Pulmonary arterial hypertension: a look to the future
Lewis J. Rubin, MD*,* and
Nazzareno Galiè, MD
* Pulmonary Vascular Center, University of California–San Diego School of Medicine, La Jolla, California, USA
Institute of Cardiology, University of Bologna, Bologna, Italy
Manuscript received January 29, 2004;
accepted February 3, 2004.
*
Reprint requests and correspondence: Dr. Lewis J. Rubin, UCSD Medical Center, 9300 Campus Point Drive, M/C 7372, La Jolla, California 92037, USA.
ljrubin{at}ucsd.edu
 |
Abstract
|
|---|
The Third World Symposium on Pulmonary Arterial Hypertension served not only as a forum for the presentation of state-of-the art overviews of the pathobiologic and clinical aspects of pulmonary arterial hypertension (PAH), but also afforded an opportunity to the international scientific community to explore future directions of research and collaboration. This summary provides a brief overview of future directions in the field.
|
Abbreviations and Acronyms
| | BMPR2 | = bone morphogenetic protein receptor-2 | | FPAH | = familial pulmonary artery hypertension | | PAH | = pulmonary arterial hypertension | | PDE5 | = phosphodiesterase-5 |
|
Identification of mutations in the bone morphogenetic protein receptor-2 (BMPR2) in the majority of cases of familial pulmonary arterial hypertension (FPAH) has been a major advance in the elucidation of the pathogenic sequence in pulmonary arterial hypertension (PAH) (1,2). However, fewer than 20% of individuals with a BMPR2 mutation develop FPAH, and most individuals who develop PAH do not have an identifiable mutation (3); accordingly, it is likely that other factors, including genes and environmental stimuli, are needed to initiate the pathological sequence that leads to vascular injury and the pulmonary hypertensive state. Both the role of these other factors in initiating the vasculopathic process and the mechanisms through which they interface with genetic abnormalities are unknown (4).
Various cellular pathway abnormalities have been described that may play important roles in the development and progression of PAH (5–9). These include altered synthesis of nitric oxide, prostacyclin and endothelin, impaired potassium channel and growth factor receptor function, altered serotonin transporter regulation, increased oxidant stress, and enhanced matrix production. However, the relative importance of each of these processes is unknown, and the interactions between these various pathways should be explored. Additionally, the intermediate steps involved in the transduction of signals related to BMPR2 are unknown; clarification of these pathways will lead to a more complete understanding of how impaired BMPR2 signaling leads to hypertensive pulmonary vascular disease (10,11).
|
Therapy of PAH
|
|---|
Less than a decade ago, the treatment of PAH was based on a limited understanding of the disease pathogenesis and was largely empiric and usually ineffective. The treatment of PAH has advanced dramatically since then, with a number well-designed clinical trials demonstrating efficacy of several therapies that target specific abnormalities present in PAH (12–15). Furthermore, the complexity of these treatments has devolved from continuous intravenous (IV) delivery to oral and inhaled modes of drug delivery. Despite these successes, the response to therapy of PAH is not universal and is often incomplete. Future studies targeting newly identified alterations in endothelial and smooth muscle cell function, including phosphodiesterase-5 (PDE5) and angiotensin activity, vasoactive intestinal peptide synthesis and activity (16), and the serotonin pathway (9,17) may provide novel treatments.
Drugs currently marketed to treat other conditions may have effects that are beneficial in PAH as well. For example, the hydroxymethylglutaryl-coenzyme-A reductase inhibitors manifest pleiotropic effects that have been suggested to be responsible for a component of their benefit in arteriosclerotic disease (18), and these agents attenuate the pulmonary arteriopathy induced by the administration of monocrotaline to experimental animals (19,20). Formal clinical studies with the statins may, therefore, be appropriate. Similarly, currently available platelet inhibitors (i.e., aspirin) and newer antithrombotic agents may have a role in the treatment of PAH, in light of the beneficial effects (and inherent risks) of anticoagulation with warfarin in idiopathic PAH.
As with other diseases with a complex pathogenesis, targeting a single pathway in PAH is unlikely to be uniformly successful. With the development of several pathway-specific therapies, the opportunity exists for evaluating multidrug therapy in PAH: for example, studies combining an endothelin receptor antagonist with a prostanoid or a PDE5 inhibitor may lead to either a more aggressive first-line treatment strategy combining several drugs, or to a strategy of layered therapy for disease progression, or both.
|
Measuring outcomes and monitoring the course of therapy
|
|---|
The development of treatments for PAH has prompted the challenge of how to best assess and monitor the efficacy of long-term therapy. Because it is believed that randomized, placebo-controlled trials using survival as an end point would be unethical to perform in PAH, alternative strategies are required to measure and compare the relative effects of the available treatments. Similarly, noninvasive markers of disease severity, either biomarkers or physiological tests, are needed that can be widely applied to reliably monitor clinical course. Studies that assess the value of these outcome measures, alone or in combination, will enable physicians to time and select therapy in a more structured fashion.
Conclusions.
Although major advances in our understanding of the mechanism of disease development and in the treatment of PAH have been achieved over the past decade, substantial gaps in our knowledge remain. Bringing together physicians and scientists representing multiple disciplines and expertise, all sharing an interest in PAH, afforded the opportunity to explore areas of mutual interest and collaboration that will, it is hoped, narrow these gaps of knowledge in the future. Ultimately, the success of the Third World Symposium on Pulmonary Arterial Hypertension will be best measured by the progress achieved in understanding and treating PAH over the next few years.
|
References
|
|---|
1. Deng Z, Morse JH, Slager SL, et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Gen. 2000;67:737–744
2. Lane KB, Machado RD, Pauciulo MW, et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. The International PPH Consortium. Nat Genet. 2000;26:81–84
3. Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR2, a receptor member of the TGF-beta family. J Med Genet. 2000;37:741–745
4. Derynck R, Zhang YE. TGF-beta-induced signalling pathways. Nature. 2003;425:581–583
5. Christman BW, McPherson CD, Newman JH, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med. 1992;327:70–75
6. Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med. 1999;159:1925–1932
7. Yuan JX, Aldinger AM, Juhaszova M, et al. Dysfunctional voltage-gated K+ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation. 1998;98:400–406
8. Mandegar M, Remillard CV, Yuan JX. Ion channels in pulmonary arterial hypertension. Prog Cardiovasc Dis. 2002;45:81–114
9. Eddhaibi S, Humbert M, Fadel E, et al. Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J Clin Invest. 2001;108:1141–1150
10. Du L, Sullivan CC, Chu D, et al. Signaling molecules in nonfamilial pulmonary hypertension. N Engl J Med. 2003;348:500–509
11. Krick S, Platoshyn O, McDaniel SS, et al. Augmented K (+) currents and mitochondrial membrane depolarization in pulmonary artery myocyte apoptosis. Am J Physiol Lung Cell Mol Physiol. 2001;281:L887–L894
12. Barst RJ, Rubin LJ, Long WA, et alPrimary Pulmonary Hypertension Study Group. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334:296–301
13. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896–903
14. Galie N, Humbert M, Vachiery JL, et al. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: A randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2002;39:1496–1502
15. Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002;347:322–329
16. Petkov V, Mosgeoller W, Ziesche, et al. Vasoactive intestinal polypeptide as a new drug for treatment of primary pulmonary hypertension. J Clin Invest 2003;111:1339–46
17. Fanburg BL, Lee SL. A new role for an old molecule: Serotonin as a mitogen. Am J Physiol. 1997;272:L795–L806
18. Indolfi C, Cioppa A, Stabile E, et al. Effects of hydroxymethylglutaryl coenzyme-A reductase inhibitor simvastatin on smooth muscle cell proliferation in vitro and neointimal formation in vivo after vascular injury. J Am Coll Cardiol. 2000;35:214–221
19. Nishimura T, Faul JL, Berry GJ, et al. Simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in rats. Am J Respir Crit Care Med. 2002;166:1403–1408
20. Nishimura T, Vaszar LT, Faul JL, et al. Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis in neointimal smooth muscle. Circulation. 2003;108:1640–1645
This article has been cited by other articles:
|
|
|
|
 
T. M. Bull, C. A. Meadows, C. D. Coldren, M. Moore, S. M. Sotto-Santiago, S. P. Nana-Sinkam, T. B. Campbell, and M. W. Geraci
Human Herpesvirus-8 Infection of Primary Pulmonary Microvascular Endothelial Cells
Am. J. Respir. Cell Mol. Biol.,
December 1, 2008;
39(6):
706 - 716.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. H. Leuchte, C. Baezner, R. A. Baumgartner, D. Bevec, G. Bacher, C. Neurohr, and J. Behr
Inhalation of vasoactive intestinal peptide in pulmonary hypertension
Eur. Respir. J.,
November 1, 2008;
32(5):
1289 - 1294.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Warwick, P. S. Thomas, and D. H. Yates
Biomarkers in pulmonary hypertension
Eur. Respir. J.,
August 1, 2008;
32(2):
503 - 512.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
National Pulmonary Hypertension Centres of the UK
Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland
Heart,
March 1, 2008;
94(Suppl_1):
i1 - i41.
[Full Text]
[PDF]
|
|
|
|
|
|
|
National Pulmonary Hypertension Centres of the UK
Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland
Thorax,
March 1, 2008;
63(Suppl_2):
ii1 - ii41.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. H. Newman, J. A. Phillips III, and J. E. Loyd
Narrative Review: The Enigma of Pulmonary Arterial Hypertension: New Insights from Genetic Studies
Ann Intern Med,
February 19, 2008;
148(4):
278 - 283.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Voswinckel, B. Enke, F. Reichenberger, M. Kohstall, A. Kreckel, S. Krick, H. Gall, T. Gessler, T. Schmehl, H. A. Ghofrani, et al.
Favorable Effects of Inhaled Treprostinil in Severe Pulmonary Hypertension: Results From Randomized Controlled Pilot Studies
J. Am. Coll. Cardiol.,
October 17, 2006;
48(8):
1672 - 1681.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Therapy of PAH