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Aktuelle Kardiologie 2018; 7(03): 211-219
DOI: 10.1055/a-0632-4497
Übersichtsarbeit
Georg Thieme Verlag KG Stuttgart · New York

Familiäre Kardiomyopathien – von der Phänomenologie zur zielgerichteten Therapie

Familial Cardiomyopathies and the Road to Precision Medicine
Ali Amr
1   Klinik für Kardiologie, Angiologie und Pneumologie, Institut für Cardiomyopathien Heidelberg, UniversitätsKlinikum Heidelberg
2   Deutsches Zentrum für Herz-Kreislauf-Forschung e. V., Heidelberg
,
Hugo A. Katus
1   Klinik für Kardiologie, Angiologie und Pneumologie, Institut für Cardiomyopathien Heidelberg, UniversitätsKlinikum Heidelberg
2   Deutsches Zentrum für Herz-Kreislauf-Forschung e. V., Heidelberg
,
Benjamin Meder
1   Klinik für Kardiologie, Angiologie und Pneumologie, Institut für Cardiomyopathien Heidelberg, UniversitätsKlinikum Heidelberg
2   Deutsches Zentrum für Herz-Kreislauf-Forschung e. V., Heidelberg
› Author Affiliations
Further Information

Publication History

Publication Date:
28 June 2018 (online)

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Zusammenfassung

Kardiomyopathien stellen eine heterogene Gruppe von Herzmuskelerkrankungen dar, die häufig durch genetische Mechanismen bedingt sind oder in ihrem Verlauf durch solche beeinflusst werden. Im Bereich der genetischen Diagnostik spielen insbesondere die monogenen und syndromalen Formen eine wichtige Rolle, da durch die Identifikation einer pathogenen genetischen Variante nicht nur eine Bestätigung der Diagnose, sondern auch eine Abklärung auf Anlageträgerschaft und damit Erkrankungsrisiko bei Angehörigen möglich ist, sowie in bestimmten Fällen eine Vorhersage des zu erwartenden Krankheitsverlaufs erfolgen kann. Schon heute ergeben sich durch Nachweis von bestimmten Genvarianten therapeutische Konsequenzen, was durch die zunehmende Anzahl an molekularen Therapieentwicklungen in Zukunft deutlich zunehmen wird. Die genetische Diagnostik von Patienten und Angehörigen ist dabei eingebettet in ein strukturiertes Kardiomyopathie-Management und folgt 3 Hauptkonzepten: 1) Identifizierung und, falls möglich, Behandlung der Krankheitsursache, 2) Erkennung und Verringerung des Risikos für den plötzlichen Herztod und 3) Prävention oder Behandlung von Herzinsuffizienz und deren Folgen. In dem vorliegenden Übersichtsartikel sollen aktuelle Entwicklungen zu den überwiegend genetischen, strukturellen Kardiomyopathien reflektiert werden.

Abstract

Cardiomyopathies are a heterogeneous group of myocardial diseases that commonly have an underlying genetic cause or are influenced by genetic mechanisms. Genetic testing plays an increasingly important diagnostic role, especially in monogenic and syndromic forms of disease. It can aid clinicians through confirmation of diagnosis and offers the possibility of performing family cascade genetic testing. The identification of the underlying genetic cause can also give valuable insights on the probability of disease outbreak, clinical course and prognosis. At present, certain genetic mutations already warrant a therapeutic clinical consequence. This strategy is expected to become more important with the development of novel molecular therapy targets. Thus, current guidelines already incorporate genetic testing in the clinical management of familial cardiomyopathies, which accompanies the three main therapeutic concepts: 1) identification and treatment of an underlying cause, 2) reduction of sudden cardiac death risk and 3) prevention or treatment of heart failure and its consequences.

Was ist wichtig?

Durch methodische Weiterentwicklungen mittels Next-Generation-Sequencing-Gen-Panels konnte in den letzten Jahren die Anzahl an parallel untersuchten Genen deutlich gesteigert werden [1]. Gleichzeitig haben populationsgenetische Studien das Wissen über die natürliche Variabilität unserer Gene auf ein komplett anderes Niveau gehoben und hierdurch viele der früher als kausal angesehenen Gene bzw. Genvarianten falsifiziert. Durch eine standardisierte Interpretation von Genvarianten unter Berücksichtigung dieser Entwicklung ist es jedoch heute mehr denn je möglich, Patienten und deren Angehörigen eine zuverlässige Gendiagnostik anzubieten. Entsprechend wurde der Stellenwert der genetischen Testung und Familienabklärung bei Kardiomyopathien in nationalen und internationalen Leitlinien gestärkt. Gerade am Beispiel der dilatativen Kardiomyopathie (DCM) wird die rasante Entwicklung deutlich: Alleine durch Nachweis von Non-Sense-Varianten im Titin-Gen können heute 15 – 20% aller DCM-Fälle ätiologisch aufgeklärt werden. Durch Hinzunahme der weiteren Krankheitsgene erhöht sich die Aufklärungsquote auf über 50%. In neuesten Studien konnte die Bedeutung von strukturellen genetischen Varianten ([Abb. 1]) [2] und epigenetischen Faktoren untermauert werden [3].

Durch das zunehmende Verständnis über die genetischen Ursachen und molekularen Mechanismen der Kardiomyopathien werden neue Ansätze für eine zielgerichtete Behandlung möglich. Durch Nachweis von „Hochrisikovarianten“ zum Beispiel in den Genen Lamin A/C, RBM20, SCN5A und PLN können bereits jetzt wichtige therapeutische Konsequenzen, wie die Implantation eines Defibrillators, abgeleitet werden. Durch sogenannte „Precision Medicine“-Strategien werden in Zukunft detailliert phäno- und genotypisierte Patienten nach den zugrunde liegenden Mechanismen ihrer Kardiomyopathie-Unterform therapiert. Ein Beispiel stellt die selektive Inhibition der p38-MAP-Kinase dar, welche in einer Phase-II-Studie erfolgreich bei Patienten mit Varianten in Lamin A/C angewandt wurde. Aktuelle Phase-I/II/III-Studien laufen für zahlreiche dieser „Precision Medicine Trials“ bei genetischen Kardiomyopathien.

Schlüsselwörter

Herzinsuffizienz - arrhythmogene Kardiomyopathie - dilatative Kardiomyopathie - genetische Sequenzierung - hypertrophe Kardiomyopathie - plötzlicher Herztod

Key words

dilated cardiomyopathy - hypertrophic cardiomyopathy - arrhythmogenic cardiomyopathy - genetic testing - precision medicine - familial cardiomyopathies
 

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