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Jörg Stypmann

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Andrea Marzullo

Università degli Studi di Bari

Università degli Studi di Padova

Università degli Studi di Padova

St Georges University

Khurram Shahzad

Indonesian Capital Market and Financial Institution Supervisory Agency (Bapepam-LK)

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Papers by Jörg Stypmann

Concordance Among Pathologists in the Second Cardiac Allograft Rejection Gene Expression Observational Study (CARGO II)

by Jörg Stypmann and Uwe Schulz

Transplantation Journal, 2012

Background. There has been no large evaluation of the ISHLT 2004 acute cellular rejection grading... more Background. There has been no large evaluation of the ISHLT 2004 acute cellular rejection grading scheme for heart graft endomyocardial biopsy specimens (EMBs). Methods. We evaluated agreement within the CARGO II pathology panel and between the panel (acting by majority) and the collaborating centers (treated as a single entity), regarding the ISHLT grades of 937 EMBs (with all grades Q2R merged because of small numbers).

81 Prediction of Allograft Clinical Outcomes and Risk of Acute Cellular Rejection with a Non-Invasive Gene-Expression Profiling Test (AlloMap): Results from the Cargo 2 European-Based Multicenter Trial

by Jörg Stypmann and Uwe Schulz

The Journal of Heart and Lung Transplantation, 2012

A protocol was set up based on antigen-specific immunoadsorption to remove existing anti-A or ant... more A protocol was set up based on antigen-specific immunoadsorption to remove existing anti-A or anti-B antibodies and rituximab to prevent rebound of antibodies in combination with conventional tacrolimus, mycophenolate mofetil and prednisolone immunosuppression. Based on the experience of 60 successfully performed ABOincompatible renal transplantations the protocol included postoperativ, pre-emptive apheresis sessions every third day for 9 days. Six of 13 patients on the waiting list had the anti-A or anti-B antibody levels low enough to be included in this protocol. Results: Two patients have successfully performed ABO-incompatible transplantation following this protocol. At 1 year of follow up both patients are in NYHA I with normal cardiac performance, normal coronary angiograms and without signs of chronic rejection. During the first year protocol biopsies from both patients stained diffusely positive for C4D, as have been described in ABO-incompatible renal transplantation, and which may be explained by a continuos low grade degradation of A or B antibodies within the organ but without signs of myocardial damage. Conclusions: Based on acceptance of certain anti-A or anti-B antibody levels, ABO-incompatible heart transplantation is a safe and successful procedure and acceptance of any blood group may lead to a substantial reduction in the time on the waiting list.

582 Pharmacogenetics of Nephrotoxicity in Heart Transplantation Candidates Receiving Calcineurin Inhibitor (CNI) Medication

by Uwe Schulz and Jörg Stypmann

The Journal of Heart and Lung Transplantation, 2011

Thrombomodulin's lectin-like domain reduces myocardial damage by interfering with HMGB1-mediated TLR2 signalling

by Jörg Stypmann and Martina Schmitz

Cardiovascular Research, 2014

Thrombomodulin (TM), via its lectin-like domain (LLD), exhibits anti-inflammatory properties part... more Thrombomodulin (TM), via its lectin-like domain (LLD), exhibits anti-inflammatory properties partly by sequestering the pro-inflammatory cytokine, high-mobility group box 1 (HMGB1). Since myocardial damage after ischaemia and reperfusion is mediated by inflammation, we evaluated the cardioprotective effects of the LLD of TM. Using an in vivo mouse model of transient ischaemia and in vitro models of cardiomyocyte hypoxia, we assessed the ability of the LLD to suppress HMGB1-mediated activation of the receptors, receptor for advanced glycation endproducts (RAGEs) and Toll-like receptors (TLRs) 2 and 4.

The Mandela study: A multicenter, randomized, open-label, parallel group trial to refine the use of everolimus after heart transplantation

by Jörg Stypmann, Martina Porstner, and Uwe Schulz

Contemporary clinical trials, Jan 9, 2015

In recent years a series of trials has sought to define the optimal protocol for everolimus-based... more In recent years a series of trials has sought to define the optimal protocol for everolimus-based immunosuppression in heart transplantation, with the goal of minimizing exposure to calcineurin inhibitors (CNIs) and harnessing the non-immunosuppressive benefits of everolimus. Randomized studies have demonstrated that immunosuppressive potency can be maintained in heart transplant patients receiving everolimus despite marked CNI reduction, although very early CNI withdrawal may be inadvisable. A potential renal advantage has been shown for everolimus, but the optimal time for conversion and the adequate reduction in CNI exposure remain to be defined. Other reasons for use of everolimus include a substantial reduction in the risk of cytomegalovirus infection, and evidence for inhibition of cardiac allograft vasculopathy, a major cause of graft loss. The ongoing MANDELA study is a 12-month multicenter, randomized, open-label, parallel-group study in which efficacy, renal function and s...

D ynamic regulation of MEK / Erks and Akt / GSK-3b in human end- stage heart failure after left ventricular mechanical support: myocardial mechanotransduction-sensitivity as a possible molecular mechanism

bc ,g g , * ¨ Abstract Objective: Left ventricular assist devices (LVAD) are used to 'bridge&... more bc ,g g , * ¨ Abstract Objective: Left ventricular assist devices (LVAD) are used to 'bridge' patients with end-stage heart failure to transplantation. After long-term LVAD support, ventricular function may partially recover, a process called 'reverse remodeling'. As several kinase-mediated signal transduction pathways have been implicated in the development of cardiac hypertrophy and failure, we examined the activities of

841 Tissue doppler imaging (TDI) in patients with aortic valve stenosis-clinical usefulness and diagnostic accuracy

European Heart Journal – Cardiovascular Imaging

Background: Evaluation of aortic valve stenoses is one to the most important current clinical app... more Background: Evaluation of aortic valve stenoses is one to the most important current clinical applications of echocardiography. The widely employed continuity equation requires measurement of the left ventricular outflow tract (LVOT) area. We aimed at investigating whether direct measurement in a volume data set is superior to conventional calculation from the LVOT-diameter. Methods: We performed left ventricular outflow tract measurement in 20 normal subjects and 15 patients with moderate to severe aortic stenosis with a newly developed transthoracic real-time three-dimensional echocardiography technique (SONOS 7500, Philips, Best, Netherlands). The off-line 3D-evaluation software (TomTec, Munich, Germany) allows free choice of section plains within the acquired volume data set. The aortic valve area was calculated by two independent observers according to the continuity equation from the mean of LVOT area values as determined from several sequential systolic frames. These results were compared to area estimates obtained by M-mode LVOT-diameters (area = Pi * (d/2)exp2). Additionally the sonographically calculated aortic valve orifices were compared to direct planimetry by transesophageal examination or invasive measurements. Results: In all cases both observers found a significant reduction in LVOT-area during systole (p<0,01). Frequently, the contraction of the LVOT resulted in an elliptical shape, as underscored by a significant decrease of the longitudinal/transverse axis ratio (p<0,01). Determination of aortic valvular orifice deviated less from invasively or planimetrically measured values (mean difference: 0,04cm 2 ) than conventionally calculated LVOT-areas based on M-mode (mean difference: 0,16cm 2 ). Conclusion: The transthoracic real-time 3D-echocardiography technique offers better estimates of aortic valve area, approximating planimetric and invasive measurements, as compared to application of the continuity equation to conventional M-mode echocardiography.

Low-Energy Ultrasound Treatment Improves Regional Tumor Vessel Infarction by Retargeted Tissue Factor

Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine, 2015

To enhance the regional antitumor activity of the vascular-targeting agent truncated tissue facto... more To enhance the regional antitumor activity of the vascular-targeting agent truncated tissue factor (tTF)-NGR by combining the therapy with low-energy ultrasound (US) treatment. For the in vitro US exposure of human umbilical vein endothelial cells (HUVECs), cells were put in the focus of a US transducer. For analysis of the US-induced phosphatidylserine (PS) surface concentration on HUVECs, flow cytometry was used. To demonstrate the differences in the procoagulatory efficacy of TF-derivative tTF-NGR on binding to HUVECs with a low versus high surface concentration of PS, we performed factor X activation assays. For low-energy US pretreatment, HT1080 fibrosarcoma xenotransplant-bearing nude mice were treated by tumor-regional US-mediated stimulation (ie, destruction) of microbubbles. The therapy cohorts received the tumor vessel-infarcting tTF-NGR protein with or without US pretreatment (5 minutes after US stimulation via intraperitoneal injection on 3 consecutive days). Combination...

Minimally-invasive versus conventional aortic valve replacement - perioperative course and mid-term resultsq

Objective: We performed a case-control-study to compare perioperative and mid-term results of min... more Objective: We performed a case-control-study to compare perioperative and mid-term results of minimally invasive with conventional aortic valve replacement. Methods: Between 8/96 and 7/97, 113 patients underwent isolated aortic valve replacement (minimally invasive: 29, conventional: 84) in our Department. Diagnosis, ejection fraction, pressure gradient/regurgitation fraction, age, gender and body-mass- index were used as matching criteria for the case-control-study. For qualitative

Cardiac involvement in female Duchenne and Becker muscular dystrophy carriers in comparison to their first-degree male relatives: a comparative cardiovascular magnetic resonance study

by Jörg Stypmann and Sabine Rösch

European heart journal cardiovascular Imaging, Jan 25, 2015

Duchenne (DMD) and Becker (BMD) muscular dystrophies are X-linked recessive disorders associated ... more Duchenne (DMD) and Becker (BMD) muscular dystrophies are X-linked recessive disorders associated with both skeletal myopathy and progressive cardiomyopathy in males. Female DMD/BMD carriers (DMDc/BMDc) are mostly free of skeletal muscle symptoms, but they are also prone to cardiomyopathy. The aim of the current study was to characterize the frequency, pattern, and extent of cardiomyopathy in female DMD/BMD carriers (DMDc/BMDc) in comparison to their first-degree male MD relatives. Thirty-six (age 44 ± 14 years) female MD carriers (20 DMDc and 16 BMDc) constituted the 'MD carrier group' and were prospectively enrolled. All MD carriers underwent a complete CMR study comprising cine- and late gadolinium enhancement (LGE) imaging. In 22 of these women ('female MD carrier comparison group', 7 DMD and 15 BMD), at least one first-degree male relative with a previously established diagnosis of MD underwent the same CMR protocol and was assigned to the 'male MD comparison...

509 Noninvasive cardiovascular phenotyping of PKD2 — Knock-out-mice

European Journal of Echocardiography, 1999

Granulocyte colony–stimulating factor–induced blood stem cell mobilisation in patients with chronic heart failure

Basic Research in Cardiology, 2006

Bone marrow–derived stem cells may contribute to the regeneration of non–haematopoietic organs. I... more Bone marrow–derived stem cells may contribute to the regeneration of non–haematopoietic organs. In order to test whether an increase in circulating stem cell numbers improves impaired myocardial function we treated 16 male patients with chronic heart failure due to dilated (DCM; n = 7) or ischaemic cardiomyopathy (ICM; n = 9) with the stem cell mobilising cytokine granulocyte colony–stimulating factor

Ultrasonographic Characterization of Murine DSS-Colitis – 40 Mhz In Vivo Hydrosonography Monitors Features of Colonic Inflammation in Mice

Gastroenterology, 2011

Serum-Mediated Inhibition of Enzyme Replacement Therapy in Fabry Disease

by Jörg Stypmann and Malte Lenders

Journal of the American Society of Nephrology : JASN, Jan 30, 2015

Fabry disease (FD) is a progressive multisystemic disorder, treatable with recombinant enzyme rep... more Fabry disease (FD) is a progressive multisystemic disorder, treatable with recombinant enzyme replacement therapy (agalsidase). However, recent studies suggest an endogenous inhibition of agalsidase in patients with FD, as reported for other lysosomal storage diseases. To assess the clinical consequences of serum-mediated agalsidase inhibition in affected patients, we determined the agalsidase inhibition status of 168 patients (68 male) with FD and compared outcomes of inhibition-positive patients with those of inhibition-negative patients. The assessment included clinical events during time on agalsidase, determination of renal and cardiac function, and evaluation of FD-related symptoms. The frequency of serum-mediated agalsidase inhibition was 40% in agalsidase-treated males. Inhibition did not depend on the compound initially used (agalsidase-α or -β). Agalsidase inhibition was associated with higher lyso-globotriaosylceramide levels and worse disease severity scores in patients....

$Research paper thumbnail of Dronedarone and digitalis: individually reduced post-repolarization refractoriness enhances life-threatening arrhythmias$

Dronedarone and digitalis: individually reduced post-repolarization refractoriness enhances life-threatening arrhythmias

Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology, Jan 20, 2015

Interaction between dronedarone and digitalis has been discussed as a possible cause for increase... more Interaction between dronedarone and digitalis has been discussed as a possible cause for increased mortality in the presence of dronedarone observed in the PALLAS trial. The aim of this study was to assess possible proarrhythmic effects of dronedarone in combination with digitalis in an experimental whole heart model. Twenty-six female rabbits underwent chronic oral treatment with dronedarone (50 mg/kg/day for 6 weeks). Twenty-four rabbits received placebo. Heart failure was induced by rapid ventricular pacing. Sham-operated rabbits received a right-ventricular pacing lead but were not paced. Thereafter, hearts were isolated and Langendorff-perfused. Monophasic action potentials and a 12 lead electrocardiogram showed a dose-dependent decrease of QT interval, APD90, effective refractory periods, and postrepolarization refractoriness in control hearts and dronedarone-pretreated hearts after application of ouabain (0.1 and 0.2 µM). After acute application of ouabain, ventricular fibril...

Dilated cardiomyopathy in mice deficient for the lysosomal cysteine peptidase cathepsin L

Proceedings of the National Academy of Sciences of the United States of America, Jan 30, 2002

Dilated cardiomyopathy is a frequent cause of heart failure and is associated with high mortality... more Dilated cardiomyopathy is a frequent cause of heart failure and is associated with high mortality. Progressive remodeling of the myocardium leads to increased dimensions of heart chambers. The role of intracellular proteolysis in the progressive remodeling that underlies dilated cardiomyopathy has not received much attention yet. Here, we report that the lysosomal cysteine peptidase cathepsin L (CTSL) is critical for cardiac morphology and function. One-year-old CTSL-deficient mice show significant ventricular and atrial enlargement that is associated with a comparatively small increase in relative heart weight. Interstitial fibrosis and pleomorphic nuclei were found in the myocardium of the knockout mice. By electron microscopy, CTSL-deficient cardiomyocytes contained multiple large and apparently fused lysosomes characterized by storage of electron-dense heterogeneous material. Accordingly, the assessment of left ventricular function by echocardiography revealed severely impaired ...

Clinical experience with nine patients supported by the continuous flow Debakey VAD

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 2001

Optimizing the technique of contrast transcranial Doppler ultrasound in the detection of right-to-left shunts

Stroke; a journal of cerebral circulation, 2002

A cardiac right-to-left shunt (RLS) can be identified by transesophageal echocardiography and tra... more A cardiac right-to-left shunt (RLS) can be identified by transesophageal echocardiography and transcranial Doppler ultrasound (TCD) with contrast agents and a Valsalva maneuver (VM) as a provocation procedure. This article applies the modalities of these tests detailed in previous studies to a large patient cohort and compares 2 contrast agents (saline and Echovist-300). Eighty-one patients were investigated by both transesophageal echocardiography and bilateral TCD of the middle cerebral arteries. The following protocol with injections of 10 mL agitated saline was applied in a randomized way: (1) no VM, (2) VM for 5 seconds starting 5 seconds after the beginning of contrast injection, and (3) repetition of the test with VM if the first test with VM was negative. The VM was performed for 5 seconds starting exactly 5 seconds after the beginning of saline injection. Thereafter, the same protocol was repeated with 10 mL Echovist-300 instead of saline. Thirty-one patients had a cardiac ...

Excessive Daytime Sleepiness Is a Common Symptom in Fabry Disease

Case reports in neurology, 2009

Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by a deficient activit... more Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by a deficient activity of the enzyme α-galactosidase A, resulting in a vasculopathic involvement of various organ systems, e.g. cerebral structures. Marked cerebral vasculopathy with subsequent white matter lesions (WML) are a frequent finding in FD patients. Recent studies discussed an association between cerebral white matter changes and sleep-related disturbances of breathing, which may lead to excessive daytime sleepiness (EDS). A 56-year-old Caucasian female FD patient with EDS was admitted to our sleep laboratory. Overnight polysomnography showed a Cheyne-Stokes respiration pattern with significant O(2) desaturation. MR imaging revealed confluent WML including the brain stem, but no renal or cardiac involvement. We then evaluated the clinical data of 49 genetically proven FD patients (27 males; mean age 43 years) from our FD centre. With a frequency of 68%, EDS exceeds the prevalence of other common sy...

Everolimus in Heart Transplantation: An Update

by Jörg Stypmann and Uwe Schulz

Journal of Transplantation, 2013

Concordance Among Pathologists in the Second Cardiac Allograft Rejection Gene Expression Observational Study (CARGO II)

by Jörg Stypmann and Uwe Schulz

Transplantation Journal, 2012

Background. There has been no large evaluation of the ISHLT 2004 acute cellular rejection grading... more Background. There has been no large evaluation of the ISHLT 2004 acute cellular rejection grading scheme for heart graft endomyocardial biopsy specimens (EMBs). Methods. We evaluated agreement within the CARGO II pathology panel and between the panel (acting by majority) and the collaborating centers (treated as a single entity), regarding the ISHLT grades of 937 EMBs (with all grades Q2R merged because of small numbers).

81 Prediction of Allograft Clinical Outcomes and Risk of Acute Cellular Rejection with a Non-Invasive Gene-Expression Profiling Test (AlloMap): Results from the Cargo 2 European-Based Multicenter Trial

by Jörg Stypmann and Uwe Schulz

The Journal of Heart and Lung Transplantation, 2012

A protocol was set up based on antigen-specific immunoadsorption to remove existing anti-A or ant... more A protocol was set up based on antigen-specific immunoadsorption to remove existing anti-A or anti-B antibodies and rituximab to prevent rebound of antibodies in combination with conventional tacrolimus, mycophenolate mofetil and prednisolone immunosuppression. Based on the experience of 60 successfully performed ABOincompatible renal transplantations the protocol included postoperativ, pre-emptive apheresis sessions every third day for 9 days. Six of 13 patients on the waiting list had the anti-A or anti-B antibody levels low enough to be included in this protocol. Results: Two patients have successfully performed ABO-incompatible transplantation following this protocol. At 1 year of follow up both patients are in NYHA I with normal cardiac performance, normal coronary angiograms and without signs of chronic rejection. During the first year protocol biopsies from both patients stained diffusely positive for C4D, as have been described in ABO-incompatible renal transplantation, and which may be explained by a continuos low grade degradation of A or B antibodies within the organ but without signs of myocardial damage. Conclusions: Based on acceptance of certain anti-A or anti-B antibody levels, ABO-incompatible heart transplantation is a safe and successful procedure and acceptance of any blood group may lead to a substantial reduction in the time on the waiting list.

582 Pharmacogenetics of Nephrotoxicity in Heart Transplantation Candidates Receiving Calcineurin Inhibitor (CNI) Medication

by Uwe Schulz and Jörg Stypmann

The Journal of Heart and Lung Transplantation, 2011

Thrombomodulin's lectin-like domain reduces myocardial damage by interfering with HMGB1-mediated TLR2 signalling

by Jörg Stypmann and Martina Schmitz

Cardiovascular Research, 2014

Thrombomodulin (TM), via its lectin-like domain (LLD), exhibits anti-inflammatory properties part... more Thrombomodulin (TM), via its lectin-like domain (LLD), exhibits anti-inflammatory properties partly by sequestering the pro-inflammatory cytokine, high-mobility group box 1 (HMGB1). Since myocardial damage after ischaemia and reperfusion is mediated by inflammation, we evaluated the cardioprotective effects of the LLD of TM. Using an in vivo mouse model of transient ischaemia and in vitro models of cardiomyocyte hypoxia, we assessed the ability of the LLD to suppress HMGB1-mediated activation of the receptors, receptor for advanced glycation endproducts (RAGEs) and Toll-like receptors (TLRs) 2 and 4.

The Mandela study: A multicenter, randomized, open-label, parallel group trial to refine the use of everolimus after heart transplantation

by Jörg Stypmann, Martina Porstner, and Uwe Schulz

Contemporary clinical trials, Jan 9, 2015

In recent years a series of trials has sought to define the optimal protocol for everolimus-based... more In recent years a series of trials has sought to define the optimal protocol for everolimus-based immunosuppression in heart transplantation, with the goal of minimizing exposure to calcineurin inhibitors (CNIs) and harnessing the non-immunosuppressive benefits of everolimus. Randomized studies have demonstrated that immunosuppressive potency can be maintained in heart transplant patients receiving everolimus despite marked CNI reduction, although very early CNI withdrawal may be inadvisable. A potential renal advantage has been shown for everolimus, but the optimal time for conversion and the adequate reduction in CNI exposure remain to be defined. Other reasons for use of everolimus include a substantial reduction in the risk of cytomegalovirus infection, and evidence for inhibition of cardiac allograft vasculopathy, a major cause of graft loss. The ongoing MANDELA study is a 12-month multicenter, randomized, open-label, parallel-group study in which efficacy, renal function and s...

D ynamic regulation of MEK / Erks and Akt / GSK-3b in human end- stage heart failure after left ventricular mechanical support: myocardial mechanotransduction-sensitivity as a possible molecular mechanism

bc ,g g , * ¨ Abstract Objective: Left ventricular assist devices (LVAD) are used to 'bridge&... more bc ,g g , * ¨ Abstract Objective: Left ventricular assist devices (LVAD) are used to 'bridge' patients with end-stage heart failure to transplantation. After long-term LVAD support, ventricular function may partially recover, a process called 'reverse remodeling'. As several kinase-mediated signal transduction pathways have been implicated in the development of cardiac hypertrophy and failure, we examined the activities of

841 Tissue doppler imaging (TDI) in patients with aortic valve stenosis-clinical usefulness and diagnostic accuracy

European Heart Journal – Cardiovascular Imaging

Background: Evaluation of aortic valve stenoses is one to the most important current clinical app... more Background: Evaluation of aortic valve stenoses is one to the most important current clinical applications of echocardiography. The widely employed continuity equation requires measurement of the left ventricular outflow tract (LVOT) area. We aimed at investigating whether direct measurement in a volume data set is superior to conventional calculation from the LVOT-diameter. Methods: We performed left ventricular outflow tract measurement in 20 normal subjects and 15 patients with moderate to severe aortic stenosis with a newly developed transthoracic real-time three-dimensional echocardiography technique (SONOS 7500, Philips, Best, Netherlands). The off-line 3D-evaluation software (TomTec, Munich, Germany) allows free choice of section plains within the acquired volume data set. The aortic valve area was calculated by two independent observers according to the continuity equation from the mean of LVOT area values as determined from several sequential systolic frames. These results were compared to area estimates obtained by M-mode LVOT-diameters (area = Pi * (d/2)exp2). Additionally the sonographically calculated aortic valve orifices were compared to direct planimetry by transesophageal examination or invasive measurements. Results: In all cases both observers found a significant reduction in LVOT-area during systole (p<0,01). Frequently, the contraction of the LVOT resulted in an elliptical shape, as underscored by a significant decrease of the longitudinal/transverse axis ratio (p<0,01). Determination of aortic valvular orifice deviated less from invasively or planimetrically measured values (mean difference: 0,04cm 2 ) than conventionally calculated LVOT-areas based on M-mode (mean difference: 0,16cm 2 ). Conclusion: The transthoracic real-time 3D-echocardiography technique offers better estimates of aortic valve area, approximating planimetric and invasive measurements, as compared to application of the continuity equation to conventional M-mode echocardiography.

Low-Energy Ultrasound Treatment Improves Regional Tumor Vessel Infarction by Retargeted Tissue Factor

Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine, 2015

To enhance the regional antitumor activity of the vascular-targeting agent truncated tissue facto... more To enhance the regional antitumor activity of the vascular-targeting agent truncated tissue factor (tTF)-NGR by combining the therapy with low-energy ultrasound (US) treatment. For the in vitro US exposure of human umbilical vein endothelial cells (HUVECs), cells were put in the focus of a US transducer. For analysis of the US-induced phosphatidylserine (PS) surface concentration on HUVECs, flow cytometry was used. To demonstrate the differences in the procoagulatory efficacy of TF-derivative tTF-NGR on binding to HUVECs with a low versus high surface concentration of PS, we performed factor X activation assays. For low-energy US pretreatment, HT1080 fibrosarcoma xenotransplant-bearing nude mice were treated by tumor-regional US-mediated stimulation (ie, destruction) of microbubbles. The therapy cohorts received the tumor vessel-infarcting tTF-NGR protein with or without US pretreatment (5 minutes after US stimulation via intraperitoneal injection on 3 consecutive days). Combination...

Minimally-invasive versus conventional aortic valve replacement - perioperative course and mid-term resultsq

Objective: We performed a case-control-study to compare perioperative and mid-term results of min... more Objective: We performed a case-control-study to compare perioperative and mid-term results of minimally invasive with conventional aortic valve replacement. Methods: Between 8/96 and 7/97, 113 patients underwent isolated aortic valve replacement (minimally invasive: 29, conventional: 84) in our Department. Diagnosis, ejection fraction, pressure gradient/regurgitation fraction, age, gender and body-mass- index were used as matching criteria for the case-control-study. For qualitative

Cardiac involvement in female Duchenne and Becker muscular dystrophy carriers in comparison to their first-degree male relatives: a comparative cardiovascular magnetic resonance study

by Jörg Stypmann and Sabine Rösch

European heart journal cardiovascular Imaging, Jan 25, 2015

Duchenne (DMD) and Becker (BMD) muscular dystrophies are X-linked recessive disorders associated ... more Duchenne (DMD) and Becker (BMD) muscular dystrophies are X-linked recessive disorders associated with both skeletal myopathy and progressive cardiomyopathy in males. Female DMD/BMD carriers (DMDc/BMDc) are mostly free of skeletal muscle symptoms, but they are also prone to cardiomyopathy. The aim of the current study was to characterize the frequency, pattern, and extent of cardiomyopathy in female DMD/BMD carriers (DMDc/BMDc) in comparison to their first-degree male MD relatives. Thirty-six (age 44 ± 14 years) female MD carriers (20 DMDc and 16 BMDc) constituted the 'MD carrier group' and were prospectively enrolled. All MD carriers underwent a complete CMR study comprising cine- and late gadolinium enhancement (LGE) imaging. In 22 of these women ('female MD carrier comparison group', 7 DMD and 15 BMD), at least one first-degree male relative with a previously established diagnosis of MD underwent the same CMR protocol and was assigned to the 'male MD comparison...

509 Noninvasive cardiovascular phenotyping of PKD2 — Knock-out-mice

European Journal of Echocardiography, 1999

Granulocyte colony–stimulating factor–induced blood stem cell mobilisation in patients with chronic heart failure

Basic Research in Cardiology, 2006

Bone marrow–derived stem cells may contribute to the regeneration of non–haematopoietic organs. I... more Bone marrow–derived stem cells may contribute to the regeneration of non–haematopoietic organs. In order to test whether an increase in circulating stem cell numbers improves impaired myocardial function we treated 16 male patients with chronic heart failure due to dilated (DCM; n = 7) or ischaemic cardiomyopathy (ICM; n = 9) with the stem cell mobilising cytokine granulocyte colony–stimulating factor

Ultrasonographic Characterization of Murine DSS-Colitis – 40 Mhz In Vivo Hydrosonography Monitors Features of Colonic Inflammation in Mice

Gastroenterology, 2011

Serum-Mediated Inhibition of Enzyme Replacement Therapy in Fabry Disease

by Jörg Stypmann and Malte Lenders

Journal of the American Society of Nephrology : JASN, Jan 30, 2015

Fabry disease (FD) is a progressive multisystemic disorder, treatable with recombinant enzyme rep... more Fabry disease (FD) is a progressive multisystemic disorder, treatable with recombinant enzyme replacement therapy (agalsidase). However, recent studies suggest an endogenous inhibition of agalsidase in patients with FD, as reported for other lysosomal storage diseases. To assess the clinical consequences of serum-mediated agalsidase inhibition in affected patients, we determined the agalsidase inhibition status of 168 patients (68 male) with FD and compared outcomes of inhibition-positive patients with those of inhibition-negative patients. The assessment included clinical events during time on agalsidase, determination of renal and cardiac function, and evaluation of FD-related symptoms. The frequency of serum-mediated agalsidase inhibition was 40% in agalsidase-treated males. Inhibition did not depend on the compound initially used (agalsidase-α or -β). Agalsidase inhibition was associated with higher lyso-globotriaosylceramide levels and worse disease severity scores in patients....

$Research paper thumbnail of Dronedarone and digitalis: individually reduced post-repolarization refractoriness enhances life-threatening arrhythmias$

Dronedarone and digitalis: individually reduced post-repolarization refractoriness enhances life-threatening arrhythmias

Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology, Jan 20, 2015

Interaction between dronedarone and digitalis has been discussed as a possible cause for increase... more Interaction between dronedarone and digitalis has been discussed as a possible cause for increased mortality in the presence of dronedarone observed in the PALLAS trial. The aim of this study was to assess possible proarrhythmic effects of dronedarone in combination with digitalis in an experimental whole heart model. Twenty-six female rabbits underwent chronic oral treatment with dronedarone (50 mg/kg/day for 6 weeks). Twenty-four rabbits received placebo. Heart failure was induced by rapid ventricular pacing. Sham-operated rabbits received a right-ventricular pacing lead but were not paced. Thereafter, hearts were isolated and Langendorff-perfused. Monophasic action potentials and a 12 lead electrocardiogram showed a dose-dependent decrease of QT interval, APD90, effective refractory periods, and postrepolarization refractoriness in control hearts and dronedarone-pretreated hearts after application of ouabain (0.1 and 0.2 µM). After acute application of ouabain, ventricular fibril...

Dilated cardiomyopathy in mice deficient for the lysosomal cysteine peptidase cathepsin L

Proceedings of the National Academy of Sciences of the United States of America, Jan 30, 2002

Dilated cardiomyopathy is a frequent cause of heart failure and is associated with high mortality... more Dilated cardiomyopathy is a frequent cause of heart failure and is associated with high mortality. Progressive remodeling of the myocardium leads to increased dimensions of heart chambers. The role of intracellular proteolysis in the progressive remodeling that underlies dilated cardiomyopathy has not received much attention yet. Here, we report that the lysosomal cysteine peptidase cathepsin L (CTSL) is critical for cardiac morphology and function. One-year-old CTSL-deficient mice show significant ventricular and atrial enlargement that is associated with a comparatively small increase in relative heart weight. Interstitial fibrosis and pleomorphic nuclei were found in the myocardium of the knockout mice. By electron microscopy, CTSL-deficient cardiomyocytes contained multiple large and apparently fused lysosomes characterized by storage of electron-dense heterogeneous material. Accordingly, the assessment of left ventricular function by echocardiography revealed severely impaired ...

Clinical experience with nine patients supported by the continuous flow Debakey VAD

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 2001

Optimizing the technique of contrast transcranial Doppler ultrasound in the detection of right-to-left shunts

Stroke; a journal of cerebral circulation, 2002

A cardiac right-to-left shunt (RLS) can be identified by transesophageal echocardiography and tra... more A cardiac right-to-left shunt (RLS) can be identified by transesophageal echocardiography and transcranial Doppler ultrasound (TCD) with contrast agents and a Valsalva maneuver (VM) as a provocation procedure. This article applies the modalities of these tests detailed in previous studies to a large patient cohort and compares 2 contrast agents (saline and Echovist-300). Eighty-one patients were investigated by both transesophageal echocardiography and bilateral TCD of the middle cerebral arteries. The following protocol with injections of 10 mL agitated saline was applied in a randomized way: (1) no VM, (2) VM for 5 seconds starting 5 seconds after the beginning of contrast injection, and (3) repetition of the test with VM if the first test with VM was negative. The VM was performed for 5 seconds starting exactly 5 seconds after the beginning of saline injection. Thereafter, the same protocol was repeated with 10 mL Echovist-300 instead of saline. Thirty-one patients had a cardiac ...

Excessive Daytime Sleepiness Is a Common Symptom in Fabry Disease

Case reports in neurology, 2009

Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by a deficient activit... more Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by a deficient activity of the enzyme α-galactosidase A, resulting in a vasculopathic involvement of various organ systems, e.g. cerebral structures. Marked cerebral vasculopathy with subsequent white matter lesions (WML) are a frequent finding in FD patients. Recent studies discussed an association between cerebral white matter changes and sleep-related disturbances of breathing, which may lead to excessive daytime sleepiness (EDS). A 56-year-old Caucasian female FD patient with EDS was admitted to our sleep laboratory. Overnight polysomnography showed a Cheyne-Stokes respiration pattern with significant O(2) desaturation. MR imaging revealed confluent WML including the brain stem, but no renal or cardiac involvement. We then evaluated the clinical data of 49 genetically proven FD patients (27 males; mean age 43 years) from our FD centre. With a frequency of 68%, EDS exceeds the prevalence of other common sy...

Everolimus in Heart Transplantation: An Update

by Jörg Stypmann and Uwe Schulz

Journal of Transplantation, 2013