112 results on '"Baldus, Stephan"'
Search Results
2. Management of Myocardial Revascularization in Patients With Stable Coronary Artery Disease Undergoing Transcatheter Aortic Valve Implantation
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Costa, Giuliano, Pilgrim, Thomas, Santos, Ignacio J. Amat, De Backer, Ole, Kim, Won-Keun, Ribeiro, Henrique Barbosa, Saia, Francesco, Bunc, Matjaz, Tchetche, Didier, Garot, Philippe, Ribichini, Flavio Luciano, Mylotte, Darren, Burzotta, Francesco, Watanabe, Yusuke, De Marco, Federico, Tesorio, Tullio, Rheude, Tobias, Tocci, Marco, Franzone, Anna, Valvo, Roberto, Savontaus, Mikko, Wienemann, Hendrik, Porto, Italo, Gandolfo, Caterina, Iadanza, Alessandro, Santo Bortone, Alessandro, Mach, Markus, Latib, Azeem, Biasco, Luigi, Taramasso, Maurizio, Zimarino, Marco, Tomii, Daijiro, Nuyens, Philippe, Sondergaard, Lars, Camara, Sergio F., Palmerini, Tullio, Orzalkiewicz, Mateusz, Steblovnik, Klemen, Degrelle, Bastien, Gautier, Alexandre, Del Sole, Paolo Alberto, Mainardi, Andrea, Pighi, Michele, Lunardi, Mattia, Kawashima, Hideyuki, Criscione, Enrico, Cesario, Vincenzo, Biancari, Fausto, Zanin, Federico, Joner, Michael, Esposito, Giovanni, Adam, Matti, Grube, Eberhard, Baldus, Stephan, De Marzo, Vincenzo, Piredda, Elisa, Cannata, Stefano, Iacovelli, Fortunato, Andreas, Martin, Frittitta, Valentina, Dipietro, Elena, Reddavid, Claudia, Strazzieri, Orazio, Motta, Silvia, Angellotti, Domenico, Sgroi, Carmelo, Kargoli, Faraj, Tamburino, Corrado, Barbanti, Marco, Costa, Giuliano, Pilgrim, Thomas, Santos, Ignacio J. Amat, De Backer, Ole, Kim, Won-Keun, Ribeiro, Henrique Barbosa, Saia, Francesco, Bunc, Matjaz, Tchetche, Didier, Garot, Philippe, Ribichini, Flavio Luciano, Mylotte, Darren, Burzotta, Francesco, Watanabe, Yusuke, De Marco, Federico, Tesorio, Tullio, Rheude, Tobias, Tocci, Marco, Franzone, Anna, Valvo, Roberto, Savontaus, Mikko, Wienemann, Hendrik, Porto, Italo, Gandolfo, Caterina, Iadanza, Alessandro, Santo Bortone, Alessandro, Mach, Markus, Latib, Azeem, Biasco, Luigi, Taramasso, Maurizio, Zimarino, Marco, Tomii, Daijiro, Nuyens, Philippe, Sondergaard, Lars, Camara, Sergio F., Palmerini, Tullio, Orzalkiewicz, Mateusz, Steblovnik, Klemen, Degrelle, Bastien, Gautier, Alexandre, Del Sole, Paolo Alberto, Mainardi, Andrea, Pighi, Michele, Lunardi, Mattia, Kawashima, Hideyuki, Criscione, Enrico, Cesario, Vincenzo, Biancari, Fausto, Zanin, Federico, Joner, Michael, Esposito, Giovanni, Adam, Matti, Grube, Eberhard, Baldus, Stephan, De Marzo, Vincenzo, Piredda, Elisa, Cannata, Stefano, Iacovelli, Fortunato, Andreas, Martin, Frittitta, Valentina, Dipietro, Elena, Reddavid, Claudia, Strazzieri, Orazio, Motta, Silvia, Angellotti, Domenico, Sgroi, Carmelo, Kargoli, Faraj, Tamburino, Corrado, and Barbanti, Marco
- Abstract
Background:The best management of stable coronary artery disease (CAD) in patients undergoing transcatheter aortic valve implantation (TAVI) is still unclear due to the marked inconsistency of the available evidence. Methods:The REVASC-TAVI registry (Management of Myocardial Revascularization in Patients Undergoing Transcatheter Aortic Valve Implantation With Coronary Artery Disease) collected data from 30 centers worldwide on patients undergoing TAVI who had significant, stable CAD at preprocedural work-up. For the purposes of this analysis, patients with either complete or incomplete myocardial revascularization were compared in a propensity score matched analysis, to take into account of baseline confounders. The primary and co-primary outcomes were all-cause death and the composite of all-cause death, stroke, myocardial infarction, and rehospitalization for heart failure, respectively, at 2 years. Results:Among 2407 patients enrolled, 675 pairs of patients achieving complete or incomplete myocardial revascularization were matched. The primary (21.6% versus 18.2%, hazard ratio, 0.88 [95% CI, 0.66-1.18]; P=0.38) and co-primary composite (29.0% versus 27.1%, hazard ratio, 0.97 [95% CI, 0.76-1.24]; P=0.83) outcome did not differ between patients achieving complete or incomplete myocardial revascularization, respectively. These results were consistent across different prespecified subgroups of patients (< or >75 years of age, Society of Thoracic Surgeons score > or <4%, angina at baseline, diabetes, left ventricular ejection fraction > or <40%, New York Heart Association class I/II or III/IV, renal failure, proximal CAD, multivessel CAD, and left main/proximal anterior descending artery CAD; all P values for interaction >0.10). Conclusions:The present analysis of the REVASC-TAVI registry showed that, among TAVI patients with significant stable CAD found during the TAVI work-up, completeness of myocardial revascularization achieved either staged or concomitantly with
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- 2022
3. Recurrent Mitral Regurgitation After MitraClip: Predictive Factors, Morphology, and Clinical Implication
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Sugiura, Atsushi, Kavsur, Refik, Spieker, Maximilian, Iliadis, Christos, Goto, Tadahiro, Oeztuerk, Can, Weber, Marcel, Tabata, Noriaki, Zimmer, Sebastian, Sinning, Jan-Malte, Mauri, Victor, Horn, Patrick, Kelm, Malte, Baldus, Stephan, Nickenig, Georg, Westenfeld, Ralf, Pfister, Roman, Becher, Marc Ulrich, Sugiura, Atsushi, Kavsur, Refik, Spieker, Maximilian, Iliadis, Christos, Goto, Tadahiro, Oeztuerk, Can, Weber, Marcel, Tabata, Noriaki, Zimmer, Sebastian, Sinning, Jan-Malte, Mauri, Victor, Horn, Patrick, Kelm, Malte, Baldus, Stephan, Nickenig, Georg, Westenfeld, Ralf, Pfister, Roman, and Becher, Marc Ulrich
- Abstract
Background: Recurrent mitral regurgitation (MR) following MitraClip has not been thoroughly investigated. We aimed to examine the predictive factors, morphology, and long-term outcome of recurrent MR after MitraClip. Methods: We assessed data from the Heart Failure Network Rhineland registry from August 2010 to October 2018. Competing risk analyses were performed using the Fine and Gray model to assess the risk of recurrent MR. Results: Among 685 MitraClip patients with a reduction in MR to <= 2+, 61 patients developed recurrent MR within the first 12 months. Flail leaflet (hazard ratio, 3.68; P=0.002) and residual MR (MR grade 2+ versus <= 1+: hazard ratio, 2.56; P=0.03) were the predictors of recurrent MR in primary MR patients, while left atrial volume (per 10 mL increase: hazard ratio, 1.11; P<0.001) and residual MR (hazard ratio, 2.45; P=0.01) were independently associated with recurrent MR in secondary MR patients. In primary MR patients, loss of leaflet insertion or leaflet tear were the predominant morphologies with recurrent MR. In secondary MR patients, more than half of the patients with recurrent MR did not show any disorder of the clip or leaflets. Patients with recurrent MR were more likely to experience unplanned heart failure hospitalization or heart failure symptom with New York Heart Association scale III/IV (54.1% versus 37.8%; P=0.018) and undergo a repeat mitral valve intervention (9.8% versus 2.2%; P=0.005) during the follow-up. In the landmark survival analysis, patients with recurrent MR tended to have lower long-term survival (58.7% versus 83.9%; P=0.08) than patients without recurrent MR. Conclusions: Flail leaflet and residual MR were the predictors of recurrent MR in primary MR patients, while a larger left atrial volume and residual MR were associated with recurrent MR in secondary MR patients, which may be associated with long-term clinical outcomes of patients after MitraClip.
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- 2022
4. Transcatheter Treatment of Secondary Tricuspid Regurgitation With Direct Annuloplasty Results From a Multicenter Real-World Experience
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Koerber, Maria I., Landendinger, Melanie, Gercek, Muhammed, Beuthner, Bo E., Friedrichs, Kai P., Puls, Miriam, Baldus, Stephan, Rudolph, Volker, Jacobshagen, Claudius, Arnold, Martin, Pfister, Roman, Koerber, Maria I., Landendinger, Melanie, Gercek, Muhammed, Beuthner, Bo E., Friedrichs, Kai P., Puls, Miriam, Baldus, Stephan, Rudolph, Volker, Jacobshagen, Claudius, Arnold, Martin, and Pfister, Roman
- Abstract
Background: Treatment options for secondary tricuspid regurgitation (TR) remain limited. Early real-world data of a new percutaneous direct annuloplasty system for tricuspid repair were examined. Methods: The first 60 patients treated with the Cardioband tricuspid valve repair system at 4 centers were included in this retrospective study. The primary efficacy end point was technical success with reduction of TR >= 2 grades at discharge. Combined primary safety end point was major adverse events (death, myocardial infarction, cardiothoracic surgery, and stroke) at 30 days. Results: Median patient age was 76 years (73-82), median EuroScore II was 3.9% (2.2-8.1), heart failure with preserved ejection fraction was present in 78%, and 81.7% were in the New York Heart Association class III/IV. Massive or torrential TR was found in 51.7%, and severe TR in 48.3%. The primary efficacy end point was achieved in 45%, while 60.3% of patients had less-than-severe TR at discharge. Vena contracta was reduced by 47% from 12.9 +/- 4.8 to 7.0 +/- 3.4 mm (P<0.001). Overall, the majority of patients (81.7%) improved at least by 1 New York Heart Association class. At follow-up 81.3% of patients presented in the New York Heart Association class I or II. The primary safety end point occurred in 4 patients with 2 in-hospital deaths, both not device related. Right coronary artery complications (vessel perforation or stent implantation) occurred in 9 patients (15%). Procedural time decreased from 298 to 185 minutes (P<0.001) with efficacy remaining stable (P=0.817) when comparing procedure numbers 11 or more to the earliest 5 procedures per center. Conclusions: This first real-world experience suggests that transcatheter treatment of advanced secondary TR using direct annuloplasty is feasible and reasonably safe early in the learning curve, with significant symptomatic benefit. Further studies are warranted to provide data on long-term outcome and patient prognosis.
- Published
- 2021
5. Risk Stratification of Patients Undergoing Percutaneous Repair of Mitral and Tricuspid Valves Using a Multidimensional Geriatric Assessment
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Schaefer, Matthieu, Koerber, Maria I., Vimalathasan, Rakave, Mauri, Victor, Iliadis, Christos, Metze, Clemens, ten Freyhaus, Henrik, Baldus, Stephan, Polidori, M. Cristina, Pfister, Roman, Schaefer, Matthieu, Koerber, Maria I., Vimalathasan, Rakave, Mauri, Victor, Iliadis, Christos, Metze, Clemens, ten Freyhaus, Henrik, Baldus, Stephan, Polidori, M. Cristina, and Pfister, Roman
- Abstract
Background: Given their advanced age and high comorbidity, individual risk assessment is crucial in patients undergoing transcatheter mitral and tricuspid valve repair. Therefore, we evaluated the use of a comprehensive geriatric assessment score, the multidimensional prognostic index (MPI), for risk stratification in these patients. Methods: We conducted a prospective, observational single-center study, including 226 patients undergoing percutaneous repair for mitral or tricuspid regurgitation. The MPI was calculated preprocedural and covers 8 domains (activities of daily living, instrumental activities of daily living, mental status, nutrition, risk of pressure ulcers, comorbidity, medication, and marital/cohabitation status). We sought to identify an association of MPI score with procedural outcomes and 6-month mortality. Results: A total of 53.1% of patients were stratified as low risk according to MPI (MPI-1 group), 44.2% as medium risk (MPI-2 group), and 2.7% as high risk (MPI-3 group). Procedural efficacy and safety were similar between groups. The estimated survival rate at 6 months was 97 +/- 2% in MPI-1 group, 79 +/- 4% in MPI-2 group (hazard ratio, 6.90 [95% CI, 2.36-12.2]; P <= 0.001) and 50 +/- 20% in MPI-3 group (hazard ratio, 20.3 [95% CI, 4.51-91.3]; P<0.001). An increase in 1 SD of the MPI score (0.14 points, possible range of MPI score 0-1) was associated with a hazard ratio of 2.13 (95% CI, 1.58-2.73; P <= 0.001) for death after 6 months. The risk association of the MPI with mortality remained significant in multivariate analysis including risk factors, such as peripheral artery disease and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. Conclusions: A comprehensive geriatric assessment with the MPI score provides additional information on mortality risk beyond established cardiovascular risk factors.
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- 2021
6. Hypoxia and Cardiac Function in Patients With Prior Myocardial Infarction.
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Hönemann, Jan-Niklas, Gerlach, Darius, Hoffmann, Fabian, Kramer, Tilmann, Weis, Henning, Hellweg, Christine E., Konda, Bikash, Zaha, Vlad G., Sadek, Hesham A., van Herwarden, Antonius E., Olthaar, André J., Reuter, Hannes, Baldus, Stephan, Levine, Benjamin D., Jordan, Jens, Tank, Jens, and Limper, Ulrich
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- 2023
- Full Text
- View/download PDF
7. Response by Luker et al to Letter Regarding Article, Internal Versus External Electrical Cardioversion of Atrial Arrhythmia in Patients With Implantable Cardioverter-Defibrillator: A Randomized Clinical Trial
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Lueker, Jakob, Kuhr, Kathrin, Sultan, Arian, Noelker, Georg, Omran, Hazem, Willems, Stephan, Andrie, Rene, Schrickel, Jan W., Winter, Stefan, Vollmann, Dirk, Tilz, Roland R., Jobs, Alexander, Heeger, Christian-H., Metzner, Andreas, Meyer, Sven, Mischke, Karl, Napp, Andreas, Fahrig, Andreas, Steinhauser, Susanne, Brachmann, Johannes, Baldus, Stephan, Mahajan, Rajiv, Sanders, Prashanthan, Steven, Daniel, Lueker, Jakob, Kuhr, Kathrin, Sultan, Arian, Noelker, Georg, Omran, Hazem, Willems, Stephan, Andrie, Rene, Schrickel, Jan W., Winter, Stefan, Vollmann, Dirk, Tilz, Roland R., Jobs, Alexander, Heeger, Christian-H., Metzner, Andreas, Meyer, Sven, Mischke, Karl, Napp, Andreas, Fahrig, Andreas, Steinhauser, Susanne, Brachmann, Johannes, Baldus, Stephan, Mahajan, Rajiv, Sanders, Prashanthan, and Steven, Daniel
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- 2020
8. Evolution of Pulmonary Hypertension During Severe Sustained Hypoxia
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Hoffmann, Fabian, Limper, Ulrich, Zaha, Vlad G., Reuter, Hannes, Zange, Leonora, Schulz-Menger, Jeanette, Hein, Marc, Baldus, Stephan, Levine, Benjamin D., Jordan, Jens, Tank, Jens, Hoffmann, Fabian, Limper, Ulrich, Zaha, Vlad G., Reuter, Hannes, Zange, Leonora, Schulz-Menger, Jeanette, Hein, Marc, Baldus, Stephan, Levine, Benjamin D., Jordan, Jens, and Tank, Jens
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- 2020
9. Pulmonary hypertension associated with left-sided heart failure
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Adler, Joana, Gerhardt, Felix, Wissmueller, Max, Adler, Christoph, Baldus, Stephan, Rosenkranz, Stephan, Adler, Joana, Gerhardt, Felix, Wissmueller, Max, Adler, Christoph, Baldus, Stephan, and Rosenkranz, Stephan
- Abstract
Purpose of review Pulmonary hypertension is a common phenomenon in heart failure patients that is highly relevant for morbidity and outcome. Although postcapillary in nature, the pathophysiology of pulmonary hypertension in patients with heart failure with reduced or preserved ejection fraction is complex, and decisions about management strategies remain challenging. Recent findings Recently, the hemodynamic definitions and subclassification of postcapillary pulmonary hypertension have been revisited. The distinction between isolated postcapillary pulmonary hypertension (IpcPH) and combined post and precapillary pulmonary hypertension (CpcPH) and their definition are essential. Novel data on the prognostic impact of hemodynamic variables and right ventricular function highlight the importance of cardiopulmonary interaction in patients with left-sided heart failure (LHF). Furthermore, the impact of management strategies including medical therapy, remote hemodynamic monitoring, and interventional approaches on hemodynamics and outcome has recently been investigated. Here, we critically review recent developments and future considerations in this field, and highlight distinct treatment strategies targeting the underlying left heart condition, the pulmonary circulation, and/or impaired right ventricular function. Detailed hemodynamic characterization and proper phenotyping are essential for prognostication and the management of patients with pulmonary hypertension associated with LHF, both in clinical practice and when addressing research questions.
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- 2020
10. PULMONARY HYPERTENSION DOES NOT LIMIT TRANSLATIONAL APPROACHES OF HYPOXIA MEDIATED MYOCARDIAL REGENERATION.
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Hoenemann, Jan -Niklas, Hoffmann, Fabian, Weis, Henning, Gerlach, Darius, Zaha, Vlad G, Sadek, Hesham, Reuter, Hannes, Baldus, Stephan, Splettstoesser, Frank, Frede, Stilla, Levine, Benjamin D, Jordan, Jens, Limper, Ulrich, and Tank, Jens
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- 2024
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11. Internal Versus External Electrical Cardioversion of Atrial Arrhythmia in Patients With Implantable Cardioverter-Defibrillator A Randomized Clinical Trial
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Lueker, Jakob, Kuhr, Kathrin, Sultan, Arian, Noelker, Georg, Omran, Hazem, Willems, Stephan, Andrie, Rene, Schrickel, Jan W., Winter, Stefan, Vollmann, Dirk, Tilz, Roland R., Jobs, Alexander, Heeger, Christian-H., Metzner, Andreas, Meyer, Sven, Mischke, Karl, Napp, Andreas, Fahrig, Andreas, Steinhauser, Susanne, Brachmann, Johannes, Baldus, Stephan, Mahajan, Rajiv, Sanders, Prashanthan, Steven, Daniel, Lueker, Jakob, Kuhr, Kathrin, Sultan, Arian, Noelker, Georg, Omran, Hazem, Willems, Stephan, Andrie, Rene, Schrickel, Jan W., Winter, Stefan, Vollmann, Dirk, Tilz, Roland R., Jobs, Alexander, Heeger, Christian-H., Metzner, Andreas, Meyer, Sven, Mischke, Karl, Napp, Andreas, Fahrig, Andreas, Steinhauser, Susanne, Brachmann, Johannes, Baldus, Stephan, Mahajan, Rajiv, Sanders, Prashanthan, and Steven, Daniel
- Abstract
Background: Atrial arrhythmias are common in patients with implantable cardioverter-defibrillator (ICD). External shocks and internal cardioversion through commanded ICD shock for electrical cardioversion are used for rhythm-control. However, there is a paucity of data on efficacy of external versus internal cardioversion and on the risk of lead and device malfunction. We hypothesized that external cardioversion is noninferior to internal cardioversion for safety, and superior for successful restoration of sinus rhythm. Methods: Consecutive patients with ICD undergoing elective cardioversion for atrial arrhythmias at 13 centers were randomized in 1:1 fashion to either internal or external cardioversion. The primary safety end point was a composite of surrogate events of lead or device malfunction. Conversion of atrial arrhythmia to sinus rhythm was the primary efficacy end point. Myocardial damage was studied by measuring troponin release in both groups. Results: N=230 patients were randomized. Shock efficacy was 93% in the external cardioversion group and 65% in the internal cardioversion group (P<0.001). Clinically relevant adverse events caused by external or internal cardioversion were not observed. Three cases of pre-existing silent lead malfunction were unmasked by internal shock, resulting in lead failure. Troponin release did not differ between groups. Conclusions: This is the first randomized trial on external vs internal cardioversion in patients with ICDs. External cardioversion was superior for the restoration of sinus rhythm. The unmasking of silent lead malfunction in the internal cardioversion group suggests that an internal shock attempt may be reasonable in selected ICD patients presenting for electrical cardioversion.
- Published
- 2019
12. Transcatheter Treatment of Secondary Tricuspid Regurgitation With Direct Annuloplasty.
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Körber, Maria I., Landendinger, Melanie, Gerçek, Muhammed, Beuthner, Bo E., Friedrichs, Kai P., Puls, Miriam, Baldus, Stephan, Rudolph, Volker, Jacobshagen, Claudius, Arnold, Martin, and Pfister, Roman
- Abstract
BACKGROUND: Treatment options for secondary tricuspid regurgitation (TR) remain limited. Early real-world data of a new percutaneous direct annuloplasty system for tricuspid repair were examined. METHODS: The first 60 patients treated with the Cardioband tricuspid valve repair system at 4 centers were included in this retrospective study. The primary efficacy end point was technical success with reduction of TR ≥2 grades at discharge. Combined primary safety end point was major adverse events (death, myocardial infarction, cardiothoracic surgery, and stroke) at 30 days. RESULTS: Median patient age was 76 years (73-82), median EuroScore II was 3.9% (2.2-8.1), heart failure with preserved ejection fraction was present in 78%, and 81.7% were in the New York Heart Association class III/IV. Massive or torrential TR was found in 51.7%, and severe TR in 48.3%. The primary efficacy end point was achieved in 45%, while 60.3% of patients had less-than-severe TR at discharge. Vena contracta was reduced by 47% from 12.9±4.8 to 7.0±3.4 mm (P<0.001). Overall, the majority of patients (81.7%) improved at least by 1 New York Heart Association class. At follow-up 81.3% of patients presented in the New York Heart Association class I or II. The primary safety end point occurred in 4 patients with 2 in-hospital deaths, both not device related. Right coronary artery complications (vessel perforation or stent implantation) occurred in 9 patients (15%). Procedural time decreased from 298 to 185 minutes (P<0.001) with efficacy remaining stable (P=0.817) when comparing procedure numbers 11 or more to the earliest 5 procedures per center. CONCLUSIONS: This first real-world experience suggests that transcatheter treatment of advanced secondary TR using direct annuloplasty is feasible and reasonably safe early in the learning curve, with significant symptomatic benefit. Further studies are warranted to provide data on long-term outcome and patient prognosis. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
13. Systemic Upregulation of IL-10 (Interleukin-10) Using a Nonimmunogenic Vector Reduces Growth and Rate of Dissecting Abdominal Aortic Aneurysm
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Adam, Matti, Kooreman, Nigel Geoffrey, Jagger, Ann, Wagenhaeuser, Markus U., Mehrkens, Dennis, Wang, Yongming, Kayama, Yosuke, Toyama, Kensuke, Raaz, Uwe, Schellinger, Isabel N., Maegdefessel, Lars, Spin, Joshua M., Hamming, Jaap F., Quax, Paul H. A., Baldus, Stephan, Wu, Joseph C., Tsao, Philip S., Adam, Matti, Kooreman, Nigel Geoffrey, Jagger, Ann, Wagenhaeuser, Markus U., Mehrkens, Dennis, Wang, Yongming, Kayama, Yosuke, Toyama, Kensuke, Raaz, Uwe, Schellinger, Isabel N., Maegdefessel, Lars, Spin, Joshua M., Hamming, Jaap F., Quax, Paul H. A., Baldus, Stephan, Wu, Joseph C., and Tsao, Philip S.
- Abstract
Objective Recruitment of immunologic competent cells to the vessel wall is a crucial step in formation of abdominal aortic aneurysms (AAA). Innate immunity effectors (eg, macrophages), as well as mediators of adaptive immunity (eg, T cells), orchestrate a local vascular inflammatory response. IL-10 (interleukin-10) is an immune-regulatory cytokine with a crucial role in suppression of inflammatory processes. We hypothesized that an increase in systemic IL-10-levels would mitigate AAA progression. Approach and Results Using a single intravenous injection protocol, we transfected an IL-10 transcribing nonimmunogenic minicircle vector into the Ang II (angiotensin II)-ApoE(-/-) infusion mouse model of AAA. IL-10 minicircle transfection significantly reduced average aortic diameter measured via ultrasound at day 28 from 166.110.8% (control) to 131.0 +/- 5.8% (IL-10 transfected). Rates of dissecting AAA were reduced by IL-10 treatment, with an increase in freedom from dissecting AAA from 21.5% to 62.3%. Using flow cytometry of aortic tissue from minicircle IL-10-treated animals, we found a significantly higher percentage of CD4(+)/CD25(+)/Foxp3 (forkhead box P3)(+) regulatory T cells, with fewer CD8(+)/GZMB(+) (granzyme B) cytotoxic T cells. Furthermore, isolated aortic macrophages produced less TNF- (tumor necrosis factor-), more IL-10, and were more likely to be MRC1 (mannose receptor, C type 1)-positive alternatively activated macrophages. These results concurred with gene expression analysis of lipopolysaccharide-stimulated and Ang II-primed human peripheral blood mononuclear cells. Conclusions Taken together, we provide an effective gene therapy approach to AAA in mice by enhancing antiinflammatory and dampening proinflammatory pathways through minicircle-induced augmentation of systemic IL-10 expression.
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- 2018
14. MPO (Myeloperoxidase) Reduces Endothelial Glycocalyx Thickness Dependent on Its Cationic Charge
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Manchanda, Kashish, Kolarova, Hana, Kerkenpass, Christina, Mollenhauer, Martin, Vitecek, Jan, Rudolph, Volker, Kubala, Lukas, Baldus, Stephan, Adam, Matti, Klinke, Anna, Manchanda, Kashish, Kolarova, Hana, Kerkenpass, Christina, Mollenhauer, Martin, Vitecek, Jan, Rudolph, Volker, Kubala, Lukas, Baldus, Stephan, Adam, Matti, and Klinke, Anna
- Abstract
Objective The leukocyte heme-enzyme MPO (myeloperoxidase) exerts proinflammatory effects on the vascular system primarily linked to its catalytic properties. Recent studies have shown that MPO, depending on its cationic charge, mediates neutrophil recruitment and activation. Here, we further investigated MPO's extracatalytic properties and its effect on endothelial glycocalyx (EG) integrity. Approach and Results In vivo staining of murine cremaster muscle vessels with Alcian Blue 8GX provided evidence of an MPO-dependent decrease in anionic charge of the EG. MPO binding to the glycocalyx was further characterized using Chinese hamster ovary cells and its glycosaminoglycan mutantspgsA-745 (mutant Chinese hamster ovary cells lacking heparan sulfate and chondroitin sulfate glycosaminoglycan) and pgsD-677 (mutant Chinese hamster ovary cells lacking heparan sulfate glycosaminoglycan), which revealed heparan sulfate as the main mediator of MPO binding. Further, EG integrity was assessed in terms of thickness using intravital microscopy of murine cremaster muscle. A significant reduction in EG thickness was observed on infusion of catalytically active MPO, as well as mutant inactive MPO and cationic polymer polylysine. Similar effects were also observed in wild-type mice after a local inflammatory stimulus but not in MPO-knockout mice. The reduction in EG thickness was reversed after removal of vessel-bound MPO, suggesting a possible physical collapse of the EG. Last, experiments with in vivo neutrophil depletion revealed that MPO also induced neutrophil-mediated shedding of the EG core protein, Sdc1 (syndecan-1). Conclusions These findings provide evidence that MPO, via ionic interaction with heparan sulfate side chains, can cause neutrophil-dependent Sdc1 shedding and collapse of the EG structure.
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- 2018
15. PI3-Kinase Delta Protects Against Atherosclerosis Progression by Controlling Regulatory T-Cell Homeostasis and Function
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Zierden, Mario, Millarg, Christopher, Berghausen, Eva M., Baldus, Stephan, Vantler, Marius, Rosenkranz, Stephan, Zierden, Mario, Millarg, Christopher, Berghausen, Eva M., Baldus, Stephan, Vantler, Marius, and Rosenkranz, Stephan
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- 2018
16. Macitentan as an Additive Therapeutic Option in Patients With Inoperable or Persistent Chronic Thromboembolic Pulmonary Hypertension
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Kramer, Tilmann T., Gerhardt, Felix, Dumitrescu, Daniel, Brensing, Pia, Baldus, Stephan, Rosenkranz, Stephan, Kramer, Tilmann T., Gerhardt, Felix, Dumitrescu, Daniel, Brensing, Pia, Baldus, Stephan, and Rosenkranz, Stephan
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- 2018
17. Pulmonary Arterial Hypertension: Rapid Sequential Combination Therapy With PDE5 Inhibitors and Endothelin Receptor Antagonists Substantially Improves Hemodynamics at Early Follow-Up
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Kramer, Tilmann T., Dumitrescu, Daniel, Gerhardt, Felix, Nattmann, Phillip, Hohmann, Christopher, Baldus, Stephan, Rosenkranz, Stephan, Kramer, Tilmann T., Dumitrescu, Daniel, Gerhardt, Felix, Nattmann, Phillip, Hohmann, Christopher, Baldus, Stephan, and Rosenkranz, Stephan
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- 2018
18. SAFETY AND FEASIBILITY OF HYPOXIA EXPOSURE IN PATIENTS WITH PRIOR MYOCARDIAL INFARCTION.
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Hönemann, Jan-Niklas, Gerlach, Darius, Hoffmann, Fabian, Kramer, Tilmann, Weis, Henning, Zaha, Vlad G., Sadek, Hesham, Herwarden, Andonuis E., Olthaar, Andre, Reuter, Hannes, Baldus, Stephan, Levine, Benjamin D, Jordan, Jens, Tank, Jens, and Limper, Ulrich
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- 2023
- Full Text
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19. Myeloperoxidase Mediates Postischemic Arrhythmogenic Ventricular Remodeling
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Mollenhauer, Martin, Friedrichs, Kai, Lange, Max, Gesenberg, Jan, Remane, Lisa, Kerkenpass, Christina, Krause, Jenny, Schneider, Johanna, Ravekes, Thorben, Maass, Martina, Halbach, Marcel, Peinkofer, Gabriel, Saric, Tomo, Mehrkens, Dennis, Adam, Matti, Deuschl, Florian G., Lau, Denise, Geertz, Birgit, Manchanda, Kashish, Eschenhagen, Thomas, Kubala, Lukas, Rudolph, Tanja K., Wu, Yuping, Tang, W. H. Wilson, Hazen, Stanley L., Baldus, Stephan, Klinke, Anna, Rudolph, Volker, Mollenhauer, Martin, Friedrichs, Kai, Lange, Max, Gesenberg, Jan, Remane, Lisa, Kerkenpass, Christina, Krause, Jenny, Schneider, Johanna, Ravekes, Thorben, Maass, Martina, Halbach, Marcel, Peinkofer, Gabriel, Saric, Tomo, Mehrkens, Dennis, Adam, Matti, Deuschl, Florian G., Lau, Denise, Geertz, Birgit, Manchanda, Kashish, Eschenhagen, Thomas, Kubala, Lukas, Rudolph, Tanja K., Wu, Yuping, Tang, W. H. Wilson, Hazen, Stanley L., Baldus, Stephan, Klinke, Anna, and Rudolph, Volker
- Abstract
Rationale: Ventricular arrhythmias remain the leading cause of death in patients suffering myocardial ischemia. Myeloperoxidase, a heme enzyme released by polymorphonuclear neutrophils, accumulates within ischemic myocardium and has been linked to adverse left ventricular remodeling. Objective: To reveal the role of myeloperoxidase for the development of ventricular arrhythmias. Methods and Results: In different murine models of myocardial ischemia, myeloperoxidase deficiency profoundly decreased vulnerability for ventricular tachycardia on programmed right ventricular and burst stimulation and spontaneously as assessed by ECG telemetry after isoproterenol injection. Experiments using CD11b/CD18 integrin-deficient (CD11b(-/-)) mice and intravenous myeloperoxidase infusion revealed that neutrophil infiltration is a prerequisite for myocardial myeloperoxidase accumulation. Ventricles from myeloperoxidase-deficient (Mpo(-/-)) mice showed less pronounced slowing and decreased heterogeneity of electric conduction in the peri-infarct zone than wildtype mice. Expression of the redox-sensitive gap junctional protein Cx43 (Connexin 43) was reduced in the peri-infarct area of wild-type compared with Mpo(-/-) mice. In isolated wild-type cardiomyocytes, Cx43 protein content decreased on myeloperoxidase/H2O2 incubation. Mapping of induced pluripotent stem cell-derived cardiomyocyte networks and in vivo investigations linked Cx43 breakdown to myeloperoxidase-dependent activation of matrix metalloproteinase 7. Moreover, Mpo(-/-) mice showed decreased ventricular postischemic fibrosis reflecting reduced accumulation of myofibroblasts. Ex vivo, myeloperoxidase was demonstrated to induce fibroblast-to-myofibroblast transdifferentiation by activation of p38 mitogen-activated protein kinases resulting in upregulated collagen generation. In support of our experimental findings, baseline myeloperoxidase plasma levels were independently associated with a history of ventricular arrhythmias
- Published
- 2017
20. Short-Term Outcome and Hemodynamic Performance of Next-Generation Self-Expanding Versus BalloonExpandable Transcatheter Aortic Valves in Patients With Small Aortic Annulus A Multicenter Propensity-Matched Comparison
- Author
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Mauri, Victor, Kim, Won K., Abumayyaleh, Mohammad, Walther, Thomas, Moellmann, Helge, Schaefer, Ulrich, Conradi, Lenard, Hengstenberg, Christian, Hilker, Michael, Wahlers, Thorsten, Baldus, Stephan, Rudolph, Volker, Madershahian, Navid, Rudolph, Tanja K., Mauri, Victor, Kim, Won K., Abumayyaleh, Mohammad, Walther, Thomas, Moellmann, Helge, Schaefer, Ulrich, Conradi, Lenard, Hengstenberg, Christian, Hilker, Michael, Wahlers, Thorsten, Baldus, Stephan, Rudolph, Volker, Madershahian, Navid, and Rudolph, Tanja K.
- Abstract
Background-Surgical aortic valve replacement in patients with small annular dimensions is challenging because they are at increased risk for prosthesis-patient mismatch and impaired outcomes. Transcatheter aortic valve replacement might be a good alternative; however, comparative data on different transcatheter heart valves are missing. Methods and Results-This multicenter, propensity score-matched study compared hemodynamics and early clinical outcomes in 246 patients with an aortic annulus area <400 mm(2) undergoing transcatheter aortic valve replacement with either a self-expanding transcatheter heart valve (Symetis ACURATE neo, n=129) or a balloon-expandable transcatheter heart valve (Edwards SAPIEN 3, n=117). The 1: 1 propensity score matching resulted in 92 matched pairs. For ACURATE neo versus SAPIEN 3-treated patients, 30-day mortality (0.0% versus 1.0%), 1-year mortality (8.3% versus 13.3%), incidence of stroke (3.3% versus 2.2%), life-threatening bleeding (1.1% versus 1.1%), and major vascular complications (2.2% versus 6.5%), as well as pacemaker implantation rate (12.0% versus 15.2%), were similar. Paravalvular regurgitation >= moderate was rare in both groups (4.5% versus 3.6%). The ACURATE neo presented lower mean transvalvular gradients (9.3 versus 14.5 mm Hg; P<0.001), larger indexed effective orifice areas (0.96 versus 0.80 cm(2)/m(2); P=0.003), and lower rates of severe prosthesis-patient mismatch (3% versus 22%; P=0.004). Hemodynamics were sustained at 1-year follow-up. Conclusions-Albeit a similar safety profile with low clinical event rates, transcatheter aortic valve replacement with the ACURATE neo valve resulted in lower transvalvular gradients and consequently less prosthesis-patient mismatch compared with the SAPIEN 3 in patients with small annulus. These results emphasize the need of careful prosthesis selection in each individual patient.
- Published
- 2017
21. Class IA Phosphatidylinositol 3-Kinase Isoform p110 alpha Mediates Vascular Remodeling
- Author
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Vantler, Marius, Jesus, Joana, Leppaenen, Olli, Scherner, Maximilian, Berghausen, Eva Maria, Mustafov, Lenard, Chen, Xin, Kramer, Tilmann, Zierden, Mario, Gerhardt, Maximilian, ten Freyhaus, Henrik, Blaschke, Florian, Sterner-Kock, Anja, Baldus, Stephan, Zhao, Jean J., Rosenkranz, Stephan, Vantler, Marius, Jesus, Joana, Leppaenen, Olli, Scherner, Maximilian, Berghausen, Eva Maria, Mustafov, Lenard, Chen, Xin, Kramer, Tilmann, Zierden, Mario, Gerhardt, Maximilian, ten Freyhaus, Henrik, Blaschke, Florian, Sterner-Kock, Anja, Baldus, Stephan, Zhao, Jean J., and Rosenkranz, Stephan
- Abstract
Objective-Neointima formation after vascular injury remains a significant problem in clinical cardiology, and current preventive strategies are suboptimal. Phosphatidylinositol 3'-kinase is a central downstream mediator of growth factor signaling, but the role of phosphatidylinositol 3'-kinase isoforms in vascular remodeling remains elusive. We sought to systematically characterize the precise role of catalytic class IA phosphatidylinositol 3'-kinase isoforms (p110 alpha, p110 beta, p110 delta), which signal downstream of receptor tyrosine kinases, for vascular remodeling in vivo. Approach and Results-Western blot analyses revealed that all 3 isoforms are abundantly expressed in smooth muscle cells. To analyze their significance for receptor tyrosine kinases-dependent cellular responses, we used targeted gene knockdown and isoform-specific small molecule inhibitors of p110 alpha (PIK-75), p110 beta (TGX-221), and p110 delta (IC-87114), respectively. We identified p110 alpha to be crucial for receptor tyrosine kinases signaling, thus affecting proliferation, migration, and survival of rat, murine, and human smooth muscle cells, whereas p110 beta and p110 delta activities were dispensable. Surprisingly, p110 delta exerted noncatalytic functions in smooth muscle cell proliferation, but had no effect on migration. Based on these results, we generated a mouse model of smooth muscle cell-specific p110 alpha deficiency (sm-p110 alpha(-/-)). Targeted deletion of p110 alpha in sm-p110 alpha(-/-) mice blunted growth factor-induced cellular responses and abolished neointima formation after balloon injury of the carotid artery in mice. In contrast, p110 delta deficiency did not affect vascular remodeling in vivo. Conclusions-Receptor tyrosine kinases-induced phosphatidylinositol 3'-kinase signaling via the p110 alpha isoform plays a central role for vascular remodeling in vivo. Thus, p110 alpha represents a selective target for the prevention of neointima formation after vascul
- Published
- 2015
22. Increased A(3)AR-dependent Vasoconstriction in Diabetic Mice Is Promoted by Myeloperoxidase
- Author
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Nishat, Shamama, Klinke, Anna, Baldus, Stephan, Khan, Luqman Ahmad, Basir, Seemi Farhat, Nishat, Shamama, Klinke, Anna, Baldus, Stephan, Khan, Luqman Ahmad, and Basir, Seemi Farhat
- Abstract
Vascular dysfunction importantly contributes to mortality and morbidity in various cardiac and metabolic diseases. Among endogenous molecules regulating vascular tone is adenosine, with the adenosine A(3) receptor (A(3)AR) exerting cardioprotective properties in ischemia and reperfusion. However, overexpression of A(3)AR is suggested to result in vascular dysfunction and inflammation. The leukocyte enzyme myeloperoxidase (MPO) is an important modulator of vascular function with nitric oxide-consuming and proinflammatory properties. Increased MPO plasma levels are observed in patients with cardiovascular disorders like heart failure, acute coronary syndromes, and arrhythmias. Given that vascular dysfunction and inflammation are also hallmarks of diabetes, the role of MPO in adenosine-dependent vasomotor function was investigated in a murine model of diabetes mellitus. Wild-type (WT) and MPO-deficient (Mpo(-/-)) mice were treated with Streptozotocin (STZ), which induced an increase of MPO plasma levels in WT mice and led to enhanced aortic superoxide generation as assessed by dihydroethidium staining in STZ-treated WT mice as compared with controls. The vasoconstriction of aortic segments in response to the A(3)AR agonist Cl-IB-MECA (2-Chloro-N6-(3-iodobenzyl)-N-methyl-5-carbamoyladenosine) as determined by isometric force measurements was augmented in diabetic WT as compared with diabetic Mpo(-/-) mice. Moreover, A(3)AR protein expression was enhanced in STZ-treated mice but was attenuated by MPO deficiency. The current data reveal an MPO-mediated increase of vascular A(3)AR expression under diabetic conditions, which leads to enhanced vasoconstriction in response to A(3)AR agonists and discloses an additional mechanism of MPO-mediated vascular dysfunction.
- Published
- 2014
23. Short-Term Outcome and Hemodynamic Performance of Next-Generation Self-Expanding Versus Balloon-Expandable Transcatheter Aortic Valves in Patients With Small Aortic Annulus: A Multicenter Propensity-Matched Comparison.
- Author
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Mauri, Victor, Kim, Won K., Abumayyaleh, Mohammad, Walther, Thomas, Moellmann, Helge, Schaefer, Ulrich, Conradi, Lenard, Hengstenberg, Christian, Hilker, Michael, Wahlers, Thorsten, Baldus, Stephan, Rudolph, Volker, Madershahian, Navid, and Rudolph, Tanja K.
- Abstract
Background—Surgical aortic valve replacement in patients with small annular dimensions is challenging because they are at increased risk for prosthesis–patient mismatch and impaired outcomes. Transcatheter aortic valve replacement might be a good alternative; however, comparative data on different transcatheter heart valves are missing. Methods and Results—This multicenter, propensity score–matched study compared hemodynamics and early clinical outcomes in 246 patients with an aortic annulus area <400 mm
2 undergoing transcatheter aortic valve replacement with either a self-expanding transcatheter heart valve (Symetis ACURATE neo, n=129) or a balloon-expandable transcatheter heart valve (Edwards SAPIEN 3, n=117). The 1:1 propensity score matching resulted in 92 matched pairs. For ACURATE neo versus SAPIEN 3-treated patients, 30-day mortality (0.0% versus 1.0%), 1-year mortality (8.3% versus 13.3%), incidence of stroke (3.3% versus 2.2%), life-threatening bleeding (1.1% versus 1.1%), and major vascular complications (2.2% versus 6.5%), as well as pacemaker implantation rate (12.0% versus 15.2%), were similar. Paravalvular regurgitation ≥moderate was rare in both groups (4.5% versus 3.6%). The ACURATE neo presented lower mean transvalvular gradients (9.3 versus 14.5 mm Hg; P<0.001), larger indexed effective orifice areas (0.96 versus 0.80 cm2 /m2 ; P=0.003), and lower rates of severe prosthesis–patient mismatch (3% versus 22%; P=0.004). Hemodynamics were sustained at 1-year follow-up. Conclusions—Albeit a similar safety profile with low clinical event rates, transcatheter aortic valve replacement with the ACURATE neo valve resulted in lower transvalvular gradients and consequently less prosthesis–patient mismatch compared with the SAPIEN 3 in patients with small annulus. These results emphasize the need of careful prosthesis selection in each individual patient. [ABSTRACT FROM AUTHOR]- Published
- 2017
- Full Text
- View/download PDF
24. Homoarginine Levels Are Regulated by L-Arginine: Glycine Amidinotransferase and Affect Stroke Outcome Results From Human and Murine Studies
- Author
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Choe, Chi-un, Atzler, Dorothee, Wild, Philipp S., Carter, Angela M., Boeger, Rainer H., Ojeda, Francisco, Simova, Olga, Stockebrand, Malte, Lackner, Karl, Nabuurs, Christine, Marescau, Bart, Streichert, Thomas, Mueller, Christian, Lueneburg, Nicole, De Deyn, Peter P., Benndorf, Ralf A., Baldus, Stephan, Gerloff, Christian, Blankenberg, Stefan, Heerschap, Arend, Grant, Peter J., Magnus, Tim, Zeller, Tanja, Isbrandt, Dirk, Schwedhelm, Edzard, Choe, Chi-un, Atzler, Dorothee, Wild, Philipp S., Carter, Angela M., Boeger, Rainer H., Ojeda, Francisco, Simova, Olga, Stockebrand, Malte, Lackner, Karl, Nabuurs, Christine, Marescau, Bart, Streichert, Thomas, Mueller, Christian, Lueneburg, Nicole, De Deyn, Peter P., Benndorf, Ralf A., Baldus, Stephan, Gerloff, Christian, Blankenberg, Stefan, Heerschap, Arend, Grant, Peter J., Magnus, Tim, Zeller, Tanja, Isbrandt, Dirk, and Schwedhelm, Edzard
- Abstract
Background Endogenous arginine homologues, including homoarginine, have been identified as novel biomarkers for cardiovascular disease and outcomes. Our studies of human cohorts and a confirmatory murine model associated the arginine homologue homoarginine and its metabolism with stroke pathology and outcome. Methods and Results Increasing homoarginine levels were independently associated with a reduction in all-cause mortality in patients with ischemic stroke (7.4 years of follow-up; hazard ratio for 1-SD homoarginine, 0.79 [95% confidence interval, 0.64-0.96]; P=0.019; n=389). Homoarginine was also independently associated with the National Institutes of Health Stroke Scale+age score and 30-day mortality after ischemic stroke (P<0.05; n=137). A genome-wide association study revealed that plasma homoarginine was strongly associated with single nucleotide polymorphisms in the l-arginine:glycine amidinotransferase (AGAT) gene (P<2.1x10(-8); n=2806), and increased AGAT expression in a cell model was associated with increased homoarginine. Next, we used 2 genetic murine models to investigate the link between plasma homoarginine and outcome after experimental ischemic stroke: (1) an AGAT deletion (AGAT(-/-)) and (2) a guanidinoacetate N-methyltransferase deletion (GAMT(-/-)) causing AGAT upregulation. As suggested by the genome-wide association study, homoarginine was absent in AGAT(-/-) mice and increased in GAMT(-/-) mice. Cerebral damage and neurological deficits in experimental stroke were increased in AGAT(-/-) mice and attenuated by homoarginine supplementation, whereas infarct size in GAMT(-/-) mice was decreased compared with controls. Conclusions Low homoarginine appears to be related to poor outcome after ischemic stroke. Further validation in future trials may lead to therapeutic adjustments of homoarginine metabolism that alleviate stroke and other vascular disorders.
- Published
- 2013
25. Class IA Phosphatidylinositol 3-Kinase Isoform p110a Mediates Vascular Remodeling.
- Author
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Vantler, Marius, Jesus, Joana, Leppänen, Olli, Scherner, Maximilian, Berghausen, Eva Maria, Mustafov, Lenard, Xin Chen, Kramer, Tilmann, Zierden, Mario, Gerhardt, Maximilian, Freyhaus, Henrik ten, Blaschke, Florian, Sterner-Kock, Anja, Baldus, Stephan, Jean J. Zhao, and Rosenkranz, Stephan
- Published
- 2015
- Full Text
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26. Genetic Ablation of PDGF-Dependent Signaling Pathways Abolishes Vascular Remodeling and Experimental Pulmonary Hypertension.
- Author
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Freyhaus, Henrik ten, Berghausen, Eva M., Janssen, Wiebke, Leuchs, Maike, Zierden, Mario, Murmann, Kirsten, Klinke, Anna, Vantler, Marius, Caglayan, Evren, Kramer, Tilmann, Baldus, Stephan, Schermuly, Ralph T., Tallquist, Michelle D., and Rosenkranz, Stephan
- Published
- 2015
- Full Text
- View/download PDF
27. Increased A3AR-dependent Vasoconstriction in Diabetic Mice Is Promoted by Myeloperoxidase.
- Author
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Nishat, Shamama, Klinke, Anna, Baldus, Stephan, Khan, Luqman Ahmad, and Basir, Seemi Farhat
- Published
- 2014
- Full Text
- View/download PDF
28. EFFECTS OF ACUTE NORMOBARIC HYPOXIA-INDUCED PULMONARY HYPERTENSION ON ELECTROCARDIGRAPHIC MEASURES IN POST-MYOCARDIAL INFARCTION PATIENTS.
- Author
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Kramer, Tilmann, Hoenemann, Jan, Weis, Henning, Jordan, Jens, Tank, Jens, Rosenkranz, Stephan, Baldus, Stephan, and Limper, Ulrich
- Published
- 2022
- Full Text
- View/download PDF
29. Homoarginine levels are regulated by L-arginine:glycine amidinotransferase and affect stroke outcome: results from human and murine studies.
- Author
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Choe, Chi-Un, Atzler, Dorothee, Wild, Philipp S, Carter, Angela M, Böger, Rainer H, Ojeda, Francisco, Simova, Olga, Stockebrand, Malte, Lackner, Karl, Nabuurs, Christine, Marescau, Bart, Streichert, Thomas, Müller, Christian, Lüneburg, Nicole, De Deyn, Peter P, Benndorf, Ralf A, Baldus, Stephan, Gerloff, Christian, Blankenberg, Stefan, and Heerschap, Arend
- Published
- 2013
- Full Text
- View/download PDF
30. Homoarginine Levels Are Regulated by L-Arginine: Glycine Amidinotransferase and Affect Stroke Outcome.
- Author
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Chi-un Choe, Atzler, Dorothee, Wild, Philipp S., Carter, Angela M., Böger, Rainer H., Ojeda, Francisco, Simova, Olga, Stockebrand, Malte, Lackner, Karl, Nabuurs, Christine, Marescau, Bart, Streichert, Thomas, Müller, Christian, Lüneburg, Nicole, De Deyn, Peter P., Benndorf, Ralf A., Baldus, Stephan, Gerloff, Christian, Blankenberg, Stefan, and Heerschap, Arend
- Published
- 2013
- Full Text
- View/download PDF
31. Characterization of squamous cell cancers of the vulvar anterior fourchette by human papillomavirus, p16INK4a, and p53.
- Author
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Reuschenbach, Miriam, Roos, Judith, Panayotopoulos, Dimitrios, Baldus, Stephan E, Schnürch, Hans-Georg, Berger, Annemarie, Petry, Karl Ulrich, Dürst, Matthias, Seiz, Mirjam, von Knebel Doeberitz, Magnus, Hampl, Monika, and German Study Group for Colposcopy
- Published
- 2013
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32. Characterization of Squamous Cell Cancers of the Vulvar Anterior Fourchette by Human Papillomavirus, pl6INK4a, and p53.
- Author
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Reuschenbach, Miriam, Roos, Judith, Panayotopoulos, Dimitrios, Baldus, Stephan E., Schnürch, Hans-Georg, Berger, Annemarie, Petry, Karl Ulrich, Durst, Matthias, Seiz, Mirjam, von Knebel Doeberitz, Magnus, and Hampl, Monika
- Published
- 2013
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33. Prognostic Significance of EpCAM-Positive Disseminated Tumor Cells in Rectal Cancer Patients With Stage I Disease.
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Dhayat, Sameer, Sorescu, Sorina, Vallböhmer, Daniel, Kraus, Sebastian, Baldus, Stephan Ernst, Rehders, Alexander, Kröpil, Feride, Krieg, Andreas, Knoefel, Wolfram Trudo, and Stoecklein, Nikolas Hendrik
- Published
- 2012
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34. Diagnostic and Prognostic Performance of Myeloperoxidase Plasma Levels Compared With Sensitive Troponins in Patients Admitted With Acute Onset Chest Pain.
- Author
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Rudolph, Volker, Keller, Till, Schulz, Andreas, Ojeda, Francisco, Rudolph, Tanja K., Tzikas, Stergios, Bickel, Christoph, Meinertz, Thomas, Münzel, Thomas, Blankenberg, Stefan, and Baldus, Stephan
- Subjects
MYELOPEROXIDASE ,TROPONIN I ,PATIENTS ,ACUTE coronary syndrome ,BIOMARKERS - Abstract
The article discusses the prospective assessment on the diagnostic and prognostic properties of myeloperoxidase (MPO) in comparison to sensitive troponin I (sTNI) in patients admitted to the emergency room with chest pain (CP). The assessment showed that although MPO and B-ntriuretic peptide were predictive for increased risk of adverse events at 30 days and six months, both were not able to provide incremental information for patients with acute onset CP when added to sensitive troponin.
- Published
- 2012
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35. Variable 18F-fluorodeoxyglucose uptake in gastric cancer is associated with different levels of GLUT-1 expression.
- Author
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Alakus, Hakan, Batur, Mert, Schmidt, Matthias, Drebber, Uta, Baldus, Stephan E., Vallböhmer, Daniel, Prenzel, Klaus L., Metzger, Ralf, Bollschweiler, Elfriede, Hölscher, Arnulf H., and Mönig, Stefan P.
- Published
- 2010
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36. [18F]-Fluorodeoxyglucose-Positron Emission Tomography for the Assessment of Histopathologic Response and Prognosis After Completion of Neoadjuvant Chemoradiation in Esophageal Cancer.
- Author
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Vallböhmer, Daniel, Hölscher, Arnulf H., Dietlein, Markus, Bollschweiler, Elfriede, Baldus, Stephan E., Mönig, Stefan P., Metzger, Ralf, Schicha, Harald, and Schmidt, Matthias
- Abstract
To evaluate the potential of [
18 F]-fluorodeoxyglucose-positron emission tomography (FDG-PET) after the completion of neoadjuvant chemoradiation for the assessment of histopathologic response and prognosis in the multimodality treatment of patients with esophageal cancer.Combined chemoradiation with and without surgery are widely accepted treatment options for patients with locally advanced esophageal cancer. Evidence suggests that patients with response to chemoradiation have no additional benefit from surgery compared with definitive chemoradiation. However, there is still a great lack in noninvasive markers for response assessment in patients with esophageal cancer undergoing multimodality treatment. Interestingly, recent studies imply that FDG-PET significantly correlates with histopathologic response and survival in patients with esophageal cancer undergoing neoadjuvant chemotherapy followed by surgical resection.Study patients were recruited from a prospective clinical observation trial on neoadjuvant chemoradiation for esophageal cancer between 1997 and 2006. The study included 119 (98 men, 21 women; median age, 59.4 years; squamous cell cancer: 66; adenocarcinoma: 53) patients with locally advanced esophageal cancer (cT2-4, Nx , M0 ). All patients received neoadjuvant chemoradiation (cisplatin, 5-FU, 36 Gy) and subsequently underwent transthoracic en bloc esophagectomy. Histomorphologic regression was defined as major histopathologic response when resected specimens contained less than 10% vital residual tumor cells (major response: 47 patients [39.5%]; minor response: 72 patients [60.5%]). FDG-PET was performed before and 2 to 3 weeks after the end of chemoradiation with assessment of the intratumoral FDG-uptake (pretreatment standardized uptake value; post-treatment standardized uptake value; percentage change). These variables were correlated with histopathologic response and survival.Major histomorphologic response was confirmed as an important prognostic factor (P = 0.005; log-rank test). Neoadjuvant chemoradiation led to a significant reduction of intratumoral FDG-uptake (P < 0.0001). A nonsignificant association was seen between major responders and FDG-PET results (P = 0.056). However, the receiver operating characteristic analysis could not identify a standardized uptake value threshold with a relevant predictive value for histomorphologic response. No significant association between metabolic imaging and prognosis was found.FDG-PET seems not to be an imaging system that effectively characterizes the groups of major and minor response as well as survival in patients with esophageal cancer after multimodality treatment. [ABSTRACT FROM AUTHOR]- Published
- 2009
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37. Significant Down-Regulation of the Plasminogen Activator Inhibitor 1 mRNA in Pancreatic Cancer.
- Author
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Warnecke-Eberz, Ute, Prenzel, Klaus L., Baldus, Stephan E., Metzger, Ralf, Dienes, Hans P., Bollschweiler, Elfriede, Hoelscher, Arnulf H., and Schneider, Paul M.
- Published
- 2008
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38. Splenic rupture: an unusual complication of colonoscopy: case report and review of the literature.
- Author
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Luebke T, Baldus SE, Holscher AH, Monig SP, Luebke, Thomas, Baldus, Stephan E, Holscher, Arnulf H, and Monig, Stefan P
- Published
- 2006
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39. Risk Stratification of Patients Undergoing Percutaneous Repair of Mitral and Tricuspid Valves Using a Multidimensional Geriatric Assessment.
- Author
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Schäfer, Matthieu, Körber, Maria I., Vimalathasan, Rakave, Mauri, Victor, Iliadis, Christos, Metze, Clemens, ten Freyhaus, Henrik, Baldus, Stephan, Polidori, M. Cristina, and Pfister, Roman
- Subjects
TRICUSPID valve surgery ,RESEARCH ,PREDICTIVE tests ,RESEARCH methodology ,GERIATRIC assessment ,ACTIVITIES of daily living ,PROGNOSIS ,TRICUSPID valve ,MEDICAL cooperation ,EVALUATION research ,RISK assessment ,COMPARATIVE studies ,LONGITUDINAL method - Abstract
Background: Given their advanced age and high comorbidity, individual risk assessment is crucial in patients undergoing transcatheter mitral and tricuspid valve repair. Therefore, we evaluated the use of a comprehensive geriatric assessment score, the multidimensional prognostic index (MPI), for risk stratification in these patients.Methods: We conducted a prospective, observational single-center study, including 226 patients undergoing percutaneous repair for mitral or tricuspid regurgitation. The MPI was calculated preprocedural and covers 8 domains (activities of daily living, instrumental activities of daily living, mental status, nutrition, risk of pressure ulcers, comorbidity, medication, and marital/cohabitation status). We sought to identify an association of MPI score with procedural outcomes and 6-month mortality.Results: A total of 53.1% of patients were stratified as low risk according to MPI (MPI-1 group), 44.2% as medium risk (MPI-2 group), and 2.7% as high risk (MPI-3 group). Procedural efficacy and safety were similar between groups. The estimated survival rate at 6 months was 97±2% in MPI-1 group, 79±4% in MPI-2 group (hazard ratio, 6.90 [95% CI, 2.36-12.2]; P≤0.001) and 50±20% in MPI-3 group (hazard ratio, 20.3 [95% CI, 4.51-91.3]; P<0.001). An increase in 1 SD of the MPI score (0.14 points, possible range of MPI score 0-1) was associated with a hazard ratio of 2.13 (95% CI, 1.58-2.73; P≤0.001) for death after 6 months. The risk association of the MPI with mortality remained significant in multivariate analysis including risk factors, such as peripheral artery disease and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels.Conclusions: A comprehensive geriatric assessment with the MPI score provides additional information on mortality risk beyond established cardiovascular risk factors. [ABSTRACT FROM AUTHOR]- Published
- 2021
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40. Abstract 12164: Macitentan as an Additive Therapeutic Option in Patients With Inoperable or Persistent Chronic Thromboembolic Pulmonary Hypertension.
- Author
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Kramer, Tilmann T, Gerhardt, Felix, Dumitrescu, Daniel, Brensing, Pia, Baldus, Stephan, and Rosenkranz, Stephan
- Published
- 2018
41. Abstract 12152: Pulmonary Arterial Hypertension: Rapid Sequential Combination Therapy With PDE5 Inhibitors and Endothelin Receptor Antagonists Substantially Improves Hemodynamics at Early Follow-Up.
- Author
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Kramer, Tilmann T, Dumitrescu, Daniel, Gerhardt, Felix, Nattmann, Phillip, Hohmann, Christopher, Baldus, Stephan, and Rosenkranz, Stephan
- Published
- 2018
42. Abstract 14689: PI3-Kinase Delta Protects Against Atherosclerosis Progression by Controlling Regulatory T-Cell Homeostasis and Function.
- Author
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Zierden, Mario, Millarg, Christopher, Berghausen, Eva M, Baldus, Stephan, Vantler, Marius, and Rosenkranz, Stephan
- Published
- 2018
43. Analysis of Cerebral CT Based on Supervised Machine Learning as a Predictor of Outcome After Out-of-Hospital Cardiac Arrest.
- Author
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Gramespacher H, Schmieschek MHT, Warnke C, Adler C, Bittner S, Dronse J, Richter N, Zaeske C, Gietzen C, Schlamann M, Baldus S, Fink GR, and Onur OA
- Subjects
- Humans, Male, Female, Middle Aged, Aged, Retrospective Studies, Prognosis, Gray Matter diagnostic imaging, Gray Matter pathology, Brain diagnostic imaging, Cohort Studies, Out-of-Hospital Cardiac Arrest diagnostic imaging, Tomography, X-Ray Computed, Supervised Machine Learning
- Abstract
Background and Objectives: In light of limited intensive care capacities and a lack of accurate prognostic tools to advise caregivers and family members responsibly, this study aims to determine whether automated cerebral CT (CCT) analysis allows prognostication after out-of-hospital cardiac arrest., Methods: In this monocentric, retrospective cohort study, a supervised machine learning classifier based on an elastic net regularized logistic regression model for gray matter alterations on nonenhanced CCT obtained after cardiac arrest was trained using 10-fold cross-validation and tested on a hold-out sample (random split 75%/25%) for outcome prediction. Following the literature, a favorable outcome was defined as a cerebral performance category of 1-2 and a poor outcome of 3-5. The diagnostic accuracy was compared with established and guideline-recommended prognostic measures within the sample, that is, gray matter-white matter ratio (GWR), neuron-specific enolase (NSE), and neurofilament light chain (NfL) in serum., Results: Of 279 adult patients, 132 who underwent CCT within 14 days of cardiac arrest with good imaging quality were identified. Our approach discriminated between favorable and poor outcomes with an area under the curve (AUC) of 0.73 (95% CI 0.59-0.82). Thus, the prognostic power outperformed the GWR (AUC 0.66, 95% CI 0.56-0.76). The biomarkers NfL, measured at days 1 and 2, and NSE, measured at day 2, exceeded the reliability of the imaging markers derived from CT (AUC NfL day 1: 0.87, 95% CI 0.75-0.99; AUC NfL day 2: 0.90, 95% CI 0.79-1.00; AUC NSE day: 2 0.78, 95% CI 0.62-0.94)., Discussion: Our data show that machine learning-assisted gray matter analysis of CCT images offers prognostic information after out-of-hospital cardiac arrest. Thus, CCT gray matter analysis could become a reliable and time-independent addition to the standard workup with serum biomarkers sampled at predefined time points. Prospective studies are warranted to replicate these findings.
- Published
- 2024
- Full Text
- View/download PDF
44. Management of Myocardial Revascularization in Patients With Stable Coronary Artery Disease Undergoing Transcatheter Aortic Valve Implantation.
- Author
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Costa G, Pilgrim T, Amat Santos IJ, De Backer O, Kim WK, Barbosa Ribeiro H, Saia F, Bunc M, Tchetche D, Garot P, Ribichini FL, Mylotte D, Burzotta F, Watanabe Y, De Marco F, Tesorio T, Rheude T, Tocci M, Franzone A, Valvo R, Savontaus M, Wienemann H, Porto I, Gandolfo C, Iadanza A, Bortone AS, Mach M, Latib A, Biasco L, Taramasso M, Zimarino M, Tomii D, Nuyens P, Sondergaard L, Camara SF, Palmerini T, Orzalkiewicz M, Steblovnik K, Degrelle B, Gautier A, Del Sole PA, Mainardi A, Pighi M, Lunardi M, Kawashima H, Criscione E, Cesario V, Biancari F, Zanin F, Joner M, Esposito G, Adam M, Grube E, Baldus S, De Marzo V, Piredda E, Cannata S, Iacovelli F, Andreas M, Frittitta V, Dipietro E, Reddavid C, Strazzieri O, Motta S, Angellotti D, Sgroi C, Kargoli F, Tamburino C, and Barbanti M
- Subjects
- Humans, Stroke Volume, Risk Factors, Treatment Outcome, Ventricular Function, Left, Myocardial Revascularization adverse effects, Aortic Valve diagnostic imaging, Aortic Valve surgery, Coronary Artery Disease diagnostic imaging, Coronary Artery Disease therapy, Coronary Artery Disease complications, Transcatheter Aortic Valve Replacement adverse effects, Aortic Valve Stenosis diagnostic imaging, Aortic Valve Stenosis surgery, Aortic Valve Stenosis complications, Myocardial Infarction complications, Stroke etiology, Stroke surgery, Percutaneous Coronary Intervention adverse effects
- Abstract
Background: The best management of stable coronary artery disease (CAD) in patients undergoing transcatheter aortic valve implantation (TAVI) is still unclear due to the marked inconsistency of the available evidence., Methods: The REVASC-TAVI registry (Management of Myocardial Revascularization in Patients Undergoing Transcatheter Aortic Valve Implantation With Coronary Artery Disease) collected data from 30 centers worldwide on patients undergoing TAVI who had significant, stable CAD at preprocedural work-up. For the purposes of this analysis, patients with either complete or incomplete myocardial revascularization were compared in a propensity score matched analysis, to take into account of baseline confounders. The primary and co-primary outcomes were all-cause death and the composite of all-cause death, stroke, myocardial infarction, and rehospitalization for heart failure, respectively, at 2 years., Results: Among 2407 patients enrolled, 675 pairs of patients achieving complete or incomplete myocardial revascularization were matched. The primary (21.6% versus 18.2%, hazard ratio' 0.88 [95% CI, 0.66-1.18]; P =0.38) and co-primary composite (29.0% versus 27.1%, hazard ratio' 0.97 [95% CI, 0.76-1.24]; P =0.83) outcome did not differ between patients achieving complete or incomplete myocardial revascularization, respectively. These results were consistent across different prespecified subgroups of patients (< or >75 years of age, Society of Thoracic Surgeons score > or <4%, angina at baseline, diabetes, left ventricular ejection fraction > or <40%, New York Heart Association class I/II or III/IV, renal failure, proximal CAD, multivessel CAD, and left main/proximal anterior descending artery CAD; all P values for interaction >0.10)., Conclusions: The present analysis of the REVASC-TAVI registry showed that, among TAVI patients with significant stable CAD found during the TAVI work-up, completeness of myocardial revascularization achieved either staged or concomitantly with TAVI was similar to a strategy of incomplete revascularization in reducing the risk of all cause death, as well as the risk of death, stroke, myocardial infarction, and rehospitalization for heart failure at 2 years, regardless of the clinical and anatomical situations.
- Published
- 2022
- Full Text
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45. Recurrent Mitral Regurgitation After MitraClip: Predictive Factors, Morphology, and Clinical Implication.
- Author
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Sugiura A, Kavsur R, Spieker M, Iliadis C, Goto T, Öztürk C, Weber M, Tabata N, Zimmer S, Sinning JM, Mauri V, Horn P, Kelm M, Baldus S, Nickenig G, Westenfeld R, Pfister R, and Becher MU
- Subjects
- Humans, Mitral Valve diagnostic imaging, Mitral Valve surgery, Registries, Treatment Outcome, Heart Failure, Heart Valve Prosthesis Implantation adverse effects, Mitral Valve Insufficiency diagnostic imaging, Mitral Valve Insufficiency etiology, Mitral Valve Insufficiency surgery
- Abstract
Background: Recurrent mitral regurgitation (MR) following MitraClip has not been thoroughly investigated. We aimed to examine the predictive factors, morphology, and long-term outcome of recurrent MR after MitraClip., Methods: We assessed data from the Heart Failure Network Rhineland registry from August 2010 to October 2018. Competing risk analyses were performed using the Fine and Gray model to assess the risk of recurrent MR., Results: Among 685 MitraClip patients with a reduction in MR to ≤2+, 61 patients developed recurrent MR within the first 12 months. Flail leaflet (hazard ratio, 3.68; P =0.002) and residual MR (MR grade 2+ versus ≤1+: hazard ratio, 2.56; P =0.03) were the predictors of recurrent MR in primary MR patients, while left atrial volume (per 10 mL increase: hazard ratio, 1.11; P <0.001) and residual MR (hazard ratio, 2.45; P =0.01) were independently associated with recurrent MR in secondary MR patients. In primary MR patients, loss of leaflet insertion or leaflet tear were the predominant morphologies with recurrent MR. In secondary MR patients, more than half of the patients with recurrent MR did not show any disorder of the clip or leaflets. Patients with recurrent MR were more likely to experience unplanned heart failure hospitalization or heart failure symptom with New York Heart Association scale III/IV (54.1% versus 37.8%; P =0.018) and undergo a repeat mitral valve intervention (9.8% versus 2.2%; P =0.005) during the follow-up. In the landmark survival analysis, patients with recurrent MR tended to have lower long-term survival (58.7% versus 83.9%; P =0.08) than patients without recurrent MR., Conclusions: Flail leaflet and residual MR were the predictors of recurrent MR in primary MR patients, while a larger left atrial volume and residual MR were associated with recurrent MR in secondary MR patients, which may be associated with long-term clinical outcomes of patients after MitraClip.
- Published
- 2022
- Full Text
- View/download PDF
46. Evolution of Pulmonary Hypertension During Severe Sustained Hypoxia.
- Author
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Hoffmann F, Limper U, Zaha VG, Reuter H, Zange L, Schulz-Menger J, Hein M, Baldus S, Levine BD, Jordan J, and Tank J
- Subjects
- Acclimatization, Altitude, Altitude Sickness diagnosis, Altitude Sickness physiopathology, Disease Progression, Female, Humans, Hypertension, Pulmonary diagnosis, Hypertension, Pulmonary physiopathology, Hypoxia diagnosis, Male, Middle Aged, Pilot Projects, Severity of Illness Index, Time Factors, Ventricular Function, Right, Altitude Sickness etiology, Hemodynamics, Hypertension, Pulmonary etiology, Hypoxia complications, Pulmonary Artery physiopathology
- Published
- 2020
- Full Text
- View/download PDF
47. Response by Lüker et al to Letter Regarding Article, "Internal Versus External Electrical Cardioversion of Atrial Arrhythmia in Patients With Implantable Cardioverter-Defibrillator: A Randomized Clinical Trial".
- Author
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Lüker J, Kuhr K, Sultan A, Nölker G, Omran H, Willems S, Andrié R, Schrickel JW, Winter S, Vollmann D, Tilz RR, Jobs A, Heeger CH, Metzner A, Meyer S, Mischke K, Napp A, Fahrig A, Steinhauser S, Brachmann J, Baldus S, Mahajan R, Sanders P, and Steven D
- Subjects
- Electric Countershock, Humans, Atrial Fibrillation, Defibrillators, Implantable
- Published
- 2020
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48. Internal Versus External Electrical Cardioversion of Atrial Arrhythmia in Patients With Implantable Cardioverter-Defibrillator: A Randomized Clinical Trial.
- Author
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Lüker J, Kuhr K, Sultan A, Nölker G, Omran H, Willems S, Andrié R, Schrickel JW, Winter S, Vollmann D, Tilz RR, Jobs A, Heeger CH, Metzner A, Meyer S, Mischke K, Napp A, Fahrig A, Steinhauser S, Brachmann J, Baldus S, Mahajan R, Sanders P, and Steven D
- Subjects
- Aged, Aged, 80 and over, Equipment Failure, Female, Humans, Male, Middle Aged, Risk, Arrhythmias, Cardiac therapy, Atrial Fibrillation therapy, Defibrillators, Implantable, Electric Countershock methods
- Abstract
Background: Atrial arrhythmias are common in patients with implantable cardioverter-defibrillator (ICD). External shocks and internal cardioversion through commanded ICD shock for electrical cardioversion are used for rhythm-control. However, there is a paucity of data on efficacy of external versus internal cardioversion and on the risk of lead and device malfunction. We hypothesized that external cardioversion is noninferior to internal cardioversion for safety, and superior for successful restoration of sinus rhythm., Methods: Consecutive patients with ICD undergoing elective cardioversion for atrial arrhythmias at 13 centers were randomized in 1:1 fashion to either internal or external cardioversion. The primary safety end point was a composite of surrogate events of lead or device malfunction. Conversion of atrial arrhythmia to sinus rhythm was the primary efficacy end point. Myocardial damage was studied by measuring troponin release in both groups., Results: N=230 patients were randomized. Shock efficacy was 93% in the external cardioversion group and 65% in the internal cardioversion group ( P <0.001). Clinically relevant adverse events caused by external or internal cardioversion were not observed. Three cases of pre-existing silent lead malfunction were unmasked by internal shock, resulting in lead failure. Troponin release did not differ between groups., Conclusions: This is the first randomized trial on external vs internal cardioversion in patients with ICDs. External cardioversion was superior for the restoration of sinus rhythm. The unmasking of silent lead malfunction in the internal cardioversion group suggests that an internal shock attempt may be reasonable in selected ICD patients presenting for electrical cardioversion., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03247738.
- Published
- 2019
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49. MPO (Myeloperoxidase) Reduces Endothelial Glycocalyx Thickness Dependent on Its Cationic Charge.
- Author
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Manchanda K, Kolarova H, Kerkenpaß C, Mollenhauer M, Vitecek J, Rudolph V, Kubala L, Baldus S, Adam M, and Klinke A
- Subjects
- Animals, CHO Cells, Cations, Cricetulus, Endothelial Cells metabolism, Endothelial Cells pathology, Glycocalyx metabolism, Glycocalyx pathology, Heparan Sulfate Proteoglycans metabolism, Human Umbilical Vein Endothelial Cells drug effects, Human Umbilical Vein Endothelial Cells metabolism, Human Umbilical Vein Endothelial Cells pathology, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Neutrophil Activation, Neutrophils drug effects, Neutrophils metabolism, Peroxidase deficiency, Peroxidase genetics, Peroxidase pharmacology, Protein Binding, Syndecan-1 metabolism, Abdominal Muscles blood supply, Endothelial Cells drug effects, Glycocalyx drug effects, Peroxidase metabolism
- Abstract
Objective- The leukocyte heme-enzyme MPO (myeloperoxidase) exerts proinflammatory effects on the vascular system primarily linked to its catalytic properties. Recent studies have shown that MPO, depending on its cationic charge, mediates neutrophil recruitment and activation. Here, we further investigated MPO's extracatalytic properties and its effect on endothelial glycocalyx (EG) integrity. Approach and Results- In vivo staining of murine cremaster muscle vessels with Alcian Blue 8GX provided evidence of an MPO-dependent decrease in anionic charge of the EG. MPO binding to the glycocalyx was further characterized using Chinese hamster ovary cells and its glycosaminoglycan mutants-pgsA-745 (mutant Chinese hamster ovary cells lacking heparan sulfate and chondroitin sulfate glycosaminoglycan) and pgsD-677 (mutant Chinese hamster ovary cells lacking heparan sulfate glycosaminoglycan), which revealed heparan sulfate as the main mediator of MPO binding. Further, EG integrity was assessed in terms of thickness using intravital microscopy of murine cremaster muscle. A significant reduction in EG thickness was observed on infusion of catalytically active MPO, as well as mutant inactive MPO and cationic polymer polylysine. Similar effects were also observed in wild-type mice after a local inflammatory stimulus but not in MPO-knockout mice. The reduction in EG thickness was reversed after removal of vessel-bound MPO, suggesting a possible physical collapse of the EG. Last, experiments with in vivo neutrophil depletion revealed that MPO also induced neutrophil-mediated shedding of the EG core protein, Sdc1 (syndecan-1). Conclusions- These findings provide evidence that MPO, via ionic interaction with heparan sulfate side chains, can cause neutrophil-dependent Sdc1 shedding and collapse of the EG structure.
- Published
- 2018
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50. Systemic Upregulation of IL-10 (Interleukin-10) Using a Nonimmunogenic Vector Reduces Growth and Rate of Dissecting Abdominal Aortic Aneurysm.
- Author
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Adam M, Kooreman NG, Jagger A, Wagenhäuser MU, Mehrkens D, Wang Y, Kayama Y, Toyama K, Raaz U, Schellinger IN, Maegdefessel L, Spin JM, Hamming JF, Quax PHA, Baldus S, Wu JC, and Tsao PS
- Subjects
- Aortic Dissection chemically induced, Aortic Dissection genetics, Aortic Dissection metabolism, Angiotensin II, Animals, Aorta, Abdominal immunology, Aorta, Abdominal pathology, Aortic Aneurysm, Abdominal chemically induced, Aortic Aneurysm, Abdominal genetics, Aortic Aneurysm, Abdominal metabolism, Cells, Cultured, Dilatation, Pathologic, Disease Models, Animal, Inflammation Mediators metabolism, Interleukin-10 genetics, Interleukin-10 immunology, Macrophage Activation, Macrophages immunology, Macrophages metabolism, Male, Mice, Inbred C57BL, Mice, Knockout, ApoE, T-Lymphocytes, Cytotoxic immunology, T-Lymphocytes, Cytotoxic metabolism, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Up-Regulation, Aortic Dissection prevention & control, Aorta, Abdominal metabolism, Aortic Aneurysm, Abdominal prevention & control, Gene Transfer Techniques, Genetic Therapy methods, Genetic Vectors, Interleukin-10 biosynthesis
- Abstract
Objective- Recruitment of immunologic competent cells to the vessel wall is a crucial step in formation of abdominal aortic aneurysms (AAA). Innate immunity effectors (eg, macrophages), as well as mediators of adaptive immunity (eg, T cells), orchestrate a local vascular inflammatory response. IL-10 (interleukin-10) is an immune-regulatory cytokine with a crucial role in suppression of inflammatory processes. We hypothesized that an increase in systemic IL-10-levels would mitigate AAA progression. Approach and Results- Using a single intravenous injection protocol, we transfected an IL-10 transcribing nonimmunogenic minicircle vector into the Ang II (angiotensin II)-ApoE
-/- infusion mouse model of AAA. IL-10 minicircle transfection significantly reduced average aortic diameter measured via ultrasound at day 28 from 166.1±10.8% (control) to 131.0±5.8% (IL-10 transfected). Rates of dissecting AAA were reduced by IL-10 treatment, with an increase in freedom from dissecting AAA from 21.5% to 62.3%. Using flow cytometry of aortic tissue from minicircle IL-10-treated animals, we found a significantly higher percentage of CD4+ /CD25+ /Foxp3 (forkhead box P3)+ regulatory T cells, with fewer CD8+ /GZMB+ (granzyme B) cytotoxic T cells. Furthermore, isolated aortic macrophages produced less TNF-α (tumor necrosis factor-α), more IL-10, and were more likely to be MRC1 (mannose receptor, C type 1)-positive alternatively activated macrophages. These results concurred with gene expression analysis of lipopolysaccharide-stimulated and Ang II-primed human peripheral blood mononuclear cells. Conclusions- Taken together, we provide an effective gene therapy approach to AAA in mice by enhancing antiinflammatory and dampening proinflammatory pathways through minicircle-induced augmentation of systemic IL-10 expression.- Published
- 2018
- Full Text
- View/download PDF
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