Andreas Mügge

Publications of Andreas Mügge

• Atrial Fibrillation and Wolff-Parkinson-White Syndrome:: Mechanisms Revisited?

  Authors: Thomas Deneke, Andreas Mügge

  Journal of cardiovascular electrophysiology. 12/2011;

• High frequency of diastolic dysfunction in a population-based cohort of elderly women--but poor association with the symptom dyspnea.

  Authors: Alfried Germing, Michael Gotzmann, Tamara Schikowski, Andrea Vierkötter, Ulrich Ranft, Ursula Krämer, Andreas Mügge

  BMC geriatrics. 11/2011; 11:71.

  The European Society of Cardiology recently proposed a new algorithm "How to diagnose heart failure with normal ejection fraction". Central element of the diagnostic strategy is the demonstration ofThe European Society of Cardiology recently proposed a new algorithm "How to diagnose heart failure with normal ejection fraction". Central element of the diagnostic strategy is the demonstration of diastolic dysfunction, either by tissue Doppler-derived indices in first line, or in second line by a combination of elevated blood levels of natriuretic peptide with abnormal tissue Doppler findings. We thought to use this diagnostic flowchart in a population-based cohort of elderly women, in whom the prevalence of diastolic dysfunction and heart failure is believed to be high. The purpose was to evaluate the association of dyspnea with the presence of diastolic dysfunction. The study cohort recruited from a cross-sectional follow-up examination of the SALIA cohort (study on the influence of air pollution on lung function, inflammation, and aging). Participants with cardiac or pulmonary disease were excluded, 291 participants formed the final study group (all women, age range 69 to 79 years, all in sinus rhythm, LV ejection fraction > 50%, LV enddiastolic volume index < 97 mL/m2). Quality of life was assessed by the Minnesota living with heart failure questionnaire, and actual symptoms by a structural questionnaire; the examination consisted of a physical examination, measurement of B-type natriuretic peptide, ECG and tissue Doppler echocardiography. Diastolic dysfunction was assumed when the E/E' ratio exceeded 15 as derived from tissue Doppler. In case, tissue Doppler yielded an E/E' ratio ranging from 8 to 15, additional non-invasive parameters had to be fulfilled: left atrial volume index > 40 ml/m2 body surface, or left ventricular mass index > 122 g/m2 body surface, or transmitral E/A ratio < 0.5 plus deceleration time > 280 ms, or blood level of brain natriuretic peptide (BNP) > 200 pg/mL. The examinations were concordant with the presence of diastolic dysfunction in 122/291 participants (41.9%). The diagnosis based in 94% of cases on two criteria: in 50 cases on the criterion "E/E' ratio > 15", and in 65 cases on the criterion "15 > E/E'>8 and LV mass index > 122 g/m2". The participants with diastolic dysfunction had on average a higher body mass index, more frequent a history of arterial hypertension and of hospitalization for congestive heart failure, poorer quality of life, and higher BNP blood levels as compared to those participants without signs of diastolic dysfunction. The number of participants complaining exertional dyspnea, however, was similar distributed among the subgroups with and without signs of diastolic dysfunction (40.2 vs 40.8%; p = n.s). In a logistic regression model, the symptom dyspnea was best predicted by systolic pulmonary artery pressure, followed by left atrial volume index, BNP, and body mass index. The demonstration of diastolic dysfunction showed only a poor association with the symptom dyspnea in a cohort of elderly women with otherwise normal systolic function. Additional structural or hemodynamic changes are necessary to "explain" the symptom dyspnea. It is unclear whether these additional factors are secondary to a more advanced stage of diastolic dysfunction, or are related to cardiovascular co-morbidities, or both.

• Which is the best anticoagulant for whole blood aggregometry platelet function testing? Comparison of six anticoagulants and diverse storage conditions.

  Authors: Andreas Friedrich Christoph Kaiser, Horst Neubauer, Cora Christina Franken, Jan-Christoph Krüger, Andreas Mügge, Saskia Hannah Meves

  Platelets. 10/2011;

  Major hindrances of impedance aggregometry are caused by limited storage time and the requirement of ex vivo anticoagulation. Data on the influence of different anticoagulants and storage conditionsMajor hindrances of impedance aggregometry are caused by limited storage time and the requirement of ex vivo anticoagulation. Data on the influence of different anticoagulants and storage conditions are rare and incomplete. This study has systematically examined the influence of six different anticoagulants (sodium and lithium heparin, 20 µg/mL and 45 µg/mL r-hirudin, benzylsulfonyl-D-Arg-Pro-4-amidinobenzylamide (BAPA), and citrate) on the results of Adenosine 5'-diphosphate (ADP) and arachidonic acid (AA) induced measurements using multiple-electrode impedance aggregometer (MEA). Measurements were carried out in a time frame of 0 min up to 48 h after blood withdrawal. In addition, the influence of storage temperatures of 4°C and 37°C was evaluated. Results of ADP-induced tests significantly varied within the first 30 min in all tested anticoagulants, in citrated blood even within the first 60 min. They remained stable up to 2 h in 20 µg/mL r-hirudin and BAPA, 4 h in citrate, 8 h in 45 µg/mL r-hirudin, and lithium heparin and up to a maximum of 12 h in sodium heparin anticoagulated blood. The analysis of AA-induced tests revealed no significantly different results up to 6 h when BAPA was used, 8 h in lithium heparin, 20 µg/mL r-hirudin and citrate, 12 h in 45 µg/mL r-hirudin, and even 24 h in sodium heparin-anticoagulated samples. A storage temperature of either 4°C or 37°C in contrast to room temperature had a negative influence on the stability of results. In conclusion, sodium heparin and 45 µg/mL r-hirudin as anticoagulants guarantee the longest storage time for impedance aggregometry.

• Do not confuse the edge-to-edge technique with mitral valve stenosis: methodological considerations for echocardiography after mitral valve repair.

  Authors: Alfried Germing, Matthias Bechtel, Andreas Mügge

  Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine. 08/2011; 30(8):1156-7.

• Transcatheter aortic valve implantation in patients with severe symptomatic aortic valve stenosis-predictors of mortality and poor treatment response.

  Authors: Michael Gotzmann, Azem Pljakic, Waldemar Bojara, Michael Lindstaedt, Aydan Ewers, Alfried Germing, Andreas Mügge

  American heart journal. 08/2011; 162(2):238-245.e1.

  Transcatheter aortic valve implantation (TAVI) has emerged as an alternative technique in patients with severe symptomatic aortic valve stenosis. However, a number of patients have no benefit afterTranscatheter aortic valve implantation (TAVI) has emerged as an alternative technique in patients with severe symptomatic aortic valve stenosis. However, a number of patients have no benefit after implantation. This prospective study attempted to identify predictors of poor treatment response. From June 2008 to September 2010, consecutive patients with symptomatic severe aortic valve stenosis and high surgical risk were submitted to TAVI with the CoreValve prosthesis (Medtronic, Minneapolis, MN). The primary end point was all-cause mortality at 6 months. Secondary end point (poor treatment response) was defined as no improvement of symptoms assessed with the New York Heart Association class 6 months after TAVI. A total of 145 patients (mean age 79.1 ± 6.4 years, mean logistic EuroSCORE 21% ± 16.2%) were included. During the follow-up period, 23 (15.9%) patients died. Independent predictors of all-cause mortality were as follows: aortic mean gradient ≤40 mm Hg (odds ratio [OR] 3.93), moderate and severe tricuspid valve regurgitation (OR 4.50), and moderate and severe postprocedural aortic valve regurgitation (OR 4.26). In 122 surviving patients, 25 patients (20%) showed no improvement in symptoms. Independent predictors of poor treatment response were severe mitral valve regurgitation (OR 7.42) and moderate and severe postprocedural aortic valve regurgitation (OR 10.1). Cardiac comorbidities (low-gradient aortic stenosis, tricuspidal valve regurgitation) are associated with all-cause mortality, whereas mitral valve regurgitation is a risk factor for poor treatment response after TAVI. Postprocedural aortic valve regurgitation is a strong predictor of both-mortality and poor treatment response.

• Catheter ablation of electrical storm.

  Authors: Thomas Deneke, Bernd Lemke, Andreas Mügge, Dong-In Shin, Peter H Grewe, Marc Horlitz, Osman Balta, Leif Bösche, Thomas Lawo

  Expert review of cardiovascular therapy. 08/2011; 9(8):1051-8.

  Electrical storm (ES) is defined as the occurrence of ≥ three distinct episodes of ventricular arrhythmia (VA) in patients with implanted defibrillators within 24 h. Whereas conventional strategiesElectrical storm (ES) is defined as the occurrence of ≥ three distinct episodes of ventricular arrhythmia (VA) in patients with implanted defibrillators within 24 h. Whereas conventional strategies for acute rhythm stabilization may be effective in some patients the occurrence of ES impairs survival and predicts recurrent VA. Catheter ablation in the setting of ES is complex and involves decisive strategies for individualized ablation approaches adapted to the patient's cardiac abnormalities. Success rates have been documented to be between 79 and 94% in larger studies and effective ablation improves survival and freedom from any VA. Ablation should be considered early in the treatment plan and availability may be improved by interhospital collaboration with highly experienced VA intervention centers.

• Treatment of persistent atrial fibrillation using phased radiofrequency ablation technology.

  Authors: Thomas Deneke, Andreas Mügge, Osman Balta, Marc Horlitz, Peter H Grewe, Dong-In Shin

  Expert review of cardiovascular therapy. 08/2011; 9(8):1041-9.

  A novel ablation system consisting of a duty-cycled phased radiofrequency generator and multielectrode mapping and ablation catheters has been introduced to provide ablation therapy in patients withA novel ablation system consisting of a duty-cycled phased radiofrequency generator and multielectrode mapping and ablation catheters has been introduced to provide ablation therapy in patients with symptomatic atrial fibrillation (AF). Contiguous lesions may be created using anatomically designed ablation catheters maneuvered under fluoroscopic guidance without the use of a 3D electroanatomic mapping system. In addition to pulmonary vein isolation using a circular, decapolar ablation catheter, an ablation strategy targeting complex fractionated atrial electrograms can be performed using two supplemental multiarray catheters specifically designed for ablation at the left atrial septum and within the left atrial body. Procedural times for treating persistent AF using phased radiofrequency are reported as being between 2 and 2.5 h. Freedom from AF ranges between 33 and 75% after a single procedure, which is comparable to other conventional ablation approaches (utilizing electroanatomic mapping). Additional studies in larger patient numbers are needed to understand the long-term maintenance of results and potential adverse effects of the technology.

• Clinical outcome of transcatheter aortic valve implantation in patients with low-flow, low gradient aortic stenosis.

  Authors: Michael Gotzmann, Michael Lindstaedt, Waldemar Bojara, Aydan Ewers, Andreas Mügge

  Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions. 07/2011;

  Background: Low-flow, low-gradient aortic stenosis is associated with relevant postoperative mortality whereas conservative management results in dismal prognosis. We present the initial experienceBackground: Low-flow, low-gradient aortic stenosis is associated with relevant postoperative mortality whereas conservative management results in dismal prognosis. We present the initial experience of low-flow, low-gradient aortic stenosis treated with transcatheter aortic valve implantation (TAVI). Methods: From June 2008 to December 2010 167 consecutive patients with native severe aortic stenosis and an excessive operative risk underwent TAVI. Of these, 15 patients presented with low-flow, low-gradient aortic stenosis (aortic valve area < 1 cm(2) , left ventricular (LV) ejection fraction < 40%, aortic mean gradient < 40 mm Hg). The CoreValve prosthesis 18-F-generation (Medtronic, Minneapolis, Minnesota) was inserted retrograde. Clinical follow-up and echocardiography were performed 6 months after procedure. Results: Patients with low-flow, low-gradient aortic stenosis (mean LV ejection fraction 32 ± 6%, mean aortic gradient 27 ± 7 mm Hg) had higher all-cause mortality 6 months after TAVI compared to patients without low-flow, low-gradient aortic stenosis (33% vs. 13%, P = 0.037). In the surviving 10 patients with low-flow, low-gradient aortic stenosis, LV ejection fraction increased (34 ± 6% before vs. 46 ± 11% 6 months after TAVI, p = 0.005) and more distance covered in the 6-minute walk test (218 ± 102 meters before vs. 288 ± 129 meters 6 months after TAVI, p = 0.038). Conclusion: Our study suggests that TAVI is feasible in patients with severe co-morbidities and low-flow, low-gradient aortic stenosis. Within the first 6 months after treatment all-cause mortality was considerable high, but the surviving patients showed symptomatic benefit and significant improvement of myocardial function and exercise capacity. © 2011 Wiley-Liss, Inc.

• Postablation asymptomatic cerebral lesions: long-term follow-up using magnetic resonance imaging.

  Authors: Thomas Deneke, Dong-In Shin, Osman Balta, Kathrin Bünz, Frank Fassbender, Andreas Mügge, Helge Anders, Marc Horlitz, Markus Päsler, Sinthu Karthikapallil, Thomas Arentz, Dieter Beyer, Martin Bansmann

  Heart rhythm : the official journal of the Heart Rhythm Society. 07/2011; 8(11):1705-11.

  Catheter ablation of atrial fibrillation (AF) is complicated by cerebral emboli resulting in acute ischemia. Recently, cerebral ischemic microlesions have been identified with diffusion-weightedCatheter ablation of atrial fibrillation (AF) is complicated by cerebral emboli resulting in acute ischemia. Recently, cerebral ischemic microlesions have been identified with diffusion-weighted magnet resonance imaging (MRI). The clinical course and longer-term characteristics of these lesions are not known and were investigated in this study. Of 86 patients, 33 (38%) had new asymptomatic cerebral lesions documented on MRI after catheter ablation for AF; 14 of these 33 (42%) underwent repeat MRI at different time intervals (2 weeks to 1 year) during follow-up, and clinical symptoms as well as size and number of residual lesions were documented. In postablation cerebral MRI, 50 new lesions were identified (3.6 lesions/patient) in 14 patients. No patient presented any neurological symptoms. Distribution of the lesions was predominantly in the left hemisphere (60%) and the cerebellum (26%); 52% of the lesions were small (≤3 mm maximum diameter), 42% were medium (4 to 10 mm) and 3 lesions (6%) had a maximum diameter >10 mm. Follow-up MRI after a median of 3 months revealed 3 residual lesions in 3 of 14 patients corresponding to the large acute postablation lesions (>10 mm). The remaining 47 of 50 (94%) of the small or medium-sized lesions were not detectable at follow-up evaluation. Most asymptomatic cerebral lesions observed acutely after AF ablation procedures were ≤10 mm in diameter. 94% of all lesions healed without scarring at follow-up >2 weeks after ablation. The larger acute lesions produced chronic glial scars. Neither chronic nor acute lesions were associated with neurological symptoms.

• Central serotonergic activity correlates with salivary cortisol after waking in depressed patients.

  Authors: Idun Uhl, Christine Norra, Pia-Alexandra Pirkl, Anna Hägele, Andreas Mügge, Frank Petrak, Horst Neubauer, Florian Lederbogen, Stephan Herpertz, Georg Juckel

  Psychopharmacology. 05/2011; 217(4):605-7.

• Catheter ablation of electrical storm in a collaborative hospital network.

  Authors: Thomas Deneke, Dong-in Shin, Thomas Lawo, Leif Bösche, Osman Balta, Helge Anders, Kathrin Bünz, Marc Horlitz, Peter Hubert Grewe, Bernd Lemke, Andreas Mügge

  The American journal of cardiology. 04/2011; 108(2):233-9.

  An electrical storm (ES) is defined as multiple ventricular arrhythmia episodes leading to implantable cardioverter defibrillator interventions. Although conventional rhythm stabilization might be ofAn electrical storm (ES) is defined as multiple ventricular arrhythmia episodes leading to implantable cardioverter defibrillator interventions. Although conventional rhythm stabilization might be of help acutely, ES involves high mortality and morbidity. We evaluated the effect of catheter ablation strategies in the setting of an interhospital collaborative network on the recurrence of ventricular arrhythmia episodes and mortality in patients with ES. Consecutive patients presenting for invasive treatment of ES from December 2007 to December 2009 were included. All patients underwent catheter ablation of ventricular arrhythmia. The strategies were adapted to the individual cardiac pathologic features. The follow-up examination constituted periodic implantable cardioverter defibrillator interrogation. A total of 32 patients were included. Of the 32 patients, 29 (91%) had monomorphic ventricular tachycardia and 3 ventricular fibrillation. The mean number of implantable cardioverter defibrillator-treated episodes within 7 days before ablation was 16 ± 11. Of the 32 patients, 27 underwent ablation within 24 hours after admission, and 5 underwent acute ablation within 8 hours. In 3 patients, epicardial ablation was performed. In all but 2 patients (6%), the clinical arrhythmia was successfully ablated. During a median follow-up of 15 months, 10 patients (31%) had recurrences of sustained ventricular arrhythmia, including 2 patients (6%) with recurrent ES. Three patients (9%) died during the follow-up period. In conclusion, catheter ablation effectively suppressed ventricular arrhythmia midterm recurrences in patients presenting with ES. Catheter ablation is complex in these severely sick patients. The recurrence rate of ventricular arrhythmia appears to be 31% and the mortality rate to be 9%. Collaborative hospital networks to increase the prompt availability of ES ablation might help to optimize the ES outcome.

• Shift in the pattern of autonomic atrial innervation in subjects with persistent atrial fibrillation.

  Authors: Thomas Deneke, Huda Chaar, Joris R de Groot, Arthur A Wilde, Thomas Lawo, Johanna Mundig, Leif Bösche, Andreas Mügge, Peter H Grewe

  Heart rhythm : the official journal of the Heart Rhythm Society. 04/2011; 8(9):1357-63.

  Atrial fibrillation (AF) is a multifactorial disease of the atria. We studied the differences in the atrial autonomic innervation pattern in subjects with AF compared with sinus rhythmAtrial fibrillation (AF) is a multifactorial disease of the atria. We studied the differences in the atrial autonomic innervation pattern in subjects with AF compared with sinus rhythm (SR). Preparation of postmortem isolated hearts of subjects with documented persistent AF (group A) and SR (group B) included: (1) histological sectioning of predefined areas and quantification of nerve density, and (2) differentiation using immunohistochemistry in adrenergic (sympathetic, tyrosine-hydroxylase antibody), cholinergic (parasympathetic, choline-acetyltransferase antibody) and mixed (adrenergic and cholinergic staining) nerves. Characteristics of subjects in group A (N = 15) and group B (N = 24) did not differ. The mean overall nerve density was similar between groups (A: 0.31 ± 0.25/mm(2); B: 0.35 ± 0.25/mm(2); P = .87). Nerve density appeared higher in the region of the pulmonary vein ostia and antrum (group A: 0.38 ± 0.21/mm(2); group B: 0.32 ± 0.19/mm(2),) compared with other locations of the right and left atrium. A total of 2,224 (group A: 685; group B: 1539) nerves were differentiated using immunohistochemistry. There was a high degree of colocalization of adrenergic and cholinergic nerves (group A: 80% mixed staining, group B: 69% mixed staining). In group A hearts there was a significantly lower density of predominantly cholinergic nerves (0.025 ± 0.052/mm(2) vs. 0.058 ± 0.099/mm(2); P = .008) and a higher density of nerves containing adrenergic components (0.24 ± 0.18/mm(2) vs. 0.18 ± 0.17/mm(2), P = .046). Overall autonomic nerve density did not differ between atria with persistent AF compared with SR. On a morphological level, we detected a shift toward a lower density of cholinergic nerves and a higher density of nerves containing adrenergic components in AF subjects.

• Fatal prosthetic valve endocarditis of the CoreValve ReValving System.

  Authors: Michael Gotzmann, Andreas Mügge

  Clinical research in cardiology : official journal of the German Cardiac Society. 04/2011; 100(8):715-7.

• Acetylsalicylate reduces endothelial and platelet-derived microparticles in patients with coronary artery disease.

  Authors: Daniel Bulut, Vanessa Becker, Andreas Mügge

  Canadian journal of physiology and pharmacology. 04/2011; 89(4):239-44.

  Previous studies suggest that endothelial progenitor cells (EPCs) contribute to vascular repair processes. In contrast, circulating microparticles (MPs) are reported to be part of a process that isPrevious studies suggest that endothelial progenitor cells (EPCs) contribute to vascular repair processes. In contrast, circulating microparticles (MPs) are reported to be part of a process that is damaging to vascular cells. Numerous studies suggest that the "balance" between EPCs and MPs is important for the integrity of vascular cells and preservation of endothelial function. In the present study, we assess the impact of acetylsalicylate (ASA) - which is, beside statins and physical exercise, a third basic column in the preventive therapy of coronary artery disease (CAD) - on EPCs and MPs in patients with CAD. We investigated the effect of treatment (8 weeks) with ASA (100 mg/d) on endothelial function (flow-mediated vasodilation, FMD), number of circulating EPCs, and endothelial- and platelet-derived microparticles (eMP, pMP) in 15 male patients (age 59.5 ± 12.3 years) with CAD but nonsignificant stenosis. The number of pMPs and eMPs decreased by 62.7% (p < 0.05) and 28.4% (p < 0.05), respectively. The number of circulating EPCs (VEGFR2(+)CD34(+)), expressed as ‰ of circulating polymorphonuclear leukocytes, remained unchanged. Despite the reduced number of pMPs and eMPs in response to the ASA therapy, the FMD responses and the maximal dilator effects of nitroglycerin were unaffected. In a control experiment, patients (n = 6) treated with the selective COX-2 inhibitor etoricoxib (90 mg/day) for 8 weeks showed no changes in the number of pMPs, eMPs, and EPCs and in FMD. We report on a novel effect of ASA treatment on the number of circulating endothelial- and platelet-derived microparticles in patients with cardiovascular disease. The mechanism remains elusive, and appears not to be associated with the COX-2 pathway.

• One-year results of transcatheter aortic valve implantation in severe symptomatic aortic valve stenosis.

  Authors: Michael Gotzmann, Waldemar Bojara, Michael Lindstaedt, Aydan Ewers, Leif Bösche, Alfried Germing, Thomas Lawo, Matthias Bechtel, Axel Laczkovics, Andreas Mügge

  The American journal of cardiology. 03/2011; 107(11):1687-92.

  Transcatheter aortic valve implantation (TAVI) is an alternative therapy for symptomatic severe aortic valve stenosis in high-risk patients with several co-morbidities. We evaluated the 1-yearTranscatheter aortic valve implantation (TAVI) is an alternative therapy for symptomatic severe aortic valve stenosis in high-risk patients with several co-morbidities. We evaluated the 1-year effects of TAVI on quality of life, exercise capacity, neurohormonal activation, and myocardial hypertrophy. From June 2008 to October 2009, consecutive patients aged ≥75 years with symptomatic severe aortic valve stenosis (area <1 cm(2)) and a logistic euroSCORE ≥15% or aged >60 years with additional specified risk factors underwent TAVI. An aortic valve prosthesis (CoreValve) was inserted in a retrograde fashion. Examinations were performed before and 30 days and 1 year after TAVI. An assessment of the quality of life (Minnesota Living with Heart Failure Questionnaire), a 6-minute walking test, measurement of B-type natriuretic peptide, and echocardiography were performed. In 51 patients (mean age 78 ± 6.6 years, mean left ventricular ejection fraction 58.4 ± 12.2%), the follow-up examinations were performed after TAVI. The 1-year follow-up visit after TAVI revealed significantly improved quality of life (baseline Minnesota Living with Heart Failure Questionnaire score 39.6 ± 19 vs 26.1 ± 18, p <0.001) and more distance covered in the 6-minute walking test (baseline 185 ± 106 vs 266 ± 118 m, p <0.001). The B-type natriuretic peptide level had decreased (baseline 642 ± 634 vs 323 ± 266 pg/ml, p <0.001), and the left ventricular mass index had decreased (156 ± 45 vs 130 ± 42 g/m(2), p <0.001). The left ventricular diameter and ejection fraction remained unchanged. In conclusion, TAVI leads to significantly reduced neurohormonal activation, regression of myocardial hypertrophy, and lasting enhancement of quality of life and exercise capacity in patients with symptomatic and severe aortic stenosis 1 year after intervention.

• Apoptosis in esophagus and pancreas carcinoma cells induced by circulating microparticles is related to phosphatidyl serine and microparticle-associated caspases.

  Authors: Jan Schneider, Ansgar M Chromik, Waldemar Uhl, Andreas Mügge, Daniel Bulut

  Medical oncology (Northwood, London, England). 03/2011;

  Circulating microparticles (MPs) are recently discussed as "biologically active", participating in the pathology of diseases rather than being a marker of damaging processes. It was the purpose ofCirculating microparticles (MPs) are recently discussed as "biologically active", participating in the pathology of diseases rather than being a marker of damaging processes. It was the purpose of the present study to investigate the effects of MPs, as isolated from the blood of healthy volunteers, on the induction of apoptosis and necrosis in cultured KYSE-270 esophageal and ASPC1 pancreas carcinoma cells. MPs were obtained from the blood of 20 healthy volunteers (11 women; mean age 33.3 years). Viability, apoptosis, and necrosis were determined by flow cytometry using Annexin V/propidium iodide and tetramethylrhodamine ethyl ester perchlorate (TMRE)/propidium iodide for staining. Incubation of KYSE and ASPC1 carcinoma cells with MPs (1-20.000/μl) for 48 h reduced significantly viability of the cells, and induced apoptosis, but not necrosis. This apoptotic effect was significant at a concentration of ≥1.000 MPs/μl in both cell types. Pre-treatment of MPs with either the global caspase inhibitor ZVAD-FMK or Annexin V which blocks phosphatidyl serine in the outer membrane of MPs with high affinity, almost abolished MP-induced apoptosis. A specific enzyme assay as well Western blot analysis confirmed the presence (activity, protein) of the apoptotic enzyme caspase-3 in MPs. Incubation of carcinoma cells with MPs (20.000/μl) resulted in an increase in caspase-3 protein in carcinoma cells; this increase could be prevented by pre-treatment of MPs with Annexin V. It is suggested that MPs induce concentration-dependent apoptosis in KSYE esophageal and ASPC1 pancreas carcinoma cells in vitro by transferring caspases into target cells. This process probably requires a target cell-MP interaction, and membrane-bound anionic phosphatidyl serine may be involved.

• Effects of immunoadsorption on endothelial function, circulating endothelial progenitor cells and circulating microparticles in patients with inflammatory dilated cardiomyopathy.

  Authors: Daniel Bulut, Michael Scheeler, Lisa Marie Niedballa, Thomas Miebach, Andreas Mügge

  Clinical research in cardiology : official journal of the German Cardiac Society. 02/2011; 100(7):603-10.

  Immunoadsorption (IA) is used in patients with chronic inflammatory dilative cardiomyopathy (iDCM) to remove cardiotoxic autoantibodies, and to improve myocardial function. We examined the effects ofImmunoadsorption (IA) is used in patients with chronic inflammatory dilative cardiomyopathy (iDCM) to remove cardiotoxic autoantibodies, and to improve myocardial function. We examined the effects of IA on endothelial function, circulating endothelial progenitor cells, and circulating microparticles, including endothelial-derived microparticles, in patients with chronic iDCM. Thirteen patients (10 males, 3 females, mean age 52.3 years) with advanced congestive heart failure (NYHA III and IV) secondary due to chronic iDCM (with signs of myocardial inflammation in biopsies, but without persistence of virus genome), and reduced left ventricular ejection fraction (EF < 35%) underwent IA. Blood samples were drawn before an IA course of 5 days, and 6 months after IA. Blood levels of endothelial progenitor cells (EPCs as defined as VEGFR2(+)CD34(+) cells), of microparticles (MPs as defined as Annexin V(+) particles with a diameter between 0.1 and 1 μm), and of endothelial-derived MPs (eMPs as defined as CD31(+bright) CD42b(-)/Annexin V(+) particles) were analyzed by flow cytometry. Endothelial function (expressed as reactive hyperemia index (RHI)) and arterial stiffness were assessed by PAT-technology (peripheral arterial tone) using fingertips. Left ventricular systolic function (EF%) improved on average at 6 months from 26.3 ± 4.8 to 37.9 ± 9.6% (mean ± SEM; p < 0.05). The LV end-diastolic diameter reduced after 6 months from 68.4 ± 8.2 to 61.6 ± 7.9 mm; p < 0.05). Endothelial function improved from 1.53 ± 0.09 to 1.80 ± 0.12 (p < 0.05). The arterial stiffness index remained unchanged. Number of total MPs decreased on average by 36.8% (p < 0.05), the number of eMPs by 39.6% (p < 0.05), respectively. The level of circulating EPC remained unchanged (EPC/PMNC 0.26 ± 0.07 vs. 0.27 ± 0.05 ‰, p = n.s.). IA treatment improves endothelial function in patients with chronic iDCM. This effect is associated with a significant drop in circulating microparticles. The causal relationship between circulating microparticles and endothelial function is discussed.

• BAPA, a synthetic dual inhibitor of Factor Xa and Thrombin, extends the storage-time to a maximum of 12 hours in ADP- and 24 hours in arachidonic acid-induced impedance aggregometry.

  Authors: Andreas F C Kaiser, Heinz G Endres, Andreas Mügge, Horst Neubauer

  Scandinavian journal of clinical and laboratory investigation. 02/2011; 71(3):253-6.

  Impedance aggregometry is mainly limited by the time-dependent instability of platelets in whole blood samples, caused by the influence of ex-vivo anticoagulants. The synthesis of a newImpedance aggregometry is mainly limited by the time-dependent instability of platelets in whole blood samples, caused by the influence of ex-vivo anticoagulants. The synthesis of a new anticoagulant, Benzylsulfonyl-D-Arg-Pro-4-amidinobenzylamide (BAPA), has recently been introduced. Data from recent studies suggest stable results for up to 32 h. In view of this data we were interested in the results of ADP- and arachidonic acid (AA)-induced measurements after a prolonged storage time depending on the use of citrate or BAPA. Blood samples from 24 healthy individuals were anticoagulated with either citrate or BAPA. ADP- and AA-induced measurements were carried out between 2 h and up to 48 h after blood samples were taken. Results of ADP-induced measurements remained stable for 8 h in citrated and for a maximum of 12 h in BAPA-anticoagulated samples. AA-induced measurements yielded stable results up to 12 h in citrated and up to 24 h in BAPA anticoagulated blood. These data demonstrate that the storage time for whole blood impedance aggregometry can be prolonged when BAPA is used as an anticoagulant. However, in contrast to previous studies implicating considerably longer potential storage times we could not see a clear overall purpose in using BAPA. Further studies including blood samples of patients and the comparison of BAPA to other anticoagulants are necessary to define the potential role of BAPA anticoagulated samples.

• Tailored antiplatelet therapy can overcome clopidogrel and aspirin resistance - The BOchum CLopidogrel and Aspirin Plan (BOCLA-Plan) to improve antiplatelet therapy

  Authors: Horst Neubauer, Andreas Kaiser, Heinz Endres, Jan Krüger, Andreas Engelhardt, Sebastian Lask, Fenena Pepinghege, Andreas Kusber, Andreas Mügge

  BMC Medicine. 01/2011;

  Abstract Background Dual antiplatelet therapy using acetylsalicylic acid (ASA, aspirin) and clopidogrel is of great importance following coronary stenting. However, the variable platelet inhibitoryAbstract Background Dual antiplatelet therapy using acetylsalicylic acid (ASA, aspirin) and clopidogrel is of great importance following coronary stenting. However, the variable platelet inhibitory effectiveness compromises the antithrombotic advantages provided by dual antiplatelet therapy. The aim of this single-center prospective study was to reduce the low response incidence of dual antiplatelet therapy with ASA and clopidogrel according to a prespecified therapy algorithm. Methods Platelet function testing using whole blood aggregometry (Chronolog 590) was performed 48 hours following coronary stenting (for either acute coronary syndromes or stable coronary artery disease) on 504 patients. The antiplatelet therapy included a loading dose of 600 mg clopidogrel and 500 mg ASA, followed by 75 mg clopidogrel and 100 mg ASA once daily. Clopidogrel low responders (CLR: >5 ohm; adenosine diphosphate (ADP) 5 μM) and/or ASA low responders (ALR: >0 ohm; arachidonic acid 10 μM) were treated according to a structured therapy plan: in the case of CLR, the maintenance + dose was doubled (repeated loading dose followed by 150 mg daily), and when still ineffective ticlopidine or prasugrel, if available and not contraindicated, were used. ALR was treated by increasing the dose to 300 mg in a first step or to 500 mg ASA when the first modification did not take effect sufficiently. In addition, ADP receptor antagonist 2-methylthioadenosine 5&apos;-monophosphate triethylammonium salt (MeSAMP) testing and ASA incubation were performed to rule out either a platelet ADP-receptor defect or an ASA pharmacokinetic resistance. Results Of the total cohort of 504 patients, we detected 30.8% clopidogrel low-responders and 19.4% aspirin low-responders. For ALR, with a dose adjustment of 300 mg ASA daily, 94.6% of ALR were effectively treated and the residual 5.4% by administration of daily dosages of 500 mg ASA. This means that after modification of the ASA maintenance dose, all initial ALRs had an adequate antiplatelet response. The results for clopidogrel revealed that 69% of the CLR were treated effectively by increasing the clopidogrel dose to 150 mg daily. When prasugrel was not available or contraindicated, 12.7% of the remaining low responders showed an adequate result after being switched to ticlopidine. Consequently, by applying the therapy algorithm, we were able to reduce the CLR prevalence by 86.6%. On including prasugrel in the therapy plan, we were finally able to eliminate thienopyridine low response. In addition, no ADP receptor defect was found in this study as a potential reason for CLR. We identified the following factors associated with both CLR and ALR status: acute coronary syndromes, positive troponin values as well as diabetes mellitus and elevated HbA1C values and a higher platelet count. Furthermore, our data revealed for CLR elevated C-reactive protein values and a high PREDICT-score (including an age >65 years, acute coronary syndrome, diabetes mellitus, renal failure, and reduced left ventricular function) as risk factors. The following factors correlated with the risk of ASA low response: patients with elevated hemoglobin, serum creatinine and C-reactive protein values. In addition, medication with nitrates reduced the risk of being CLR. As also holds true for CLR, we found the PREDICT-score to be correlated to the risk of being ALR. However, by far the strongest risk factor for CLR or ALR was the fact of dual resistance. Conclusion Following a structured therapy plan based on a "test and treat" strategy, the prevalence of clopidogrel or aspirin low response can be significantly reduced and the risk of inadequate dual antiplatelet therapy minimized. Trial Registration NCT01212302 (Clinicaltrials.gov)

• Diastolic dysfunction without abnormalities in left atrial and left ventricular geometry does not affect quality of life in elderly women.

  Authors: Alfried Germing, Michael Gotzmann, Tamara Schikowski, Andrea Vierkötter, Ulrich Ranft, Andreas Mügge

  Experimental and clinical cardiology. 01/2011; 16(2):37-9.

  Advanced age and female sex are associated with increased myocardial stiffness, even in the absence of cardiovascular disease. Left ventricular (LV) hypertrophy and left atrial (LA) enlargement areAdvanced age and female sex are associated with increased myocardial stiffness, even in the absence of cardiovascular disease. Left ventricular (LV) hypertrophy and left atrial (LA) enlargement are typical findings in patients with LV diastolic dysfunction (DD). Because DD has been described in asymptomatic subjects, its clinical impact remains controversial. It has previously been hypothesized that mild DD has no clinical impact when natriuretic peptide levels are normal. The present study aimed to determine the impact of LA volume and LV mass on DD in elderly women. A cross-sectional survey was used to investigate a cohort of 311 randomly selected, nonhospitalized elderly women (mean [± SD] age 74.3±2.9 years). Examination comprised quality of life, measurement of brain natriuretic peptide (BNP) levels and echocardiography. The prevalences of different degrees of DD were as follows: mild 47.9% (n=149), moderate 36.7% (n=114) and severe 4.8% (n=15). Compared with normal diastolic function, moderate and severe DD were associated with higher BNP levels (P=0.038 and P<0.001, respectively) and elevated indexes of LA volume (LAVI) (P=0.007 and P<0.001, respectively) and LV mass (LVMI) (P=0.074 and P=0.017, respectively). Participants with normal diastolic function and mild DD had no significant differences in quality of life, BNP levels, LAVI or LVMI. Mild DD is common in elderly women and is not associated with increased BNP levels or poor quality of life. Compared with individuals with moderate and severe DD, LAVI and LVMI are normal in patients with mild DD.