Degeneration und Kalzifizierung von Herzklappen

Zusammenfassung

Die Zahlen degenerativer Herzklappenerkrankungen steigen in Deutschland über die letzten Jahre kontinuierlich an. Histologisches Korrelat aller degenerativen Klappenveränderungen ist die Sequenz von initialer fibrotischer Klappenverdickung mit begleitender Inflammation hin zu fortschreitender destruierender Kalzifizierung. Diese valvuläre Kalzifizierung galt in der Vergangenheit als passive Begleiterscheinung des physiologischen Alterungsprozesses. Erst in den letzten Jahren konnte die klinische Relevanz der fortgeschrittenen Kalzifizierung als potenter Prädiktor kardiovaskulärer Morbidität und Mortalität aufgezeigt werden. Darüber hinaus konnten komplexe Regulationsmechanismen der aktiv regulierten Kalzifizierung analog der Vorgänge zum Knochenstoffwechsel entschlüsselt werden: So führen nach heutigem Verständnis allgemeine Endothelnoxen wie Inflammation, Hypertonus oder eine Hyperlipoproteinämie im Bereich des Klappenendothels zur Freisetzung von Morphogenen wie BMP-2 und BMP-4. Diese begünstigen den Vorgang der endothelialen mesenchymalen Transition mit lokaler Entstehung von Myofibroblasten, sekundärer Osteoblastendifferenzierung innerhalb des Klappenapparats und abschließender Mineralisation. Letztere wird als chemischer Prozess der Calcium-Phosphat-Präzipitation zusätzlich durch kalzifizierungsinhibitorische Proteine wie Fetuin-A oder Matrix-Gla-Protein moduliert. Diese Zusammenhänge verdeutlichen, dass die valvuläre Kalzifizierung das Resultat eines komplex regulierten multikausalen Prozesses darstellt. In Zukunft werden multimodale Therapiekonzepte auch unter Berücksichtigung lokaler Regulationsmechanismen zusammen mit der Betrachtung des individuellen Risikoprofils die Basis für die Behandlung degenerativer Klappenerkrankungen bilden können.

Abstract

The prevalence of degenerative cardiac valve diseases in Germany has increased continuously over the last few years. The histological correlate of degenerative valvular heart disease is the sequence of initial fibrotic valvular thickening with associated inflammation towards progressive calcification leading to destruction of the valve. In the past, valvular calcification was predominantly regarded as a passive process occurring during physiological aging-processes. It is only in recent years that the clinical significance of progressive calcification has become evident as potent predictor of cardiovascular morbidity and mortality. Furthermore complex regulatory pathomechanisms of unwanted calcification in analogy to processes of physiological bone formation have been decoded: The current understanding is that the general endothelial noxins as inflammation, hypertension or a hyperlipoproteinaemia in the area of the valvular endothelium lead to release of morphogens as BMP-2 and BMP-4. These may promote the process of endothelial mesenchymal transition including a local emergence of myofibroblasts and the development of a secondary differentiation of osteoblasts within the valve apparatus, followed by the final mineralization step. The latter, as part of the chemical process of calcium phosphate precipitation will be modulated additionally through calcification inhibiting proteins, such as fetuin-A or Matrix Gla Protein (MGP). These connections particularly highlight that valvular calcification is the outcome of a complex regulated and multicausal process. Future multimodal therapy concepts will have to take into consideration local regulatory mechanism as well as the individual risk profile of each patient.

Schlüsselwörter

Klappenerkrankung - Kalzifizierung - Kalzifizierungsinhibitoren - Fetuin-A - Matrix-Gla-Protein - Knochenbildung

Key words

valvular disease - calcification - calcification inhibitors - fetuin-A - matrix-gla protein - bone formation

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