Emerging treatments
Emerging therapeutic strategies for pulmonary arterial hypertension
The application of newer therapies for pulmonary arterial hypertension (PAH) such as prostanoids, endothelin receptor antagonists and phosphodieasterase inhibitors have ameliorated exercise capacity and quality of life in many affected patients. However, there is still no cure. Therefore, based on the known pathobiology, new drugs are under investigation, some of which we like to present below.
Cyclic nucleotide pathways
The efficacy of prostanoids (which stimulate cyclic AMP (cAMP) synthesis), nitric oxide (which increases cyclic GMP production) and Sildenafil (which inhibits cyclic GMP (cGMP) degradation) demonstrate the efficacy of pharmacological manipulation of the cyclic nucleotide pathways as a strategy for treating PAH. Additional strategies directed at elevating intracellular cAMP levels and amplifying the effect of prostacyclin signaling by inhibiting other phosphodieasterase enzymes may also be useful. Alternative pathways in increasing cGMP and cAMP may prove effective. Simple L-arginine supplementation to stimulate NO production is of limited value (1), as the concentration of L-arginine needed to halve the enzyme velocity of the endothelial nitric oxide synthetase (eNOS) is very low (Km ≈3µM), while plasma levels of L-arginine are around 100 µM. Moreover, endothelial cells express arginases, which can reduce L-arginine availability, and circulating endogenous inhibitors of the eNOS, such as asymmetric dimethyl-L-arginine (ADMA), which compete with L-arginine for eNOS. Pharmacological modulation of these pathways might provide future therapies for PAH.
Another mechanism to increase NO bioavailability might be the increase in expression and activity of the eNOS, for example by HMG-CoA-reductase inhibitors, known as statins, or directly by gene transfer (for both see below), and ensuring sufficient level of the essential enzyme co-factor tetrahydrobiopteridin (BH4) (2). In the absence or relative deficiency of BH4, the NOS become “uncoupled”, allowing the production of superoxide radicals in place of NO. PAH is associated with increased oxidative stress, which may result in the reduction of BH4 to BH2 and BH4 knockout mice develop PAH, while increased endothelial BH4 protects them. Combined treatment with BH4 and superoxide dismutase has already been shown to restore endothelial function in a porcine model of persistent PAH of the newborn.
NO independent soluble guanylyl cyclase (sGC) activators, such as BAY41-2272 and BAY58-2267 also have a therapeutic potential based on their pulmonary vasodilator effect and ability to attenuate and reverse PAH in an animal models and an anti-proliferative effect in isolated pulmonary arterial smooth muscle cells (3-6).
HMG-CoA reductase inhibitors ("statins")
Statins have been demonstrated to have antiproliferative, anti-inflammatory, anti-thrombotic and anti-oxidant effects in addition to their cholesterol lowering effect (7,8). Simvastatin has been tested in an open-label observational study of patients with PAH and was found to be safe and effective (7). Furthermore, statins enhance BNPR2-expression and have also been reported to increase numbers of peripherally circulating endothelial precursor cells (9, 10) Circulating endothelial precursor cells are considered as therapy in several ischemic diseases, such as coronary heart or peripheral vascular disease (10). Randomized controlled trials to address the efficacy of statins in PH are currently under way.
TGF-beta / BMP signaling
TGF-beta signaling and impaired BMPR2 signal transduction are involved in the pathogenesis of PAH. Recent reports indicate that BMP signaling regulates potassium channels and hypoxia downregulates the expression of BMPR II (11, 12). In the future, it might be possible to influence some of these pathways to modulate BMP receptor expression and downstream pathways which might be dysfunctional in PAH.
Vasoactive peptides
Adrenomodullin (AM)
AM is a 52 amino acid vasodilator peptide that shares some homology with calcitonin-gene related peptide and amylin. Plasma levels are elevated in patients with PAH and correlate with disease severity. AM acts vasodilatative through the calcitonin receptor-like receptors (CRCL). Infusion of AM significantly decreases the pulmonary vascular resistance (PVR) but also decreases systemic blood pressure. In a uncontrolled study inhalation of AM decreased PVR without significant systemic side effect (13, 14).
Vasoactive intestinal peptide (VIP)
In addition to regulation of water and electrolyte secretion in the gut, VIP also acts as potent vasodilator. VIP has shown a favorable effect on pulmonary hemodynamics in preliminary studies (15, 16).
Serotonin
Serotonin or 5-hydroxytryptamine (5-HT) has been implicated in the pathogenesis of PAH (17, 18). 5-HT levels are increased in the plasma of patients with idiopathic and anorexigen-associated PAH whereas platelet levels are low (19-22). The mechanisms by which serotonin contributes to the development of PAH are still incompletely understood, however, recent experimental models suggest a role in both, vasoconstriction and cell proliferation (23). Serotonin reuptake inhibitors (SSRI) have been shown to reverse PH in rats and recently, a retrospective cohort study has shown a reduced mortality of patients under SSRI (24, 25). As SSRI’s are well tolerated and widely used in patients with depression, the clinical investigation of the effect of SSRI’s in PH seems reasonable. A randomized controlled pilot trial addressing this question is currently under way. Until the results of these or comparable further studies are available, no recommendation about SSRI’s in PH can be provided.
Rho and Rho-kinases as therapeutic targets
The pleiotropic effects of statins in the vascular wall may be attributed in part to the inhibition of GTPases such as RhoA and the downstream mediator Rho-kinase (ROCK) (26, 27). The Rho-ROCK pathway is involved in mediating the effects of several vasoactive agents, such as ET-1, Serotonin and Angiotensin, and cellular processes implicated in the pathogenesis of cardiovascular diseases such as PAH. Selective inhibitors of Rho-kinase have been developed, which are effective in inhibiting experimental PAH (eg. Y-27632, fasudil and hydroxyfasudil). Inhibition of the Rho-ROCK pathway may also be involved in the beneficial effect of Sildenafil in PAH, by enhancing the phosphorylation and cytoplasmatic localization of RhoA and thereby preventing the activation of downstream effectors (28). The acute iv application of fasudil has been shown to reduce the PVR in patients with PAH, but its long term effects have still to be determined (29).
Potassium channels
Potassium channels represent another promising target for regulating pulmonary vascular tone and structure. Reduced potassium channel activity leads to membrane depolarisation, activation of calcium channels and increasing intracellular calcium, causing vasoconstriction and smooth muscle cell proliferation (30, 31). The activity of potassium channels is modulated by a variety of factors, such as hypoxia, anorexic agents, ET-1, Serotonin, NO and prostacyclin. Dichloroacetate, a mitochondrial pyruvate dehydrogenase kinase inhibitor, reverses downregulation of potassium channels, selectively modulates pulmonary hemodynamics and abnormal smooth muscle cell proliferation by increasing apoptosis and inhibiting proliferation in the pulmonary arterial wall of experimental animal models (32, 33). Dichloroacetate has been used as a lactate lowering drug and appeared safe in the acute and chronic treatment of metabolic disorders, but might be associated with peripheral nerve disorders (34, 35).
Growth factor receptor tyrosine kinases
Platelet derived growth factor (PDGF) and endothelial growth factor (EGF) have both been implicated in the abnormal proliferation and migration of pulmonary arterial smooth muscle cells. PDGF receptor expression is increased in lung tissue of PAH patients. Blockade of PDGF signaling by the receptor tyrosine kinase (RTK) inhibitor STI571 (imatinib mesylate, Glivec®) has been reported to reverse vascular proliferation in a mouse model of PAH (36). One case report of a patient with severe, refractory PAH with a favorable response to imatinib has been published so far (37). Despite this promising report, well designed randomized controlled trials to investigate the role of PDGF-inhibitors in the therapy of PAH are crucial before any therapeutic guidelines can be released. Two further RTK inhibitors (nilotinib and dastinib) are currently undergoing trials in patients with chronic myeloid leukemia who became resistant to imatinib. They might even be more potent inhibitors and will possibly be investigated in PAH as well.
Inflammation and immune response
PH is a frequent and potentially deadly complication of a heterogeneous assortment of systemic inflammatory and autoimmune conditions, such as scleroderma, systemic lupus, mixed connective tissue disease and thyroiditis (38-41). A significant number of patients with IPAH have laboratory evidence of autoimmunity and inflammation (42, 43) It is also well recognized, that patients with human immunodeficiency virus (HIV) infection are at risk for developing PH and that the presence of PAH significantly worsens survival in this patient population (44-48). The mechanism by which HIV infection contributes to PH and why antiretroviral therapy improves PH in some patients are still unclear, the virus itself has never been located in the pulmonary vessels.
The putative role of inflammation and autoimmunity in the development of PAH raises the question about a beneficial effect of anti-inflammatory therapy. There exists numerous case reports of patients with PAH associated with connective tissue disease improving clinically and hemodynamically after immunosuppressive therapy. However, there are no prospective cohort or randomized controlled studies published to date addressing the efficacy of immunosuppressive therapy in PAH. It is therefore difficult to make recommendations regarding the use of immunosuppressive therapy in the treatment of PAH. But most experts agree, that the associated condition in connective tissue disease associated PH should be addressed according to best clinical practice.
Erythropoietin
There is compelling evidence that erythropoietin provides protection from injury to neurological and myocardial tissue through a distinct heteroreceptor complex, comprising the erythropoietin-receptor (EPOR) and the common beta-receptor subunit, and that this tissue protective activity is independent of the effect on erythropoiesis (49). Chronically hypoxic erythropoietin treated rats exhibited significantly reduced pulmonary vascular resistance and remodeling (50). Erythropoietin treatment also enhances the mobilization of progenitor cells and repair of injured endothelium in the femoral artery of mice, preventing neointimal hyperplasia (51). Nonetheless, the potential therapeutic value of erythropoietin in PAH is still to be established in experimental models.
Phosphodiesterase inhibitors (PDEI) others than PEDI 5
In a recent study it was shown that real-time PCR and immunoblotting demonstrated increased expression of PDE 1A, PDE 1C, PDE 3B, and PDE 5A in pulmonary artery smooth muscle cells from PAH patients compared with controls (52). As a result, agonist-stimulated cAMP levels were significantly reduced unless a PDE inhibitor was present. Treatment with PDE1C-targeted small interference RNA enhanced cAMP accumulation and inhibited cellular proliferation. These results imply that an increase in PDE1C, contributes to decreased cAMP and increased proliferation of PASMC in patients with PHT. Thus, PDE1 inhibition may provide novel targets for the treatment of PAH.
References:
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22. Eddahibi S, Raffestin B, Hamon M, Adnot S. Is the serotonin transporter involved in the pathogenesis of pulmonary hypertension? JLab ClinMed 2002;139:194-201.
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24. Marcos E, Adnot S, Pham MH, Nosjean A, Raffestin B, Hamon M, Eddahibi S. Serotonin transporter inhibitors protect against hypoxic pulmonary hypertension. AmJRespirCrit Care Med 2003;168:487-493.
25. Kawut SM, Horn EM, Berekashvili KK, Lederer DJ, Widlitz AC, Rosenzweig EB, Barst RJ. Selective serotonin reuptake inhibitor use and outcomes in pulmonary arterial hypertension. Pulm Pharmacol Ther 2006;19:370-374.
26. Budzyn K, Marley PD, Sobey CG. Targeting Rho and Rho-kinase in the treatment of cardiovascular disease. Trends Pharmacol Sci 2006;27:97-104.
27. Loirand G, Guerin P, Pacaud P. Rho kinases in cardiovascular physiology and pathophysiology. Circ Res 2006;98:322-334.
28. Guilluy C, Sauzeau V, Rolli-Derkinderen M, Guerin P, Sagan C, Pacaud P, Loirand G. Inhibition of RhoA/Rho kinase pathway is involved in the beneficial effect of sildenafil on pulmonary hypertension. Br J Pharmacol 2005;146:1010-1018.
29. Fukumoto Y, Matoba T, Ito A, Tanaka H, Kishi T, Hayashidani S, Abe K, Takeshita A, Shimokawa H. Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension. Heart 2005;91:391-392.
30. Hong Z, Smith AJ, Archer SL, Wu XC, Nelson DP, Peterson D, Johnson G, Weir EK. Pergolide is an inhibitor of voltage-gated potassium channels, including Kv1.5, and causes pulmonary vasoconstriction. Circulation 2005;112:1494-1499.
31. Platoshyn O, Golovina VA, Bailey CL, Limsuwan A, Krick S, Juhaszova M, Seiden JE, Rubin LJ, Yuan JX. Sustained membrane depolarization and pulmonary artery smooth muscle cell proliferation. Am J Physiol Cell Physiol 2000;279:C1540-1549.
32. McMurtry MS, Bonnet S, Wu X, Dyck JR, Haromy A, Hashimoto K, Michelakis ED. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res 2004;95:830-840.
33. Michelakis ED, McMurtry MS, Wu XC, Dyck JR, Moudgil R, Hopkins TA, Lopaschuk GD, Puttagunta L, Waite R, Archer SL. 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;105:244-250.
34. Kaufmann P, Engelstad K, Wei Y, Jhung S, Sano MC, Shungu DC, Millar WS, Hong X, Gooch CL, Mao X, Pascual JM, Hirano M, Stacpoole PW, DiMauro S, De Vivo DC. Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology 2006;66:324-330.
35. Stacpoole PW, Nagaraja NV, Hutson AD. Efficacy of dichloroacetate as a lactate-lowering drug. J Clin Pharmacol 2003;43:683-691.
36. Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, Roth M, Sydykov A, Lai YJ, Weissmann N, Seeger W, Grimminger F. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 2005;115:2811-2821.
37. Ghofrani HA, Seeger W, Grimminger F. Imatinib for the treatment of pulmonary arterial hypertension. N Engl J Med 2005;353:1412-1413.
38. Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, Christman BW, Weir EK, Eickelberg O, Voelkel NF, Rabinovitch M. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:13S-24S.
39. Voelkel NF, Cool C, Lee SD, Wright L, Geraci MW, Tuder RM. Primary pulmonary hypertension between inflammation and cancer. Chest 1998;114:225S-230S.
40. Dorfmuller P, Perros F, Balabanian K, Humbert M. Inflammation in pulmonary arterial hypertension. Eur Respir J 2003;22:358-363.
41. Humbert M, Monti G, Brenot F, Sitbon O, Portier A, Grangeot-Keros L, Duroux P, Galanaud P, Simonneau G, Emilie D. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med 1995;151:1628-1631.
42. Nicolls MR, Taraseviciene-Stewart L, Rai PR, Badesch DB, Voelkel NF. Autoimmunity and pulmonary hypertension: a perspective. Eur Respir J 2005;26:1110-1118.
43. Carreira PE. Pulmonary hypertension in autoimmune rheumatic diseases. Autoimmun Rev 2004;3:313-320.
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45. Speich R, Jenni R, Opravil M, Jaccard R. Regression of HIV-associated pulmonary arterial hypertension and long-term survival during antiretroviral therapy. Swiss Med Wkly 2001;131:663-665.
46. Speich R, Jenni R, Opravil M, Pfab M, Russi EW. Primary pulmonary hypertension in HIV infection. Chest 1991;100:1268-1271.
47. Mehta NJ, Khan IA, Mehta RN, Sepkowitz DA. HIV-Related pulmonary hypertension: analytic review of 131 cases. Chest 2000;118:1133-1141.
48. Zuber JP, Calmy A, Evison JM, Hasse B, Schiffer V, Wagels T, Nuesch R, Magenta L, Ledergerber B, Jenni R, Speich R, Opravil M. Pulmonary arterial hypertension related to HIV infection: improved hemodynamics and survival associated with antiretroviral therapy. Clin Infect Dis 2004;38:1178-1185.
49. Petit RD, Warburton RR, Ou LC, Brinck-Johnson T, Hill NS. Exogenous erythropoietin fails to augment hypoxic pulmonary hypertension in rats. Respir Physiol 1993;91:271-282.
50. Petit RD, Warburton RR, Ou LC, Hill NS. Pulmonary vascular adaptations to augmented polycythemia during chronic hypoxia. J Appl Physiol 1995;79:229-235.
51. Weissmann N, Manz D, Buchspies D, Keller S, Mehling T, Voswinckel R, Quanz K, Ghofrani HA, Schermuly RT, Fink L, Seeger W, Gassmann M, Grimminger F. Congenital erythropoietin over-expression causes "anti-pulmonary hypertensive" structural and functional changes in mice, both in normoxia and hypoxia. Thromb Haemost 2005;94:630-638.
52. Murray F, Patel HH, Suda RY, Zhang S, Thistlethwaite PA, Yuan JX, Insel PA. Expression and activity of cAMP phosphodiesterase isoforms in pulmonary artery smooth muscle cells from patients with pulmonary hypertension: role for PDE1. Am J Physiol Lung Cell Mol Physiol 2007;292:L294-303.
The application of newer therapies for pulmonary arterial hypertension (PAH) such as prostanoids, endothelin receptor antagonists and phosphodieasterase inhibitors have ameliorated exercise capacity and quality of life in many affected patients. However, there is still no cure. Therefore, based on the known pathobiology, new drugs are under investigation, some of which we like to present below.
Cyclic nucleotide pathways
The efficacy of prostanoids (which stimulate cyclic AMP (cAMP) synthesis), nitric oxide (which increases cyclic GMP production) and Sildenafil (which inhibits cyclic GMP (cGMP) degradation) demonstrate the efficacy of pharmacological manipulation of the cyclic nucleotide pathways as a strategy for treating PAH. Additional strategies directed at elevating intracellular cAMP levels and amplifying the effect of prostacyclin signaling by inhibiting other phosphodieasterase enzymes may also be useful. Alternative pathways in increasing cGMP and cAMP may prove effective. Simple L-arginine supplementation to stimulate NO production is of limited value (1), as the concentration of L-arginine needed to halve the enzyme velocity of the endothelial nitric oxide synthetase (eNOS) is very low (Km ≈3µM), while plasma levels of L-arginine are around 100 µM. Moreover, endothelial cells express arginases, which can reduce L-arginine availability, and circulating endogenous inhibitors of the eNOS, such as asymmetric dimethyl-L-arginine (ADMA), which compete with L-arginine for eNOS. Pharmacological modulation of these pathways might provide future therapies for PAH.
Another mechanism to increase NO bioavailability might be the increase in expression and activity of the eNOS, for example by HMG-CoA-reductase inhibitors, known as statins, or directly by gene transfer (for both see below), and ensuring sufficient level of the essential enzyme co-factor tetrahydrobiopteridin (BH4) (2). In the absence or relative deficiency of BH4, the NOS become “uncoupled”, allowing the production of superoxide radicals in place of NO. PAH is associated with increased oxidative stress, which may result in the reduction of BH4 to BH2 and BH4 knockout mice develop PAH, while increased endothelial BH4 protects them. Combined treatment with BH4 and superoxide dismutase has already been shown to restore endothelial function in a porcine model of persistent PAH of the newborn.
NO independent soluble guanylyl cyclase (sGC) activators, such as BAY41-2272 and BAY58-2267 also have a therapeutic potential based on their pulmonary vasodilator effect and ability to attenuate and reverse PAH in an animal models and an anti-proliferative effect in isolated pulmonary arterial smooth muscle cells (3-6).
HMG-CoA reductase inhibitors ("statins")
Statins have been demonstrated to have antiproliferative, anti-inflammatory, anti-thrombotic and anti-oxidant effects in addition to their cholesterol lowering effect (7,8). Simvastatin has been tested in an open-label observational study of patients with PAH and was found to be safe and effective (7). Furthermore, statins enhance BNPR2-expression and have also been reported to increase numbers of peripherally circulating endothelial precursor cells (9, 10) Circulating endothelial precursor cells are considered as therapy in several ischemic diseases, such as coronary heart or peripheral vascular disease (10). Randomized controlled trials to address the efficacy of statins in PH are currently under way.
TGF-beta / BMP signaling
TGF-beta signaling and impaired BMPR2 signal transduction are involved in the pathogenesis of PAH. Recent reports indicate that BMP signaling regulates potassium channels and hypoxia downregulates the expression of BMPR II (11, 12). In the future, it might be possible to influence some of these pathways to modulate BMP receptor expression and downstream pathways which might be dysfunctional in PAH.
Vasoactive peptides
Adrenomodullin (AM)
AM is a 52 amino acid vasodilator peptide that shares some homology with calcitonin-gene related peptide and amylin. Plasma levels are elevated in patients with PAH and correlate with disease severity. AM acts vasodilatative through the calcitonin receptor-like receptors (CRCL). Infusion of AM significantly decreases the pulmonary vascular resistance (PVR) but also decreases systemic blood pressure. In a uncontrolled study inhalation of AM decreased PVR without significant systemic side effect (13, 14).
Vasoactive intestinal peptide (VIP)
In addition to regulation of water and electrolyte secretion in the gut, VIP also acts as potent vasodilator. VIP has shown a favorable effect on pulmonary hemodynamics in preliminary studies (15, 16).
Serotonin
Serotonin or 5-hydroxytryptamine (5-HT) has been implicated in the pathogenesis of PAH (17, 18). 5-HT levels are increased in the plasma of patients with idiopathic and anorexigen-associated PAH whereas platelet levels are low (19-22). The mechanisms by which serotonin contributes to the development of PAH are still incompletely understood, however, recent experimental models suggest a role in both, vasoconstriction and cell proliferation (23). Serotonin reuptake inhibitors (SSRI) have been shown to reverse PH in rats and recently, a retrospective cohort study has shown a reduced mortality of patients under SSRI (24, 25). As SSRI’s are well tolerated and widely used in patients with depression, the clinical investigation of the effect of SSRI’s in PH seems reasonable. A randomized controlled pilot trial addressing this question is currently under way. Until the results of these or comparable further studies are available, no recommendation about SSRI’s in PH can be provided.
Rho and Rho-kinases as therapeutic targets
The pleiotropic effects of statins in the vascular wall may be attributed in part to the inhibition of GTPases such as RhoA and the downstream mediator Rho-kinase (ROCK) (26, 27). The Rho-ROCK pathway is involved in mediating the effects of several vasoactive agents, such as ET-1, Serotonin and Angiotensin, and cellular processes implicated in the pathogenesis of cardiovascular diseases such as PAH. Selective inhibitors of Rho-kinase have been developed, which are effective in inhibiting experimental PAH (eg. Y-27632, fasudil and hydroxyfasudil). Inhibition of the Rho-ROCK pathway may also be involved in the beneficial effect of Sildenafil in PAH, by enhancing the phosphorylation and cytoplasmatic localization of RhoA and thereby preventing the activation of downstream effectors (28). The acute iv application of fasudil has been shown to reduce the PVR in patients with PAH, but its long term effects have still to be determined (29).
Potassium channels
Potassium channels represent another promising target for regulating pulmonary vascular tone and structure. Reduced potassium channel activity leads to membrane depolarisation, activation of calcium channels and increasing intracellular calcium, causing vasoconstriction and smooth muscle cell proliferation (30, 31). The activity of potassium channels is modulated by a variety of factors, such as hypoxia, anorexic agents, ET-1, Serotonin, NO and prostacyclin. Dichloroacetate, a mitochondrial pyruvate dehydrogenase kinase inhibitor, reverses downregulation of potassium channels, selectively modulates pulmonary hemodynamics and abnormal smooth muscle cell proliferation by increasing apoptosis and inhibiting proliferation in the pulmonary arterial wall of experimental animal models (32, 33). Dichloroacetate has been used as a lactate lowering drug and appeared safe in the acute and chronic treatment of metabolic disorders, but might be associated with peripheral nerve disorders (34, 35).
Growth factor receptor tyrosine kinases
Platelet derived growth factor (PDGF) and endothelial growth factor (EGF) have both been implicated in the abnormal proliferation and migration of pulmonary arterial smooth muscle cells. PDGF receptor expression is increased in lung tissue of PAH patients. Blockade of PDGF signaling by the receptor tyrosine kinase (RTK) inhibitor STI571 (imatinib mesylate, Glivec®) has been reported to reverse vascular proliferation in a mouse model of PAH (36). One case report of a patient with severe, refractory PAH with a favorable response to imatinib has been published so far (37). Despite this promising report, well designed randomized controlled trials to investigate the role of PDGF-inhibitors in the therapy of PAH are crucial before any therapeutic guidelines can be released. Two further RTK inhibitors (nilotinib and dastinib) are currently undergoing trials in patients with chronic myeloid leukemia who became resistant to imatinib. They might even be more potent inhibitors and will possibly be investigated in PAH as well.
Inflammation and immune response
PH is a frequent and potentially deadly complication of a heterogeneous assortment of systemic inflammatory and autoimmune conditions, such as scleroderma, systemic lupus, mixed connective tissue disease and thyroiditis (38-41). A significant number of patients with IPAH have laboratory evidence of autoimmunity and inflammation (42, 43) It is also well recognized, that patients with human immunodeficiency virus (HIV) infection are at risk for developing PH and that the presence of PAH significantly worsens survival in this patient population (44-48). The mechanism by which HIV infection contributes to PH and why antiretroviral therapy improves PH in some patients are still unclear, the virus itself has never been located in the pulmonary vessels.
The putative role of inflammation and autoimmunity in the development of PAH raises the question about a beneficial effect of anti-inflammatory therapy. There exists numerous case reports of patients with PAH associated with connective tissue disease improving clinically and hemodynamically after immunosuppressive therapy. However, there are no prospective cohort or randomized controlled studies published to date addressing the efficacy of immunosuppressive therapy in PAH. It is therefore difficult to make recommendations regarding the use of immunosuppressive therapy in the treatment of PAH. But most experts agree, that the associated condition in connective tissue disease associated PH should be addressed according to best clinical practice.
Erythropoietin
There is compelling evidence that erythropoietin provides protection from injury to neurological and myocardial tissue through a distinct heteroreceptor complex, comprising the erythropoietin-receptor (EPOR) and the common beta-receptor subunit, and that this tissue protective activity is independent of the effect on erythropoiesis (49). Chronically hypoxic erythropoietin treated rats exhibited significantly reduced pulmonary vascular resistance and remodeling (50). Erythropoietin treatment also enhances the mobilization of progenitor cells and repair of injured endothelium in the femoral artery of mice, preventing neointimal hyperplasia (51). Nonetheless, the potential therapeutic value of erythropoietin in PAH is still to be established in experimental models.
Phosphodiesterase inhibitors (PDEI) others than PEDI 5
In a recent study it was shown that real-time PCR and immunoblotting demonstrated increased expression of PDE 1A, PDE 1C, PDE 3B, and PDE 5A in pulmonary artery smooth muscle cells from PAH patients compared with controls (52). As a result, agonist-stimulated cAMP levels were significantly reduced unless a PDE inhibitor was present. Treatment with PDE1C-targeted small interference RNA enhanced cAMP accumulation and inhibited cellular proliferation. These results imply that an increase in PDE1C, contributes to decreased cAMP and increased proliferation of PASMC in patients with PHT. Thus, PDE1 inhibition may provide novel targets for the treatment of PAH.
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5th International Congress of the Swiss Society of Pulmonary Hypertension (SSPH)
28.-29. September 2012, Thun, Congress Hotel Seepark Thun
Informationen: www.imk.ch/sgph2012
SSPH Research Prize 2012
Deadline for submission: April 30, 2012
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