Die pulmonale Hypertonie – historische Entwicklung, derzeitiger Stand der Therapie und Ausblick

Zusammenfassung

Dieser Artikel bietet eine kurze Übersicht über die Geschichte der pulmonalen Hypertonie, angefangen mit den Erstbeschreibungen der entsprechenden Lungengefäßveränderungen durch Ernst von Romberg und Victor Eisenmenger Ende des 19. Jahrhunderts. Die histopathologischen Veränderungen, die wir heute bei den verschiedenen Formen der pulmonalen Hypertonie kennen, waren zum Teil bereits in der ersten Hälfte des 20. Jahrhunderts charakterisiert, aber erst in den 50er-Jahren gelang die Katheterisierung des rechten Herzens und der Lungengefäße, insbesondere durch die Pionierleistungen von Forßmann und Cournand. Erst dadurch wurde es möglich, das klinische Spektrum dieser Krankheitsentität und die Effekte therapeutischer Interventionen zu untersuchen. Die ersten Behandlungsversuche mit Vasodilatatoren verliefen überwiegend erfolglos und erst in den 80er-Jahren des letzten Jahrhunderts stand mit intravenösem Prostacyclin eine wirksame Therapie zumindest einer Variante der pulmonalen Hypertonie zur Verfügung. Mittlerweile hat das Verständnis der Pathogenese des Lungenhochdrucks deutlich zugenommen. Das Gleiche gilt für die Zahl der verfügbaren Therapien und Deutschland verfügt mittlerweile über eine gut etablierte Versorgungsstruktur für diese Erkrankung. Allerdings gibt es für die meisten Formen der pulmonalen Hypertonie noch keine kurativen Behandlungsmöglichkeiten und nach wie vor viele ungelöste Fragen.

Abstract

This article provides a brief overview on the history of pulmonary hypertension, starting with the first descriptions of the accompanying pulmonary vascular lesions by Ernst von Romberg and Victor Eisenmenger at the end of the 19^th century. Many of the histopathological changes in the pulmonary vasculature found in the various forms of pulmonary hypertension had already been described in the first half of the 20^th century. However, only through the pioneering work by Forßmann and Cournand during the middle of the 20^th century was it finally possible to catheterise the right ventricle and the pulmonary arteries. After this it became feasible to study the clinical spectrum of the various forms of pulmonary hypertension as well as the effects of therapeutic interventions. Early treatment attempts with vasodilators, however, were not successful. Intravenous prostacyclin, used to treat some forms of pulmonary hypertension since 1980, became the first effective treatment. Since that time, our understanding of the pathogenesis of pulmonary hypertension has increased substantially, as has the number of effective therapies, at least for some forms of pulmonary hypertension. Many aspects of the disease, however, remain poorly understood and a cure is still not achievable for the majority of the affected patients.

Literatur

• 1 Romberg E von. Dtsch Arch Klin Med. 1891;  48 197-206
• 2 Eisenmenger V. Z Klin Med. 1897;  32 1-28
• 3 Wood P. The Eisenmenger syndrome or pulmonary hypertension with reversed central shunt.  Br Med J. 1958;  2 755-762
• 4 Arriliga . Bull Mem Soc Med Hop Paris. 1924;  48 292-303
• 5 Brenner O. Sclerosis of pulmonary artery with thrombosis.  Arch Intern Med. 1931;  47 799-805
• 6 Heath D, Smith P, Gosney J. et al . The pathology of the early and late stages of primary pulmonary hypertension.  Br Heart J. 1987;  58 204-213
• 7 Wagenvoort C A. Vasoconstrictive primary pulmonary hypertension and pulmonary veno-occlusive disease.  Cardiovasc Clin. 1972;  4 97-113
• 8 Wagenvoort C A. The pathology of primary pulmonary hypertension.  J Pathol. 1970;  101 i
• 9 Brenner O. Arch Intern Med. 1935;  56 211-237
• 10 Cournand A, Riley R L, Breed E S. et al . Measurement of cardiac output in man using the technique of catheterization of the right auricle or ventricle.  J Clin Invest. 1945;  24 106-116
• 11 Wood P. Pulmonary hypertension with special reference to the vasoconstrictive factor.  Br Heart J. 1958;  20 557-570
• 12 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;  34 888-894
• 13 Galie N, Hoeper M M, Humbert M. et al . 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 Respir J. 2009;  34 1219-1263
• 14 Galie N, Hoeper M M, Humbert M. et al . 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 2493-2537
• 15 Greiser E, Gahl K. [Causality demonstration of primary vascular pulmonary hypertension induced by aminorexfumarate].  Verh Dtsch Ges Inn Med. 1972;  78 1073-1076
• 16 Bass O, Gurtner H P. [Evolution of primary vascular pulmonary hypertension following ingestion of aminorex fumarate (Menocil). Preliminary communication].  Schweiz Med Wochenschr. 1973;  103 1794
• 17 Kramer M S, Lane D A. Aminorex, dexfenfluramine, and primary pulmonary hypertension.  J Clin Epidemiol. 1998;  51 361-364
• 18 Rothman R B, Ayestas M A, Dersch C M, Baumann M H. Aminorex, fenfluramine, and chlorphentermine are serotonin transporter substrates. Implications for primary pulmonary hypertension.  Circulation. 1999;  100 869-875
• 19 Abenhaim L, Moride Y, Brenot F. et al . Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group.  N Engl J Med. 1996;  335 609-616
• 20 Hoeper M M, Mayer E, Simonneau G, Rubin L J. Chronic Thromboembolic Pulmonary Hypertension.  Circulation. 2006;  113 2011-2020
• 21 Hoeper M M, Barbera J A, Channick R N. et al . Diagnosis, assessment, and treatment of non-pulmonary arterial hypertension pulmonary hypertension.  J Am Coll Cardiol. 2009;  54 S85-S96
• 22 Lam C S, Roger V L, Rodeheffer R J. et al . Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study.  J Am Coll Cardiol. 2009;  53 1119-1126
• 23 Lam C S, Borlaug B A, Kane G C. et al . Age-associated increases in pulmonary artery systolic pressure in the general population.  Circulation. 2009;  119 2663-2670
• 24 Behr J, Ryu J H. Pulmonary hypertension in interstitial lung disease.  Eur Respir J. 2008;  31 1357-1367
• 25 Chaouat A, Naeije R, Weitzenblum E. Pulmonary hypertension in COPD.  Eur Respir J. 2008;  32 1371-1385
• 26 Simonneau G, Galie N, Rubin L J. et al . Clinical classification of pulmonary hypertension.  J Am Coll Cardiol. 2004;  43 5S-12S
• 27 Simonneau G, Robbins I M, Beghetti M. et al . Updated clinical classification of pulmonary hypertension.  J Am Coll Cardiol. 2009;  54 S43-S54
• 28 Badesch D B, Champion H C, Sanchez M A. et al . Diagnosis and assessment of pulmonary arterial hypertension.  J Am Coll Cardiol. 2009;  54 S55-S66
• 29 Hoeper M M. The new definition of pulmonary hypertension.  Eur Respir J. 2009;  34 790-791
• 30 Dresdale D T, Michtom R J, Schultz M. Recent studies in primary pulmonary hypertension, including pharmacodynamic observations on pulmonary vascular resistance.  Bull N Y Acad Med. 1954;  30 195-207
• 31 Rich S, Brundage B H. High-dose calcium channel-blocking therapy for primary pulmonary hypertension: evidence for long-term reduction in pulmonary arterial pressure and regression of right ventricular hypertrophy.  Circulation. 1987;  76 135-141
• 32 Rich S, Kaufmann E. High dose titration of calcium channel blocking agents for primary pulmonary hypertension: guidelines for short-term drug testing.  J Am Coll Cardiol. 1991;  18 1323-1327
• 33 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 76-81
• 34 Sitbon O, Humbert M, Jais X. et al . Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension.  Circulation. 2005;  111 3105-3111
• 35 Thenappan T, Shah S J, Rich S. et al . Survival in pulmonary arterial hypertension: a reappraisal of the NIH risk stratification equation.  Eur Respir J. 2010;  35 1079-1087
• 36 Deng Z, Morse J H, Slager S L. 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
• 37 Machado R D, Pauciulo M W, Thomson J R. et al . BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension.  Am J Hum Genet. 2001;  68 92-102
• 38 Humbert M, Hoeper M M. Severe pulmonary arterial hypertension: a forme fruste of cancer?.  Am J Respir Crit Care Med. 2008;  178 551-552
• 39 Voelkel N F, Cool C, Lee S D. et al . Primary pulmonary hypertension between inflammation and cancer.  Chest. 1998;  114 225S-230S
• 40 Higenbottam T, Wheeldon D, Wells F, Wallwork J. Long-term treatment of primary pulmonary hypertension with continuous intravenous epoprostenol (prostacyclin).  Lancet. 1984;  1 1046-1047
• 41 Barst R J, Rubin L J, McGoon M D. et al . Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin.  Ann Intern Med. 1994;  121 409-415
• 42 Reitz B A, Wallwork J L, Hunt S A. et al . Heart-lung transplantation: successful therapy for patients with pulmonary vascular disease.  N Engl J Med. 1982;  306 557-564
• 43 Barst R J, Rubin L J, Long W A. 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;  334 296-302
• 44 Dupuis J, Hoeper M M. Endothelin receptor antagonists in pulmonary arterial hypertension.  Eur Respir J. 2008;  31 407-414
• 45 Wilkins M R, Wharton J, Grimminger F, Ghofrani H A. Phosphodiesterase inhibitors for the treatment of pulmonary hypertension.  Eur Respir J. 2008;  32 198-209
• 46 Olschewski H, Gomberg-Maitland M. Prostacyclin therapies for the treatment of pulmonary arterial hypertension.  Eur Respir J. 2008;  31 801-901
• 47 Hoeper M M, Markevych I, Spiekerkoetter E. et al . Goal-oriented treatment and combination therapy for pulmonary arterial hypertension.  Eur Respir J. 2005;  26 858-863
• 48 Hoeper M M, Ghofrani H A, Gorenflo M. et al . Diagnosis and Treatment of Pulmonary Hypertension: European Guidelines 2009.  Pneumologie. 2010;  64 401-414
• 49 Moser K M, Braunwald N S. Successful surgical intervention in severe chronic thromboembolic pulmonary hypertension.  Chest. 1973;  64 29-35
• 50 Olschewski H, Walmrath D, Schermuly R. et al . Aerosolized prostacyclin and iloprost in severe pulmonary hypertension.  Ann Intern Med. 1996;  124 820-824
• 51 Olschewski H, Ghofrani H A, Walmrath D. et al . Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to lung fibrosis.  Am J Respir Crit Care Med. 1999;  160 600-607
• 52 Olschewski H, Simonneau G, Galie N. et al . Inhaled iloprost for severe pulmonary hypertension.  N Engl J Med. 2002;  347 322-329
• 53 Ghofrani H A, Wiedemann R, Rose F. et al . Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension.  Ann Intern Med. 2002;  136 515-522
• 54 Ghofrani H A, Rose F, Schermuly R T. et al . Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension.  J Am Coll Cardiol. 2003;  42 158-164
• 55 Ghofrani H A, Schermuly R T, Rose F. et al . Sildenafil for long-term treatment of nonoperable chronic thromboembolic pulmonary hypertension.  Am J Respir Crit Care Med. 2003;  167 1139-1141
• 56 Ghofrani H A, Voswinckel R, Reichenberger F. et al . Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension: a randomized prospective study.  J Am Coll Cardiol. 2004;  44 1488-1496
• 57 Ghofrani H A, Reichenberger F, Kohstall M G. et al . Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest base camp: a randomized, double-blind, placebo-controlled crossover trial.  Ann Intern Med. 2004;  141 169-177
• 58 Ghofrani H A, Seeger W, Grimminger F. Imatinib for the treatment of pulmonary arterial hypertension.  N Engl J Med. 2005;  353 1412-1413
• 59 Schermuly R T, Stasch J P, Pullamsetti S S. et al . Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension.  Eur Respir J. 2008;  32 881-891
• 60 Schermuly R T, Pullamsetti S S, Kwapiszewska G. et al . Phosphodiesterase 1 upregulation in pulmonary arterial hypertension: target for reverse-remodeling therapy.  Circulation. 2007;  115 2331-2339
• 61 Grimminger F, Weimann G, Frey R. et al . First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension.  Eur Respir J. 2009;  33 785-792
• 62 Ghofrani H A, Morrell N W, Hoeper M M. et al . Imatinib in Pulmonary Arterial Hypertension Patients with Inadequate Response to Established Therapy.  Am J Respir Crit Care Med. 2010;  epub June 25
• 63 Ghofrani H A, Hoeper M M, Halank M. et al . Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study.  Eur Respir J. 2010;  epub June 7
• 64 Schermuly R T, Dony E, Ghofrani H A. et al . Reversal of experimental pulmonary hypertension by PDGF inhibition.  J Clin Invest. 2005;  115 2811-2821
• 65 Gaine S P, Rubin L J. Primary pulmonary hypertension.  Lancet. 1998;  352 719-725