TY - THES A1 - Janz, Anna T1 - Human induced pluripotent stem cells (iPSCs) in inherited cardiomyopathies: Generation and characterization of an iPSC-derived cardiomyocyte model system of dilated cardiomyopathy with ataxia (DCMA) T1 - Humane induzierte pluripotente Stammzellen in vererbbaren Kardiomyopathien: Generierung und Charakterisierung eines auf Stammzellen basierenden Herzmuskelmodellsystems der Dilatativen Kardiomyopathie mit Ataxie (DCMA) N2 - The emergence of human induced pluripotent stem cells (iPSCs) and the rise of the clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) gene editing technology innovated the research platform for scientists based on living human pluripotent cells. The revolutionary combination of both Nobel Prize-honored techniques enables direct disease modeling especially for research focused on genetic diseases. To allow the study on mutation-associated pathomechanisms, we established robust human in vitro systems of three inherited cardiomyopathies: arrhythmogenic cardiomyopathy (ACM), dilated cardiomyopathy with juvenile cataract (DCMJC) and dilated cardiomyopathy with ataxia (DCMA). Sendai virus vectors encoding OCT3/4, SOX2, KLF4, and c-MYC were used to reprogram human healthy control or mutation-bearing dermal fibroblasts from patients to an embryonic state thereby allowing the robust and efficient generation of in total five transgene-free iPSC lines. The nucleofection-mediated CRISPR/Cas9 plasmid delivery in healthy control iPSCs enabled precise and efficient genome editing by mutating the respective disease genes to create isogenic mutant control iPSCs. Here, a PKP2 knock-out and a DSG2 knock-out iPSC line were established to serve as a model of ACM. Moreover, a DNAJC19 C-terminal truncated variant (DNAJC19tv) was established to mimic a splice acceptor site mutation in DNAJC19 of two patients with the potential of recapitulating DCMA-associated phenotypes. In total eight self-generated iPSC lines were assessed matching internationally defined quality control criteria. The cells retained their ability to differentiate into cells of all three germ layers in vitro and maintained a stable karyotype. All iPSC lines exhibited a typical stem cell-like morphology as well as expression of characteristic pluripotency markers with high population purities, thus validating the further usage of all iPSC lines in in vitro systems of ACM, DCMA and DCMJC. Furthermore, cardiac-specific disease mechanisms underlying DCMA were investigated using in vitro generated iPSC-derived cardiomyocytes (iPSC-CMs). DCMA is an autosomal recessive disorder characterized by life threatening early onset cardiomyopathy associated with a metabolic syndrome. Causal mutations were identified in the DNAJC19 gene encoding an inner mitochondrial membrane (IMM) protein with a presumed function in mitochondrial biogenesis and cardiolipin (CL) remodeling. In total, two DCMA patient-derived iPSC lines (DCMAP1, DCMAP2) of siblings with discordant cardiac phenotypes, a third isogenic mutant control iPSC line (DNAJC19tv) as well as two control lines (NC6M and NC47F) were directed towards the cardiovascular lineage upon response to extracellular specification cues. The monolayer cardiac differentiation approach was successfully adapted for all five iPSC lines and optimized towards ventricular subtype identity, higher population purities and enhanced maturity states to fulfill all DCMA-specific requirements prior to phenotypic investigations. To provide a solid basis for the study of DCMA, the combination of lactate-based metabolic enrichment, magnetic-activated cell sorting, mattress-based cultivation and prolonged cultivation time was performed in an approach-dependent manner. The application of the designated strategies was sufficient to ensure adult-like characteristics, which included at least 60-day-old iPSC-CMs. Therefore, the novel human DCMA platform was established to enable the study of the pathogenesis underlying DCMA with respect to structural, morphological and functional changes. The disease-associated protein, DNAJC19, is constituent of the TIM23 import machinery and can directly interact with PHB2, a component of the membrane bound hetero-oligomeric prohibitin ring complexes that are crucial for phospholipid and protein clustering in the IMM. DNAJC19 mutations were predicted to cause a loss of the DnaJ interaction domain, which was confirmed by loss of full-length DNAJC19 protein in all mutant cell lines. The subcellular investigation of DNAJC19 demonstrated a nuclear restriction in mutant iPSC-CMs. The loss of DNAJC19 co-localization with mitochondrial structures was accompanied by enhanced fragmentation, an overall reduction of mitochondrial mass and smaller cardiomyocytes. Ultrastructural analysis yielded decreased mitochondria sizes and abnormal cristae providing a link to defects in mitochondrial biogenesis and CL remodeling. Preliminary data on CL profiles revealed longer acyl chains and a more unsaturated acyl chain composition highlighting abnormities in the phospholipid maturation in DCMA. However, the assessment of mitochondrial function in iPSCs and dermal fibroblasts revealed an overall higher oxygen consumption that was even more enhanced in iPSC-CMs when comparing all three mutants to healthy controls. Excess oxygen consumption rates indicated a higher electron transport chain (ETC) activity to meet cellular ATP demands that probably result from proton leakage or the decoupling of the ETC complexes provoked by abnormal CL embedding in the IMM. Moreover, in particular iPSC-CMs presented increased extracellular acidification rates that indicated a shift towards the utilization of other substrates than fatty acids, such as glucose, pyruvate or glutamine. The examination of metabolic features via double radioactive tracer uptakes (18F-FDG, 125I-BMIPP) displayed significantly decreased fatty acid uptake in all mutants that was accompanied by increased glucose uptake in one patient cell line only, underlining a highly dynamic preference of substrates between mutant iPSC-CMs. To connect molecular changes directly to physiological processes, insights on calcium kinetics, contractility and arrhythmic potential were assessed and unraveled significantly increased beating frequencies, elevated diastolic calcium concentrations and a shared trend towards reduced cell shortenings in all mutant cell lines basally and upon isoproterenol stimulation. Extended speed of recovery was seen in all mutant iPSC-CMs but most striking in one patient-derived iPSC-CM model, that additionally showed significantly prolonged relaxation times. The investigations of calcium transient shapes pointed towards enhanced arrhythmic features in mutant cells comprised by both the occurrence of DADs/EADs and fibrillation-like events with discordant preferences. Taken together, new insights into a novel in vitro model system of DCMA were gained to study a genetically determined cardiomyopathy in a patient-specific manner upon incorporation of an isogenic mutant control. Based on our results, we suggest that loss of full-length DNAJC19 impedes PHB2-complex stabilization within the IMM, thus hindering PHB-rings from building IMM-specific phospholipid clusters. These clusters are essential to enable normal CL remodeling during cristae morphogenesis. Disturbed cristae and mitochondrial fragmentation were observed and refer to an essential role of DNAJC19 in mitochondrial morphogenesis and biogenesis. Alterations in mitochondrial morphology are generally linked to reduced ATP yields and aberrant reactive oxygen species production thereby having fundamental downstream effects on the cardiomyocytes` functionality. DCMA-associated cellular dysfunctions were in particular manifested in excess oxygen consumption, altered substrate utilization and abnormal calcium kinetics. The summarized data highlight the usage of human iPSC-derived CMs as a powerful tool to recapitulate DCMA-associated phenotypes that offers an unique potential to identify therapeutic strategies in order to reverse the pathological process and to pave the way towards clinical applications for a personalized therapy of DCMA in the future. N2 - Die Entwicklung von induzierten pluripotenten Stammzellen (iPS-Zellen) und die biotechnologische Anwendung des „clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9“ (CRISPR/Cas9) Gen-Editierungssystems bilden eine innovative Forschungsplattform für Wissenschaftler basierend auf lebenden menschlichen pluripotenten Stammzellen. Die bahnbrechende Kombination beider nobelpreisprämierter Techniken erlaubt eine direkte Krankheitsmodellierung insbesondere für die Erforschung von genetisch bedingten Erkrankungen. Um die Untersuchung von mutationsassoziierten Pathomechanismen zu ermöglichen, etablierten wir robuste humane in vitro Systeme von drei vererbbaren Kardiomyopathien: die arrhythmogene Kardiomyopathie (AKM), die dilatative Kardiomyopathie mit juveniler Katarakt (DKMJK) und die dilatative Kardiomyopathie mit Ataxie (DKMA). Zur Generierung von transgenfreien iPS-Zellen wurden für OCT3/4, SOX2, KLF4 und c-MYC kodierende Sendai-Virus-Vektoren verwendet um humane gesunde Kontroll- oder mutationstragende dermale Fibroblasten von Patienten in einen embryonalen Zustand zu reprogrammieren. Die Verwendung der SeV-vermittelten Reprogrammierung ermöglichte uns eine effiziente und robuste Herstellung von insgesamt fünf transgen-freien iPS-Zelllinien. Zudem befähigt die Nukleofektion der CRISPR/Cas9-Plasmide in gesunden Kontroll-iPS-Zellen eine präzise und effiziente Genom-Editierung krankheitsrelevanter Gene und damit die Generierung von isogenen mutierten iPS-Zelllinien. Mit diesem Verfahren wurden eine PKP2-Knock-out- und eine DSG2-Knock-out iPSZ-Linie hergestellt, die jeweils als Modell für AKM dienen. Darüber hinaus wurde eine mit DKMA-assoziierte Spleißakzeptormutation auf genetischer Basis imitiert, um die mit dem Phänotyp zweier Patienten in Verbindung gebrachte C-terminal verkürzte DNAJC19-Variante (DNAJC19tv) auf translationaler Ebene rekapitulieren zu können. Alle acht eigens generierten iPS-Zelllinien entsprachen international definierten Qualitätskontrollkriterien. Die hergestellten iPS-Zellen behielten die Fähigkeit in vitro in Zellen der drei Keimblätter zu differenzieren und zeigten darüber hinaus einen normalen Karyotyp. Alle iPS-Zelllinien wiesen eine typische stammzellähnliche Morphologie sowie die Expression charakteristischer Pluripotenzmarker bei gleichzeitig hoher Populationsreinheit auf. Die experimentelle Qualtitätskontrolle hat somit die weitere Verwendung aller iPS-Zelllinien in in vitro Systemen von AKM, DKMA und DKMJK validiert. Die der DKMA zugrundeliegenden herzspezifischen Krankheitsmechanismen wurden zudem mithilfe von in vitro produzierten iPSZ-abgeleiteten Kardiomyozyten (iPSZ-KMs) untersucht. DKMA ist eine autosomal rezessiv vererbte Erkrankung, die durch Mutationen im DNAJC19 Gen hervorgerufen wird. Das wichtigste klinische Merkmal der Patienten ist eine früh einsetzende und lebensbedrohliche dilatative Kardiomyopathie, die oftmals mit einem metabolischen Syndrom einhergeht. DNAJC19 kodiert für ein Protein der inneren mitochondrialen Membran (IMM), dessen postulierte Funktion in der mitochondrialen Biogenese und der Remodellierung von Cardiolipin liegt. Zur Modellierung der DKMA wurden zwei von DKMA-Patienten abgeleitete iPS-Zelllinien (DCMAP1, DCMAP2) eines Geschwisterpaares mit unterschiedlich ausgeprägten kardialen Phänotypen, eine dritte isogene mutierte iPS-Zelllinie (DNAJC19tv) sowie zwei gesunden Kontroll-iPS-Zelllinien (NC6M und NC47F) mithilfe extrazellulärer Spezifikationsfaktoren zur kardiovaskulären Differenzierung angeregt. Das Monolayer-Protokoll zur kardialen Differenzierung wurde erfolgreich für alle fünf iPSZ-Linien adaptiert und in Bezug auf die Anreicherung des ventrikulären Herzmuskelzellsubtyps, höhere Zellpopulationsreinheiten und adulte Reifegrade optimiert. Die Kombination der Laktat-basierten metabolischen Aufreinigung, der magnetisch-aktivierten Zellsortierung, der Anwendung einer Mattress-basierten Kultivierungsstrategie und verlängerte Kultivierungszeiten ermöglichte die Erfüllung aller DKMA-spezifischen Anforderungen. Zusammengefasst konnten insbesondere adulte Charakteristika durch die Kombination der benannten experimentellen Strategien unter Verwendung von mindestens 60 Tage kultivierten iPSZ-KMs nachgewiesen werden, um eine zuverlässige phänotypische Untersuchung der DKMA gewährleisten zu können. Die innovative humane Untersuchungsplattform wurde etabliert, um die Pathogenese der DKMA im Hinblick auf strukturelle, morphologische und funktionelle Veränderungen entschlüsseln zu können. Das mit DKMA assoziierte Protein DNAJC19 ist Bestandteil der TIM23-Importmaschinerie und besitzt zudem die Fähigkeit einer direkten Interaktion mit PHB2. PHB2 trägt zur Bildung der membrangebundenen hetero-oligomeren Prohibitin-Ringkomplexe bei, deren Hauptfunktion in der Anreicherung von Phospholipiden und Proteinen innerhalb von Clustern in der IMM liegt. Der durch DNAJC19 Mutationen vermutete hervorgerufenen Verlust der DnaJ-Interaktionsdomäne wurde durch die fehlende Expression des DNAJC19 Proteins in voller Länge in allen mutationstragenden Zellen bestätigt. Die subzelluläre Untersuchung von DNAJC19 zeigte ein auf den Kern beschränktes Expressionsmuster in mutierten iPSZ-KMs. Der Verlust der DNAJC19 Ko-Lokalisation mit mitochondrialen Strukturen ging mit einer abnormen mitochondrialen Fragmentierung, einer signifikanten Abnahme der mitochondrialen Masse und einer signifikant reduzierten Kardiomyozytengröße einher. Ultrastrukturelle Analysen ergaben zudem kleinere Mitochondrien und abnorme Cristae, die eine krankheitsrelevante Verbindung zu Defekten in der mitochondrialen Biogenese und der CL-Reifung darlegen. Vorläufige Daten zu CL-Profilen zeigten längere Acylketten und eine ungesättigtere Acylkettenzusammensetzung, was auf Anomalien in der Phospholipidmaturierung bei DKMA hinweist. Der Vergleich aller Mutanten mit gesunden Kontrollen hinsichtlich der mitochondrialen Funktion in iPS-Zellen und Hautzellen (dermale Fibroblasten), zeigte eine insgesamt höhere Sauerstoffverbrauchsrate, die in iPSZ-KMs noch stärker ausgeprägt war. Der erhöhte Sauerstoffverbrauch deutet auf eine höhere Aktivität der Elektronentransportkette hin um den zellulären Energiebedarf decken zu können. Wir vermuten einen erhöhten Sauerstoffverbrauch als Konsequenz des Protonendurchsickerns oder der Entkopplung der ETC-Komplexe, das durch eine abnorme CL-Einbettung in der IMM bedingt sein könnte. Darüber hinaus wiesen insbesondere iPSZ-KMs erhöhte extrazelluläre Säuerungsraten auf, die auf eine Verstoffwechselung anderer Substrate wie Glukose, Pyruvat oder Glutamin hinweisen, im Gegensatz zu der ansonsten bevorzugten Verstoffwechslung von Fettsäuren. Die Untersuchung der metabolischen Eigenschaften mittels der radioaktiven Tracer 18F-FDG und 125I-BMIPP zeigte eine signifikant verringerte Fettsäureaufnahme in allen Mutanten, die nur in einer Patientenzelllinie von einer erhöhten Glukoseaufnahme begleitet wurde. Diese Ergebnisse weisen auf eine DKMA-spezifische hochdynamische Präferenz der Substrate zwischen den unterschiedlichen Mutanten hin. Um den Einfluss der molekularen Veränderungen direkt mit physiologischen Prozessen in Verbindung bringen zu können, wurden Untersuchungen der Kalziumkinetik, der Kontraktilität und des arrhythmischen Potentials durchgeführt. Einzelzellmessungen ergaben eine signifikant erhöhte Kontraktionsfrequenz, erhöhte diastolische Kalziumkonzentrationen und eine Tendenz zu reduzierten Zellverkürzungen in allen mutierten Zelllinien basal und verstärkt nach Isoproterenol-Stimulation. Zudem wurden verlangsamte Erholungsgeschwindigkeiten in allen mutierten iPSZ-KMs festgestellt, das in den iPSZ-KMs des einen Patienten besonders auffällig war und mit verlängerten Relaxationszeiten einherging. Die Evaluation der Kalziumtransientenformen deutet auf verstärkte arrhythmische Merkmale in den mutierten Zellen hin, die sowohl das Auftreten von DADs/EADs als auch Fibrillations-ähnlichen Ereignissen mit gegensätzlichen Präferenzen umfasste. Insgesamt wurden unter der Verwendung patientenspezifischer iPS-Zellen und einer isogenen Mutantenkontrolle neue Einblicke in ein innovatives in vitro Modellsystem der DKMA gewonnen. Basierend auf unseren Ergebnissen vermuten wir, dass der Verlust des DNAJC19 Proteins in voller Länge die Stabilisierung von PHB-Komplexen innerhalb der IMM beeinträchtigt und damit PHB-Ringe an der Bildung von IMM-spezifischen Phospholipid-Clustern hindert. Diese Cluster sind essentiell um eine normale Cardiolipin-Reifung und dessen Funktion in der Cristae-Morphogenese gewährleisten zu können. Abnorme Cristae und fragmentierte mitochondriale Strukturen wurden beobachtet und deuten so auf eine essentielle Rolle von DNAJC19 in der mitochondrialen Morphogenese und Biogenese hin. Abnorme Veränderungen in der mitochondrialen Morphologie werden in der Regel mit einer verminderten ATP-Verfügbarkeit und einer erhöhten Produktion an freien Sauerstoffradikalen assoziiert, das nachfolgend die gesamte Funktionalität der Kardiomyozyten negativ beeinflussen kann. Diese Veränderungen konnten anhand einer erhöhten Sauerstoffverbrauchsrate, unterschiedliche metabolische Eigenschaften und einer abnormalen Kalziumkinetik gemessen werden. Die zusammengefassten Daten unterstreichen die Verwendbarkeit von humanen iPSZ-KMs als ein eindrucksvolles System zur Rekapitulation von herzspezifischen Phänotypen und haben damit neue Einblicke in die Pathogenese der DKMA ermöglicht. Das Modellsystem bietet ein einzigartiges Potenzial zur Identifizierung therapeutischer Strategien, um pathologische Prozesse umkehren zu können und so den Weg für zukünftige klinische Anwendungen im Rahmen der personalisierten Therapie zu ebnen. KW - in vitro model system of inherited cardiomyopathies KW - Induzierte pluripotente Stammzelle KW - CRISPR/Cas-Methode KW - induced pluripotent stem cells (iPSCs) KW - iPSC-derived CMs (iPSC-CMs) KW - CRISPR/Cas9 KW - dilated cardiomyopathy with ataxia (DCMA) Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240966 ER - TY - THES A1 - Cellini, Antonella T1 - Die Rolle der Na\(^+\)/K\(^+\)-ATPase in der Herzinsuffizienz T1 - The Na\(^+\)/K\(^+\)-ATPase and its role in heart failure N2 - Die Na+ /K+ -ATPase (NKA) ist maßgeblich an der Regulation der kardialen Na+ -Homöostase beteilligt. Im Myokard werden hauptsächlich zwei Isoformen exprimiert: die α1 (NKA-α1) und die α2-Isoform (NKA-α2). Diese beiden Isoformen unterscheiden sich sowohl in ihrer Lokalisation als auch in ihrer zellulären Funktion. So ist die NKA-α1 recht homogen entlang des Sarkolemms zu finden und ist verantwortlich für die Regulation der globalen intrazellulären Na+ -Konzentration ([Na+ ]i). Die NKA-α2 hingegen konzentriert sich hauptsächlich in den T-Tubuli und beeinflusst über Veränderung der lokalen [Na+ ]i die Ca2+ -Transienten und die Kontraktilität. Im Rahmen einer Herzinsuffizienz wurde eine verminderte Expression und Aktivität der NKA beobachtet. Gleichzeitig werden Inhibitoren der NKA, sogenannte Digitalisglykoside, in fortgeschrittenen Herzinsuffizienz-Stadien eingesetzt. Die Studienlage über den Einsatz dieser Therapeutika ist recht uneinheitlich und reicht von einer verringerten Hospitalisierung bis hin zu einer erhöhten Mortalität. Ziel dieser Arbeit war es die Folgen einer NKA-α2 Aktivierung während einer Herzinsuffizienz mit Hilfe eines murinen Überexpressionsmodells zu analysieren. 11-Wochen alte Mäuse mit einer kardialen NKA-α2 Überexpression (NKA-α2) und Wildtyp (WT) Versuchstiere wurden einem 8-wöchigen Myokardinfarkt (MI) unterzogen. NKA-α2 Versuchstiere waren vor einem pathologischem Remodeling und einer kardialen Dysfunktion geschützt. NKA-α2 Kardiomyozyten zeigten eine erhöhte Na+ /Ca2+ -Austauscher (NCX) Aktivität, die zu niedrigeren diastolischen und systolischen Ca2+ -Spiegeln führte und einer Ca2+ -Desensitisierung der Myofibrillen entgegenwirkte. WT Versuchstiere zeigten nach chronischem MI eine sarkoplasmatische Ca2+ -Akkumulation, die in NKA-α2 Kardiomyozyten ausblieb. Gleichzeitig konnte in der NKA-α2 MI Kohorte im Vergleich zu den WT MI Versuchstieren eine erhöhte Expression von β1-adrenergen Rezeptoren (β1AR) beobachtet werden, die eine verbesserte Ansprechbarkeit gegenüber β-adrenergen Stimuli bewirkte. Zudem konnte in unbehandelten Versuchstieren eine Interaktion zwischen NKA-α2 und dem β1AR nachgewiesen werden, welche in der WT Kohorte größer ausfiel als in der NKA-α2 Versuchsgruppe. Gleichzeitig zeigten unbehandelte NKA-α2 Kardiomyozyten eine erhöhte Sensitivität gegenüber β-adrenerger Stimulation auf, welche nicht mit einer erhöhten Arrhythmie-Neigung oder vermehrten Bildung reaktiver Sauerstoffspezies einherging. Diese Untersuchungen zeigen, dass eine NKA-α2 Überexpression vor pathologischem Remodeling und einer kardialen Funktionbeeinträchtigung schützt, indem eine systolische, diastolische und sarkoplasmatische Ca2+ -Akkumulation verhindert wird. Gleichzeitig wird die β1AR Expression stabilisert, wodurch es zu einer verminderten neurohumoralen Aktivierung und einer Durchbrechung des Circulus vitiosus kommen könnte. Insgesamt scheint eine Aktivierung der NKA-α2 durchaus ein vielversprechendes Target in der Herzinsuffizienz Therapie darzustellen. Therapie darzustellen. N2 - The Na+ /K+ -ATPase (NKA) is significantly involved in the regulation of the cardiac Na+ homeostasis. Two isoforms are mainly expressed in the myocardium: the α1- (NKA-α1) and the α2-isoform (NKA-α2). These two isoforms differ regarding their localization as well as their cellular function. The NKA-α1 is located along the sarcolemma and is responsible for the regulation of the global intracellular Na+ concentration ([Na+ ]i). In contrast , the NKA-α2 is concentrated mostly in the t-tubules and influences the Ca2+ transients and contractility by changing the local [Na+ ]i. During heart failure, a reduced activity and expression of the NKA has been observed. At the same time, inhibitors of the NKA, so-called digitalis glycosides, are used in the treatment of advanced stages of heart failure. The current evidence for the use of these substances remains still inconsistent ranging from decreased hospitalization to increased mortality. The aim of this project was to analyze the consequences of an NKA-α2 activation during heart failure by using a murine overexpression system. 11-weeks old mice with a cardiac-specific overexpression of the NKA-α2 (NKA-α2) and wildtype (WT) animals were subjected to 8 weeks of myocardial infarction (MI). NKA-α2 mice were protected against pathological remodeling and functional impairment. NKA-α2 cardiomyocytes showed an increased Na+ /Ca2+ -exhanger (NCX) activity, which led to a reduction of the diastolic and systolic Ca2+ levels and prevented a Ca2+ desensitization of the myofilaments. WT animals showed a sarcoplasmic Ca2+ accumulation after MI, which did not occur in NKA-α2 cardiomyoctes. At the same time, NKA-α2 MI mice showed an increased expression of β1-adrenergic receptor (β1AR), which induced an improved response towards β-adrenergic stimuli. In addition, an interaction between the NKA-α2 and the β1AR was detected in untreated animals, which was tighter in the WT cohort than in the NKA-α2 group. Furthermore, untreated NKA-α2 cardiomyocytes showed an increased sensitivity towards β-adrenergic stimulation, which was not associated with a higher arrhythmic tendency or augmented generation of reative oxygen species. These results show that an NKA-α2 overexpression protects against pathological remodeling and cardiac dysfunction by preventing systolic, diastolic and sarcoplasmic Ca2+ accumulation. Concurrently, a β1AR downregulation is countercated, probably inducing a reduced neurohormonal activation and an ending of the vicious circle. Altogether, it seems that an activation of the NKA-α2 might be a promising target in the therapy of heart failure. KW - Herzinsuffizienz KW - Natrium-Kalium-Pumpe KW - Herzmuskelzelle KW - Na+/K+-ATPase KW - heart failure KW - myocardial infarction KW - Myokardinfarkt Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297894 ER - TY - THES A1 - Hock, Michael T1 - Methods for Homogenization of Spatio-Temporal B\(_0\) Magnetic Field Variations in Cardiac MRI at Ultra-High Field Strength T1 - Methoden zur Homogenisierung räumlicher und zeitlicher Variationen des B\(_0\)-Feldes in der kardialen Ultrahochfeld-MRT N2 - Cardiovascular disease is one of the leading causes of death worldwide and, so far, echocardiography, nuclear cardiology, and catheterization are the gold standard techniques used for its detection. Cardiac magnetic resonance (CMR) can replace the invasive imaging modalities and provide a "one-stop shop" characterization of the cardiovascular system by measuring myocardial tissue structure, function and perfusion of the heart, as well as anatomy of and flow in the coronary arteries. In contrast to standard clinical magnetic resonance imaging (MRI) scanners, which are often operated at a field strength of 1.5 or 3 Tesla (T), a higher resolution and subsequent cardiac parameter quantification could potentially be achieved at ultra-high field, i.e., 7 T and above. Unique insights into the pathophysiology of the heart are expected from ultra-high field MRI, which offers enhanced image quality in combination with novel contrast mechanisms, but suffers from spatio-temporal B0 magnetic field variations. Due to the resulting spatial misregistration and intra-voxel dephasing, these B0-field inhomogeneities generate a variety of undesired image artifacts, e.g., artificial image deformation. The resulting macroscopic field gradients lead to signal loss, because the effective transverse relaxation time T2* is shortened. This affects the accuracy of T2* measurements, which are essential for myocardial tissue characterization. When steady state free precession-based pulse sequences are employed for image acquisition, certain off-resonance frequencies cause signal voids. These banding artifacts complicate the proper marking of the myocardium and, subsequently, systematic errors in cardiac function measurements are inevitable. Clinical MR scanners are equipped with basic shim systems to correct for occurring B0-field inhomogeneities and resulting image artifacts, however, these are not sufficient for the advanced measurement techniques employed for ultra-high field MRI of the heart. Therefore, this work focused on the development of advanced B0 shimming strategies for CMR imaging applications to correct the spatio-temporal B0 field variations present in the human heart at 7 T. A novel cardiac phase-specific shimming (CPSS) technique was set up, which featured a triggered B0 map acquisition, anatomy-matched selection of the shim-region-of-interest (SROI), and calibration-based B0 field modeling. The influence of technical limitations on the overall spherical harmonics (SH) shim was analyzed. Moreover, benefits as well as pitfalls of dynamic shimming were debated in this study. An advanced B0 shimming strategy was set up and applied in vivo, which was the first implementation of a heart-specific shimming approach in human UHF MRI at the time. The spatial B0-field patterns which were measured in the heart throughout this study contained localized spots of strong inhomogeneities. They fluctuated over the cardiac cycle in both size and strength, and were ideally addressed using anatomy-matched SROIs. Creating a correcting magnetic field with one shim coil, however, generated eddy currents in the surrounding conducting structures and a resulting additional, unintended magnetic field. Taking these shim-to-shim interactions into account via calibration, it was demonstrated for the first time that the non-standard 3rd-order SH terms enhanced B0-field homogeneity in the human heart. However, they were attended by challenges for the shim system hardware employed in the presented work, which was indicated by the currents required to generate the optimal 3rd-order SH terms exceeding the dynamic range of the corresponding shim coils. To facilitate dynamic shimming updated over the cardiac cycle for cine imaging, the benefit of adjusting the oscillating CPSS currents was found to be vital. The first in vivo application of the novel advanced B0 shimming strategy mostly matched the simulations. The presented technical developments are a basic requirement to quantitative and functional CMR imaging of the human heart at 7 T. They pave the way for numerous clinical studies about cardiac diseases, and continuative research on dedicated cardiac B0 shimming, e.g., adapted passive shimming and multi-coil technologies. N2 - Herz-Kreislauf-Erkrankungen zählen zu den häufigsten Todesursachen weltweit und werden bisher in der Regel mittels Echokardiographie, Nuklearkardiologie und Katheterisierung untersucht. Die kardiale Magnetresonanztomographie hat das Potential diese invasiven Bildgebungsmodalitäten zu ersetzen. Dabei können sowohl das kardiovaskuläre System anhand der myokardialen Gewebestruktur sowie der Funktion und Perfusion des Herzens als auch Anatomie und Blutfluss der Koronararterien während einer einzigen Untersuchung charakterisiert werden. Im Gegensatz zu den weit verbreiteten klinischen Magnetresonanztomographie- (MRT) Geräten, welch häufig bei magnetischen Feldstärken zwischen 1.5 und 3T operieren, ermöglichen Feldstärken von 7 Tesla und mehr eine höhere Auflösung und somit eine akkuratere Quantifizierung kardialer Parameter. Die Ultrahochfeld-Magnetresonanztomographie (UHF-MRT) ermöglicht einzigartige Einblicke in die Pathophysiologie des Herzens. Neuartige Kontrastmechanismen und die verbesserte Bildqualität leiden jedoch unter Inhomogenitäten des statischen magnetischen B0-Feldes. Aufgrund der daraus resultierenden falschen räumlichen Registrierung der Voxel und einer Dephasierung des Signals innerhalb eines Voxels erzeugen diese Inhomogenitäten des B0-Feldes eine Vielzahl unerwünschter Bildartefakte, beispielsweise eine künstliche Deformation des Bildes. Die resultierenden makroskopischen Gradienten führen zu Signalverlust und beeinträchtigen die Messung der effektiven transversalen T2*-Relaxationszeit, welche für die Charakterisierung myokardialen Gewebes essentiell ist. Vor allem bei der Bildakquisition mittels der Steady State Free Precession Methode führen Inhomogenitäten des B0-Feldes zu Signalauslöschungen. Die dadurch entstehenden Bildartefakte erschweren die genaue Markierung des Myokards und haben so systematische Fehler bei der Bestimmung der kardialen Funktion zur Folge. Klinische MRT-Geräte sind dabei mit sogenannten Shim-Systemen ausgestattet um die Inhomogenitäten des B0-Feldes zu korrigieren. Für die kardiale UHF-MRT des Herzens sind diese standardisierten Shim-Systeme allerdings nicht mehr ausreichend. Im Fokus stand deshalb die Entwicklung moderner Methoden zur räumlichen und zeitlichen Korrektur der B0-Inhomogenitäten, welche als „Shimming“ bezeichnet wird, für die kardiale UHF-MRT. Es wurde eine neue, herzphasen-spezifische Shimming-Strategie untersucht, welche auf der getriggerten Datenaufnahme, der Optimierung für die Anatomie des Herzens, sowie der kalibrierungsbasierten Modellierung des korrigierenden Magnetfeldes basierte. Zudem wurde der Einfluss technischer Limitationen der Hardware auf das Shimming, insbesondere das dynamische Shimming, in dieser Studie erörtert. Schließlich wurde die entwickelte neuartige Shimming-Strategie in vivo evaluiert, welche zu diesem Zeitpunkt die erste Implementierung einer herzspezifischen Shimming-Strategie in der humanen kardialen UHF-MRT darstellte. Räumlich wies das B0-Feld, welches im Rahmen dieser Studie im Herzen gemessen wurde, lokalisierte Inhomogenitäten im Myokardium auf. Diese variierten zudem in ihrer Größe sowie der Stärke der B0-Inhomogenität zeitlich über den Herzzyklus hinweg und ließen sich mittels anatomisch angepasstem, kalibrierungsbasiertem Shimming deutlich reduzieren. Erzeugt man ein korrigierendes Magnetfeld mittels einer Shim-Spule, so werden jedoch Wirbelströme in nahen leitenden Strukturen und weiterhin ein zusätzliches, unerwünschtes Magnetfeld erzeugt. Berücksichtigt man diese Wechselwirkungen zwischen den verschiedenen Shim-Spulen, konnte erstmalig der Vorteil von korrigierenden Magnetfeldern in der Form von Kugelflächenfunktionen der dritten Ordnung für die kardiale UHF-MRT gezeigt werden. Hierbei waren jedoch die erforderlichen, besonders starken Ströme in den Shim-Spulen zu berücksichtigen, welche über den Herzzyklus hinweg oszillierten und für dynamisches Shimming angepasst werden sollten. Die erste in vivo Anwendung der neu entwickelten Shim-Strategie stimmte gut mit den vorigen Simulationen überein. Die vorgestellten technischen Entwicklungen stellen grundlegende Anforderungen an die quantitative und funktionelle kardialer UHF-MRT dar. Klinische Studien zu kardialen Erkrankungen wie der Herzinsuffizienz erscheinen nun ebenso in Reichweite wie weitere Forschung zu kardialem B0-Shimming basierend auf angepasstem passiven Shimming sowie Multikanal-Spulen. KW - Kernspintomografie KW - Bildgebendes Verfahren KW - 7 T KW - B0 KW - Cardiac MRI KW - Shimming KW - Ultrahigh field Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-348213 ER - TY - JOUR A1 - Janz, Anna A1 - Walz, Katharina A1 - Cirnu, Alexandra A1 - Surjanto, Jessica A1 - Urlaub, Daniela A1 - Leskien, Miriam A1 - Kohlhaas, Michael A1 - Nickel, Alexander A1 - Brand, Theresa A1 - Nose, Naoko A1 - Wörsdörfer, Philipp A1 - Wagner, Nicole A1 - Higuchi, Takahiro A1 - Maack, Christoph A1 - Dudek, Jan A1 - Lorenz, Kristina A1 - Klopocki, Eva A1 - Ergün, Süleyman A1 - Duff, Henry J. A1 - Gerull, Brenda T1 - Mutations in DNAJC19 cause altered mitochondrial structure and increased mitochondrial respiration in human iPSC-derived cardiomyocytes JF - Molecular Metabolism N2 - Highlights • Loss of DNAJC19's DnaJ domain disrupts cardiac mitochondrial structure, leading to abnormal cristae formation in iPSC-CMs. • Impaired mitochondrial structures lead to an increased mitochondrial respiration, ROS and an elevated membrane potential. • Mutant iPSC-CMs show sarcomere dysfunction and a trend to more arrhythmias, resembling DCMA-associated cardiomyopathy. Background Dilated cardiomyopathy with ataxia (DCMA) is an autosomal recessive disorder arising from truncating mutations in DNAJC19, which encodes an inner mitochondrial membrane protein. Clinical features include an early onset, often life-threatening, cardiomyopathy associated with other metabolic features. Here, we aim to understand the metabolic and pathophysiological mechanisms of mutant DNAJC19 for the development of cardiomyopathy. Methods We generated induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of two affected siblings with DCMA and a gene-edited truncation variant (tv) of DNAJC19 which all lack the conserved DnaJ interaction domain. The mutant iPSC-CMs and their respective control cells were subjected to various analyses, including assessments of morphology, metabolic function, and physiological consequences such as Ca\(^{2+}\) kinetics, contractility, and arrhythmic potential. Validation of respiration analysis was done in a gene-edited HeLa cell line (DNAJC19tv\(_{HeLa}\)). Results Structural analyses revealed mitochondrial fragmentation and abnormal cristae formation associated with an overall reduced mitochondrial protein expression in mutant iPSC-CMs. Morphological alterations were associated with higher oxygen consumption rates (OCRs) in all three mutant iPSC-CMs, indicating higher electron transport chain activity to meet cellular ATP demands. Additionally, increased extracellular acidification rates suggested an increase in overall metabolic flux, while radioactive tracer uptake studies revealed decreased fatty acid uptake and utilization of glucose. Mutant iPSC-CMs also showed increased reactive oxygen species (ROS) and an elevated mitochondrial membrane potential. Increased mitochondrial respiration with pyruvate and malate as substrates was observed in mutant DNAJC19tv HeLa cells in addition to an upregulation of respiratory chain complexes, while cellular ATP-levels remain the same. Moreover, mitochondrial alterations were associated with increased beating frequencies, elevated diastolic Ca\(^{2+}\) concentrations, reduced sarcomere shortening and an increased beat-to-beat rate variability in mutant cell lines in response to β-adrenergic stimulation. Conclusions Loss of the DnaJ domain disturbs cardiac mitochondrial structure with abnormal cristae formation and leads to mitochondrial dysfunction, suggesting that DNAJC19 plays an essential role in mitochondrial morphogenesis and biogenesis. Moreover, increased mitochondrial respiration, altered substrate utilization, increased ROS production and abnormal Ca\(^{2+}\) kinetics provide insights into the pathogenesis of DCMA-related cardiomyopathy. KW - cell biology KW - molecular biology KW - dilated cardiomyopathy with ataxia KW - genetics KW - metabolism KW - mitochondria KW - OXPHOS KW - ROS KW - contractility Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350393 SN - 2212-8778 VL - 79 ER - TY - JOUR A1 - Steinhardt, Maximilian J. A1 - Cejka, Vladimir A1 - Chen, Mengmeng A1 - Bäuerlein, Sabrina A1 - Schäfer, Julia A1 - Adrah, Ali A1 - Ihne-Schubert, Sandra M. A1 - Papagianni, Aikaterini A1 - Kortüm, K. Martin A1 - Morbach, Caroline A1 - Störk, Stefan T1 - Safety and tolerability of SGLT2 inhibitors in cardiac amyloidosis — a clinical feasibility study JF - Journal of Clinical Medicine N2 - Sodium-glucose transport protein 2 inhibitors (SGLT2i) slow the progression of renal dysfunction and improve the prognosis of patients with heart failure. Amyloidosis constitutes an important subgroup for which evidence is lacking. Amyloidotic fibrils originating from misfolded transthyretin and light chains are the causal agents in ATTR and AL amyloidosis. In these most frequent subtypes, cardiac involvement is the most common organ manifestation. Because cardiac and renal function frequently deteriorate over time, even under best available treatment, SGLT2i emerge as a promising treatment option due to their reno- and cardioprotective properties. We retrospectively analyzed patients with cardiac amyloidosis, who received either dapagliflozin or empagliflozin. Out of 79 patients, 5.1% had urinary tract infections; 2 stopped SGLT2i therapy; and 2.5% died unrelated to the intake of SGLT2i. No genital mycotic infections were observed. As expected, a slight drop in the glomerular filtration rate was noted, while the NYHA functional status, cardiac and hepatic function, as well as the 6 min walk distance remained stable over time. These data provide a rationale for the use of SGLT2i in patients with amyloidosis and concomitant cardiac or renal dysfunction. Prospective randomized data are desired to confirm safety and to prove efficacy in this increasingly important group of patients. KW - heart failure KW - chronic kidney disease KW - amyloidosis KW - SGLT2 inhibitors Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-356024 SN - 2077-0383 VL - 13 IS - 1 ER - TY - THES A1 - Kutschka, Ilona T1 - Activation of the integrated stress response induces remodeling of cardiac metabolism in Barth Syndrome T1 - Aktivierung der "Integrated Stress Response" führt zur Umstellung des kardialen Metabolismus im Barth Syndrom N2 - Barth Syndrome (BTHS) is an inherited X-chromosomal linked disorder, characterized by early development of cardiomyopathy, immune system defects, skeletal muscle myopathy and growth retardation. The disease displays a wide variety of symptoms including heart failure, exercise intolerance and fatigue due to the muscle weakness. The cause of the disease are mutations in the gene encoding for the mitochondrial transacylase Tafazzin (TAZ), which is important for remodeling of the phospholipid cardiolipin (CL). All mutations result in a pronounced decrease of the functional enzyme leading to an increase of monolysocardiolipin (MLCL), the precursor of mature CL, and a decrease in mature CL itself. CL is a hallmark phospholipid of mitochondrial membranes, highly enriched in the inner mitochondrial membrane (IMM). It is not only important for the formation of the cristae structures, but also for the function of different protein complexes associated with the mitochondrial membrane. Reduced levels of mature CL cause remodeling of the respiratory chain supercomplexes, impaired respiration, defects in the Krebs cycle and a loss of mitochondrial calcium uniporter (MCU) protein. The defective Ca2+ handling causes impaired redox homeostasis and energy metabolism resulting in cellular arrhythmias and defective electrical conduction. In an uncompensated situation, blunting mitochondrial Ca2+ uptake provokes increased mitochondrial emission of H2O2 during workload transitions, related to oxidation of NADPH, which is required to regenerate anti-oxidative enzymes. However, in the hearts and cardiac myocytes of mice with a global knock-down of the Taz gene (Taz-KD), no increase in mitochondrial ROS was observed, suggesting that other metabolic pathways may have compensated for reduced Krebs cycle activation. The healthy heart produces most of its energy by consuming fatty acids. In this study, the fatty acid uptake into mitochondria and their further degradation was investigated, which showed a switch of the metabolism in general in the Taz-KD mouse model. In vivo studies revealed an increase of glucose uptake into the heart and decreased fatty acid uptake and oxidation. Disturbed energy conversion resulted in activation of retrograde signaling pathways, implicating overall changes in the cell metabolism. Upregulated integrated stress response (ISR) was confirmed by increased levels of the downstream target, i.e., the activating transcription factor 4 (ATF4). A Tafazzin knockout mouse embryonal fibroblast cell model (TazKO) was used to inhibit the ISR using siRNA transfection or pharmaceutical inhibition. This verified the central role of II the ISR in regulating the metabolism in BTHS. Moreover, an increased metabolic flux into glutathione biosynthesis was observed, which supports redox homeostasis. In vivo PET-CT scans depicted elevated activity of the xCT system in the BTHS mouse heart, which transports essential amino acids for the biosynthesis of glutathione precursors. Furthermore, the stress induced signaling pathway also affected the glutamate metabolism, which fuels into the Krebs cycle via -ketoglutarate and therefore supports energy converting pathways. In summary, this thesis provides novel insights into the energy metabolism and redox homeostasis in Barth syndrome cardiomyopathy and its regulation by the integrated stress response, which plays a central role in the metabolic alterations. The aim of the thesis was to improve the understanding of these metabolic changes and to identify novel targets, which can provide new possibilities for therapeutic intervention in Barth syndrome. N2 - Barth Syndrome (BTHS) ist eine X-chromosomal vererbbare Erkrankung, welche sich in der frühen Entstehung von Kardiomyopathie, Störungen des Immunsystems, Skelettmuskelschwäche und Wachstumsverzögerungen manifestiert. Das Krankheitsbild ist sehr variabel mit milden Symptomen bis hin zu sehr schwerwiegenden Fällen, bei denen die schnelle Verschlechterung der Kardiomyopathie bereits in jungen Jahren eine Herztransplantation erfordern kann. Betroffenen Patienten zeigen eine deutliche Intoleranz gegenüber körperlicher Anstrengung, welche mit schneller Müdigkeit einhergeht. Die Krankheit wird durch verschiedene Mutationen auf dem Gen für die mitochondriale Transacylase Tafazzin (TAZ) ausgelöst. Die Mutationen führen zu einem Funktionsverlust des Enzyms, welches in der Biosynthese des Phospholipids Cardiolipin (CL) eine entscheidende Rolle spielt. Die Vorstufe des Lipids, das sogenannte Monolysocardiolipin (MLCL), reichert sich dadurch an, wohingegen die Menge an reifem CL entscheidend verringert ist. CL ist ein bedeutendes Phospholipid in den Mitochondrien, wo es vor allem in der inneren Mitochondrien Membran vorkommt. CL ist einerseits wichtig für die Ausbildung der Cristae Strukturen der inneren Mitochondrien Membran. Darüber hinaus ist es notwendig für die Struktur und Funktion verschiedenster Proteinkomplexe in der Membran, welche dadurch erst ihre volle Funktionsfähigkeit erhalten. Es wurde bereits gezeigt, dass der Verlust von reifem CL in BTHS zu einer Dissoziation der Superkomplexe der Atmungskette führt, welche dadurch in ihrer Funktion beeinträchtigt ist. Zusätzlich sind Störungen im Krebs Zyklus und der Kalziumaufnahme durch den mitochondriellen Kalzium (Ca2+) -Uniporter (MCU) Komplex bekannt. Die beeinträchtigte mitochondriale Ca2+ Aufnahme beeinflusst sowohl die Redox Homöostase als auch den Energie Metabolismus, was zu Arrhythmien und einer Störung der elektrischen Weiterleitung im Herzen führt. Im gesunden Herzen gewinnen die Herzmuskelzellen den Hauptanteil ihrer Energie aus dem Abbau von Fettsäuren. In dieser Studie wurde durch die Untersuchung des Fettsäurestoffwechsels im Taz knockdown Mausmodell (Taz-KD) gezeigt, dass eine deutliche Reduktion in Proteinen vorliegt, welche für die Aufnahme und die Verstoffwechselung der Fettsäuren in den Mitochondrien verantwortlich sind. Diese Veränderungen führten in vivo zu einer verringerten Aufnahme und Verstoffwechselung von Fettsäuren und einer Erhöhten Aufnahme von Glucose. Dysfunktionale Mitochondrien aktivieren retrograde Signalwege, welche eine generelle IV Umstellung des Metabolismus zur Folge haben. Eine erhöhte Menge des Transkriptionsfaktors ATF4, welcher sowohl Fettsäure- als auch Aminosäuremetabolismus beeinflusst, zeigte die Aktivierung der sogenannten „Integrated stress response“ (ISR). Ein Zellmodel embryonaler Fibroblasten aus der Maus mit einem Taz knockout (TazKO) wurde verwendet um die ISR durch siRNA Transfektion oder einem pharmakologischen Inhibitor zu blockieren. Dadurch konnte die zentrale Rolle der ISR in der Umstellung des Metabolismus bestätigt werden. Zusätzlich konnte eine erhöhte metabolische Aktivität in Richtung der Glutathion Biosynthese beobachtet werden, welche für die Redox Homöostase in den Mitochondrien von Bedeutung ist. In vivo PET-CT Untersuchungen zeigten eine erhöhte Aktivität des xCT Systems im Herzen des BTHS Mausmodells auf. Dies dient der Aufnahme von Aminosäuren, welche für die Glutathion Biosynthese benötigt werden. Hinzu kommt, dass die Aktivierung des Stresssignalweges den Glutamat Stoffwechsel in der Zelle beeinflusste. Über -Ketoglutarat trägt Glutamat so vermehrt zur Energiegewinnung bei. Das Ziel dieser Doktorarbeit war es, die metabolischen Veränderungen in BTHS zu untersuchen, um die veränderten Vorgänge besser zu verstehen und so neue mögliche Angriffspunkte für Therapiemöglichkeiten zu identifizieren. KW - Herzmuskelkrankheit KW - Mitochondrium KW - Stoffwechsel KW - Barth Syndrome Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-358186 ER - TY - THES A1 - Hapke, Nils T1 - Cardiac antigen derived T cell epitopes in the frame of myocardial infarction T1 - T-Zell-Epitope von kardialen Antigenen im Kontext des Myokardinfarktes N2 - Cardiovascular disease and the acute consequence of myocardial infarc- tion remain one of the most important causes of morbidity and mortality in all western societies. While much progress has been made in mitigating the acute, life-threatening ischemia caused by infarction, heart failure of the damaged my- ocardium remains prevalent. There is mounting evidence for the role of T cells in the healing process after myocardial infarction, but relevant autoantigens, which might trigger and regulate adaptive immune involvement have not been discov- ered in patients. In this work, we discovered an autoantigenic epitope in the adrenergic receptor beta 1, which is highly expressed in the heart. This autoantigenic epitope causes a pro-inflammatory immune reaction in T cells isolated from pa- tients after myocardial infarction (MI) but not in control patients. This immune reaction was only observed in a subset of MI patients, which carry at least one allele of the HLA-DRB1*13 family. Interestingly, HLA-DRB1*13 was more com- monly expressed in patients in the MI group than in the control group. Taken together, our data suggests antigen-specific priming of T cells in MI patients, which leads to a pro-inflammatory phenotype. The primed T cells react to a cardiac derived autoantigen ex vivo and are likely to exhibit a similar phenotype in vivo. This immune phenotype was only observed in a certain sub- set of patients sharing a common HLA-allele, which was more commonly ex- pressed in MI patients, suggesting a possible role as a risk factor for cardiovas- cular disease. While our results are observational and do not have enough power to show strong clinical associations, our discoveries provide an essential tool to further our understanding of involvement of the immune system in cardiovascu- lar disease. We describe the first cardiac autoantigen in the clinical context of MI and provide an important basis for further translational and clinical research in cardiac autoimmunity. N2 - Die koronare Herzerkrankung und die akute Konsequenz des Myokardin- farktes (MI) sind eine der häufigsten Ursachen von Morbidität und Mortalität in unserer westlichen Gesellschaft. Obwohl es große Fortschritte in der Behand- lung von akut lebensbedrohlichen ischämischen Ereignissen gab, bleibt die re- sultierende Herzinsuffizienz nach Infarkt ein häufiges klinisches Problem. Immer mehr Evidenz weist auf eine wichtige Rolle von T-Zellen im Heilungsprozess nach MI hin, aber relevante Autoantigene, die adaptive Immunantworten auslö- sen und regulieren könnten, wurden in Patienten mit MI noch nicht entdeckt. In dieser Arbeit beschreiben wir ein Epitop des Adrenergen Rezeptors Beta 1, der im Herz hoch exprimiert ist und als Autoantigen fungiert. Dieses Au- toantigen verursacht eine pro-inflammatorische Immunreaktion in T-Zellen, die von MI-Patienten isoliert wurden, aber nicht in Kontrollpatienten. Diese Immun- reaktion beobchten wir jedoch nur in einem Teil der Patienten, der ein Allel der Familie HLA-DRB1*13 trägt. Interessanterweise sind MI-Patienten häufiger Trä- ger eines solchen Allels als Kontroll-Patienten. Zusammenfassend legen unsere Ergebnisse nahe, dass T-Zellen in MI- Patienten antigen-spezifisch aktiviert werden und einen pro-inflammatorischen Phänotyp ausbilden. Die aktivierten T-Zellen reagieren ex vivo auf ein kardiales Autoantigen und entwickeln vermutlich in vivo einen ähnlichen Phänotyp. Dieser ist abhängig von einem HLA-Allel, welches in Infarkt-Patienten häufiger war als in der Kontrollgruppe, was eine mögliche Rolle als Risikofaktor für kardiovasku- läre Erkrankungen suggeriert. Unsere Ergebnisse stellen eine wichtige Grundlage dar, um unser Ver- ständnis des Immunsystems in kardiovaskulären Erkrankungen zu vertiefen. Wir beschreiben in dieser Arbeit das erste kardiale Autoantigen, das im klinischen Kontext des Myokardinfarktes entdeckt wurde und bieten somit eine wichtige Grundlage für weitere translationale und klinische Forschung in der Immunkar- diologie. KW - Immunologie KW - Kardiologie KW - Immunkardiologie KW - Immunocardiology Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-301963 ER - TY - THES A1 - Stefenelli, Ulrich T1 - Der „Würzburger Herz-Score“, ein Modell zur tageweisen Vorhersage des Sterberisikos in den ersten 4 Wochen nach Herzklappen- oder Bypass-Operation bei 5555 Patienten T1 - The Wuerzburg Heart-Score, a model to predict the mortality risk (daily ) in the first 4 weeks after heart valve or bypass surgery in 5555 patients N2 - Bei 5555 Patienten des Würzburger Zentrums für operative Medizin wurden Sterberisiken und assoziierte Faktoren nach Bypass- oder Aortenklappen-OP beschrieben. Eine Risikovorhersage war frühzeitig, sogar tageweise möglich, und nicht (wie bisher) mit Blick auf den 30. postoperativen Tag. Das stärkste Risiko ist ein fehlender Entlassungs-Sinusrhythmus, gefolgt von einer schweren präoperativen Einschränkung (ASA) und einem erhöhten Kreatinin, gefolgt vom kardiogenen anamnestischen Schock, vom zerebrovaskulären Ereignis, der Notwendigkeit von Frischplasma, von einer respiratorischen Insuffizienz, aber auch der Notwendigkeit mechanischer Kreislaufunterstützung. Hochprädiktiv war auch ein kürzlich stattgefundener Myokardinfarkt und eine Angina Pectoris in Ruhe. Liegen bis 4 dieser Ereignisse vor, so zeigt sich das Mortalitätsrisiko als statistisch normal (Verlauf der Grundgesamtheit): Es steigt je Woche nach OP um etwa 1% auf rund 5% nach 4 Wochen an. Bestehen 5 oder 6 Risiken, so erhöht sich das Sterberisiko deutlich: Es steigt um +10% je weitere Woche an und erreicht etwa 40% in der 4. postoperativen Woche. Ab 7 oder mehr erfüllte Risiken nimmt das Sterberisiko drastisch zu. Es erhöht sich um +20% je weitere Woche und kumuliert nach 3 Wochen auf rund 70%. Festzuhalten ist: Bis 4 Risiken ergibt sich je weitere Woche +1% Mortalitätsrisiko, ab 5 Risikofaktoren +10%, ab 7 und mehr Risikofaktoren finden sich je Woche nach der OP ein um +20% erhöhtes Sterberisiko. Diese Erkenntnisse wurden verwendet, um einen Risikoscore zu konstruieren. Die Einzelrisiken werden summiert, d.h. man betrachtet das Risiko als erfüllt oder nicht, und zählt. Das tageweise Risiko ist graphisch ablesbar und ist für die klinische Routine verwendbar, für Studien (Risikostratifizierung) oder für das präoperative Aufklärungsgespräch. Neu ist, dass dieser Score im klinischen Verlauf angepaßt werden kann, wenn neue Risikofaktoren auftreten hinzukommen oder Faktoren therapiebedingt wegfallen. N2 - Mortality risks and associated factors after bypass or aortic valve surgery were described in 5555 patients at the Würzburg Center for Operative Medicine. A risk prediction was possible at an early stage, even on a daily basis, and not - as before - only with a view to the 30th postoperative day. The greatest risk is an absent discharge sinus rhythm, followed by severe impairment (ASA) and elevated creatinine, followed by a history of cardiogenic shock, cerebrovascular event, the need for fresh plasma, respiratory failure, but also the need for mechanical circulatory support . A recent history of myocardial infarction and angina pectoris at rest were also highly predictive. If up to 4 of these events are present, the mortality risk is statistically normal, because it roughly corresponds to the course of the population: it increases by around 1% per postoperative week to around 5% after 4 weeks (+ 2nd % as confidence range). If the patient has 5 or 6 risks, the risk of death increases significantly: it increases by +10% for each additional week and reaches about 40% in the 4th postoperative week. From 7 or more risk factors fulfilled, the risk of death increases drastically. It increases by +20% for each additional postoperative week and accumulates to around 70% (+ 15%) after 3 weeks of intensive care. It should be noted: Up to 4 risk factors result in a +1% mortality risk for each additional week, from 5 risk factors +10%, from 7 and more risk factors there is a +20% increased risk of death per week after the operation. Findings from this work were used to construct a risk score. The individual risks mentioned above are added up, i.e. the risk is considered to be fulfilled or not and counted. The daily risk can then be read graphically. This could be used for clinical routine, for studies (risk stratification) or for preoperative informational discussions. What is also new is that this score can be adjusted in the clinical course if new risk factors are added or factors are removed. KW - Überleben KW - Survival KW - Bypass KW - Aortenklappe KW - Risiko KW - Sterblichkeit KW - Score KW - KHK KW - Mortalität KW - heart valve bypass KW - prognosis Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-303828 ER - TY - THES A1 - Klein, Andrea T1 - Einfluss der intrahospitalen Nierenfunktion auf das Überleben von Patient:innen mit akuter Herzinsuffizienz T1 - The influence of in-hospital renal function on the survival of patients with acute heart failure N2 - Herzinsuffizienz ist eines der häufigsten Krankheitsbilder, das trotz großer therapeutischer Fortschritte noch immer mit einer eingeschränkten Lebensqualität und schlechten Prognose einhergeht. Eine akute Dekompensation ist in Deutschland der häufigste Grund für einen Krankenhausaufenthalt, wobei sich die Prognose mit jeder Hospitalisierung zusätzlich verschlechtert. Pathophysiologisch besteht ein enger Zusammenhang zwischen kardialer und renaler Funktion. Bei einer chronischen Herzinsuffizienz liegt häufig zusätzlich eine CKD vor und im Rahmen einer akuten kardialen Dekompensation kommt es häufig auch zu einer akuten Verschlechterung der Nierenfunktion. Das AHF-Register verfolgte als prospektive Kohortenstudie einen umfassenden Forschungsansatz: Ätiologie, klinische Merkmale und medizinische Bedürfnisse sowie Kosten und Prognose sollten bei Patient:innen während und nach Krankenhausaufenthalt aufgrund akuter Herzinsuffizienz untersucht werden. Über ca. 6 Jahre wurden insgesamt 1000 Patient:innen eingeschlossen, die im Vergleich zu anderen AHF- Studienkollektiven älter waren, mehr Komorbiditäten aufwiesen und häufiger in die Gruppe der HFpEF fielen. Über drei Viertel der Patient:innen hatten eine vorbekannte chronische Herzinsuffizienz, nur bei ca. 22% erfolgte die Erstdiagnose einer akuten Herzinsuffizienz. Ein WRF während der Indexhospitalisierung trat im untersuchten Kollektiv bei über einem Drittel der Patient:innen auf und damit häufiger als in vergleichbaren Studien (Inzidenz hier ca. 25%). Dabei zeigten sich nur geringfügige Unterschiede zwischen der Definition eines WRF über einen absoluten Kreatinin-Anstieg (WRF-Crea) oder eine relative eGFR-Abnahme (WRF-GFR). Als wichtige Risikofaktoren für ein WRF zeigten sich ein höheres Lebensalter, Komorbiditäten wie eine KHK oder CKD sowie die Höhe der Nierenfunktionswerte bei Aufnahme. Sowohl bei WRF-Crea als auch bei WRF-GFR kam es zu einer relevanten Verlängerung der Index-Hospitalisierungsdauer um jeweils drei Tage. Nur für WRF-Crea jedoch ließ sich ein 33% höheres 6-Monats-Rehospitalisierungsrisiko nachweisen, das aber in einer multivariablen Analyse nicht bestätigt werden konnte. Dagegen zeigten sich in multivariablen Modellen vor allem die Nierenfunktionsparameter selbst bei Aufnahme und Entlassung als starke Prädiktoren für eine erhöhte Mortalität und ein erhöhtes Rehospitalisierungsrisiko. Wichtig erscheint im Hinblick auf die Prognose die Unterscheidung von Echtem WRF und Pseudo-WRF. Das Mortalitätsrisiko war bei Echtem WRF bis zu 4,4-fach, das Rehospitalisierungsrisiko bis zu 2,5-fach erhöht. Ziel sollte sein, diese beiden pathophysiologisch und prognostisch unterschiedlichen Entitäten anhand von klinischen oder laborchemischen Markern sicher differenzieren zu können. Ein Konzept für die Betreuung von Patient:innen mit Echtem WRF, z. B. im Rahmen einer „Decongestion Stewardship“ (in Analogie zum Antibiotic Stewardship) mit engmaschigen Therapiekontrollen und -anpassungen könnte erarbeitet werden, um die Prognose dieser besonders gefährdeten Gruppe zu verbessern. N2 - Heart failure is one of the most common diseases that, despite great therapeutic progress, still leads to reduced quality of life and poor prognosis. Acute heart failure (AHF) is the most frequent reason for hospitalization in adults in Germany. Heart and kidneys are strongly interconnected: in chronic heart failure, patients often suffer from chronic kidney disease and acute heart failure can lead to an acute decline in kidney function. The AHF-Registry Würzburg is a prospective cohort study that assessed etiology, clinical features, medical needs, costs, and prognosis in patients during and after hospitalization for acute heart failure. 1000 patients were included in the study, compared to other AHF-studies, they were older, presented more comorbidities and had a higher left ventricular ejection fraction (LVEF). An acute decline in kidney function during hospitalization (Worsening renal function, WRF) occurred in over one third of the patients. Main risk factors for WRF were age, comorbidities like coronary artery disease or chronic kidney disease as well as the level of kidney values at admission. WRF lead to a longer hospitalization and higher in-hospital mortality. It increased the risk of rehospitalization at six months but had no influence on 6-months-mortality. Combing WRF with the patients’ clinical condition improved the prognostic value. True WRF (WRF while deterioration of severe heart failure symptoms/ persistent severe heart failure symptoms) lead to a poor prognosis while Pseudo-WRF (WRF while improvement of symptoms/ during effective heart failure therapy) had no effect on prognosis. Future studies should focus on finding criteria to distinguish these two entities and develop strategies to improve the prognosis in True WRF patients. KW - Herzinsuffizienz KW - Niereninsuffizienz KW - Herzdekompensation KW - Kreatinin KW - akute Niereninsuffizienz KW - akute Herzinsuffizienz KW - AHF-Register Würzburg KW - eGFR KW - Echtes WRF KW - Pseudo-WRF Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-317085 ER - TY - THES A1 - Hartleb, Annika T1 - Auswirkungen eines Tandem-Peptids auf den intrazellulären Kalziumhaushalt und Arrhythmien von humanen iPS-Kardiomyozyten mit Mutationen in desmosomalen Proteinen T1 - Effects of a tandem peptide on intracellular calcium cycling and arrhythmias of human iPSC cardiomyocytes with mutations in desmosomal proteins N2 - Die arrhythmogene Kardiomyopathie (ACM) ist eine Herzmuskelerkrankung, die durch den fett- und bindegewebigen Umbau von Herzmuskelgewebe charakterisiert ist. Klinisch treten häufig ventrikuläre Herzrhythmusstörungen auf, teilweise bis hin zum plötzlichen Herztod. ACM ist eine genetisch bedingte Erkrankung, die durch Mutationen in desmosomalen Proteinen, wie Plakophilin-2 (PKP2) und Desmoglein-2 (DSG2), entsteht. Die molekularen Mechanismen sind nur teilweise verstanden und aktuell gibt es keine spezifischen Therapiemöglichkeiten. Ziel der Arbeit war es, die therapeutische Wirkung eines DSG2-spezifischen Tandem-Peptids (TP) durch desmosomale Stabilisierung an humanen Kardiomyozyten (KM) in einem ACM-Modell zu untersuchen. KM wurden aus humanen induzierten pluripotenten Stammzellen (hiPS) einer PKP2-Knockout- (PKP2-KO), DSG2-Knockout- (DSG2-KO) und deren isogener Kontrollzelllinie differenziert. Zunächst wurden verschiedene Methoden der beschleunigten Zellreifung getestet. Dann wurden die PKP2- und DSG2-KO-KM anhand von intrazellulären Kalzium-Messungen und Arrhythmie-Analysen phänotypisch charakterisiert. Letztlich wurde die Wirkung des TPs, das an die DSG2 der geschwächten Zellbindungen von PKP2-KO-KM binden sollte, im Vergleich zu entsprechenden Kontrollen untersucht. Die Ergebnisse zeigen, dass mit der Matrigel-Mattress-Kultivierung und einer Hormonbehandlung elektrisch stimulierbare hiPS-KM mit reifen Eigenschaften hergestellt werden konnten. Der Phänotyp der mutationstragenden PKP2-KO-KM und DSG2-KO-KM zeichnete sich durch erhöhte diastolische Kalzium-Konzentrationen und erniedrigte Kalzium-Amplituden sowie durch beschleunigte Kalzium-Kinetik im Sinne der Relaxationszeiten aus. Weiterhin war bei den PKP2-KO-KM die Häufigkeit der Arrhythmien erhöht, die unter beta-adrenerger Stimulation nachließen. Insgesamt konnte keine eindeutige Wirkung des TPs im ACM-Modell gezeigt werden. Das TP hatte nur auf die diastolischen Kalzium-Konzentrationen der PKP2-KO-KM einen therapeutischen Einfluss, allerdings auch auf DSG2-KO-KM, weshalb der Hinweis auf eine fehlende DSG2-Spezifität des TPs entstand. Schlussfolgernd wurde bestätigt, dass sich reife hiPS-KM mit genetischen Veränderungen als Modell zur Untersuchung der Kalziumhomöostase und von Arrhythmien bei der ACM eignen. Sie können grundsätzlich zum Test von therapeutischen Anwendungen genutzt werden. Die Wirksamkeit und Spezifität des getesteten TPs sollte zukünftig weiter überprüft werden. N2 - Arrhythmogenic cardiomyopathy (ACM) is a myocardial disease characterized by fibrofatty remodeling of myocardial tissue. Clinically, ventricular arrhythmias occur, sometimes leading to sudden cardiac death. ACM is a genetic disease that results from desmosomal mutations, such as plakophilin-2 (PKP2) and desmoglein-2 (DSG2). The molecular mechanisms are only partially understood and currently there are no specific therapeutic options. The aim of this work was to investigate the therapeutic effect of a DSG2-specific tandem peptide (TP) by desmosomal stabilization on human cardiomyocytes (CMs) in an ACM model. CMs were differentiated from human induced pluripotent stem cells (hiPSC) of a PKP2 knockout (PKP2-KO), DSG2 knockout (DSG2-KO) and their isogenic control cell line. First, methods of accelerated cell maturation were tested. Then, PKP2- and DSG2-KO-CMs were phenotypically characterized by using intracellular calcium measurements and arrhythmia analyses. Finally, the effect of a TP designed to bind to DSG2 of the weakened cell binding of PKP2-KO-CMs was examined in comparison with corresponding controls. The results show that matrigel mattress cultivation and hormone treatment were able to produce electrically stimulable hiPSC-CMs with mature characteristics. The phenotype of mutant PKP2-KO-CMs and DSG2-KO-CMs was characterized by increased diastolic calcium concentrations and decreased calcium amplitudes, as well as accelerated calcium kinetics in terms of relaxation times. Furthermore, the frequency of arrhythmias was increased in PKP2-KO-CMs and decreased under beta-adrenergic stimulation. Overall, no clear effect of TP was demonstrated in the ACM model. TP only had a therapeutic effect on diastolic calcium concentrations of PKP2-KO-CMs, although it also had an effect on DSG2-KO-CMs, thus suggesting a lack of DSG2 specificity of TP. In conclusion, it was confirmed that mature hiPSC-CMs with genetic alterations are suitable as a model to study calcium cycling and arrhythmias in ACM. In principle, they can be used to test therapeutic applications. The efficacy and specificity of the tested TP should be further evaluated in the future. KW - Herzmuskelkrankheit KW - Arrhythmie KW - Mutation KW - Calcium KW - Induzierte pluripotente Stammzelle KW - Arrhythmogene Kardiomyopathie KW - Tandem-Peptid KW - PKP2 KW - DSG2 KW - Arrhythmogenic cardiomyopathy KW - desmosomal mutations KW - human induced pluripotent stem cells (hiPSC) KW - calcium cycling KW - arrhythmia KW - tandem peptide Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-316579 ER - TY - THES A1 - Werner, Jana Sophia T1 - Frequenzabhängigkeit der IP3-induzierten Calciumregulation in murinen ventrikulären Kardiomyozyten T1 - Frequency dependence of IP3-induced calcium regulation in murine ventricular cardiomyocytes N2 - In Kardiomyozyten ist Calcium (Ca2+) ein wichtiges Signalmolekül und eine präzise Regulation der Ca2+ Konzentration in den Zellkompartimenten erforderlich. Ca2+ wird Angiotensin II-induziert und vom Botenstoff IP3 vermittelt aus IP3 Rezeptoren des Sarkoplasmatischen Retikulum (SR) freigesetzt, was zur mitochondrialen Ca2+ Aufnahme führt. Diese Kommunikationswege zwischen SR und Mitochondrium sind u.a. bei der Herzinsuffizienz durch pathologische Umbauprozesse gestört. Zudem zirkulieren bei Herzinsuffizienz vermehrt Hormone wie AngII, welches u.a. die intrazelluläre IP3 Konzentration steigert und als Hypertrophie Signal wirkt. Dieser Arbeit geht die Vermutung voraus, dass eine gestörte mitochondriale Ca2+ Aufnahme durch Veränderung des nukleären Ca2+ Transienten die hypertrophe Genexpression beeinflussen kann. Es wurde an ventrikulären Kardiomyozyten von adulten Mäusen mit kardiospezifischem MCU Knock out oder MCU Wildtyp untersucht, wie sich Ca2+ Transienten in Zytosol und Nukleus bei AngII-Stimulation und Störung der mitochondrialen Ca2+ Aufnahme durch Blockade des mRyR1 oder des MCU verändern. Zum Vergleich wurde der Effekt des β adrenerg vermittelten, IP3 unabhängigen Ca2+ Anstiegs beobachtet. Zur Untersuchung der Frequenzabhängigkeit der Effekte wurde die elektrische Stimulation wurde variiert. Die Arbeit zeigt, dass sich die Blockade der mitochondrialen Ca2+ Aufnahme unterschiedlich auf den nukleären Ca2+ Transienten auswirkt: Bei AngII-Stimulation kam es in Folge der Blockade des mRyR1, nicht aber des MCU, zur Steigerung des nukleären Ca2+ Transienten. Dieser Effekt war bei 1 Hz Stimulationsfrequenz, nicht aber nach einer Steigerung auf 4 Hz zu beobachten. Bei β adrenerger Stimulation hingegen veränderte die Blockade des MCU oder des mRyR1 die Ca2+ Transienten im Kern nicht signifikant. Die Arbeit verdeutlicht die Bedeutung der IP3 vermittelten Ca2+ Freisetzung für die Kontrolle der Ca2+ Konzentrationen in unterschiedlichen zellulären Kompartimenten. N2 - Calcium (Ca2+) serves as a critical signaling molecule within cardiomyocytes, necessitating precise regulation of Ca2+ concentrations across cellular compartments. Angiotensin II (AngII) triggers Ca2+ release through inositol trisphosphate (IP3) receptors located on the sarcoplasmic reticulum (SR), a process mediated by the secondary messenger IP3, resulting in mitochondrial Ca2+ uptake. Perturbations in these communication pathways have been implicated in heart failure due to pathological remodeling processes. Additionally, in heart failure elevated levels of hormones like AngII have been observed, which increases intracellular IP3 concentration, thereby acting as a signal for hypertrophy. This work is based on the assumption that impaired mitochondrial Ca2+ uptake can influence hypertrophic gene expression by altering the nuclear Ca2+ transient. The investigation was conducted using ventricular cardiomyocytes obtained from adult mice with cardiac-specific MCU (mitochondrial calcium uniporter) knockout and MCU wildtype, analyzing alterations in cytosolic and nuclear Ca2+ transients upon AngII stimulation and impairment of mitochondrial Ca2+ uptake by blocking mRyR1 (ryanodine receptor) or MCU. Additionally, the impact of β-adrenergic mediated IP3-independent Ca2+ elevation was assessed, with varying electrical stimulation frequencies to explore frequency-dependent effects. The findings reveal distinct effects of mitochondrial Ca2+ uptake blockade on nuclear Ca2+ transients. While mRyR1 blockade, but not MCU blockade, augmented nuclear Ca2+ transients during AngII stimulation, this effect was evident at 1 Hz stimulation frequency and not after increase to 4 Hz. Conversely, β-adrenergic stimulation yielded no significant changes in nuclear Ca2+ transients upon MCU or mRyR1 blockade. This work underscores the significance of IP3-mediated Ca2+ release in controlling Ca2+ concentrations across diverse cellular compartments. KW - Calciumtransport KW - Herzinsuffizienz KW - Angiotensin II KW - Mitochondrium KW - Inositoltrisphosphat KW - mitochondrialer Ryanodin-Rezeptor (mRyR1) KW - calcium signaling KW - Excitation-Transcription-Coupling KW - IP3 signaling KW - Mitochondrialer Uniporter (MCU) KW - Mitochondrialer Uniporter Knock out (MCU-KO) Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-323158 ER - TY - THES A1 - Kern [verh. Bischof], Melanie T1 - Effekte von Acylcarnitinen auf die Funktion kardialer Mausherzmitochondrien T1 - Effects of acylcarnitines on the function of cardiac mouse heart mitochondria N2 - Langkettige Acylcarnitine wie Oleoylcarnitn sind arrhythmogen wirkende Metaboliten, deren Rolle im Zusammenhang mit Vorhofflimmern noch unvollständig erforscht sind. Ziel dieser Dissertation war es, dazu beizutragen, den Einfluss langkettiger Acylcarnitine auf den kardialen Metabolismus besser zu verstehen. Dabei wurden für die Daten aktuelle Studien genutzt, welche sich mit dem Einfluss von Acylcarnitinen auf kardiales Gewebe bzw. kardial vorerkrankten Patienten beschäftigten. Hierzu zählten unter anderem die Daten einer Kohorten-Studie mit 9660 Probanden von Professor Dr. rer. nat. Tanja Zeller in Hamburg. Diese Daten zeigten, dass Patienten mit Vorhofflimmern erhöhte Acylcarnitin-Blutplasma-Werte aufwiesen. Bei den Acylcarnitinen handelt es sich um Fettsäuren mit 18 Kohlenstoff- (C-) Atomen und einer Doppelbindung. Der Hauptvertreter dieser Fettsäuren ist Oleoylcarnitin. Dass Oleoylcarnitin eine besondere Rolle bei der Entwicklung von Arrhythmien zufällt, konnten andere Studien bestätigen. Auf Grund dieser Grundlage wurden initiale Experimente durchgeführt. Für alle Experimente wurde Oleoylcarnitin mit 18 C-Atomen und einer Doppelbindung bzw. Stearoylcarnitin mit 18 C-Atomen ohne Doppelbindung in verschiedenen Konzentrationen verwendet. Um den Einfluss der Acylcarnitine auf den kardialen Metabolismus bestimmen zu können, wurden aus C57BL/6N Mäusen kardiale Mitochondrien isoliert und deren Respiration (Sauerstoffverbrauch) als Ausdruck der metabolischen Leistung und damit der Vitalität der Mitochondrien mit Hilfe der Clark Elektrode bestimmt. Die Mitochondrien wurden mit verschiedenen Substraten, d.h., mit Pyruvat/Malat (Komplex 1 Substrat), Glutamat/Malat (Komplex 1 Substrat nach Anaplerose) oder Palmitoyl-CoA (β-Oxidations-Substrat) und unterschiedlichen Konzentrationen von Acylcarnitinen behandelt und die Respiration gemessen. Im Gegensatz zur Pyruvat/Malat-gestützten Respiration, die durch den Einfluss von hohen (bis 25 µM) Oleoylcarnitin Konzentrationen vermindert bis inhibiert wurde, steigerte zumindest zeitweise Oleoylcarnitin die PalmitoylCoA- sowie die Glutamat/Malat-gestützte Respiration. Wobei kritisch zu betrachten ist, dass die Respirationslevel einer Glutamat/Malat-gestützten Respiration insgesamt auf einem niedrigeren Level sind als mit Pyruvat/Malat als Substrat. Der inhibierende Acylcarnitin-Effekt auf die Pyruvat/Malat-Atmung konnte nicht mit Etomoxir, einem Inhibitor der Carnitin Palmitoyl-Transferase 1 (CPT1), beeinflusst werden, aber als CPT1-Inhibitor konnte Etomoxir die auf PalmitoylCoA gestützte Respiration konzentrationsabhängig reduzieren. Die inhibierenden Effekte der Acylcarnitine waren zudem reversibel und verursachten somit keine irreversiblen Schäden an den Mitochondrien. Es wird geschlussfolgert, dass die hier getesteten Oleoyl- und Stearoylcarnitine eine regulierende Funktion auf die flexible Substratverarbeitung des Herzens haben. Sie können den Abbau der Glycolyse-Endprodukte inhibieren, gleichzeitig die Fettsäure-Respiration unterstützen und somit mit einem Substratswitch den Stoffwechsel der Mitochondrien beeinflussen. Gleichzeitig könnte es bei Situationen mit gestörtem oxidativem Stoffwechsel, z.B. während Myokardischämie zur Überlastung des Metabolismus oder sogar Blockade der Respiration kommen. Diese Respirationsblockade könnte ein Auslöser für Arrhythmien und Vorhofflimmern sein. N2 - Long-chain acylcarnitines such as oleoylcarnitine are arrhythmogenic metabolites whose role in connection with atrial fibrillation is still incompletely researched. The aim of this dissertation was to contribute to a better understanding of the influence of long-chain acylcarnitines on cardiac metabolism. Current studies were used for the data, which dealt with the influence of acylcarnitines on cardiac tissue or patients with previous cardiac disease. This included, among other things, the data from a cohort study with 9,660 test subjects by Professor Dr. rer. nat. Tanja Zeller in Hamburg. These data showed that patients with atrial fibrillation had elevated plasma acylcarnitine levels. Acylcarnitines are fatty acids with 18 carbon (c) atoms and one double bond. The main representative of these fatty acids is oleoylcarnitine. Other studies have confirmed that oleoylcarnitine plays a special role in the development of arrhythmias. On this basis, initial experiments were carried out. For all experiments, oleoylcarnitine with 18 carbon atoms and one double bond or stearoylcarnitine with 18 carbon atoms without a double bond was used in various concentrations. In order to determine the influence of acylcarnitines on cardiac metabolism, cardiac mitochondria were isolated from C57BL/6N mice and their respiration (oxygen consumption) as an expression of the metabolic performance and thus the vitality of the mitochondria was determined using the Clark electrode. The mitochondria were treated with different substrates, i.e. with pyruvate/malate (complex 1 substrate), glutamate/malate (complex 1 substrate) or palmitoyl-CoA (β-oxidation substrate) and different concentrations of acylcarnitines, and respiration was measured . In contrast to pyruvate/malate-assisted respiration, which was reduced or even inhibited by the influence of high (up to 25 µM) oleoylcarnitine concentrations, oleoylcarnitine at least temporarily increased palmitoylCoA- and glutamate/malate-assisted respiration. It should be considered critically that the respiration levels of glutamate/malate-supported respiration are overall at a lower level than with pyruvate/malate as a substrate. The inhibitory acylcarnitine effect on pyruvate/malate respiration could not be influenced with etomoxir, an inhibitor of carnitine palmitoyl transferase 1 (CPT1), but as a CPT1 inhibitor, etomoxir could reduce palmitoylCoA-assisted respiration in a concentration-dependent manner. The inhibitory effects of acylcarnitines were also reversible and therefore did not cause irreversible damage to the mitochondria. It is concluded that the oleoyl and stearoyl carnitines tested here have a regulatory function on the flexible substrate processing of the heart. They can inhibit the breakdown of glycolysis end products, at the same time support fatty acid respiration and thus influence the metabolism of the mitochondria with a substrate switch. At the same time, in situations with disturbed oxidative metabolism, e.g. during myocardial ischemia, overloading of the metabolism or even blocking of respiration could occur. This respiratory blockage could be a trigger for arrhythmias and atrial fibrillation. KW - Acylcarnitin Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-322773 ER - TY - JOUR A1 - Kerwagen, Fabian A1 - Fuchs, Konrad F. A1 - Ullrich, Melanie A1 - Schulze, Andres A1 - Straka, Samantha A1 - Krop, Philipp A1 - Latoschik, Marc E. A1 - Gilbert, Fabian A1 - Kunz, Andreas A1 - Fette, Georg A1 - Störk, Stefan A1 - Ertl, Maximilian T1 - Usability of a mHealth solution using speech recognition for point-of-care diagnostic management JF - Journal of Medical Systems N2 - The administrative burden for physicians in the hospital can affect the quality of patient care. The Service Center Medical Informatics (SMI) of the University Hospital Würzburg developed and implemented the smartphone-based mobile application (MA) ukw.mobile1 that uses speech recognition for the point-of-care ordering of radiological examinations. The aim of this study was to examine the usability of the MA workflow for the point-of-care ordering of radiological examinations. All physicians at the Department of Trauma and Plastic Surgery at the University Hospital Würzburg, Germany, were asked to participate in a survey including the short version of the User Experience Questionnaire (UEQ-S) and the Unified Theory of Acceptance and Use of Technology (UTAUT). For the analysis of the different domains of user experience (overall attractiveness, pragmatic quality and hedonic quality), we used a two-sided dependent sample t-test. For the determinants of the acceptance model, we employed regression analysis. Twenty-one of 30 physicians (mean age 34 ± 8 years, 62% male) completed the questionnaire. Compared to the conventional desktop application (DA) workflow, the new MA workflow showed superior overall attractiveness (mean difference 2.15 ± 1.33), pragmatic quality (mean difference 1.90 ± 1.16), and hedonic quality (mean difference 2.41 ± 1.62; all p < .001). The user acceptance measured by the UTAUT (mean 4.49 ± 0.41; min. 1, max. 5) was also high. Performance expectancy (beta = 0.57, p = .02) and effort expectancy (beta = 0.36, p = .04) were identified as predictors of acceptance, the full predictive model explained 65.4% of its variance. Point-of-care mHealth solutions using innovative technology such as speech-recognition seem to address the users’ needs and to offer higher usability in comparison to conventional technology. Implementation of user-centered mHealth innovations might therefore help to facilitate physicians’ daily work. KW - mHealth KW - digital Health KW - speech recognition KW - usability KW - user-centered design KW - clinical systems Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324002 VL - 47 IS - 1 ER - TY - JOUR A1 - Gerhardt, Louisa M. S. A1 - Kordsmeyer, Maren A1 - Sehner, Susanne A1 - Güder, Gülmisal A1 - Störk, Stefan A1 - Edelmann, Frank A1 - Wachter, Rolf A1 - Pankuweit, Sabine A1 - Prettin, Christiane A1 - Ertl, Georg A1 - Wanner, Christoph A1 - Angermann, Christiane E. T1 - Prevalence and prognostic impact of chronic kidney disease and anaemia across ACC/AHA precursor and symptomatic heart failure stages JF - Clinical Research in Cardiology N2 - Background The importance of chronic kidney disease (CKD) and anaemia has not been comprehensively studied in asymptomatic patients at risk for heart failure (HF) versus those with symptomatic HF. We analysed the prevalence, characteristics and prognostic impact of both conditions across American College of Cardiology/American Heart Association (ACC/AHA) precursor and HF stages A–D. Methods and results 2496 participants from three non-pharmacological German Competence Network HF studies were categorized by ACC/AHA stage; stage C patients were subdivided into C1 and C2 (corresponding to NYHA classes I/II and III, respectively). Overall, patient distribution was 8.1%/35.3%/32.9% and 23.7% in ACC/AHA stages A/B/C1 and C2/D, respectively. These subgroups were stratified by the absence ( – ) or presence ( +) of CKD (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73m2) and anaemia (haemoglobin in women/men < 12/ < 13 g/dL). The primary outcome was all-cause mortality at 5-year follow-up. Prevalence increased across stages A/B/C1 and C2/D (CKD: 22.3%/23.6%/31.6%/54.7%; anaemia: 3.0%/7.9%/21.7%/33.2%, respectively), with concordant decreases in median eGFR and haemoglobin (all p < 0.001). Across all stages, hazard ratios [95% confidence intervals] for all-cause mortality were 2.1 [1.8–2.6] for CKD + , 1.7 [1.4–2.0] for anaemia, and 3.6 [2.9–4.6] for CKD + /anaemia + (all p < 0.001). Population attributable fractions (PAFs) for 5-year mortality related to CKD and/or anaemia were similar across stages A/B, C1 and C2/D (up to 33.4%, 30.8% and 34.7%, respectively). Conclusions Prevalence and severity of CKD and anaemia increased across ACC/AHA stages. Both conditions were individually and additively associated with increased 5-year mortality risk, with similar PAFs in asymptomatic patients and those with symptomatic HF. KW - anaemia KW - ACC/AHA classification KW - chronic kidney disease KW - comorbidity KW - heart failure KW - mortality Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-323990 VL - 112 IS - 7 ER - TY - JOUR A1 - Gelbrich, Götz A1 - Morbach, Caroline A1 - Deutschbein, Timo A1 - Fassnacht, Martin A1 - Störk, Stefan A1 - Heuschmann, Peter U. T1 - The population comparison index: an intuitive measure to calibrate the extent of impairments in patient cohorts in relation to healthy and diseased populations JF - International Journal of Environmental Research and Public Health N2 - We assume that a specific health constraint, e.g., a certain aspect of bodily function or quality of life that is measured by a variable X, is absent (or irrelevant) in a healthy reference population (Ref0), and it is materially present and precisely measured in a diseased reference population (Ref1). We further assume that some amount of this constraint of interest is suspected to be present in a population under study (SP). In order to quantify this issue, we propose the introduction of an intuitive measure, the population comparison index (PCI), that relates the mean value of X in population SP to the mean values of X in populations Ref0 and Ref1. This measure is defined as PCI[X] = (mean[X|SP] − mean[X|Ref0])/(mean[X|Ref1] − mean[X|Ref0]) × 100[%], where mean[X|.] is the average value of X in the respective group of individuals. For interpretation, PCI[X] ≈ 0 indicates that the values of X in the population SP are similar to those in population Ref0, and hence, the impairment measured by X is not materially present in the individuals in population SP. On the other hand, PCI[X] ≈ 100 means that the individuals in SP exhibit values of X comparable to those occurring in Ref1, i.e., the constraint of interest is equally present in populations SP and Ref1. A value of 0 < PCI[X] < 100 indicates that a certain percentage of the constraint is present in SP, and it is more than in Ref0 but less than in Ref1. A value of PCI[X] > 100 means that population SP is even more affected by the constraint than population Ref1. KW - reference data KW - normal values KW - disease severity KW - disease score KW - comparability Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304933 SN - 1660-4601 VL - 20 IS - 3 ER - TY - JOUR A1 - Traub, Jan A1 - Frey, Anna A1 - Störk, Stefan T1 - Chronic neuroinflammation and cognitive decline in patients with cardiac disease: evidence, relevance, and therapeutic implications JF - Life N2 - Acute and chronic cardiac disorders predispose to alterations in cognitive performance, ranging from mild cognitive impairment to overt dementia. Although this association is well-established, the factors inducing and accelerating cognitive decline beyond ageing and the intricate causal pathways and multilateral interdependencies involved remain poorly understood. Dysregulated and persistent inflammatory processes have been implicated as potentially causal mediators of the adverse consequences on brain function in patients with cardiac disease. Recent advances in positron emission tomography disclosed an enhanced level of neuroinflammation of cortical and subcortical brain regions as an important correlate of altered cognition in these patients. In preclinical and clinical investigations, the thereby involved domains and cell types of the brain are gradually better characterized. Microglia, resident myeloid cells of the central nervous system, appear to be of particular importance, as they are extremely sensitive to even subtle pathological alterations affecting their complex interplay with neighboring astrocytes, oligodendrocytes, infiltrating myeloid cells, and lymphocytes. Here, we review the current evidence linking cognitive impairment and chronic neuroinflammation in patients with various selected cardiac disorders including the aspect of chronic neuroinflammation as a potentially druggable target. KW - neuroinflammation KW - cognitive impairment KW - dementia KW - myocardial infarction KW - heart failure KW - hypertension KW - coronary artery disease KW - atrial fibrillation KW - cardiac arrest KW - aortic valve stenosis Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304869 SN - 2075-1729 VL - 13 IS - 2 ER - TY - JOUR A1 - Higuchi, Takahiro A1 - Werner, Rudolf A. T1 - Unfolding the cardioprotective potential of sigma-1 receptor-directed molecular imaging JF - Journal of Nuclear Cardiology N2 - No abstract available. KW - Journal of Nuclear Cardiology KW - editorial KW - sigma-1 receptor-directed molecular imaging KW - cardioprotective potential Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324600 VL - 30 IS - 2 ER - TY - JOUR A1 - Ungethüm, K. A1 - Wiedmann, S. A1 - Wagner, M. A1 - Leyh, R. A1 - Ertl, G. A1 - Frantz, S. A1 - Geisler, T. A1 - Karmann, W. A1 - Prondzinsky, R. A1 - Herdeg, C. A1 - Noutsias, M. A1 - Ludwig, T. A1 - Käs, J. A1 - Klocke, B. A1 - Krapp, J. A1 - Wood, D. A1 - Kotseva, K. A1 - Störk, S. A1 - Heuschmann, P. U. T1 - Secondary prevention in diabetic and nondiabetic coronary heart disease patients: insights from the German subset of the hospital arm of the EUROASPIRE IV and V surveys JF - Clinical Research in Cardiology N2 - Background Patients with coronary heart disease (CHD) with and without diabetes mellitus have an increased risk of recurrent events requiring multifactorial secondary prevention of cardiovascular risk factors. We compared prevalences of cardiovascular risk factors and its determinants including lifestyle, pharmacotherapy and diabetes mellitus among patients with chronic CHD examined within the fourth and fifth EUROASPIRE surveys (EA-IV, 2012–13; and EA-V, 2016–17) in Germany. Methods The EA initiative iteratively conducts European-wide multicenter surveys investigating the quality of secondary prevention in chronic CHD patients aged 18 to 79 years. The data collection in Germany was performed during a comprehensive baseline visit at study centers in Würzburg (EA-IV, EA-V), Halle (EA-V), and Tübingen (EA-V). Results 384 EA-V participants (median age 69.0 years, 81.3% male) and 536 EA-IV participants (median age 68.7 years, 82.3% male) were examined. Comparing EA-IV and EA-V, no relevant differences in risk factor prevalence and lifestyle changes were observed with the exception of lower LDL cholesterol levels in EA-V. Prevalence of unrecognized diabetes was significantly lower in EA-V as compared to EA-IV (11.8% vs. 19.6%) while the proportion of prediabetes was similarly high in the remaining population (62.1% vs. 61.0%). Conclusion Between 2012 and 2017, a modest decrease in LDL cholesterol levels was observed, while no differences in blood pressure control and body weight were apparent in chronic CHD patients in Germany. Although the prevalence of unrecognized diabetes decreased in the later study period, the proportion of normoglycemic patients was low. As pharmacotherapy appeared fairly well implemented, stronger efforts towards lifestyle interventions, mental health programs and cardiac rehabilitation might help to improve risk factor profiles in chronic CHD patients. KW - coronary heart disease KW - diabetes mellitus KW - secondary prevention KW - EUROASPIRE Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324037 VL - 112 IS - 2 ER - TY - JOUR A1 - Weiß, Martin A1 - Gründahl, Marthe A1 - Deckert, Jürgen A1 - Eichner, Felizitas A. A1 - Kohls, Mirjam A1 - Störk, Stefan A1 - Heuschmann, Peter U. A1 - Hein, Grit T1 - Differential network interactions between psychosocial factors, mental health, and health-related quality of life in women and men JF - Scientific Reports N2 - Psychosocial factors affect mental health and health-related quality of life (HRQL) in a complex manner, yet gender differences in these interactions remain poorly understood. We investigated whether psychosocial factors such as social support and personal and work-related concerns impact mental health and HRQL differentially in women and men during the first year of the COVID-19 pandemic. Between June and October 2020, the first part of a COVID-19-specific program was conducted within the “Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB)” cohort study, a representative age- and gender-stratified sample of the general population of Würzburg, Germany. Using psychometric networks, we first established the complex relations between personal social support, personal and work-related concerns, and their interactions with anxiety, depression, and HRQL. Second, we tested for gender differences by comparing expected influence, edge weight differences, and stability of the networks. The network comparison revealed a significant difference in the overall network structure. The male (N = 1370) but not the female network (N = 1520) showed a positive link between work-related concern and anxiety. In both networks, anxiety was the most central variable. These findings provide further evidence that the complex interplay of psychosocial factors with mental health and HRQL decisively depends on gender. Our results are relevant for the development of gender-specific interventions to increase resilience in times of pandemic crisis. KW - anxiety KW - depression KW - human behaviour KW - quality of life Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357858 VL - 13 ER - TY - JOUR A1 - Rodriguez-Rozada, Silvia A1 - Frantz, Stefan A1 - Tovote, Philip T1 - Cardiac optogenetics: regulating brain states via the heart JF - Signal Transduction and Targeted Therapy N2 - No abstract available. KW - cardiology KW - neurology KW - neuroscience KW - systems biology Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357625 VL - 8 ER - TY - JOUR A1 - Tutov, Anna A1 - Chen, Xinyu A1 - Werner, Rudolf A. A1 - Mühlig, Saskia A1 - Zimmermann, Thomas A1 - Nose, Naoko A1 - Koshino, Kazuhiro A1 - Lapa, Constantin A1 - Decker, Michael A1 - Higuchi, Takahiro T1 - Rationalizing the binding modes of PET radiotracers targeting the norepinephrine transporter JF - Pharmaceutics N2 - Purpose: A new PET radiotracer \(^{18}\)F-AF78 showing great potential for clinical application has been reported recently. It belongs to a new generation of phenethylguanidine-based norepinephrine transporter (NET)-targeting radiotracers. Although many efforts have been made to develop NET inhibitors as antidepressants, systemic investigations of the structure–activity relationships (SARs) of NET-targeting radiotracers have rarely been performed. Methods: Without changing the phenethylguanidine pharmacophore and 3-fluoropropyl moiety that is crucial for easy labeling, six new analogs of \(^{18}\)F-AF78 with different meta-substituents on the benzene-ring were synthesized and evaluated in a competitive cellular uptake assay and in in vivo animal experiments in rats. Computational modeling of these tracers was established to quantitatively rationalize the interaction between the radiotracers and NET. Results: Using non-radiolabeled reference compounds, a competitive cellular uptake assay showed a decrease in NET-transporting affinity from meta-fluorine to iodine (0.42 and 6.51 µM, respectively), with meta-OH being the least active (22.67 µM). Furthermore, in vivo animal studies with radioisotopes showed that heart-to-blood ratios agreed with the cellular experiments, with AF78(F) exhibiting the highest cardiac uptake. This result correlates positively with the electronegativity rather than the atomic radius of the meta-substituent. Computational modeling studies revealed a crucial influence of halogen substituents on the radiotracer–NET interaction, whereby a T-shaped π–π stacking interaction between the benzene-ring of the tracer and the amino acid residues surrounding the NET binding site made major contributions to the different affinities, in accordance with the pharmacological data. Conclusion: The SARs were characterized by in vitro and in vivo evaluation, and computational modeling quantitatively rationalized the interaction between radiotracers and the NET binding site. These findings pave the way for further evaluation in different species and underline the potential of AF78(F) for clinical application, e.g., cardiac innervation imaging or molecular imaging of neuroendocrine tumors. KW - positron emission tomography KW - norepinephrine transporter KW - sympathetic nervous system KW - structure–activity relationships KW - T-shaped π–π stacking Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-303949 SN - 1999-4923 VL - 15 IS - 2 ER - TY - JOUR A1 - Herrmann, Johannes A1 - Müller, Kerstin A1 - Notz, Quirin A1 - Hübsch, Martha A1 - Haas, Kirsten A1 - Horn, Anna A1 - Schmidt, Julia A1 - Heuschmann, Peter A1 - Maschmann, Jens A1 - Frosch, Matthias A1 - Deckert, Jürgen A1 - Einsele, Hermann A1 - Ertl, Georg A1 - Frantz, Stefan A1 - Meybohm, Patrick A1 - Lotz, Christopher T1 - Prospective single-center study of health-related quality of life after COVID-19 in ICU and non-ICU patients JF - Scientific Reports N2 - Long-term sequelae in hospitalized Coronavirus Disease 2019 (COVID-19) patients may result in limited quality of life. The current study aimed to determine health-related quality of life (HRQoL) after COVID-19 hospitalization in non-intensive care unit (ICU) and ICU patients. This is a single-center study at the University Hospital of Wuerzburg, Germany. Patients eligible were hospitalized with COVID-19 between March 2020 and December 2020. Patients were interviewed 3 and 12 months after hospital discharge. Questionnaires included the European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L), patient health questionnaire-9 (PHQ-9), the generalized anxiety disorder 7 scale (GAD-7), FACIT fatigue scale, perceived stress scale (PSS-10) and posttraumatic symptom scale 10 (PTSS-10). 85 patients were included in the study. The EQ5D-5L-Index significantly differed between non-ICU (0.78 ± 0.33 and 0.84 ± 0.23) and ICU (0.71 ± 0.27; 0.74 ± 0.2) patients after 3- and 12-months. Of non-ICU 87% and 80% of ICU survivors lived at home without support after 12 months. One-third of ICU and half of the non-ICU patients returned to work. A higher percentage of ICU patients was limited in their activities of daily living compared to non-ICU patients. Depression and fatigue were present in one fifth of the ICU patients. Stress levels remained high with only 24% of non-ICU and 3% of ICU patients (p = 0.0186) having low perceived stress. Posttraumatic symptoms were present in 5% of non-ICU and 10% of ICU patients. HRQoL is limited in COVID-19 ICU patients 3- and 12-months post COVID-19 hospitalization, with significantly less improvement at 12-months compared to non-ICU patients. Mental disorders were common highlighting the complexity of post-COVID-19 symptoms as well as the necessity to educate patients and primary care providers about monitoring mental well-being post COVID-19. KW - health care KW - public health KW - quality of life Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357174 VL - 13 ER - TY - JOUR A1 - Wu, Hao A1 - Zhao, Xiufeng A1 - Hochrein, Sophia M. A1 - Eckstein, Miriam A1 - Gubert, Gabriela F. A1 - Knöpper, Konrad A1 - Mansilla, Ana Maria A1 - Öner, Arman A1 - Doucet-Ladevèze, Remi A1 - Schmitz, Werner A1 - Ghesquière, Bart A1 - Theurich, Sebastian A1 - Dudek, Jan A1 - Gasteiger, Georg A1 - Zernecke, Alma A1 - Kobold, Sebastian A1 - Kastenmüller, Wolfgang A1 - Vaeth, Martin T1 - Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming JF - Nature Communications N2 - T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells. At the molecular level, we find that mitochondrial dysfunction causes redox stress, which inhibits the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and promotes the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T cells. Our findings also bear clinical significance, as metabolic engineering of chimeric antigen receptor (CAR) T cells is a promising strategy to enhance the stemness and functionality of Tpex cells for cancer immunotherapy. KW - cytotoxic T cells KW - infection KW - lymphocyte differentiation KW - translational research Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-358052 VL - 14 ER - TY - JOUR A1 - Schreiber, Laura M. A1 - Lohr, David A1 - Baltes, Steffen A1 - Vogel, Ulrich A1 - Elabyad, Ibrahim A. A1 - Bille, Maya A1 - Reiter, Theresa A1 - Kosmala, Aleksander A1 - Gassenmaier, Tobias A1 - Stefanescu, Maria R. A1 - Kollmann, Alena A1 - Aures, Julia A1 - Schnitter, Florian A1 - Pali, Mihaela A1 - Ueda, Yuichiro A1 - Williams, Tatiana A1 - Christa, Martin A1 - Hofmann, Ulrich A1 - Bauer, Wolfgang A1 - Gerull, Brenda A1 - Zernecke, Alma A1 - Ergün, Süleyman A1 - Terekhov, Maxim T1 - Ultra-high field cardiac MRI in large animals and humans for translational cardiovascular research JF - Frontiers in Cardiovascular Medicine N2 - A key step in translational cardiovascular research is the use of large animal models to better understand normal and abnormal physiology, to test drugs or interventions, or to perform studies which would be considered unethical in human subjects. Ultrahigh field magnetic resonance imaging (UHF-MRI) at 7 T field strength is becoming increasingly available for imaging of the heart and, when compared to clinically established field strengths, promises better image quality and image information content, more precise functional analysis, potentially new image contrasts, and as all in-vivo imaging techniques, a reduction of the number of animals per study because of the possibility to scan every animal repeatedly. We present here a solution to the dual use problem of whole-body UHF-MRI systems, which are typically installed in clinical environments, to both UHF-MRI in large animals and humans. Moreover, we provide evidence that in such a research infrastructure UHF-MRI, and ideally combined with a standard small-bore UHF-MRI system, can contribute to a variety of spatial scales in translational cardiovascular research: from cardiac organoids, Zebra fish and rodent hearts to large animal models such as pigs and humans. We present pilot data from serial CINE, late gadolinium enhancement, and susceptibility weighted UHF-MRI in a myocardial infarction model over eight weeks. In 14 pigs which were delivered from a breeding facility in a national SARS-CoV-2 hotspot, we found no infection in the incoming pigs. Human scanning using CINE and phase contrast flow measurements provided good image quality of the left and right ventricle. Agreement of functional analysis between CINE and phase contrast MRI was excellent. MRI in arrested hearts or excised vascular tissue for MRI-based histologic imaging, structural imaging of myofiber and vascular smooth muscle cell architecture using high-resolution diffusion tensor imaging, and UHF-MRI for monitoring free radicals as a surrogate for MRI of reactive oxygen species in studies of oxidative stress are demonstrated. We conclude that UHF-MRI has the potential to become an important precision imaging modality in translational cardiovascular research. KW - ultrahigh-field MRI KW - large animal models KW - translational research KW - research infrastructure KW - heart KW - organoid KW - pig KW - cardiovascular MRI Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-317398 SN - 2297-055X VL - 10 ER - TY - JOUR A1 - Hampf, Chantal A1 - Scherf-Clavel, Maike A1 - Weiß, Carolin A1 - Klüpfel, Catherina A1 - Stonawski, Saskia A1 - Hommers, Leif A1 - Lichter, Katharina A1 - Erhardt-Lehmann, Angelika A1 - Unterecker, Stefan A1 - Domschke, Katharina A1 - Kittel-Schneider, Sarah A1 - Menke, Andreas A1 - Deckert, Jürgen A1 - Weber, Heike T1 - Effects of anxious depression on antidepressant treatment response JF - International Journal of Molecular Sciences N2 - Anxious depression represents a subtype of major depressive disorder and is associated with increased suicidality, severity, chronicity and lower treatment response. Only a few studies have investigated the differences between anxious depressed (aMDD) and non-anxious depressed (naMDD) patients regarding treatment dosage, serum-concentration and drug-specific treatment response. In our naturalistic and prospective study, we investigated whether the effectiveness of therapy including antidepressants (SSRI, SNRI, NaSSA, tricyclics and combinations) in aMDD patients differs significantly from that in naMDD patients. In a sample of 346 patients, we calculated the anxiety somatization factor (ASF) and defined treatment response as a reduction (≥50%) in the Hamilton Depression Rating Scale (HDRS)-21 score after 7 weeks of pharmacological treatment. We did not observe an association between therapy response and the baseline ASF-scores, or differences in therapy outcomes between aMDD and naMDD patients. However, non-responders had higher ASF-scores, and at week 7 aMDD patients displayed a worse therapy outcome than naMDD patients. In subgroup analyses for different antidepressant drugs, venlafaxine-treated aMDD patients showed a significantly worse outcome at week 7. Future prospective, randomized-controlled studies should address the question of a worse therapy outcome in aMDD patients for different psychopharmaceuticals individually. KW - pharmacotherapy KW - depressive disorder KW - anxious depression KW - anxiety KW - therapy response Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-355801 SN - 1422-0067 VL - 24 IS - 24 ER - TY - JOUR A1 - Kerwagen, Fabian A1 - Riemer, Uwe A1 - Wachter, Rolf A1 - von Haehling, Stephan A1 - Abdin, Amr A1 - Böhm, Michael A1 - Schulz, Martin A1 - Störk, Stefan T1 - Impact of the COVID-19 pandemic on implementation of novel guideline-directed medical therapies for heart failure in Germany: a nationwide retrospective analysis JF - The Lancet Regional Health - Europe N2 - Background Guideline-directed medical therapy (GDMT) is the cornerstone in the treatment of patients with heart failure and reduced ejection fraction (HFrEF) and novel substances such as sacubitril/valsartan (S/V) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) have demonstrated marked clinical benefits. We investigated their implementation into real-world HF care in Germany before, during, and after the COVID-19 pandemic period. Methods The IQVIA LRx data set is based on ∼80% of 73 million people covered by the German statutory health insurance. Prescriptions of S/V were used as a proxy for HFrEF. Time trends were analysed between Q1/2016 and Q2/2023 for prescriptions for S/V alone and in combination therapy with SGLT2i. Findings The number of patients treated with S/V increased from 5260 in Q1/2016 to 351,262 in Q2/2023. The share of patients with combination therapy grew from 0.6% (29 of 5260) to 14.2% (31,128 of 219,762) in Q2/2021, and then showed a steep surge up to 54.8% (192,429 of 351,262) in Q2/2023, coinciding with the release of the European Society of Cardiology (ESC) guidelines for HF in Q3/2021. Women and patients aged >80 years were treated less often with combined therapy than men and younger patients. With the start of the COVID-19 pandemic, the number of patients with new S/V prescriptions dropped by 17.5% within one quarter, i.e., from 26,855 in Q1/2020 to 22,145 in Q2/2020, and returned to pre-pandemic levels only in Q1/2021. Interpretation The COVID-19 pandemic was associated with a 12-month deceleration of S/V uptake in Germany. Following the release of the ESC HF guidelines, the combined prescription of S/V and SGLT2i was readily adopted. Further efforts are needed to fully implement GDMT and strengthen the resilience of healthcare systems during public health crises. KW - health policy KW - oncology KW - internal medicine KW - heart failure KW - COVID-19 KW - sacubitril-valsartan KW - sodium-glucose co-transporter-2 inhibitors KW - guideline-directed medical therapy KW - evidence-based practice KW - real-world Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350510 SN - 2666-7762 VL - 35 ER - TY - JOUR A1 - Rebs, Sabine A1 - Streckfuss-Bömeke, Katrin T1 - How can we use stem cell-derived cardiomyocytes to understand the involvement of energetic metabolism in alterations of cardiac function? JF - Frontiers in Molecular Medicine N2 - Mutations in the mitochondrial-DNA or mitochondria related nuclear-encoded-DNA lead to various multisystemic disorders collectively termed mitochondrial diseases. One in three cases of mitochondrial disease affects the heart muscle, which is called mitochondrial cardiomyopathy (MCM) and is associated with hypertrophic, dilated, and noncompact cardiomyopathy. The heart is an organ with high energy demand, and mitochondria occupy 30%–40% of its cardiomyocyte-cell volume. Mitochondrial dysfunction leads to energy depletion and has detrimental effects on cardiac performance. However, disease development and progression in the context of mitochondrial and nuclear DNA mutations, remains incompletely understood. The system of induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CM) is an excellent platform to study MCM since the unique genetic identity to their donors enables a robust recapitulation of the predicted phenotypes in a dish on a patient-specific level. Here, we focus on recent insights into MCM studied by patient-specific iPSC-CM and further discuss research gaps and advances in metabolic maturation of iPSC-CM, which is crucial for the study of mitochondrial dysfunction and to develop novel therapeutic strategies. KW - mitochondrial cardiomyopathy KW - iPSC-cardiomyocytes KW - maturation strategies KW - Barth syndrome KW - Friedreich’s ataxia KW - lysosomal storage disorders Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-327344 VL - 3 ER - TY - JOUR A1 - Göpfert, Dennis A1 - Traub, Jan A1 - Sell, Roxane A1 - Homola, György A. A1 - Vogt, Marius A1 - Pham, Mirko A1 - Frantz, Stefan A1 - Störk, Stefan A1 - Stoll, Guido A1 - Frey, Anna T1 - Profiles of cognitive impairment in chronic heart failure—A cluster analytic approach JF - Frontiers in Human Neuroscience N2 - Background Cognitive impairment is a major comorbidity in patients with chronic heart failure (HF) with a wide range of phenotypes. In this study, we aimed to identify and compare different clusters of cognitive deficits. Methods The prospective cohort study “Cognition.Matters-HF” recruited 147 chronic HF patients (aged 64.5 ± 10.8 years; 16.2% female) of any etiology. All patients underwent extensive neuropsychological testing. We performed a hierarchical cluster analysis of the cognitive domains, such as intensity of attention, visual/verbal memory, and executive function. Generated clusters were compared exploratively with respect to the results of cardiological, neurological, and neuroradiological examinations without correction for multiple testing. Results Dendrogram and the scree plot suggested three distinct cognitive profiles: In the first cluster, 42 patients (28.6%) performed without any deficits in all domains. Exclusively, the intensity of attention deficits was seen in the second cluster, including 55 patients (37.4%). A third cluster with 50 patients (34.0%) was characterized by deficits in all cognitive domains. Age (p = 0.163) and typical clinical markers of chronic HF, such as ejection fraction (p = 0.222), 6-min walking test distance (p = 0.138), NT-proBNP (p = 0.364), and New York Heart Association class (p = 0.868) did not differ between clusters. However, we observed that women (p = 0.012) and patients with previous cardiac valve surgery (p = 0.005) prevailed in the “global deficits” cluster and the “no deficits” group had a lower prevalence of underlying arterial hypertension (p = 0.029). Total brain volume (p = 0.017) was smaller in the global deficit cluster, and serum levels of glial fibrillary acidic protein were increased (p = 0.048). Conclusion Apart from cognitively healthy and globally impaired HF patients, we identified a group with deficits only in the intensity of attention. Women and patients with previous cardiac valve surgery are at risk for global cognitive impairment when suffering HF and could benefit from special multimodal treatment addressing the psychosocial condition. KW - chronic heart failure KW - cluster analysis KW - cognitive impairment KW - intensity of attention KW - glial fibrillary acidic protein Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313429 VL - 17 ER - TY - JOUR A1 - Bellinger, Daniel A1 - Wehrmann, Kristin A1 - Rohde, Anna A1 - Schuppert, Maria A1 - Störk, Stefan A1 - Flohr-Jost, Michael A1 - Gall, Dominik A1 - Pauli, Paul A1 - Deckert, Jürgen A1 - Herrmann, Martin J. A1 - Erhardt-Lehmann, Angelika T1 - The application of virtual reality exposure versus relaxation training in music performance anxiety: a randomized controlled study JF - BMC Psychiatry N2 - Background Performance anxiety is the most frequently reported anxiety disorder among professional musicians. Typical symptoms are - on a physical level - the consequences of an increase in sympathetic tone with cardiac stress, such as acceleration of heartbeat, increase in blood pressure, increased respiratory rate and tremor up to nausea or flush reactions. These symptoms can cause emotional distress, a reduced musical and artistical performance up to an impaired functioning. While anxiety disorders are preferably treated using cognitive-behavioral therapy with exposure, this approach is rather difficult for treating music performance anxiety since the presence of a public or professional jury is required and not easily available. The use of virtual reality (VR) could therefore display an alternative. So far, no therapy studies on music performance anxiety applying virtual reality exposure therapy have investigated the therapy outcome including cardiovascular changes as outcome parameters. Methods This mono-center, prospective, randomized and controlled clinical trial has a pre-post design with a follow-up period of 6 months. 46 professional and semi-professional musicians will be recruited and allocated randomly to an VR exposure group or a control group receiving progressive muscle relaxation training. Both groups will be treated over 4 single sessions. Music performance anxiety will be diagnosed based on a clinical interview using ICD-10 and DSM-5 criteria for specific phobia or social anxiety. A behavioral assessment test is conducted three times (pre, post, follow-up) in VR through an audition in a concert hall. Primary outcomes are the changes in music performance anxiety measured by the German Bühnenangstfragebogen and the cardiovascular reactivity reflected by heart rate variability (HRV). Secondary outcomes are changes in blood pressure, stress parameters such as cortisol in the blood and saliva, neuropeptides, and DNA-methylation. Discussion The trial investigates the effect of VR exposure in musicians with performance anxiety compared to a relaxation technique on anxiety symptoms and corresponding cardiovascular parameters. We expect a reduction of anxiety but also a consecutive improvement of HRV with cardiovascular protective effects. Trial registration This study was registered on clinicaltrials.gov. (ClinicalTrials.gov Number: NCT05735860) KW - music performance anxiety KW - virtual reality exposure therapy KW - progressive muscle relaxation KW - heart rate variability Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357833 VL - 23 ER - TY - JOUR A1 - Güder, Gülmisal A1 - Rein, Eva von A1 - Flohr, Thomas A1 - Weismann, Dirk A1 - Schmitt, Dominik A1 - Störk, Stefan A1 - Frantz, Stefan A1 - Kratzer, Vincent A1 - Kendi, Christian T1 - Motion detectors as additional monitoring devices in the intensive care unit — a proof-of-concept study JF - Applied Sciences N2 - Background: Monitoring the vital signs of delirious patients in an intensive care unit (ICU) is challenging, as they might (un-)intentionally remove devices attached to their bodies. In mock-up scenarios, we systematically assessed whether a motion detector (MD) attached to the bed may help in identifying emergencies. Methods: We recruited 15 employees of the ICU and equipped an ICU bed with an MD (IRON Software GmbH, Grünwald, Germany). Participants were asked to replay 22 mock-up scenes of one-minute duration each: 12 scenes with movements and 10 without movements, of which 5 were emergency scenes (“lying dead-still, with no or very shallow breathing”). Blinded recordings were presented to an evaluation panel consisting of an experienced ICU nurse and a physician, who was asked to assess and rate the presence of motions. Results: Fifteen participants (nine women; 173 ± 7.0 cm; 78 ± 19 kg) joined the study. In total, 286 out of 330 scenes (86.7%) were rated correctly. Ratings were false negative (FN: “no movements detected, but recorded”) in 7 out of 180 motion scenes (3.9%). Ratings were false positive (FP: “movements detected, but not recorded”) in 37 out of 150 scenes (24.7%), more often in men than women (26 out of 60 vs. 11 out of 90, respectively; p < 0.001). Of note, in 16 of these 37 FP-rated scenes, a vibrating mobile phone was identified as a potential confounder. The emergency scenes were correctly rated in 64 of the 75 runs (85.3%); 10 of the 11 FP-rated scenes occurred in male subjects. Conclusions: The MD allowed for identifying motions of test subjects with high sensitivity (96%) and acceptable specificity (75%). Accuracy might increase further if activities are recorded continuously under real-world conditions. KW - motion detector KW - noncontact monitoring KW - Internet of Things devices Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-362404 SN - 2076-3417 VL - 13 IS - 16 ER - TY - THES A1 - Göttler, David Johannes T1 - Smoking cessation patterns in patients with established coronary heart disease T1 - Entwicklung des Rauchverhaltens bei Patienten*innen mit Koronarer Herzerkrankung N2 - Background Tobacco smoking is accountable for more than one in ten deaths in patients with cardiovascular disease. Thus, smoking cessation has a high priority in secondary prevention of coronary heart disease (CHD). The present study meant to assess smoking cessation patterns, identify parameters associated with smoking cessation and investigate personal reasons to change or maintain smoking habits in patients with established CHD. Methods Quality of CHD care was surveyed in 24 European countries in 2012/13 by the fourth European Survey of Cardiovascular Disease Prevention and Diabetes. Patients 18 to 79 years of age at the date of the CHD index event hospitalized due to first or recurrent diagnosis of coronary artery bypass graft, percutaneous coronary intervention, acute myocardial infarction or acute myocardial ischemia without infarction (troponin negative) were included. Smoking status and clinical parameters were iteratively obtained a) at the cardiovascular disease index event by medical record abstraction, b) during a face-to-face interview 6 to 36 months after the index event (i.e. baseline visit) and c) by telephone-based follow-up interview two years after the baseline visit. Parameters associated with smoking status at the time of follow-up interview were identified by logistic regression analysis. Personal reasons to change or maintain smoking habits were assessed in a qualitative interview and analyzed by qualitative content analysis. Results One hundred and four of 469 (22.2%) participants had been classified current smokers at the index event and were available for follow-up interview. After a median observation period of 3.5 years (quartiles 3.0, 4.1), 65 of 104 participants (62.5%) were classified quitters at the time of follow-up interview. There was a tendency of diabetes being more prevalent in quitters vs non-quitters (37.5% vs 20.5%, p=0.07). Higher education level (15.4% vs 33.3%, p=0.03) and depressed mood (17.2% vs 35.9%, p=0.03) were less frequent in quitters vs non-quitters. Quitters more frequently participated in cardiac rehabilitation programs (83.1% vs 48.7%, p<0.001). Cardiac rehabilitation appeared as factor associated with smoking cessation in multivariable logistic regression analysis (OR 5.19, 95%CI 1.87 to 14.46, p=0.002). Persistent smokers at telephone-based follow-up interview reported on addiction as wells as relaxation and pleasure as reasons to continue their habit. Those current and former smokers who relapsed at least once after a quitting attempt, stated future health hazards as their main reason to undertake quitting attempts. Prevalent factors leading to relapse were influence by their social network and stress. Successful quitters at follow-up interview referred to smoking-related harm done to their health having had been their major reason to quit. Interpretation Participating in a cardiac rehabilitation program was strongly associated with smoking cessation after a cardiovascular disease index event. Smoking cessation counseling and relapse prophylaxis may include alternatives for the pleasant aspects of smoking and incorporate effective strategies to resist relapse. N2 - Einleitung Bei Patienten*innen mit kardiovaskulären Erkrankungen ist mehr als einer von zehn Todesfällen auf Tabakrauchen zurückzuführen. Daher ist Rauchentwöhnung ein wichtiger Aspekt der Sekundärprävention der koronaren Herzerkrankung. In dieser Studie wurde der Verlauf des Rauchverhalten von Patienten*innen mit bekannter koronarer Herzerkrankung erfasst, Einflussfaktoren für Tabakabstinenz untersucht und die persönlichen Beweggründe zur Änderung oder Beibehaltung des Rauchverhaltens analysiert. Methoden Die Güte der Behandlung der koronaren Herzerkrankung wurde in 24 Europäischen Staaten in den Jahren 2012/13 im Rahmen des vierten European Survey of Cardiovascular Disease Prevention and Diabetes erfasst. Eingeschlossen wurden Patienten*innen zwischen 18 und 79 Jahren zum Zeitpunkt des kardiovaskulären Indexereignisses. Als kardiovaskuläres Indexereignis wurde eine stationäre Behandlung aufgrund der folgenden Erst- oder Rezidiv Diagnosen definiert: Koronararterien-Bypass, perkutane Koronarintervention, akuter Myokardinfarkt und akute myokardiale Ischämie ohne Infarkt (Troponin negativ). Rauchgewohnheiten und klinische Parameter wurden bei Patienten*innen im Studienverlauf wiederholt erhoben: a) Anhand der Behandlungsunterlagen während des kardiovaskulären Indexereignis, b) während eines persönlichen Interviews 6-36 Monate nach dem Indexereignis (i.e. Baseline Untersuchung) und c) im Rahmen eines telefonischen Follow-Up Interviews zwei Jahre nach der Baseline Untersuchung. Einflussfaktoren für Tabakabstinenz zum Zeitpunkt des telefonischen Follow-Up Interviews wurden über logistische Regressionsmodelle ermittelt. Die persönlichen Beweggründe das individuelle Rauchverhalten beizubehalten oder zu ändern wurden im Rahmen eines qualitativen Interviews erhoben und mithilfe der qualitativen Inhaltsanalyse ausgewertet. Ergebnisse 104 von 469 (22,2%) Studienteilnehmer*innen wurden zum Zeitpunkt des Indexereignisses als Raucher*innen klassifiziert und nahmen an dem Follow-Up Interview teil. 65 von 104 (62,5%) dieser Raucher*innen gaben median 3,5 Jahre (Quartilen 3,0; 4,1) nach dem kardiovaskulären Indexereignis an mit dem Rauchen aufgehört zu haben. Es gab eine Tendenz zu höheren Prävalenzen von Diabetes bei nicht mehr Rauchenden im Vergleich zu weiterhin Rauchenden (37,5% vs. 20,5%; p=0,07). Höherer Bildungsgrad (15,4% vs. 33,3%; p=0,03) und Symptome einer depressiven Verstimmung (17,2% vs. 35,9%; p=0,03) waren bei nicht mehr Rauchenden seltener als bei weiterhin Rauchenden. Nicht mehr Rauchende nahmen überdurchschnittlich häufig an einem kardialen Rehabilitationsprogramm teil (83,1% vs. 48,7%; p<0,001). Kardiale Rehabilitation war ein signifikanter Einflussfaktor auf Tabakabstinenz in der multivariaten logistischen Regression (OR 5,19; 95% Konfidenzintervall 1,87-14,46; p=0,002). Weiterhin Rauchende berichteten von Sucht sowie von Entspannung und Freude als Gründe nach wie vor zu rauchen. Diejenigen aktiven und ehemaligen Raucher*innen, welche mindestens einmal einen Rückfall nach einem Aufhörversuch erlebten, gaben Sorgen vor den gesundheitlichen Folgeschäden des Rauchens als Hauptgrund für Aufhörversuche an. Ihr soziales Umfeld und Stress waren häufige Gründe für Rückfälle. Ehemalige Raucher*innen berichteten von bereits eingetretenen gesundheitlichen Problemen, welche sie mit dem Rauchen in Verbindung gebracht hatten, als treibende Kräfte um nachhaltig abstinent sein zu können. Interpretation Die Teilnahme an einem kardialen Rehabilitationsprogramm war bei Patienten*innen mit kardiovaskulärer Erkrankung deutlich mit dem Verzicht auf Tabakrauchen assoziiert. Beratung zur Raucherentwöhnung und Rückfallprophylaxe könnten Alternativen für die, in der subjektiven Wahrnehmung, angenehmen Aspekte des Rauchens bieten und effektive Strategien zur Vermeidung von Rückfällen berücksichtigen. KW - Tabakkonsum KW - Koronare Herzkrankheit KW - Tobacco smoking KW - Coronary heart disease Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223955 ER - TY - JOUR A1 - Gram, Maximilian A1 - Gensler, Daniel A1 - Albertova, Petra A1 - Gutjahr, Fabian Tobias A1 - Lau, Kolja A1 - Arias-Loza, Paula-Anahi A1 - Jakob, Peter Michael A1 - Nordbeck, Peter T1 - Quantification correction for free-breathing myocardial T1ρ mapping in mice using a recursively derived description of a T\(_{1p}\)\(^{*}\) relaxation pathway JF - Journal of Cardiovascular Magnetic Resonance N2 - Background Fast and accurate T1ρ mapping in myocardium is still a major challenge, particularly in small animal models. The complex sequence design owing to electrocardiogram and respiratory gating leads to quantification errors in in vivo experiments, due to variations of the T\(_{1p}\) relaxation pathway. In this study, we present an improved quantification method for T\(_{1p}\) using a newly derived formalism of a T\(_{1p}\)\(^{*}\) relaxation pathway. Methods The new signal equation was derived by solving a recursion problem for spin-lock prepared fast gradient echo readouts. Based on Bloch simulations, we compared quantification errors using the common monoexponential model and our corrected model. The method was validated in phantom experiments and tested in vivo for myocardial T\(_{1p}\) mapping in mice. Here, the impact of the breath dependent spin recovery time T\(_{rec}\) on the quantification results was examined in detail. Results Simulations indicate that a correction is necessary, since systematically underestimated values are measured under in vivo conditions. In the phantom study, the mean quantification error could be reduced from − 7.4% to − 0.97%. In vivo, a correlation of uncorrected T\(_{1p}\) with the respiratory cycle was observed. Using the newly derived correction method, this correlation was significantly reduced from r = 0.708 (p < 0.001) to r = 0.204 and the standard deviation of left ventricular T\(_{1p}\) values in different animals was reduced by at least 39%. Conclusion The suggested quantification formalism enables fast and precise myocardial T\(_{1p}\) quantification for small animals during free breathing and can improve the comparability of study results. Our new technique offers a reasonable tool for assessing myocardial diseases, since pathologies that cause a change in heart or breathing rates do not lead to systematic misinterpretations. Besides, the derived signal equation can be used for sequence optimization or for subsequent correction of prior study results. KW - T1rho KW - radial KW - cardiac KW - correction KW - quantitative MRI KW - mapping KW - spin-lock KW - T1ρ Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300491 VL - 24 IS - 1 ER - TY - JOUR A1 - Wech, Tobias A1 - Ankenbrand, Markus Johannes A1 - Bley, Thorsten Alexander A1 - Heidenreich, Julius Frederik T1 - A data-driven semantic segmentation model for direct cardiac functional analysis based on undersampled radial MR cine series JF - Magnetic Resonance in Medicine N2 - Purpose Image acquisition and subsequent manual analysis of cardiac cine MRI is time-consuming. The purpose of this study was to train and evaluate a 3D artificial neural network for semantic segmentation of radially undersampled cardiac MRI to accelerate both scan time and postprocessing. Methods A database of Cartesian short-axis MR images of the heart (148,500 images, 484 examinations) was assembled from an openly accessible database and radial undersampling was simulated. A 3D U-Net architecture was pretrained for segmentation of undersampled spatiotemporal cine MRI. Transfer learning was then performed using samples from a second database, comprising 108 non-Cartesian radial cine series of the midventricular myocardium to optimize the performance for authentic data. The performance was evaluated for different levels of undersampling by the Dice similarity coefficient (DSC) with respect to reference labels, as well as by deriving ventricular volumes and myocardial masses. Results Without transfer learning, the pretrained model performed moderately on true radial data [maximum number of projections tested, P = 196; DSC = 0.87 (left ventricle), DSC = 0.76 (myocardium), and DSC =0.64 (right ventricle)]. After transfer learning with authentic data, the predictions achieved human level even for high undersampling rates (P = 33, DSC = 0.95, 0.87, and 0.93) without significant difference compared with segmentations derived from fully sampled data. Conclusion A 3D U-Net architecture can be used for semantic segmentation of radially undersampled cine acquisitions, achieving a performance comparable with human experts in fully sampled data. This approach can jointly accelerate time-consuming cine image acquisition and cumbersome manual image analysis. KW - undersampling KW - cardiovascular magnetic resonance (CMR) KW - deep learning KW - radial KW - semantic segmentation Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-257616 VL - 87 IS - 2 ER - TY - JOUR A1 - Kayvanpour, Elham A1 - Wisdom, Michael A1 - Lackner, Maximilian K. A1 - Sedaghat-Hamedani, Farbod A1 - Boeckel, Jes-Niels A1 - Müller, Marion A1 - Eghbalian, Rose A1 - Dudek, Jan A1 - Doroudgar, Shirin A1 - Maack, Christoph A1 - Frey, Norbert A1 - Meder, Benjamin T1 - VARS2 depletion leads to activation of the integrated stress response and disruptions in mitochondrial fatty acid oxidation JF - International Journal of Molecular Sciences N2 - Mutations in mitochondrial aminoacyl-tRNA synthetases (mtARSs) have been reported in patients with mitochondriopathies: most commonly encephalopathy, but also cardiomyopathy. Through a GWAS, we showed possible associations between mitochondrial valyl-tRNA synthetase (VARS2) dysregulations and non-ischemic cardiomyopathy. We aimed to investigate the possible consequences of VARS2 depletion in zebrafish and cultured HEK293A cells. Transient VARS2 loss-of-function was induced in zebrafish embryos using Morpholinos. The enzymatic activity of VARS2 was measured in VARS2-depleted cells via northern blot. Heterozygous VARS2 knockout was established in HEK293A cells using CRISPR/Cas9 technology. BN-PAGE and SDS-PAGE were used to investigate electron transport chain (ETC) complexes, and the oxygen consumption rate and extracellular acidification rate were measured using a Seahorse XFe96 Analyzer. The activation of the integrated stress response (ISR) and possible disruptions in mitochondrial fatty acid oxidation (FAO) were explored using RT-qPCR and western blot. Zebrafish embryos with transient VARS2 loss-of-function showed features of heart failure as well as indications of CNS and skeletal muscle involvements. The enzymatic activity of VARS2 was significantly reduced in VARS2-depleted cells. Heterozygous VARS2-knockout cells showed a rearrangement of ETC complexes in favor of complexes III\(_2\), III\(_2\) + IV, and supercomplexes without significant respiratory chain deficiencies. These cells also showed the enhanced activation of the ISR, as indicated by increased eIF-2α phosphorylation and a significant increase in the transcript levels of ATF4, ATF5, and DDIT3 (CHOP), as well as disruptions in FAO. The activation of the ISR and disruptions in mitochondrial FAO may underlie the adaptive changes in VARS2-depleted cells. KW - VARS2 KW - heart failure KW - integrated stress response KW - mitochondrial FAO Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284590 SN - 1422-0067 VL - 23 IS - 13 ER - TY - JOUR A1 - Ghafoor, Hina A1 - Nordbeck, Peter A1 - Ritter, Oliver A1 - Pauli, Paul A1 - Schulz, Stefan M. T1 - Can Religiosity and Social Support Explain Effects of Trait Emotional Intelligence on Health-Related Quality of Life: A Cross-Cultural Study JF - Journal of Religion and Health N2 - Religion and social support along with trait emotional intelligence (EI) help individuals to reduce stress caused by difficult situations. Their implications may vary across cultures in reference to predicting health-related quality of life (HRQoL). A convenience sample of N = 200 chronic heart failure (CHF) patients was recruited at cardiology centers in Germany (n = 100) and Pakistan (n = 100). Results indicated that trait-EI predicted better mental component of HRQoL in Pakistani and German CHF patients. Friends as social support appeared relevant for German patients only. Qualitative data indicate an internal locus of control in German as compared to Pakistani patients. Strengthening the beneficial role of social support in Pakistani patients is one example of how the current findings may inspire culture-specific treatment to empower patients dealing with the detrimental effects of CHF. KW - cross-cultural comparison KW - chronic heart failure KW - religion KW - social support KW - trait emotional intelligence KW - health-related quality of life Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232823 SN - 0022-4197 VL - 61 IS - 1 ER - TY - THES A1 - Wissel, Stephanie T1 - Stellenwert der kognitiven Leistungsfähigkeit für die generische und krankheitsspezifische Lebensqualität bei chronischer Herzinsuffizienz T1 - Importance of cognitive performance for generic and disease-specific quality of life in chronic heart failure N2 - Cognitive impairment is highly prevalent in patients with chronic heart failure, but little is known about the health-related quality of life (HRQL) of this special patient group. We aimed to examine whether cognitive impairment is associated with HRQL in heart failure patients and hypothesized that cognitive impairment would negatively impact HRQL. We examined the HRQL of 148 patients of the Cognition.Matters-HF study with chronic heart failure and objectified cognitive impairment ranging from no to severe deficits. With the exception of the self-efficacy scale of the KCCQ, cognitive impairment was not associated with lower health-related quality of life in heart failure patients. The association of self-efficacy with severity of cognitive impairment remained significant after adjustment for duration and severity of heart failure, age, and sex (p<0.001). The self-efficacy scale gives information about patients’ ability to prevent acute heart failure decompensations and could become a promising tool to detect individuals who are unable to adhere to a proper heart failure treatment regimen and manage arising complications. These patients may benefit from enhanced care, e.g. in the frame of a heart failure nurse led disease-management program. N2 - Kognitive Beeinträchtigungen sind bei Patient*innen mit chronischer Herzinsuffizienz weit verbreitet. Auswertungen der Beobachtungsstudie „Cognition.Matters-HF“ konnten belegen, dass Patient*innen mit einer Herzschwäche häufig Gedächtnisstörungen und Aufmerksamkeitsdefizite aufweisen. Die Evidenz für einen Zusammenhang zwischen Kognition und Lebensqualität bei Herzinsuffizienz ist jedoch spärlich. Unser Ziel war es zu untersuchen, ob kognitive Einschränkungen Auswirkungen auf die Lebensqualität (HRQL) von Herzinsuffizienzpatient*innen haben. Anhand der Cognition.Matters-HF Kohorte untersuchten wir die HRQL von 148 Patient*innen mit chronischer Herzinsuffizienz und objektivierten kognitiven Beeinträchtigungen, die von keinen bis hin zu schweren Defiziten reichten. Die Lebensqualität der Teilnehmer*innen wurde über die beiden Selbstbeurteilungsfragebögen, Short Form-36 (SF-36) und Kansas City Cardiomyopathy Questionnaire (KCCQ), erfasst. Mit Ausnahme der Selbstwirksamkeitsskala des KCCQ war der Schweregrad der kognitiven Beeinträchtigung nicht mit Einschränkungen in der Lebensqualität bei Patient*innen mit chronischer Herzinsuffizienz verbunden. Der Zusammenhang zwischen Selbstwirksamkeit und Schweregrad der kognitiven Beeinträchtigung blieb auch nach Anpassung für Dauer und Schweregrad der Herzinsuffizienz, Alter und Geschlecht der Teilnehmer signifikant bestehen (p<0,001). Die Selbstwirksamkeitsskala stellt ein vielversprechendes Instrument dar, um Personen zu identifizieren, die nicht in der Lage sind, sich an ein empfohlenes, leitliniengerechtes Behandlungsschema für Herzinsuffizienz zu halten. Diese Patient*innen könnten von einer intensiveren Versorgung, z.B. im Rahmen eines von einer speziell geschulten Herzinsuffizienz-Schwester geleiteten Versorgungsprogramms, deutlich profitieren. KW - Chronische Herzinsuffizienz KW - Quality of life KW - Heart failure KW - Self-efficacy KW - Versorgungsforschung KW - Herzinsuffizienz KW - Cognitive impairment KW - Kognitive Defizite KW - Lebensqualität KW - Selbstwirksamkeit KW - Versorgungsprogramm Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-287853 ER - TY - JOUR A1 - Montellano, Felipe A. A1 - Kluter, Elisabeth J. A1 - Rücker, Viktoria A1 - Ungethüm, Kathrin A1 - Mackenrodt, Daniel A1 - Wiedmann, Silke A1 - Dege, Tassilo A1 - Quilitzsch, Anika A1 - Morbach, Caroline A1 - Frantz, Stefan A1 - Störk, Stefan A1 - Haeusler, Karl Georg A1 - Kleinschnitz, Christoph A1 - Heuschmann, Peter U. T1 - Cardiac dysfunction and high-sensitive C-reactive protein are associated with troponin T elevation in ischemic stroke: insights from the SICFAIL study JF - BMC Neurology N2 - Background Troponin elevation is common in ischemic stroke (IS) patients. The pathomechanisms involved are incompletely understood and comprise coronary and non-coronary causes, e.g. autonomic dysfunction. We investigated determinants of troponin elevation in acute IS patients including markers of autonomic dysfunction, assessed by heart rate variability (HRV) time domain variables. Methods Data were collected within the Stroke Induced Cardiac FAILure (SICFAIL) cohort study. IS patients admitted to the Department of Neurology, Würzburg University Hospital, underwent baseline investigation including cardiac history, physical examination, echocardiography, and blood sampling. Four HRV time domain variables were calculated in patients undergoing electrocardiographic Holter monitoring. Multivariable logistic regression with corresponding odds ratios (OR) and 95% confidence intervals (CI) was used to investigate the determinants of high-sensitive troponin T (hs-TnT) levels ≥14 ng/L. Results We report results from 543 IS patients recruited between 01/2014–02/2017. Of those, 203 (37%) had hs-TnT ≥14 ng/L, which was independently associated with older age (OR per year 1.05; 95% CI 1.02–1.08), male sex (OR 2.65; 95% CI 1.54–4.58), decreasing estimated glomerular filtration rate (OR per 10 mL/min/1.73 m2 0.71; 95% CI 0.61–0.84), systolic dysfunction (OR 2.79; 95% CI 1.22–6.37), diastolic dysfunction (OR 2.29; 95% CI 1.29–4.02), atrial fibrillation (OR 2.30; 95% CI 1.25–4.23), and increasing levels of C-reactive protein (OR 1.48 per log unit; 95% CI 1.22–1.79). We did not identify an independent association of troponin elevation with the investigated HRV variables. Conclusion Cardiac dysfunction and elevated C-reactive protein, but not a reduced HRV as surrogate of autonomic dysfunction, were associated with increased hs-TnT levels in IS patients independent of established cardiovascular risk factors. KW - echocardiography KW - ischemic stroke KW - troponin KW - heart failure KW - biomarkers Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300119 VL - 22 IS - 1 ER - TY - JOUR A1 - Gram, Maximilian A1 - Gensler, Daniel A1 - Winter, Patrick A1 - Seethaler, Michael A1 - Arias-Loza, Paula Anahi A1 - Oberberger, Johannes A1 - Jakob, Peter Michael A1 - Nordbeck, Peter T1 - Fast myocardial T\(_{1P}\) mapping in mice using k-space weighted image contrast and a Bloch simulation-optimized radial sampling pattern JF - Magnetic Resonance Materials in Physics, Biology and Medicine N2 - Purpose T\(_{1P}\) dispersion quantification can potentially be used as a cardiac magnetic resonance index for sensitive detection of myocardial fibrosis without the need of contrast agents. However, dispersion quantification is still a major challenge, because T\(_{1P}\) mapping for different spin lock amplitudes is a very time consuming process. This study aims to develop a fast and accurate T\(_{1P}\) mapping sequence, which paves the way to cardiac T1ρ dispersion quantification within the limited measurement time of an in vivo study in small animals. Methods A radial spin lock sequence was developed using a Bloch simulation-optimized sampling pattern and a view-sharing method for image reconstruction. For validation, phantom measurements with a conventional sampling pattern and a gold standard sequence were compared to examine T\(_{1P}\) quantification accuracy. The in vivo validation of T\(_{1P}\) mapping was performed in N = 10 mice and in a reproduction study in a single animal, in which ten maps were acquired in direct succession. Finally, the feasibility of myocardial dispersion quantification was tested in one animal. Results The Bloch simulation-based sampling shows considerably higher image quality as well as improved T\(_{1P}\) quantification accuracy (+ 56%) and precision (+ 49%) compared to conventional sampling. Compared to the gold standard sequence, a mean deviation of - 0.46 ± 1.84% was observed. The in vivo measurements proved high reproducibility of myocardial T\(_{1P}\) mapping. The mean T\(_{1P}\) in the left ventricle was 39.5 ± 1.2 ms for different animals and the maximum deviation was 2.1% in the successive measurements. The myocardial T\(_{1P}\) dispersion slope, which was measured for the first time in one animal, could be determined to be 4.76 ± 0.23 ms/kHz. Conclusion This new and fast T\(_{1P}\) quantification technique enables high-resolution myocardial T\(_{1P}\) mapping and even dispersion quantification within the limited time of an in vivo study and could, therefore, be a reliable tool for improved tissue characterization. KW - TT\(_{1rho}\) mapping KW - small animal KW - KWIC KW - radial KW - cardiac KW - mice KW - spin lock KW - T\(_{1P}\) dispersion KW - T\(_{1P}\) mapping Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-268903 SN - 1352-8661 VL - 35 IS - 2 ER - TY - JOUR A1 - Güder, Gülmisal A1 - Wilkesmann, Joana A1 - Scholz, Nina A1 - Leppich, Robert A1 - Düking, Peter A1 - Sperlich, Billy A1 - Rost, Christian A1 - Frantz, Stefan A1 - Morbach, Caroline A1 - Sahiti, Floran A1 - Stefenelli, Ulrich A1 - Breunig, Margret A1 - Störk, Stefan T1 - Establishing a cardiac training group for patients with heart failure: the "HIP-in-Würzburg" study JF - Clinical Research in Cardiology N2 - Background Exercise training in heart failure (HF) is recommended but not routinely offered, because of logistic and safety-related reasons. In 2020, the German Society for Prevention&Rehabilitation and the German Society for Cardiology requested establishing dedicated ""HF training groups."" Here, we aimed to implement and evaluate the feasibility and safety of one of the first HF training groups in Germany. Methods Twelve patients (three women) with symptomatic HF (NYHA class II/III) and an ejection fraction ≤ 45% participated and were offered weekly, physician-supervised exercise training for 1 year. Patients received a wrist-worn pedometer (M430 Polar) and underwent the following assessments at baseline and after 4, 8 and 12 months: cardiopulmonary exercise test, 6-min walk test, echocardiography (blinded reading), and quality of life assessment (Kansas City Cardiomyopathy Questionnaire, KCCQ). Results All patients (median age [quartiles] 64 [49; 64] years) completed the study and participated in 76% of the offered 36 training sessions. The pedometer was worn ≥ 1000 min per day over 86% of the time. No cardiovascular events occurred during training. Across 12 months, NT-proBNP dropped from 986 pg/ml [455; 1937] to 483 pg/ml [247; 2322], and LVEF increased from 36% [29;41] to 41% [32;46]%, (p for trend = 0.01). We observed no changes in exercise capacity except for a subtle increase in peak VO2% predicted, from 66.5 [49; 77] to 67 [52; 78]; p for trend = 0.03. The physical function and social limitation domains of the KCCQ improved from 60 [54; 82] to 71 [58; 95, and from 63 [39; 83] to 78 [64; 92]; p for trend = 0.04 and = 0.01, respectively. Positive trends were further seen for the clinical and overall summary scores. Conclusion This pilot study showed that the implementation of a supervised HF-exercise program is feasible, safe, and has the potential to improve both quality of life and surrogate markers of HF severity. This first exercise experiment should facilitate the design of risk-adopted training programs for patients with HF. KW - m exercise training KW - heart failure KW - cardiac training group KW - heart failure training group Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-266678 SN - 1861-0692 VL - 111 ER - TY - THES A1 - Bausch, Severin Ferdinand Andreas T1 - Effekt von Spironolacton auf die vaskuläre Funktion bei Hämodialysepatienten T1 - Effect of spironolactone on vascular function in hemodialysis patients N2 - Chronische Nierenerkrankungen gehen mit einer erhöhten kardiovaskulären Morbidität und Mortalität einher. Charakteristisch für chronische Nierenerkrankungen, insbesondere im Stadium der Dialysepflichtigkeit, ist eine ausgeprägte Voralterung der Gefäße. Die Vorgänge, die den beschleunigten vaskulären Alterungsprozessen zugrunde liegen, umfassen ein Zusammenspiel aus einem gestörten Mineralstoffwechsel, der Akkumulation urämischer Toxine und chronischer Inflammation. Das Renin-Angiotensin-Aldosteron-System (RAAS) nimmt dabei eine zentrale Rolle ein. Eine gesteigerte Aktivität des RAAS ist ein Merkmal von kardiorenalen Syndromen und moduliert jenseits seiner Effekte auf den Blutdruck vaskuläre Entzündungs- und Remodelingprozesse. Durch das vaskuläre Altern kommt es zur Abnahme arterieller Compliance und zur Erhöhung der Pulswellengeschwindigkeit (PWV). Dadurch erhöht sich das Risiko für Endorganschäden. Die arterielle Gefäßsteifigkeit ist ein unabhängiger Prädiktor für Mortalität bei chronisch-dialysepflichtiger Niereninsuffizienz und eine Reduktion arterieller Rigidität geht mit einem verbesserten Überleben einher. Randomisierte Studien bei Dialysepatienten konnten bislang keinen eindeutigen Nutzen etablierter pharmakologischer Interventionen zur Reduktion des kardiovaskulären Risikos und vaskulärer «Stiffeningprozesse» feststellen. Als ein potentiell wirksamer Therapieansatz werden Mineralokortikoidrezeptorantagonisten (MRA) angesehen. Die vorliegende Arbeit evaluierte im Rahmen der Placebo-kontrollierten, randomisierten «Mineralocorticoid-Receptor Antagonists in End-Stage Renal Disease» (MiREnDa) Studie, ob die tägliche Einnahme von 50 mg Spironolacton über neun Monate einen Effekt auf die vaskuläre Funktion bei Patienten mit dialysepflichtiger chronischer Nierenerkrankung hat. Neben aortaler PWV, Augmentationsindex, zentralem Puls- und Blutdruck wurden zur Evaluation der vaskulären Funktion die Compliance der thorakalen Aorta und der A. carotis communis sowie die Distensibilität der A. carotis communis und die fluss-vermittelte Dilatation der A. brachialis vor Studienbeginn als sekundäre Endpunkte festgelegt. Ein weiterer Aspekt, der evaluiert wurde, war die Frage nach Korrelationen zwischen PWV und Augmentationsindex einerseits und weiteren Parametern vaskulärer Funktion, klinischen Merkmalen und Biomarkern andererseits. Die vorliegende Arbeit versuchte darüber hinaus, klinische Merkmale (Komorbiditäten, Inflammation), die ein Therapieansprechen von MRA potentiell modulieren, zu identifizieren. Das zentrale Ergebnis der Arbeit war, dass eine MRA-Therapie mit 50 mg Spironolacton täglich über neun Monate im untersuchten Kollektiv keinen Effekt auf die vaskuläre Funktion zeigte. N2 - Chronic kidney disease (CKD) is associated with increased cardiovascular (CV) morbidity and mortality. CKD and especially end-stage kidney disease are characterized by pronounced premature vascular aging and arterial stiffness (AS). Several contributors such as a dysregulated mineral metabolism, the accumulation of uremic toxins and chronic inflammation are involved in the process of increasing AS in CKD. The renin-angiotensin-aldosterone system (RAAS) plays a key role in this complex interaction. An overactivity of the RAAS is a hallmark of cardiorenal syndromes and modulates inflammation and remodeling beyond its effects on blood pressure. Declining arterial compliance results in an increase of pulse wave velocity (PWV), which is associated with a higher risk of organ damage. AS is an independent predictor of CV and all-cause mortality in hemodialysis (HD) patients and its reduction is associated with an improved survival. Mineralocorticoid receptor antagonism (MRA) is considered to be a potential beneficial pharmacological intervention to reduce AS and thus CV morbidity and mortality in HD. Randomized controlled trials assessing the effect of MRA on vascular function in HD patients are scarce. The current study was part of the randomized placebo-controlled Mineralocorticoid-Receptor Antagonists in End-Stage Renal Disease (MiREnDa) trial and evaluated the effect of daily oral intake of 50 mg spironolactone for nine months on vascular function. Vascular parameters including aortic PWV and pulse wave analysis (PWA), aortic and carotid compliance, carotid distensibility and brachial flow-mediated dilation were predefined as secondary endpoints. Furthermore, we investigated the associations of PWV and PWA and other parameters of vascular function, clinical features and biomarkers. Finally, we tried to identify factors determining treatment response (such as comorbidities and inflammation) of MRA in HD patients. The main finding of this study was that treatment with 50 mg spironolactone daily for nine months had no effect on vascular function. KW - Hämodialyse KW - Spironolacton KW - Pulswelle KW - Arterielle Gefäßsteifigkeit KW - Vaskuläre Funktion KW - Chronische Nierenerkrankung Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-293479 ER - TY - JOUR A1 - Lorenz, Kristina A1 - Rosner, Marsha Rich T1 - Harnessing RKIP to combat heart disease and cancer JF - Cancers N2 - Cancer and heart disease are leading causes of morbidity and mortality worldwide. These diseases have common risk factors, common molecular signaling pathways that are central to their pathogenesis, and even some disease phenotypes that are interdependent. Thus, a detailed understanding of common regulators is critical for the development of new and synergistic therapeutic strategies. The Raf kinase inhibitory protein (RKIP) is a regulator of the cellular kinome that functions to maintain cellular robustness and prevent the progression of diseases including heart disease and cancer. Two of the key signaling pathways controlled by RKIP are the β-adrenergic receptor (βAR) signaling to protein kinase A (PKA), particularly in the heart, and the MAP kinase cascade Raf/MEK/ERK1/2 that regulates multiple diseases. The goal of this review is to discuss how we can leverage RKIP to suppress cancer without incurring deleterious effects on the heart. Specifically, we discuss: (1) How RKIP functions to either suppress or activate βAR (PKA) and ERK1/2 signaling; (2) How we can prevent cancer-promoting kinase signaling while at the same time avoiding cardiotoxicity. KW - RKIP KW - ERK1/2 KW - PKA KW - βAR KW - heart failure KW - cancer Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262185 SN - 2072-6694 VL - 14 IS - 4 ER - TY - JOUR A1 - Herz, Stefan A1 - Stefanescu, Maria R. A1 - Lohr, David A1 - Vogel, Patrick A1 - Kosmala, Aleksander A1 - Terekhov, Maxim A1 - Weng, Andreas M. A1 - Grunz, Jan-Peter A1 - Bley, Thorsten A. A1 - Schreiber, Laura M. T1 - Effects of image homogeneity on stenosis visualization at 7 T in a coronary artery phantom study: With and without B1-shimming and parallel transmission JF - PloS One N2 - Background To investigate the effects of B\(_1\)-shimming and radiofrequency (RF) parallel transmission (pTX) on the visualization and quantification of the degree of stenosis in a coronary artery phantom using 7 Tesla (7 T) magnetic resonance imaging (MRI). Methods Stenosis phantoms with different grades of stenosis (0%, 20%, 40%, 60%, 80%, and 100%; 5 mm inner vessel diameter) were produced using 3D printing (clear resin). Phantoms were imaged with four different concentrations of diluted Gd-DOTA representing established arterial concentrations after intravenous injection in humans. Samples were centrally positioned in a thorax phantom of 30 cm diameter filled with a custom-made liquid featuring dielectric properties of muscle tissue. MRI was performed on a 7 T whole-body system. 2D-gradient-echo sequences were acquired with an 8-channel transmit 16-channel receive (8 Tx / 16 Rx) cardiac array prototype coil with and without pTX mode. Measurements were compared to those obtained with identical scan parameters using a commercially available 1 Tx / 16 Rx single transmit coil (sTX). To assess reproducibility, measurements (n = 15) were repeated at different horizontal angles with respect to the B0-field. Results B\(_1\)-shimming and pTX markedly improved flip angle homogeneity across the thorax phantom yielding a distinctly increased signal-to-noise ratio (SNR) averaged over a whole slice relative to non-manipulated RF fields. Images without B\(_1\)-shimming showed shading artifacts due to local B\(_1\)\(^+\)-field inhomogeneities, which hampered stenosis quantification in severe cases. In contrast, B\(_1\)-shimming and pTX provided superior image homogeneity. Compared with a conventional sTX coil higher grade stenoses (60% and 80%) were graded significantly (p<0.01) more precise. Mild to moderate grade stenoses did not show significant differences. Overall, SNR was distinctly higher with B\(_1\)-shimming and pTX than with the conventional sTX coil (inside the stenosis phantoms 14%, outside the phantoms 32%). Both full and half concentration (10.2 mM and 5.1 mM) of a conventional Gd-DOTA dose for humans were equally suitable for stenosis evaluation in this phantom study. Conclusions B\(_1\)-shimming and pTX at 7 T can distinctly improve image homogeneity and therefore provide considerably more accurate MR image analysis, which is beneficial for imaging of small vessel structures. KW - stenosis KW - magnetic resonance imaging KW - thorax KW - in vivo imaging KW - coronary arteries KW - image processing KW - 3D printing KW - signal to noise ratio Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300129 VL - 17 IS - 6 ER - TY - THES A1 - Sahiti, Floran T1 - Myocardial Work – Application and Clinical Characterization of a New Echocardiographic Tool T1 - Myocardial Work – Anwendung und klinische Charakterisierung einer neuen Echokardiographie-basierten Methode N2 - 1 Summary Left ventricular (LV) ejection fraction (EF) and global longitudinal strain (GLS) are the most commonly used measures of LV function. Yet, they are highly dependent on loading conditions since higher afterload yields lower systolic deformation and thereby a lower LVEF and GLS – despite presumably unchanged LV myocardial contractile strength. Invasive pressure-volume loop measurements represent the reference standard to assess LV function, also considering loading conditions. However, this procedure cannot be used in serial investigations or large sample populations due to its invasive nature. The novel concept of echocardiography-derived assessment of myocardial work (MyW) is based on LV pressure-strain loops, may be a valuable alternative to overcome these challenges, and may also be used with relative ease in large populations. As MyW also accounts for afterload, it is considered less load-dependent than LVEF and GLS. The current PhD work addresses the application and clinical characterization of MyW, an innovative echocardiographic tool. As the method is new, we focused on four main topics: (a) To establish reference values for MyW indices, i.e., Global Work Index (GWI), Global Constructive Work (GCW), Global Wasted Work (GWW), and Global Work Efficiency (GWE); we addressed a wide age range and evaluated the association of MyW indices with age, sex and other clinical and echocardiography parameters in apparently cardiovascular healthy individuals. (b) To investigate the impact of cardiovascular (CV) risk factors on MyW indices and characterize the severity of subclinical LV deterioration in the general population. (c) To assess the association of the LV geometry, i.e., LV mass and dimensions, with MyW indices. (d) To evaluate in-hospital dynamics of MyW indices in patients hospitalized for acute heart failure (AHF). For the PhD thesis, we could make use of two larger cohorts: The STAAB population-based cohort study prospectively recruited and phenotyped a representative sample (5,000 individuals) of the general population of the City of Würzburg, aged 30-79 years and free from symptomatic heart failure at the time of inclusion. We focused on the first half of the study sample (n=2473 individuals), which fulfilled the anticipated strata regarding age and sex. The Acute Heart Failure (AHF) Registry is a prospective clinical registry recruiting and phenotyping consecutive patients admitted for decompensated AHF to the Department of Medicine I, University Hospital Würzburg, and observing the natural course of the disease. The AHF Registry focuses on the pathophysiological understanding, particularly in relation to the early phase after cardiac decompensation, with the aim to improve diagnosis and better-tailored treatment of patients with AHF. For the current study, we concentrated on patients who provided pairs of echocardiograms acquired early after index hospital admission and prior to discharge. The main findings of the PhD thesis were: From the STAAB cohort study, we determined the feasibility of large-scale MyW derivation and the accuracy of the method. We established reference values for MyW indices based on 779 analyzable, apparently healthy participants (mean age 49 ± 10 years, 59% women), who were in sinus rhythm, free from CV risk factors or CV disease, and had no significant LV valve disease. Apart from GWI, there were no associations of other MyW indices with sex. Further, we found a disparate association with age, where MyW showed stable values until the age of 45 years, with an upward shift occurring beyond the age of 45. A higher age decade was associated with higher GWW and lower GWE, respectively. MyW indices only correlated weakly with common echocardiographic parameters, suggesting that MyW may add incremental information to clinically established parameters. Further analyses from the STAAB cohort study contributed to a better understanding of the impact of CV risk factors on MyW indices and the association of LV geometry with LV performance. We demonstrated that CV risk factors impacted selectively on GCW and GWW. Hypertension appears to profoundly compromise the work of the myocardium, in particular, by increasing both GCW and GWW. The LV in hypertension seems to operate at a higher energy level yet lower efficiency. Other classical CV risk factors (Diabetes mellitus, Obesity, Dyslipidemia, Smoking) – independent of blood pressure – impacted consistently and adversely on GCW but did not affect GWW. Further, all CV risk factors affected GWE adversely. We observed that any deviation from a normal LV geometric profile was associated with alterations on MyW. Of note, MyW was sensitive to early changes in LV mass and dimensions. Individuals with normal LV geometry yet established arterial hypertension exhibited a MyW pattern that is typically found in LV hypertrophy. Therefore, such a pattern might serve as an early sign of myocardial damage in hypertensive heart disease and might aid in risk stratification and primary prevention. From the AHF Registry, we selected individuals with serial in-hospital echocardiograms and described in-hospital changes in myocardial performance during recompensation. In patients presenting with a reduced ejection fraction (HFrEF), decreasing N-terminal pro-natriuretic peptide (NT-proBNP) levels as a surrogate of successful recompensation were associated with an improvement in GCW and GWI and consecutively in GWE. In contrast, in patients presenting with a preserved ejection fraction (HFpEF), there was no significant change in GCW and GWI. However, unsuccessful recompensation, i.e., no change or an increase in NT-proBNP levels, was associated with an increase in GWW. This suggests a differential myocardial response to de- and recompensation depending on the HF phenotype. Further, GWW as a surrogate of inappropriate LV energy consumption was elevated in all patients with AHF (compared to reference values) and was not associated with conventional markers as LVEF or NT-proBNP. In an exploratory analysis, GWW predicted the risk of death or rehospitalization within six months after discharge. Hence, GWW might carry incremental information beyond conventional markers of HF severity. N2 - 2 Zusammenfassung Die linksventrikuläre (LV) Ejektionsfraktion (EF) und der Global Longitudinal Strain (GLS) sind die am häufigsten verwendeten Maße der LV-Funktion. Sie sind jedoch stark von den jeweiligen Belastungsbedingungen abhängig, da eine höhere Nachlast zu einer geringeren systolischen Deformation und somit zu einer niedrigeren LVEF und GLS führt, trotz einer vermutlich unveränderten myokardialen Kontraktionsstärke. Intrakardiale Druck-Volumen-Schleifenmessungen stellen den Referenzstandard zur Beurteilung der LV-Funktion dar, da hiermit auch die umfassende Berücksichtigung der Lastbedingungen (Vorlast, Nachlast) möglich ist. Dieses Verfahren lässt sich jedoch aufgrund des invasiven Charakters nur schwer in Follow-up Untersuchungen oder großen Studienpopulationen einsetzen. Angelehnt an die Prinzipien dieser invasiven Technik, wurde vor kurzem das neuartige Konzept der Echokardiographie-abgeleiteten Beurteilung der Myokardarbeit (MyW) entwickelt. Dieser Ansatz wertet Druck-Strain-Schleifen aus und berücksichtigt den Einfluss der Nachlast, so dass MyW als weniger lastabhängig gilt verglichen mit LVEF und GLS. Die Analyse von MyW könnte deshalb eine wertvolle Alternative sein, um den o.g. Herausforderungen zu begegnen. Die Methode lässt sich in großen Stichproben, ggf. auch wiederholt, einsetzen. Die hier vorgelegte Dissertation befasst sich mit der Anwendung und klinischen Charakterisierung von MyW, einer innovativen echokardiographischen Methode. Der Fokus lag auf vier Themenbereichen: (a) Festlegung von Referenzwerten für MyW-Indizes, d. h. Global Work Index (GWI), Global Constructive Work (GCW), Global Wasted Work (GWW) und Global Work Efficiency (GWE); wir adressierten einen breiten Altersbereich und quantifizierten die Assoziation der MyW-Indizes mit Alter, Geschlecht und weiteren klinischen und echokardiographischen Parametern bei kardiovaskulär gesunden Normalpersonen. (b) Untersuchung des Einflusses kardiovaskulärer Risikofaktoren auf die MyW-Indizes und die Charakterisierung einer subklinischen LV-Verschlechterung in der Allgemeinbevölkerung. (c) Bewertung der Assoziation der MyW-Indizes mit der LV-Geometrie, insbesondere der LV-Masse und der LV-Dimensionen. (d) Bewertung der Dynamik der MyW-Indizes im Krankenhaus bei Patienten, die wegen akuter Herzinsuffizienz (AHF) ins Krankenhaus aufgenommen wurden. Im Rahmen der hier vorgelegten Dissertation wurden die Daten zweier größerer Kohorten herangezogen: Die bevölkerungsbasierte STAAB-Kohortenstudie rekrutierte und phänotypisierte prospektiv eine repräsentative Stichprobe (5.000 Personen) der Allgemeinbevölkerung der Stadt Würzburg im Alter von 30-79 Jahren, die zum Zeitpunkt des Einschlusses keine vorbeschriebene Herzinsuffizienz hatten. Wir konzentrierten uns auf die erste Hälfte der Studienstichprobe (n=2473 Personen), welche die erwarteten Stratifizierung bezüglich Alter und Geschlecht erfüllten. Das Acute Heart Failure (AHF) Register ist ein klinisches Register zur Rekrutierung und Phänotypisierung von konsekutiven Patienten, die wegen akut dekompensierter Herzinsuffizienz in die Medizinische Klinik I des Universitätsklinikums Würzburg aufgenommen wurden. Ziel dieser Studie ist es, das pathophysiologische Verständnis insbesondere in Bezug auf die Frühphase nach einer kardialen Dekompensation zu verbessern und damit die gezielte Diagnostik und Therapie von Patienten mit AHF zu verbessern. Wir fokussierten hier auf Patienten, bei denen im Krankenhaus zwei Echokardiogramme durchgeführt wurden: früh nach Aufnahme ins Krankenhaus und kurz vor der Entlassung. Die wichtigsten Erkenntnisse der hier vorgelegten Dissertation sind: Aus den Daten der STAAB-Kohortenstudie wurden Referenzwerte für MyW-Indizes etabliert, die auf Auswertungen von insgesamt 779 gesunden Normalpersonen (mittleres Alter 49 ± 10 Jahre, 59% Frauen) mit Sinusrhythmus beruhen. Diese Probanden wiesen gemäß der Ergebnisse einer umfangreichen Eingangsuntersuchung keine kardiovaskulären Risikofaktoren oder Erkrankungen auf und zeigten echokardiographisch keinen Hinweis auf eine LV-Klappenerkrankung. Mit der Ausnahme von GWI fanden sich keine Assoziationen der MyW-Indizes mit dem Geschlecht. Darüber hinaus zeigte sich eine Altersabhängigkeit der MyW-Indizes. Bis zum Alter von 45 Jahren wies MyW stabile Werte auf, jenseits des 45. Lebensjahres jedoch eine Aufwärtsverschiebung: dabei war eine zunehmend höhere Altersdekade mit mehr GWW bzw. weniger GWE verbunden. Die MyW-Indizes korrelierten nur schwach mit üblichen echokardiographischen Parametern, was darauf hindeuten könnte, dass MyW zusätzliche Informationen jenseits klinisch etablierter Variablen beitragen kann. Weitere Analysen aus der STAAB-Kohortenstudie trugen zu einem besseren Verständnis des Einflusses kardiovaskulärer Risikofaktoren auf die MyW-Indizes und der Assoziation der LV-Geometrie mit der LV-Leistung bei. Wir zeigten, dass kardiovaskuläre Risikofaktoren sich selektiv auf GCW und GWW auswirken. Hypertonie beeinträchtigte die Arbeit des Myokards zutiefst, insbesondere durch die Erhöhung sowohl des GCW als auch des GWW. Der LV arbeitet demnach bei Hypertonie auf einem höheren Energieniveau – jedoch mit geringerer Effizienz. Andere klassische kardiovaskuläre Risikofaktoren (Diabetes mellitus, Adipositas, Dyslipidämie, Rauchen), wirkten sich unabhängig vom Blutdruck durchweg negativ auf GCW aus, zeigten jedoch keinen Einfluss auf GWW. Darüber hinaus wirkten sich alle kardiovaskulären Risikofaktoren nachteilig auf GWE aus. Jede Abweichung von einem normalen LV-Geometrie Profil war mit Änderungen der MyW verbunden. Bemerkenswert war, dass MyW empfindlich auf frühe Veränderungen der LV-Masse und -Dimensionen reagierte. Personen mit arterieller Hypertonie aber noch normaler LV-Geometrie zeigten ein myokardiales Arbeitsmuster, das ansonsten typischerweise bei LV-Hypertrophie zu finden ist. Somit könnte dieses Muster als frühes Zeichen einer Myokardschädigung bei hypertensiver Herzerkrankung dienen und bei der Risikostratifizierung und Primärprävention helfen. Aus dem AHF-Register wählten wir Personen mit seriellen Echokardiogrammen im Krankenhaus aus und beschrieben Veränderungen der myokardialen Leistung während der Rekompensationsphase beschrieben. Als Surrogat einer Rekompensation zogen wir während der Hospitalisierung sinkende Spiegel von N-terminalem pro-natriuretischem Peptid (NT-proBNP) heran. Bei Patienten mit reduzierter Ejektonfraktion (HFrEF) waren fallende NT-proBNP Werte (i. S. einer erfolgreichen Rekompensation) mit einer Verbesserung von GCW und GWI und konsekutiv auch von GWE verbunden. Im Gegensatz dazu gab es bei Patienten, die eine erhaltene Ejektonfraktionsfraktion aufwiesen (HFpEF), keine signifikante Veränderung von GCW und GWI. Eine erfolglose Rekompensation, d. h. keine Veränderung oder ein potenzieller Anstieg von NT-proBNP, war jedoch mit einem Anstieg von GWW verbunden. Wir interpretierten dies als unterschiedliche myokardiale Reaktion auf De- und Rekompensation in Abhängigkeit vom Herzinsuffizienz-Phänotyp. Darüber hinaus war GWW als Surrogat eines unangemessenen LV-Energieverbrauchs bei allen Patienten mit AHF erhöht (im Vergleich zu Referenzwerten) und korrelierte mit keinem der konventionellen Marker. In einer explorativen Analyse war GWW ein starker Prädiktor für das Risiko, im Verlauf der nächsten sechs Monaten nach Krankenhausentlassung zu sterben oder erneut hospitalisiert zu werden. Damit könnte die GWW zusätzliche Informationen enthalten, die über die konventionellen Marker für den Schweregrad der Herzinsuffizienz hinausgehen. KW - Myocardial Work KW - Echocardiography KW - Heart Failure KW - Hypertension KW - STAAB Cohort Study KW - Wasted Work KW - Cardiac Efficiency KW - Herzinsuffizienz KW - Echokardiographie KW - myokardiale Arbeit KW - LV Function Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-282261 ER - TY - JOUR A1 - Henneges, Carsten A1 - Morbach, Caroline A1 - Sahiti, Floran A1 - Scholz, Nina A1 - Frantz, Stefan A1 - Ertl, Georg A1 - Angermann, Christiane E. A1 - Störk, Stefan T1 - Sex-specific bimodal clustering of left ventricular ejection fraction in patients with acute heart failure JF - ESH Heart Failure N2 - Aims There is an ongoing discussion whether the categorization of patients with heart failure according to left ventricular ejection fraction (LVEF) is scientifically justified and clinically relevant. Major efforts are directed towards the identification of appropriate cut-off values to correctly allocate heart failure-specific pharmacotherapy. Alternatively, an LVEF continuum without definite subgroups is discussed. This study aimed to evaluate the natural distribution of LVEF in patients presenting with acutely decompensated heart failure and to identify potential subgroups of LVEF in male and female patients. Methods and results We identified 470 patients (mean age 75 ± 11 years, n = 137 female) hospitalized for acute heart failure in whom LVEF could be quantified by Simpson's method in an in-hospital echocardiogram. Non-parametric modelling revealed a bimodal shape of the LVEF distribution. Parametric modelling identified two clusters suggesting two LVEF peaks with mean (variance) of 61% (9%) and 31% (10%), respectively. Sub-differentiation by sex revealed a sex-specific bimodal clustering of LVEF. The respective threshold differentiating between ‘high’ and ‘low’ LVEF was 45% in men and 52% in women. Conclusions In patients presenting with acute heart failure, LVEF clustered in two subgroups and exhibited profound sex-specific distributional differences. These findings might enrich the scientific process to identify distinct subgroups of heart failure patients, which might each benefit from respectively tailored (pharmaco)therapies. KW - heart failure KW - left ventricular ejection fraction KW - sex differences Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265839 VL - 9 IS - 1 ER - TY - JOUR A1 - Tolstik, Elen A1 - Ali, Nairveen A1 - Guo, Shuxia A1 - Ebersbach, Paul A1 - Möllmann, Dorothe A1 - Arias-Loza, Paula A1 - Dierks, Johann A1 - Schuler, Irina A1 - Freier, Erik A1 - Debus, Jörg A1 - Baba, Hideo A. A1 - Nordbeck, Peter A1 - Bocklitz, Thomas A1 - Lorenz, Kristina T1 - CARS imaging advances early diagnosis of cardiac manifestation of Fabry disease JF - International Journal of Molecular Sciences N2 - Vibrational spectroscopy can detect characteristic biomolecular signatures and thus has the potential to support diagnostics. Fabry disease (FD) is a lipid disorder disease that leads to accumulations of globotriaosylceramide in different organs, including the heart, which is particularly critical for the patient’s prognosis. Effective treatment options are available if initiated at early disease stages, but many patients are late- or under-diagnosed. Since Coherent anti-Stokes Raman (CARS) imaging has a high sensitivity for lipid/protein shifts, we applied CARS as a diagnostic tool to assess cardiac FD manifestation in an FD mouse model. CARS measurements combined with multivariate data analysis, including image preprocessing followed by image clustering and data-driven modeling, allowed for differentiation between FD and control groups. Indeed, CARS identified shifts of lipid/protein content between the two groups in cardiac tissue visually and by subsequent automated bioinformatic discrimination with a mean sensitivity of 90–96%. Of note, this genotype differentiation was successful at a very early time point during disease development when only kidneys are visibly affected by globotriaosylceramide depositions. Altogether, the sensitivity of CARS combined with multivariate analysis allows reliable diagnostic support of early FD organ manifestation and may thus improve diagnosis, prognosis, and possibly therapeutic monitoring of FD. KW - coherent anti-Stokes Raman scattering (CARS) microscopy KW - Raman micro-spectroscopy KW - cardiovascular diseases KW - Fabry Disease (FD) KW - Gb3 and lyso-Gb3 biomarkers KW - multivariate data analysis KW - immunohistochemistry Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284427 SN - 1422-0067 VL - 23 IS - 10 ER - TY - JOUR A1 - Sahiti, Floran A1 - Morbach, Caroline A1 - Cejka, Vladimir A1 - Tiffe, Theresa A1 - Wagner, Martin A1 - Eichner, Felizitas A. A1 - Gelbrich, Götz A1 - Heuschmann, Peter U. A1 - Störk, Stefan T1 - Impact of cardiovascular risk factors on myocardial work-insights from the STAAB cohort study JF - Journal of Human Hypertension N2 - Myocardial work is a new echocardiography-based diagnostic tool, which allows to quantify left ventricular performance based on pressure-strain loops, and has been validated against invasively derived pressure-volume measurements. Myocardial work is described by its components (global constructive work [GCW], global wasted work [GWW]) and indices (global work index [GWI], global work efficiency [GWE]). Applying this innovative concept, we characterized the prevalence and severity of subclinical left ventricular compromise in the general population and estimated its association with cardiovascular (CV) risk factors. Within the Characteristics and Course of Heart Failure STAges A/B and Determinants of Progression (STAAB) cohort study we comprehensively phenotyped a representative sample of the population of Würzburg, Germany, aged 30-79 years. Indices of myocardial work were determined in 1929 individuals (49.3% female, mean age 54 ± 12 years). In multivariable analysis, hypertension was associated with a mild increase in GCW, but a profound increase in GWW, resulting in higher GWI and lower GWE. All other CV risk factors were associated with lower GCW and GWI, but not with GWW. The association of hypertension and obesity with GWI was stronger in women. We conclude that traditional CV risk factors impact selectively and gender-specifically on left ventricular myocardial performance, independent of systolic blood pressure. Quantifying active systolic and diastolic compromise by derivation of myocardial work advances our understanding of pathophysiological processes in health and cardiac disease. KW - myocardial work KW - left ventricular performance KW - cardiovascular risk factors Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-271770 SN - 1476-5527 VL - 36 IS - 3 ER - TY - JOUR A1 - Sommer, Kim K. A1 - Amr, Ali A1 - Bavendiek, Udo A1 - Beierle, Felix A1 - Brunecker, Peter A1 - Dathe, Henning A1 - Eils, Jürgen A1 - Ertl, Maximilian A1 - Fette, Georg A1 - Gietzelt, Matthias A1 - Heidecker, Bettina A1 - Hellenkamp, Kristian A1 - Heuschmann, Peter A1 - Hoos, Jennifer D. E. A1 - Kesztyüs, Tibor A1 - Kerwagen, Fabian A1 - Kindermann, Aljoscha A1 - Krefting, Dagmar A1 - Landmesser, Ulf A1 - Marschollek, Michael A1 - Meder, Benjamin A1 - Merzweiler, Angela A1 - Prasser, Fabian A1 - Pryss, Rüdiger A1 - Richter, Jendrik A1 - Schneider, Philipp A1 - Störk, Stefan A1 - Dieterich, Christoph T1 - Structured, harmonized, and interoperable integration of clinical routine data to compute heart failure risk scores JF - Life N2 - Risk prediction in patients with heart failure (HF) is essential to improve the tailoring of preventive, diagnostic, and therapeutic strategies for the individual patient, and effectively use health care resources. Risk scores derived from controlled clinical studies can be used to calculate the risk of mortality and HF hospitalizations. However, these scores are poorly implemented into routine care, predominantly because their calculation requires considerable efforts in practice and necessary data often are not available in an interoperable format. In this work, we demonstrate the feasibility of a multi-site solution to derive and calculate two exemplary HF scores from clinical routine data (MAGGIC score with six continuous and eight categorical variables; Barcelona Bio-HF score with five continuous and six categorical variables). Within HiGHmed, a German Medical Informatics Initiative consortium, we implemented an interoperable solution, collecting a harmonized HF-phenotypic core data set (CDS) within the openEHR framework. Our approach minimizes the need for manual data entry by automatically retrieving data from primary systems. We show, across five participating medical centers, that the implemented structures to execute dedicated data queries, followed by harmonized data processing and score calculation, work well in practice. In summary, we demonstrated the feasibility of clinical routine data usage across multiple partner sites to compute HF risk scores. This solution can be extended to a large spectrum of applications in clinical care. KW - medical informatics initiative KW - HiGHmed KW - medical data integration center KW - clinical routine data KW - heart failure KW - risk prediction scores KW - semantic interoperability KW - openEHR Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-275239 SN - 2075-1729 VL - 12 IS - 5 ER - TY - JOUR A1 - Dudek, Jan A1 - Maack, Christoph T1 - Mechano-energetic aspects of Barth syndrome JF - Journal of Inherited Metabolic Disease N2 - Energy-demanding organs like the heart are strongly dependent on oxidative phosphorylation in mitochondria. Oxidative phosphorylation is governed by the respiratory chain located in the inner mitochondrial membrane. The inner mitochondrial membrane is the only cellular membrane with significant amounts of the phospholipid cardiolipin, and cardiolipin was found to directly interact with a number of essential protein complexes, including respiratory chain complexes I to V. An inherited defect in the biogenesis of cardiolipin causes Barth syndrome, which is associated with cardiomyopathy, skeletal myopathy, neutropenia and growth retardation. Energy conversion is dependent on reducing equivalents, which are replenished by oxidative metabolism in the Krebs cycle. Cardiolipin deficiency in Barth syndrome also affects Krebs cycle activity, metabolite transport and mitochondrial morphology. During excitation-contraction coupling, calcium (Ca\(^{2+}\)) released from the sarcoplasmic reticulum drives sarcomeric contraction. At the same time, Ca\(^{2+}\) influx into mitochondria drives the activation of Krebs cycle dehydrogenases and the regeneration of reducing equivalents. Reducing equivalents are essential not only for energy conversion, but also for maintaining a redox buffer, which is required to detoxify reactive oxygen species (ROS). Defects in CL may also affect Ca\(^{2+}\) uptake into mitochondria and thereby hamper energy supply and demand matching, but also detoxification of ROS. Here, we review the impact of cardiolipin deficiency on mitochondrial function in Barth syndrome and discuss potential therapeutic strategies. KW - Barth syndrome KW - respiratory chain KW - reactive oxygen species KW - cardiolipin KW - mitochondria Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-257512 VL - 45 IS - 1 ER - TY - JOUR A1 - Brodehl, Andreas A1 - Gerull, Brenda T1 - Genetic insights into primary restrictive cardiomyopathy JF - Journal of Clinical Medicine N2 - Restrictive cardiomyopathy is a rare cardiac disease causing severe diastolic dysfunction, ventricular stiffness and dilated atria. In consequence, it induces heart failure often with preserved ejection fraction and is associated with a high mortality. Since it is a poor clinical prognosis, patients with restrictive cardiomyopathy frequently require heart transplantation. Genetic as well as non-genetic factors contribute to restrictive cardiomyopathy and a significant portion of cases are of unknown etiology. However, the genetic forms of restrictive cardiomyopathy and the involved molecular pathomechanisms are only partially understood. In this review, we summarize the current knowledge about primary genetic restrictive cardiomyopathy and describe its genetic landscape, which might be of interest for geneticists as well as for cardiologists. KW - restrictive cardiomyopathy KW - cardiomyopathy KW - cardiovascular genetics KW - desmin KW - troponin KW - filamin-C Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270621 SN - 2077-0383 VL - 11 IS - 8 ER - TY - JOUR A1 - Traub, Jan A1 - Otto, Markus A1 - Sell, Roxane A1 - Homola, György A. A1 - Steinacker, Petra A1 - Oeckl, Patrick A1 - Morbach, Caroline A1 - Frantz, Stefan A1 - Pham, Mirko A1 - Störk, Stefan A1 - Stoll, Guido A1 - Frey, Anna T1 - Serum glial fibrillary acidic protein indicates memory impairment in patients with chronic heart failure JF - ESC Heart Failure N2 - Aims Cognitive dysfunction occurs frequently in patients with heart failure (HF), but early detection remains challenging. Serum glial fibrillary acidic protein (GFAP) is an emerging biomarker of cognitive decline in disorders of primary neurodegeneration such as Alzheimer's disease. We evaluated the utility of serum GFAP as a biomarker for cognitive dysfunction and structural brain damage in patients with stable chronic HF. Methods and results Using bead-based single molecule immunoassays, we quantified serum levels of GFAP in patients with HF participating in the prospective Cognition.Matters-HF study. Participants were extensively phenotyped, including cognitive testing of five separate domains and magnetic resonance imaging (MRI) of the brain. Univariable and multivariable models, also accounting for multiple testing, were run. One hundred and forty-six chronic HF patients with a mean age of 63.8 ± 10.8 years were included (15.1% women). Serum GFAP levels (median 246 pg/mL, quartiles 165, 384 pg/mL; range 66 to 1512 pg/mL) did not differ between sexes. In the multivariable adjusted model, independent predictors of GFAP levels were age (T = 5.5; P < 0.001), smoking (T = 3.2; P = 0.002), estimated glomerular filtration rate (T = −4.7; P < 0.001), alanine aminotransferase (T = −2.1; P = 0.036), and the left atrial end-systolic volume index (T = 3.4; P = 0.004). NT-proBNP but not serum GFAP explained global cerebral atrophy beyond ageing. However, serum GFAP levels were associated with the cognitive domain visual/verbal memory (T = −3.0; P = 0.003) along with focal hippocampal atrophy (T = 2.3; P = 0.025). Conclusions Serum GFAP levels are affected by age, smoking, and surrogates of the severity of HF. The association of GFAP with memory dysfunction suggests that astroglial pathologies, which evade detection by conventional MRI, may contribute to memory loss beyond ageing in patients with chronic HF. KW - Glial fibrillary acidic protein KW - GFAP KW - Chronic heart failure KW - Cognitive decline KW - Memory dysfunction KW - Brain atrophy Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312736 VL - 9 IS - 4 ER -