http://www.ikem.cz IKEM - Institut klinické a experimentální medicíny http://www.ikem.cz/img/logo_small.png http://www.ikem.cz 111 97 http://www.ikem.cz/en/sex-specific-and-reproductive-status-dependent-effects-of-liraglutide-on-metabolic-disorders-associated-with-prediabetes/a-5221/ http://www.ikem.cz/en/sex-specific-and-reproductive-status-dependent-effects-of-liraglutide-on-metabolic-disorders-associated-with-prediabetes/a-5221/ Wed, 26 Aug 2026 13:24:50 AbstractGlucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been shown to have beneficial effects in T2D, reducing hepatic lipid storage and improving metabolic dysfunction-associated steatotic liver disease. However, sex and reproductive age may influence their effect. We investigated the effect of liraglutide administration (0.2 mg/kg/day subcutaneously for 8 weeks) on metabolic disorders in relation to sex and reproductive age, using male, female and ovariectomized female hereditary hypertriglyceridemic (HHTg) rats as a prediabetic model. Liraglutide improved glucose tolerance in all HHTg rats. Female and ovariectomized (OVX) female rats showed a stronger effect of lipid metabolism and visceral adiposity than males. Moreover, no changes in hepatic triacylglycerol (TAG) accumulation were observed in males. Liraglutide partially reversed ovariectomy effects, such as increased body weight, visceral obesity and impaired glucose tolerance. Compared with males, female and OVX female rats showed more significant changes in hepatic gene expression involved in lipogenesis (Scd-1, Srebp1, Pparγ), fatty acid and lipid metabolism (Pparα, Hmgcr, Srebp2) and fibrosis (Tgfβ), which may improve hepatic lipid metabolism. Females of fertile age showed greater improvements in insulin sensitivity, reductions in ectopic lipid accumulation, and improvements in lipid metabolism. Depending on sex and reproductive status, liraglutide can mitigate fatty liver before diabetes onset.ConclusionsThe results suggest that sex and reproductive age could be vital factors in determining the efficacy of liraglutide with regard to its metabolic effects. In a prediabetic model, liraglutide treatment improved glucose tolerance independently of sex and reproductive age. However, prediabetic females experienced a reduction in hepatic lipid accumulation and exhibited greater improvements in insulin sensitivity and hepatic lipid metabolism compared to prediabetic males. Both fertile and ovariectomized females observed a favorable effect of liraglutide on hepatic lipid accumulation and visceral adiposity; however, the beneficial effect on insulin sensitivity in prediabetic females was reduced after ovariectomy. Our findings suggest that the response to liraglutide treatment may vary according to sex and reproductive age, emphasizing the need for an individualized approach in people with prediabetes.Published: 9 June 2026 https://www.mdpi.com/2076-3921/15/6/729 http://www.ikem.cz/en/dietary-intake-nutritional-status-and-health-outcomes-among-vegan-vegetarian-and-omnivorous-czech-families/a-5160/ http://www.ikem.cz/en/dietary-intake-nutritional-status-and-health-outcomes-among-vegan-vegetarian-and-omnivorous-czech-families/a-5160/ Fri, 22 May 2026 12:37:44 Background:Vegan diets are gaining popularity in the general population because of their perceived environmental and health benefits. However, concerns remain regarding potential nutrient deficiencies, particularly during critical growth periods. We aimed to compare growth, cardiovascular health, bone turnover, iodine, and overall micronutrient status among families adhering to vegan, vegetarian, and omnivorous dietary habits.Methods:A cross-sectional study was conducted among 95 Czech families (47 vegan, 23 vegetarian, and 25 omnivore), comprising 187 adults and 142 children. Clinical examination, fasting blood, and 3-day prospective diet records were collected to compare growth, cardiovascular health, bone turnover, iodine, and overall micronutrient status among dietary groups and across ages. We used robust mixed-effect models, adjusted for confounders and accounting for family clustering, for group comparison and elastic net logistic regression.Results:No significant differences in children’s growth characteristics between the dietary groups are found. Vegan children have the best cardiometabolic indices (low-density lipoprotein and total cholesterol) observed as well as in adults. Comparable indices of bone turnover among groups are observed, although vitamin D levels are generally highest and urinary phosphate levels lowest in vegan groups. While vegan children show lower urinary iodine, it is not associated with differences in thyroid-stimulating hormone levels compared to other groups. Mixed-effects models demonstrate familial clustering of height, uric acid, high-density lipoprotein, parathormone, and vitamins B12 and D in children and selenium, zinc, iodine, vitamin B12, and folate in adults.Conclusions:Our results show that dietary habits significantly predict nutritional biomarkers, with familial influences contributing to interindividual variability. While vegans have better cardiometabolic profiles, low iodine status could be of concern.Published: November 2025https://www.nature.com/articles/s43856-025-01257-z http://www.ikem.cz/en/archetypal-analysis-of-deceased-donor-kidneys-a-molecular-approach-for-posttransplant-outcomes/a-5156/ http://www.ikem.cz/en/archetypal-analysis-of-deceased-donor-kidneys-a-molecular-approach-for-posttransplant-outcomes/a-5156/ Tue, 5 May 2026 10:24:10 AbstractDonor kidney tissue-based transcriptomics may represent a new dimension for the prediction of kidney transplant outcomes. In this prospective, single-center study, 276 kidneys from 174 deceased brain-death donors were assessed by microarrays to identify phenotypes of procurement biopsies. Molecular classifiers (extreme gradient boosting, logistic, and Poisson regression) with 10-fold cross-validation were employed to categorize donors based on clinical variables (age, body mass index, hypertension, expanded criteria donor kidney) and histologic scores (vascular fibrous intimal thickening, interstitial fibrosis, tubular atrophy, arteriolar hyaline thickening). Archetypal analysis and linear mixed model were applied to determine molecular phenotypes and their association with 1-year posttransplant estimated glomerular filtration rate (eGFR) in 234 donor kidneys. Three molecular archetypes were identified. The “ideal” archetype (median donor age 42 years, low Kidney Donor Risk Index [KDRI], minimal chronic histologic changes) was associated with the highest 1-year eGFR, whereas the “marginal” archetype (68 years, extensive chronic changes, high KDRI) was associated with the lowest one. The “intermediate” archetype yielded better 1-year eGFR despite donor profiles similar to the marginal group. Although KDRI predicted 1-year eGFR, adding molecular archetypes improved model performance (Akaike Information Criterion [AIC] 80.0 vs 83.7; P < .05). External validation in an independent data set (n = 174, GSE147451) confirmed the predictive value of the model. Molecular profiling of procurement biopsies may help to identify donor kidneys with higher posttransplant eGFR.Materials and methodsThis is a single-center prospective observational study. Wedge donor kidney procurement biopsies were performed at the back table between April 2021 and November 2022. In addition to histology, biopsy specimens were stored at –80 °C in RNAlater for future transcriptomics. The primary aim of the study was to create a molecular classifier of the donor kidney quality useful for posttransplant outcome prediction. A total of 12 kidney biopsies in donors after circulatory death (DCD) were assessed separately as warm ischemia before procurement may affect molecular signals. Finally, 276 kidney biopsies in 174 brain-death deceased donors were analyzed and posttransplant outcomes were available in 234 of them. The primary endpoint was 1-year estimated glomerular filtration rate (eGFR) after transplantation, calculated using the 2009 CKD-EPI equation. All biopsies were scored for vascular fibrous intimal thickening, interstitial fibrosis and tubular atrophy, and arteriolar hyaline thickening.https://doi.org/10.1016/j.ajt.2025.09.024Published: 5 March 2026 http://www.ikem.cz/en/a-vegan-diet-signature-from-a-multi-omics-study-on-different-european-populations-is-related-to-favorable-metabolic-outcomes/a-5137/ http://www.ikem.cz/en/a-vegan-diet-signature-from-a-multi-omics-study-on-different-european-populations-is-related-to-favorable-metabolic-outcomes/a-5137/ Mon, 16 Mar 2026 13:36:15 AbstractVegan and omnivorous diets differ markedly in composition, but their effects on the gut microbiome, metabolome, and lipidome across populations remain insufficiently characterized. While both diet and country of origin influence these molecular layers, the relative contribution of diet versus country-specific factors has not yet been systematically evaluated within a multi-omics framework.In this cross-sectional, bicentric, observational study, we profiled healthy vegans (n = 100) and omnivores (n = 73) from the Czech Republic and Italy using integrated microbiome, metabolome, and lipidome analyses. Findings were subsequently validated in an independent cohort (n = 142).Significant differences across all omics layers were observed for both country and diet. The predictive models confirmed diet-associated separation, with validation cohort AUCs of 0.99 (lipidome), 0.89 (metabolome), and 0.87 (microbiome). Functional metagenome analysis revealed enrichment of amino acid biosynthesis, inositol degradation, and the pentose phosphate pathway in vegans, while omnivores presented greater potential for amino acid fermentation, fatty acid biosynthesis, and propanoate metabolism. Linear models identified a robust, country-independent “vegan signature” consisting of 27 lipid metabolites, five non-lipid metabolites, and 11 bacterial species. Several lipid features associated with an omnivorous diet were inversely related to the duration of vegan diet adherence. Some of the vegan-associated metabolites and bacteria have been previously linked to favorable cardiometabolic profiles, although causality remains to be established.These findings demonstrate that vegan diets are associated with reproducible, country-independent molecular and microbial signatures. Our results highlight diet-driven shifts in host–microbiota interactions and provide a framework for understanding how dietary patterns relate to host–microbiota interactions.Published December 2025https://www.tandfonline.com/doi/10.1080/19490976.2025.2593050?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed#abstract http://www.ikem.cz/en/exploring-the-potential-of-soluble-guanylyl-cyclase-stimulators-and-activators-in-heart-failure/a-5092/ http://www.ikem.cz/en/exploring-the-potential-of-soluble-guanylyl-cyclase-stimulators-and-activators-in-heart-failure/a-5092/ Tue, 23 Dec 2025 12:53:10 AbstractHeart failure (HF) is a life-threatening disease characterized by substantial morbidity and mortality. Yet despite recent advances, prognosis remains poor. Cyclic guanosine 3',5'-monophosphate (cGMP) mediates a wide range of physiological processes in various cell types. Its deficiency has been implicated in numerous pathological cardiovascular diseases, including HF, pulmonary hypertension (PH), and kidney disease. Therefore, restoring and enhancing the nitric oxide (NO)-soluble guanylyl cyclase (sGC)-cGMP signalling pathway appears to have far-reaching therapeutic potential. The discovery of sGC stimulators and activators marked a milestone in the field of NO-sGC-cGMP pharmacology, enabling NO-independent and long-acting enhancement of cGMP signalling without the formation of NO-derived radicals. Over a decade ago, the sGC stimulator riociguat was approved for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH). More recently, the sGC stimulator vericiguat was approved for symptomatic chronic HF. A number of sGC activators are currently being investigated for the treatment of chronic kidney diseases. This review summarizes the evidence for NO-sGC-cGMP signalling in the regulation of cardiovascular and cardiac function, focusing on preclinical and clinical evidence for sGC stimulators and sGC activators in HF subtypes. Promising results have been observed in clinical trials of HF with reduced ejection fraction (HFrEF), but not in clinical trials of HF with preserved ejection fraction (HFpEF). Further studies are needed to determine the precise mechanisms of action of sGC agonists in HF and associated cardiorenal diseases to fully leverage their therapeutic potential and address the challenges of implementing these agents in routine clinical practice.Summary of the preclinical findingsSGC stimulators and activators exhibit significant therapeutic potential in multiple preclinical models of CV diseases. Given the role of impaired NO–cGMP signalling in CV diseases, both sGC stimulators and sGC activators represent promising therapeutic classes due to their unique mode of action in restoring cGMP levels independently of NO.One of the key mechanisms by which sGC stimulators and activators exert beneficial effects is through lowering BP, achieved through vascular smooth muscle relaxation mediated by cGMP-mediated vasodilation. HTN is considered the most common risk factor for the development of hypertensive heart disease and can exacerbate ventricular remodelling, fibrosis, and the progression of both HFrEF and HFpEF. By reducing afterload, these agents improve CO and LV performance, as demonstrated in numerous models of pressure-overload and HTN-induced HF. Importantly, this BP-lowering effect also contributes to improved survival in models of malignant hypertension and volume overload, indirectly relieving cardiac stress and preventing adverse remodelling. However, while BP reduction is beneficial in the earlier phases of HF progression, there is a risk of hypotension in patients with already established HF, particularly those with compromised cardiac function who are concurrently receiving other therapies (RAAS inhibitors and beta-blockers) with hypotensive effects.Published: December 2025https://doi.org/10.1016/j.bcp.2025.117363 http://www.ikem.cz/en/acute-durability-of-cavotricuspid-isthmus-block-after-pulsed-electric-field-ablation-randomized-comparison-of-two-pentaspline-catheter-configurations/a-5087/ http://www.ikem.cz/en/acute-durability-of-cavotricuspid-isthmus-block-after-pulsed-electric-field-ablation-randomized-comparison-of-two-pentaspline-catheter-configurations/a-5087/ Tue, 16 Dec 2025 10:57:09 Cavotricuspid isthmus (CTI) ablation is commonly performed alongside catheter ablation of atrial fibrillation (AF). However, the acute efficacy of the CTI ablation using the pentaspline catheter and pulsed electric field (PEF) energy has not been systematically evaluated. This randomized study assessed the acute efficacy and extent of haemolysis associated with CTI ablation when performed using two different configurations of the pentaspline catheter.Methods and resultsA total of 178 patients (age 65 ± 10 years, 66% of males) undergoing PEF ablation of the CTI in conjunction with AF ablation were randomly assigned to receive ablation using either the basket configuration (n = 95) or the flower configuration (n = 83) of the pentaspline catheter. The CTI ablation was performed before left atrial ablation. It was guided by intracardiac echocardiography, and bidirectional block was confirmed by pacing manoeuvres. Venous blood samples to assess haemolytic biomarkers were collected before and immediately after the CTI ablation. The groups were broadly comparable in baseline characteristics. The flower group demonstrated superior procedural efficiency, with fewer applications required to achieve a CTI block (3.4 ± 3.1 vs. 8.0 ± 4.1, P < 0.001), a shorter time to block (96 ± 289 vs. 177 ± 192 s, P < 0.001), and fewer total applications (10.1 ± 3.4 vs. 13.3 ± 5.1, P < 0.001). Acute reconduction occurred in 20% of cases overall, but was significantly lower in the flower group (6% vs. 32%, P < 0.001; hazard ratio: 0.14, 95% confidence interval: 0.06–0.40). Haemolysis was notably lower in the flower group, with significantly less post-procedural free haemoglobin (154 ± 112 vs. 210 ± 115 mg/L, P < 0.001). One case of transient ST elevations occurred in the flower group without clinical consequence.ConclusionPulsed electric field ablation of the CTI using the flower configuration of the pentaspline catheter demonstrated higher acute efficacy in achieving CTI block and a more favourable safety profile regarding haemolysis compared to the basket configuration. This is likely due to the larger footprint and improved tissue contact of all electrodes, minimizing the leakage of PEF energy into the blood pool.https://doi.org/10.1093/europace/euaf234Published: 23 September 2025 http://www.ikem.cz/en/transpulmonary-proteome-gradients-identify-pathways-involved-in-pulmonary-vascular-disease-due-to-heart-failure/a-5048/ http://www.ikem.cz/en/transpulmonary-proteome-gradients-identify-pathways-involved-in-pulmonary-vascular-disease-due-to-heart-failure/a-5048/ Wed, 5 Nov 2025 15:27:43 ##VIDEO_5047####VIDEO_5046##Transpulmonary Proteome Gradients Identify Pathways Involved in Pulmonary Vascular Disease Due To Heart Failure | Circulation: Heart FailureMelenovsky V, Jarolim P, Kutilkova E, Jenca D, Binova J, Al-Hiti H, Franekova J, Kikerlova S, Yarnykh S, Adamova M, Miklovic M, Borlaug BA. Transpulmonary Proteome Gradients Identify Pathways Involved in Pulmonary Vascular Disease Due To Heart Failure. Circ Heart Fail. 2025 Sep 23:e013208. doi: 10.1161/CIRCHEARTFAILURE.125.013208. Epub ahead of print. IF 8,900. (2024)AbstractBACKGROUND:Some, but not all, patients with heart failure (HF) develop pulmonary vascular disease (PVD), which contributes to poor prognosis. Mechanisms leading to PVD in HF are poorly understood. We aimed to analyze transpulmonary gradients of proteins consumed or elaborated across the lungs to identify mediators of PVD by unbiased proteomics.METHODS:Overall, 21 controls and 160 patients with HF with reduced ejection fraction underwent pulmonary artery catheterization with blood sampling from postcapillary (wedged balloon) and precapillary (unwedged) position to obtain transpulmonary gradients. The samples from controls and HF from the highest (Q4, n=40) and lowest quartile (Q1, n=40) of pulmonary vascular resistance (PVR) were analyzed using the proteomic proximity extension assay (Olink) of 275 proteins. Venous blood concentrations or transpulmonary gradients were analyzed to identify biomarkers or potential mediators of PVD.RESULTS:Comparison of Q1 and Q4 of PVR identified PSP-D (pulmonary surfactant-associated protein D) as a marker of PVD. Examination of gradients across the lungs in high PVR HF revealed significant uptake of 18 proteins, mostly associated with inflammation (chemokines, oncostatin-M, MMP9 [matrix metalloproteinase 9]) or with TGF (transforming growth factor)/activin pathway (GDF2 [growth differentiation factor 2]/BMP9 [bone morphogenic protein 9]), and release of 5 proteins, notably IL (interleukin) 6 and IL33. In contrast, these protein gradients were negligible in controls and low PVR patients with HF. Active pulmonary release of IL6 contributed to systemic elevation of IL6 and correlated with right ventricular functionCONCLUSIONS:The lungs of patients with HF with high PVR display abnormal uptake and release of proinflammatory cytokines from IL6/gp130 family (IL6, IL33, oncostatin-M), along with increased transpulmonary uptake of GDF2/BMP9. The study shows that proteins orchestrating inflammation or pulmonary vessel remodeling in group 1 pulmonary hypertension, are also operating in patients with PVD due to HF.https://www.ahajournals.org/doi/10.1161/CIRCHEARTFAILURE.125.013208 http://www.ikem.cz/en/glucose-control-in-type-1-diabetes-after-pancreas-transplantation-does-automated-delivery-offer-comparable-results/a-5036/ http://www.ikem.cz/en/glucose-control-in-type-1-diabetes-after-pancreas-transplantation-does-automated-delivery-offer-comparable-results/a-5036/ Thu, 16 Oct 2025 13:56:22 ##VIDEO_5034####VIDEO_5035##Glucose Control in Type 1 Diabetes after Pancreas Transplantation: Does Automated Delivery Offer Comparable Results?Zahradnická Martina 1, Nemétová Lenka 1, Kahle Michal 2, Vávra David 1, Bém Robert 1, Girman Peter 1, Haluzík Martin 1, Saudek František 3Affiliations(1) Diabetes Center, Institute of Clinical and Experimental Medicine, Prague, Czech Republic;(2) Department of statistics, Institute of Clinical and Experimental Medicine, Prague, Czech Republic; (3) Center for Experimental Medicine, Laboratory for Pancreatic Islets, Institute of Clinical and Experimental Medicine, Prague, Czech Republic Aims     Pancreas transplantation ensures long-term near-normal glycemic control for patients with type 1 diabetes but transplantation procedure carry risks including surgical complications, infection, graft loss, and the need for long-term immunosuppressive medication Recent technological advancements have included the automated insulin delivery systems (AID), that combine continuous glucose monitoring with insulin pumps to automatically adjust insulin delivery based on real-time glucose readings. In this prospective study, we compared glycemic control outcomes in patients with type-1 diabetes who underwent a simultaneous pancreas-kidney transplantation versus with an AID system. Patients and methods     As a part of the prospective SIMA SPK study (Eudra CT No. 2019–002240-24) we performed a comparative analysis including parameters from 31 consecutive pancreas–kidney transplantation recipients versus from 377 people using an AID—either MiniMed 780G (n = 200) or Tandem t:slim X2 Control-IQ (n = 177) using an AID system for at least 3 months and reflecting >75% of time using an AID control regimen. Results are presented with 95% confidence intervals (CIs) to provide estimates of effect sizes and their precision. For comparison, P-values are also provided.Results     Compared to the MiniMed and Tandem AID groups, transplant recipients at one month (mean ± SD: 36 ± 12 days) after pancreas transplantation exhibited significantly lower HbA1c (mean [95% CI]) (38 mmol/mol [36, 40] versus 55 [53, 57], and 56 [55, 57], respectively), lower mean glycemia (6.4 mmol/L [6, 6.8] versus 8.5 [8.3, 8.7] and 8.2 [8.0, 8.4], respectively), and spent more time “in range” (90% [86, 93] versus 72% [70, 74] and 75% [73, 77], respectively). Time below range (glycemia 3.0 – 3.8 mmol/L and < 3.0 mmol/L) did not differ significantly between the transplant and the entire AID group (P = 0.14 and P = 0.86, resp.). Pancreatic graft function remained stable, with HbA1c of 39 ± 4.2 mmol/mol at 3 months, and 39 ± 3.6 mmol/mol at 1 year post-transplantation without the need of exogenous insulin treatment.  Conclusions     In conclusion, our study demonstrates that at 1-month post-transplant, pancreas-kidney transplant recipients exhibit better metabolic control, compared with patients treated with commonly used AID systems. The exception was hypoglycemia, for which the AID systems showed efficacy comparable with that of pancreas transplantation.  Funding InformationThis trial was an independent investigator-initiated study funded by the: 1. AZV MZ ČR (NW24-01-00138), Czech Ministry of Health; 2. the project National Institute for Research of Metabolic and Cardiovascular Diseases (Programme EXCELES, ID Project No. LX22NPO5104), funded by the European Union, Next Generation EU; and 3. supported by MH CZ – DRO (IKEM, IN 00023001)Glucose Control in Type 1 Diabetes after Pancreas Transplantation: Does Automated Delivery Offer Comparable Results? | Diabetes Technology & Therapeutics http://www.ikem.cz/en/efficacy-of-autologous-cell-therapy-on-limb-salvage-in-patients-with-chronic-limb-threatening-ischemia-16-year-single-center-experience/a-5019/ http://www.ikem.cz/en/efficacy-of-autologous-cell-therapy-on-limb-salvage-in-patients-with-chronic-limb-threatening-ischemia-16-year-single-center-experience/a-5019/ Tue, 23 Sep 2025 15:52:47 ##VIDEO_5017####VIDEO_5018##Efficacy of autologous cell therapy on limb salvage in patients with chronic limb-threatening ischemia: 16-year single-center experienceAimsAutologous cell therapy (ACT) could be a treatment option for patients with chronic limb-threatening ischemia (CLTI) when standard vascular intervention is impossible. This study aimed to analyze risk factors affecting therapeutic success and identify patients with diabetes most responsive to ACT.MethodsIn this prospective study, 129 treatments were provided to 118 limbs in 107 no-option CLTI patients with diabetes. Bone marrow was obtained, and stem cells were processed and injected into the calf muscles of the affected limb. After 16 years, we analyzed the influence of baseline factors related to patients (diabetes parameters, comorbidities, medications), limb ischemia (TcPO2 value, Graziani and GLASS classifications), ulcer (descriptions according to Wagner, WIfI, SINBAD and Texas classifications), and infection (the value of CRP, the presence of the osteomyelitis, resistant bacteria and clinical signs of infections). Outcomes were limb salvage (LS) and amputation-free survival (AFS), which were assessed using Cox regression models. SummaryThis study presented ACT as a prospective method of revascularization for no-option CLTI patients. Our results suggest that the best initial clinical status of the patient at the time of stem cell administration is the absence of any signs of infection, and stenosis of FP segments. ACT therapy should be more strictly considered in patients with the presence of severe stages of CKD, hemodialysis and those treated with immunosuppressive therapy. Because most of the amputations have been performed within the first year after the therapy, it is the most important period for reducing major amputation rates and prolonging AFS by close follow-up and aggressive management of risk factors such as infection and poor nutritional status.https://doi.org/10.1186/s13287-025-04493-1Published: 15 July 2025 http://www.ikem.cz/en/deep-visual-proteomics-maps-proteotoxicity-in-a-genetic-liver-disease/a-5007/ http://www.ikem.cz/en/deep-visual-proteomics-maps-proteotoxicity-in-a-genetic-liver-disease/a-5007/ Mon, 8 Sep 2025 16:13:25 ##VIDEO_5005####VIDEO_5006##Deep Visual Proteomics maps proteotoxicity in a genetic liver diseaseAimsProtein misfolding diseases, including α1-antitrypsin deficiency (AATD), pose substantial healthchallenges, with their cellular progression still poorly understood. We use spatial proteomics by massspectrometry and machine learning to map AATD in human liver tissue. Combining Deep VisualProteomics (DVP) with single-cell analysis we probe intact patient biopsies to resolve molecularevents during hepatocyte stress in pseudotime across fibrosis stages. We achieve proteome depth of up to 4,300 proteins from one-third of a single cell in formalin-fixed, paraffin-embedded tissue. Thisdataset reveals a potentially clinically actionable peroxisomal upregulation that precedes the canonicalunfolded protein response. Our single-cell proteomics data show α1-antitrypsin accumulation islargely cell-intrinsic, with minimal stress propagation between hepatocytes. We integrated proteomicdata with artificial intelligence-guided image-based phenotyping across several disease stages, revealing a late-stage hepatocyte phenotype characterized by globular protein aggregates and distinctproteomic signatures, notably including elevated TNFSF10 (also known as TRAIL) amounts. Thisphenotype may represent a critical disease progression stage. Our study offers new insights into AATD pathogenesis and introduces a powerful methodology for high-resolution, insitu proteomic analysis ofcomplex tissues. This approach holds potential to unravel molecular mechanisms in various protein misfolding disorders, setting a new standard for understanding disease progression at the single-cell level in human tissue. MethodsClinical cohorts and sample preparationPatient biopsies and explant samples were obtained at two different sites, Odense University Hospital(OUH) and Aachen RWTH University Hospital (UKA). The sample origin is indicated in Supplementary Table. Following ethica guidelines, the clinical data provided here are deidentified by reporting only sample type, fibrosis score and site of origin.Summary Spatial omics technologies are revolutionizing our ability to deconvolute molecular events at single-cell resolution within a tissue context. Whereas much focus has been placed on spatial genomics and transcriptomics, recent advances in multiplexed imaging and proteomics are beginning to shed light on the functional proteomic layer. Mass spectrometry (MS)-based proteomics has made significant stridestowards biologically informative single-cell analysis, now enabling quantification of up to 5,000 proteins in cultured cells. In the tissue context, we have recently introduced Deep Visual Proteomics(DVP), which integrates staining, artificial intelligence-guided cell segmentation and classification, laser microdissection of single-cell shapes and high-sensitivity MS. DVP excels in digital pathologyapplications with pronounced spatial and visual components, providing simultaneous and deepproteomic characterization at the level of thousands of proteins.We reasoned that these emerging technologies would be ideally suited to elucidate molecular eventsduring the progressive worsening of proteotoxicity as it unfolds in patients. Proteotoxicity, characterized by the accumulation of misfolded and aggregated proteins leading to cell damage, is a hallmark of many diseases, including neurodegenerative pathologies such as Alzheimer’s disease and Parkinson’s disease. The underlying cause of proteotoxicity is a disruption in protein homeostasis, resulting in an imbalance between protein synthesis, folding and clearance mechanisms.To investigate proteotoxicity in a clinically relevant context, we focused on a disorder with unmetclinical need that exemplifies the challenges of protein misfolding and aggregation in a vital organ. The fibrogenic liver disease α1-antitrypsin (AAT) deficiency (AATD) is a genetic disorder caused by autosomal, codominant mutations in the SERPINA1 gene, resulting in misfolding and accumulation ofAAT in hepatocytes. Most severe AATD cases are caused by a homozygous Z-variant (Pi*ZZ genotype) with a peak incidence of 1:2,000 in individuals of European descent. Current hypothesessuggest that the severity of liver damage correlates with the amount of accumulated AAT. However, the mechanisms driving fibrogenesis or hepatocyte survival versus death remain unclear, leavingpotentially druggable targets unexplored.To address this challenge, we curated a cohort of formalin-fixed paraffin-embedded (FFPE) biopsiesand liver explants from patients homozygous for the pathogenic Z-variant, encompassing all fibrosisstages (n = 34; Extended Data Fig. and Supplementary Table). Despite the same underlying disease-causing mutation at a similar median age (58 ± 10 (s.d.) years) and BMI (25.2 ± 4.0), fibrosis stagesvaried drastically, indicating unexplored molecular resilience or risk profiles.https://www.nature.com/articles/s41586-025-08885-4Published: 16 April 2025 http://www.ikem.cz/en/economic-burden-of-podiatric-care-for-diabetic-foot-ulcers-in-czech-republic-prospective-multicenter-study/a-4993/ http://www.ikem.cz/en/economic-burden-of-podiatric-care-for-diabetic-foot-ulcers-in-czech-republic-prospective-multicenter-study/a-4993/ Fri, 22 Aug 2025 14:53:32 ##VIDEO_4991####VIDEO_4992##Economic burden of podiatric care for diabetic foot ulcers in Czech Republic: Prospective multicenter studyAims (DF), especially  (DFUs) are a relatively frequent and financially burdensome late-stage . However, data on the costs of podiatric care in the Czech Republic are scarce. The aim of this prospective multicenter study was to determine the total costs associated with long-term podiatric care in selected foot clinics across the Czech Republic.Research Design and MethodsA total of 119 patients with DFUs (mean age of 68 ± 11 years, diabetes duration of 19 ± 11 years,  level of 62 ± 14 mmol/mol, composite  score of 3 ± 2, 33 % had new DFUs, 37 % previous amputations, and 50 % had  (PAD)) from 10 podiatric foot clinics in the Czech Republic were enrolled in our financial analysis. Direct and indirect costs associated with podiatric care − diagnostic and treatment methods – including angiological, radiological, and , blood sampling, prescribed materials for local therapy, antibiotics, surgical procedures, offloading devices, hospital services and additional expenses such as patient transportation, doctors’ visits, home care assistance, and work incapacity – were monitored over a 6-month period using an electronic database.ResultsThe average cost of podiatric care per patient over a 6-month period was €2,506 with median €1,320. The largest expenses were spent on therapeutic procedures (51.4 %). Costs for patients hospitalized during the study period were significantly higher than for outpatients (€7,923 vs. €1,304 on average; P < 0.001). Among hospitalized patients, the main costs were hospital services (32 %), therapeutic procedures (26 %), and  and local therapies (20 %). Among outpatients, therapeutic procedures accounted for 74 % of the total costs. Newly developed DFUs or PAD were not linked to significantly increased costs. The composite  score, primarily the wound component, was the only parameter that significantly positively correlated with the total podiatric costs (r = 0.434; 95 % CI 0.279–0.559; P < 0.0001). Other  such as age, diabetes duration, DFU duration, and  level did not show significant cost correlations.ConclusionsOn average, podiatric care for patients with DFUs in the Czech Republic is 3 to 9 times more expensive than standard diabetes healthcare. The expenses for hospitalized patients are almost 6 times higher than for outpatients. The composite  score was the most significant indicator of podiatric financial burden. https://doi.org/10.1016/j.diabres.2025.112141Published: 18 July 2025 http://www.ikem.cz/en/renal-denervation-improves-cardiac-function-independently-of-afterload-and-restores-myocardial-norepinephrine-levels-in-a-rodent-heart-failure-model/a-4853/ http://www.ikem.cz/en/renal-denervation-improves-cardiac-function-independently-of-afterload-and-restores-myocardial-norepinephrine-levels-in-a-rodent-heart-failure-model/a-4853/ Wed, 5 Feb 2025 15:05:50 ##VIDEO_4851####VIDEO_4852##AbstractRenal nerves play a critical role in cardiorenal interactions. Renal denervation (RDN) improved survival in some experimental heart failure (HF) models. It is not known whether these favorable effects are indirect, explainable by a decrease in vascular afterload, or diminished neurohumoral response in the kidneys, or whether RDN procedure per se has direct myocardial effects in the failing heart. To elucidate mechanisms how RDN affects failing heart, we studied load-independent indexes of ventricular function, gene markers of myocardial remodeling, and cardiac sympathetic signaling in HF, induced by chronic volume overload (aorto-caval fistula, ACF) of Ren2 transgenic rats. Volume overload by ACF led to left ventricular (LV) hypertrophy and dysfunction, myocardial remodeling (upregulated Nppa, MYH 7/6 genes), increased renal and circulating norepinephrine (NE), reduced myocardial NE content, increased monoaminoxidase A (MAO-A), ROS production and decreased tyrosine hydroxylase (+) nerve staining. RDN in HF animals decreased congestion in the lungs and the liver, improved load-independent cardiac function (Ees, PRSW, Ees/Ea ratio), without affecting arterial elastance or LV pressure, reduced adverse myocardial remodeling (Myh 7/6, collagen I/III ratio), decreased myocardial MAO-A and inhibited renal neprilysin activity. RDN increased myocardial expression of acetylcholinesterase (Ache) and muscarinic receptors (Chrm2), decreased circulating and renal NE, but increased myocardial NE content, restoring so autonomic control of the heart. These changes likely explain improvements in survival after RDN in this model. The results suggest that RDN has remote, load-independent and favorable intrinsic myocardial effects in the failing heart. RDN therefore could be a useful therapeutic strategy in HF.ResultsWeights, cardiac dimensions and principal LV hemodynamicsTable 1 shows organ weights and hemodynamics in the sham-operated control group, in a group with HF induced by ACF, and in a group with ACF and RDN. The sham/RDN group compared to the sham/intact group displayed no significant changes in organ weight parameters but significantly decreased end-systolic pressure (149 ± 3.8 vs. 169 ± 3.7 mmHg, p < 0.05) and mean LV pressure (65 ± 2.2 vs. 75.4 ± 3.7 mmHg, p < 0.05).ACF had an impact on multiple organ weight parameters that are typically changed in HF, with no effect on the body weight or tibia length (not shown). ACF/intact rats had increased heart weight and LV weight. Similarly, compared to the sham group, ACF/intact rats had significantly increased weight of the left atrium (LA) and weight of the lungs, reflecting HF-related congestion. Compared to the sham/intact group, ACF/intact rats had significantly increased stroke volume, stroke work, and cardiac output. End-systolic and end-diastolic pressure (EDP) measured by PV analysis were increased in ACF/intact group compared to the sham/intact group, similar to echocardiographic measurements (Fig. 1b, c). Moreover, ACF rats had also a significant decrease in end-systolic pressure (143 ± 3.1 vs. 169 ± 3.7 mmHg, p < 0.05) compared to sham rats.Fig. 1figure 1In vivo measurement of LV contractility and dimensions. a Representative pressure-volume loops from invasive pressure-volume analysis. Red line—end-systolic elastance (Ees), blue line—end-diastolic pressure-volume relationship (EDPVR). b Echocardiographic M mode images of parasternal long axis view. LV AWd left ventricular anterior wall thickness in diastole, LV AWs left ventricular anterior wall thickness in systole, LVIDd left ventricular internal diameter in diastole, LVIDs left ventricular internal diameter in systole, LV PWd left ventricular posterior wall thickness in diastole, LV PWs left ventricular posterior wall thickness in systole. c Diameter of left ventricle in systole (LVIDs) and diastole (LVIDd) measured during each week of experiment (3 weeks); FS fractional shortening. N = 10 in sham/intact, N = 19 in ACF/intact, N = 13 in ACF/RDN. ###p < 0.001; ##p < 0.01; #p < 0.05, ACF/intact vs. ACF/RDN group, compared to the day 14Compared to intact ACF, RDN significantly decreased heart weight, LA, LV weight, and congestion of the lungs and liver. RDN in ACF rats significantly decreased stroke work and normalized stroke volume and cardiac output. RDN in ACF rats also decreased dilatation of LV (Fig. 1b, c), which was shown as reduced LV end-systolic and end-diastolic volumes. We observed that ACF/RDN group had also reduced EDP (8.2 ± 0.69 vs. 12.7 ± 1.63 mmHg, p < 0.05) compared to ACF intact group. Heart rate was not affected by ACF or RDN in any groups.LV function and HF markers: the impact of ACFACF/intact group had significantly decreased systolic function compared to the sham/intact group. ACF/intact group had also decreased end-systolic elastance (Ees) and preload recruitable stroke work (PRSW) compared to the sham/intact group. ACF/intact had also decreased ventricular-arterial coupling compared to sham/intact (Ees/Ea ratio, Fig. 2a).Fig. 2figure 2LV function and gene expression of selected HF markers and the impact of RDN. a Systolic function parameters measured by invasive PV analysis, Ees/Ea, ventricular-arterial coupling ratio. b Gene expression of markers of fibrosis—collagen I/III (Col1a1/Col3a1) ratio, myocardial stress—Myosin heavy chain 7/6 (Myh 7/6) ratio, natriuretic peptide A (Nppa) and mitochondrial fatty acid beta-oxidation pathway, acyl-CoA dehydrogenase medium chain (Acadm). N = 9 in sham/intact, N = 9 in ACF/intact, N = 10 in ACF/RDNACF/intact group had extensive upregulation of markers of myocardial damage/remodeling compared to the sham/intact group. ACF/intact group had increased fibrotic marker collagen I/III (Col1a1/Col3a1) gene expression ratio. Similarly, maladaptive hypertrophy markers myosin heavy chain isotype ratio (Myh 7/6) and myocardial stress gene natriuretic peptide A (Nppa) were increased in ACF/intact group compared to the sham/intact group. ACF/intact group had a significantly decreased (p = 0.05) medium-chain acyl-Coa dehydrogenase (Acadm, Fig. 2b).Cardiac autonomic nervous system: the impact of ACFACF rats had significantly increased NE levels in plasma and kidney (Fig. 3a, b), but depleted LV content of NE compared to the sham group (Fig. 3c). Correspondingly, we observed decreased LV protein expression of the key NE-synthetizing enzyme tyrosine hydroxylase (TH) in the LV (Fig. 3d) and diminished LV myocardial density of TH-positive sympathetic nerves (Fig. 4a, c, d). From proteins involved in the myocardial fate of NE, we observed an increased expression (p = 0.03) of presynaptic norepinephrine transporter (NET, responsible for synaptic NE reuptake, Fig. 3e) and significant decrease of organic cation transporter (OCT3, responsible for myocardial uptake of NE) in ACF compared to the sham/control group (Fig. 3f). MAO-A, NE-degrading enzyme was upregulated (Fig. 3g) and correspondingly, ROS generated by MAO-A (Fig. 3h) were increased in ACF LV, while gene expression of Adrb1 was downregulated compared to sham/intact group (Fig. 3i).Fig. 3figure 3Impact of ACF and effects of RDN on selected parameters of sympathetic nervous system in left ventricle. a Plasma norepinephrine (NE). b NE content in kidney. c NE content in left ventricle (LV). d Biosynthesis of NE—protein expression of tyrosine hydroxylase (TH). e Preganglionic NE transport—protein expression of NE transporter (NET). f NE transport to cardiomyocyte—protein expression of organic cation transporter 3 (OCT3). g Degradation of NE—protein expression of monoamine oxidase A (MAO-A). h Production of reactive oxygen species (ROS) by MAO-A. i Gene expression of beta-1 adrenergic receptor (Adrb1). j Gene expression of choline muscarinic receptor type 2 (Chrm2). k Gene expression of acetylcholinesterase (Ache). l Neprilysin activity measured in kidney. N = 8 in sham/intact, N = 8 in ACF/intact, N = 8 in ACF/RDNFig. 4figure 4Results of immunohistochemical staining of tyrosine hydroxylase (TH, red color) in left ventricle. Zoom 25x in a smaller square embedded in an illustrative zoom 2x in a larger square. a Ratio of sympathetic nerves immunostained with TH antibody to the total area. b sham/intact. c ACF/intact. d ACF/RDN. N = 4 in sham/intact, N = 5 in ACF/intact, N = 4 in ACF/RDNIn parasympathetic cardiac signalization, ACF/intact rats had decreased acetylcholinesterase (Ache) and an unsignificant trend to decreased choline muscarinic receptor type 2 (Chrm2, Fig. 3j, k) in the LV compared to sham/intact.ACF/intact rats displayed increased neprilysin activity in the kidney, compared to the sham/intact group (Fig. 3l).LV function and HF markers: the impact of RDNRDN procedure significantly improved LV systolic function in ACF/RDN animals compared to the ACF/intact group. ACF/RDN group had increased Ees, PRSW, and Ees/Ea ratio compared to ACF/intact group (Fig. 2a). Peak LV pressure or effective arterial elastance (Ea) was not affected by RDN (2 ± 0.23 vs. 2.2 ± 0.22, p = 0.5, see Supplementary Information).ACF/RDN group had less elevated markers of adverse myocardial remodeling compared to ACF/intact group—reduced gene expression of fibrotic markers (Col1a1/Col3a1 ratio), decreased the Myh 7/6 ratio compared to ACF/intact group, while Nppa gene expression was not significantly reduced. After RDN in the ACF group, we did not observe any changes in medium-chain fatty acids in gene expression of Acadm compared to ACF/intact rats (Fig. 2b).Cardiac autonomic nervous system in HF: the impact of RDNRDN in ACF rats significantly reduced NE in the plasma and in the kidney (Fig. 3a, b). Despite we targeted the sympathetic nervous system in the kidney, we observed profound changes of sympathetic nerves in the heart—RDN led to increased NE levels in LV compared to ACF/intact rats (Fig. 3c).In ACF/RDN group, we observed a numerically higher, but not significant increase in protein expression of TH (Fig. 3d). Sympathetic nerve density measured by TH staining was not significantly changed in ACF/RDN compared to ACF/intact (Fig. 4a, d). There was no difference in OCT3 (Fig. 3f), but strong trend to reduce protein expression of NET (presynaptic NE reuptake, p = 0.06, Fig. 3e) and significantly reduced MAO-A in ACF/RDN group, compared to ACF/intact rats (Fig. 3g). RDN/ACF rats displayed a trend to (p = 0.07) to higher gene expression of Adrb1 (Fig. 3i), and significantly increased gene expression of Chrm2 and Ache (Fig. 3j, k). We observed a significant positive correlation between gene expression of Adrb1 and TH among all groups (see Supplementary Information). RDN in ACF rats significantly reduced the activity of neprilysin in the kidney, compared to ACF/intact rats (Fig. 3l).DOIhttps://doi.org/10.1038/s41440-024-01580-3Hypertension Research volume 47, pages2718–2730 (2024)Published02 February 2024 http://www.ikem.cz/en/a-prospective-randomized-trial-of-direct-oral-anticoagulant-therapy-with-a-fully-magnetically-levitated-lvad-the-dot-hm3-study/a-4808/ http://www.ikem.cz/en/a-prospective-randomized-trial-of-direct-oral-anticoagulant-therapy-with-a-fully-magnetically-levitated-lvad-the-dot-hm3-study/a-4808/ Fri, 20 Dec 2024 12:19:47 ##VIDEO_4806####VIDEO_4807##AimsA therapeutic standard has been established with evidence of long-term survival by use of a fully magnetically levitated HeartMate 3 (HM3) left ventricular assist device (LVAD) (Abbott Industries, Abbott Park, IL) in patients with advanced heart failure.1 Outcomes with this pump have shown low rates of hemocompatibility-related adverse events (pump thrombosis, stroke, nonsurgical bleeding), and it has been argued that the thrombo-resistance demonstrated with this pump may facilitate consideration of direct oral anticoagulants (DOACs) that inhibit Factor Xa, although studies in legacy LVADs such as the HeartWare HVAD (Medtronic, Minneapolis, MN) demonstrated an increase in thrombotic complications with the use of dabigatran.2We conducted a safety and feasibility study, the Direct Oral Anticoagulant Therapy with the HeartMate 3 LVAD (DOT-HM3) and enrolled 45 patients with the HM3 LVAD > 3 months post-implant, free of a bleeding episode or stroke, who tolerated a vitamin K antagonist (VKA) targeted to an international normalized ratio of 2–3. Primary trial outcomes were published.3 Patients were randomly allocated to either apixaban 5 mg twice daily (apixaban plus aspirin, n = 15 and apixaban alone, n = 16) or continued therapy with VKA (warfarin plus aspirin, n = 14) in an open-label trial. The primary endpoint was survival free of pump thrombosis, disabling stroke or major bleeding at 6 months. Patients who were listed as bridge-to-transplantation were allowed enrollment, and occurrence of heart transplantation was considered success, provided patients survived the procedure to discharge from the hospital. All patients reached 6 months unless they were withdrawn or underwent transplantation without occurrence of thromboembolism (pump thrombosis, stroke or arterial thromboembolism) in either arm. Sporadic cases of bleeding were observed in the VKA arm with apixaban and 100 mg aspirin. Aspirin was used because the ARIES-HM3 (Antiplatelet Removal and Hemocompatibility Events With the HeartMate 3 Pump) trial had not concluded.4In this analysis of heart transplantations performed in the apixaban arm (with or without aspirin), we describe the perioperative protocol, use of blood products, vascular complications, use of temporary mechanical circulatory support, renal-replacement therapy, and duration of hospital stay. Descriptive statistics are provided with the use of medians (range minimum–maximum).Methods and resultsA total of 8 heart transplants from brain-death donors were performed in apixaban-treated patients (6 of whom were within the 6-month duration and 2 who were beyond that timeframe), and the recipients ages were 55.5 years (42–64); donor ages were 47.5 years (36–58), and duration of LVAD implant was 626.5 days (range 250–2499). Once a donor organ was identified, recipients were instructed to hold apixaban immediately with the intent to avoid such use for at least 24 hours prior to transplant surgery. Four-factor prothrombin complex concentrate (4F-PCC) was used in all 8 patients and in 7 of 8 patients transplanted, a cytokine adsorption system was employed in cardiopulmonary bypass (CPB). Reversal agents to apixaban were not used in any case. Only 1 patient in the warfarin (plus aspirin) arm underwent transplantation, and this patient had a particularly complex course but was discharged with normal allograft function at 60 days. This isolated case is insufficient to provide a comparison to apixaban-treated patients.Clinical OutcomesIndividual characteristics of the apixaban-arm patients who underwent transplantation are shown in Table 1. Chest closure was delayed in 7 of 8 patients, with a median time of 43 hours (0–52). The total ischemic time was 98 minutes (64–130) in 6 of 8 organs recovered after cold storage, and CPB time was 166.5 minutes (140–289). Two patients developed vascular complications (a ruptured aorta and bleeding from an internal thoracic artery). In 4 patients, extracorporeal membrane oxygenation support was required temporarily to allow recovery of the allograft function (4, 6, 6, and 14 days of support), while 6 of 8 patients required short-term renal-replacement therapy for a median of 14.5 days (5–37). The median use of blood products included packed red blood cells of 10.5 units (7–29), fresh-frozen plasma 15.5 units (10–39), and platelets of 6 units (4–10). The hospital stay was 45.5 days (30–71), of which 16 days (6–40) were in an intensive care setting. No cases of thromboembolism were encountered. All patients were discharged from the hospital setting with preserved allograft function (left ventricular ejection fraction of > 0.55 and without right-heart failure requiring pharmacological support)https://doi.org/10.1016/j.cardfail.2024.05.005Published: 6 August 2024 http://www.ikem.cz/en/sodium-glucose-cotransporter-2-inhibitors-induce-anti-inflammatory-and-anti-ferroptotic-shift-in-epicardial-adipose-tissue-of-subjects-with-severe-heart-failure/a-4803/ http://www.ikem.cz/en/sodium-glucose-cotransporter-2-inhibitors-induce-anti-inflammatory-and-anti-ferroptotic-shift-in-epicardial-adipose-tissue-of-subjects-with-severe-heart-failure/a-4803/ Tue, 17 Dec 2024 16:08:08 ##VIDEO_4801####VIDEO_4802##Sodium-glucose cotransporter 2 inhibitors induce anti-inflammatory and anti-ferroptotic shift in epicardial adipose tissue of subjects with severe heart failureAimsSodium-glucose cotransporter 2 inhibitors (SGLT-2i) are glucose-lowering agents used for the treatment of type 2 diabetes mellitus, which also improve heart failure and decrease the risk of cardiovascular complications. Epicardial adipose tissue (EAT) dysfunction was suggested to contribute to the development of heart failure. We aimed to elucidate a possible role of changes in EAT metabolic and inflammatory profile in the beneficial cardioprotective effects of SGLT-2i in subjects with severe heart failure.Methods and results26 subjects with severe heart failure, with reduced ejection fraction, treated with SGLT-2i versus 26 subjects without treatment, matched for age (54.0 ± 2.1 vs. 55.3 ± 2.1 years, n.s.), body mass index (27.8 ± 0.9 vs. 28.8 ± 1.0 kg/m2 , n.s.) and left ventricular ejection fraction (20.7 ± 0.5 vs. 23.2 ± 1.7%, n.s.), who were scheduled for heart transplantation or mechanical support implantation, were included in the study. A complex metabolomic and gene expression analysis of EAT obtained during surgery was performed. SGLT-2i ameliorated inflammation, as evidenced by the improved gene expression profile of proinflammatory genes in adipose tissue and decreased infiltration of immune cells into EAT. Enrichment of ether lipids with oleic acid noted on metabolomic analysis suggests a reduced disposition to ferroptosis, potentially further contributing to decreased oxidative stress in EAT of SGLT-2i treated subjects.ConclusionOur results show decreased inflammation in EAT of patients with severe heart failure treated by SGLT-2i, as compared to patients with heart failure without this therapy. Modulation of EAT inflammatory and metabolic status could represent a novel mechanism behind SGLT-2i-associated cardioprotective effects in patients with heart failure.Kasperova et al. Cardiovascular Diabetology (2024) 23:223 https://doi.org/10.1186/s12933-024-02298-9Published: 28 June 2024 http://www.ikem.cz/en/efficacy-and-safety-of-focal-pulsed-field-ablation-for-ventricular-arrhythmias-two-centre-experience-and-mapping-and-ablation-of-ventricular-tachycardia-using-dual-energy-lattice-tip-focal-catheter-early-feasibility-and-safety-study/a-4784/ http://www.ikem.cz/en/efficacy-and-safety-of-focal-pulsed-field-ablation-for-ventricular-arrhythmias-two-centre-experience-and-mapping-and-ablation-of-ventricular-tachycardia-using-dual-energy-lattice-tip-focal-catheter-early-feasibility-and-safety-study/a-4784/ Fri, 15 Nov 2024 9:50:45 ##VIDEO_4782####VIDEO_4783##Efficacy and safety of focal pulsed-field ablation for ventricular arrhythmias: two-centre experience AimsA pulsed electric field (PF) energy source is a novel potential option for catheter ablation of ventricular arrhythmias (VAs) as it can create deeper lesions, particularly in scarred tissue. However, very limited data exist on its efficacy and safety. This prospective observational study reports the initial experience with VA ablation using focal PF.Methods and resultsThe study population consisted of 44 patients (16 women, aged 61 ± 14years) with either frequent ventricular premature complexes (VPCs, 48%) or scar-related ventricular tachycardia (VT, 52%). Ablation was performed using an irrigated 4 mm tip catheter and a commercially available PF generator. On average, 16 ± 15 PF applications (25 A) were delivered per patient. Acute success was achieved in 84% of patients as assessed by elimination of VPC or reaching non-inducibility of VT. In three cases (7%), a transient conduction system block was observed during PF applications remotely from the septum. Root analysis revealed that this event was caused by current leakage from the proximal shaft electrodes in contact with the basal interventricular septum. Acute elimination of VPC was achieved in 81% patients and non-inducibility of VT in 83% patients. At the 3-month follow-up, persistent suppression of the VPC was confirmed on Holter monitoring in 81% patients. In the VT group, the mean follow-up was 116 ± 75 days and a total of 52% patients remained free of any VA.ConclusionPulsed electric field catheter ablation of a broad spectrum of VA is feasible with acute high efficacy; however, the short-term follow-up is less satisfactory for patients with scar-related VT.EP Europace, Volume 26, Issue 7, July 2024, euae192, https://doi.org/10.1093/europace/euae192 Published: 11 July 2024Mapping and ablation of ventricular tachycardia using dual-energy lattice-tip focal catheter: early feasibility and safety study BackgroundCatheter ablation is an effective treatment method for recurrent ventricular tachycardias (VT). However, at least in part, procedural and clinical outcomes are limited by challenges in generating an adequate lesion size in the ventricular myocardium.ObjectiveWe investigated procedural and clinical outcomes of VT ablation using a novel “large-footprint” catheter that allows the creation of larger lesions either by radiofrequency (RF) or by pulsed field (PF) energy.ResultsThe study population consisted of 18 patients (aged 55±15 years, 1 woman, structural heart disease: 94%, ischemic heart disease: 56%, left ventricular ejection fraction: 34±10%, electrical storm: 22%) with recurrent sustained VTs and ≥1 previously failed endocardial RF ablation with conventional irrigated-tip catheter in 66% of patients. On average, 12±7 RF and 8±9 PF applications were delivered per patient. In 3/4 of patients undergoing percutaneous epicardial ablation, spasms in coronary angiography were observed after PF applications. All resolved after intracoronary administration of nitrates. No acute phrenic nerve palsy was noted. One patient suffered from a stroke that resolved without sequelae. Post-ablation non-inducibility of VT was achieved in 89% of patients. Ventricular-arrhythmia-free survival at three months was 78%.ConclusionVT ablation using a dual-energy lattice-tip catheter and a novel electroanatomical mapping system is feasible. It allows rapid mapping and effective substrate modification with good outcomes during short-term follow-up.EP Europace, euae275, https://doi.org/10.1093/europace/euae275 Published: 31 October 2024 http://www.ikem.cz/en/endoluminal-radiofrequency-ablation-in-patients-with-malignant-biliary-obstruction-a-randomised-trial/a-4558/ http://www.ikem.cz/en/endoluminal-radiofrequency-ablation-in-patients-with-malignant-biliary-obstruction-a-randomised-trial/a-4558/ Wed, 6 Dec 2023 15:40:20 ##VIDEO_4556####VIDEO_4557##Background Endoluminal radiofrequency ablation (RFA) has been promoted as palliative treatment for patients with cholangiocarcinoma (CCA) and pancreatic ductal adenocarcinoma (PDAC) in order to improve biliary drainage and eventually prolong survival. No high level evidence is, however, available on this technique.Results A total of 161 patients (male:female 90:71, mean age 71±9 years) were randomised before recruitment was terminated for futility after an interim analysis. Eighty-five patients had CCA (73 hilar, 12 distal) and 76 had pancreatic cancer. There was no difference in survival in both subgroups: for patients with CCA, median survival was 10.5 months (95% CI 6.7 to 18.3) in the RFA group vs 10.6 months (95% CI 9.0 to 24.8), p=0.58)) in the control group. In the subgroup with pancreatic cancer, median survival was 6.4 months (95% CI 4.3 to 9.7) for the RFA vs 7.7 months (95% CI 5.6 to 11.3), p=0.73) for the control group. No benefit was seen in the RFA group with regard to stent patency (at 12 months 40% vs 36% in CCA and 66% vs 65% in PDAC), and quality of life was unchanged by either treatment and comparable between the groups. Adverse events occurred in seven patients in each groups.Conclusion A combination of endoluminal RFA and stenting was not superior to stenting alone in prolonging survival or improving stent patency in patients with malignant biliary obstruction. This article was published on October 31, 2023, at GutDOI:10.1136/gutjnl-2023-329700https://gut.bmj.com/content/72/12/2286 http://www.ikem.cz/en/apixaban-for-stroke-prevention-in-subclinical-atrial-fibrillation/a-4546/ http://www.ikem.cz/en/apixaban-for-stroke-prevention-in-subclinical-atrial-fibrillation/a-4546/ Mon, 20 Nov 2023 12:44:17 ##VIDEO_4548####VIDEO_4547##BACKGROUNDSubclinical atrial fibrillation is short-lasting and asymptomatic and can usually be detected only by long-term continuous monitoring with pacemakers or defibrillators. Subclinical atrial fibrillation is associated with an increased risk of stroke by a factor of 2.5; however, treatment with oral anticoagulation is of uncertain benefit.RESULTSWe included 4012 patients with a mean (±SD) age of 76.8±7.6 years and a mean CHA2DS2-VASc score of 3.9±1.1 (scores range from 0 to 9, with higher scores in- dicating a higher risk of stroke); 36.1% of the patients were women. After a mean follow-up of 3.5±1.8 years, stroke or systemic embolism occurred in 55 patients in the apixaban group (0.78% per patient-year) and in 86 patients in the aspirin group (1.24% per patient-year) (hazard ratio, 0.63; 95% confidence interval [CI], 0.45 to 0.88; P=0.007). In the on-treatment population, the rate of major bleeding was 1.71% per patient-year in the apixaban group and 0.94% per patient-year in the aspirin group (hazard ratio, 1.80; 95% CI, 1.26 to 2.57; P=0.001). Fatal bleeding occurred in 5 pa- tients in the apixaban group and 8 patients in the aspirin group.CONCLUSIONSAmong patients with subclinical atrial fibrillation, apixaban resulted in a lower risk of stroke or systemic embolism than aspirin but a higher risk of major bleeding. (Funded by the Canadian Institutes of Health Research and others; ARTESIA ClinicalTrials.gov number, NCT01938248.)This article was published on November 12, 2023, at NEJM.org.DOI: 10.1056/NEJMoa2310234https://www.nejm.org/doi/full/10.1056/NEJMoa2310234 http://www.ikem.cz/en/aspirin-and-hemocompatibility-events-with-a-left-ventricular-assist-device-in-advanced-heart-failure/a-4542/ http://www.ikem.cz/en/aspirin-and-hemocompatibility-events-with-a-left-ventricular-assist-device-in-advanced-heart-failure/a-4542/ Wed, 15 Nov 2023 15:34:48 ##VIDEO_4543####VIDEO_4544##Aspirin and Hemocompatibility Events With a Left Ventricular Assist Device in Advanced Heart FailureThe ARIES-HM3 Randomized Clinical TrialIMPORTANCELeft ventricular assist devices (LVADs) enhance quality and duration of life in advanced heart failure. The burden of nonsurgical bleeding events is a leading morbidity. Aspirin as an antiplatelet agent is mandated along with vitamin K antagonists (VKAs) with continuous-flow LVADs without conclusive evidence of efficacy and safety.OBJECTIVE To determine whether excluding aspirin as part of the antithrombotic regimen with a fully magnetically levitated LVAD is safe and decreases bleeding.DESIGN, SETTING, AND PARTICIPANTSThis international, randomized, double-blind, placebo-controlled study of aspirin (100 mg/d) vs placebo with VKA therapy in patients with advanced heart failure with an LVAD was conducted across 51 centers with expertise in treating patients with advanced heart failure across 9 countries. The randomized population included 628 patients with advanced heart failure implanted with a fully magnetically levitated LVAD (314 in the placebo group and 314 in the aspirin group), of whom 296 patients in the placebo group and 293 in the aspirin group were in the primary analysis population, which informed the primary end point analysis. The study enrolled patients from July 2020 to September 2022; median follow-up was 14 months.INTERVENTIONPatients were randomized in a 1:1 ratio to receive aspirin (100 mg/d) or placebo in addition to an antithrombotic regimen.MAIN OUTCOMES AND MEASURESThe composite primary end point, assessed for noninferiority (−10% margin) of placebo, was survival free of a major nonsurgical (>14 days after implant) hemocompatibility-related adverse events (including stroke, pump thrombosis, major bleeding, or arterial peripheral thromboembolism) at 12 months.The principal secondary end point was nonsurgical bleeding events.RESULTSOf the 589 analyzed patients, 77% were men; one-third were Black and 61% were White. More patients were alive and free of hemocompatibility events at 12 months in the placebo group (68%) vs those taking aspirin (74%). Noninferiority of placebo was demonstrated (absolute between-group difference, 6.0% improvement in event-free survival with placebo [lower 1-sided 97.5% CI, −1.6%]; P < .001). Aspirin avoidance was associated with reduced nonsurgical bleeding events (relative risk, 0.66 [95% confidence limit, 0.51-0.85]; P = .002) with no increase in stroke or other thromboembolic events,a finding consistent among diverse subgroups of patient characteristics.CONCLUSIONS AND RELEVANCEIn patients with advanced heart failure treated with a fully magnetically levitated LVAD, avoidance of aspirin as part of an antithrombotic regimen, which includes VKA, is not inferior to a regimen containing aspirin, does not increase thromboembolism risk, and is associated with a reduction in bleeding events.JAMA. doi:10.1001/jama.2023.23204https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2023.23204?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2023.23204 http://www.ikem.cz/en/clanek-v-casopise-gut-prestizni-titul-publikuje-studii-lekaru-ikem-o-lecbe-gastroparezy/a-4302/ http://www.ikem.cz/en/clanek-v-casopise-gut-prestizni-titul-publikuje-studii-lekaru-ikem-o-lecbe-gastroparezy/a-4302/ Thu, 15 Sep 2022 10:01:19 Endoscopic pyloromyotomy for the treatment of severe and refractory gastroparesis: a pilot, randomised, sham-controlled trial Jan Martinek1, Rastislav Hustak2,3, Jan Mares4, Zuzana Vackova1, Julius Spicak1, Eva Kieslichova5, Marie Buncova6, Daniel Pohl7, Sunil Amin8, Jan Tack9AbstractObjective Endoscopic pyloromyotomy (G-POEM) is a minimally invasive treatment option with promising uncontrolled outcome results in patients with gastroparesis.Design In this prospective randomised trial, we compared G-POEM with a sham procedure in patients with severe gastroparesis. The primary outcome was the proportion of patients with treatment success (defined as a decrease in the Gastroparesis Cardinal Symptom Index (GCSI) by at least 50%) at 6 months. Patients randomised to the sham group with persistent symptoms were offered cross-over G-POEM.Results The enrolment was stopped after the interim analysis by the Data and Safety Monitoring Board prior to reaching the planned sample of 86 patients. A total of 41 patients (17 diabetic, 13 postsurgical, 11 idiopathic; 46% male) were randomised (21 G-POEM, 20-sham). Treatment success rate was 71% (95% CI 50 to 86) after G-POEM versus 22% (8–47) after sham (p=0.005). Treatment success in patients with diabetic, postsurgical and idiopathic gastroparesis was 89% (95% CI 56 to 98), 50% (18–82) and 67% (30–90) after G-POEM; the corresponding rates in the sham group were 17% (3–57), 29% (7–67) and 20% (3–67).Median gastric retention at 4 hours decreased from 22% (95% CI 17 to 31) to 12% (5–22) after G-POEM and did not change after sham: 26% (18–39) versus 24% (11–35). Twelve patients crossed over to G-POEM with 9 of them (75%) achieving treatment success.Conclusion In severe gastroparesis, G-POEM is superior to a sham procedure for improving both symptoms and gastric emptying 6 months after the procedure. These results are not entirely conclusive in patients with idiopathic and postsurgical aetiologies.Endoscopic pyloromyotomy for the treatment of severe and refractory gastroparesis: a pilot, randomised, sham-controlled trial  http://www.ikem.cz/en/annals-of-internal-medicine-studie-v-prestiznim-vedeckem-casopise-o-ockovani-proti-covid-19-vyznamne-chrani-i-velmi-zranitelne-skupiny-pacientu/a-4224/ http://www.ikem.cz/en/annals-of-internal-medicine-studie-v-prestiznim-vedeckem-casopise-o-ockovani-proti-covid-19-vyznamne-chrani-i-velmi-zranitelne-skupiny-pacientu/a-4224/ Mon, 16 May 2022 14:46:49 Studie českých vědců v prestižním vědeckém časopise: očkování proti covid-19 významně chrání i velmi zranitelné skupiny pacientůPrestižní časopis Annals of Internal Medicine otiskl v květnu 2022 výsledky studie autorů Institutu klinické a experimentální medicíny (IKEM) a Ústavu zdravotnických informací a statistiky ČR (ÚZIS), která prokázala významný ochranný efekt očkování proti COVID-19 u pacientů po transplantaci ledvin.Do studie bylo zařazeno 2 101 pacientů po transplantaci ledvin, kteří do té doby neprodělali onemocnění COVID-19. Sledování pacientů pokrylo období od února do května 2021, tedy etapu vrcholného šíření varianty viru Alfa. Analýza primárních dat prokázala až 65% ochranný efekt očkování proti nákaze. Významná redukce rizika nákazy, téměř o 50%, byla u očkovaných pacientů potvrzena i po komplexní analýze zohledňující široké spektrum faktorů, které mohou ovlivňovat pravděpodobnost nákazy u jednotlivých pacientů.Článek autorů: Ivan Zahradka, MD*, Vojtech Petr, MD*, Istvan Modos, MSc, PhD, Maria Magicova, MD, Ladislav Dusek, PhD, a Ondrej Viklicky, MD, PhD s názvem “Association Between SARS-CoV-2 Messenger RNA Vaccines and Lower Infection Rates in Kidney Transplant Recipients” je k nalezení na https://www.acpjournals.org/doi/10.7326/M21-2973 http://www.ikem.cz/en/clanek-v-prestiznim-casopise-nature-communications-mitochondrially-targeted-tamoxifen-alleviates-markers-of-obesity-and-type-2-diabetes-mellitus-in-mice/a-4207/ http://www.ikem.cz/en/clanek-v-prestiznim-casopise-nature-communications-mitochondrially-targeted-tamoxifen-alleviates-markers-of-obesity-and-type-2-diabetes-mellitus-in-mice/a-4207/ Tue, 3 May 2022 9:27:20 Mitochondrially targeted tamoxifen alleviates markers of obesity and type 2 diabetes mellitus in miceEliska Vacurova, Jaroslava Trnovska, Petr Svoboda, Vojtech Skop, Vendula Novosadova, David Pajuelo Reguera, Silvia Petrezselyová, Benoit Piavaux, Berwini Endaya, Frantisek Spoutil, Dagmar Zudova, Jan Stursa, Magdalena Melcova, Zuzana Bielcikova, Lukas Werner, Jan Prochazka, Radislav Sedlacek, Martina Huttl, Sona Stemberkova Hubackova, Martin Haluzik & Jiri Neuzil AbstractType 2 diabetes mellitus represents a major health problem with increasing prevalence worldwide. Limited efficacy of current therapies has prompted a search for novel therapeutic options. Here we show that treatment of pre-diabetic mice with mitochondrially targeted tamoxifen, a potential anti-cancer agent with senolytic activity, improves glucose tolerance and reduces body weight with most pronounced reduction of visceral adipose tissue due to reduced food intake, suppressed adipogenesis and elimination of senescent cells. Glucose-lowering effect of mitochondrially targeted tamoxifen is linked to improvement of type 2 diabetes mellitus-related hormones profile and is accompanied by reduced lipid accumulation in liver. Lower senescent cell burden in various tissues, as well as its inhibitory effect on pre-adipocyte differentiation, results in lower level of circulating inflammatory mediators that typically enhance metabolic dysfunction. Targeting senescence with mitochodrially targeted tamoxifen thus represents an approach to the treatment of type 2 diabetes mellitus and its related comorbidities, promising a complex impact on senescence-related pathologies in aging population of patients with type 2 diabetes mellitus with potential translation into the clinic.IntroductionThe increasing prevalence of type 2 diabetes mellitus (T2DM) with its chronic debilitating complications represents one of the most significant health threats worldwide1. Diabetes, currently affecting 422 million people around the globe, is expected to become the seventh leading cause of death by 20301. This is particularly evident in elderly patients, where it can affect as many as 30–40% of the population compared to ~6–25% of patients under 65 years of age2.A combination of genetic predisposition, sedentary lifestyle, and excessive intake of calorie-rich food leads to obesity that, in turn, considerably increases the risk of T2DM development3,4. Excessive accumulation of adipose tissue and its functional changes largely contribute to the etiopathogenesis of T2DM and accompanying diseases, such as arterial hypertension, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), and many other pathologies5. In patients with obesity, markedly enlarged adipocytes, in particular in the visceral fat compartment, are more prone to apoptosis that stimulates mobilization of pro-inflammatory macrophages and other immunocompetent cells into visceral fat6. As a result, adipose tissue produces excessive amounts of pro-inflammatory factors that are released into the circulation and contribute to the development of sub-clinical inflammation, typically present in patients with T2DM and obesity7. Furthermore, chronic/enhanced ectopic lipid accumulation in non-adipose tissues contributes to the development of insulin resistance in the liver and muscles, and to increased apoptosis of insulin-producing β-cells in the pancreas8.Changes induced by long-standing, poorly controlled obesity followed by the development of T2DM are linked to premature senescence in various tissues, contributing to further deterioration of their function and eventually to the development of chronic irreversible complications9. Cellular senescence is a form of cell cycle arrest that limits the proliferative potential of cells10. Despite the arrest, senescent cells are metabolically active and produce various cytokines, chemokines, proteases, and growth factors (collectively referred to as “senescence-associated secretory phenotype”, SASP) that affect the surrounding environment11. The inability of immune cells to eliminate senescent cells from the organism results in chronic inflammation and gradual tissue damage, as seen in the panoply of age-related pathologies, including T2DM12.Senescent cells play an important role in the induction of T2DM pathogenesis13. Considering that metabolic and signaling changes associated with T2DM can promote senescence, senescent cells are components of the “pathogenic loop” in diabetes. In obese and diabetic mice, visceral adipose tissue (VAT) is the most prominent compartment of senescent cells accumulation. VAT, therefore, presents the nexus of mechanisms involved in longevity and age-related metabolic dysfunctions14. A close relationship between visceral fat content and the risk of T2DM and cardiovascular complications has also been demonstrated in humans. Components of SASP secreted by adipose‐derived senescent cells confer insulin resistance to metabolic tissues and attract immune cells that can exacerbate the effects of insulin resistance14,15. Moreover, there is a close relationship between senescence and fat accumulation in hepatocytes followed by the development of steatosis in diabetic mice16.Senolytic agents may improve glucose control and obesity- and diabetes-related pathologies14, supporting the idea that targeting senescent cells may be a promising strategy for T2DM management. Mitochondrial function is an important determinant of the aging process (reviewed in ref. 17), and we have recently reported that targeting mitochondria in senescent cells presents a plausible way to eliminate such cells in the context of pathological senescence as well as senescence-associated diseases18. Using mitochondrially targeted tamoxifen (MitoTam), our proprietary agent with anticancer activity19 that has recently undergone Phase 1/1b clinical trial (EudraCT 2017-004441-25), we have achieved specific elimination of senescent cells. Treatment with MitoTam effectively reduces oxidative phosphorylation (OXPHOS) and mitochondrial membrane potential in senescent cells, and severely affects mitochondrial morphology based on a low level of the ADP/ATP translocation channel ANT2 (adenine nucleotide translocase 2). These cells cannot, therefore, pump ATP inside mitochondria in order to maintain mitochondrial potential by cleavage of ATP by ATPase, resulting in the collapse of mitochondrial integrity and function18. Based on these results, we reasoned that MitoTam may present a non-cannonical therapeutic modality to treat senescence-associated pathologies, such as T2DM.Here we show that MitoTam considerably improves glucose control, decreases body weight, and reduces diabetic markers as well as diabetic comorbidities in mice with diet-induced obesity and prediabetes. These improvements are associated not only with a reduction of food intake (FI) and a drop in the number of senescent cells in the organism but also with rejuvenation of the adipose tissue, suggesting the role of MitoTam in T2DM treatment and prevention of chronic diabetic complications.Results http://www.ikem.cz/en/v-ramci-kardiocentra-ikem-jsou-od-1-1-2022-konstituovana-2-klinicka-mezioborova-pracoviste/a-4125/ http://www.ikem.cz/en/v-ramci-kardiocentra-ikem-jsou-od-1-1-2022-konstituovana-2-klinicka-mezioborova-pracoviste/a-4125/ Mon, 3 Jan 2022 10:11:56 Center for Hereditary Cardiovascular Diseases and Center for Comprehensive Treatment of Ventricular Arrhythmias. The aim is to simplify referencing patients for examinations or interventions.Center for Inherited Cardiovascular DiseasesHead: MUDr. Alice Krebsová, Ph.D.E-mail: kardiogenetika@ikem.cz,Phone (during working hours): 739 528 024Center for comprehensive treatment of ventricular arrhythmiasHead: doc. MUDr. Petr Peichl, Ph.D.E-mail: komorovky@ikem.cz.Phone for emergency (available 24h per day): hotline KK IKEM:  730 182 222 http://www.ikem.cz/en/human-uterus-transplantation-from-living-and-deceased-donors-the-interim-results-of-the-first-10-cases-of-the-czech-trial/a-3962/ http://www.ikem.cz/en/human-uterus-transplantation-from-living-and-deceased-donors-the-interim-results-of-the-first-10-cases-of-the-czech-trial/a-3962/ Thu, 11 Feb 2021 16:00:20 Human Uterus Transplantation from Living and Deceased Donors: The Interim Results of the First 10 Cases of the Czech TrialbyJiri Fronek 1,2,3,*, Jakub  Kristek 1,2, Jaroslav Chlupac 1,2, Libor  Janousek 1,3 and Michael  Olausson 4 1 Department of Transplantation Surgery, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 140 21 Prague, Czech Republic2 Department of Anatomy, Second Faculty of Medicine, Charles University, V Uvalu 84, 150 06 Prague, Czech Republic3 First Faculty of Medicine, Charles University, Katerinska 1660/32, 121 08 Prague, Czech Republic4 Department of Transplantation Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital, Bla Straket 5, 413 45 Gothenburg, Sweden* Author to whom correspondence should be addressed.AbstractIntroduction: Uterus transplantation (UTx) is a rapidly evolving treatment of uterine-factor infertility. We report the results of the first 10 UTx procedures performed at our institution. Methods: The program started in April 2016 as a two-arm study comparing the efficacy of UTx from live donors (LD) and deceased donors (DD). Results: Between April 2016 and April 2018, we performed five DD UTx and five LD UTx. Two grafts had to be removed early due to thrombosis. One graft was removed due to chronic rejection and previous herpes simplex infection at month 7. Graft survival is 70% at one year. Recipient survival is 100% at two years. Live donor survival is 100% at three years. Three live-births have been achieved, two from a LD and one from a graft from a nulliparous DD. Vaginal anastomotic stenosis occurred in 63% (5/8) of grafts. Self-expanding stents have shown preliminary suitability for the treatment of vaginal stenosis. Three recipients developed severe acute rejection. Conclusion: The interim results of our study demonstrate mid-term viability in 70% of grafts. The LD UTx produced two live births and the DD UTx produced one live birth. Nulliparous donors should be considered for donation.IntroductionUterus transplantation (UTx) has evolved from a purely experimental to a single method of treatment for women affected with absolute uterine-factor infertility (AUFI) [1,2,3]. Albeit quite novel, the method soon demonstrated its feasibility [4,5] and has rapidly spread to multiple transplant centers over the world. Despite the procedure becoming more common, many aspects of it remain unclear due to its complexity and overall limited amount of experience. Many medical, technical, and ethical issues need to be clarified. For instance, due to the risk of morbidity along with ethical issues associated with the procurement of a graft from a living donor (LD) [6], it is vitally important to establish the potential of grafts procured from deceased donors (DD). Complications up to grade IVa according to the Clavien-Dindo classification [7], have been encountered in LDs and in recipients [3,8,9,10,11]. Although livebirths have been reported from DD grafts [2,12,13], the overwhelming majority of UTx has relied on grafts from LDs [1,14,15,16,17,18]. The aim of this report is to retrospectively present the interim results of our first 10 cases of UTx that represent the first half of the Czech UTx trial using both LDs and DDs.Human Uterus Transplantation  from Living and Deceased Donors: The Interim Results of the First 10 Cases of  the Czech Trial http://www.ikem.cz/en/desminopathy-novel-desmin-variants-a-new-cardiac-phenotype-and-further-evidence-for-secondary-mitochondrial-dysfunction/a-3890/ http://www.ikem.cz/en/desminopathy-novel-desmin-variants-a-new-cardiac-phenotype-and-further-evidence-for-secondary-mitochondrial-dysfunction/a-3890/ Wed, 14 Oct 2020 9:57:54 by Miloš Kubánek 1,*, Tereza  Schimerová 1,2, Lenka Piherová 3, Andreas Brodehl 4, Alice Krebsová 1, Sandra  Ratnavadivel 4, Caroline  Stanasiuk 4, Hana Hansíková 5, Jiří Zeman 5, Tomáš Paleček 6, Josef Houštěk 7, Zdeněk Drahota 7, Hana Nůsková 7, Jana Mikešová 7, Josef Zámečník 8, Milan Macek, Jr. 9, Petr Ridzoň 10, Jana Malusková 11, Viktor Stránecký 3, Vojtěch  Melenovský 1, Hendrik Milting 4 and Stanislav Kmoch 31              Department of Cardiology, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic2              Institute of Physiology, First Faculty of Medicine, Charles University, 11636 Prague, Czech Republic3              Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University, 11636 Prague, Czech Republic4              Erich and Hanna Klessmann Institute, Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum, 32545 Bad Oeynhausen, Germany5              Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12108 Prague, Czech Republic6              2nd Department of Medicine–Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12108 Prague, Czech Republic7              Institute of Physiology, Czech Academy of Sciences, 11720 Prague, Czech Republic8              Department of Pathology and Molecular Medicine, Second Faculty of Medicine, Charles University, 11636 Prague, Czech Republic9              Department of Biology and Medical Genetics, Second Faculty of Medicine, Charles University, 11636 Prague, Czech Republic10            Department of Neurology, Thomayer’s Hospital, 14059 Prague, Czech Republic11            Department of Pathology, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic; Institute for Clinical and Experimental Medicine, 14021 Prague, Czech RepublicAbstract:Background: The pleomorphic clinical presentation makes the diagnosis of desminopathy difficult. We aimed to describe the prevalence, phenotypic expression, and mitochondrial function of individuals with putative disease-causing desmin (DES) variants identified in patients with an unexplained etiology of cardiomyopathy. Methods: A total of 327 Czech patients underwent whole exome sequencing and detailed phenotyping in probands harboring DES variants. Results: Rare, conserved, and possibly pathogenic DES variants were identified in six (1.8%) probands. Two DES variants previously classified as variants of uncertain significance (p.(K43E), p.(S57L)), one novel DES variant (p.(A210D)), and two known pathogenic DES variants (p.(R406W), p.(R454W)) were associated with characteristic desmin-immunoreactive aggregates in myocardial and/or skeletal biopsy samples. The individual with the novel DES variant p.(Q364H) had a decreased myocardial expression of desmin with absent desmin aggregates in myocardial/skeletal muscle biopsy and presented with familial left ventricular non-compaction cardiomyopathy (LVNC), a relatively novel phenotype associated with desminopathy. An assessment of the mitochondrial function in four probands heterozygous for a disease-causing DES variant confirmed a decreased metabolic capacity of mitochondrial respiratory chain complexes in myocardial/skeletal muscle specimens, which was in case of myocardial succinate respiration more profound than in other cardiomyopathies. Conclusions: The presence of desminopathy should also be considered in individuals with LVNC, and in the differential diagnosis of mitochondrial diseases.Desminopathy: Novel Desmin Variants, a New Cardiac Phenotype, and Further Evidence for Secondary Mitochondrial Dysfunction http://www.ikem.cz/en/endoscopic-or-surgical-myotomy-in-patients-with-idiopathic-achalasia/a-3813/ http://www.ikem.cz/en/endoscopic-or-surgical-myotomy-in-patients-with-idiopathic-achalasia/a-3813/ Wed, 20 May 2020 9:54:24 Yuki B. Werner, M.D., Bengt Hakanson, M.D., Jan Martinek, M.D., Alessandro Repici, M.D., Burkhard H.A. von Rahden, M.D., Albert J. Bredenoord, M.D., Raf Bisschops, M.D., Helmut Messmann, M.D.,Marius C. Vollberg, M.Sc., Tania Noder, R.N., Jan F. Kersten, M.Sc.,Oliver Mann, M.D., Jakob Izbicki, M.D., Alexander Pazdro, M.D., Uberto Fumagalli, M.D., Riccardo Rosati, M.D., Christoph-Thomas Germer, M.D., Marlies P. Schijven, M.D., Alice Emmermann, M.D., Daniel von Renteln, M.D., Paul Fockens, M.D., Guy Boeckxstaens, M.D., and Thomas Rösch, M.D.BACKGROUNDPneumatic dilation and laparoscopic Heller’s myotomy (LHM) are established treatments for idiopathic achalasia. Peroral endoscopic myotomy (POEM) is a less invasive therapy with promising early study results.METHODSIn a multicenter, randomized trial, we compared POEM with LHM plus Dor’s fundoplica-tion in patients with symptomatic achalasia. The primary end point was clinical success, defined as an Eckardt symptom score of 3 or less (range, 0 to 12, with higher scores indi-cating more severe symptoms of achalasia) without the use of additional treatments, at the 2-year follow-up; a noninferiority margin of −12.5 percentage points was used in the pri-mary analysis. Secondary end points included adverse events, esophageal function, Gas-trointestinal Quality of Life Index score (range, 0 to 144, with higher scores indicating better function), and gastroesophageal reflux.RESULTSA total of 221 patients were randomly assigned to undergo either POEM (112 patients) or LHM plus Dor’s fundoplication (109 patients). Clinical success at the 2-year follow-up was observed in 83.0% of patients in the POEM group and 81.7% of patients in the LHM group (difference, 1.4 percentage points; 95% confidence interval [CI], −8.7 to 11.4; P = 0.007 for noninferiority). Serious adverse events occurred in 2.7% of patients in the POEM group and 7.3% of patients in the LHM group. Improvement in esophageal func-tion from baseline to 24 months, as assessed by measurement of the integrated relax-ation pressure of the lower esophageal sphincter, did not differ significantly between the treatment groups (difference, −0.75 mm Hg; 95% CI, −2.26 to 0.76), nor did improve-ment in the score on the Gastrointestinal Quality of Life Index (difference, 0.14 points; 95% CI, −4.01 to 4.28). At 3 months, 57% of patients in the POEM group and 20% of patients in the LHM group had reflux esophagitis, as assessed by endoscopy; at 24 months, the corresponding percentages were 44% and 29%.CONCLUSIONSIn this randomized trial, POEM was noninferior to LHM plus Dor’s fundoplication in controlling symptoms of achalasia at 2 years. Gastroesophageal reflux was more common among patients who underwent POEM than among those who underwent LHM. (Funded by the European Clinical Research Infrastructure Network and others; ClinicalTrials.gov number, NCT01601678.)Endoscopic or Surgical Myotomy in Patients with Idiopathic Achalasia http://www.ikem.cz/en/koronavirus/a-3773/ http://www.ikem.cz/en/koronavirus/a-3773/ Thu, 27 Feb 2020 11:41:52 INFORMATION ON COVID-19 INFECTION CAUSED BY „CHINESE“ CORONAVIRUSImportant warning!The Institute for clinical and experimental medicine has taken the following measures:all the visitors are asked to refrain from visiting patients in the hospital;the ambulances are limited – please contact your doctor or transplant coordinator;the canteens are strictly limited only for IKEM’s employees.Thank you for your understanding.Risk areas affected by coronavirus:China, Hong Kong, Iran, Italy, Japan, Singapore, South KoreaIf you have acute health problems such as high fever above 38 degrees Celsius, cough, rhinitis, etc., and have stayed in coronavirus-affected countries for the past 14 days,DO NOT VISIT A HOSPITAL BUT CONTACT YOUR PRACTICAL DOCTOR OR EPIDEMIOLOGIST OF THE LOCAL REGIONAL HYGIENE STATION at 733 673 900.You can also use contacts HYGIENE STATIONS HL. CITY OF PRAGUE TEL .: 773 782 856 and 773 782 850.Map of other confirmed occurrences  worldwide at the Center for Disease Control and Prevention (CDC)Recommended preventive measures of the Ministry of Health of the Czech Republic against infection COVID-19.It is important to proceed as in a classical respiratory disease, as in the current flu period:avoid those who are obviously illobserve basic hygienic rulesuse disinfection, for example, when in contact with people suffering from acute respiratory problemsnot to be in places with higher numbers of peopleindividuals suffering from respiratory disease should observe the rules of respiratory hygiene - ie when sneezing and coughing properly take, preferably disposable handkerchiefs, when coughing and sneezing cover their mouths with arms / sleeves, not hands! (droplets can then pass on)of course, health professionals themselves should protect themselves, as it is they who are most in contact with patients http://www.ikem.cz/en/mitochondrial-function-skeletal-muscle-metabolism-and-iron-deficiency-in-heart-failure/a-3717/ http://www.ikem.cz/en/mitochondrial-function-skeletal-muscle-metabolism-and-iron-deficiency-in-heart-failure/a-3717/ Wed, 15 Jan 2020 12:32:26 Peter van der Meer; Haye H. van der Wal; Vojtech MelenovskyIron deficiency is one of the most prevalent comorbidities in chronic heart failure (HF), affecting more than half of all HF patients. The detrimental clinical and prognostic consequences of iron deficiency have been stressed by numerous studies.1 However, the pathophysiology of iron deficiency in HF is largely unclear. Although anemia, as a consequence of iron deficiency, may seem a reasonable explanation for the adverse effects, iron deficiency without anemia was also strongly and independently associated with impaired quality of life, exercise intolerance, and mortality.1 Furthermore, the beneficial effects of intravenous iron in iron-deficient HF patients (ie, improvement in exercise tolerance, New York Heart Association Functional Classification, and quality of life) were irrespective of attained hemoglobin levels.2,3 These findings shifted the focus from hemoglobin toward more direct effects of iron itself on nonhematopoietic tissues that are important for exercise capacity, such as skeletal and cardiac muscle. It has also been acknowledged that the exercise intolerance of chronic HF patients is not solely explained by peripheral muscle underperfusion associated with cardiac dysfunction. Several in vitro studies showed direct detrimental effects of iron deficiency on mitochondrial function and morphology, among others in human cardiomyocytes and myoblasts.4–6 Impaired mitochondrial respiration and contractility of iron-deficient human cardiomyocytes could be rescued by adding transferrin-bound iron to these cells.4 A more direct way to study the effects of iron status on exercise tolerance is to analyze mitochondrial respiratory function in skeletal muscle biopsies.7 However, this method provides static results and is associated with excessive burden to the patients, especially when multiple biopsies are taken.To study the consequences of iron deficiency on exercise capacity, a more dynamic approach is needed. Phosphorus-31 magnetic resonance spectroscopy (31P MRS) is such a method, allowing noninvasive, real-time, in vivo measurement of oxidative skeletal muscle metabolism, both at rest and during exercise. With a phosphorus-31 coil, phosphorus-containing metabolites such as phosphocreatine (PCr), inorganic phosphate, and adenosine triphosphate (ATP) can be detected and quantified in human tissue. The high-energy bond between creatine and a phosphate group makes PCr a rapidly available anaerobic store of chemical energy in skeletal muscle cells. During exercise, PCr is depleted by donating high-energy phosphate groups to ADP, which converts into ATP, and the tight balance between ATP use and production is therefore kept intact. This process, facilitated by the enzyme creatine kinase, is later reverted in postexercise rest to regenerate the PCr pool from creatine and ATP. The largest portion of all ATP is derived by mitochondrial processes, of which many are iron-dependent. Iron is directly involved in several complexes of the respiratory chain, containing iron–sulfur clusters, but is also a critical component of multiple other heme-containing enzymes involved in energetic machinery.8 When applying 31P MRS in a dynamic exercise protocol, PCr kinetics can be assessed before, during, and after exercise.9To date, no randomized clinical trial has been performed focusing on the effect of intravenous iron administration on oxidative skeletal muscle metabolism in HF patients. Therefore, the results of the Ferric Iron in Heart Failure II Trial (FERRIC-HF II), which are published in the current issue of this journal, are important to better understand the mode of action of iron repletion in HF patients.10 In this randomized, double-blind, placebo-controlled trial, Charles-Edwards et al prospectively studied the influence of intravenous iron therapy on PCr kinetics in HF patients using 31P MRS. They enrolled 40 patients with symptomatic chronic HF, at least a moderately reduced left ventricular ejection fraction (≤45%) and iron deficiency (ferritin <100 µg/L or ferritin <300 µg/L with transferrin saturation <20%). Patients were randomized to either a single dose of intravenous iron (iron isomaltoside) or matching placebo. Using 31P MRS, the authors studied several aspects of oxidative metabolism of the quadriceps muscle, both at rest and during low-intensity exercise. These measurements were performed at baseline (predose) and 2 weeks postdose of either intravenous iron or placebo. The primary end point of the study was the change in PCr recovery half-time postexercise 2 weeks after iron administration. Patients receiving iron isomaltoside showed a significant improvement in PCr recovery halftime during follow-up. Other, secondary parameters reflecting PCr kinetics (eg, resting and exercise PCr, inorganic phosphate, and pH) were not affected by administration of iron isomaltoside (see the Figure). In subgroup analyses (ie, anemic versus nonanemic patients), PCr recovery rate improved significantly in anemic patients, whereas a trend toward improvement was observed in patients without anemia. However, no formal test for interaction was provided and nonanemic patients generally received a lower iron repletion dose.Figure. Oxidative skeletal muscle metabolism in heart failure patients with iron deficiency in rest, during exercise, and postexercise. Iron has a critical role in several aspects of the energetic machinery (eg, complexes of the mitochondrial respiratory chain, containing iron-sulfur clusters, and the citric acid cycle). In patients who remained iron-deficient (ie, placebo arm), phosphocreatine regeneration rate is significantly prolonged (gray arrows), compared to patients who received a single dose of iron isomaltoside. Several graphical elements were adapted from Servier Medical Art (https://smart.servier.com), licensed under a Creative Commons Attribution 3.0 Unported License. ATP indicates adenosine triphosphate; CAC, citric acid cycle; Cr, creatine; PCr, phosphocreatine; Pi, inorganic phosphate.Several other research groups have studied PCr kinetics as a noninvasive and in vivo proxy for mitochondrial function in chronic HF patients using 31P MRS. Observational studies on skeletal muscle energetics from the past century showed that symptomatic HF patients had impaired oxidative mitochondrial capacity of the forearm flexor muscle compared to healthy controls.11 More recently, Weiss et al12 studied calf muscle energetics using 31P MRS in both heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) patients. Compared to healthy controls and HFrEF patients, HFpEF patients showed the most impaired oxidative skeletal muscle metabolism, already at low exercise intensity. Moreover, the PCr recovery rate in both HFrEF and HFpEF patients was markedly longer, with most delay in HFpEF patients.12 Another study confirmed these findings in a cohort of chronic HF patients who underwent 31P MRS of the calf muscle. HF patients had lower PCr at baseline, lower pH during exercise, and more impaired PCr recovery postexercise, compared with healthy controls. The HF cohort was further stratified based on the presence or absence of iron deficiency using the conventional definition. Compared with chronic HF without iron deficiency, muscle energetics in iron-deficient patients were even more impaired, reflected by the largest PCr depletion and lower intracellular pH. The PCr recovery time was not affected by iron deficiency in the HF cohort (44 patients), although this study might have been underpowered to assess this component of the PCr kinetics.13The findings from FERRIC-HF II add valuable pieces to the iron puzzle. Interestingly, hemoglobin levels only marginally increased in the iron isomaltoside arm; this increase was not correlated to the change in PCr recovery rate. This was in contrast with the change in ferritin levels during follow-up, which was inversely related to PCr recovery. Taken together, this study provides additional evidence that exercise intolerance in iron-deficient HF patients is at least partly independent of hemoglobin. Second, the data from Charles-Edwards et al show a substantial improvement in PCr kinetics in patients receiving only a single dose of iron isomaltose, comparable with several weeks of exercise training.14 Finally, both resting and exercise PCr levels were comparable between treatment arms; only PCr regeneration was affected by administration of iron isomaltoside. This finding is not entirely surprising; it is this step that is critically dependent on adequate oxidative mitochondrial function for ATP resynthesis postexercise, in which iron plays a crucial role.8However, many questions remain to be answered in the pathophysiology of iron deficiency in HF and its treatment. Rather than a negative iron balance leading to absolute iron deficit, iron deficiency in HF can also develop because of altered distribution of systemic iron as a consequence of inflammation, neurohumoral activation, or tissue stress associated with mechanical overload or ischemia. Whereas iron metabolism was mapped in great detail in hematopoietic organs (bone marrow, spleen, liver), cellular iron uptake and intracellular homeostasis on nondividing cells, such as skeletal or cardiac myocytes, were rarely studied and are poorly understood.15 There is a paucity of data about distinct differences between various intravenous iron preparations, about persistence of clinical improvement in HF patients receiving intravenous iron, and about possible direct effects of intravenous iron on cardiac muscle. It is also unclear which cellular component of the bioenergetic machinery is mostly affected by HF-related iron deficiency and its response to iron administration. From a clinical standpoint, patients with HFpEF were excluded in the FERRIC-HF II. Particularly HFpEF patients seem to have even worse oxidative skeletal muscle metabolism compared with HFrEF patients, which may be attributable to coexisting muscle steatosis.12 Unfortunately, the study was not powered to detect differences between anemic and nonanemic patients; anemic patients received a clinically significant higher dose of iron isomaltoside. Adequately powered studies should be conducted in a nonanemic cohort to completely rule out the possible confounding effect of low hemoglobin levels. Moreover, PCr kinetics should be assessed at multiple time points after intravenous iron administration to better understand the effect on skeletal muscle energetics over time.No adequately powered randomized clinical trial has been published showing that correction of iron deficiency using intravenous iron supplementation leads to a reduction of (cardiovascular) mortality and morbidity in iron-deficient HF patients, although such trials are currently ongoing with different iron preparations (AFFIRM-AHF [Study to Compare Ferric Carboxymaltose With Placebo in Patients With Acute Heart Failure and Iron Deficiency], NCT02937454; FAIR-HF2 [Intravenous Iron in Patients With Systolic Heart Failure and Iron Deficiency to Improve Morbidity and Mortality], NCT03036462; HEART-FID [Randomized Placebo-controlled Trial of FCM as Treatment for Heart Failure With Iron Deficiency], NCT03037931; IRONMAN [Intravenous Iron Treatment in Patients With Heart Failure and Iron Deficiency], NCT02642562). While the results of these major outcome trials are eagerly awaited, mechanistic studies such as the FERRIC-HF II provide very useful insights into the mode of action of intravenous iron.DisclosuresDr van der Meer received speaker’s fees and grant support from Vifor Pharma. The other authors report no conflicts.References http://www.ikem.cz/en/prague-endoscopy-days/a-3648/ http://www.ikem.cz/en/prague-endoscopy-days/a-3648/ Thu, 3 Oct 2019 16:06:35 Prague Endoscopy DaysWOMEN IN ENDOSCOPY30. a 31. ledna 2020CORINTHIA HOTEL PRAGUEPRAHA, ČESKÁ REPUBLIKA http://www.ikem.cz/en/contribution-of-non-hla-incompatibility-between-donor-and-recipient-to-kidney-allograft-survival-genome-wide-analysis-in-a-prospective-cohort/a-3594/ http://www.ikem.cz/en/contribution-of-non-hla-incompatibility-between-donor-and-recipient-to-kidney-allograft-survival-genome-wide-analysis-in-a-prospective-cohort/a-3594/ Wed, 10 Jul 2019 9:15:44 Contribution of non-HLA incompatibility between donor and recipient to kidney allograft survival: genome-wide analysis in a prospective cohortRomanReindl-SchwaighoferMDa* AndreasHeinzelMSa* AlexanderKainzPhDa Jessicavan SettenPhDd KiraJelencsicsPhDa KarinHuBSca Bao-LiLozaPhDe MichaelKammerMSbGeorgHeinzePhDb PetraHrubaPhDf AlenaKoňaříkováMDg ProfOndrejViklickyMDfg Georg ABoehmigMDa FarsadEskandaryMDa GottfriedFischerMDc ProfFransClaasMDhJohn TanPhDiTom JAlbertPhDi JigarPatelPhDi BrendanKeatingDPhile ProfRainerOberbauerMDa for the iGeneTRAiN consortium†a - Department of Nephrology, Medical University of Vienna, Vienna, Austriab - Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austriac - Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austriad - Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, Netherlandse - Department of Surgery, University of Pennsylvania, Philadelphia, PA, USAf - Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republicg - Department of Nephrology, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republich - Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden, Netherlandsi - Roche Madison, Madison, WI, USASummaryBackgroundThe introduction of HLA matching of donors and recipients was a breakthrough in kidney transplantation. However, half of all transplanted kidneys still fail within 15 years after transplantation. Epidemiological data suggest a fundamental role of non-HLA alloimmunity.MethodsWe genotyped 477 pairs of deceased donors and first kidney transplant recipients with stable graft function at three months that were transplanted between Dec 1, 2005, and April 30, 2015. Genome-wide genetic mismatches in non-synonymous single nucleotide polymorphisms (nsSNPs) were calculated to identify incompatibilities in transmembrane and secreted proteins. We estimated the association between nsSNP mismatch and graft loss in a Cox proportional hazard model, adjusting for HLA mismatch and clinical covariates. Customised peptide arrays were generated to screen for antibodies against genotype-derived mismatched epitopes in 25 patients with biopsy-confirmed chronic antibody-mediated rejection.Findings59 268 nsSNPs affecting a transmembrane or secreted protein were analysed. The median number of nsSNP mismatches in immune-accessible transmembrane and secreted proteins between donors and recipients was 1892 (IQR 1850–1936). The degree of nsSNP mismatch was independently associated with graft loss in a multivariable model adjusted for HLA eplet mismatch (HLA-A, HLA-B, HLA-C, HLA-DP, HLA-DQ, and HLA-DR). Each increase by a unit of one IQR had an HR of 1·68 (95% CI 1·17–2·41, p=0·005). 5-year death censored graft survival was 98% in the quartile with the lowest mismatch, 91% in the second quartile, 89% in the third quartile, and 82% in the highest quartile (p=0·003, log-rank test). Customised peptide arrays verified a donor-specific alloimmune response to genetically predicted mismatched epitopes.InterpretationGenetic mismatch of non-HLA haplotypes coding for transmembrane or secreted proteins is associated with an increased risk of functional graft loss independently of HLA incompatibility. As in HLA alloimmunity, donor-specific alloantibodies can be identified against genotype derived non-HLA epitopes.FundingAustrian Science Fund, WWTF (Vienna Science and Technology Fund), and Ministry of Health of the Czech Republic.ScienceDirect http://www.ikem.cz/en/22-rocnik-ablacniho-workshopu/a-3301/ http://www.ikem.cz/en/22-rocnik-ablacniho-workshopu/a-3301/ Mon, 20 Aug 2018 14:09:21 Save the date!22nd Prague Workshop on Catheter Ablation with live demostrations will be held in April 14-16, 2019, together with pre-workshop Practical Sessions on April 13,2019. More information and complete programme is avaliable on workshop website.ABLATIONWORKSHOP