Dokument: Mitochondrialer Energiestoffwechsel und Inflammation im Myokard bei Herzinsuffizienz unterschiedlicher Ätiologie

Titel:

Mitochondrialer Energiestoffwechsel und Inflammation im Myokard bei Herzinsuffizienz unterschiedlicher Ätiologie

Weiterer Titel:

Mitochondrial Energy Metabolism and Inflammation in the Myocardium in Different Heart Failure Etiologies

URL für Lesezeichen:

https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=65109

URN (NBN):

urn:nbn:de:hbz:061-20240308-112332-7

Kollektion:

Dissertationen

Sprache:

Deutsch

Dokumententyp:

Wissenschaftliche Abschlussarbeiten » Dissertation

Medientyp:

Text

Autor:

Borger, Julius Benedict Erwin [Autor]

Dateien:

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Dateien vom 02.03.2024 / geändert 02.03.2024

Beitragende:

Prof. Dr. med. Polzin, Amin [Gutachter]
PD Dr. med. Buchbender, Christian [Gutachter]

Stichwörter:

Mitochondrien; Herzinsuffizienz; Inflammation

Dewey Dezimal-Klassifikation:

600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit

Beschreibungen:

Herzinsuffizienz (HF) ist der häufigste Grund für Krankenhauseinweisungen in Deutschland und kann verschiedene zugrundeliegende Ätiologien haben. Obwohl mitochondriale Dysfunktion, oxidativer Stress, myokardiale Inflammation und Fibrose zentrale Merkmale der HF sind, ist unklar, inwiefern sich verschiedene Ätiologien diesbezüglich unterscheiden. Bei Patienten mit nicht-ischämischer HF und myokardialer Inflammation hat immunsuppressive Therapie zu verbesserter linksventrikulärer Pumpfunktion und Überleben beigetragen. Zur Wirksamkeit von Immunsuppression bei ischämisch bedingter HF liegen kaum Erkenntnisse vor.
Ziel der vorliegenden Studie war, den mitochondrialen Energiestoffwechsel bei Patienten mit ischämischer bzw. dilatativer Kardiomyopathie (ICM bzw. DCM) genauer zu beschreiben und das Ausmaß myokardialer Inflammation bei diesen verschiedenen Ätiologien zu erfassen. Hierfür stellten wir die Hypothesen auf: Patienten mit ICM bzw. DCM unterscheiden sich hinsichtlich [1] der mitochondrialen oxidativen Kapazität und [2] des Ausmaßes myokardialer Inflammation und Fibrose. [3] Außerdem korrelieren Fibrose und Inflammation mit myokardialer oxidativer Kapazität und oxidativem Stress.
Hierzu wurden 81 Patienten (n=44 ICM, n=37 DCM) eingeschlossen, welche aufgrund terminaler HF ein Linksherzunterstützungssystem (n=59) bzw. eine Herztransplantation (n=22) erhielten. Die mitochondriale Respiration im intraoperativ entfernten linksventrikulären Myokard wurde mittels hochauflösender Respirometrie bestimmt, Citratsynthase-Aktivität (CSA) als Marker mitochondrialer Dichte spektrophotometrisch gemessen und mittels Immunhistochemie die lymphozytäre Infiltration des Myokards und Fibrosierung quantifiziert. Lymphozytäre Infiltration mit mehr als 14 Zellen pro mm2 wurde als Schwelle zu relevanter Inflammation betrachtet.
Die Patienten unterschieden sich nicht hinsichtlich des Alters (61,5±5,7 vs. 56,5±12,7 Jahre, p=0,164), des Geschlechts (86% vs. 84% männlich, p=0,725), des Auftretens von Typ 2 Diabetes mellitus (34% vs. 18%, p=0,126) oder chronischer Niereninsuffizienz (8% vs. 11%, p=0,994). Die mitochondriale oxidative Kapazität war bei Patienten mit ICM um 23% geringer als bei DCM (108,6±41,4 vs. 141,9±59,9 pmol/(s*mg), p=0,006). CSA war in ICM gegenüber DCM reduziert (359,6±164,1 vs. 503,0±198,5 nmol/min/mg Protein, p=0,002). Patienten mit ICM wiesen größere fibrosierte Areale auf (20,9±21,2 vs. 7,2±5,6% des Querschnitts, p=0,002); dies hing nicht mit oxidativer Kapazität zusammen (r=-0,13, p=0,327). Patienten mit ICM zeigten häufiger relevante myokardiale Inflammation verglichen zu DCM-Patienten (27% vs. 6%, p=0,024). Höhere myokardiale Inflammation war mit geringerer oxidativer Kapazität assoziiert (r=-0,296, p=0,019).
Bei Patienten mit ICM zeigte sich eine gesteigerte myokardiale Infiltration mit inflammatorischen Zellen, welche mit reduzierter mitochondrialer oxidativer Kapazität einherging. Zukünftige Studien sollten auf den Einfluss höherer myokardialer Inflammation auf den klinischen Verlauf von ICM-Patienten eingehen, um die Wirksamkeit immunsuppressiver Therapie zu untersuchen. Hierdurch könnte eine bereits etablierte Therapiestrategie einer neuen Patientengruppe zugänglich gemacht werden.

Heart Failure (HF) is the most frequent reason for hospital admissions in Germany. The underlying etiologies are variable. Mitochondrial dysfunction, oxidative stress, myocardial inflammation, and fibrosis are hallmarks of HF pathophysiology, yet it is unclear whether patients with different HF-etiologies differ in these aspects. In non-ischemic HF with marked myocardial inflammation, immunosuppression has yielded benefits in left ventricular ejection fraction, and survival. However, little is known about possible benefits of immunosuppression in ischemic HF.
We aimed at characterizing mitochondrial metabolism in patients with ischemic or dilated cardiomyopathy (ICM or DCM), respectively, and at evaluating the extent of myocardial inflammation in these different etiologies. We hypothesized that patients with ICM or DCM would exhibit [1] different mitochondrial oxidative capacity, and [2] different myocardial inflammation and fibrosis, and that [3] oxidative capacity and oxidative stress correlate with myocardial inflammation and fibrosis.
We included 81 patients with advanced HF (n=44 ICM, n=37 DCM) undergoing implantation of a left ventricular assist device (n=59) or heart transplantation (n=22). Left ventricular myocardium was excised intraoperatively. We assessed mitochondrial respiration via high resolution respirometry, and citrate synthase activity (CSA), as a marker of mitochondrial content, spectrophotometrically. Myocardial inflammation and fibrosis were quantified using immunohistochemistry staining. Lymphocytic infiltration of more than 14 cells per mm2 was considered relevant inflammation.
Patient with ICM or DCM did not differ regarding age (61.5±5.7 vs. 56.5±12.7 years, p=0.164), sex (86% vs. 84% male, p=0.725), Type 2 Diabetes mellitus (34% vs. 18%, p=0.126), or chronic kidney disease (8% vs. 11%, p=0.994). Mitochondrial oxidative capacity was 23% lower in patients with ICM than DCM (108.6±41.4 vs. 141.9±59.9 pmol/(s*mg), p=0.006), and CSA was reduced in ICM compared with DCM (359.6±164.1 vs. 503.0±198.5 nmol/min/mg protein, p=0.002). Despite greater fibrotic area in ICM than DCM (20.9±21.2 vs. 7.2±5.6% of area, p=0.002), no association of fibrosis with oxidative capacity was found (r=-0.13, p=0.327). Patients with ICM had relevant myocardial inflammation more often than patients with DCM (27% vs. 6%, p=0.024). Higher inflammation was associated with lower oxidative capacity (r=-0.296, p=0.019).
We found enhanced myocardial infiltration with inflammatory cells in patients with ICM compared with DCM that was associated with impaired mitochondrial oxidative capacity. Future studies should address possible influences of myocardial inflammation on the clinical course in patients with ischemic HF to evaluate a potential efficacy of immunosuppression in ICM. This could make an already established therapy available to a new group of patients.

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Medizinische Fakultät

Dokument erstellt am:

08.03.2024

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08.03.2024

Promotionsantrag am:

26.10.2023

Datum der Promotion:

29.02.2024

Heinrich-Heine-Universität Düsseldorf

Dokument: Mitochondrialer Energiestoffwechsel und Inflammation im Myokard bei Herzinsuffizienz unterschiedlicher Ätiologie