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DOI: 10.1055/s-0033-1355439
Idiopathic Pulmonary Arterial Hypertension
Publikationsverlauf
Publikationsdatum:
13. September 2013 (online)
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Abstract
Idiopathic pulmonary arterial hypertension (IPAH), formerly called primary pulmonary hypertension, is a rare disease (incidence and prevalence rates of approximately one and six cases per million inhabitants, respectively) with different clinical phenotypes. A group of diverse conditions manifest pulmonary arterial hypertension (PAH) and share similar pathological and/or clinical findings with IPAH. By definition, IPAH is diagnosed only after alternative diagnoses have been ruled out. Extensive investigation is needed to determine if PAH is associated with thyroid diseases, infectious diseases, autoimmune conditions, exposure to certain drugs (particularly anorexigens), certain genetic mutations, and so on. The presence of genetic abnormalities and risk factors (such as specific drug exposures) reinforces the “multiple hit” concept for the development of pulmonary hypertension. Fortunately, within the past two decades, therapeutic options have become available for IPAH, resulting in improved survival and clinical outcomes. At least seven different compounds have been registered for PAH treatment. However, even with aggressive PAH-specific therapy, mortality rates remain high (∼40% at 5 years). Given the high mortality rates, the use of combinations of agents that work by different pathways has been advocated (either as “add-on” therapy or initial “up front” therapy). Further, new therapeutic agents and treatment strategies are on the near horizon, aiming to further improve survival from the remarkable progress already seen.
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References
- 1 Souza R, Jardim C. Trends in pulmonary arterial hypertension. Eur Respir Rev 2009; 18 (111) 7-12
- 2 Humbert M. The fifth world symposium on pulmonary hypertension will REVEAL the impact of registries. Eur Respir Rev 2012; 21 (123) 4-5
- 3 Simonneau G, Robbins IM, Beghetti M , et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009; 54 (61, Suppl): S43-S54
- 4 Galiè N, Hoeper MM, Humbert M , et al; ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009; 30 (20) 2493-2537
- 5 Kovacs G, Berghold A, Scheidl S, Olschewski H. Pulmonary arterial pressure during rest and exercise in healthy subjects: a systematic review. Eur Respir J 2009; 34 (4) 888-894
- 6 Badesch DB, Champion HC, Sanchez MA , et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54 (1, Suppl): S55-S66
- 7 Cogan JD, Pauciulo MW, Batchman AP , et al. High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension. Am J Respir Crit Care Med 2006; 174 (5) 590-598
- 8 Thomson JR, Machado RD, Pauciulo MW , et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet 2000; 37 (10) 741-745
- 9 Machado RD, Eickelberg O, Elliott CG , et al. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54 (1, Suppl): S32-S42
- 10 Sztrymf B, Coulet F, Girerd B , et al. Clinical outcomes of pulmonary arterial hypertension in carriers of BMPR2 mutation. Am J Respir Crit Care Med 2008; 177 (12) 1377-1383
- 11 Germain M, Eyries M, Montani D , et al. Genome-wide association analysis identifies a susceptibility locus for pulmonary arterial hypertension. Nat Genet 2013; 45 (5) 518-521
- 12 Girerd B, Montani D, Coulet F , et al. Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med 2010; 181 (8) 851-861
- 13 Girerd B, Montani D, Eyries M , et al. Absence of influence of gender and BMPR2 mutation type on clinical phenotypes of pulmonary arterial hypertension. Respir Res 2010; 11: 73
- 14 Gurtner HP. Aminorex and pulmonary hypertension. A review. Cor Vasa 1985; 27 (2-3) 160-171
- 15 Souza R, Humbert M, Sztrymf B , et al. Pulmonary arterial hypertension associated with fenfluramine exposure: report of 109 cases. Eur Respir J 2008; 31 (2) 343-348
- 16 Walker AM, Langleben D, Korelitz JJ , et al. Temporal trends and drug exposures in pulmonary hypertension: an American experience. Am Heart J 2006; 152 (3) 521-526
- 17 Boutet K, Frachon I, Jobic Y , et al. Fenfluramine-like cardiovascular side-effects of benfluorex. Eur Respir J 2009; 33 (3) 684-688
- 18 Frachon I, Etienne Y, Jobic Y, Le Gal G, Humbert M, Leroyer C. Benfluorex and unexplained valvular heart disease: a case-control study. PLoS ONE 2010; 5 (4) e10128
- 19 Savale L, Chaumais MC, Cottin V , et al. Pulmonary hypertension associated with benfluorex exposure. Eur Respir J 2012; 40 (5) 1164-1172
- 20 Montani D, Bergot E, Günther S , et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation 2012; 125 (17) 2128-2137
- 21 Yuan JX, Rubin LJ. Pathogenesis of pulmonary arterial hypertension: the need for multiple hits. Circulation 2005; 111 (5) 534-538
- 22 Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest 2012; 122 (12) 4306-4313
- 23 Firth AL, Mandel J, Yuan JX. Idiopathic pulmonary arterial hypertension. Dis Model Mech 2010; 3 (5–6) 268-273
- 24 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 (24) 1732-1739
- 25 Montani D, Souza R, Binkert C , et al. Endothelin-1/endothelin-3 ratio: a potential prognostic factor of pulmonary arterial hypertension. Chest 2007; 131 (1) 101-108
- 26 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) 464-469
- 27 Michelakis ED. The role of the NO axis and its therapeutic implications in pulmonary arterial hypertension. Heart Fail Rev 2003; 8 (1) 5-21
- 28 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 (14) 1400-1406
- 29 Price LC, Wort SJ, Perros F , et al. Inflammation in pulmonary arterial hypertension. Chest 2012; 141 (1) 210-221
- 30 Humbert M, Souza R, Galiè N, McLaughlin V, Simonneau G, Rubin L. Pulmonary arterial hypertension: bridging the present to the future. Eur Respir Rev 2012; 21 (126) 267-270
- 31 Rich S, Dantzker DR, Ayres SM , et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med 1987; 107 (2) 216-223
- 32 D'Alonzo GE, Barst RJ, Ayres SM , et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991; 115 (5) 343-349
- 33 Humbert M, Sitbon O, Chaouat A , et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 2006; 173 (9) 1023-1030
- 34 Humbert M, Sitbon O, Chaouat A , et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 2010; 122 (2) 156-163
- 35 Humbert M, Sitbon O, Yaïci A , et al; French Pulmonary Arterial Hypertension Network. Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. Eur Respir J 2010; 36 (3) 549-555
- 36 Badesch DB, Raskob GE, Elliott CG , et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest 2010; 137 (2) 376-387
- 37 Benza RL, Miller DP, Gomberg-Maitland M , et al. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation 2010; 122 (2) 164-172
- 38 Ling Y, Johnson MK, Kiely DG , et al. Changing demographics, epidemiology, and survival of incident pulmonary arterial hypertension: results from the pulmonary hypertension registry of the United Kingdom and Ireland. Am J Respir Crit Care Med 2012; 186 (8) 790-796
- 39 Lee WT, Ling Y, Sheares KK, Pepke-Zaba J, Peacock AJ, Johnson MK. Predicting survival in pulmonary arterial hypertension in the UK. Eur Respir J 2012; 40 (3) 604-611
- 40 Naeije R, Vachiery JL, Yerly P, Vanderpool R. The transpulmonary pressure gradient for the diagnosis of pulmonary vascular disease. Eur Respir J 2013; 41 (1) 217-223
- 41 Vachiéry JL, Gaine S. Challenges in the diagnosis and treatment of pulmonary arterial hypertension. Eur Respir Rev 2012; 21 (126) 313-320
- 42 Costa EL, Jardim C, Bogossian HB, Amato MB, Carvalho CR, Souza R. Acute vasodilator test in pulmonary arterial hypertension: evaluation of two response criteria. Vascul Pharmacol 2005; 43 (3) 143-147
- 43 Sitbon O, Humbert M, Jaïs X , et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005; 111 (23) 3105-3111
- 44 Barst RJ, Rubin LJ, Long WA , et al; 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 (5) 296-301
- 45 Rubin LJ, Mendoza J, Hood M , et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Ann Intern Med 1990; 112 (7) 485-491
- 46 Barst RJ, Gibbs JS, Ghofrani HA , et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54 (1, Suppl): S78-S84
- 47 Olschewski H, Simonneau G, Galiè N , et al; Aerosolized Iloprost Randomized Study Group. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002; 347 (5) 322-329
- 48 Higenbottam T, Butt AY, McMahon A, Westerbeck R, Sharples L. Long-term intravenous prostaglandin (epoprostenol or iloprost) for treatment of severe pulmonary hypertension. Heart 1998; 80 (2) 151-155
- 49 Simonneau G, Barst RJ, Galie N , et al; Treprostinil Study Group. 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; 165 (6) 800-804
- 50 Tapson VF, Gomberg-Maitland M, McLaughlin VV , et al. Safety and efficacy of IV treprostinil for pulmonary arterial hypertension: a prospective, multicenter, open-label, 12-week trial. Chest 2006; 129 (3) 683-688
- 51 Tapson VF, Torres F, Kermeen F , et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C study): a randomized controlled trial. Chest 2012; 142 (6) 1383-1390
- 52 Jing ZC, Parikh K, Pulido T , et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial. Circulation 2013; 127 (5) 624-633
- 53 Rubin LJ, Badesch DB, Barst RJ , et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346 (12) 896-903
- 54 Humbert M, Segal ES, Kiely DG, Carlsen J, Schwierin B, Hoeper MM. Results of European post-marketing surveillance of bosentan in pulmonary hypertension. Eur Respir J 2007; 30 (2) 338-344
- 55 Galiè N, Olschewski H, Oudiz RJ , et al; Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies (ARIES) Group. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation 2008; 117 (23) 3010-3019
- 56 McGoon MD, Frost AE, Oudiz RJ , et al. Ambrisentan therapy in patients with pulmonary arterial hypertension who discontinued bosentan or sitaxsentan due to liver function test abnormalities. Chest 2009; 135 (1) 122-129
- 57 Rubin L, Pulido T, Channick R , et al. Effect of macitentan on morbidity and mortality in pulmonary arterial hypertension (PAH): Results from the SERAPHIN trial. [Abstract]. Chest 2012; 142 (4) 1026A
- 58 Galiè N, Ghofrani HA, Torbicki A , et al; Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005; 353 (20) 2148-2157
- 59 Galiè N, Brundage BH, Ghofrani HA , et al; Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study Group. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009; 119 (22) 2894-2903
- 60 Jing ZC, Yu ZX, Shen JY , et al; Efficacy and Safety of Vardenafil in the Treatment of Pulmonary Arterial Hypertension (EVALUATION) Study Group. Vardenafil in pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med 2011; 183 (12) 1723-1729
- 61 Ghofrani HA, Voswinckel R, Gall H , et al. Riociguat for pulmonary hypertension. Future Cardiol 2010; 6 (2) 155-166
- 62 Ghofrani HA, Hoeper MM, Halank M , et al. Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study. Eur Respir J 2010; 36 (4) 792-799
- 63 Ghofrani H, Galie N, Grimminger F , et al. Riociguat for the treatment of pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled study (PATENT-1). [Abstract]. Chest 2012; 142 (4) 1027A DOI: 10.1378/chest.1462799.
- 64 Ghofrani H, Grimminger F, Hoeper M , et al. Riociguat for the treatment of inoperable chronic thromboembolic pulmonary hypertension: a randomized, double-blind, placebo-controlled study (CHEST-1). [Abstract]. Chest 2012; 142 (4) 1023A
- 65 McLaughlin VV, Benza RL, Rubin LJ , et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol 2010; 55 (18) 1915-1922
- 66 Simonneau G, Rubin LJ, Galiè N , et al; PACES Study Group. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med 2008; 149 (8) 521-530
- 67 Humbert M, Barst RJ, Robbins IM , et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J 2004; 24 (3) 353-359
- 68 Kemp K, Savale L, O'Callaghan DS , et al. Usefulness of first-line combination therapy with epoprostenol and bosentan in pulmonary arterial hypertension: an observational study. J Heart Lung Transplant 2012; 31 (2) 150-158
- 69 Souza R, Jardim C, Martins B , et al. Effect of bosentan treatment on surrogate markers in pulmonary arterial hypertension. Curr Med Res Opin 2005; 21 (6) 907-911
- 70 Galiè N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani ML, Branzi A. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J 2009; 30 (4) 394-403
- 71 dos Santos Fernandes CJ, Jardim CV, Hovnanian A , et al. Survival in schistosomiasis-associated pulmonary arterial hypertension. J Am Coll Cardiol 2010; 56 (9) 715-720
- 72 Sitbon O, McLaughlin VV, Badesch DB , et al. Survival in patients with class III idiopathic pulmonary arterial hypertension treated with first line oral bosentan compared with an historical cohort of patients started on intravenous epoprostenol. Thorax 2005; 60 (12) 1025-1030
- 73 O'Callaghan DS, Humbert M. A critical analysis of survival in pulmonary arterial hypertension. Eur Respir Rev 2012; 21 (125) 218-222