Dokument: Energiestoffwechsel des humanen Myokards bei Herzinsuffizienz und Diabetes Mellitus Typ 2
| Titel: | Energiestoffwechsel des humanen Myokards bei Herzinsuffizienz und Diabetes Mellitus Typ 2 | |||||||
| Weiterer Titel: | Myocardial Energy Metabolism in Heart Failure and Type 2 Diabetes Mellitus | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=57876 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20211102-082905-0 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Zweck, Elric [Autor] | |||||||
| Dateien: |
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| Beitragende: | PD. Dr. PhD Szendrödi, Julia [Gutachter] Prof. Dr. med. Boege, Fritz [Gutachter] Prof. Dr. med. Backs, Johannes [Gutachter] | |||||||
| Stichwörter: | Metabolismus, Diabetes, Mitochondrien, Herzinsuffizienz, Diabetische Kardiomyopathie | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibungen: | Typ 2 Diabetes Mellitus (T2DM) kann unabhängig von anderen Risikofaktoren zu einer Herzinsuffizienz führen. Jüngere Studien geben Hinweise darauf, dass bei Menschen mit koronarer Herzkrankheit bei Vorliegen eines T2DM eine reduzierte myokardiale mitochondriale Funktion vorliegt. Es bleibt jedoch unklar, welchen Einfluss T2DM auf Mitochondrien im humanen Myokard unabhängig von vaskulären Erkrankungen hat.
Es wurden die Hypothesen überprüft, dass (1) die myokardiale Mitochondrienfunktion des linken Ventrikels von jener in den Vorhöfen abweicht, (2) eine fortgeschrittene Herzinsuffizienz mit einer eingeschränkten mitochondrialen oxidativen Kapazität im humanen Ventrikelmyokard assoziiert ist und (3) T2DM zu metabolischen Veränderungen des ventrikulären Myokards führt. Konkret wurde postuliert, dass (i) T2DM, Hyperglykämie und Insulinresistenz eine reduzierte ventrikuläre myokardiale oxidative Kapazität induzieren, (ii) zugleich eine subklinische Einschränkung kardialer Funktion in vivo besteht und (iii) die T2DM-induzierten Veränderungen mit erhöhtem systemischen oxidativen Stress und myokardialer Inflammation assoziiert sind. Hierzu wurde in myokardialen Gewebeproben verschiedener Kohorten die mitochondriale oxidative Kapazität mittels hochauflösender Respirometrie untersucht. Bei 11 Probanden wurden Mitochondrienfunktion und Citrat-Synthase-Aktivität von Myokard aus rechtem und linkem Atrium, rechtem Ventrikel und interventrikulärem Septum mit linksventrikulärem Myokard verglichen. Weiterhin wurde ventrikuläres Myokard von 85 herzinsuffizienten Probanden mit jenem von 60 kardial asymptomatischen Herztransplantierten verglichen. Schließlich wurde der Einfluss des T2DM entsprechend Hypothesen 1 und 2 an ventrikulärem nicht-insuffizienten Myokard untersucht. Hierzu wurden 17 Herztransplantierte mit T2DM und 32 Herztransplantierte ohne Diabetes (Non-DM) verglichen. Alle Probanden beider Gruppen hatten Herzen von Spendern ohne Diabetes erhalten, welches in der Folge dem Empfänger-Stoffwechsel ausgesetzt war. Es wurden Mitochondrienfunktion, Glukosetoleranz und Insulinresistenz (über orale Glukosetoleranztests), ventrikuläre Pumpfunktion, T2-Relaxationszeiten, die myokardiale Expression von nuclear factor 'kappa-light-chain-enhancer' of activated B-cells Subunit 1 (Nf-κB1) als zellulärer Stress-Marker und zirkulierender oxidativer Stress erfasst. Die myokardiale mitochondriale oxidative Kapazität, Kopplungseffizienz und Citrat-Synthase-Aktivität waren in linken und rechtem Atrium niedriger als im linken Ventrikel. Innerhalb des ventrikulären Myokards bestand hinsichtlich dieser Parameter kein Unterschied. Bei Herzinsuffizienten war die ventrikuläre myokardiale oxidative Kapazität niedriger als in Menschen nach Transplantation. Zudem korrelierte die myokardiale mitochondriale oxidative Kapazität mit dem Herzindex als Parameter der kardialen Funktion. Bei Herztransplantierten mit T2DM war die mitochondriale oxidative Kapazität des ventrikulären Myokards gegenüber Non-DM für alle Substrate reduziert. T2DM wies zudem eine eingeschränkte diastolische Funktion (Strainrate) bei erhaltener systolischer Funktion und eine höhere myokardiale T2-Relaxationszeit als Hinweis myokardialer Inflammation auf. Die myokardiale Nf-κB1-Expression und der systemische oxidative Stress waren in T2DM ebenfalls höher. Über beide Gruppen korrelierte nüchtern-Plasmaglukose invers mit der mitochondrialen Respiration (R²=0.12; p<0,05) und der diastolischen Funktion (R²=0.33; p<0.001), jedoch positiv mit der Expression von Nf-κB1 (R²=0.09; p<0,05). Die Orale Glukose-Insulinsensitivität korrelierte positiv mit der myokardialen oxidativen Kapazität (R2=0.24; p<0,05), jedoch invers mit myokardialen T2-Relaxationszeiten (R²=0.25; p<0,05). Dies zeigt, dass T2DM die respiratorische Funktion des humanen Ventrikelmyokards unabhängig von strukturellen oder vaskulären Erkrankungen beeinträchtigt. Diese Veränderungen werden von myokardialem Stress und Inflammation begleitet und sind mit Hyperglykämie und Insulinresistenz assoziiert. Somit könnte der myokardiale Energiestoffwechsel zukünftig einen diagnostischen und therapeutischen Ansatzpunkt bei diabetes-assoziierter Herzinsuffizienz darstellen.Type 2 Diabetes Mellitus (T2DM) can lead to heart failure independent of other risk factors. Recent studies suggest that in humans with coronary artery disease, myocardial mitochondrial function is reduced in presence of T2DM. However, the direct impact of T2DM on mitochondria in the human myocardium independent of vascular disease remains unclear. It was hypothesized that (1) human left ventricular and atrial myocardium differ in mitochondrial function, (2) advanced heart failure is associated with an impairment of ventricular myocardial oxidative capacity, and (3) T2DM directly induces specific metabolic alterations in the ventricular myocardium. Concretely, it was postulated that (i) T2DM, hyperglycemia and insulin resistance lead to a reduction of ventricular myocardial oxidative capacity, (ii) concurrently, there is a subclinical cardiac functional impairment in vivo, and (iii) these T2DM-related alterations are accompanied by increased systemic oxidative stress and myocardial inflammation. For this purpose, myocardial mitochondrial oxidative capacity was assessed in myocardial tissue specimens of participants from different cohorts using high-resolution respirometry. In 11 of these patients, myocardium was examined for regional differences. Mitochondrial function and citrate synthase activity in the right atrium, left atrium, right ventricle, and interventricular septum was compared to the respective values in the left ventricular free wall. Furthermore, ventricular myocardium from 85 patients undergoing cardiac surgery was compared to ventricular myocardium from 60 heart transplant recipients without apparent heart failure which was collected percutaneously. Finally, in accordance with hypotheses 1 and 2, the impact of T2DM on human ventricular myocardium was then scrutinized in apparently non-failing ventricular myocardium. We compared 32 heart transplant recipients without diabetes (Non-DM group) with 17 heart transplant recipients with T2DM (T2DM group). All participants in both groups had received hearts of donors without diabetes, which were exposed to the recipient’s metabolism after transplantation. Beyond mitochondrial function, we assessed glucose tolerance and insulin resistance using oral glucose tolerance tests (OGTT), ventricular function and T2 relaxation times using cardiac magnetic resonance imaging (cMRI), myocardial expression of nuclear factor 'kappa-light-chain-enhancer' of activated B-cells Subunit 1 (Nf-κB1) as a stress marker, as well as circulating markers of oxidative stress. Myocardial mitochondrial oxidative capacity, coupling efficiency and citrate synthase activity were lower in the left and right atrium compared to the left ventricle. Within ventricular myocardium, there were no differences regarding these parameters. Heart failure patients exhibited lower myocardial oxidative capacity, albeit similar mitochondrial coupling efficiency, compared to patients after heart transplantation. Across both groups, cardiac index as a marker of cardiac function related positively to myocardial oxidative capacity. The T2DM group exhibited lower ventricular myocardial mitochondrial oxidative capacity and higher proton leak for all substrates used compared to Non-DM. Moreover, cMRI revealed preserved systolic but impaired diastolic function (diastolic strain rate) in T2DM, accompanied by increased T2 relaxation times, indicating myocardial inflammation. Myocardial expression of Nf-κB1 and systemic oxidative stress were higher in T2DM. Across both groups, fasting plasma glucose correlated inversely with mitochondrial oxidative capacity (R²=0.12; p<0,05) and diastolic function (R²=0.33; p<0.001), but positively with Nf-κB1 expression (R²=0.09; p<0,05). Oral glucose insulin sensitivity related to myocardial mitochondrial oxidative capacity (R²= 0.24; p<0,05), but inversely to myocardial T2 relaxation times (R²=0.25; p<0,05). The reported data reveal that T2DM impairs mitochondrial respiratory function in human ventricular myocardium independent of structural or vascular disease. These alterations are accompanied by myocardial stress and inflammation and are related to both, hyperglycemia, and insulin resistance. These findings point towards myocardial energy metabolism as a promising diagnostic and therapeutic target in diabetes-related heart failure. | |||||||
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| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät | |||||||
| Dokument erstellt am: | 02.11.2021 | |||||||
| Dateien geändert am: | 02.11.2021 | |||||||
| Promotionsantrag am: | 05.02.2021 | |||||||
| Datum der Promotion: | 26.10.2021 |
