Zusammenfassung
Aortenerkrankungen sind komplexe und herausfordernde chirurgische Krankheitsbilder, deren molekulare Grundlagen immer noch erforscht werden. Die häufigsten Aortopathien sind Aneurysmen der abdominellen und der thorakalen Aorta. Für beide Krankheitsbilder ist die einzige lebensverlängernde Therapie die chirurgische bzw. endovaskuläre Intervention. Um einen kausalen Therapieansatz zu ermöglichen, ist es essenziell, die molekularen Mechanismen dieser Aortopathien zu ergründen. Im vorliegenden Beitrag werden die aktuellen wissenschaftlichen Erkenntnisse hierzu skizziert. Häufige Ursachen für thorakale Aortenaneurysmen sind syndromale (z. B. Marfan-Syndrom) und nichtsyndromale (z. B. ACTA-2-Mutationen, bikuspidale Aortenklappen) Erkrankungen. Bei beiden finden sich die für eine Aneurysmabildung ursächlichen Faktoren in den lamellaren Einheiten der Aorta. Hier spielen sich alle Prozesse ab, die für die Stabilität der Aortenwand verantwortlich sind, z. B. Auf- und Abbau der Extrazellularmatrix oder Signalkaskaden in den aortalen glatten Muskelzellen. Bei den syndromalen Bindegewebserkankungen sind für das Marfan-Syndrom Mutationen im Fibrillin-1-Gen und eine Dysregulation der „Transforming-growth-factor“(TGF)-β-Signalkaskade sowie für das Loeys-Dietz-Syndrom Mutationen im TGF-β-Rezeptor ursächlich. Eine genetische Komponente bikuspidaler Aortenklappen wird ebenso diskutiert wie die mechanische Schädigung der Aortenwand durch eine veränderte Zirkulation. Die nichtsyndromalen familiären Aortenaneurysmen weisen verschiedene genetische Komponenten auf. Daher zielen die meisten experimentellen, kausalen Therapien auf die Kontrolle der dysregulierten TGF-β-Signalkaskade ab. Die vielversprechendsten Optionen sind Sartane, Statine und Tetrazykline.
Abstract
Aortic diseases are complex and surgically challenging disorders for which the molecular pathways are still under investigation. The most common aortopathies are abdominal and thoracic aneurysms but the only life extending treatment for both entities is a surgical or endovascular intervention. For a causal therapeutic approach to these life-threatening diseases it is necessary to understand the underlying molecular mechanisms. Common causes of aortopathies are syndromic, e.g. Marfan syndrome and non-syndromic disorders, e.g. ACTA2 mutations and bicuspid aortic valves. In both subgroups the processes which cause aneurysm development can be found in the lamellar unit, which consists of collagen fibers, extracellular matrix and smooth muscle cells and harbors all factors, which are vital for stability of the aortic wall. The underlying molecular mechanisms in syndromic connective tissue diseases, such as Marfan syndrome are mutations in the fibrillin 1 gene and dysregulation of the transforming growth factor β (TGF-β) signaling pathway and in Loeys-Dietz syndrome mutations in TGF-β receptor genes. The causes of biscuspid aortic valves are still under debate but evidence suggests both mechanical blood flow changes and genetic factors are responsible. The non-syndromic familial aortic aneurysms show multiple different genetic mutations which can cause either a destruction of aortic smooth muscle cells or a dysregulation of the TGF-β signaling pathway, similar to syndromic disorders; therefore, most of the still experimental drugs target the TGF-β pathway. The most promising options are angiotensin receptor blockers, statins or tetracyclines.
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M. Zaradzki und K. Kallenbach geben an, dass kein Interessenkonflikt besteht.
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Zaradzki, M., Kallenbach, K. Molekulare Mechanismen von Aortenerkrankungen. Z Herz- Thorax- Gefäßchir 30, 198–203 (2016). https://doi.org/10.1007/s00398-016-0068-3
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DOI: https://doi.org/10.1007/s00398-016-0068-3