Publications by authors named "Kay Neumann"

19 Publications

  • Page 1 of 1

Strong variation in progesterone production of the placenta in early pregnancy - what are the clinical implications?

Reprod Biomed Online 2020 10 18;41(4):748-749. Epub 2020 Jul 18.

Department of Gynaecological Endocrinology and Reproductive Medicine, University Hospital of Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, Luebeck 23538, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.rbmo.2020.07.009DOI Listing
October 2020

Characterization of early pregnancy placental progesterone production by use of dydrogesterone in programmed frozen-thawed embryo transfer cycles.

Reprod Biomed Online 2020 May 31;40(5):743-751. Epub 2020 Jan 31.

Department of Gynaecological Endocrinology and Reproductive Medicine, University Hospital of Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, Luebeck 23538, Germany. Electronic address:

Research Question: When and how does the gradual transition of the endocrine control of early pregnancy from the corpus luteum to the placenta, termed luteoplacental shift, take place?

Design: Prospective analysis of serum progesterone levels in pregnancies (n = 88) resulting from programmed frozen-thawed embryo transfer cycles in which ovulation was suppressed and no corpus luteum was present. Dydrogesterone, which does not cross-react with progesterone in immunoassay or spectrometric assay, was used for luteal phase and early pregnancy support. Progesterone, oestradiol and hCG were measured at regular intervals from before pregnancy achievement until +65 to 71 days after embryo transfer by Roche Elecsys electrochemiluminescence immunoassay (Elecsys ECLIA) and liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Results: Serum progesterone remained at baseline levels on first blood analysis +9 to 15 days after embryo transfer and increased only marginally independently from the type of pregnancy up to +16 to 22 days after embryo transfer. From +23 to 29 days after embryo transfer, progesterone increased non-linearly above 1.0 ng/ml and increased further throughout the first trimester with elevated levels in multiples. Oestradiol levels increased in parallel with progesterone; hCG plateaued around +37 to 43 days. Progesterone levels were significant predictors for pregnancy viability from +23 to 29 days after embryo transfer onwards with best accuracy +37 to 43 days after embryo transfer (receiver operator characteristic analysis area under the curve 0.98; 95% CI 0.94 to 1; P = 0.0009).

Conclusions: The onset of substantial progesterone production is the 7th gestational week. Progesterone increase is non-linear, depends on chorionicity and zygosity, and may have predictive potential on the outcome of pregnancies originating from frozen embryo transfer cycles.
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http://dx.doi.org/10.1016/j.rbmo.2020.01.019DOI Listing
May 2020

An Economic Analysis of Aneuploidy Screening of Oocytes in Assisted Reproduction in Germany.

Geburtshilfe Frauenheilkd 2020 Feb 21;80(2):172-178. Epub 2020 Feb 21.

Sektion für gynäkologische Endokrinologie und Reproduktionsmedizin, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.

The randomized ESTEEM trial reported that preimplantation genetic aneuploidy testing of oocytes by polar body biopsy (PGT-A) with array comparative genomic hybridization (aCGH) in women aged 36 - 40 years undergoing assisted reproduction treatment reduces the number of embryo transfers and the risk of miscarriage while not impacting the live birth rate. A decision tree model based on data from the ESTEEM trial was created and analyzed, using three cost scenarios for assisted reproduction treatment in Germany (statutory health insurance [GKV] = the deductible is 50% of the standard medical costs; private medical insurance [PKV] = invoicing is based on the German medical fee schedule [GOÄ]; private medical insurance with a simple GOÄ factor [simple GOÄ factor] = invoicing is based on the standard medical fees multiplied by a linear GOÄ factor). The scenarios were compared for cost-effectiveness (cost per live birth), cost per prevented miscarriage and the threshold values for cost and effectiveness. PGT-A increased the costs per live birth in all scenarios (GKV: + 208%; PKV: + 49%; simple GOÄ factor: + 89%). A threshold analysis showed a substantial cost discrepancy between the actual cost of the intervention based on GOÄ (€ 5801) vs. the theoretically tolerable PGT-A cost (GKV: € 561, PKV: € 1037, single GOÄ-factor: € 743). The incremental cost per one prevented miscarriage was approximately € 70 000 - 75 000 for all cost scenarios. The use of PGT-A with aCGH in assisted reproduction cannot be recommended from a cost-effectiveness perspective.
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http://dx.doi.org/10.1055/a-1079-5283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035128PMC
February 2020

Introduction of a novel ELISA assay for serum AMH determination.

Clin Chem Lab Med 2019 07;57(8):e183-e185

Department of Gynaecological Endocrinology and Reproductive Medicine, University Hospital of Schleswig-Holstein, Lübeck, Germany.

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http://dx.doi.org/10.1515/cclm-2018-0855DOI Listing
July 2019

The use of intracytoplasmic sperm injection is associated with a shift in the secondary sex ratio.

Reprod Biomed Online 2018 Dec 6;37(6):703-708. Epub 2018 Oct 6.

Department of Reproductive Medicine and Gynecological Endocrinology, as well as Medical Biometry and Statistics, Ratzeburger Allee 160, Luebeck 23538, Germany.

Research Question: What is the association between assisted reproductive technologies and human sex ratio as a proportion of male offspring at birth.

Design: A total of 59,628 singleton deliveries resulting from IVF, intracytoplasmic sperm injection (ICSI) and intrauterine insemination (IUI) or ovulation induction from 101 IVF clinics in Germany, that had been documented in a national German IVF registry, were analysed. Sex ratio after assisted reproductive technology was also compared with the sex ratio reported in the birth records of the German Federal Statistical Office.

Results: The sex ratio was 50.0% (95% CI 49.5% to 50.5%) for ICSI, 52.2% (95% CI 51.5% to 52.9%) for IVF, 52.2% (95% CI 50.9% to 53.5%) for IUI or ovulation induction and 51.3% in the national birth records, respectively. Significant differences existed across the three treatment groups (P = 6.86 × 10) as well as in pairwise comparisons between ICSI versus IVF (P = 6.88 × 10) and ICSI versus IUI or ovulation induction (P = 0.003). No difference existed between the groups IUI or ovulation induction versus IVF. Same results were also present after stratification by maternal age: IVF versus ICSI (P = 6.433 × 10), ICSI versus IUI or ovulation induction (P = 0.003), and IVF versus IUI or ovulation induction (non-significant). Compared with the national birth records, ICSI is associated with a lower sex ratio compared with the reference group (P < 0.001), whereas IVF is associated with a higher sex ratio (P = 0.015).

Conclusions: The use of ICSI is associated with an equal proportion of sexes at birth, which is not the case for IVF, IUI or ovulation induction, or natural conception. This phenomenon is not influenced by maternal age.
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http://dx.doi.org/10.1016/j.rbmo.2018.09.009DOI Listing
December 2018

Can a quality-of-life assessment assist in identifying women at risk of prematurely discontinuing IVF treatment? A prospective cohort study utilizing the FertiQoL questionnaire.

Arch Gynecol Obstet 2018 07 4;298(1):223-229. Epub 2018 Jun 4.

Department of Gynaecological Endocrinology and Reproductive Medicine, University Hospital of Schleswig-Holstein, Campus Luebeck, Luebeck, Germany.

Purpose: This study aimed at assessing quality of life (QoL) by means of a validated measurement tool (FertiQoL) in German infertile patients before a first IVF/ICSI cycle with ancillary assessment of changes in FertiQoL scores after a failed first cycle and the predictive capacity of FertiQoL scores for treatment discontinuation.

Methods: The validated FertiQoL tool consisting of 24 questions regarding fertility-specific aspects of QoL was used for this prospective cohort study conducted at a university affiliated IVF center in Germany. Female patients (n = 119) filled out the FertiQoL form and questionnaire on sociodemographic variables on initiation of a first- and second-cycle IVF/ICSI treatment, respectively.

Results: On initiation of a first IVF/ICSI cycle, the mean scores (± standard deviation) for subscales emotional, mind-body, relational, and social items were 62 (± 19), 75 (± 17), 82 (± 13), and 78 (± 14), respectively; the total FertiQoL score was 73 (± 12). The mean total FertiQoL score at initiation of a first treatment cycle did not differ between patients who continued vs. discontinued treatment in case of no pregnancy achievement in the first cycle (73) (± 10) vs. 74 (± 14), p = 0.46). Furthermore, the mean total FertiQoL score did not change after an unsuccessful first IVF cycle (74 vs. 76, p = 0.46).

Conclusions: There was no statistical difference in a small sample size for FertiQoL scores between all groups. In this study, FertiQoL scores were, therefore, not usable to predict withdrawal from infertility treatment.
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http://dx.doi.org/10.1007/s00404-018-4797-2DOI Listing
July 2018

Follicular flushing in patients with poor ovarian response: a systematic review and meta-analysis.

Reprod Biomed Online 2018 Apr 29;36(4):408-415. Epub 2017 Dec 29.

Department of Gynaecological Endocrinology and Reproductive Medicine, University Hospital of Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, 23538, Luebeck, Germany. Electronic address:

A systematic literature review and meta-analysis was conducted to evaluate the effect of follicular flushing on clinical outcomes (primary outcome: mean number of cumulus-oocyte-complexes [COC]) in poor-response IVF patients). The bibliographic databases OvidMedline (includes Pubmed), Cochrane Library and Web of Science were searched electronically for randomized controlled trials (RCT) comparing follicular flushing with no flushing. Three RCT with a total of 210 patients could be included. The mean number of COC did not increase with flushing (weighted mean difference: -0.45 COC, 95% CI -1.14 to 0.25, I = 70%; P = 0.21; three RCT, n = 210). Mean number of metaphase II oocytes and the proportion of randomized patients having at least one COC retrieved were no different between groups. No difference was observed between groups for mean number of embryos, the proportion of randomized patients achieving embryo transfer, clinical pregnancy and live birth rates. Procedure duration was significantly increased with flushing (P = 0.0006). A positive effect of flushing on any of the investigated outcomes could not be observed in the existing literature in patients with poor ovarian response. Flushing is unlikely to significantly increase the number of oocytes, and the routine use of follicular flushing should, therefore, be scrutinized.
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http://dx.doi.org/10.1016/j.rbmo.2017.12.014DOI Listing
April 2018

Excisions of severe cervical dysplasia: Are there mandatory diameters of the cone that need to be considered?

J Turk Ger Gynecol Assoc 2017 Dec;18(4):185-189

Department of Obstetrics and Gynaecology, Schleswig-Holstein University, Campus Luebeck, Luebeck, Germany.

Objective: To achieve optimal depth for negative margin cones after loop electrosurgical excision procedures (LEEP) for cervical dysplasia.

Material And Methods: Retrospective cohort analysis of LEEP cones of 201 patients with cervical dysplasia during a four-year period. Analysed cones were divided into two different groups: cones with negative margins without dysplasia, and cones with margins positive for dysplasia. In order to determine the cut-off value of the depth of the resected cones, receiver operating characteristic (ROC) analysis was performed.

Results: Negative margins were found in 71.0% (n=49) of all cones, whereas positive margins were reported in 29.0% (n=20). Negative margin cones were achieved in 100% with a cone depth of ≥20 mm. A resection depth between 10-19.9 mm led to 73.0% negative margin cones. Calculation of cone volume shows for 2.0 cm3, a sensitivity of 79% and a specificity of 64%. Statistical analysis using an ROC model showed p=0.002.

Conclusion: Forth greatest safety of patients, cone depths from LEEPs for cervical dysplasia should be ≥20 mm to achieve negative margins.
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http://dx.doi.org/10.4274/jtgga.2017.0036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776157PMC
December 2017

Is surgical plume developing during routine LEEPs contaminated with high-risk HPV? A pilot series of experiments.

Arch Gynecol Obstet 2018 02 13;297(2):421-424. Epub 2017 Dec 13.

Department of Obstetrics and Gynecology, Westplaz-Klinikum GmbH, Hellmut-Hartert-Strasse 1, 67655, Kaiserslautern, Germany.

Introduction: Growing evidence shows a causal role of high-risk humane papillomavirus (HPV) infections in the development of head and neck cancer. A recent case report shows two patients suffering from tonsillar cancer without any risk factors apart from their work as gynecologists doing laser ablations and loop electrosurgical excision procedures (LEEP). The aim of the present investigation is to evaluate whether surgical plume resulting from routine LEEPs of HSIL of the cervix uteri might be contaminated with the DNA of high-risk HPV.

Materials And Methods: The prospective pilot study is done at the Department of Gynecology and Obstetrics of the University of Lübeck, Germany. The primary outcome was defined as HPV subtype in resected cone and in surgical plume resulting from LEEPs of HSIL of the cervix uteri. Plume resulting from LEEPs was analyzed using a Whatman FTA Elute Indicating Card which was placed in the tube of an exhaust suction device used to remove the resulting aerosols. For detection of HPV and analysis of its subtype, the novel EUROArray HPV test was performed. Resected cones of LEEPs were evaluated separately for HPV subtypes.

Results: Four samples of surgical plume resulting from routine LEEPs indicated contamination with high-risk HPV and showed the same HPV subtype as identified in the resected cones.

Conclusion: Surgical plume resulting from routine LEEPs for HSIL of the cervix uteri has the risk of contamination with high-risk HPV. Further investigations of infectiousness of surgical plume are necessary for evaluation of potential hazards to involved healthcare professionals.
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http://dx.doi.org/10.1007/s00404-017-4615-2DOI Listing
February 2018

What is the net effect of introducing vitrification for cryopreservation of surplus 2PN oocytes in an IVF program?

Arch Gynecol Obstet 2018 02 11;297(2):529-537. Epub 2017 Dec 11.

Department of Gynecological Endocrinology and Reproductive Medicine and Universitaeres Kinderwunschzentrum Luebeck, University Hospital of Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, 23538, Luebeck, Germany.

Purpose: The aim of this study was to accurately describe outcome differences (cryo-survival, pregnancy rate and live birth rate, both per ET and cumulatively), between the vitrification method and slow-freezing method of surplus 2PN oocytes in an IVF program.

Methods: In 2004, the freezing method for 2PN oocytes was changed from slow-cooling to vitrification. The data of 711 patients (timespan: 1/1999-7/2011; 410 vitrification and 301 slow-cooling events) undergoing a first IVF/ICSI cycles with freezing of 2PN oocytes were retrospectively analyzed. The outcome of one, the first, IVF cycle per patient was explored. The data were analyzed per freezing-thawing attempt as well as cumulatively per one complete IVF cycle, taking pregnancy occurrence after a fresh embryo transfer preceding the cryo-cycle(s) and other confounders (such as female age, elective vs. surplus 2PN cryopreservation) into account by means of exploratory regression analyses.

Results: In the vitrification and slow-cooling group, 756 and 376, respectively, attempts of thawing 2PN oocytes were recorded. Each attempt of thawing 2PN oocytes showed statistically significantly higher mean cryo-survival rates after vitrification (effect size approximately 30-40%, with vitrification cryo-survival consistently above 90% in all thawing attempts). Furthermore, the incidence of "zero survival" was lower after vitrification (0.5 vs. 7.3%, p < 0.01). It is estimated that the odds of achieving a live birth per one IVF cycle (fresh and frozen transfers combined) with vitrification of 2PN oocytes is increased approximately 1.4-fold (OR of 1.405, 95% CI 0.968-2.038; p = 0.07); however, statistical significance was not achieved due to sample size. Female age and elective cryopreservation of all 2PN oocytes without a fresh transfer (e.g., hyperresponders) were found to be negatively and positively, respectively, associated with the chance of achieving a live birth.

Conclusions: The introduction of vitrification has a measurable impact on the efficacy of an IVF program. However, this effect is not large despite the impressively higher cryo-survival rates with vitrification. The "true" net efficacy effect of introducing 2PN vitrification in an IVF program will, in real life, be lower due to patients not having surplus 2PN oocytes available for freezing and later transfer.
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http://dx.doi.org/10.1007/s00404-017-4606-3DOI Listing
February 2018

C-Section Prevalence Among Obese Mothers and Neonatal Hypoglycemia: a Cohort Analysis of the Department of Gynecology and Obstetrics of the University of Lübeck.

Geburtshilfe Frauenheilkd 2017 May 24;77(5):487-494. Epub 2017 May 24.

Westpfalz-Klinikum GmbH, Kaiserslautern, Germany.

Introduction: Data from the World Health Organization (WHO) demonstrates an increasing prevalence of obesity in Western countries. This study investigates the influence of obesity on the mode of delivery and the occurrence of hypoglycemia in newborns.

Materials And Methods: A retrospective analysis of all deliveries at the Department of Gynecology and Obstetrics of the University of Lübeck, Germany was conducted over a period of eleven years with the primary outcome as non-elective C-sections and hypoglycemia of newborns from obese mothers. Patients were divided into six subgroups according to WHO weight classifications as follows: control group body mass index (BMI) 18.5 - 24.9 kg/m , n = 7712; general obesity BMI ≥ 25 kg/m , n = 4227; overweight BMI 25 - 29.9 kg/m , n = 2628; obesity I° BMI 30 - 34.9 kg/m , n = 1017; obesity II° BMI 35 - 39.9 kg/m , n = 370; obesity III° BMI ≥ 40 kg/m , n = 212.

Results: Analysis of the primary outcome shows an increased incidence of non-elective C-sections with an elevated BMI (general obesity vs. control group: 20.5 vs. 15.9%, p < 0.001; OR 1.3; 95% CI 1.2 - 1.4) and elevated rates of neonatal hypoglycemia in newborns of obese mothers (general obesity vs. control group: 0.6 vs. 0.3%, p < 0.05; OR 1.8; 95% CI 1.0 - 3.0).

Conclusions: Obesity is an essential obstetric risk factor. Obese women face an increased risk of non-elective C-sections, and newborns of obese mothers suffer from elevated rates of hypoglycemia.
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http://dx.doi.org/10.1055/s-0043-108763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444529PMC
May 2017

Do ART patients face higher C-section rates during their stage of delivery? A German monocenter experience.

Arch Gynecol Obstet 2017 Feb 7;295(2):481-485. Epub 2016 Dec 7.

Westpfalz-Klinikum GmbH, Hellmut-Hartert-Str. 1, 67655, Kaiserslautern, Germany.

Purpose: The mode of delivery depends on multiple parameters. After assisted reproductive technology (ART), previous studies have shown elevated C-section rates but few studies differentiated between elective and emergency operations and different protocols of cryopreservation. Because these studies did not use multiparity as exclusion criteria which reduces confounding with previous pregnancies, aim of this study is to compare mode of delivery of different techniques of ART using data of primiparae only [1, 2].

Methods: Retrospective analysis of patient data treated at the university hospital of Luebeck in a period of 12 years. Patients were divided in different groups according to their way of conception: spontaneous conception and conception after ART. The group of ART was further divided into: (a) a group of fresh transferred embryos (IVF/ICSI), (b) vitrification and (c) slow freezing. Exclusion criteria were defined as: multiparity, delivery <24. + 0 p.m., incomplete data and treatment outside university of Luebeck. Main parameter of this study was mode of delivery which was divided into spontaneous delivery or C-section. C-sections were further differentiated into elective or emergency C-sections.

Results: The group of fresh transferred embryos and slow freezing showed higher risks for elective and emergency C-sections (elective C-sections odds ratio 2.0, CI 95% 1.6-2.6, emergency C-sections odds ratio 1.4, CI 95% 1.1-1.9). Moreover, all groups of ART show enhanced risk of significant perinatal bleeding.

Conclusion: Patients after ART treatment suffer from higher C-section rates during their stage of delivery.
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http://dx.doi.org/10.1007/s00404-016-4252-1DOI Listing
February 2017

Introducing a new scoring system for pap smear in the detection of high-grade squamous intraepithelial lesions in pregnancy (The Luebeck Score).

Arch Gynecol Obstet 2016 10 14;294(4):855-60. Epub 2016 May 14.

Department of Obstetrics and Gynaecology, Schleswig- Holstein University, Campus Lübeck Ratzeburger Allee 160, 23538, Lübeck, Germany.

Purpose: To construct a scoring system for pap smears to objectify cytological appraisal and to enhance the accuracy and comparability of pap smear interpretation in pregnancy.

Materials And Methods: For development of a scoring system for cell appraisal of pap smears the style of the Modified Masood's Scoring Index for appraisal of cells from fine needle aspirations of breast lesions was used. Cohort analysis of n = 54 dysplastic pap smears for polymorphology of cells, anisonucleosis, structure of the nucleus, signs of tissue destruction, nucleus/plasma relation and signs of tumordiathesis. Each criteria was classified into three stages: The first with little evidence for dysplasia (one point), second stage with sporadic evidence (two points) or third stage with frequent evidence (three points). To further evaluate if pregnancy associated cells changes interfere with this scoring system we compared the results of pregnant and non-pregnant women. Histological result was used as an indicator of correctness of the score.

Results: Statistical analysis showed a good correlation of the scoring system with histological results. Especially in pregnancy statistical analysis shows promising results (sensitivity 86.67 %, Specificity 100 %, receiver operating characteristic analysis p ≤ 0.05).

Conclusion: The Luebeck Score seems to be a useful approach for appraisal of pap smears in pregnancy. Further studies containing high numbers of cases are needed for further evaluation of potential benefits of the scoring system compared to conventional evaluation of pap smears.
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http://dx.doi.org/10.1007/s00404-016-4113-yDOI Listing
October 2016

Cardiac CaM Kinase II genes δ and γ contribute to adverse remodeling but redundantly inhibit calcineurin-induced myocardial hypertrophy.

Circulation 2014 Oct 14;130(15):1262-73. Epub 2014 Aug 14.

From the Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (M.M.K., L.H.L., S.K., M.-O.H., U.O., J.B.); Department of Cardiology, Saarland University, Homburg, Germany (M.K., J.-C.R., C.M.); Department of Internal Medicine II, University of Regensburg, Germany (K.N., L.S.M.); British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, United Kingdom (M.D.S.); Department of Internal Medicine, University of Southwestern Texas Medical Center, Dallas (J.A.H.); Institute of Pharmacology, University of Duisburg-Essen, Germany (D.D.); Department of Molecular Pathology, German Cancer Research Center, Heidelberg, Germany (H.-J.G.); Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (H.A.K.); and the Department of Molecular Biology, University of Southwestern Texas Medical Center, Dallas (E.N.O.).

Background: Ca(2+)-dependent signaling through CaM Kinase II (CaMKII) and calcineurin was suggested to contribute to adverse cardiac remodeling. However, the relative importance of CaMKII versus calcineurin for adverse cardiac remodeling remained unclear.

Methods And Results: We generated double-knockout mice (DKO) lacking the 2 cardiac CaMKII genes δ and γ specifically in cardiomyocytes. We show that both CaMKII isoforms contribute redundantly to phosphorylation not only of phospholamban, ryanodine receptor 2, and histone deacetylase 4, but also calcineurin. Under baseline conditions, DKO mice are viable and display neither abnormal Ca(2+) handling nor functional and structural changes. On pathological pressure overload and β-adrenergic stimulation, DKO mice are protected against cardiac dysfunction and interstitial fibrosis. But surprisingly and paradoxically, DKO mice develop cardiac hypertrophy driven by excessive activation of endogenous calcineurin, which is associated with a lack of phosphorylation at the auto-inhibitory calcineurin A site Ser411. Likewise, calcineurin inhibition prevents cardiac hypertrophy in DKO. On exercise performance, DKO mice show an exaggeration of cardiac hypertrophy with increased expression of the calcineurin target gene RCAN1-4 but no signs of adverse cardiac remodeling.

Conclusions: We established a mouse model in which CaMKII's activity is specifically and completely abolished. By the use of this model we show that CaMKII induces maladaptive cardiac remodeling while it inhibits calcineurin-dependent hypertrophy. These data suggest inhibition of CaMKII but not calcineurin as a promising approach to attenuate the progression of heart failure.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.114.006185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4316667PMC
October 2014

Ionizing radiation regulates cardiac Ca handling via increased ROS and activated CaMKII.

Basic Res Cardiol 2013 Nov 26;108(6):385. Epub 2013 Sep 26.

Department of Cardiology and Pneumology/Heart Center, Georg-August-University Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.

Ionizing radiation (IR) is an integral part of modern multimodal anti-cancer therapies. IR involves the formation of reactive oxygen species (ROS) in targeted tissues. This is associated with subsequent cardiac dysfunction when applied during chest radiotherapy. We hypothesized that IR (i.e., ROS)-dependently impaired cardiac myocytes' Ca handling might contribute to IR-dependent cardiocellular dysfunction. Isolated ventricular mouse myocytes and the mediastinal area of anaesthetized mice (that included the heart) were exposed to graded doses of irradiation (sham 4 and 20 Gy) and investigated acutely (after ~1 h) as well as chronically (after ~1 week). IR induced a dose-dependent effect on myocytes' systolic function with acutely increased, but chronically decreased Ca transient amplitudes, which was associated with an acutely unaltered but chronically decreased sarcoplasmic reticulum (SR) Ca load. Likewise, in vivo echocardiography of anaesthetized mice revealed acutely enhanced left ventricular contractility (strain analysis) that declined after 1 week. Irradiated myocytes showed persistently increased diastolic SR Ca leakage, which was acutely compensated by an increase in SR Ca reuptake. This was reversed in the chronic setting in the face of slowed relaxation kinetics. As underlying cause, acutely increased ROS levels were identified to activate Ca/calmodulin-dependent protein kinase II (CaMKII). Accordingly, CaMKII-, but not PKA-dependent phosphorylation sites of the SR Ca release channels (RyR2, at Ser-2814) and phospholamban (at Thr-17) were found to be hyperphosphorylated following IR. Conversely, ROS-scavenging as well as CaMKII-inhibition significantly attenuated CaMKII-activation, disturbed Ca handling, and subsequent cellular dysfunction upon irradiation. Targeted cardiac irradiation induces a biphasic effect on cardiac myocytes Ca handling that is associated with chronic cardiocellular dysfunction. This appears to be mediated by increased oxidative stress and persistently activated CaMKII. Our findings suggest impaired cardiac myocytes Ca handling as a so far unknown mediator of IR-dependent cardiac damage that might be of relevance for radiation-induced cardiac dysfunction.
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http://dx.doi.org/10.1007/s00395-013-0385-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898380PMC
November 2013

Mercury exposure and neurochemical impacts in bald eagles across several Great Lakes states.

Ecotoxicology 2011 Oct 7;20(7):1669-76. Epub 2011 Jul 7.

Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA.

In this study, we assessed mercury (Hg) exposure in several tissues (brain, liver, and breast and primary feathers) in bald eagles (Haliaeetus leucocephalus) collected from across five Great Lakes states (Iowa, Michigan, Minnesota, Ohio, and Wisconsin) between 2002-2010, and assessed relationships between brain Hg and neurochemical receptors (NMDA and GABA(A)) and enzymes (glutamine synthetase (GS) and glutamic acid decarboxylase (GAD)). Brain total Hg (THg) levels (dry weight basis) averaged 2.80 μg/g (range: 0.2-34.01), and levels were highest in Michigan birds. THg levels in liver (r(p) = 0.805) and breast feathers (r(p) = 0.611) significantly correlated with those in brain. Brain Hg was not associated with binding to the GABA(A) receptor. Brain THg and inorganic Hg (IHg) were significantly positively correlated with GS activity (THg r(p) = 0.190; IHg r(p) = 0.188) and negatively correlated with NMDA receptor levels (THg r(p) = -0245; IHg r(p) = -0.282), and IHg was negatively correlated with GAD activity (r(s) = -0.196). We also report upon Hg demethylation and relationships between Hg and Se in brain and liver. These results suggest that bald eagles in the Great Lakes region are exposed to Hg at levels capable of causing subclinical neurological damage, and that when tissue burdens are related to proposed avian thresholds approximately 14-27% of eagles studied here may be at risk.
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http://dx.doi.org/10.1007/s10646-011-0730-1DOI Listing
October 2011

CaMKII-dependent diastolic SR Ca2+ leak and elevated diastolic Ca2+ levels in right atrial myocardium of patients with atrial fibrillation.

Circ Res 2010 Apr 7;106(6):1134-44. Epub 2010 Jan 7.

Department of Cardiology and Pneumology/Heart Center, Georg-August-University Göttingen, Robert-Koch-Strasse 40, Göttingen, Germany.

Rationale: Although research suggests that diastolic Ca(2+) levels might be increased in atrial fibrillation (AF), this hypothesis has never been tested. Diastolic Ca(2+) leak from the sarcoplasmic reticulum (SR) might increase diastolic Ca(2+) levels and play a role in triggering or maintaining AF by transient inward currents through Na(+)/Ca(2+) exchange. In ventricular myocardium, ryanodine receptor type 2 (RyR2) phosphorylation by Ca(2+)/calmodulin-dependent protein kinase (CaMK)II is emerging as an important mechanism for SR Ca(2+) leak.

Objective: We tested the hypothesis that CaMKII-dependent diastolic SR Ca(2+) leak and elevated diastolic Ca(2+) levels occurs in atrial myocardium of patients with AF.

Methods And Results: We used isolated human right atrial myocytes from patients with AF versus sinus rhythm and found CaMKII expression to be increased by 40+/-14% (P<0.05), as well as CaMKII phosphorylation by 33+/-12% (P<0.05). This was accompanied by a significantly increased RyR2 phosphorylation at the CaMKII site (Ser2814) by 110+/-53%. Furthermore, cytosolic Ca(2+) levels were elevated during diastole (229+/-20 versus 164+/-8 nmol/L, P<0.05). Most likely, this resulted from an increased SR Ca(2+) leak in AF (P<0.05), which was not attributable to higher SR Ca(2+) load. Tetracaine experiments confirmed that SR Ca(2+) leak through RyR2 leads to the elevated diastolic Ca(2+) level. CaMKII inhibition normalized SR Ca(2+) leak and cytosolic Ca(2+) levels without changes in L-type Ca(2+) current.

Conclusion: Increased CaMKII-dependent phosphorylation of RyR2 leads to increased SR Ca(2+) leak in human AF, causing elevated cytosolic Ca(2+) levels, thereby providing a potential arrhythmogenic substrate that could trigger or maintain AF.
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http://dx.doi.org/10.1161/CIRCRESAHA.109.203836DOI Listing
April 2010

Calcium/calmodulin-dependent protein kinase II contributes to cardiac arrhythmogenesis in heart failure.

Circ Heart Fail 2009 Nov 31;2(6):664-75. Epub 2009 Jul 31.

Department of Cardiology and Pneumology, Heart Center, Georg-August-University, Göttingen, Germany.

Background: Transgenic (TG) Ca/calmodulin-dependent protein kinase II (CaMKII)delta(C) mice have heart failure and isoproterenol (ISO)-inducible arrhythmias. We hypothesized that CaMKII contributes to arrhythmias and underlying cellular events and that inhibition of CaMKII reduces cardiac arrhythmogenesis in vitro and in vivo.

Methods And Results: Under baseline conditions, isolated cardiac myocytes from TG mice showed an increased incidence of early afterdepolarizations compared with wild-type myocytes (P<0.05). CaMKII inhibition (AIP) completely abolished these afterdepolarizations in TG cells (P<0.05). Increasing intracellular Ca stores using ISO (10(-8) M) induced a larger amount of delayed afterdepolarizations and spontaneous action potentials in TG compared with wild-type cells (P<0.05). This seems to be due to an increased sarcoplasmic reticulum (SR) Ca leak because diastolic [Ca](i) rose clearly on ISO in TG but not in wild-type cells (+20+/-5% versus +3+/-4% at 10(-6) M ISO, P<0.05). In parallel, SR Ca leak assessed by spontaneous SR Ca release events showed an increased Ca spark frequency (3.9+/-0.5 versus 2.0+/-0.4 sparks per 100 microm(-1).s(-1), P<0.05). However, CaMKII inhibition (either pharmacologically using KN-93 or genetically using an isoform-specific CaMKIIdelta-knockout mouse model) significantly reduced SR Ca spark frequency, although this rather increased SR Ca content. In parallel, ISO increased the incidence of early (54% versus 4%, P<0.05) and late (86% versus 43%, P<0.05) nonstimulated events in TG versus wild-type myocytes, but CaMKII inhibition (KN-93 and KO) reduced these proarrhythmogenic events (P<0.05). In addition, CaMKII inhibition in TG mice (KN-93) clearly reduced ISO-induced arrhythmias in vivo (P<0.05).

Conclusions: We conclude that CaMKII contributes to cardiac arrhythmogenesis in TG CaMKIIdelta(C) mice having heart failure and suggest the increased SR Ca leak as an important mechanism. Moreover, CaMKII inhibition reduces cardiac arrhythmias in vitro and in vivo and may therefore indicate a potential role for future antiarrhythmic therapies warranting further studies.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.109.865279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835502PMC
November 2009