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Pulmonary arterial hypertension: a look to the future
Journal of the American College of Cardiology © 2004 by the American College of Cardiology Foundation Published by Elsevier Inc.
Vol. 43, No. 12 Suppl S ISSN 0735-1097/04/$30.00 doi:10.1016/j.jacc.2004.02.030
Pulmonary Arterial Hypertension: A Look to the Future Lewis J. Rubin, MD,* Nazzareno Galie`, MD† La Jolla, California, and Bologna, Italy 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. (J Am Coll Cardiol 2004;43:89S–90S) © 2004 by the American College of Cardiology Foundation
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 From the *Pulmonary Vascular Center, University of California–San Diego School of Medicine, La Jolla, California; and the †Institute of Cardiology, University of Bologna, Bologna, Italy. Manuscript received January 29, 2004; accepted February 3, 2004.
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
90S
Rubin and Galie` Future Directions in PAH
Abbreviations and Acronyms BMPR2 ⫽ bone morphogenetic protein receptor-2 FPAH ⫽ familial pulmonary artery hypertension PAH ⫽ pulmonary arterial hypertension PDE5 ⫽ phosphodiesterase-5
JACC Vol. 43, No. 12 Suppl S June 18, 2004:89S–90S
4. 5. 6.
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. Reprint requests and correspondence: Dr. Lewis J. Rubin, UCSD Medical Center, 9300 Campus Point Drive, M/C 7372, La Jolla, California 92037. E-mail: [email protected].
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: 737–44. 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;26:81–4. 3. Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the
7. 8. 9.
10. 11.
12.
13. 14.
15. 16. 17. 18.
19. 20.
gene encoding BMPR2, a receptor member of the TGF-beta family. J Med Genet 2000;37:741–5. Derynck R, Zhang YE. TGF-beta-induced signalling pathways. Nature 2003;425:581–3. 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 –5. 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;159:1925–32. Yuan JX, Aldinger AM, Juhaszova M, et al. Dysfunctional voltagegated K⫹ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation 1998;98:400 –6. Mandegar M, Remillard CV, Yuan JX. Ion channels in pulmonary arterial hypertension. Prog Cardiovasc Dis 2002;45:81–114. 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; 108:1141–50. Du L, Sullivan CC, Chu D, et al. Signaling molecules in nonfamilial pulmonary hypertension. N Engl J Med 2003;348:500 –9. 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: L887–94. Barst RJ, Rubin LJ, Long WA, et al., for the Primary 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. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896 –903. 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 –502. Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002;347:322–9. 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. Fanburg BL, Lee SL. A new role for an old molecule: serotonin as a mitogen. Am J Physiol 1997;272:L795–806. 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 –21. 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;166:1403–8. 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 –5.
Vol. 43, No. 12 Suppl S ISSN 0735-1097/04/$30.00 doi:10.1016/j.jacc.2004.02.030
Pulmonary Arterial Hypertension: A Look to the Future Lewis J. Rubin, MD,* Nazzareno Galie`, MD† La Jolla, California, and Bologna, Italy 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. (J Am Coll Cardiol 2004;43:89S–90S) © 2004 by the American College of Cardiology Foundation
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 From the *Pulmonary Vascular Center, University of California–San Diego School of Medicine, La Jolla, California; and the †Institute of Cardiology, University of Bologna, Bologna, Italy. Manuscript received January 29, 2004; accepted February 3, 2004.
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
90S
Rubin and Galie` Future Directions in PAH
Abbreviations and Acronyms BMPR2 ⫽ bone morphogenetic protein receptor-2 FPAH ⫽ familial pulmonary artery hypertension PAH ⫽ pulmonary arterial hypertension PDE5 ⫽ phosphodiesterase-5
JACC Vol. 43, No. 12 Suppl S June 18, 2004:89S–90S
4. 5. 6.
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. Reprint requests and correspondence: Dr. Lewis J. Rubin, UCSD Medical Center, 9300 Campus Point Drive, M/C 7372, La Jolla, California 92037. E-mail: [email protected].
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: 737–44. 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;26:81–4. 3. Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the
7. 8. 9.
10. 11.
12.
13. 14.
15. 16. 17. 18.
19. 20.
gene encoding BMPR2, a receptor member of the TGF-beta family. J Med Genet 2000;37:741–5. Derynck R, Zhang YE. TGF-beta-induced signalling pathways. Nature 2003;425:581–3. 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 –5. 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;159:1925–32. Yuan JX, Aldinger AM, Juhaszova M, et al. Dysfunctional voltagegated K⫹ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation 1998;98:400 –6. Mandegar M, Remillard CV, Yuan JX. Ion channels in pulmonary arterial hypertension. Prog Cardiovasc Dis 2002;45:81–114. 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; 108:1141–50. Du L, Sullivan CC, Chu D, et al. Signaling molecules in nonfamilial pulmonary hypertension. N Engl J Med 2003;348:500 –9. 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: L887–94. Barst RJ, Rubin LJ, Long WA, et al., for the Primary 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. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896 –903. 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 –502. Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002;347:322–9. 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. Fanburg BL, Lee SL. A new role for an old molecule: serotonin as a mitogen. Am J Physiol 1997;272:L795–806. 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 –21. 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;166:1403–8. 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 –5.