Pathobiologie, Pathologie und Genetik der pulmonalen Hypertonie: Empfehlungen der Kölner Konsensus-Konferenz 2016

Zusammenfassung

Die 2015 veröffentlichen Europäischen Leitlinien zur Diagnostik und Therapie der pulmonalen Hypertonie (PH) sind nunmehr auch in Deutschland gültig. Während sich die Leitlinien eingehend mit klinischen Aspekten der pulmonal arteriellen Hypertonie (PAH) und anderen Formen der PH befassen, werden neue Erkenntnisse zur Pathobiologie, Pathologie und Genetik nur relativ kurz behandelt. Diese sind für das Verständnis der Erkrankung jedoch sowohl aus klinischer als auch aus wissenschaftlicher Sicht eminent wichtig. Zudem sind sie für die Entwicklung neuer Therapiekonzepte essenziell. Hierbei sind eine Reihe aktueller Daten bedeutsam, die eine ausführliche Kommentierung der Leitlinien und in einigen Punkten eine Aktualisierung notwendig machen. Im Juni 2016 fand in Köln eine Konsensus-Konferenz statt, die von den Arbeitsgruppen PH der Deutschen Gesellschaften für Kardiologie (DGK), Pneumologie (DGP) und Pädiatrische Kardiologie (DGPK) organisiert wurde. Die Konferenz befasste sich mit der Umsetzung der Europäischen Leitlinien in Deutschland. Dazu wurden verschiedene Arbeitsgruppen eingesetzt, von denen sich eine gezielt der Pathobiologie, Pathologie und Genetik der PH widmete. Die Ergebnisse und Empfehlungen dieser Arbeitsgruppe werden in dem vorliegenden Manuskript detailliert beschrieben.

Abstract

The 2015 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension (PH) are also valid for Germany. While the guidelines contain detailed recommendations regarding clinical aspects of pulmonary arterial hypertension (PAH) and other forms of PH, they contain only a relatively short paragraph on novel findings on the pathobiology, pathology, and genetics. However, these are of great importance for our understanding of this complex disease both from a clinical and scientific point of view, and they are essential for the development of novel treatment strategies. To this end, a number of current data are relevant, prompting a detailed commentary to the guidelines, and the consideration of new scientific data. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to the pathobiology, pathology and genetics of PH. This article summarizes the results and recommendations of this working group.

Schlüsselwörter

Entzündung - Metabolismus - BMPR2 - FoxO1 - KCNK3/TASK-1

Keywords

inflammation - metabolism - BMPR2 - FoxO1 - KCNK3/TASK-1

• Literatur

• 1 Kumar R, Mickael C, Chabon J et al. The Causal Role of IL-4 and IL-13 in Schistosoma Mansoni Pulmonary Hypertension. Am J Respir Crit Care Med 2015; 192: 998-1008
• 2 Park SH, Chen WC, Durmus N et al. The Effects of Antigen-Specific IgG1 Antibody for the Pulmonary-Hypertension-Phenotype and B Cells for Inflammation in Mice Exposed to Antigen and Fine Particles From Air Pollution. PLoS One 2015; 10: e0129910
• 3 Hautefort A, Girerd B, Montani D et al. T-Helper 17 Cell Polarization in Pulmonary Arterial Hypertension. Chest 2015; 147: 1610-1620
• 4 Becker MO, Kill A, Kutsche M et al. Vascular Receptor Autoantibodies in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis. Am J Respir Crit Care Med 2014; 190: 808-817
• 5 Talati MH, Brittain EL, Fessel JP et al. Mechanisms of Lipid Accumulation in the Bone Morphogenic Protein Receptor 2 Mutant Right Ventricle. Am J Respir Crit Care Med 2016; DOI: 10.1164/rccm.201507-1444OC.
• 6 Sawada H, Saito T, Nickel NP et al. Reduced BMPR2 Expression Induces GM-CSF Translation and Macrophage Recruitment in Humans and Mice to Exacerbate Pulmonary Hypertension. J Exp Med 2014; 211: 263-280
• 7 El Kasmi KC, Pugliese SC, Riddle SR et al. Adventitial Fibroblasts Induce a Distinct Proinflammatory/Profibrotic Macrophage Phenotype in Pulmonary Hypertension. J Immunol 2014; 193: 597-609
• 8 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
• 9 Tian W, Jiang X, Tamosiuniene R et al. Blocking Macrophage Leukotriene B4 Prevents Endothelial Injury and Reverses Pulmonary Hypertension. Sci Transl Med 2013; 5: 200ra117
• 10 Savai R, Al-Tamari HM, Sedding D et al. Pro-Proliferative and Inflammatory Signaling Converge on FoxO1 Transcription Factor in Pulmonary Hypertension. Nature Medicine 2014; 20: 1289-1300
• 11 Biasin V, Marsh LM, Egemnazarov B et al. Meprin Beta, a Novel Mediator of Vascular Remodelling Underlying Pulmonary Hypertension. J Pathol 2014; 233: 7-17
• 12 van der Feen DE, Dickinson MG, Bartelds B et al. Egr-1 Identifies Neointimal Remodeling and Relates to Progression in Human Pulmonary Arterial Hypertension. J Heart Lung Transplant 2016; 35: 481-490
• 13 Vattulainen-Collanus S, Akinrinade O, Li M et al. Loss of PPARgamma in Endothelial Cells Leads to Impaired Angiogenesis. J Cell Sci 2016; 129: 693-705
• 14 Hopper RK, Moonen JR, Diebold I et al. In Pulmonary Arterial Hypertension, Reduced BMPR2 Promotes Endothelial-to-Mesenchymal Transition Via HMGA1 and Its Target Slug. Circulation 2016; 133: 1783-1794
• 15 Diebold I, Hennigs JK, Miyagawa K et al. BMPR2 Preserves Mitochondrial Function and DNA During Reoxygenation to Promote Endothelial Cell Survival and Reverse Pulmonary Hypertension. Cell Metab 2015; 21: 596-608
• 16 Mouraret N, Marcos E, Abid S et al. Activation of Lung P53 by Nutlin-3a Prevents and Reverses Experimental Pulmonary Hypertension. Circulation 2013; 127: 1664-1676
• 17 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
• 18 Nagaraj C, Tang B, Balint Z et al. Src Tyrosine Kinase Is Crucial for Potassium Channel Function in Human Pulmonary Arteries. Eur Respir J 2013; 41: 85-95
• 19 Ma L, Roman-Campos D, Austin ED et al. A Novel Channelopathy in Pulmonary Arterial Hypertension. N Engl J Med 2013; 369: 351-361
• 20 Antigny F, Hautefort A, Meloche J et al. Potassium Channel Subfamily K Member 3 (KCNK3) Contributes to the Development of Pulmonary Arterial Hypertension. Circulation 2016; 133: 1371-1385
• 21 Tabeling C, Yu H, Wang L et al. CFTR and Sphingolipids Mediate Hypoxic Pulmonary Vasoconstriction. Proc Natl Acad Sci USA 2015; 112: E1614-E1623
• 22 Malczyk M, Veith C, Fuchs B et al. Classical Transient Receptor Potential Channel 1 in Hypoxia-Induced Pulmonary Hypertension. Am J Respir Crit Care Med 2013; 188: 1451-1459
• 23 Asadi AK, Sa RC, Kim NH et al. Inhaled Nitric Oxide Alters the Distribution of Blood Flow in the Healthy Human Lung, Suggesting Active Hypoxic Pulmonary Vasoconstriction in Normoxia. J Appl Physiol (1985) 2015; 118: 331-343
• 24 Bakr A, Pak O, Taye A et al. Effects of Dimethylarginine Dimethylaminohydrolase-1 Overexpression on the Response of the Pulmonary Vasculature to Hypoxia. Am J Respir Cell Mol Biol 2013; 49: 491-500
• 25 Wenzel D, Matthey M, Bindila L et al. Endocannabinoid anandamide mediates hypoxic pulmonary vasoconstriction. Proc Natl Acad Sci USA 2013; 110: 18710-18715
• 26 Sommer N, Strielkov I, Pak O et al. Oxygen Sensing and Signal Transduction in Hypoxic Pulmonary Vasoconstriction. Eur Respir J 2016; 47: 288-303
• 27 Pugliese SC, Poth JM, Fini MA et al. The Role of Inflammation in Hypoxic Pulmonary Hypertension: From Cellular Mechanisms to Clinical Phenotypes. Am J Physiol Lung Cell Mol Physiol 2015; 308: L229-L252
• 28 Olschewski A, Weir EK. Redox Regulation of Ion Channels in the Pulmonary Circulation. Antioxid Redox Signal 2015; 22: 465-485
• 29 Moreno L, Moral-Sanz J, Morales-Cano D et al. Ceramide Mediates Acute Oxygen Sensing in Vascular Tissues. Antioxid Redox Signal 2014; 20: 1-14
• 30 Waypa GB, Marks JD, Guzy RD et al. Superoxide Generated at Mitochondrial Complex III Triggers Acute Responses to Hypoxia in the Pulmonary Circulation. Am J Respir Crit Care Med 2013; 187: 424-432
• 31 Zhou J, Zhang J, Lu Y et al. Mitochondrial Transplantation Attenuates Hypoxic Pulmonary Vasoconstriction. Oncotarget 2016; DOI: 10.18632/oncotarget.8893.
• 32 Smith KA, Voiriot G, Tang H et al. Notch Activation of Ca(2+) Signaling in the Development of Hypoxic Pulmonary Vasoconstriction and Pulmonary Hypertension. Am J Respir Cell Mol Biol 2015; 53: 355-367
• 33 Maier T, Follmann M, Hessler G et al. Discovery and Pharmacological Characterization of a Novel Potent Inhibitor of Diacylglycerol-Sensitive TRPC Cation Channels. Br J Pharmacol 2015; 172: 3650-3660
• 34 Goldenberg NM, Wang L, Ranke H et al. TRPV4 Is Required for Hypoxic Pulmonary Vasoconstriction. Anesthesiology 2015; 122: 1338-1348
• 35 Machado RD, Southgate L, Eichstaedt CA et al. Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects. Hum Mutat 2015; 36: 1113-1127
• 36 Wang G, Fan R, Ji R et al. Novel Homozygous BMP9 Nonsense Mutation Causes Pulmonary Arterial Hypertension: a Case Report. BMC Pulm Med 2016; 16: 17
• 37 Eyries M, Montani D, Girerd B et al. EIF2AK4 Mutations Cause Pulmonary Veno-Occlusive Disease, a Recessive Form of Pulmonary Hypertension. Nature Genetics 2014; 46: 65-69
• 38 Zhou G, Chen T, Raj JU. MicroRNAs in Pulmonary Arterial Hypertension. Am J Respir Cell Mol Biol 2015; 52: 139-151
• 39 Kim JD, Lee A, Choi J et al. Epigenetic Modulation As a Therapeutic Approach for Pulmonary Arterial Hypertension. Exp Mol Med 2015; 47: e175
• 40 Rothman AM, Arnold ND, Pickworth JA et al. MicroRNA-140-5p and SMURF1 Regulate Pulmonary Arterial Hypertension. J Clin Invest 2016; 126: 2495-2508
• 41 Potus F, Ruffenach G, Dahou A et al. Downregulation of MicroRNA-126 Contributes to the Failing Right Ventricle in Pulmonary Arterial Hypertension. Circulation 2015; 132: 932-943
• 42 Shi L, Kojonazarov B, Elgheznawy A et al. MiR-223-IGF-IR Signalling in Hypoxia- and Load-Induced Right-Ventricular Failure: a Novel Therapeutic Approach. Cardiovasc Res 2016; 111: 184-193
• 43 Bertero T, Lu Y, Annis S et al. Systems-Level Regulation of MicroRNA Networks by MiR-130/301 Promotes Pulmonary Hypertension. J Clin Invest 2014; 124: 3514-3528
• 44 Ehrlich M. DNA Hypomethylation in Cancer Cells. Epigenomics 2009; 1: 239-259
• 45 Lan B, Hayama E, Kawaguchi N et al. Therapeutic Efficacy of Valproic Acid in a Combined Monocrotaline and Chronic Hypoxia Rat Model of Severe Pulmonary Hypertension. PLoS One 2015; 10: e0117211
• 46 De Raaf MA, Hussaini AA, Gomez-Arroyo J et al. Histone Deacetylase Inhibition With Trichostatin A Does Not Reverse Severe Angioproliferative Pulmonary Hypertension in Rats (2013 Grover Conference Series). Pulm Circ 2014; 4: 237-243
• 47 Meloche J, Potus F, Vaillancourt M et al. Bromodomain-Containing Protein 4: The Epigenetic Origin of Pulmonary Arterial Hypertension. Circ Res 2015; 117: 525-535
• 48 Assad TR, Hemnes AR. Metabolic Dysfunction in Pulmonary Arterial Hypertension. Curr Hypertens Rep 2015; 17: 20
• 49 Ryan JJ, Archer SL. Emerging Concepts in the Molecular Basis of Pulmonary Arterial Hypertension: Part I: Metabolic Plasticity and Mitochondrial Dynamics in the Pulmonary Circulation and Right Ventricle in Pulmonary Arterial Hypertension. Circulation 2015; 131: 1691-1702
• 50 Zhao Y, Peng J, Lu C et al. Metabolomic Heterogeneity of Pulmonary Arterial Hypertension. PLoS One 2014; 9: e88727
• 51 Lewis GD, Ngo D, Hemnes AR et al. Metabolic Profiling of Right Ventricular-Pulmonary Vascular Function Reveals Circulating Biomarkers of Pulmonary Hypertension. J Am Coll Cardiol 2016; 67: 174-189
• 52 Brittain EL, Talati M, Fessel JP et al. Fatty Acid Metabolic Defects and Right Ventricular Lipotoxicity in Human Pulmonary Arterial Hypertension. Circulation 2016; 133: 1936-1944
• 53 Graham BB, Kumar R, Mickael C et al. Severe Pulmonary Hypertension Is Associated With Altered Right Ventricle Metabolic Substrate Uptake. Am J Physiol Lung Cell Mol Physiol 2015; 309: L435-L440
• 54 West J, Niswender KD, Johnson JA et al. A Potential Role for Insulin Resistance in Experimental Pulmonary Hypertension. Eur Respir J 2013; 41: 861-871
• 55 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
• 56 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
• 57 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
• 58 Kellner M, Wehling J, Warnecke G et al. Correlating 3D Morphology With Molecular Pathology: Fibrotic Remodelling in Human Lung Biopsies. Thorax 2015; 70: 1197-1198
• 59 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
• 60 Spiekerkoetter E, Tian X, Cai J et al. FK506 Activates BMPR2, Rescues Endothelial Dysfunction, and Reverses Pulmonary Hypertension. J Clin Invest 2013; 123: 3600-3613