Artículos de revistas sobre el tema "Else Kröner-Fresenius-Stiftung"

BackgroundIt is well established that patients with inflammatory rheumatic diseases have an increased cardiovascular risk [1]. Most data exists for rheumatoid arthritis, but there are also a few studies for primary Sjoegren’s syndrome (pSS)[2].ObjectivesAim of our study was to investigate the extent of subclinical atherosclerosis in a large group of patients with pSS compared to control subjects without pSS. Secondary, correlations with clinical factors, such as organ involvement or antibody positivity, and disease activity were investigated.MethodsFrom September 2021 to April 2022, pSS patients from the outpatient clinic of our hospital were consecutively included after informed consent. In addition, age- and sex-matched control subjects were recruited in a 2:1 ratio via multimedia call for participation. All pSS patients fulfilled current EULAR classification criteria for pSS and had a disease duration of at least 5 years. Participants with additional rheumatic or inflammatory diseases, tumor disease in the past 5 years, or end-organ manifestations of atherosclerotic disease were excluded. Data collection was performed by standardized questionnaire and Doppler ultrasonography for evaluation of plaque extent and intima-media thickness measurements (cIMT).ResultsAnalysis included data from 199 pSS patients and 100 control subjects. 38 (19.4%) subjects of the pSS cohort were male and the median age was 58.92 years [50.50-65.21]. The median disease duration (since initial manifestation) of pSS patients was 136 months. The cohorts were analyzed for differences regarding to the cardiovascular risk profile: There were no significant differences in age, gender distribution, tobacco consumption, body mass index (BMI), pre-existing arterial hypertension, hypercholesterolemia, or diabetes mellitus. Similarly, there were no differences in LDL cholesterol, HDL cholesterol, or HbA1c in laboratory tests at enrollment. Only a positive family history for cardiovascular disease was significantly more frequent in the pSS cohort (p=0.003).After adjustment via propensity score matching, the pSS cohort was found to have a significantly greater intima-media thickness (p= <0.001). When age was added as a covariate, there was an earlier onset of intima-media thickening recognizable in the pSS patients (p=0.014). Furthermore, there was a significantly more frequent occurrence of plaque in the pSS cohort (p=0.031). pSS-patients had a 1.82times increased odds of having plaque in comparison to the control cohort.Organ involvement in the pSS-cohort was associated with a thicker cIMT (p=0.025) and pSS-patients with organ involvement also showed a 1.74times increased odds of having plaque compared to pSS-patients without organ involvement.ConclusionPSS appears to accelerate the development and progression of atherosclerosis as an independent risk factor. It seems to promote not only an increased incidence of atherosclerotic changes, but also an earlier onset of wall thickening in the sense of vascular aging. An increased risk for patients with organ involvement was observed. Further longitudinal studies are required to answer the question if this subgroup of pSS patients in particular or all pSS patients could benefit of screening with Doppler ultrasonography and preventive medication with HMG-CoA reductase inhibitors or acetyl salicylic acid.References[1]Yong WC, Sanguankeo A, Upala S. Association between primary Sjögren’s syndrome, cardiovascular and cerebrovascular disease: a systematic review and meta-analysis. Clin Exp Rheumatol. 2018 May-Jun;36 Suppl 112(3):190-197. Epub 2018 Mar 19. PMID: 29600936.[2]Garcia AB, Dardin LP, Minali PA, Czapkowsky A, Ajzen SA, Trevisani VF. Asymptomatic Atherosclerosis in Primary Sjögren Syndrome: Correlation Between Low Ankle Brachial Index and Autoantibodies Positivity. J Clin Rheumatol. 2016 Sep;22(6):295-8. doi: 10.1097/RHU.0000000000000413. PMID: 27556236.AcknowledgementsThis study was funded by Else-Kröner-Fresenius foundation and Novartis AG.Disclosure of InterestsNadine Zehrfeld Grant/research support from: Novartis AG, Sabrina Benz: None declared, Anselm Derda: None declared, Sonja Beider: None declared, Emelie Kramer: None declared, Georgios Sogkas: None declared, Tabea Seeliger Grant/research support from: Alnylam Pharmaceuticals, Bristol-Myers Squibb Foundation for Immuno-Oncology, Claudia von Schilling Foundation, CSL Behring, Else Kröner Fresenius Foundation, Novartis, Sanofi Aventis, VHV Stiftung, Abbvie, Gerrit Ahrenstorf: None declared, Alexandra Dopfer-Jablonka: None declared, Thomas Skripuletz Grant/research support from: Alexion, Alnylam Pharmaceuticals, Bayer Vital, Biogen, Celgene, Centogene, CSL Behring, Euroimmun, Janssen, Merck Serono, Novartis, Roche, Sanofi Aventis, Siemens, Sobi, Teva, Torsten Witte Grant/research support from: Abbvie, BMS, Chugai, Galapagos, Janssen, Lilly, Pfizer, UCB and Roche, Kristina Sonnenschein: None declared, Diana Ernst Consultant of: Abbvie, Galapagos, Amgen and Novartis, Grant/research support from: Abbvie, Amgen, BMS, Chugai, Cilag-Janssen, Galapagos, GSK, Medac, Lilly, Pfizer, Novartis, Roche.

Background:Alcohol consumption has emerged as consistent protective factor for the development of autoimmune diseases such as rheumatoid arthritis (RA). The underlying mechanism for this tolerance-inducing effect of alcohol, however, is unknown.Objectives:To understand the anti-arthritogenic effect of alcoholMethods:The immune-regulatory properties of alcohol consumption in vivo were tested in the collagen-induced arthritis (CIA) and serum-induced arthritis (SIA) model as well as after immunization with T cell- dependent (NP-CGG) and independent (TNP-FICOLL) antigens. Additional experiments in vivo experiments in these models were done with acetate- the metabolite of ethanol. The models were analysed for T- cell lineage and plasma cell differentiation, germinal centre formation and IgG levels and sialylation. Molecular expression of T follicular helper cell (TFH) activation such as IL-21, Bcl-6 and PD-1, as well as TFH: B cell conjugates were also assessed. Furthermore, TFH cells were generated in vitro, exposed to ethanol or acetate and tested for IL-21 production, PD1 expression and conjugate formation with B cells.Results:Ethanol exposure significantly inhibited arthritis in the active adaptive immunity-driven model of arthritis (CIA) but not in the passive innate immunity-driven model (STA) suggesting that the immune suppressive effect of alcohol is based on interference of T- and B- cell activation. In line ethanol and even more its metabolite acetate, suppressed T cell dependent antibody formation after NP-CGG immunization, while T cell independent antibody formation after TNP-FICOLL immunization was not suppressed. Ethanol, as well as its metabolite acetate, specifically altered the functional state of T follicular helper (TFH) cells in vitro and in vivo, thereby exerting immune regulatory and tolerance-inducing properties. Alcohol-exposed mice showed reduced Bcl6 and PD-1 expression as well as interleukin (IL)-21 production by TFH cells, preventing proper spatial organization of TFH cells to form TFH: B cell conjugates in the germinal centre. This effect of alcohol on TFHcells was associated with impaired autoantibody formation, higher sialylation of autoantibodies and less arthritis. In accordance, overexpression of IL-21 in vivo completely reversed the immune regulatory effects of alcohol.Conclusion:In summary, these data provide a new mechanistic explanation for the immune regulatory and tolerance-inducing effect of alcohol consumption in arthritis.Acknowledgments:Funden by DFG-FOR2886, DFG–CRC1181, Staedtler foundation, Johannes und Frieda Marohn-Stiftung, Else Kröner-Fresenius foundation, Interdisciplinary Centre for Clinical Research, Erlangen, BMBF-MASCARA, IMI funded project RTCure.Disclosure of Interests:Vugar Azizov: None declared, Maria V Sokolova: None declared, Kerstin Sarter: None declared, Vladimir Temchura: None declared, Ulrike Steffen (née Harre): None declared, Martin Herrmann: None declared, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB, Mario Zaiss: None declared

Background:While it is known that microbial dysbiosis is associated with the onset of rheumatoid arthritis, mechanistic insights how it facilitates the development of arthritis remained largely elusive to date. It is especially interesting how microbial dysbiosis affects the transition from asymptomatic autoimmunity to arthritis. We speculated that a breakdown of intestinal barrier function caused by microbial dysbiosis allows immune cells to shuttle from the gut to the joints.Objectives:To test whether intestinal barrier function is impaired before the onset of human RA and experimental arthritis and to seek for evidence that immune cells from the gut migrate to the joints.Methods:In a longitudinal cohort of RA-at risk individuals markers of disturbed intestinal barrier function, such as zonulin, were analysed and linked to RA onset. Furthermore, new-onset RA patients were assessed for gut leakiness and their intestinal biopsies for the expression of tight junction proteins and immune cell infiltration. In the murine model of collagen-induced arthritis, sequential analysis of intestinal dysbiosis, intestinal barrier function and arthritis onset was carried out. Additionally, barrier function was assessed on intestinal organoids exposed to faecal supernatants from eu- and dysbiotic mice with and without inhibition of zonulin. Furthermore, three types of interventions restoring intestinal barrier function were carried out for testing their effects on the inhibition of arthritis onset. Finally, photo- converted cells from the gut were traced in the joints to test for cellular trafficking from one to the other compartment.Results:Zonulin, a potent regulator for intestinal tight junctions, was elevated in autoimmune mice and men before the onset of arthritis and predicted the onset of human RA. Intestinal barrier functions as well as epithelial tight junctions were decreased before the onset of experimental arthritis and at onset of human RA. In mice, induction of autoimmunity was followed by rapid intestinal dysbiosis followed by gut leakiness before arthritis started. Faecal supernatants of arthritic mice induce epithelial barrier dysfunction in intestinal organoids in zonulin dependent manner. Restoration of the intestinal barrier in the pre-phase of arthritis using butyrate, CB1R agonist or zonulin antagonist larazotide inhibited the development of arthritis. Finally, using photoconvertible mice, gut-borne immune cells were identified that homed to the joints when barrier function was impaired.Conclusion:In summary, these data show the intestinal barrier dysfunction precedes the onset of RA and allows the trafficking of immune cells from the gut to the joints. Targeting of intestinal tight junction function may therefore allow preventing the onset of RA.Acknowledgments:Funded by the DFG-FOR2886 PANDORA, DFG–CRC118, Staedtler foundation, Johannes und Frieda Marohn-Stiftung, Else Kröner-Fresenius foundation, Interdisciplinary Centre for Clinical Research, Erlangen (IZKF), BMBF-MASCARA and the IMI funded projectRTCure.Disclosure of Interests:Mario Zaiss: None declared, Narges Taijc: None declared, Kerstin Sarter: None declared, Vugar Azizov: None declared, laura Bucci: None declared, Yubin Luo: None declared, Juan de Dios Cañete: None declared, francesco ciccia Grant/research support from: pfizer, novartis, roche, Consultant of: pfizer, novartis, lilly, abbvie, Speakers bureau: pfizer, novartis, lilly, abbvie, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB

Abstract Background: Acute myeloid leukemia (AML) with t(8;21)(q22;q22) results in the formation of the RUNX1-RUNX1T1 fusion transcript which can be used to monitor minimal residual disease (MRD) by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Early identification of patients (pts) with a high risk of relapse will allow pre-emptive therapy including allogeneic hematopoietic cell transplantation (alloHCT). Recent studies in AML with NPM1 mutation or the CBFB-MYH11 gene fusion revealed that MRD persistence is significantly associated with a high risk of relapse. However, the prognostic impact of MRD assessment in RUNX1-RUNX1T1-positive AML is not well established. Aims: To assess the prognostic impact of qRT-PCR-based MRD monitoring in bone marrow (BM) of pts with t(8;21)/RUNX1-RUNX1T1-positive AML obtained at defined time-points (diagnosis, first and second cycle of chemotherapy, end of treatment). Methods: In total, 120 pts were included based on the availability of a diagnostic BM sample and at least two subsequent BM samples obtained during therapy and at the end of treatment; 106 pts were enrolled in one of six AMLSG treatment trials: AML HD93 (n=1), AML HD98A (NCT00146120; n=13), AMLSG 06-04 (NCT00151255; n=4), AMLSG 07-04 (NCT00151242; n=43), AMLSG 11-08 (NCT00850382; n=31), AMLSG 21-13 (NCT02013648; n=14); 14 pts were treated outside clinical trials. All pts received anthracycline- and cytarabine-based intensive induction followed by subsequent high-dose cytarabine consolidation cycles. For MRD assessment, qRT-PCR from BM specimens was performed using TaqMan technology; RUNX1-RUNX1T1 transcript levels (TL) were reported as the normalized value of RUNX1-RUNX1T1 per 106 transcripts of the housekeeping gene beta2-microglobulin. The maximum sensitivity of the assay was 10-6. Results: The median age of the pts was 47 years (yrs; range, 18-73 yrs); at the time of diagnosis there was a broad range of RUNX1-RUNX1T1 TL (18490 to 14440000) with a median of 227800. RUNX1-RUNX1T1 TL did not correlate with clinical features (age, WBC, platelets, LDH, BM blasts) or associated gene mutations such as KIT, FLT3-ITD/TKD, NRAS or ASXL2. However, pts with additional FLT3 mutation showed higher TL compared to wild-type pts (median, 412955 vs 219052). Cox regression analysis using RUNX1-RUNX1T1 TL as a log10 transformed continuous variable showed that higher RUNX1-RUNX1T1 TL were significantly associated with a higher cumulative incidence of relapse (CIR), inferior event-free survival (EFS) and shorter overall survival (OS) for the two time points "after first treatment cycle" and "at end of treatment" (CIR: HR, 1.84, p=0.001; HR, 1.60, p=0.03; EFS: HR, 1.59, p=0.01, HR, 1.74, p=0.01; OS: HR, 1.63, p=0.02, HR 2.13, p=0.009, respectively). In univariate analyses achievement of MRD negativity (n=35) at the end of treatment was significantly associated with a superior 4-yr OS (93% vs 67%; p=0.007) and 4-yr EFS (81% vs 61%; p=0.04) whereas achievement of MRD negativity after the first (1/85) and second (20/89) treatment cycle was low not reaching significance for any of the clinical endpoints. Separation of the RUNX1-RUNX1T1 TL according to quartiles of distribution showed significant differences in OS (p=0.04), and remission duration (p=0.006) "after first cycle" whereas "at end of treatment" significant differences were only found for OS (p=0.009). Finally, we evaluated the impact of concurrent KIT mutations on the kinetics of RUNX1-RUNX1T1 TL. Following the first treatment cycle, the median RUNX1-RUNX1T1 TL were significantly lower in the KIT wildtype group compared with the KIT mutated group (p=0.02); the same was true "at the end of treatment" (p=0.02). Conclusions: In our study, achievement of MRD negativity at the end of treatment was significantly associated with a better outcome in t(8;21)-positive AML. The fact that earlier time points did not allow the identification of pts with a high relapse risk is probably due to the high sensitivity of the qRT-PCR assay which is also reflected by the low number of pts achieving qRT-PCR negativity after first and second treatment cycle, respectively. Further analyses are ongoing including multivariable as well as molecular subgroup analyses. *These authors contributed equally to the work: MA, AC MA was supported by the Else-Kröner-Fresenius-Stiftung (EKFS). Disclosures Paschka: Celgene: Honoraria; Pfizer Pharma GmbH: Honoraria; Bristol-Myers Squibb: Honoraria; Medupdate GmbH: Honoraria; Novartis: Consultancy; ASTEX Pharmaceuticals: Consultancy. Lübbert:Ratiopharm: Other: Study drug valproic acid; Janssen-Cilag: Other: Travel Funding, Research Funding; Celgene: Other: Travel Funding. Fiedler:Amgen: Consultancy, Other: Travel, Patents & Royalties, Research Funding; Teva: Other: Travel; Kolltan: Research Funding; Ariad/Incyte: Consultancy; Novartis: Consultancy; Gilead: Other: Travel; GSO: Other: Travel; Pfizer: Research Funding. Heuser:Karyopharm Therapeutics Inc: Research Funding; Pfizer: Research Funding; Bayer Pharma AG: Research Funding; Celgene: Honoraria; Tetralogic: Research Funding; BerGenBio: Research Funding; Novartis: Consultancy, Research Funding. Schlenk:Pfizer: Honoraria, Research Funding; Amgen: Research Funding.

Background: Multiple myeloma (MM) is a heterogeneous disease with varying survival outcomes depending on the presence of certain genetic abnormalities. Common abnormalities include trisomies, translocations involving the chromosome 14, and amplifications or deletions of chromosomes 1, 13, and 17. t(11;14), occurring in 15% of patients with myeloma, had been considered a standard risk abnormality, but recent data suggest inferior outcome. This is important as new therapeutic options such as the BCL-2 inhibitor venetoclax has been shown to be particularly effective in t(11;14) patients. Methods: This was a multicenter study to identify the outcomes of patients with t(11;14), using a retrospectively assembled cohort. Patients with MM diagnosed between 2005 and 2015 with t(11;14) identified on FISH performed within six months of diagnosis, and with treatment details available and if alive, a minimum of 12 months of follow up, were enrolled. Results: The current analysis includes 1216 patients; median age of 62.56 years; 58.7% male. The median follow-up from diagnosis for the entire cohort was 51.9 months; 69.1% of the patients were alive at the last follow up. ISS stage distribution included: Stage I (35.7%), Stage II (34.0%) and Stage III (15.1%), data was missing for the rest. The distribution of concurrent FISH abnormalities included: trisomies (3.5%), del 13q (13.3%), 1q amp (8.8%), and del 17p or monosomy 17 (5.8%). Initial regimen included: 27.2% had an immunomodulatory (IMiD), 45.9% had a proteasome inhibitor (PI), 17.7% had both, and 9.0% had no novel agent. The drug classes by line of therapy are shown in Table 1. An early stem cell transplant (defined as within 12 months of start of first line treatment) was used in 49.4% of patients. The median time to next treatment (TTNT) after starting initial treatment was 26.6 (95% CI: 23.9 to 29.2) months. The median overall survival (OS) from diagnosis for the entire cohort was 95.1 (95% CI: 85.9 to 105.9) months; 4-year estimates for those diagnosed from January 2005 to December 2009, and from January 2010 to December 2014 were 77.5% and 78.6%, respectively. The median OS for those with any one high risk FISH lesion (del 17p/ 1q amp) was 67.5 (55.2, 97.1) versus 101.7 (89.7, 107.3) months. Patients with early SCT (within 12 months of diagnosis) had better OS: 108.3 (103.8, 133.0) vs. 69.8 (61.5, 80.3) months. Conclusion: Patients with t(11;14) without high risk FISH abnormalities have an excellent survival. Patients receiving a PI + IMiD combination and those receiving autologous SCT as part of initial therapy had best survival. Though numbers are limited, patients in the later lines receiving newer drugs such as venetoclax and daratumumab had high response rates and durable responses. Disclosures Kumar: Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Bittrich:Celgene: Other: Travel Funding, Research Funding; Else Kröner Fresenius Foundation: Research Funding; Otsuka Pharmaceuticals Europe: Other: N/A; SANOFI Aventis: Membership on an entity's Board of Directors or advisory committees, N/A, Research Funding; University Hospital Wuerzburg: Employment; Bristol Myers Squibb: Research Funding; Pfizer: Other: Travel Funding; AMGEN: Other: Travel Funding; JAZZ Pharmaceuticals: Other: Travel Funding; Wilhelm Sander Foundation: Research Funding; German Research Foundation (DFG): Other: N/A; University of Würzburg: Other: N/A. Goldschmidt:Mundipharma: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; John-Hopkins University: Research Funding; Dietmar-Hopp-Stiftung: Research Funding; Janssen: Consultancy, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Research Funding; Molecular Partners: Research Funding; John-Hopkins University: Research Funding; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Reece:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Merck: Research Funding. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; EDO: Membership on an entity's Board of Directors or advisory committees. Ludwig:Celgene: Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; PharmaMar: Consultancy; Janssen: Speakers Bureau; BMS: Speakers Bureau. Mangiacavalli:celgene: Consultancy; Amgen: Consultancy; Janssen cilag: Consultancy. Dimopoulos:Sanofi Oncology: Research Funding. Kastritis:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria. Yee:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Karyopharm: Consultancy; Adaptive: Consultancy. Raje:Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy. Rosta:Cornerstone Research Group: Employment. Haltner:Cornerstone Research Group: Employment. Cameron:Cornerstone Research Group: Employment, Equity Ownership. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

Unsere Gesprächspartnerin: Frau Prof. Dr. med. Julia Seiderer-Nack Prof. Dr. med. Julia Seiderer-Nack ist als Fachärztin für Innere Medizin und Ernährungsmedizin (DGEM) in München privatärztlich niedergelassen und in der Hochschullehre tätig. Nach Studium an der LMU München und der Harvard Medical School sowie der Promotion in der onkologischen Grundlagenforschung erfolgte die Facharztausbildung am Klinikum Großhadern der LMU München im Bereich Gastroenterologie. Für ihre Forschungsarbeiten erhielt sie u. a. den Doktorandenpreis der Deutschen Gesellschaft für Hämatologie und Onkologie (DGHO) und Fördermittel der Else-Kröner-Fresenius-Stiftung. Schwerpunkt ihrer wissenschaftlichen und ärztlichen Tätigkeit sind die immunologischen Grundlagen von Darmerkrankungen und das Zusammenspiel zwischen Ernährung, Bakterien und körpereigenem Abwehrsystem. Diese naturwissenschaftlichen Grundlagen der modernen Schulmedizin mit komplementärmedizinischen, ernährungsmedizinischen und probiotischen Behandlungsmethoden zu verbinden ist ihr Spezialgebiet. Neben umfangreichen wissenschaftlichen Publikationen hat sie mehrere Patientenratgeber zu Gesundheitsthemen veröffentlicht.

Abstract Background Transcatheter aortic valve implantation (TAVI) is the accepted state-of-the-art treatment for elderly patients suffering from severe symptomatic aortic stenosis (AS). Co-morbidities at baseline are of great impact not only for individual peri-procedural risk stratification but also for the determination of long-term prognosis. The latter is of certain clinical interest, since a variety of co-existing disorders can be effectively treated in addition to TAVI. Purpose The current study aimed to elucidate the prognostic value of a wide range of baseline characteristics and co-morbidities with respect to long-term survival of TAVI patients in a prospective real-world single-center registry study. Methods A total of 445 patients with severe AS, which were treated by transfemoral TAVI, were included. A wide range of clinical, laboratory, functional and imaging parameters were prospectively assessed at baseline prior to TAVI. Mortality was recorded at 30 days, 1 year and 2 years after TAVI. Results The mean age of patients in this typical TAVI cohort was 78.7±7.3 years, 52% were female and the mean STS score was 5±3.9%. The mortality rates were as follows: 3.6% after 30 days, 16.4% after 1 and 22.6% after 2 years. Multivariate analysis could identify the following independent predictors of 2-year mortality assessed at baseline: sex, age, AS entity other than high-gradient, atrial fibrillation (Afib), renal function, relevant TR, systolic pulmonary artery pressure (PAPsys) and six-minute walk distance (SMWD). Among those, the strongest predictive value could be shown for Afib (OR 2.505, CI 1.509–4.157, p&lt;0.001) and TR (OR 2.179, CI 1.105–4.299, p=0.025). Kaplan-Meier survival analysis displayed significantly worse 2-year survival rates in patients suffering from relevant TR (31.6% versus 17.4%, p&lt;0.001) and Afib (29.4% versus 14.8%, p&lt;0.001). Conclusions Taken together, the results of the current study demonstrate the prognostic value of cardiovascular co-morbidities assessed prior to TAVI. We identified relevant TR and Afib as the strongest independent predictors of long-term mortality in our cohort. Since both conditions are effectively treatable, special emphasis should be placed on the question, which patient might benefit from treatment, e.g., by transcatheter edge-to-edge repair of TR or rhythm control, in addition to TAVI. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Else Kröner-Fresenius-Stiftung, Research Program “Else Kröner-Forschungskolleg AntiAge”

Abstract Background In the DAPA-HF trial, SGLT inhibition reduces cardiovascular mortality in heart failure. However, the mechanism and a potential positive effect in HfpEF remain elusive. Introduction LA remodeling is a hallmark feature of HFpEF and commonly associated with LA enlargement and dysfunction. Previous studies of SGLT-2 inhibitor Empagliflozin suggest a utilization of alternative metabolites for energy consumption (i.e. ketone bodies). Additionally, alterations of sodium and calcium ion hemostasis have been reported. We investigated the effect of SGLT inhibition on mitochondrial (dys)function during atrial remodeling in HFpEF. Methods Rats (WT: Wistar Kyoto, HFpEF: ZFS-1 Obese (metabolic syndrome)) were obtained at ∼10w and fed Purina 5008 diet. At 17w, animals were randomized to treatment with either vehicle or Sota (30mg/kg/d) for 5w until primary adult cardiomyocytes were isolated for final experiments. Structural information of mitochondria was obtained with Mitotracker Red in either a glucose starved (1h incubation with mannitol) or saturated state. ROS production was assessed with H2-DCF in a starved and saturated condition. Mitochondrial calcium buffer capacity was imaged with Rhod-2 following perforation of the cellular membrane with saponin. Glycolytic dependency of calcium cycling was assessed upon glycolytic inhibition with 2-deoxyglucose during imaging of cytosolic calcium transients with Fura-2. Results In a glucose saturated state, LA cardiomyocytes in HFpEF showed increased mitochondrial density, which was ameliorated with Sota. Sota increased mitochondrial calcium buffer capacity in HFpEF, indicating a decrease in mitochondrial resting calcium. Differences in mitochondrial fission could not be detected. However, during glucose starvation cardiomyocytes showed a decrease in mitochondrial fission and ROS production with Sota. A difference in ROS production was not visible when cells were abruptly challenged with high glucose concentrations, but Sota decreased mitochondrial fission, indicating long term protective properties towards ROS. Glycolytic inhibition led to an increase of cytosolic diastolic calcium and calcium transient peak height in HFpEF vs. WT, indicating an increased glucose dependency of cytosolic calcium cycling, which was mitigated with Sota. Additionally, Sota negated an increase in diastolic calcium, when cardiomyocytes where challenged with high concentrations of glucose after starvation. Conclusion SGLT1/2 inhibition alters mitochondrial calcium uptake in HFpEF and positively affects mitochondrial structure with subsequent decreases of ROS production and enhanced calcium homeostasis. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Else-Kröner-Fresenius-Stiftung, Deutsches Zentrum für Herz-Kreislaufforschung

Abstract Background Heart failure with preserved ejection fraction (HFpEF) is a major health problem associated with substantial morbidity and mortality. However, the underlying pathophysiological mechanisms are poorly understood, and effective treatment strategies are scarce. Importantly, SGLT2i, which have been suggested to improve cellular Na and Ca homeostasis in HFrEF, have recently been shown to also improve clinical outcomes in patients with HFpEF. Interestingly, post-hoc analyses of clinical data suggest an involvement of anti-arrhythmic effects of SGLT2i. Purpose We tested, if isolated human atrial cardiomyocytes from patients with HFpEF exhibit an increased Na influx that is responsive to treatment with the SGLT2i empagliflozin (Empa) and if Empa has anti-arrhythmic properties in human atrial trabeculae. Methods Atrial biopsies were obtained from 101 patients undergoing elective cardiac surgery. Na influx was measured as increase in [Na]i during Na/K-ATPase inhibition in isolated cardiomyocytes loaded with the Na-sensitive fluorescence dye Asante Natrium Green–2 AM (ANG-2). Western Blot and HDAC4 pulldown assay were used to investigate NaV1.5 expression/phosphorylation as well as CaMKII expression/autophosphorylation and activity. Anti-arrhythmic effects of Empa were evaluated as the reduction in premature atrial complexes (PACs), which were induced in electrically field-stimulated (1Hz) human atrial trabeculae by superfusion with isoproterenol (100 nM) and high Ca (3.5 mM). Results Compared to patients without heart failure (NF), Na influx was almost doubled in HFpEF patients (NF vs HFpEF: 0.21±0.02 vs 0.38±0.04 mmol/L/min (N=7 vs 18); p=0.005) (Fig. 1D, E). CaMKII expression, CaMKII autophosphorylation, CaMKII activity, and CaMKII-dependent NaV1.5 phosphorylation were significantly increased in atrial biopsies of HFpEF patients, whereas NaV1.5 protein abundance remained unchanged (Fig. 1A–C). Consistent with these results, the increased Na influx was significantly reduced by treatment with the specific CaMKII inhibitor autocamtide-2 related inhibitory peptide (AIP) and the late INa inhibitor tetrodotoxin (TTX) (Fig. 1D, E). Importantly, Empa also abolished the increased Na influx in HFpEF cardiomyocytes (Fig. 1D, E). Multivariate linear regression analysis, adjusting for clinical co-variates, revealed HFpEF to be an independent predictor of cardiomyocyte Na handling. In line with Empa-mediated inhibition of Na influx, the frequency of PACs in human atrial trabeculae was significantly reduced by Empa (Fig. 1F, G). Conclusion This is the first study to demonstrate increased Na influx in human cardiomyocytes from HFpEF patients potentially by an increased CaMKII-dependent NaV1.5 phosphorylation. Excitingly, treatment with Empa decreases this Na influx in HFpEF cardiomyocytes and reduces isoproterenol-induced arrhythmic activity in human atrial trabeculae, which could contribute to the cardioprotective effects of this drug in patients with HFpEF. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Else Kröner-Fresenius-Stiftung,Deutsche Forschungsgemeinschaft

Abstract Background Tachycardia-induced cardiomyopathy (TCM) is a reversible form of ventricular dysfunction caused by persistent tachycardia. Characterization of TCM is mainly based on artificially RV paced animal models. Moreover, the underlying mechanisms and time course from compensation to failure remain unclear. This study aimed to investigate early cellular remodeling of tachycardia-induced myocardial dysfunction in human myocardium. Methods and results To elucidate early cellular electrophysiological targets mediating the transition to TCM, we chronically paced (120bpm vs 60bpm control) human induced pluripotent stem cell cardiomyocytes (hiPS-CM) for up to 7d. As a major substrate of cellular myocardial dysfunction, we investigated the influence of chronic tachycardia on cellular Ca cycling. After 24h of persistent tachycardia we detected a significant decrease in Ca transient (CaT) amplitude and reduced diastolic Ca levels (Fura-2). Meanwhile, Ca elimination time (RT80) was unchanged compared to control (n=44/42 cells / 8 diff.). Caffeine application was performed to evaluate sarcoplasmic reticulum (SR) Ca load. We found a shortening of caffeine-induced CaT relaxation time, whereas SR Ca load was unchanged (n=12/13 /8). Further illustrating the transition to TCM, CaT amplitude was progressively decreased after 7d of chronic tachycardia. In contrast to 24h of tachycardia, 7d persistent stimulation resulted in slowed relaxation (RT80, n=75/65 /7). These findings could be explained by a significant reduction of SERCA activity (Ksys-Kcaff) and SR Ca load (n=14/12 / 7). Diastolic Ca concentration remained reduced (n=75/65 /7), in total suggesting a shift to transsarcolemmal Ca elimination. Sodium measurements (SBFI) revealed a significant increase of intracellular sodium concentration (n=69/69 /5) after 7d of tachycardia. In patch clamp experiments we detected a prolongation of action potential duration as early as 24h after onset of tachycardia (n=26/21 /4), which persisted throughout 7d of pacing (n=8/12 /3). Resting membrane potential and action potential amplitude were not changed. Finally, we investigated tachycardia-mediated effects on pre-existing human heart failure (HF). 8h tachycardic stimulation (120bpm) of human HF ventricular trabeculae compromised systolic force, while diastolic tension and relaxation time were markedly increased compared to control (60bpm) (n=7/6 trabeculae /6 human hearts). The extensive molecular characterization of involved ion channels and pathways mediating transition to TCM is currently under investigation. Conclusion This study demonstrates that a persistent tachycardia adversely alters cardiomyocyte excitation-contraction coupling via early electrophysiological cellular remodeling. In pre-existing HF persistent tachycardia strongly aggravates ventricular dysfunction. Our first translational investigation in human myocardium may help to understand the pathophysiology of an underrated and very prevalent disease. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Else-Kröner-Fresenius-Stiftung

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Else Kröner Fresenius Stiftung Background Reticulated platelets (RPs), characterized by youth, hyper-reactivity, and RNA abundance, signify pro-thrombotic potential and serve as predictors for inadequate antiplatelet therapy response post-myocardial infarction. Their pivotal role in chronic coronary syndrome (CCS) and high on-treatment platelet reactivity highlights their significance as promising biomarkers for adverse cardiovascular events in diverse pathological settings. Purpose We aimed to compare for the first time the transcriptomic profiles of RPs and MPs in CCS patients. Methods Using fluorescent activated cell sorting (FACS), RPs and MPs were isolated based on RNA content from peripheral blood of 19 CCS patients. RNA assessment involved the Tapestation 4200 platform (Agilent), and totalRNA libraries were sequenced on a NextSeq 500 Illumina platform. RNA sequencing analysis, with a cut-off of p &lt;0.005 and a log2fc &gt;1, and alternative splicing event detection using MAJIQ, were performed. Circular RNA (circRNA) analysis employed CIRCexplorer. Results Total RNA-sequencing identified 1589 differentially expressed genes, with 1100 transcripts upregulated in RPs and 489 enriched in MPs (Figure 1 A, B and D). Notably, collagen receptor GP6 (log2FC 1.12, p=6.89x10-41), thrombin receptor PAR4 (F2RL3, log2FC 1.1, p=3.54*10-21) and Von Willebrand Factor (log2FC 1.2, p=1.26*10-38) transcripts were significantly enriched in RPs. Gene Ontology identified a higher enrichment of relevant biological categories in RPs compared to MPs, such as "platelet activation", "platelet degranulation" and "blood coagulation" (Figure 1C). These findings are consistent with our previously established discovery and support the hypothesis that RPs in cardiovascular disease are hyper-reactive and pro-thrombotic due to their different RNA content compared to other platelets. Several splicing events were detected as differentially regulated: there is an upregulation of an alternative splicing on the collagen receptor transcript GP6 in RPs (Figure 1E); by the transcript of the G-protein GNAQ, one alternative splicing event was found upregulated in RPs, whilst two others were upregulated in MPs. Moreover, we found an enrichment of the total level of circular RNAs in MPs as compared to RPs (Figure 1F). Several previously undescribed circular RNAs were discovered to be enriched in RPs, as shown in Figure 1F. Conclusion This groundbreaking transcriptomic profiling of RPs and MPs in CCS patients elucidates the biological basis for RPs' hyperreactivity, emphasizing the differential enrichment of platelet activation transcripts. The pronounced upregulation of prothrombotic signaling in RPs provides insight into their hyperactivity and correlation with cardiovascular events. These findings illuminate a novel therapeutic niche in CCS patients, although further investigations are essential to comprehend the detrimental role of RPs in coronary artery disease.

Abstract Background Tachycardia-induced cardiomyopathy (TCM) is a reversible and likely underrecognized form of heart failure. Thus, a better understanding of the TCM-pathophysiology is warranted as the underlying early mechanisms that mediate the progression of TCM remain unclear. Purpose This study aimed to identify the cellular mechanisms of TCM. Methods and results Human induced pluripotent stem cell cardiomyocytes (iPSC-CM) were utilized as a translational human-based model. We performed chronic tachycardic (120 bpm) or normofrequent (control, 60bpm) cell culture pacing to study cellular changes during TCM progression. Already after 24h of tachycardic stimulation of iPSC-CM, we detected a decrease in Ca transient amplitude compared to control (Fura-2, n=49/44 cells/9 differentiations). Diastolic Ca levels and cytosolic Ca elimination were not affected after 24h of tachycardia (n=49/44/9). We detected no difference in sarcoplasmic reticulum (SR) Ca load (assessed via caffeine application) or SERCA activity (Ksys-Kcaff) after 24h of tachycardia (n=13/15/5). However, demonstrating the progress of TCM, 7d of tachycardia resulted in progressive decline of Ca transient amplitude together with an impaired Ca elimination, while diastolic Ca concentration was unchanged (n=73/66/8). These changes may underlie the reduced systolic force and impaired relaxation in TCM. We could explain these results by a significantly reduced SR Ca load and a diminished SERCA activity after 7d tachycardia (n=13/7 vs. 13/4). Using confocal microscopy (Fluo-4) we detected no difference in SR Ca spark frequency after 24h of tachycardia (n=82/66/8), while 7d of tachycardia caused an increase of Ca spark frequency (n=76/79/7), which is a typical hallmark of maladaptive remodeling in HF and likely underlie the reduced SR Ca load. Voltage clamp data of late Na current (INaL) showed no difference in INaL after 24h of stimulation (n=17/6 vs. 19/7), whereas INaL was increased after 7d of tachycardia (n=26/7 vs. 19/6). Accordingly, whole-cell current clamp experiments revealed a prolongation of the action potential after 7d of tachycardia compared to control (n=21/6 vs. 19/5), while no difference of action potential duration could be detected after 24h (n=37/31/8). Resting membrane potential and action potential amplitude were not changed. Finally, we investigated tachycardia-mediated effects on explanted human failing hearts. 8h of tachycardic stimulation (120 bpm) of human failing ventricular trabeculae already compromised systolic force, and diastolic tension and relaxation time were markedly increased compared to control (60bpm, n=8/6 trabeculae /7/6 human hearts). Conclusion This study demonstrates that persistent tachycardia adversely alters cardiomyocyte excitation-contraction coupling via electrophysiological cellular remodeling. Our translational investigation in human myocardium may help to understand the pathophysiology of an underrated but prevalent disease. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Else Kröner-Fresenius-Stiftung (EKFS)Deutsche Gesellschaft für Innere Medizin

Abstract Atrial fibrillation (AF) is often found in patients with heart failure (HF). Clinical data indicated that the arrhythmic component of AF alone could contribute to left-ventricular (LV) dysfunction. However, the effects of non-tachycardic AF with arrhythmic excitation of the human LV, are unknown. We investigated human LV myocardium from patients with sinus rhythm (SR) or normofrequent AF (mean EF&gt;50%, matched clinical data, derived from septal resections during AVR). In histological analysis we detected no difference between SR (n=17 patients) and AF patients (n=18) regarding the amount and distribution of fibrosis. We isolated human LV cardiomyocytes (CM) and studied cellular Ca-handling (Fura-2). Systolic Ca-transient amplitude of LV CM was reduced in patients suffering from AF (n=8 AF patients vs. 11 SR), while diastolic Ca-levels and Ca-transient kinetics were not significantly changed. These results were confirmed in LV CM from non-failing donors (NF) with AF (n=4 AF patients vs. 8 SR). For the standardized investigation of a normofrequent arrhythmia, we simulated AF in vitro by using arrhythmic (60 bpm, 40% beat-to-beat variability) or rhythmic (60 bpm) field stimulation. Human LV CM from NF SR patients (n=8) showed an impaired Ca-transient amplitude after 24h arrhythmic culture pacing without changes in diastolic Ca and Ca-transient kinetics. For studying a model suitable for more standardized chronic pacing, we utilized human iPSC cardiomyocytes (iPSC-CM) from healthy donors (n=6). After 7 days, arrhythmically paced iPSC-CM exhibited a reduced systolic Ca-transient amplitude, a trend towards a prolonged Ca-elimination time and a reduced sarcoplasmic reticulum Ca-load. Confocal line-scans of arrhythmically paced cells (Fluo-4 AM) showed an increased diastolic Ca-leak from the sarcoplasmic reticulum, possibly underlying the reduced Ca-load. Coupled with the Ca changes, cytosolic Na was elevated after arrhythmia. We found an increased late INa, which could explain the detrimentally altered Ca/Na-interplay. Accordingly, Patch-clamp experiments revealed a prolonged action potential duration after arrhythmia. We further elucidated the underlying mechanisms of this electrophysiological remodeling by showing that oxidative stress (H2O2, LPO) is increased in the LV of patients suffering from AF (n=6 AF patients vs. 6 SR), which was associated with an enhanced NOX2/-4 activity. Consecutively, Ca2+/calmodulin-dependent protein kinase IIδ (CaMKII) was found to be more oxidized (CaMKII-Met281/282) in the LV of AF patients (n=7 AF patients vs. 7 SR) leading to an increased CaMKII activity, which adversely regulated EC-coupling protein phosphorylation including RyR2 hyperphosphorylation. Normofrequent arrhythmia/AF impairs human ventricular EC-coupling via increased oxidative stress and enhanced CaMKII. Thus, this translational study provides the first mechanistic characterization and the potential negative impact of isolated AF on the human LV. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Else Kröner-Fresenius-Stiftung (EKFS) and Deutsche Gesellschaft für Innere Medizin

Abstract Background Obstructive sleep apnea (OSA) is associated with structural alterations of the left atria (LA) and increased occurrence of atrial fibrillation (AF). Obstructive respiratory events lead to intermittent hypoxia (IH) and ineffective inspiration against the occluded upper airways, which result in intrathoracic and cardiac transmural pressure changes. Data on reversibility of LA-structural remodeling processes after withdrawal of OSA are still missing. Objectives Aim of the study was to develop a novel AF animal model mimicking intrathoracic pressure changes in addition to IH and to analyze the effect of OSA-withdrawal on atrial remodeling reversibility. Method In sedated rats (2% isoflurane), IH (n=9) was applied by intermittent increase in the respiratory dead volume. Standardized obstructive respiratory events were induced by defined intermittent negative upper airway pressure (INAP = inverse CPAP) applied via a customized mask connected to a negative pressure device (n=9). One minute of IH or INAP was followed by a rest period of nine minutes for four hours every second day. Rats with comparable anesthesia were used as controls (CTR). After three weeks, the animals were sacrificed. To analyze atrial structural remodeling reversibility, additional INAP-rats (n=5) were sacrificed after INAP-withdrawal of three weeks and compared to respective CTR (n=7). Result Blood pressure was not affected by IH or INAP. Intermittent desaturation and post-apneic hyperventilation were comparable in INAP- and IH-rats, but INAP-rats showed significantly higher breathing efforts during apneas compared to IH-rats. LA connexin43 (Cx43) protein expression assessed by quantitative immunofluorescence was reduced in both groups compared to CTR (0.77±0.07% in CTR vs. 0.45±0.06% in IH, p=0.02; CTR vs. 0.39±0.06% in INAP, p=0.005). However, LA interstitial fibrosis content (7.03±0.58% vs. CTR, p=0.01) and LA myocyte diameters (13.23±0.34μm vs. CTR, p=0.03) were increased in INAP-rats, but not in IH-rats. This was associated with longer inducible AF-durations in INAP-rats (11.65±4.43s vs. 0.72±0.33s in CTR, p=0.03) but not in IH-rats (1.28±0.33s vs. CTR, p=0.31). Three weeks of INAP-withdrawal (INAP-W) normalized interstitial fibrosis content (INAP-W vs. CTR, p=0.50) and LA-myocyte diameter (INAP-W vs. CTR, p=0.31). However, LA Cx43 protein expression remained low after three weeks of INAP withdrawal and inducible AF-episodes were still prolonged compared to respective CTR. Conclusion Application of INAP in rats mimics important components of OSA beyond IH and allows the study of an arrhythmogenic substrate in the atrium independent of the development of risk factors. In our model, withdrawal of INAP resulted in partial reversibility of structural LA remodeling but was not sufficient to abolish inducible AF-episodes completely. Future clinical studies are warranted to determine the anti-arrhythmic effect of isolated sleep apnea treatment in AF-patients. Acknowledgement/Funding Else Kröner-Fresenius-Stiftung, SFB-TRR219-M02/S-02