DISEASE AREA COORDINATORS

Prof. Dr. H. Ardeschir Ghofrani (UGMLC), Prof. Dr. Ralph T. Schermuly (UGMLC)

(Administr. Coordinator: Dr. Sylvia Weißmann (UGMLC)

CONTRIBUTING PARTNER SITES

ARCN, BREATH, CPC-M, TLRC, UGMLC

OVERVIEW

Pulmonary hypertension (PH) is a disease of the pulmonary vasculature, which leads to shortness of breath, dizziness, fainting, and ultimately right heart failure. Five PH subclasses have been defined and all variants of PH together are estimated to affect up to 100 million people worldwide. The vascular pathology of PH is characterized by pulmonary vasoconstriction and by abnormal (“pseudo-malignant”) remodeling processes of all vessel layers. Vascular smooth muscle cell (SMC) proliferation is a prominent feature in virtually all PH entities. These remodeling processes result in severe loss of cross-sectional area, vascular pruning, and a concomitant increase in right ventricular afterload. Current PH therapy provides symptomatic relief and improves prognosis, but falls short as to reestablishment of structural and functional lung vascular integrity as a basis for handicapped-free long-term survival. The restoration of physiological vascular structure and function (reverse remodeling) represents the major therapeutic goal of the DZL PH team.

MAJOR RESEARCH GOALS

  • Translation of research findings into proof-of-concept and larger scale clinical trials to improve long-term outcome and allow for individualization of therapeutic strategies
  • Fostering regenerative treatment strategies, including endothelial progenitor cell-based revascularization of the lung
  • Development and refinement of tailored anti-remodeling and reverse-remodeling strategies
  • Characterization of phenotypic commonalities and differences between patients with different forms of PH, utilizing large-scale comprehensive databases
  • Identification and characterization of key molecular and cellular players driving maladaptive vascular remodeling in different forms of PH

Pulmonary Hypertension:  Selected Publications from DZL Faculty Members Published Since 2010

Hoeper MM, Barst RJ, Bourge RC, Feldman J, Frost AE, Galié N, Gómez-Sánchez MA, Grimminger F, Grünig E, Hassoun PM, Morrell NW, Peacock AJ, Satoh T, Simonneau G, Tapson VF, Torres F, Lawrence D, Quinn DA, Ghofrani HA. Imatinib Mesylate as Add-on Therapy for Pulmonary Arterial Hypertension: Results of the Randomized IMPRES Study. Circulation. 2013 Mar 12;127(10):1128-38. doi: 10.1161/CIRCULATIONAHA.112.000765. Epub 2013 Feb 12.

Rhodes CJ, Wharton J, Boon RA, Roexe T, Tsang H, Wojciak-Stothard B, Chakrabarti A, Howard LS, Gibbs JS, Lawrie A, Condliffe R, Elliot CA, Kiely DG, Huson L, Ghofrani HA, Tiede H, Schermuly R, Zeiher AM, Dimmeler S, Wilkins MR. Reduced microRNA-150 is associated with poor survival in pulmonary arterial hypertension.  Am J Respir Crit Care Med. 2013 Feb 1;187(3):294-302. doi: 10.1164/rccm.201205-0839OC. Epub 2012 Dec 6.

Hoeper MM, Huscher D, Ghofrani HA, Delcroix M, Distler O, Schweiger C, Grunig E, Staehler G, Rosenkranz S, Halank M, Held M, Grohé C, Lange TJ, Behr J, Klose H, Wilkens H, Filusch A, Germann M, Ewert R, Seyfarth HJ, Olsson KM, Opitz CF, Gaine SP, Vizza CD, Vonk-Noordegraaf A, Kaemmerer H, Gibbs JS, Pittrow D. Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: Results from the COMPERA registry.  Int J Cardiol. 2012 Nov 16. doi:pii: S0167-5273(12)01401-5. 10.1016/j.ijcard.2012.10.026. [Epub ahead of print]

Pullamsetti SS, Doebele C, Fischer A, Savai R, Kojonazarov B, Dahal BK, Ghofrani HA, Weissmann N, Grimminger F, Bonauer A, Seeger W, Zeiher AM, Dimmeler S, Schermuly RT. Inhibition of microRNA-17 improves lung and heart function in experimental pulmonary hypertension.  Am J Respir Crit Care Med. 2012 Feb 15;185(4):409-19. doi: 10.1164/rccm.201106-1093OC. Epub 2011 Dec 8.

Savai R, Pullamsetti SS, Kolbe J, Bieniek E, Voswinckel R, Fink L, Scheed A, Ritter C, Dahal BK, Vater A, Klussmann S, Ghofrani HA, Weissmann N, Klepetko W, Banat GA, Seeger W, Grimminger F, Schermuly RT. Immune and inflammatory cell involvement in the pathology of idiopathic pulmonary arterial hypertension.  Am J Respir Crit Care Med. 2012 Nov 1;186(9):897-908. doi: 10.1164/rccm.201202-0335OC. Epub 2012 Sep 6.

Jonigk D, Golpon H, Bockmeyer CL, Maegel L, Hoeper MM, Gottlieb J, Nickel N, Hussein K, Maus U, Lehmann U, Janciauskiene S, Welte T, Haverich A, Rische J, Kreipe H, Laenger F. Plexiform lesions in pulmonary arterial hypertension composition, architecture, and microenvironment.  Am J Pathol. 2011 Jul;179(1):167-79. doi: 10.1016/j.ajpath.2011.03.040. Epub 2011 May 11.

Pullamsetti SS, Savai R, Schaefer MB, Wilhelm J, Ghofrani HA, Weissmann N, Schudt C, Fleming I, Mayer K, Leiper J, Seeger W, Grimminger F, Schermuly RT. cAMP phosphodiesterase inhibitors increases nitric oxide production by modulating dimethylarginine dimethylaminohydrolases. Circulation. 2011 Mar 22;123(11):1194-204. doi: 10.1161/CIRCULATIONAHA.110.941484. Epub 2011 Mar 7.

Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F. Mechanisms of disease: pulmonary arterial hypertension.  Nat Rev Cardiol. 2011 Jun 21;8(8):443-55. doi: 10.1038/nrcardio.2011.87. Review.

Seimetz M, Parajuli N, Pichl A, Veit F, Kwapiszewska G, Weisel FC, Milger K, Egemnazarov B, Turowska A, Fuchs B, Nikam S, Roth M, Sydykov A, Medebach T, Klepetko W, Jaksch P, Dumitrascu R, Garn H, Voswinckel R, Kostin S, Seeger W, Schermuly RT, Grimminger F, Ghofrani HA, Weissmann N.  Inducible NOS inhibition reverses tobacco-smoke-induced emphysema and pulmonary hypertension in mice. Cell. 2011 Oct 14;147(2):293-305. doi: 10.1016/j.cell.2011.08.035.

Ghofrani HA, Morrell NW, Hoeper MM, Olschewski H, Peacock AJ, Barst RJ, Shapiro S, Golpon H, Toshner M, Grimminger F, Pascoe S. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy.  Am J Respir Crit Care Med. 2010 Nov 1;182(9):1171-7. doi: 10.1164/rccm.201001-0123OC. Epub 2010 Jun 25.