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  • Ovid Technologies (Wolters Kluwer Health)  (15)
  • 1
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 130, No. suppl_2 ( 2014-11-25)
    Abstract: Background: We recently showed that the intercalated disc (ID) protein Myozap activates Rho-dependent SRF signaling both in vitro, and in vivo. Conversely, knockdown of its ortholog in Zebrafish led to severe contractile dysfunction and cardiomyopathy. Methods and Results: We generated a Myozap null mutant (MZP-ko) by global deletion of Myozap in mice. The absence of Myozap caused neither structural defects nor a baseline cardiac phenotype and led only to mild cardiac hypertrophy upon aging. Of note, induction of SRF target genes and the activation of SRF per se were markedly inhibited in MZP-ko mice. Nevertheless, biomechanical stress induced by transverse aortic constriction (TAC) triggered an excessive increase in cardiac hypertrophy (43% or 36% increased heart wt:body wt or LV wt:body wt ratios, p 〈 0.001), an increased cell surface area, as well as accelerated fibrosis, followed by “super”- induction of the hypertrophic gene program (ANF/BNP). Moreover, MZP-ko mice revealed a severe reduction of fractional shortening (average %FS for MZP-ko 14.5% compared to 33.5% for wild-type littermates, p 〈 0.001) and clinical signs of heart failure (54% increase in lung/body weights, p 〈 0.001) which also caused a profound increase in mortality in response to TAC. Furthermore, expression of other ID proteins like N-Cadherin, Desmoplakin and Connexin 43 was found significantly altered upon pressure overload in MZP-ko mice. Finally, we observed a downregulation of Dysbindin, a novel interaction partner of Myozap and known inducer of ERK1/2 signaling in TAC operated MZP-ko mice. Consistently, activation of ERK1/2 was blunted in MZP-ko mice after TAC. Conclusions: We here show that myozap deficiency in vivo inhibits SRF- and ERK1/2-signaling leading to a maladaptative response to increased biomechanical stress, followed by cardiomyopathy, heart failure and cardiac death. Moreover, myozap deficiency severely altered the expression of its direct ID interaction partners such as Dysbindin and Desmoplakin. In a broader perspective, our data identify signaling at the level of the intercalated disc as a critical component of cardiac remodeling.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
    detail.hit.zdb_id: 1466401-X
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  • 2
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 46, No. 10 ( 2015-10), p. 2741-2747
    Abstract: Specific coagulation assays for non–vitamin K antagonist oral anticoagulants (NOAC) are relatively slow and often lack availability. Although specific point-of-care tests (POCT) are currently not available, NOAC are known to affect established coagulation POCT. This study aimed at determining the diagnostic accuracy of the CoaguChek POCT to rule out relevant concentrations of rivaroxaban, apixaban, and dabigatran in real-life patients. Methods— We consecutively enrolled 60 ischemic stroke patients newly started on NOAC treatment and obtained blood samples at 6 prespecified time points. Samples were tested using the CoaguChek POCT, laboratory-based coagulation assays (prothrombin time and activated partial thromboplastin time, anti-Xa test and Hemoclot), and liquid chromatography–tandem mass spectrometry for direct determination of NOAC concentrations. Results— Three hundred fifty-six blood samples were collected. The CoaguChek POCT strongly correlated ( r =0.82 P 〈 0.001) with rivaroxaban concentrations but did not accurately detect dabigatran or apixaban. If used to estimate the presence of low rivaroxaban concentrations, POCT was superior to predictions based on normal prothrombin time and activated partial thromboplastin time values even if sensitive reagents were used. POCT-results ≤1.0 predicted rivaroxaban concentrations 〈 32 and 〈 100 ng/mL with a specificity of 90% and 96%, respectively. Conclusions— If anti-Xa test is not available, we propose the use of the CoaguChek POCT to guide thrombolysis decisions after individual risk assessment in rivaroxaban-treated patients having acute ischemic stroke. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT02371044.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 1467823-8
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  • 3
    In: Critical Care Medicine, Ovid Technologies (Wolters Kluwer Health), Vol. 45, No. 2 ( 2017-02), p. 241-252
    Abstract: To investigate the impact of a quality improvement initiative for severe sepsis and septic shock focused on the resuscitation bundle on 90-day mortality. Furthermore, effects on compliance rates for antiinfective therapy within the recommended 1-hour interval are evaluated. Design: Prospective observational before-after cohort study. Setting: Tertiary university hospital in Germany. Patients: All adult medical and surgical ICU patients with severe sepsis and septic shock. Intervention: Implementation of a quality improvement program over 7.5 years. Measurements: The primary endpoint was 90-day mortality. Secondary endpoints included ICU and hospital mortality rates and length of stay, time to broad-spectrum antiinfective therapy, and compliance with resuscitation bundle elements. Main Results: A total of 14,115 patients were screened. The incidence of severe sepsis and septic shock was 9.7%. Ninety-day mortality decreased from 64.2% to 45.0% ( p 〈 0.001). Hospital length of stay decreased from 44 to 36 days ( p 〈 0.05). Compliance with resuscitation bundle elements was significantly improved. Antibiotic therapy within the first hour after sepsis onset increased from 48.5% to 74.3% ( p 〈 0.001). Multivariate analysis revealed blood cultures before antibiotic therapy (hazard ratio, 0.60–0.84; p 〈 0.001), adequate calculated antibiotic therapy (hazard ratio, 0.53–0.75; p 〈 0.001), 1–2 L crystalloids within the first 6 hours (hazard ratio 0.67–0.97; p = 0.025), and greater than or equal to 6 L during the first 24 hours (hazard ratio, 0.64–0.95; p = 0.012) as predictors for improved survival. Conclusions: The continuous quality improvement initiative focused on the resuscitation bundle was associated with increased compliance and a persistent reduction in 90-day mortality over a 7.5-year period. Based on the observational study design, a causal relationship cannot be proven, and respective limitations need to be considered.
    Type of Medium: Online Resource
    ISSN: 0090-3493
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 2034247-0
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  • 4
    In: Journal of the American Heart Association, Ovid Technologies (Wolters Kluwer Health), Vol. 7, No. 19 ( 2018-10-02)
    Abstract: During treatment with direct oral anticoagulants ( DOAC ), coagulation assessment is required before thrombolysis, surgery, and if anticoagulation reversal is evaluated. Limited data support the accuracy of DOAC ‐specific coagulation assays around the current safe‐for‐treatment threshold of 30 ng/ mL . Methods and Results In 481 samples obtained from 96 patients enrolled at a single center, DOAC concentrations were measured using Hemoclot direct thrombin inhibitor assay, Biophen direct thrombin inhibitor assay or ecarin clotting time for dabigatran, chromogenic anti‐Xa assay ( AXA ) for factor Xa inhibitors (rivaroxaban, apixaban) and ultraperformance liquid chromatography–tandem mass spectrometry as reference. All dabigatran‐specific assays had high sensitivity to concentrations 〉 30 ng/ mL , but specificity was lower for Hemoclot direct thrombin inhibitor assay (78.2%) than for Biophen direct thrombin inhibitor assay (98.9%) and ecarin clotting time (94.6%). AXA provided high sensitivity and specificity for rivaroxaban, but low sensitivity for apixaban (73.8%; concentrations up to 82 ng/ mL were misclassified as 〈 30 ng/ mL ). If no DOAC ‐specific calibration for AXA is available, results 2‐fold above the upper limit of normal indicate relevant rivaroxaban concentrations. For apixaban, all elevated results should raise suspicion of relevant anticoagulation. Conclusions DOAC ‐specific tests differ considerably in diagnostic performance for concentrations close to the currently accepted safe‐for‐treatment threshold. Compared with Biophen direct thrombin inhibitor assay and ecarin clotting time, limited specificity of Hemoclot direct thrombin inhibitor assay poses a high risk of unnecessary anticoagulation reversal or treatment delays in patients on dabigatran. While AXA accurately detected rivaroxaban, the impact of low apixaban levels on the assay was weak. Hence, AXA results need to be interpreted with extreme caution when used to assess hemostatic function in patients on apixaban. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifiers: NCT 02371044, NCT 02371070.
    Type of Medium: Online Resource
    ISSN: 2047-9980
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 2653953-6
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  • 5
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 48, No. suppl_1 ( 2017-02)
    Abstract: Introduction: Non-vitamin K antagonist oral anticoagulants (NOAC) are increasingly replacing vitamin K antagonists for prevention of thromboembolism in atrial fibrillation (AF). Despite treatment, stroke rate in NOAC-treated AF-patients remains 1-2% per year. Subsequently, stroke physicians face a growing number of NOAC-treated patients with acute stroke. Rapid assessment of coagulation in NOAC-treated patients is vital prior to thrombolysis or reversal therapy, but existing point-of-care testing (POCT) is suboptimal. For the first time we evaluate NOAC-specific POCT. Hypothesis: Ecarin clotting time (ECT)- and anti-Xa activity (ENOX)-POCT predict plasma concentrations of dabigatran and apixaban/edoxaban/rivaroxaban. Methods: 80 patients receiving first NOAC-dose and 80 already on NOAC-treatment are enrolled in the SPOCT-NOAC I trial (N=40 for each NOAC). Subjects receiving other anticoagulants are excluded. Six blood samples are collected from each patient: before drug intake, 30min, 1, 2, and 8h after intake, and before next dose. NOAC-concentrations are measured by mass spectrometry. Results: 240 blood samples of 40 dabigatran-treated patients were analyzed. Dabigatran-concentrations ranged from 0-274ng/mL. ECT-POCT ranged from 20-196s. Pearson’s correlation coefficient showed strong correlation between ECT-POCT and dabigatran-concentrations (r=0.87). Performance was improved through the use of citrated in place of non-citrated whole blood (r=0.93). Dabigatran-concentrations 〉 50ng/mL (threshold for thrombolysis according to expert recommendation) were detected by ECT-POCT 〉 50s with 98% sensitivity and 79% specificity. Baseline-samples not containing any dabigatran yielded normal ECT values. Conclusions: This is the first study evaluating NOAC-specific POCT. Final results in the dabigatran group of SPOCT-NOAC show excellent correlation between ECT-POCT and dabigatran plasma concentrations; performance of ECT-POCT is even increased through the use of citrated whole blood. Relevant dabigatran-concentrations are detected with excellent sensitivity and specificity. In addition to ECT-POCT, we will present data on ENOX-POCT from apixaban-, edoxaban- and rivaroxaban-treated patients.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 1467823-8
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  • 6
    Online Resource
    Online Resource
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Stroke Vol. 46, No. suppl_1 ( 2015-02)
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 46, No. suppl_1 ( 2015-02)
    Abstract: Treatment decision for endovascular recanalization in acute ischemic stroke is based on validated outcome predictors such as age, initial infarct size, collaterals and clot burden. The CTA-based Clot Burden Score (CBS) only considers occlusions of the A1-segment of the anterior cerebral artery (ACA), but patency of the ipsilateral A2-segment is mandatory for collateral formation in a typical middle cerebral artery (MCA) occlusion. Secondly, CTA often cannot differentiate between an extra- or intra-cranial internal carotid artery (ICA) occlusion due to non-contrasting of the whole ICA in both. Thirdly, a 4-vessel angiogram, necessary to grasp the vascular basis of all pial collaterals, is often not done during acute recanalization therapy for reasons of time. To bypass these inadequacies, we propose a combined CTA/DSA score (ALITA) to assess pre-therapeutic thrombus load. We hypothesized a good outcome prediction of this score. We evaluated the ALITA score in a retrospective study including consecutive patients of the years 2010-12, who received endovascular therapy for acute stroke in the ICA-territory. Final outcome was measured with the modified Rankin Scale score (mRS) at 90 days. Reperfusion (mTICI), collaterals (CT-CS), clot burden (CBS), and the ALITA score were independently assessed. ALITA evaluates patency of the ACA and MCA in CTA and of the ICA in DSA. Data-driven ordinal regression analysis modeled outcome prediction of all scores. Of 99 patients 60% had a good reperfusion (mTICI 2b/3) and 29% had a good outcome (mRS 0-2), mortality was 23%. Age and reperfusion were independent predictors of good outcome (p 〈 .001). CT-CS (p 〈 .01), CBS (p 〈 .01) and ALITA (p 〈 .05) were significant predictors, but showed interaction regarding outcome. In the considered model CBS was a stronger predictor than ALITA. Although ALITA assesses all vessels of the anterior circulation contributing to collaterals the score was statistically different from CT-CS. This is consistent with results that describe pial collaterals as genetically determined. In conclusion, the combined CTA/DSA clot burden score better depicts the vascular basis of pial collaterals and predicts outcome in acute stroke patients.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 1467823-8
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  • 7
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 49, No. Suppl_1 ( 2018-01-22)
    Abstract: Introduction: Edoxaban, alongside other non-vitamin K antagonist oral anticoagulants (NOAC), is increasingly used for stroke prevention in patients with atrial fibrillation. Despite treatment, stroke rate in these patients remains one to two percent per year. In this growing population of edoxaban/NOAC-treated stroke patients, rapid assessment of coagulation would be useful to guide the decision for thrombolysis or reversal therapy in case of a neurovascular emergency. However, no data exists on the effect of edoxaban on available point-of-care test (POCT) systems. Hypothesis: Test assays of the commercially available CoaguChek® (CC) and Hemochron® are able to detect clinically relevant concentrations of edoxaban in a blood sample. Methods: We studied patients receiving their first dose of edoxaban. Subjects receiving other anticoagulants were excluded. Six blood samples were collected from each patient: before drug intake, 30 minutes, one, two, and eight hours after intake, as well as before the next dose. Coagulation-POCT and mass spectrometry for gold standard-determination of edoxaban plasma concentration were performed at each time point. Results: 120 blood samples from 20 edoxaban-treated patients were analyzed. Edoxaban concentrations ranged from 0 to 302ng/mL. CC-INR ranged from 0.9 to 2.3. Pearson’s correlation coefficient showed a strong correlation between CC-INR and edoxaban concentrations (r=0.73). Edoxaban concentrations 〉 30ng/mL (threshold for thrombolysis according to the European Stroke Organisation) were detected by CC-INR ≥ 1.1 with 96% sensitivity and 44% specificity (89% sensitivity and 88% specificity for CC-INR ≥ 1.2; AUC=0.92). Conclusions: Our study represents the first systematic evaluation of coagulation POCT in edoxaban-treated patients. Available coagulation POCT devices may be able to reliably detect clinically relevant edoxaban concentrations in blood samples of stroke patients in the emergency setting. In addition to edoxaban-POCT analyses, we will present further data on NOAC-specific POCT from our SPOCT-NOAC study.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 1467823-8
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  • 8
    Online Resource
    Online Resource
    Ovid Technologies (Wolters Kluwer Health) ; 2007
    In:  Journal of Cardiovascular Pharmacology Vol. 50, No. 6 ( 2007-12), p. 609-620
    In: Journal of Cardiovascular Pharmacology, Ovid Technologies (Wolters Kluwer Health), Vol. 50, No. 6 ( 2007-12), p. 609-620
    Type of Medium: Online Resource
    ISSN: 0160-2446
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2007
    detail.hit.zdb_id: 2049700-3
    SSG: 15,3
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  • 9
    Online Resource
    Online Resource
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Circulation Vol. 132, No. suppl_3 ( 2015-11-10)
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 132, No. suppl_3 ( 2015-11-10)
    Abstract: The dilated cardiomyopathy (DCM) is a major cause for heart failure. A causative genetic background is suspected in up to 50% of all DCM cases. However, the underlying molecular pathways remain incompletely understood. Here we analyze a calsarcin-1 deficient (CS1ko) mouse line as a model for DCM. These mice showed strong upregulation of fetal genes (e.g., Nppa, Nppb ) and the calcineurin-dependent gene Rcan1.4. Interestingly, we could not detect any signes of hypertrophy. In addition, there was no increase of fibrosis in CS1ko mice compared to wildtype controls. A screening experiment revealed upregulation of Cofilin2 (Cfl2), an actin depolymerisation factor and member of the ADF/Cofilin family, in Cs1ko mice (2.6-fold, p 〈 0.002), whereas its inactive, phosphorylated form (Ser3) remained unchanged. We also found increased amounts of Cfl2 in MLP-/- (1,8-fold p 〈 0.05) and Calcineurin TG mice (2.7-fold p 〈 0.01) suggesting a general role for Cfl2 in DCM. As Cfl2 is a known regulator of actin dynamics we investigated the role of Cfl2 in SRF signaling. Using an SRF-responsive luciferase reporter, overexpression of Cfl2 together with RhoA as activator of SRF signaling lead to an increase of SRF activity in C2C12 myoblasts (14-fold vs. 5.8-fold with RhoA alone, p 〈 0.001). SiRNA-mediated knockdown of Cfl2 yielded opposite effects (0.96-fold vs. 4.6-fold, p 〈 0.001). In the heart Cfl2 is predominantly expressed in cardiac myocytes as compared to fibroblasts. Overexpression of Cfl2 in cardiomyocytes (NRVCM) revealed an increase of Nppa and Nppb , which could be further increased by co-stimulation with phenylephrine (PE). In contrast to these findings, cell size analysis revealed a Cfl2-mediated decrease in cell size with and without PE, while knockdown of Cfl2 did not influence cellular hypertrophy. Taken together, our data imply a role for Cfl2 in the pathogenesis of DCM. Cs-1ko mice show a dilated phenotype, strong upregulation of the fetal gene program without a change in cell size. This correlates with the findings of overexpression of Cfl2 in NRVCM. Furthermore, increased Cfl2 levels induce SRF activity with potential influence on cardiomyocyte function. Further analyses are required to delineate the involved molecular pathways.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 1466401-X
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  • 10
    In: Shock, Ovid Technologies (Wolters Kluwer Health), Vol. 51, No. 3 ( 2019-03), p. 306-311
    Abstract: New Sepsis-3 criteria are supposed to “facilitate earlier recognition … of patients with sepsis.” To test this, we performed novel and direct comparisons of Sepsis-1 vs. Sepsis-3 criteria with respect to time differences of sepsis onset. Methods: In a cohort of intensive care unit (ICU) patients prospectively diagnosed with severe sepsis or septic shock according to Sepsis-1 criteria between 01/2010 and 12/2015, the time differences between meeting Sepsis-1 vs. Sepsis-3 criteria as time of sepsis onset and the corresponding differences in illness severity were tested. Similar comparisons were performed for septic shock subset meeting different Sepsis-1 vs. Sepsis-3 criteria. Patients with non-ICU-acquired sepsis and patients with sepsis onset more than 48 h postadmission (ICU-acquired sepsis) were analyzed separately to account for differences in availability of routinely collected organ dysfunction data. Results: A total of 10,905 ICU patients were screened; 862 patients met Sepsis-1 criteria, of whom 834 (97%) also met Sepsis-3 criteria. In patients, admitted to the ICU with sepsis, Sepsis-3 criteria compared with Sepsis-1 criteria were more frequently fulfilled within the first 3 h (84% vs. 75%, P   〈  0.001). In patients with ICU-acquired sepsis, sepsis onset was in 50% at least 1 day earlier after application of Sepsis-3 ( P  = 0.011). These patients were systemic inflammatory response syndrome negative at the earlier sepsis onset, but suffered already from organ dysfunction. Sepsis-3 criteria were timely in 86% and 1 day delayed in 7%. Only 7% (8 patients) did not meet Sepsis-3 criteria in this group. These patients had already an increased SOFA score and did develop neither a further increase nor the new septic shock criteria. Classification according to Sepsis-3 reduced the proportion of septic shock (51% vs. 75%, P   〈  0.001). Twenty-eight-day mortality was 38% for new septic shock compared with 33% of Sepsis-1 septic shock ( P   〉  0.05). Patients not detected by Sepsis-3 had a 28-day mortality of 11%. Conclusions: Sepsis-3 criteria facilitate an earlier and more predictive recognition of sepsis and septic shock in patients with non-ICU and ICU-acquired sepsis primarily diagnosed by Sepsis-1 criteria. These results require further validation with prospectively collected data.
    Type of Medium: Online Resource
    ISSN: 1073-2322 , 1540-0514
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 2011863-6
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