Pulmonary Arterial Hypertension - A Complex and Debilitating Disease

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US Cardiology 2004;2004:1(1):1-5

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Introduction

Pulmonary arterial hypertension (PAH) is a disease affecting the pulmonary vascular endothelium of the small pulmonary vessels that causes progressive elevations in pulmonary vascular resistance, leading to right ventricular failure and death. PAH can result from a number of causes or associated risk factors. A clinical classification (Evian classification) was developed in 1993 and subsequently adopted into clinical practice in an effort to group disorders that share similarities in pathophysiology, clinical presentation, and treatment options. This classification was revised recently in 2003 during the Third World Symposium on PAH held in Venice, Italy (see Table 1). From a hemodynamic standpoint, PAH is defined as a mean pulmonary arterial pressure that is >25mmHg at rest or >30mmHg during exercise. The Doppler echocardiographic definition of PAH is based on a tricuspid regurgitation get that is >2.8m/sec. Data regarding the true prevalence of PAH remain somewhat elusive. Idiopathic PAH (IPAH) occurs in one to four cases per million population. The prevalence is 15% to 60% in patients with collagen vascular disease, 2% to 4% in portal hypertension, and 0.5% among patients with HIV infection.

Pathobiology of PAH

The pathobiology of PAH is multifactorial and cannot be explained by a single factor or gene mutation. There is excessive pulmonary vasoconstriction perhaps from inhibition of one of the voltage gated potassium channels (Kv1.5 and 2.1) in the pulmonary vascular smooth muscle cells or from endothelial dysfunction, which in turn leads to impaired production of vasodilators such as nitric oxide and prostacyclin and increased production of vasoconstrictors like endothelin-1 and thromboxane. These abnormalities further increase pulmonary vascular tone and promote vascular remodeling that involves all layers of the vessel wall. Fibroblast proliferation and migration, activation of matrix metalloproteinase (MMP) 2 and 9, and disordered proteolysis of the extracellular matrix plays a key role in vascular remodeling. Inflammatory mechanisms, activation of cytokines and chemokines, serotonin, transforming growth factor (TGF)-╬▓ superfamily, and angiopoietin-1 also promote the vascular remodeling process. Finally, platelet dysfunction, enhanced interactions between platelets and the vessel wall, and thrombotic lesions are potentially important in the development of PAH. The initiating process in this cascade of cellular and molecular events is, however, as yet unknown. Mutations in two receptors of the TGF-╬▓ superfamily have been identified in patients with familial PAH.

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References
  1. Rich S, Dantzer D R,Ayers S M, et al., "Primary pulmonary hypertension: a national prospective study", Ann. Intern. Med. (1987), 107: pp. 216-228.
    Crossref | PubMed
  2. Simonneau G, Galie N, Rubin L J, Langleben D, et al.,"Clinical classification of pulmonary hypertension", J.Am.Coll. Cardiol. (2004), 43 (suppl S): pp. 5S-12S.
    Crossref | PubMed
  3. Humbert M, Nunes H, Sitbon O, et al.,"Risk factors for pulmonary arterial hypertension", Clin. Chest. Med. (2001), 22: pp. 459-475.
    Crossref | PubMed
  4. Humbert M, Morrell N W, Archer S L, et al., "Cellular and molecular pathobiology of pulmonary arterial hypertension", J.Am. Coll. Cardiol. (2004), 43 (Suppl S): pp. 13S-24S.
    Crossref | PubMed
  5. Lane K B, Machado R D, Pauciulo M W, et al.,"Heterozygous germ line mutations in a TGF-╬▓ receptor, BMPR2, are the cause of familial primary pulmonary hypertension", Nat. Genet. (2000), 26: pp. 81-84.
    Crossref | PubMed
  6. Du L, Sullivan C C, Chu D, et al., "Signalling molecules in nonfamilial pulmonary hypertension", N. Engl. J. Med. (2003), 348: pp. 500-509.
    Crossref | PubMed
  7. Trembath J R C,Thompson J R, Machado R D, et al., "Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia, N. Engl. J. Med. (2001), 345: pp. 325-334.
    Crossref | PubMed
  8. Pietra G G, Capron F, Stewart S, et al., "Pathologic assessment of vasculopathies in pulmonary hypertension",J. Am. Coll. Cardiol. (2004), 43 (Suppl S): pp. 25S-32S.
    Crossref | PubMed
  9. Barst R J, McGoon M,Torbicki A, et al.,"Diagnosis and differential assessment of pulmonary arterial hypertension", J.Am. Coll. Cardiol. (2004), 43 (Suppl S); pp. 40S-47S.
    Crossref | PubMed
  10. Borgeson D D, Seward J B, Miller F A Jr.,et al., "Frequency of Doppler measurable pulmonary artery pressures", J. Am. Soc. Echocardiogr. (1996), 9: pp. 832-837.
    Crossref | PubMed
  11. Bossone E, Rubenfire M, Bach D S, et al., "Range of tricuspid regurgitation velocity at rest and during exercise in normal adult men: implications for the diagnosis of pulmonary hypertension", J.Am. Coll. Cardiol. (1999), 33: pp. 1,662-1,666.
    Crossref | PubMed
  12. Galie N, Seeger W, Naeije R, et al.,"Comparative analysis of clinical trials and evidence-based treatment algorithm in pulmonary arterial hypertension", J.Am. Coll. Cardiol (2004), 43 (Suppl S): pp. 81S-88S.
    Crossref | PubMed
  13. FusterV, Steele P M, Edwards W D, et al.,"Primary pulmonary hypertension: natural history and the importance of thrombosis", Circulation (1984), 70: pp. 580-587.
    Crossref | PubMed
  14. Rich S, Kaufmann E, Levy P S, "The effect of high doses of calcium channel blockers on survival in primary pulmonary hypertension", N. Engl. J. Med. (1992), 327: pp. 76-81.
    Crossref | PubMed
  15. Barst R J, Rubin L J, McGoon M D, et al.,"A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension.The primary pulmonary hypertension study group", N. Engl. J. Med. (1996), 334: pp. 296-302.
    Crossref | PubMed
  16. McLaughlin V V, Genthner D E, Panella M M, et al., "Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension", N. Engl. J. Med. (1998), 338: pp. 273-277.
    Crossref | PubMed
  17. Simonneau G, Barst R J, Galie N, et al., Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double blind, randomized, placebo controlled trial", Am. J. Respir. Crit. Care. Med. (2002), 164: pp. 800-804.
    Crossref | PubMed
  18. Hoeper M M, Olschewski H, Ghotrani H A, et al., "A comparison of the acute hemodynamic effects of inhaled nitric oxide and aerosolized iloprost in primary pulmonary hypertension. German PPH Study Group", J. Am. Coll. Cardiol. (2000), 35: pp. 176-182.
    Crossref | PubMed
  19. Galie N, Humbert M,Vachiery J L, 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: pp. 1,496-1,502.
    Crossref | PubMed
  20. Giaid A,Yanagisawa M, Langleben D, et al.,"Expression of endothelin-1 in the lungs of patients with pulmonary hypertension", N. Engl. J. Med. (1993), 328: pp. 1,732-1,739.
    Crossref | PubMed
  21. Channick R N, Sitbon O, Barst R J, et al., "Endothelin receptor antagonists in pulmonary arterial hypertension", J.Am. Coll. Cardiol. (2004), 43 (Suppl S): pp. 62S-67S.
    Crossref | PubMed
  22. Rubin L J, Badesch D B, Barst R J, et al., "Bosentan therapy for pulmonary arterial hypertension", N. Engl. J. Med. (2002), 346: pp. 896-903.
    Crossref | PubMed
  23. Barst R J, et al., "Sitaxsentan therapy for pulmonary arterial hypertension", Am. J. Respir. Crit. Care Med. (2004), 169: pp. 441-447.
    Crossref | PubMed
  24. Ghofrani H A, Pepke-Zeba J, Barbera J A, et al., "Nitric oxide pathway and phosphodiesterase inhibitors in pulmonary arterial hypertension", J.Am. Coll. Cardiol. (2004), 43 (Suppl S): pp. 68S-72S.
    Crossref | PubMed
  25. Sandoval J, Gaspar J, Pulido T, et al., "Graded balloon dilation atrila septostomy in severe primary pulmonary hypertension.A therapeutic alternative for patients non-responsive to vasodilator treatment", J.Am. Coll. Cardiol. (1998), 32: pp. 297-304.
    Crossref | PubMed
  26. Archibald C J,Auger W R, Fedullo P F et al., "Long-term outcome after pulmonary thromboendarterectomy", Am. J. Respir. Crit. Care Med. (1999), 160: pp. 523-528.
    Crossref | PubMed
  27. Bando K, Armitage J M, Paradis I L, et al., "Indications for and results of single, bilateral and heart-lung transplantation for pulmonary hypertension", J.Thorac Cardiovasc. Surg. (1994), 108: pp. 1,056-1,065.
    PubMed