TY - JOUR A1 - Williams, Tatjana A1 - Machann, Wolfram A1 - Kühler, Leif A1 - Hamm, Henning A1 - Müller-Höcker, Josef A1 - Zimmer, Michael A1 - Ertl, Georg A1 - Ritter, Oliver A1 - Beer, Meinrad A1 - Schönberger, Jost T1 - Novel desmoplakin mutation: juvenile biventricular cardiomyopathy with left ventricular non-compaction and acantholytic palmoplantar keratoderma JF - Clinical Research in Cardiology N2 - Two sons of a consanguineous marriage developed biventricular cardiomyopathy. One boy died of severe heart failure at the age of 6 years, the other was transplanted because of severe heart failure at the age of 10 years. In addition, focal palmoplantar keratoderma and woolly hair were apparent in both boys. As similar phenotypes have been described in Naxos disease and Carvajal syndrome, respectively, the genes for plakoglobin (JUP) and desmoplakin (DSP) were screened for mutations using direct genomic sequencing. A novel homozygous 2 bp deletion was identified in an alternatively spliced region of DSP. The deletion 5208_5209delAG led to a frameshift downstream of amino acid 1,736 with a premature truncation of the predominant cardiac isoform DSP-1. This novel homozygous truncating mutation in the isoform-1 specific region of the DSP C-terminus caused Carvajal syndrome comprising severe early-onset heart failure with features of non-compaction cardiomyopathy, woolly hair and an acantholytic form of palmoplantar keratoderma in our patient. Congenital hair abnormality and manifestation of the cutaneous phenotype in toddler age can help to identify children at risk for cardiac death. KW - Desmoplakin KW - Juvenile biventricular cardiomyopathy KW - Palmoplantar keratoderma Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-141198 VL - 100 IS - 12 ER - TY - JOUR A1 - Güder, Gülmisal A1 - Brenner, Susanne A1 - Angermann, Christiane E. A1 - Ertl, Georg A1 - Held, Matthias A1 - Sachs, Alfred P. A1 - Lammers, Jan Willem A1 - Zanen, Peter A1 - Hoes, Arno W. A1 - Störk, Stefan A1 - Rutten, Frans H. T1 - "GOLD or lower limit of normal definition? a comparison with expert-based diagnosis of chronic obstructive pulmonary disease in a prospective cohort-study" N2 - Background: The Global initiative for chronic Obstructive Lung Disease (GOLD) defines COPD as a fixed postbronchodilator ratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC) below 0.7. Agedependent cut-off values below the lower fifth percentile (LLN) of this ratio derived from the general population have been proposed as an alternative. We wanted to assess the diagnostic accuracy and prognostic capability of the GOLD and LLN definition when compared to an expert-based diagnosis. Methods: In a prospective cohort study, 405 patients aged ≥ 65 years with a general practitioner’s diagnosis of COPD were recruited and followed up for 4.5 (median; quartiles 3.9; 5.1) years. Prevalence rates of COPD according to GOLD and three LLN definitions and diagnostic performance measurements were calculated. The reference standard was the diagnosis of COPD of an expert panel that used all available diagnostic information, including spirometry and bodyplethysmography. Results: Compared to the expert panel diagnosis, ‘GOLD-COPD’ misclassified 69 (28%) patients, and the three LLNs misclassified 114 (46%), 96 (39%), and 98 (40%) patients, respectively. The GOLD classification led to more false positives, the LLNs to more false negative diagnoses. The main predictors beyond the FEV1/FVC ratio for an expert diagnosis of COPD were the FEV1 % predicted, and the residual volume/total lung capacity ratio (RV/TLC). Adding FEV1 and RV/TLC to GOLD or LLN improved the diagnostic accuracy, resulting in a significant reduction of up to 50% of the number of misdiagnoses. The expert diagnosis of COPD better predicts exacerbations, hospitalizations and mortality than GOLD or LLN. Conclusions: GOLD criteria over-diagnose COPD, while LLN definitions under-diagnose COPD in elderly patients as compared to an expert panel diagnosis. Incorporating FEV1 and RV/TLC into the GOLD-COPD or LLN-based definition brings both definitions closer to expert panel diagnosis of COPD, and to daily clinical practice. KW - Medizin KW - COPD diagnosis KW - lower limit of normal KW - GOLD KW - validation Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75193 ER - TY - JOUR A1 - Ponnuswamy, Padmapriya A1 - Schröttle, Angelika A1 - Ostermeier, Eva A1 - Grüner, Sabine A1 - Huang, Paul L. A1 - Ertl, Georg A1 - Hoffmann, Ulrich A1 - Nieswandt, Bernhard A1 - Kuhlencordt, Peter J. T1 - eNOS Protects from Atherosclerosis Despite Relevant Superoxide Production by the Enzyme in apoE\(^{-/-}\) Mice JF - PLoS One N2 - Background: All three nitric oxide synthase (NOS) isoforms are expressed in atherosclerotic plaques. NOS enzymes in general catalyse NO production. However, under conditions of substrate and cofactor deficiency, the enzyme directly catalyse superoxide formation. Considering this alternative chemistry, the effects of NOS on key events in spontaneous hyperlipidemia driven atherosclerosis have not been investigated yet. Here, we evaluate how endothelial nitric oxide synthase (eNOS) modulates leukocyte/endothelial-(L/E) and platelet/endothelial-(P/E) interactions in atherosclerosis and the production of nitric oxide (NO) and superoxide by the enzyme. Principal Findings: Intravital microscopy (IVM) of carotid arteries revealed significantly increased L/E-interactions in apolipoproteinE/eNOS double knockout mice (apoE\(^{-/-}\)/eNOS\(^{-/-}\)), while P/E-interactions did not differ, compared to apoE\(^{-/-}\). eNOS deficiency increased macrophage infiltration in carotid arteries and vascular cell adhesion molecule-1 (VCAM-1) expression, both in endothelial and smooth muscle cells. Despite the expression of other NOS isoforms (inducible NOS, iNOS and neuronal NOS, nNOS) in plaques, Electron Spin Resonance (ESR) measurements of NO showed significant contribution of eNOS to total circulating and vascular wall NO production. Pharmacological inhibition and genetic deletion of eNOS reduced vascular superoxide production, indicating uncoupling of the enzyme in apoE\(^{-/-}\) vessels. Conclusion: Overt plaque formation, increased vascular inflammation and L/E-interactions are associated with significant reduction of superoxide production in apoE\(^{-/-}\)/eNOS\(^{-/-}\) vessels. Therefore, lack of eNOS does not cause an automatic increase in oxidative stress. Uncoupling of eNOS occurs in apoE\(^{-/-}\) atherosclerosis but does not negate the enzyme's strong protective effects. KW - platelet adhesion KW - lesion formation KW - nitric oxide synthase KW - endothelial cell interactions KW - double knockout mice KW - apolipoprotein E KW - deficient mice KW - in vivo KW - accelerated atherosclerosis KW - leukocyte adhesion Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134866 VL - 7 IS - 1 ER - TY - JOUR A1 - Blömer, Nadja A1 - Pachel, Christina A1 - Hofmann, Urlich A1 - Nordbeck, Peter A1 - Bauer, Wolfgang A1 - Mathes, Denise A1 - Frey, Anna A1 - Bayer, Barbara A1 - Vogel, Benjamin A1 - Ertl, Georg T1 - 5-Lipoxygenase facilitates healing after myocardial infarction JF - Basic Research in Cardiology N2 - Early healing after myocardial infarction (MI) is characterized by a strong inflammatory reaction. Most leukotrienes are pro-inflammatory and are therefore potential mediators of healing and remodeling after myocardial ischemia. The enzyme 5-lipoxygenase (5-LOX) has a key role in the transformation of arachidonic acid in leukotrienes. Thus, we tested the effect of 5-LOX on healing after MI. After chronic coronary artery ligation, early mortality was significantly increased in 5-LOX\(^{−/−}\) when compared to matching wildtype (WT) mice due to left ventricular rupture. This effect could be reproduced in mice treated with the 5-LOX inhibitor Zileuton. A perfusion mismatch due to the vasoactive potential of leukotrienes is not responsible for left ventricular rupture since local blood flow assessed by magnetic resonance perfusion measurements was not different. However, after MI, there was an accentuation of the inflammatory reaction with an increase of pro-inflammatory macrophages. Yet, mortality was not changed in chimeric mice (WT vs. 5-LOX\(^{−/−}\) bone marrow in 5-LOX\(^{−/−}\) animals), indicating that an altered function of 5-LOX\(^{−/−}\) inflammatory cells is not responsible for the phenotype. Collagen production and accumulation of fibroblasts were significantly reduced in 5-LOX\(^{−/−}\) mice in vivo after MI. This might be due to an impaired migration of 5-LOX\(^{−/−}\) fibroblasts, as shown in vitro to serum. In conclusion, a lack or inhibition of 5-LOX increases mortality after MI because of healing defects. This is not mediated by a change in local blood flow, but through an altered inflammation and/or fibroblast function. KW - lipoxygenase KW - myocardial infarction KW - extracellular matrix remodeling KW - inflammation Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132602 VL - 108 IS - 4 ER - TY - JOUR A1 - Liu, Dan A1 - Hu, Kai A1 - Niemann, Markus A1 - Herrmann, Sebastian A1 - Cikes, Maja A1 - Störk, Stefan A1 - Beer, Meinrad A1 - Gaudron, Philipp Daniel A1 - Morbach, Caroline A1 - Knop, Stefan A1 - Geissinger, Eva A1 - Ertl, Georg A1 - Bijnens, Bart A1 - Weidemann, Frank T1 - Impact of Regional Left Ventricular Function on Outcome for Patients with AL Amyloidosis JF - PLoS ONE N2 - Objectives The aim of this study was to explore the left ventricular (LV) deformation changes and the potential impact of deformation on outcome in patients with proven light-chain (AL) amyloidosis and LV hypertrophy. Background Cardiac involvement in AL amyloidosis patients is associated with poor outcome. Detecting regional cardiac function by advanced non-invasive techniques might be favorable for predicting outcome. Methods LV longitudinal, circumferential and radial peak systolic strains (Ssys) were assessed by speckle tracking imaging (STI) in 44 biopsy-proven systemic AL amyloidosis patients with LV hypertrophy (CA) and in 30 normal controls. Patients were divided into compensated (n = 18) and decompensated (n = 26) group based on clinical assessment and followed-up for a median period of 345 days. Results Ejection fraction (EF) was preserved while longitudinal Ssys (LSsys) was significantly reduced in both compensated and decompensated groups. Survival was significantly reduced in decompensated group (35% vs. compensated 78%, P = 0.001). LSsys were similar in apical segments and significantly reduced in basal segments between two patient groups. LSsys at mid-segments were significantly reduced in all LV walls of decompensated group. Patients were further divided into 4 subgroups according to the presence or absence of reduced LSsys in no (normal), only basal (mild), basal and mid (intermediate) and all segments of the septum (severe). This staging revealed continuously worse prognosis in proportion to increasing number of segments with reduced LSsys (mortality: normal 14%, mild 27%, intermediate 67%, and severe 64%). Mid-septum LSsys<11% suggested a 4.8-fold mortality risk than mid-septum LSsys≥11%. Multivariate regression analysis showed NYHA class and mid-septum LSsys were independent predictors for survival. Conclusions Reduced deformation at mid-septum is associated with worse prognosis in systemic amyloidosis patients with LV hypertrophy. KW - regression analysis KW - ejection fraction KW - echocardiography KW - cardiac transplantation KW - deformation KW - amyloidosis KW - prognosis KW - stem cell transplantation Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130293 VL - 8 IS - 3 ER - TY - JOUR A1 - Pachel, Christina A1 - Mathes, Denise A1 - Bayer, Barbara A1 - Dienesch, Charlotte A1 - Wangorsch, Gaby A1 - Heitzmann, Wolfram A1 - Lang, Isabell A1 - Ardehali, Hossein A1 - Ertl, Georg A1 - Dandekar, Thomas A1 - Wajant, Harald A1 - Frantz, Stefan T1 - Exogenous Administration of a Recombinant Variant of TWEAK Impairs Healing after Myocardial Infarction by Aggravation of Inflammation JF - PLoS ONE N2 - Background: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factorinducible 14 (Fn14) are upregulated after myocardial infarction (MI) in both humans and mice. They modulate inflammation and the extracellular matrix, and could therefore be important for healing and remodeling after MI. However, the function of TWEAK after MI remains poorly defined. Methods and results: Following ligation of the left coronary artery, mice were injected twice per week with a recombinant human serum albumin conjugated variant of TWEAK (HSA-Flag-TWEAK), mimicking the activity of soluble TWEAK. Treatment with HSA-Flag-TWEAK resulted in significantly increased mortality in comparison to the placebo group due to myocardial rupture. Infarct size, extracellular matrix remodeling, and apoptosis rates were not different after MI. However, HSA-Flag-TWEAK treatment increased infiltration of proinflammatory cells into the myocardium. Accordingly, depletion of neutrophils prevented cardiac ruptures without modulating all-cause mortality. Conclusion: Treatment of mice with HSA-Flag-TWEAK induces myocardial healing defects after experimental MI. This is mediated by an exaggerated neutrophil infiltration into the myocardium. KW - apoptosis KW - myocardial infarction KW - neutrophils KW - cytokines KW - inflammation KW - myocardium KW - heart KW - extracellular matrix Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129889 VL - 8 IS - 11 ER - TY - JOUR A1 - Nordbeck, Peter A1 - Bönhof, Leoni A1 - Hiller, Karl-Heinz A1 - Voll, Sabine A1 - Arias-Loza, Paula A1 - Seidlmaier, Lea A1 - Williams, Tatjana A1 - Ye, Yu-Xiang A1 - Gensler, Daniel A1 - Pelzer, Theo A1 - Ertl, Georg A1 - Jakob, Peter M. A1 - Bauer, Wolfgang R. A1 - Ritter, Oliver T1 - Impact of Thoracic Surgery on Cardiac Morphology and Function in Small Animal Models of Heart Disease: A Cardiac MRI Study in Rats JF - PLoS ONE N2 - Background Surgical procedures in small animal models of heart disease might evoke alterations in cardiac morphology and function. The aim of this study was to reveal and quantify such potential artificial early or long term effects in vivo, which might account for a significant bias in basic cardiovascular research, and, therefore, could potentially question the meaning of respective studies. Methods Female Wistar rats (n = 6 per group) were matched for weight and assorted for sham left coronary artery ligation or control. Cardiac morphology and function was then investigated in vivo by cine magnetic resonance imaging at 7 Tesla 1 and 8 weeks after the surgical procedure. The time course of metabolic and inflammatory blood parameters was determined in addition. Results Compared to healthy controls, rats after sham surgery showed a lower body weight both 1 week (267.5±10.6 vs. 317.0±11.3 g, n<0.05) and 8 weeks (317.0±21.1 vs. 358.7±22.4 g, n<0.05) after the intervention. Left and right ventricular morphology and function were not different in absolute measures in both groups 1 week after surgery. However, there was a confined difference in several cardiac parameters normalized to the body weight (bw), such as myocardial mass (2.19±0.30/0.83±0.13 vs. 1.85±0.22/0.70±0.07 mg left/right per g bw, p<0.05), or enddiastolic ventricular volume (1.31±0.36/1.21±0.31 vs. 1.14±0.20/1.07±0.17 µl left/right per g bw, p<0.05). Vice versa, after 8 weeks, cardiac masses, volumes, and output showed a trend for lower values in sham operated rats compared to controls in absolute measures (782.2±57.2/260.2±33.2 vs. 805.9±84.8/310.4±48.5 mg, p<0.05 for left/right ventricular mass), but not normalized to body weight. Matching these findings, blood testing revealed only minor inflammatory but prolonged metabolic changes after surgery not related to cardiac disease. Conclusion Cardio-thoracic surgical procedures in experimental myocardial infarction cause distinct alterations upon the global integrity of the organism, which in the long term also induce circumscribed repercussions on cardiac morphology and function. This impact has to be considered when analyzing data from respective animal studies and transferring these findings to conditions in patients. KW - heart rate KW - body weight KW - surgical and invasive medical procedures KW - magnetic resonance imaging KW - blood KW - vascular surgery KW - myocardial infarction KW - cardiac ventricles Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130064 VL - 8 IS - 8 ER - TY - JOUR A1 - Frey, Anna A1 - Popp, Sandy A1 - Post, Antonia A1 - Langer, Simon A1 - Lehmann, Marc A1 - Hofmann, Ulrich A1 - Siren, Anna-Leena A1 - Hommers, Leif A1 - Schmitt, Angelika A1 - Strekalova, Tatyana A1 - Ertl, Georg A1 - Lesch, Klaus-Peter A1 - Frantz, Stefan T1 - Experimental heart failure causes depression-like behavior together with differential regulation of inflammatory and structural genes in the brain JF - Frontiers in Behavioral Neuroscience N2 - Background: Depression and anxiety are common and independent outcome predictors in patients with chronic heart failure (CHF). However, it is unclear whether CHF causes depression. Thus, we investigated whether mice develop anxiety- and depression-like behavior after induction of ischemic CHF by myocardial infarction (MI). Methods and Results: In order to assess depression-like behavior, anhedonia was investigated by repeatedly testing sucrose preference for 8 weeks after coronary artery ligation or sham operation. Mice with large MI and increased left ventricular dimensions on echocardiography (termed CHF mice) showed reduced preference for sucrose, indicating depression-like behavior. 6 weeks after MI, mice were tested for exploratory activity, anxiety-like behavior and cognitive function using the elevated plus maze (EPM), light-dark box (LDB), open field (OF), and object recognition (OR) tests. In the EPM and OF, CHF mice exhibited diminished exploratory behavior and motivation despite similar movement capability. In the OR, CHF mice had reduced preference for novelty and impaired short-term memory. On histology, CHF mice had unaltered overall cerebral morphology. However, analysis of gene expression by RNA-sequencing in prefrontal cortical, hippocampal, and left ventricular tissue revealed changes in genes related to inflammation and cofactors of neuronal signal transduction in CHF mice, with Nr4a1 being dysregulated both in prefrontal cortex and myocardium after MI. Conclusions: After induction of ischemic CHF, mice exhibited anhedonic behavior, decreased exploratory activity and interest in novelty, and cognitive impairment. Thus, ischemic CHF leads to distinct behavioral changes in mice analogous to symptoms observed in humans with CHF and comorbid depression. KW - chronic heart failure KW - myocardial infarction KW - anxiety KW - depression KW - mice Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-118234 SN - 1662-5153 VL - 8 ER - TY - JOUR A1 - Liu, Dan A1 - Hu, Kai A1 - Störk, Stefan A1 - Herrmann, Sebastian A1 - Kramer, Bastian A1 - Cikes, Maja A1 - Gaudron, Philipp Daniel A1 - Knop, Stefan A1 - Ertl, Georg A1 - Bijnens, Bart A1 - Weidemann, Frank T1 - Predictive Value of Assessing Diastolic Strain Rate on Survival in Cardiac Amyloidosis Patients with Preserved Ejection Fraction JF - PLOS ONE N2 - Objectives: Since diastolic abnormalities are typical findings of cardiac amyloidosis (CA), we hypothesized that speckle-tracking-imaging (STI) derived longitudinal early diastolic strain rate (LSRdias) could predict outcome in CA patients with preserved left ventricular ejection fraction (LVEF >50%). Background: Diastolic abnormalities including altered early filling are typical findings and are related to outcome in CA patients. Reduced longitudinal systolic strain (LSsys) assessed by STI predicts increased mortality in CA patients. It remains unknown if LSRdias also related to outcome in these patients. Methods: Conventional echocardiography and STI were performed in 41 CA patients with preserved LVEF (25 male; mean age 65±9 years). Global and segmental LSsys and LSRdias were obtained in six LV segments from apical 4-chamber views. Results: Nineteen (46%) out of 41 CA patients died during a median of 16 months (quartiles 5–35 months) follow-up. Baseline mitral annular plane systolic excursion (MAPSE, 6±2 vs. 8±3 mm), global LSRdias and basal-septal LSRdias were significantly lower in non-survivors than in survivors (all p<0.05). NYHA class, number of non-cardiac organs involved, MAPSE, mid-septal LSsys, global LSRdias, basal-septal LSRdias and E/LSRdias were the univariable predictors of all-cause death. Multivariable analysis showed that number of non-cardiac organs involved (hazard ratio [HR] = 1.96, 95% confidence interval [CI] 1.17–3.26, P = 0.010), global LSRdias (HR = 7.30, 95% CI 2.08–25.65, P = 0.002), and E/LSRdias (HR = 2.98, 95% CI 1.54–5.79, P = 0.001) remained independently predictive of increased mortality risk. The prognostic performance of global LSRdias was optimal at a cutoff value of 0.85 S−1 (sensitivity 68%, specificity 67%). Global LSRdias <0.85 S−1 predicted a 4-fold increased mortality in CA patients with preserved LVEF. Conclusions: STI-derived early diastolic strain rate is a powerful independent predictor of survival in CA patients with preserved LVEF. KW - diagnostic medicine KW - echocardiography KW - prognosis KW - calcium imaging KW - ejection fraction KW - death rates KW - amyloidosis KW - deformation Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-118024 SN - 1932-6203 VL - 9 IS - 12 ER - TY - JOUR A1 - Boivin, Valérie A1 - Beyersdorf, Niklas A1 - Palm, Dieter A1 - Nikolaev, Viacheslav O. A1 - Schlipp, Angela A1 - Müller, Justus A1 - Schmidt, Doris A1 - Kocoski, Vladimir A1 - Kerkau, Thomas A1 - Hünig, Thomas A1 - Ertl, Georg A1 - Lohse, Martin J. A1 - Jahns, Roland T1 - Novel Receptor-Derived Cyclopeptides to Treat Heart Failure Caused by \(Anti-β_1-Adrenoceptor\) Antibodies in a Human-Analogous Rat Model JF - PLoS One N2 - Despite recent therapeutic advances the prognosis of heart failure remains poor. Recent research suggests that heart failure is a heterogeneous syndrome and that many patients have stimulating auto-antibodies directed against the second extracellular loop of the \(β_1\) adrenergic receptor \((β_1EC2)\). In a human-analogous rat model such antibodies cause myocyte damage and heart failure. Here we used this model to test a novel antibody-directed strategy aiming to prevent and/or treat antibody-induced cardiomyopathy. To generate heart failure, we immunised n = 76/114 rats with a fusion protein containing the human β1EC2 (amino-acids 195–225) every 4 weeks; n = 38/114 rats were control-injected with 0.9% NaCl. Intravenous application of a novel cyclic peptide mimicking \(β_1EC2\) (\(β_1EC2-CP\), 1.0 mg/kg every 4 weeks) or administration of the \(β_1-blocker\) bisoprolol (15 mg/kg/day orally) was initiated either 6 weeks (cardiac function still normal, prevention-study, n = 24 (16 treated vs. 8 untreated)) or 8.5 months after the 1st immunisation (onset of cardiomyopathy, therapy-study, n = 52 (40 treated vs. 12 untreated)); n = 8/52 rats from the therapy-study received \(β_1EC2-CP/bisoprolol\) co-treatment. We found that \(β_1EC2-CP\) prevented and (alone or as add-on drug) treated antibody-induced cardiac damage in the rat, and that its efficacy was superior to mono-treatment with bisoprolol, a standard drug in heart failure. While bisoprolol mono-therapy was able to stop disease-progression, \(β_1EC2-CP\) mono-therapy -or as an add-on to bisoprolol- almost fully reversed antibody-induced cardiac damage. The cyclo¬peptide acted both by scavenging free \(anti-β_1EC2-antibodies\) and by targeting \(β_1EC2\)-specific memory B-cells involved in antibody-production. Our model provides the basis for the clinical translation of a novel double-acting therapeutic strategy that scavenges harmful \(anti-β_1EC2-antibodies\) and also selectively depletes memory B-cells involved in the production of such antibodies. Treatment with immuno-modulating cyclopeptides alone or as an add-on to \(β_1\)-blockade represents a promising new therapeutic option in immune-mediated heart failure. KW - memory B cells KW - antibodies KW - T cells KW - B cells KW - heart KW - heart failure KW - kidneys KW - enzyme-linked immunoassays Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126028 VL - 10 IS - 2 ER - TY - JOUR A1 - Sherif, Mohammad A. A1 - Ince, Hüseyin A1 - Maniuc, Octavian A1 - Reiter, Therese A1 - Voelker, Wolfram A1 - Ertl, Georg A1 - Öner, Alper T1 - Two-dimensional transesophageal echocardiography for aortic annular sizing in patients undergoing transcatheter aortic valve implantation JF - BMC Cardiovascular Disorders N2 - Background: Accurate preoperative assessment of the aortic annulus dimension is crucial for successful transcatheter aortic valve implantation (TAVI). In this study we examined the accuracy of a novel method using two-dimensional transesophageal echocardiography (2D-TEE) for measurement of the aortic annulus. Methods: We evaluated the theoretical impact of the measurement of the annulus diameter and area using the circumcircle of a triangle method on the decision to perform the procedure and choice of the prosthesis size. Results: Sixty-three consecutive patients were scheduled for TAVI. Mean age was 82 +/- 4 years, and 25 patients (55.6 %) were female. Mean aortic annulus diameter was 20.3 +/- 2.2 mm assessed by TEE on the mid-esophageal long-axis view and 23.9 +/- 2.3 mm using CT (p < 0.001). There was a tendency for the TEE derived areas using the new method to be higher (p < 0.001). The TEE measurements were on average 42.33 mm(2) higher than the CT measurements without an evidence of a systematic over-or under-sizing (p = 1.00). Agreement between TEE and CT chosen valve sizes was good overall (kappa = 0.67 and weighted kappa = 0.71). For patients who turned out to have no AR, the two methods agreed in 84.6 % of patients. Conclusions: CT remanis the gold standard in sizing of the aortic valve annulus. Nevertheless, sizing of the aortic valve annulus using TEE derived area may be helpful. The impact of integration of this method in the algorithm of aortic annulus sizing on the outcome of patients undergoing TAVI should be examined in future studies. KW - multicenter KW - TAVI KW - impact KW - complex KW - anatomy KW - dimensions KW - regurgitation KW - root KW - sizing KW - echocardiography KW - multidetector computed-tomography KW - replacement KW - outcomes Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-136002 VL - 15 IS - 181 ER - TY - JOUR A1 - Sherif, Mohammad A. A1 - Herold, Joerg A1 - Voelker, Wolfram A1 - Maniuc, Octavian A1 - Ertl, Georg A1 - Praast, Christian A1 - Braun-Dullaeus, Ruediger Christian T1 - Feasibility of a new method using two-dimensional transesophageal echocardiography for aortic annular sizing in patients undergoing transcatheter aortic valve implantation; a case-control study JF - BMC Cardiovascular Disorders N2 - Background: Accurate preoperative assessment of the aortic annulus dimension is crucial for successful transcatheter aortic valve implantation (TAVI). In this study we validated a new method using two-dimensional transesophageal echocardiography (2D-TEE) for measurement of the aortic annulus prior to TAVI. Methods: We analysed 124 patients who underwent successful TAVI using a self-expandable prosthesis, divided equally into two groups; in the study group we used the cross sectional short axis 2D-TEE for measurement of the aortic annulus and in the control group we used the long axis 2D-TEE. Results: Both groups were comparable regarding the clinical parameters. On the other hand, patients in the study group had less left ventricular ejection fraction (38.9 % versus 45.6 %, p = 0.01). The aortic valve annulus was, although not statistically significant, smaller in the study group (21.58 versus 23.28 mm, p = 0.25). Post procedural quantification of the aortic regurgitation revealed that only one patient in both groups had severe aortic regurgitation (AR), in this patient the valve was implanted deep. The incidence of significant AR was higher in the control group (29.0 % versus 12.9 %, p = 0.027). Conclusions: Sizing of the aortic valve annulus using cross-sectional 2D-TEE offers a safe and plausible method for patients undergoing TAVI using the self-expandable prosthesis and is significantly superior to using long axis 2D-TEE. KW - paravalvular regurgitation KW - multicenter KW - management KW - sizing KW - echocardiography KW - replacement KW - tomography KW - guidelines KW - outcomes KW - impact KW - recommendations KW - stenosis KW - TAVI Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148328 VL - 15 IS - 78 ER - TY - JOUR A1 - Krämer, Johannes A1 - Bijnens, Bart A1 - Störk, Stefan A1 - Ritter, Christian O. A1 - Liu, Dan A1 - Ertl, Georg A1 - Wanner, Christoph A1 - Weidemann, Frank T1 - Left ventricular geometry and blood pressure as predictors of adverse progression of Fabry cardiomyopathy JF - PLoS ONE N2 - Background In spite of several research studies help to describe the heart in Fabry disease (FD), the cardiomyopathy is not entirely understood. In addition, the impact of blood pressure and alterations in geometry have not been systematically evaluated. Methods In 74 FD patients (mean age 36±12 years; 45 females) the extent of myocardial fibrosis and its progression were quantified using cardiac magnetic-resonance-imaging with late enhancement technique (LE). Results were compared to standard echocardiography complemented by 2D-speckle-tracking, 3D-sphericity-index (SI) and standardized blood pressure measurement. At baseline, no patient received enzyme replacement therapy (ERT). After 51±24 months, a follow-up examination was performed. Results Systolic blood pressure (SBP) was higher in patients with vs. without LE: 123±17 mmHg vs. 115±13 mmHg; P = 0.04. A positive correlation was found between SI and the amount of LE-positive myocardium (r = 0.51; P<0.001) indicating an association of higher SI in more advanced stages of the cardiomyopathy. SI at baseline was positively associated with the increase of LE-positive myocardium during follow-up. The highest SBP (125±19 mmHg) and also the highest SI (0.32±0.05) was found in the subgroup with a rapidly increasing LE (ie, ≥0.2% per year; n = 16; P = 0.04). Multivariate logistic regression analysis including SI, SBP, EF, left ventricular volumes, wall thickness and NT-proBNP adjusted for age and sex showed SI as the most powerful parameter to detect rapid progression of LE (AUC = 0.785; P<0.05). Conclusions LV geometry as assessed by the sphericity index is altered in relation to the stage of the Fabry cardiomyopathy. Although patients with FD are not hypertensive, the SBP has a clear impact on the progression of the cardiomyopathy. KW - cardiovascular magnetic resonance KW - clinical manifestations KW - disease KW - identification KW - fibrosis KW - 2-dimensional speckle tracking KW - myocardial infarction KW - therapy KW - diagnosis KW - impact Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145131 VL - 10 IS - 11 ER - TY - JOUR A1 - Seydelmann, Nora A1 - Liu, Dan A1 - Krämer, Johannes A1 - Drechsler, Christiane A1 - Hu, Kai A1 - Nordbeck, Peter A1 - Schneider, Andreas A1 - Störk, Stefan A1 - Bijnens, Bart A1 - Ertl, Georg A1 - Wanner, Christoph A1 - Weidemann, Frank T1 - High-Sensitivity Troponin: A Clinical Blood Biomarker for Staging Cardiomyopathy in Fabry Disease JF - Journal of the American Heart Association N2 - Background High‐sensitivity troponin (hs‐TNT), a biomarker of myocardial damage, might be useful for assessing fibrosis in Fabry cardiomyopathy. We performed a prospective analysis of hs‐TNT as a biomarker for myocardial changes in Fabry patients and a retrospective longitudinal follow‐up study to assess longitudinal hs‐TNT changes relative to fibrosis and cardiomyopathy progression. Methods and Results For the prospective analysis, hs‐TNT from 75 consecutive patients with genetically confirmed Fabry disease was analyzed relative to typical Fabry‐associated echocardiographic findings and total myocardial fibrosis as measured by late gadolinium enhancement (LE) on magnetic resonance imaging. Longitudinal data (3.9±2.0 years), including hs‐TNT, LE, and echocardiographic findings from 58 Fabry patients, were retrospectively collected. Hs‐TNT level positively correlated with LE (linear correlation coefficient, 0.72; odds ratio, 32.81 [95% CI, 3.56–302.59]; P=0.002); patients with elevated baseline hs‐TNT (>14 ng/L) showed significantly increased LE (median: baseline, 1.9 [1.1–3.3] %; follow‐up, 3.2 [2.3–4.9] %; P<0.001) and slightly elevated hs‐TNT (baseline, 44.7 [30.1–65.3] ng/L; follow‐up, 49.1 [27.6–69.5] ng/L; P=0.116) during follow‐up. Left ventricular wall thickness and EF of patients with elevated hs‐TNT were decreased during follow‐up, indicating potential cardiomyopathy progression. Conclusions hs‐TNT is an accurate, easily accessible clinical blood biomarker for detecting replacement fibrosis in patients with Fabry disease and a qualified predictor of cardiomyopathy progression. Thus, hs‐TNT could be helpful for staging and follow‐up of Fabry patients. KW - biomarker KW - cardiomyopathy KW - fabry disease KW - myocardial fibrosis KW - troponin T Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165682 VL - 5 IS - e002839 ER - TY - JOUR A1 - Liu, Dan A1 - Hu, Kai A1 - Nordbeck, Peter A1 - Ertl, Georg A1 - Störk, Stefan A1 - Weidemann, Frank T1 - Longitudinal strain bull's eye plot patterns in patients with cardiomyopathy and concentric left ventricular hypertrophy JF - European Journal of Medical Research N2 - Despite substantial advances in the imaging techniques and pathophysiological understanding over the last decades, identification of the underlying causes of left ventricular hypertrophy by means of echocardiographic examination remains a challenge in current clinical practice. The longitudinal strain bull’s eye plot derived from 2D speckle tracking imaging offers an intuitive visual overview of the global and regional left ventricular myocardial function in a single diagram. The bull’s eye mapping is clinically feasible and the plot patterns could provide clues to the etiology of cardiomyopathies. The present review summarizes the longitudinal strain, bull’s eye plot features in patients with various cardiomyopathies and concentric left ventricular hypertrophy and the bull’s eye plot features might serve as one of the cardiac workup steps on evaluating patients with left ventricular hypertrophy. KW - speckle tracking imaging KW - bull’s eye plot KW - cardiomyopathy KW - left ventricular hypertrophy Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146373 VL - 21 IS - 21 ER - TY - JOUR A1 - Oder, Daniel A1 - Vergho, Dorothee A1 - Ertl, Georg A1 - Wanner, Christoph A1 - Nordbeck, Peter T1 - Case report of a 45-year old female Fabry disease patient carrying two alpha-galactosidase A gene mutation alleles JF - BMC Medical Genetics N2 - Background X-chromosomal inheritance patterns and generally rare occurrence of Fabry disease (FD) account for mono-mutational hemizygous male and heterozygous female patients. Female mutation carriers are usually clinically much less severely affected, which has been explained by a suggested mosaicism in cell phenotype due to random allele shutdown. However, clinical evidence is scarce and potential additional effects in female gene carriers, which might account for specific clinical characteristics such as less severe chronic kidney disease, are yet unknown. Case presentation This article reports on a 45 year old female patient carrying the two alpha-galactosidase A gene mutations c.416A > G, p.N139S in exon 3 and c.708G > C, p.W236C in exon 5, but still showing only mild organ manifestations. Conclusion This current case highlights the importance of careful clinical characterization in patients with Fabry disease, who may show additional rare constellations and, therefore, are in need of personalized medicine. The impact of potential additional protective effects exceeding the presence of a non-pathogenic GLA allele in female gene carriers requires further investigation. KW - Fabry disease KW - cryptogenic stroke KW - Pain KW - hypertrophic cardiomyopathy KW - chronic kidney disease Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146617 VL - 17 IS - 46 ER - TY - JOUR A1 - Oder, Daniel A1 - Üceyler, Nurcan A1 - Liu, Dan A1 - Hu, Kai A1 - Petritsch, Bernhard A1 - Sommer, Claudia A1 - Ertl, Georg A1 - Wanner, Christoph A1 - Nordbeck, Peter T1 - Organ manifestations and long-term outcome of Fabry disease in patients with the GLA haplotype D313Y JF - BMJ Open N2 - Objectives: The severity of Fabry disease is dependent on the type of mutation in the α-galactosidase A (AgalA) encoding gene (GLA). This study focused on the impact of the GLA haplotype D313Y on long-term organ involvement and function. Setting and participants: In this monocentric study, all participants presenting with the D313Y haplotype between 2001 and 2015 were comprehensively clinically investigated at baseline and during a 4-year follow-up if available. Five females and one male were included. Primary and secondary outcome measures: Cardiac, nephrological, neurological, laboratory and quality of life data. Results: AgalA enzyme activity in leucocytes (0.3±0.9 nmol/min/mg protein (mean±SD)) and serum lyso-Gb3 (0.6±0.3 ng/mL at baseline) were in normal range in all patients. Cardiac morphology and function were normal (left-ventricular (LV) ejection fraction 66±8%; interventricular septum 7.7±1.4 mm; LV posterior wall 7.5±1.4 mm; normalised LV mass in MRI 52±9 g/m2; LV global longitudinal strain −21.6±1.9%) and there were no signs of myocardial fibrosis in cardiac MRI. Cardiospecific biomarkers were also in normal range. Renal function was not impaired (estimated glomerular filtration rate MDRD 103±15 mL/min; serum-creatinine 0.75±0.07 mg/dL; cystatin-c 0.71±0.12 mg/L). One female patient (also carrying a Factor V Leiden mutation) had a transitory ischaemic attack. One patient showed white matter lesions in brain MRI, but none had Fabry-associated pain attacks, pain crises, evoked pain or permanent pain. Health-related quality of life analysis revealed a reduction in individual well-being. At long-term follow-up after 4 years, no significant change was seen in any parameter. Conclusions: The results of the current study suggest that the D313Y genotype does not lead to severe organ manifestations as seen in genotypes known to be causal for classical FD." KW - inherited metabolic disorders KW - Anderson-Fabry Disease KW - D313Y genotype KW - Fabry cardiomyopathy KW - Fabry nephropathy KW - Fabry-associated pain Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161210 VL - 6 ER - TY - JOUR A1 - Gaudron, Philipp Daniel A1 - Liu, Dan A1 - Scholz, Friederike A1 - Hu, Kai A1 - Florescu, Christiane A1 - Herrmann, Sebastian A1 - Bijnens, Bart A1 - Ertl, Georg A1 - Störk, Stefan A1 - Weidemann, Frank T1 - The septal bulge - an early echocardiographic sign in hypertensive heart disease JF - Journal of the American Society of Hypertension N2 - Patients in the early stage of hypertensive heart disease tend to have normal echocardiographic findings. The aim of this study was to investigate whether pathology-specific echocardiographic morphologic and functional parameters can help to detect subclinical hypertensive heart disease. One hundred ten consecutive patients without a history and medication for arterial hypertension (AH) or other cardiac diseases were enrolled. Standard echocardiography and two-dimensional speckle tracking -imaging analysis were performed. Resting blood pressure (BP) measurement, cycle ergometer test (CET), and 24-hour ambulatory BP monitoring (ABPM) were conducted. Patients were referred to "septal bulge (SB)" group (basal-septal wall thickness >= 2 mm thicker than mid-septal wall thickness) or "no-SB" group. Echocardiographic SB was found in 48 (43.6%) of 110 patients. In this SB group, 38 (79.2%) patients showed AH either by CET or ABPM. In contrast, in the no-SB group (n = 62), 59 (95.2%) patients had no positive test for AH by CET or ABPM. When AH was solely defined by resting BP, SB was a reasonable predictive sign for AH (sensitivity 73%, specificity 76%). However, when AH was confirmed by CET or ABPM the echocardiographic SB strongly predicted clinical AH (sensitivity 93%, specificity 86%). In addition, regional myocardial deformation of the basal-septum in SB group was significantly lower than in no-SB group (14 +/- 4% vs. 17 +/- 4%; P < .001). In conclusion, SB is a morphologic echocardiographic sign for early hypertensive heart disease. Sophisticated BP evaluation including resting BP, ABPM, and CET should be performed in all patients with an accidental finding of a SB in echocardiography. KW - Septal bulge KW - hypertension KW - blood pressure monitoring KW - echocardiography KW - heart disease Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191433 VL - 10 IS - 1 ER - TY - JOUR A1 - Rücker, Viktoria A1 - Keil, Ulrich A1 - Fitzgerald, Anthony P A1 - Malzahn, Uwe A1 - Prugger, Christof A1 - Ertl, Georg A1 - Heuschmann, Peter U A1 - Neuhauser, Hannelore T1 - Predicting 10-Year Risk of Fatal Cardiovascular Disease in Germany: An Update Based on the SCORE-Deutschland Risk Charts JF - PLoS ONE N2 - Estimation of absolute risk of cardiovascular disease (CVD), preferably with population-specific risk charts, has become a cornerstone of CVD primary prevention. Regular recalibration of risk charts may be necessary due to decreasing CVD rates and CVD risk factor levels. The SCORE risk charts for fatal CVD risk assessment were first calibrated for Germany with 1998 risk factor level data and 1999 mortality statistics. We present an update of these risk charts based on the SCORE methodology including estimates of relative risks from SCORE, risk factor levels from the German Health Interview and Examination Survey for Adults 2008–11 (DEGS1) and official mortality statistics from 2012. Competing risks methods were applied and estimates were independently validated. Updated risk charts were calculated based on cholesterol, smoking, systolic blood pressure risk factor levels, sex and 5-year age-groups. The absolute 10-year risk estimates of fatal CVD were lower according to the updated risk charts compared to the first calibration for Germany. In a nationwide sample of 3062 adults aged 40–65 years free of major CVD from DEGS1, the mean 10-year risk of fatal CVD estimated by the updated charts was lower by 29% and the estimated proportion of high risk people (10-year risk > = 5%) by 50% compared to the older risk charts. This recalibration shows a need for regular updates of risk charts according to changes in mortality and risk factor levels in order to sustain the identification of people with a high CVD risk. KW - fatal cardiovascular disease KW - SCORE KW - Germany Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166804 VL - 11 IS - 9 ER - TY - JOUR A1 - Weidemann, Frank A1 - Maier, Sebastian K. G. A1 - Störk, Stefan A1 - Brunner, Thomas A1 - Liu, Dan A1 - Hu, Kai A1 - Seydelmann, Nora A1 - Schneider, Andreas A1 - Becher, Jan A1 - Canan-Kühl, Sima A1 - Blaschke, Daniela A1 - Bijnens, Bart A1 - Ertl, Georg A1 - Wanner, Christoph A1 - Nordbeck, Peter T1 - Usefulness of an implantable loop recorder to detect clinically relevant arrhythmias in patients with advanced fabry cardiomyopathy JF - The American Journal of Cardiology N2 - Patients with genetic cardiomyopathy that involves myocardial hypertrophy often develop clinically relevant arrhythmias that increase the risk of sudden death. Consequently, guidelines for medical device therapy were established for hypertrophic cardiomyopathy, but not for conditions with only anecdotal evidence of arrhythmias, like Fabry cardiomyopathy. Patients with Fabry cardiomyopathy progressively develop myocardial fibrosis, and sudden cardiac death occurs regularly. Because 24-hour Holier electrocardiograms (ECGs) might not detect clinically important arrhythmias, we tested an implanted loop recorder for continuous heart rhythm surveillance and determined its impact on therapy. This prospective study included 16 patients (12 men) with advanced Fabry cardiomyopathy, relevant hypertrophy, and replacement fibrosis in "loco typico." No patients previously exhibited clinically relevant arrhythmias on Holier ECGs. Patients received an implantable loop recorder and were prospectively followed with telemedicine for a median of 1.2 years (range 0.3 to 2.0 years). The primary end point was a clinically meaningful event, which required a therapy change, captured with the loop recorder. Patients submitted data regularly (14 +/- 11 times per month). During follow-up, 21 events were detected (including 4 asystole, i.e., ECG pauses >= 3 seconds) and 7 bradycardia events; 5 episodes of intermittent atrial fibrillation (>3 minutes) and 5 episodes of ventricular tachycardia (3 sustained and 2 nonsustained). Subsequently, as defined in the primary end point, 15 events leaded to a change of therapy. These patients required therapy with a pacemaker or cardioverter defibrillator implantation and/or anticoagulation therapy for atrial fibrillation. In conclusion, clinically relevant arrhythmias that require further device and/or medical therapy are often missed with Holier ECGs in patients with advanced stage Fabry cardiomyopathy, but they can be detected by telemonitoring with an implantable loop recorder. KW - Cardiovascular magnetic-resonance KW - Coronary artery disease KW - Ventricular-arrhythmias KW - Task force KW - Management KW - Enzyme replacement therapy KW - Hypertrophic cardiomyopathy KW - Myocardial fibrosis KW - Guidelines KW - Manifestation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188093 VL - 118 IS - 2 ER -