Download PDF
Pneumologie 2016; 70(10): 630-637
DOI: 10.1055/s-0042-100537
Serie: Translationale Forschung in der Pneumologie
© Georg Thieme Verlag KG Stuttgart · New York

Pulmonal (arterielle) Hypertonie

Pulmonary (Arterial) Hypertension
G. Kwapiszewska   *
1   Universitätsklinik für Anästhesiologie und Intensivmedizin, Medizinische Universität Graz
2   Ludwig Boltzmann Institut für Lungengefäßforschung, Graz
,
J. Hoffmann
2   Ludwig Boltzmann Institut für Lungengefäßforschung, Graz
,
G. Kovacs   *
2   Ludwig Boltzmann Institut für Lungengefäßforschung, Graz
3   Universitätsklinik für Innere Medizin, Klinische Abteilung für Lungenkrankheiten, Medizinische Universität Graz
,
E. Stacher   *
4   Institut für Pathologie, Medizinische Universität Graz
,
A. Olschewski   *
1   Universitätsklinik für Anästhesiologie und Intensivmedizin, Medizinische Universität Graz
2   Ludwig Boltzmann Institut für Lungengefäßforschung, Graz
,
H. Olschewski
3   Universitätsklinik für Innere Medizin, Klinische Abteilung für Lungenkrankheiten, Medizinische Universität Graz
› Author Affiliations
Subject Editor: M. Witzenrath, Berlin
Further Information

Publication History

eingereicht 03 December 2015

akzeptiert nach Revision 18 December 2015

Publication Date:
06 April 2016 (online)

Also available at
   Permissions and Reprints

Zusammenfassung

Die pulmonal arterielle Hypertonie (PAH) ist eine seltene Erkrankung, charakterisiert durch einen Gefäßumbau von kleinen Lungenarterien, der zu einer Verringerung des Lumens bis hin zur Okklusion führt. Nach den aktuellen Leitlinien wird eine PAH durch einen pulmonal arteriellen Druck ≥ 25 mmHg, durch einen arteriellen Wedgedruck ≤ 15 mmHg und durch einen erhöhten pulmonal vaskulären Widerstand (PVR > 3 WU) definiert. Die aktuellen pathophysiologischen Konzepte über die Entstehung der Krankheit schließen Störungen in der Produktion, Deposition und Komposition von Faktoren der extrazellulären Matrix, Entzündungsprozesse, Mutationen im BMPR2-Gen und Mutationen im KCNK3-Gen mit ein. In den letzten Jahren brachten epigenetische und genetische Untersuchungen neue Erkenntnisse, welche eine große Relevanz für die Diagnostik, Prognose und Therapie der PAH haben. Diese Ergebnisse könnten zur Entwicklung neuer, personalisierter Therapiestrategien führen. Zurzeit laufen mehrere Dutzend Phase-I- und Phase-II-Studien, in denen vielversprechende neue Substanzen geprüft werden.

Abstract

Pulmonary arterial hypertension (PAH) is a rare disease characterised by vascular remodelling of the small lung arteries leading to a decrease of the vessel lumen and eventually to occlusion. According to the current guidelines, PAH is defined by a pulmonary arterial pressure ≥ 25 mmHg, an arterial wedge pressure ≤ 15 mmHg, and an elevated pulmonary vascular resistance (PVR > 3 WU). The current pathophysiological concepts include disturbances in the production, deposition and composition of the extracellular matrix, inflammatory processes, mutations in the BMPR2 gene as well as mutations in the KCNK3 gene. During the last few years, epigenetic and genetic investigations resulted in new findings which are highly relevant for the diagnosis, prognosis and therapy of PAH. These findings could lead to the development of new, individualised therapy strategies. Currently, several phase I and phase II studies are in progress, in which promising new substances are examined.

* Diese Autoren haben gleichermaßen zur Arbeit beigetragen.


 

  • Literatur

  • 1 Kovacs G, Berghold A, Scheidl S et al. Pulmonary arterial pressure during rest and exercise in healthy subjects A systematic review. Eur Respir J 2009; 34: 888-894
    CrossrefPubMedGoogle Scholar
  • 2 Simonneau G, Gatzoulis MA, Adatia I et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013; 62: D34-D41
    CrossrefPubMedGoogle Scholar
  • 3 Hoffmann J, Marsh LM, Pieper M et al. Compartment-specific expression of collagens and their processing enzymes in intrapulmonary arteries of IPAH patients. Am J Physiol Lung Cell Mol Physiol 2015; 308: L1002-L1013
    CrossrefPubMedGoogle Scholar
  • 4 Seeger W, Adir Y, Barberà JA et al. Pulmonary hypertension in chronic lung diseases. J Am Coll Cardiol 2013; 62 (Suppl. 25) D109-D116
    CrossrefPubMedGoogle Scholar
  • 5 Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest 2012; 122: 4306-4313
    CrossrefPubMedGoogle Scholar
  • 6 Rabinovitch M. Pathobiology of pulmonary hypertension. Extracellular matrix. Clin Chest Med 2001; 22: 433-449
    CrossrefPubMedGoogle Scholar
  • 7 Tu L, Guignabert C. Emerging molecular targets for anti-proliferative strategies in pulmonary arterial hypertension. Handb Exp Pharmacol 2013; 218: 409-436
    PubMedGoogle Scholar
  • 8 Dodson RB, Morgan MR, Galambos C et al. Chronic intrauterine pulmonary hypertension increases main pulmonary artery stiffness and adventitial remodeling in fetal sheep. Am J Physiol Lung Cell Mol Physiol 2014; 307: L822-L828
    CrossrefPubMedGoogle Scholar
  • 9 Merklinger SL, Wagner RA, Spiekerkoetter E et al. (2005) Increased fibulin-5 and elastin in S100A4/Mts1 mice with pulmonary hypertension. Circ Res 2005; 97: 596-604
    CrossrefPubMedGoogle Scholar
  • 10 Lammers SR, Kao PH, Qi HJ. Changes in the structure-function relationship of elastin and its impact on the proximal pulmonary arterial mechanics of hypertensive calves. Am J Physiol Heart Circ Physiol 2008; 295: H1451-H1459
    CrossrefPubMedGoogle Scholar
  • 11 Golledge J, Clancy P, Maguire J et al. The role of tenascin C in cardiovascular disease. Cardiovasc Res 2011; 92: 19-28
    CrossrefPubMedGoogle Scholar
  • 12 Chelladurai P, Seeger W, Pullamsetti SS. Matrix metalloproteinases and their inhibitors in pulmonary hypertension. Eur Respir J 2012; 40: 766-782
    CrossrefPubMedGoogle Scholar
  • 13 Nave AH, Mižíková I, Niess G et al. Lysyl oxidases play a causal role in vascular remodeling in clinical and experimental pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol 2014; 34: 1446-1458
    CrossrefPubMedGoogle Scholar
  • 14 Damico R, Kolb TM, Valera L et al. Serum endostatin is a genetically determined predictor of survival in pulmonary arterial hypertension. Am J Respir Crit Care Med 2015; 191: 208-218
    CrossrefPubMedGoogle Scholar
  • 15 Safdar Z, Tamez E, Chan W et al. Circulating collagen biomarkers as indicators of disease severity in pulmonary arterial hypertension. JACC Heart Fail 2014; 2: 412-21
    CrossrefPubMedGoogle Scholar
  • 16 Stacher E, Graham BB, Hunt JM et al. Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med 2012; 186: 261-272
    CrossrefPubMedGoogle Scholar
  • 17 Price LC, Wort SJ, Perros F et al. Inflammation in pulmonary arterial hypertension. Chest 2012; 141: 210-221
    CrossrefPubMedGoogle Scholar
  • 18 Huertas A, Tu L, Gambaryan N et al. Leptin and regulatory T-lymphocytes in idiopathic pulmonary arterial hypertension. Eur Respir J 2012; 40: 895-904
    CrossrefPubMedGoogle Scholar
  • 19 Soon E, Crosby A, Southwood M et al. Bone Morphogenetic Protein Receptor Type II Deficiency and Increased Inflammatory Cytokine Production. A Gateway to Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 2015; 192: 859-872
    CrossrefPubMedGoogle Scholar
  • 20 Deng Z, Haghighi F, Helleby L et al. Fine mapping of PPH1, a gene for familial primary pulmonary hypertension, to a 3-cM region on chromosome 2q33. Am J Respir Crit Care Med 2000; 161: 1055-1059
    CrossrefPubMedGoogle Scholar
  • 21 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 Genet 2000; 67: 737-744
    CrossrefPubMedGoogle Scholar
  • 22 Long L, Ormiston ML, Yang X et al. Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension. Nat Med 2015; 21: 777-785
    CrossrefPubMedGoogle Scholar
  • 23 Ma L, Roman-Campos D, Austin ED et al. A novel channelopathy in pulmonary arterial hypertension. N Engl J Med 2013; 369: 351-361
    CrossrefPubMedGoogle Scholar
  • 24 Olschewski A, Papp R, Nagaraj C et al. Ion channels and transporters as therapeutic targets in the pulmonary circulation. Pharmacol Ther 2014; 144: 349-368
    CrossrefPubMedGoogle Scholar
  • 25 Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular disease; a description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation 1958; 18: 533-547
    CrossrefPubMedGoogle Scholar
  • 26 Bjornsson J, Edwards WD. Primary pulmonary hypertension: a histopathologic study of 80 cases. Mayo Clin Proc 1985; 60: 16-25
    CrossrefPubMedGoogle Scholar
  • 27 Chazova I, Loyd JE, Zhdanov VS et al. Pulmonary artery adventitial changes and venous involvement in primary pulmonary hypertension. Am J Pathol 1995; 146: 389-397
    PubMedGoogle Scholar
  • 28 Overbeek MJ, Vonk MC, Boonstra A et al. Pulmonary arterial hypertension in limited cutaneous systemic sclerosis: a distinctive vasculopathy. Eur Respir J 2009; 34: 371-379
    CrossrefPubMedGoogle Scholar
  • 29 Pietra GG, Edwards WD, Kay JM et al. Histopathology of primary pulmonary hypertension. A qualitative and quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung, and Blood Institute, Primary Pulmonary Hypertension Registry. Circulation 1989; 80: 1198-1206
    CrossrefPubMedGoogle Scholar
  • 30 Rabinovitch M, Haworth SG, Castaneda AR et al. Lung biopsy in congenital heart disease: a morphometric approach to pulmonary vascular disease. Circulation 1978; 58: 1107-1122
    CrossrefPubMedGoogle Scholar
  • 31 Wagenvoort CA. Lung biopsy specimens in the evaluation of pulmonary vascular disease. Chest 1980; 77: 614-625
    CrossrefPubMedGoogle Scholar
  • 32 Wagenvoort CA, Wagenvoort N. Primary pulmonary hypertension: a pathologic study of the lung vessels in 156 clinically diagnosed cases. Circulation 1970; 42: 1163-1184
    CrossrefPubMedGoogle Scholar
  • 33 Yamaki S, Wagenvoort CA. Comparison of primary plexogenic arteriopathy in adults and children. A morphometric study in 40 patients. Br Heart J 1985; 54: 428-434
    CrossrefPubMedGoogle Scholar
  • 34 Yi ES, Kim H, Ahn H et al. Distribution of obstructive intimal lesions and their cellular phenotypes in chronic pulmonary hypertension. A morphometric and immunohistochemical study. Am J Respir Crit Care Med 2000; 162: 1577-1586
    CrossrefPubMedGoogle Scholar
  • 35 Hoffmann J, Wilhelm J, Marsh LM et al. Distinct differences in gene expression patterns in pulmonary arteries of patients with chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis with pulmonary hypertension. Am J Respir Crit Care Med 2014; 190: 98-111
    CrossrefPubMedGoogle Scholar
  • 36 Galiè N, Humbert M, Vachiery JL et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint 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: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2015; ehv317
    PubMedGoogle Scholar
  • 37 Galiè N, Ghofrani AH. New horizons in pulmonary arterial hypertension therapies. Eur Respir Rev 2013; 22: 503-514
    CrossrefPubMedGoogle Scholar
  • 38 Gomberg-Maitland M, Bull TM, Saggar R et al. New trial designs and potential therapies for pulmonary artery hypertension. J Am Coll Cardiol 2013; 62: D82-D91
    CrossrefPubMedGoogle Scholar
  • 39 Morrell NW, Archer SL, Defelice A et al. Anticipated classes of new medications and molecular targets for pulmonary arterial hypertension. Pulm Circ 2013; 3: 226-244
    CrossrefPubMedGoogle Scholar
  • 40 Pullamsetti SS, Schermuly R, Ghofrani A et al. Novel and emerging therapies for pulmonary hypertension. Am J Respir Crit Care Med 2014; 189: 394-400
    CrossrefPubMedGoogle Scholar
  • 41 Robbins IM, Hemnes Arm Gibbs JS et al. Safety of sapropterin dihydrochloride (6r-bh4) in patients with pulmonary hypertension. Exp Lung Res 2011; 37: 26-34
    CrossrefPubMedGoogle Scholar
  • 42 Fujita H, Fukumoto Y, Saji K et al. Acute vasodilator effects of inhaled fasudil, a specific Rho-kinase inhibitor, in patients with pulmonary arterial hypertension. Heart Vessels 2010; 25: 144-149
    CrossrefPubMedGoogle Scholar
  • 43 Jiang X, Wang YF, Zhao QH et al. Acute hemodynamic response of infused fasudil in patients with pulmonary arterial hypertension: a randomized, controlled, crossover study. Int J Cardiol 2014; 177: 61-65
    CrossrefPubMedGoogle Scholar
  • 44 Jiang R, Ai ZS, Jiang X et al. Intravenous fasudil improves in-hospital mortality of patients with right heart failure in severe pulmonary hypertension. Hypertens Res 2015; 38: 539-544
    CrossrefPubMedGoogle Scholar
  • 45 Fukumoto Y, Yamada N, Matsubara H et al. Double-blind, placebo-controlled clinical trial with a rho-kinase inhibitor in pulmonary arterial hypertension. Circ J 2013; 77: 2619-2625
    CrossrefPubMedGoogle Scholar
  • 46 Ghofrani HA, Al-Hiti H, Vonk-Noordegraaf A et al. Proof-of-concept study to investigate the efficacy, hemodynamics and tolerability of terguride vs. placebo in subjects with pulmonary arterial hypertension: results of a double blind, randomised, prospective phase Iia study. Am J Respir Crit Care Med 2012; 185: A2496
    PubMedGoogle Scholar
  • 47 Brash L, Barnes G, Brewis M et al. Apelin improves cardiac output in patients with pulmonary arterial hypertension. Eur Respir J 2015; 46 (Suppl. 59)
    PubMedGoogle Scholar
  • 48 Waxman A, Oudiz R, Shapiro S et al. Cicletanine in pulmonary arterial hypertension (PAH): Results from a phase 2 radomized placebo-controlled trial. Eur Respir J 2012; 40 (Suppl. 56)
    PubMedGoogle Scholar
  • 49 Furuya Y, Satoh T, Kuwana M. Interleukin-6 as a potential therapeutic target for pulmonary arterial hypertension. Int J Rheumatol 2010; 720305
    PubMedGoogle Scholar
  • 50 Spiekerkoetter E, Sung YK, Sudheendra D et al. Low-Dose FK506 (Tacrolimus) in End-Stage Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 2015; 192: 254-257
    CrossrefPubMedGoogle Scholar
  • 51 Foris V, Kovacs G, Tscherner M et al. Biomarkers in pulmonary hypertension: what do we know?. Chest 2013; 144: 274-283
    CrossrefPubMedGoogle Scholar
  • 52 Wang XX, Zhang FR, Shang YP et al. Transplantation of autologous endothelial progenitor cells may be beneficial in patients with idiopathic pulmonary arterial hypertension: a pilot randomized controlled trial. J Am Coll Cardiol 2007; 49: 1566-1571
    CrossrefPubMedGoogle Scholar
  • 53 Granton J, Langleben D, Kutryk MB et al. Endothelial NO-synthase gene-enhanced progenitor cell therapy for pulmonary arterial hypertension: the PHACeT trial. Circ Res 2015; 117: 645-654
    CrossrefPubMedGoogle Scholar
  • 54 Ghofrani HA, Morrell NW, Hoeper MM et al. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am J Respir Crit Care Med 2010; 182: 1171-1177
    CrossrefPubMedGoogle Scholar
  • 55 Hoeper MM, Barst RJ, Bourge RC et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation 2013; 127: 1128-1138
    CrossrefPubMedGoogle Scholar
  • 56 Gomberg-Maitland M, Maitland ML, Barst RJ et al. A dosing/cross-development study of the multikinase inhibitor sorafenib in patients with pulmonary arterial hypertension. Clin Pharmacol Ther 2010; 87: 303-310
    CrossrefPubMedGoogle Scholar
  • 57 Grinnan D, Bogaard HJ, Grizzard J et al. Treatment of group I pulmonary arterial hypertension with carvedilol is safe. Am J Respir Crit Care Med 2014; 189: 1562-1564
    CrossrefPubMedGoogle Scholar
  • 58 Wang YY, Yang YX, Zhe H et al. Bardoxolone methyl (CDDO-Me) as a therapeutic agent: an update on its pharmacokinetic and pharmacodynamic properties. Drug Des Devel Ther 2014; 8: 2075-2088
    PubMedGoogle Scholar
  • 59 Mair KM, Wright AF, Duggan N et al. Sex-dependent influence of endogenous estrogen in pulmonary hypertension. Am J Respir Crit Care Med 2014; 190: 456-467
    CrossrefPubMedGoogle Scholar
  • 60 Bhatt DL, Kandzari DE, O’Neill WW et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med 2014; 370: 1393-1401
    CrossrefPubMedGoogle Scholar
  • 61 Chen SL, Zhang FF, Xu J et al. Pulmonary artery denervation to treat pulmonary arterial hypertension: the single-center, prospective, first-in-man PADN-1 study (first-in-man pulmonary artery denervation for treatment of pulmonary artery hypertension). J Am Coll Cardiol 2013; 62: 1092-1100
    CrossrefPubMedGoogle Scholar