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Pulmoner arteriyel hipertansiyon: patogenez

Year 2008, Volume: 15 Issue: 4, 46 - 53, 29.05.2009

Abstract

Süleyman Demirel Üniversitesi
TIP FAKÜLTESİ DERGİSİ: 2008 Aralık; 15 (4)


Pulmoner arteriyel hipertansiyon: patogenez

Önder Öztürk, Ahmet Akaya



Özet
Pulmoner arteriyel hipertansiyon (PAH), endotel ve düz kas hücre proliferasyonu, media
tabakasında hipertrofi, in situ trombozis ile ilişkilidir. Buna karşın PAH patogenezi
tam olarak açıklanamamıştır. Vazodilatör ve vazokonstriktörler arasındaki dengenin
bozulması sonucu pulmoner damar direnci artmakta ve damar duvarında yeniden
yapılanma meydana gelerek PAH oluştuðu düşünülmektedir. Bu derleme ile PAH
patogenezinde rol oynayan mekanizmaları ve aralarındaki ilişkiyi açıklamak istedik.

Anahtar kelimeler: pulmoner arteriyel hipertansiyon, patogenez, genetik.

Abstract

Pulmonary arterıal hypertensıon: pathogenesıs

Pulmonary arterial hypertension (PAH) is histologically characterized by endothelial and smooth muscle cell proliferation, medial hypertrophy, and thrombosis in situ. However the pathogenesis of PAH remains unclear. Elevated pulmonary vascular resistance seems to result from an imbalance between locally produced vasodilators and vasoconstrictors, in addition to vascular wall remodeling. This article reviews the mechanisms of PAH and their relationships with each
other.

Key words: pulmonar arterial hypertension, pathogenesis, genetic

References

  • Sak SD, Perçinel S. Pulmoner hipertansiyonda histopatolojik bulgular In: Karabýyýkoðlu G. ed. Pulmoner Hipertansiyon. Ankara: Antýp Basýmevi; 2007;13-17
  • Said IS. Mediators and modulators of pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 2006; 291(4): 547–58.
  • Karabýyýkoðlu G. Pulmoner arteryal hipertansiyon. In: Karabýyýkoðlu G. ed. Pulmoner Hipertansiyon. Ankara: Antýp Basýmevi; 2007;112-30
  • Lee SH. Rubin LJ. Current treatmnet strategies for pulmonary arterial hypertension. J. Int. Med.2005;258(3):199-215
  • Travis WD, Colby TV, Koss MN, Rosado-de Christenson M, Müller NL, King TE. Pulmonary hypertension and other vascular disorders in nonneoplastic disorders of the lower respiratory tract. AFIP 2002;767-92
  • Önen ZP, Karabýyýkoðlu G. Pulmoner damarlarýn yeniden yapýlanmasý. In: Karabýyýkoðlu G. ed. Pulmoner Hipertansiyon. Ankara: Antýp Basýmevi; 2007; 18-25.
  • Li G, Chen SJ, Oparil S, Yiu-Fai C, Thompson JA. Direct in vivo evidence demonstrating neointimal migration of adventitial fibroblast after balon of rat carotid arteries. Circulation 2000;101(12):1362-65
  • Ghamra ZW, Dweik RA. Primary pulmonary hypertension: an overview of epidemiology and pathogenesis. 2003;70 (Suppl 1): S 2-8
  • Loyd JE, Atkinson JB, Pietra GG, , . Heterogeneity of pathologic lesions in familial primary pulmonary hypertension. Am Rev Respir Dis 1988; 138(4):952- 57
  • Bjornsson J, Edwards WD. Primary pulmonary hypertension: a histopathologic study of 80 cases. Mayo Clin Proc 1985; 60 (1):16-25
  • Olschewski A, Li Y, Tang B, Hanze J, Eul B, Bohle RM, et al. Impact of TASK-1 in human pulmoner artery smooth muscle cells. Circ Res. 2006;98(8):1072-80
  • Piacentini L, Gray M, Honbo NY, Chentoufi J, Bergman M, Karliner JS. Endothelin-1 stimulates cardiac fibroblast proliferation through activation of protein kinase C. J Mol Cell Cardiol. 2000;32(4):565–76
  • Miyauchi T, Masaki T. Pathophysiology of endothelin in the cardiovascular system. Annu Rev Physiol. 1999;61:391–415
  • Genetik Mutasyon BMPRII
  • Kolaylaþtýrýcý Genler
  • Pulmoner vazokontriksiyon ve
  • damarda yeniden yapýlanma Tromboksan A2 Anorejigenler PDGF Prostosiklin Endotelyal NOS ANP VIP/PACAP Adrenomedullin VEGF PAH
  • Sirois MG, Filep JG, Rousseau A, Fournier A, Plante GE, Sirois P. Endothelin-1 enhances vascular permeability in conscious rats: role of thromboxane A2. Eur J Pharmacol. 1992;214(2):119–25
  • Rae GA, Henriques MGMO. Endothelins in inflammation. In Said SI, ed. Proinflammatory and antiinflammatory peptides. New York: Marcel Dekker Inc; 1998:163–202
  • Kedzierski RM, Yanagisawa M. Endothelin system: the double-edged sword in health and disease. Annu Rev Pharmacol Toxicol. 2001;41:851–76
  • Dagassan PH, Breu V, Clozel M, Künzli A, Vogt P, Turina M, et al. Up-regulation of endothelin-B receptors in atherosclerotic human coronary arteries. J Cardiovasc Pharmacol. 1996;27(1):147–53
  • Kim NH, Rubin LJ. Endothelin in health and disease: endothelin receptor antagonists in the management of pulmonary artery hypertension. J Cardiovasc Pharmacol Ther 2002;7(1):9–19
  • Shi-Wen X, Denton CP, Dashwood MR, Holmes AM, Bou-Gharios G, Pearson JD, et al. Fibroblast matrix gene expression and connective tissue remodeling: role of endothelin-1. J Invest Dermatol. 2001;116(3):417–25
  • Dweik RA. Pulmonary hypertension and the search for the selective pulmonary vasodilator. Lancet 2002;360 (9337): 886-7
  • Dweik RA. The promise and reality of nitric oxide in the diagnosis and treatment of lung disease. Cleve Clin J Med 2001; 68(6):486-93
  • 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(3):917-23
  • 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(4):233-43
  • Ozkan M, Dweik RA, Ahmad M. Drug-induced lung disease. Cleve Clin J Med 2001; 68(9):782-95
  • Arroliga AC, Dweik RA, Kaneko FJ, Erzurum SC. Primary pulmonary hypertension: update on pathogenesis and novel therapies. Cleve Clin J Med 2000; 67(3):175-90
  • Dweik RA, Erzurum SC. Effects of nitric oxide and cyclic GMP on smooth muscle proliferation. In: Moss J, ed. LAM and other diseases characterized by smooth muscle proliferation (Lung Biology in Health and Disease series). New York: Marcel Dekker, 1999;131:333-49
  • Dweik RA, Laskowski D, Abu-Soud HM, Kaneko F, Hutte R, Stuehr DJ, al. Nitric oxide synthesis in the lung. Regulation by oxygen through a kinetic mechanism. J Clin Invest 1998;101(3):660-66
  • Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993; 329(27):2002-12
  • Nathan C, Xie QW. Nitric oxide synthases: roles, tolls, and controls. Cell 1994;78(6): 915-18
  • Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332(6163):411-15
  • Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993; 328(24):1732-39
  • 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(6): 464-69
  • Moncada S, Vane JR. Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2, and prostacyclin. Pharmacol Rev 1978; 30(3):293- 331
  • Gorman RR, Bunting S, Miller OV. Modulation of human platelet adenylate cyclase by prostacyclin (PGX). Prostaglandins 1977;13(3):377-88
  • Geraci MW, Gao B, Shepherd DC, Moore MD, Westcott JY, Fagan KA, et al. Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension. J Clin Invest 1999;103(11):1509-15
  • Tuder RM, Cool CD, Geraci MW, Wang J, Abman SH, Wright L, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 1999;159(6):1925-32
  • Davie N, Haleen SJ, Upton PD, Polak JM, Yacoub MH, Morrell NW, et al. ETA and ETB receptors modulate the proliferation of human pulmonary artery smooth muscle cells. Am J Respir Crit Care 2002;165(3):398–405
  • Christman BW, McPherson CD, Newman JH, King GA, Bernard GR, Groves BM, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 1992; 327(2):70-5
  • Das M, Dempsey EC, Bouchey D, Reyland MR, Stenmark KR. Chronic hypoxia induces aggregated growth responses in pulmonary arterial adventitial fibroblast. Am J Respir Crit Care Med 2000;22(1):15- 25
  • Welsh CH, Hassell KL, Badesch DB, Kressin DC, Marlar RA. Coagulation and fibrinolytic profiles in patients with severe pulmonary hypertension. Chest 1996;110(3):710-17
  • Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, MatsuoH, et al. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun 1993;192(2):553–60
  • Westphal M, Booke M, Dinh-Xuan AT. Adrenomedullin: a smart road from pheochromocytoma to treatment of pulmonary hypertension. Eur Respir J 2004;24(4): 518–20
  • 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(5):927–34
  • 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(3):737–44
  • Blobe GC, Schiemann WP, Lodish HF. Role of transforming growth factor in human disease. N Engl J Med 2000;342(18):1350–58
  • Machado RD, Aldred MA, James V, Harrison RE, Patel B, Schwalbe EC, et al. Mutations of the TGF- type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat 2006; 27(2):121–32
  • Jason X, Yuan J, Rubin LJ. Pathogenesis of pulmonary arterial hypertension. The need for multiple hits. Circulation 2005;111(5):534-38
  • Runo JR, Loyd JE. Primary pulmonary hypertension. 2003. Lancet 361(9368):1533–44
  • Derynck R, Zhang YE. Smad-dependent and Smadin- independent pathways in TGF-beta family signalling. Nature 2003;425(6958):577–84
  • Yang X, Long L, Southwood M, Rudarakanchana N, Upton PD, Jeffery TK, et al. Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension. Circ Res 2005;96(10):1053-63
  • Austin ED, Loyd JE. Genetics and mediators in pulmonary arterial hypertension. Clin Chest Med 2007; 28(1):43–57
  • Elliott CG. Genetics of pulmonary arterial hypertension: current and future implications. Semin Respir Crit Care Med 2005;26(4):365–71
  • Newman JH. Pulmonary hypertension. Am J Respir Crit Care Med 2005;172(9): 1072–77
  • Beppu H, Ichinose F, Kawai N, Jones RC, Yu PB, Zapol WM, et al. BMPR-II heterozygous mice have mild pulmonary hypertension and an impaired pulmonary vascular remodeling response to prolonged hypoxia. Am J Physiol Lung Cell Mol Physiol 2004;287(6):1241–47
Year 2008, Volume: 15 Issue: 4, 46 - 53, 29.05.2009

Abstract

References

  • Sak SD, Perçinel S. Pulmoner hipertansiyonda histopatolojik bulgular In: Karabýyýkoðlu G. ed. Pulmoner Hipertansiyon. Ankara: Antýp Basýmevi; 2007;13-17
  • Said IS. Mediators and modulators of pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 2006; 291(4): 547–58.
  • Karabýyýkoðlu G. Pulmoner arteryal hipertansiyon. In: Karabýyýkoðlu G. ed. Pulmoner Hipertansiyon. Ankara: Antýp Basýmevi; 2007;112-30
  • Lee SH. Rubin LJ. Current treatmnet strategies for pulmonary arterial hypertension. J. Int. Med.2005;258(3):199-215
  • Travis WD, Colby TV, Koss MN, Rosado-de Christenson M, Müller NL, King TE. Pulmonary hypertension and other vascular disorders in nonneoplastic disorders of the lower respiratory tract. AFIP 2002;767-92
  • Önen ZP, Karabýyýkoðlu G. Pulmoner damarlarýn yeniden yapýlanmasý. In: Karabýyýkoðlu G. ed. Pulmoner Hipertansiyon. Ankara: Antýp Basýmevi; 2007; 18-25.
  • Li G, Chen SJ, Oparil S, Yiu-Fai C, Thompson JA. Direct in vivo evidence demonstrating neointimal migration of adventitial fibroblast after balon of rat carotid arteries. Circulation 2000;101(12):1362-65
  • Ghamra ZW, Dweik RA. Primary pulmonary hypertension: an overview of epidemiology and pathogenesis. 2003;70 (Suppl 1): S 2-8
  • Loyd JE, Atkinson JB, Pietra GG, , . Heterogeneity of pathologic lesions in familial primary pulmonary hypertension. Am Rev Respir Dis 1988; 138(4):952- 57
  • Bjornsson J, Edwards WD. Primary pulmonary hypertension: a histopathologic study of 80 cases. Mayo Clin Proc 1985; 60 (1):16-25
  • Olschewski A, Li Y, Tang B, Hanze J, Eul B, Bohle RM, et al. Impact of TASK-1 in human pulmoner artery smooth muscle cells. Circ Res. 2006;98(8):1072-80
  • Piacentini L, Gray M, Honbo NY, Chentoufi J, Bergman M, Karliner JS. Endothelin-1 stimulates cardiac fibroblast proliferation through activation of protein kinase C. J Mol Cell Cardiol. 2000;32(4):565–76
  • Miyauchi T, Masaki T. Pathophysiology of endothelin in the cardiovascular system. Annu Rev Physiol. 1999;61:391–415
  • Genetik Mutasyon BMPRII
  • Kolaylaþtýrýcý Genler
  • Pulmoner vazokontriksiyon ve
  • damarda yeniden yapýlanma Tromboksan A2 Anorejigenler PDGF Prostosiklin Endotelyal NOS ANP VIP/PACAP Adrenomedullin VEGF PAH
  • Sirois MG, Filep JG, Rousseau A, Fournier A, Plante GE, Sirois P. Endothelin-1 enhances vascular permeability in conscious rats: role of thromboxane A2. Eur J Pharmacol. 1992;214(2):119–25
  • Rae GA, Henriques MGMO. Endothelins in inflammation. In Said SI, ed. Proinflammatory and antiinflammatory peptides. New York: Marcel Dekker Inc; 1998:163–202
  • Kedzierski RM, Yanagisawa M. Endothelin system: the double-edged sword in health and disease. Annu Rev Pharmacol Toxicol. 2001;41:851–76
  • Dagassan PH, Breu V, Clozel M, Künzli A, Vogt P, Turina M, et al. Up-regulation of endothelin-B receptors in atherosclerotic human coronary arteries. J Cardiovasc Pharmacol. 1996;27(1):147–53
  • Kim NH, Rubin LJ. Endothelin in health and disease: endothelin receptor antagonists in the management of pulmonary artery hypertension. J Cardiovasc Pharmacol Ther 2002;7(1):9–19
  • Shi-Wen X, Denton CP, Dashwood MR, Holmes AM, Bou-Gharios G, Pearson JD, et al. Fibroblast matrix gene expression and connective tissue remodeling: role of endothelin-1. J Invest Dermatol. 2001;116(3):417–25
  • Dweik RA. Pulmonary hypertension and the search for the selective pulmonary vasodilator. Lancet 2002;360 (9337): 886-7
  • Dweik RA. The promise and reality of nitric oxide in the diagnosis and treatment of lung disease. Cleve Clin J Med 2001; 68(6):486-93
  • 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(3):917-23
  • 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(4):233-43
  • Ozkan M, Dweik RA, Ahmad M. Drug-induced lung disease. Cleve Clin J Med 2001; 68(9):782-95
  • Arroliga AC, Dweik RA, Kaneko FJ, Erzurum SC. Primary pulmonary hypertension: update on pathogenesis and novel therapies. Cleve Clin J Med 2000; 67(3):175-90
  • Dweik RA, Erzurum SC. Effects of nitric oxide and cyclic GMP on smooth muscle proliferation. In: Moss J, ed. LAM and other diseases characterized by smooth muscle proliferation (Lung Biology in Health and Disease series). New York: Marcel Dekker, 1999;131:333-49
  • Dweik RA, Laskowski D, Abu-Soud HM, Kaneko F, Hutte R, Stuehr DJ, al. Nitric oxide synthesis in the lung. Regulation by oxygen through a kinetic mechanism. J Clin Invest 1998;101(3):660-66
  • Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993; 329(27):2002-12
  • Nathan C, Xie QW. Nitric oxide synthases: roles, tolls, and controls. Cell 1994;78(6): 915-18
  • Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332(6163):411-15
  • Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993; 328(24):1732-39
  • 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(6): 464-69
  • Moncada S, Vane JR. Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2, and prostacyclin. Pharmacol Rev 1978; 30(3):293- 331
  • Gorman RR, Bunting S, Miller OV. Modulation of human platelet adenylate cyclase by prostacyclin (PGX). Prostaglandins 1977;13(3):377-88
  • Geraci MW, Gao B, Shepherd DC, Moore MD, Westcott JY, Fagan KA, et al. Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension. J Clin Invest 1999;103(11):1509-15
  • Tuder RM, Cool CD, Geraci MW, Wang J, Abman SH, Wright L, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 1999;159(6):1925-32
  • Davie N, Haleen SJ, Upton PD, Polak JM, Yacoub MH, Morrell NW, et al. ETA and ETB receptors modulate the proliferation of human pulmonary artery smooth muscle cells. Am J Respir Crit Care 2002;165(3):398–405
  • Christman BW, McPherson CD, Newman JH, King GA, Bernard GR, Groves BM, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 1992; 327(2):70-5
  • Das M, Dempsey EC, Bouchey D, Reyland MR, Stenmark KR. Chronic hypoxia induces aggregated growth responses in pulmonary arterial adventitial fibroblast. Am J Respir Crit Care Med 2000;22(1):15- 25
  • Welsh CH, Hassell KL, Badesch DB, Kressin DC, Marlar RA. Coagulation and fibrinolytic profiles in patients with severe pulmonary hypertension. Chest 1996;110(3):710-17
  • Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, MatsuoH, et al. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun 1993;192(2):553–60
  • Westphal M, Booke M, Dinh-Xuan AT. Adrenomedullin: a smart road from pheochromocytoma to treatment of pulmonary hypertension. Eur Respir J 2004;24(4): 518–20
  • 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(5):927–34
  • 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(3):737–44
  • Blobe GC, Schiemann WP, Lodish HF. Role of transforming growth factor in human disease. N Engl J Med 2000;342(18):1350–58
  • Machado RD, Aldred MA, James V, Harrison RE, Patel B, Schwalbe EC, et al. Mutations of the TGF- type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat 2006; 27(2):121–32
  • Jason X, Yuan J, Rubin LJ. Pathogenesis of pulmonary arterial hypertension. The need for multiple hits. Circulation 2005;111(5):534-38
  • Runo JR, Loyd JE. Primary pulmonary hypertension. 2003. Lancet 361(9368):1533–44
  • Derynck R, Zhang YE. Smad-dependent and Smadin- independent pathways in TGF-beta family signalling. Nature 2003;425(6958):577–84
  • Yang X, Long L, Southwood M, Rudarakanchana N, Upton PD, Jeffery TK, et al. Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension. Circ Res 2005;96(10):1053-63
  • Austin ED, Loyd JE. Genetics and mediators in pulmonary arterial hypertension. Clin Chest Med 2007; 28(1):43–57
  • Elliott CG. Genetics of pulmonary arterial hypertension: current and future implications. Semin Respir Crit Care Med 2005;26(4):365–71
  • Newman JH. Pulmonary hypertension. Am J Respir Crit Care Med 2005;172(9): 1072–77
  • Beppu H, Ichinose F, Kawai N, Jones RC, Yu PB, Zapol WM, et al. BMPR-II heterozygous mice have mild pulmonary hypertension and an impaired pulmonary vascular remodeling response to prolonged hypoxia. Am J Physiol Lung Cell Mol Physiol 2004;287(6):1241–47
There are 58 citations in total.

Details

Primary Language English
Journal Section Reviews
Authors

Önder Öztürk

Ahmet Akkaya This is me

Publication Date May 29, 2009
Submission Date May 29, 2009
Published in Issue Year 2008 Volume: 15 Issue: 4

Cite

Vancouver Öztürk Ö, Akkaya A. Pulmoner arteriyel hipertansiyon: patogenez. Med J SDU. 2009;15(4):46-53.

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