-II initiates intracellular signaling in response to specific ligands: BMP-2, BMP-4, BMP-6, BMP-7, growth and differentiation factor-5 (GDF-5), and GDF-6 (20). Ligand specificity for different components of the receptor complex are emerging that may have functional significance to the tissue-specific nature of BMP signaling. The extreme tissue specificity of BMP signaling is highlighted by the diverse human diseases associated with mutations in type I and II receptors. Although BMPR-II mutation is associated with FPAH, BMPRIA mutation causes familial juvenile colonic polyposis (22), and BMPRIB mutation causes hereditary brachydactyly (23). The majority of ligands (BMP-2, BMP-4, BMP-7, and GDF-5 and GDF-6) bind with high affinity to the type I receptors, predominantly BMPRIA activin-like receptor kinase-3 (ALK-3) or BMPRIB (ALK-6), and with very low affinity to BMPR-II. GDF-5 demonstrates specificity for BMPRIB (24). In contrast, BMP6 binds with high affinity to BMPR-II. After ligand binding, the type II receptor phosphorylates a glycine-serine rich domain on the proximal intracellular portion of an associated type I receptor. Conformational changes that occur in the ligand-receptor complex when both receptor types contacting the ligand are required for cross-linking of the ligand to BMPR-II and intracellular signal transduction.
Smad-DEPENDENT SIGNALING
In the presence of ligand, activated type I receptors phosphorylate cytoplasmic signaling proteins known as Smads, which are responsible for TGF-ß superfamily signal transduction (25). BMPs signal via a restricted set of receptor-mediated Smads (R-Smads), Smads 1, 5, and 8, which must complex with the common partner Smad (co-Smad), Smad-4, to translocate to the nucleus. TGF-ß and activins signal via a different set of R-Smads, Smads 2 and 3. Target gene transcription is regulated by a variety of mechanisms, including direct binding of the Smad complex to DNA, interaction with other DNA proteins (e.g., activator protein-1 [AP-1] and transcription factor E-3), and recruitment of transcriptional coactivators or co-repressors (25). Switching off Smad signaling in the cell is achieved via Smad ubiquitination and regulatory factors (Smurfs) (26) and by recently identified Smad phosphatases (27).
MITOGEN-ACTIVATED PROTEIN KINASE–DEPENDENT SIGNALING
Although Smad signaling has been recognized as the canonic BMP signaling pathway, there is mounting evidence that the mitogen-activated protein kinases (MAPKs), including p38MAPK, p42/44MAPK (ERK1/2), and c-Jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK), are regulated by BMPs and TGF-ßs in certain cell types (28, 29). MAPK signaling has been reported to positively and negatively regulate Smad signaling, depending on the cell type and system studied. The specific pathway activated by BMPR-II may depend on whether preformed type I/type II heterodimers are stimulated by ligand (Smad-dependent pathway) or whether ligand leads to recruitment of type I and II receptors to the signaling complex (MAPK-dependent pathway) (30). It is likely that preformed complexes are heterodimers containing one type I and one type II receptor, whereas ligand-recruited complexes consist of homooligomerized type I receptors and one type II receptor. Thus, structural differences in the receptor complex may account for the selection of distinct signaling pathways.
INTERACTIONS BETWEEN MAPK AND Smad SIGNALING
R-Smads consist of a conserved globular mad-homology 1 (MH1) and an MH2 domain connected by a linker region. The MH1 domain is involved in DNA binding, and the MH2 domain is involved in binding to cytoplasmic retention factors, activated receptors, nucleoporins in the nuclear pore, and DNA-binding cofactors, coactivators, and co-repressors in the nucleus. Receptor-mediated phosphorylation occurs at the carboxy-terminal sequence SXS (25, 29). This enables the nuclear accumulation of Smads and their association with the shared partner Smad4 to form transcriptional complexes that are interpreted by the cell as a function of the context. In contrast, the linker region of Smad1 contains four PXSP sites that are susceptible to phosphorylation by MAPK, specifically ERK1/2. This prevents the nuclear localization of Smad1 and inhibits BMP signaling. These results led to the proposal that the BMP and epidermal growth factor (EGF)/Ras/MAPK pathways converge on Smad1 by phosphorylating the carboxy-terminal tail and the linker region, respectively, with opposite effects (31, 32). The balance of these two inputs determines the level of Smad1 activity in the nucleus and thus determines the participation of BMP signaling in the control of cell fate.
BMP signaling is regulated at many different levels, for example by endogenous inhibitors of BMP binding/signaling (e.g., Noggin, Chordin, Follistatin, BAMBI, and Smurf-1), the levels of expression of specific BMPs, activation of the inhibitory Smads, Smad 6 and 7, interactions with other growth signaling pathways (possibly such as those downstream of serotonin receptors), and nuclear coactivators and co-repressors. In addition, BMP signaling may be regulated by the type and density of type I and II receptors available for dimerization, dictating the relative levels of preformed versus ligand-induced receptor complexes and therefore the differential activation of downstream signaling pathways. Such diverse levels of regulation may be responsible for the tissue specificity of BMP signaling and may, for example, underlie the pulmonary specific pathology seem in PAH.
THE CONSEQUENCES OF BMPR2 MUTATION FOR BMP/TGF-ß SIGNALING
Two recent studies have shown that the mechanism by which BMPR-II mutants disrupt BMP/Smad signaling is heterogeneous and mutation specific (33, 34). Of the missense mutations, substitution of cysteine residues within the ligand binding or kinase domain of BMPR-II leads to reduced trafficking of the mutant protein to the cell surface, a process that may also interfere with BMP type I receptor trafficking. In contrast, noncysteine mutations within the kinase domain reach the cell surface but fail to activate Smad-responsive luciferase reporter genes due to an inability to phosphorylate BMP type I receptors. Mutations in the ligand binding and kinase domains exhibit a dominant-negative effect on wild-type receptor function in terms of Smad signaling. Interestingly, BMPR-II mutants with missense mutations involving the cytoplasmic tail are able to traffic to the cell surface and are capable of activating Smad-responsive luciferase reporter genes to some extent but are almost certainly relatively deficient in their ability to transduce signals via Smads. In addition, pulmonary artery smooth muscle cells from mice heterozygous for a null mutation in the BMPR2 gene are deficient in Smad signaling (35, 36). Thus, haploinsufficiency or missense mutation seems to lead to a loss of signaling via the Smad1/5 pathway. One study has reported that marked siRNA knockdown of BMPR-II leads to increased Smad signaling in response to some ligands (e.g., BMP7) (35). The significance of this observation remains to be determined. Another potential gain of function as a consequence of BMPR-II mutation was reported in a mouse epithelial cell line. In these cells, transfection with BMPR-II mutant constructs led to ligand-independent activation of p38MAPK (33). Furthermore, these cells showed enhanced serum-induced proliferation as compared with wild-type transfected cells; this abnormal proliferation was abolished by treatment with a selective p38MAPK inhibitor, SB203580. Subsequently, however, we were unable to find evidence for constitutive activation of MAPK pathways in pulmonary artery smooth muscle cells (PASMCs) isolated from patients with FPAH (37) or in cells from heterozygous BMPR-II knockout mice (36). The constitutive activation of MAPK pathways by mutant BMPR-II may be cell-type specific. Further studies are needed to elucidate how BMPR-II mutation affects on MAPK signaling.
Our group has previously shown that PASMCs isolated from patients with IPAH or FPAH exhibit an exaggerated growth response to TGF-ß1 (38). TGF-ß1 is not a ligand for the BMP receptors. In addition, the abnormal response to TGF-ß does not seem to be caused by alterations in the expression of TGF-ß type I, II, or III receptors (38). Mutations in the type I TGF-ß receptor, ALK-1, have been observed in patients with severe PAH occurring in families with hereditary hemorrhagic telangiectasia (39). ALK-1 is unusual among the TGF-ß receptors in that it signals via Smad1/5 rather than Smad2/3. This highlights the potential importance of a loss of Smad1/5 signaling in the vasculature as a cause of pulmonary vascular remodeling. However, a further important functional consequence of loss of Smad1/5 signaling may be a gain of TGF-ß signaling via Smad2/3. Support for this concept comes from experiments in endothelial cells designed to elucidate the diverse responses of cells to TGF-ß (40–42). In endothelial cells, Smad1/5 functionally antagonizes Smad2/3 signaling. This may be because Smad1/5 signaling competes for availability of the co-Smad, Smad4. In addition, Smad1 may physically interact with Smad3 and lead to degradation or prevent phosphorylation. This antagonism between TGF-ß and BMP signaling pathways provides a mechanism for their often-observed functional antagonism in diverse settings. For example, BMP7 can antagonize the epithelial–mesenchymal cell transition induced by TGF-ß (43, 44). BMP7 inhibits TGF-ß–dependent renal fibrosis in animal models (45). In cultured cells BMPs can antagonize TGF-ß–induced COX-2 expression (46) and TGF-ß–dependent myofibroblast transformation (47). Thus, failure of BMP signaling via Smad1/5 can increase TGF-ß/ALK-5/Smad2/3 signaling, which may be part of the molecular switch that determines the altered responsiveness to TGF-ß. In fibroblasts, the profibrotic response to TGF-ß is partly due to activation of the Abelson kinase c-Abl (48), a target of the drug imatinib, which has been recently shown to be effective in a case of FPAH (49). In addition, TGF-ß is known to increase expression of the platelet-derived growth factor (PDGF) receptor, particularly in the context of scleroderma (50). Imatinib is also an effective PDGF receptor kinase inhibitor. The potential importance of this is that strategies aimed at reducing TGF-ß/PDGF signaling become rational and realistic therapeutic goals in the treatment of FPAH (Figure 1).
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BMPR-II expression is widely expressed in normal tissues and cells (20). In the lung, BMPR-II is highly expressed on the vascular endothelium of the pulmonary arteries (51). The receptor is also expressed, albeit at a lower level in PASMCs and fibroblasts. We have demonstrated that expression of BMPR-II is markedly reduced in the pulmonary vasculature of patients with mutations in the BMPR-II gene (51). BMPR-II expression was also significantly reduced in the pulmonary vasculature of patients with IPAH in whom no mutation in the BMPR2 gene was identified. These studies suggest that a critical reduction in the expression of BMPR-II may be important to the pathogenesis of PAH, whether or not there is a mutation in the gene. In addition, because the level of BMPR-II expression in familial cases was considerably lower than predicted from the state of haploinsufficiency, this suggests that some additional environmental or genetic factor may be necessary to further reduce BMPR-II expression below the threshold, which triggers profound vascular remodeling. Studies of BMPR2 gene promoter activity may reveal important regulatory elements responsible for expression of BMPR-II transcripts. HIV-1 tat protein has been shown to inhibit expression of BMPR-II, which is of interest given the increased prevalence of PAH in HIV-infected patients (52). In addition, the HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitor, simvastatin, prevents pulmonary hypertension in rat models and enhances BMPR-II promoter activity (53).
In further studies we provided evidence that phosphorylation of Smad1/5 was reduced in the pulmonary arterial wall of patients with underlying BMPR2 mutations and in patients with IPAH with no identifiable mutation (37). Thus, not only is BMPR-II expression reduced but also activation of the main downstream signaling pathway in patients with FPAH and IPAH is reduced. Other investigators have demonstrated that expression of the type I receptor BMPRIA is reduced in PAH due to diverse underlying causes (54). Animal models of pulmonary hypertension, such as that induced by high flow in pigs (55) or chronic hypoxia in rats (56), have also demonstrated reduced BMPR-II expression. Whether these changes in BMPR-II expression observed in animal models are a cause or the consequence of pulmonary vascular remodeling remains to be determined. One study has demonstrated increased expression of phospho-Smad2 in small pulmonary arteries of patients with IPAH, lending support for the concept that a reduction in BMPR-II/Smad1,5 signaling can lead to increased signaling via TGF-ß/ALK-5/Smad2,3 (57). Earlier studies in idiopathic PAH lung had confirmed increased expression of TGF-ß isoforms in remodeling arteries (58).
Several groups have begun to explore the response of pulmonary vascular cells from patients and control subjects in vitro. The response of PASMCs to BMP ligands depends to some extent on the anatomic origin of cells. The serum-stimulated proliferation of cells harvested from the main or lobar pulmonary arteries tends to be inhibited by TGF-ß1 and BMPs 2, 4, and 7 (37). BMPs may induce apoptosis in these cells (59). A dominant-negative Smad1 construct has been used to show that the growth inhibitory effects of BMPs are Smad1 dependent (37). In contrast, in PASMCs isolated from pulmonary arteries of 1–2 mm diameter, BMPs 2 and 4 stimulate proliferation (37). This proproliferative effect of BMPs in peripheral cells is dependent on the activation of ERK1/2 and p38MAPK. Smad and MAPK pathways are activated to a similar extent in cells from both locations, but the integration of these signals by the cell seems to differ.
PASMCs from patients with FPAH and mutations in BMPR-II can be shown to have a reduced capacity to activate Smad1/5 (37). This is coupled to a reduced ability to suppress proliferation of PASMCs isolated from lobar pulmonary arteries. In PASMCs from peripheral small arteries, which proliferate in response to BMPs in a MAPK-dependent manner, the prediction would be that, in the absence of a counteractive Smad pathway, the MAPK-dependent proliferation would go unchecked.
The response of vascular endothelial cells to BMPs in vitro is in contrast to PASMCs. Endothelial cells proliferate, migrate, and form tubular structures in response to BMP4 (60). The proliferation is driven via Smad1/5 activation and is dependent on the induction of the inhibitors of DNA binding family of transcription factors. In addition, BMPs protect endothelial cells from apoptosis (61). Knockdown of BMPR-II with siRNA increases the susceptibility of pulmonary artery endothelial cells to apoptosis.
The contrasting effects of BMPs in the pulmonary vascular endothelium and the underlying PASMCs provide a compelling model for pulmonary vascular damage and remodeling in FPAH (Figure 2). A critical reduction in BMPR-II function in the endothelium may promote increased endothelial apoptosis, which compromises the integrity of the endothelial barrier and contributes to endothelial dysfunction. This allows ingress of serum factors to the underlying intima and stimulates activation of vascular elastases. It is conceivable that high rates of apoptosis in the endothelium would favor the development of apoptosis-resistant clones of endothelial cells and lead to plexiform lesion formation. In addition, apoptosis and engulfment of apoptotic cells are known to be accompanied by the robust release of TGF-ß (62). In the underlying media, PASMCs already compromised in their ability to respond to the growth suppressive effects of BMPs are exposed to TGF-ß, which, because of a deficient Smad1/5 pathway, causes an exaggerated growth response. This emerging hypothesis is open to direct testing in vitro and in vivo.
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Studies of knockout mice reveal the critical role of the BMP pathway in early embryogenesis and vascular development. Homozygosity for a null mutation in BMPR2 is lethal before gastrulation (63). Mice deficient in Smad-5, one of the BMP-restricted Smads, die due to defects in angiogenesis (specifically, failure to recruit vascular smooth muscle to endothelial structures) (64). Heterozygous BMPR-II+/– mice survive to adulthood and breed normally with no readily discernable phenotype. This mouse, at least at the genetic level, might mimic the state of haploinsufficiency underlying the majority of families with PAH. In general, the mouse pulmonary vascular bed seems resistant to the extensive and severe vascular remodeling seen in human disease. Heterozygous BMPR2+/– mice have been shown to have no (36) or little (65) resting elevation of pulmonary arterial pressure under normal conditions. However, when heterozygotes are exposed to lung overexpression of interleukin-1ß (66) or are chronically infused with serotonin (36), they develop a greater elevation of pulmonary artery pressure compared with wild-type littermate control animals. These observations support the hypothesis that BMPR-II dysfunction increases the susceptibility to pulmonary hypertension when exposed to another environmental stimulus. However, this response depends on the stimulus because chronic hypoxia, a commonly used animal model, did not increase susceptibility to pulmonary hypertension in BMPR2+/– mice (36). The relatively low penetrance of the PAH within families supports a "two-hit" hypothesis in which the vascular abnormalities characteristic of idiopathic PAH are triggered by accumulation of genetic and/or environmental insults in a susceptible individual. For example, a germline BMPR-II mutation in combination with a somatic mutation in the BMP pathway or one of the related pathways regulating cell growth and apoptosis may be sufficient to generate clinical disease. We recently excluded somatic mutation in BMPR-II in microdissected lesions of pulmonary vascular lesions of FPAH (67). Environmental injury, such as the ingestion of appetite suppressants resulting in an increase in serotonin signaling, may impose an additional burden predisposing to disease. Acquired somatic mutations in the TGF-ß type II receptor and Smad-4 are well-recognized associations with certain gastrointestinal cancers (68), a disease process in which such a two-hit paradigm is well recognized.
There is evidence that increasing the level of BMPR-II dysfunction causes pulmonary hypertension in mice. Thus, transgenic overexpression of a dominant-negative kinase domain mutant BMPR-II in vascular smooth muscle causes increased pulmonary vascular remodeling and pulmonary hypertension (69). Transgenic mice expressing a hypomorphic BMPR-II survive gastrulation but die at midgestation with cardiovascular and skeletal defects, including defects in the outflow tract of the heart (70). This study demonstrates the importance of gene dosage in BMP signaling. In addition, cardiac defects have been recognized in some individuals with BMPR2 mutations (71). Further studies are needed with conditional knockout mice to overcome the essential requirement of BMPR-II during early embryogenesis and to examine the importance of endothelial versus smooth muscle expression of mutant BMPR-II. If a more robust model of PAH could be established, this would benefit the search for targeted therapies and would provide a means of searching for genetic modifiers of disease expression.
BMPs AS INHIBITORS OF TISSUE REMODELING
Evidence shows that BMP-2 inhibits serum-stimulated and growth-factor–induced proliferation of human aortic smooth muscle cells and induces the expression of smooth muscle cell differentiation markers (72). Adenovirus-mediated overexpression of BMP-2 has been shown to inhibit injury-induced intimal hyperplasia in a rat carotid artery balloon injury model (73). BMP-7, but not BMP-4, ameliorates renal fibrosis induced by TGF-ß in rat models of glomerular sclerosis (44, 74). In addition, adenoviral delivery of BMP-7, Id2, or Id3 suppressed the epithelial to mesenchymal cell transition in the injured mouse lens (75). Few, if any, studies have addressed the role of BMP pathways in lung fibrosis, injury, or remodeling. BMPs play a major role during lung morphogenesis (26, 76, 77), but the role in diseased states has not been explored beyond the pulmonary circulation. Because TGF-ß signaling plays such a dominant role in lung remodeling, studies of the interaction with the BMP pathway in airway and parenchymal lung disease are needed.
CONCLUSIONS
The role of BMPs and BMP signaling in lung disease remains at an early stage. Although clearly of direct relevance to PAH, this pathway is likely to contribute to other lung pathologies characterized by tissue remodeling, such as lung fibrosis and chronic obstructive pulmonary disease. Further exploration of the contribution of BMPs and the functional antagonism with the TGF-ß pathway may reveal new targets for therapeutic intervention. Well-planned and large-scale genetic studies are required to identify additional genetic factors that increase susceptibility to PAH. Such factors may further worsen the state of BMPR-II dysfunction. Future functional studies need to identify the cell- and tissue-specific abnormalities in gene expression and cell growth/survival that are responsible for pulmonary vascular remodeling. In addition, studies are required to determine the molecular mechanism of the interaction between BMP and TGF-ß pathways in lung cells. Further refinement of animal models using conditional cell-specific transgenic and knockout mice are necessary to aid in our understanding of the lung specificity of FPAH.
FOOTNOTES
Supported by the British Heart Foundation.
Conflict of Interest Statement: N.W.M. has participated as a speaker at scientific meetings organized and financed by various pharmaceutical companies (AstraZeneca, Pfizer, Actelion, and GlaxoSmithkine). He serves as a consultant to Novartis and has received a research grant from Novartis.
(Received in original form May 15, 2006; accepted in final form June 26, 2006)
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