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/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/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/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/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