Fischer A.,Goethe University Frankfurt |
Fischer A.,Institute for Cardiovascular Regeneration |
Roxe T.,Goethe University Frankfurt |
Roxe T.,Institute for Cardiovascular Regeneration |
And 10 more authors.
Circulation: Heart Failure | Year: 2012
Background-Chronic heart failure (CHF) is associated with a 4-fold increased risk for osteoporotic fractures. Therefore, we sought to identify the pathophysiological link between chronic heart failure and catabolic bone remodeling. Methods and Results-In a total cohort of 153 subjects (123 patients with CHF, 30 patients with coronary artery disease and preserved cardiac function) as well as mice with heart failure, bone marrow (BM) plasma levels of the catabolic receptor activator of NF-?B ligand (RANKL), and its antagonist, osteoprotegerin were measured. The osteoclast inducing activity of BM plasma was tested in cell culture. BM plasma levels of RANKL and of the ratio RANKL/osteoprotegerin were significantly elevated in patients with CHF. On multivariate regression analysis, parameters of severity and duration of heart failure were independent determinants of elevated BM plasma RANKL levels. BM plasma levels of RANKL were directly correlated with the systemic marker of bone turnover C-telopeptide of type 1 collagen (r=0.6; P<0.001). Alterations in BM plasma levels of RANKL/osteoprotegerin were confirmed in a mouse model of postinfarction heart failure. Stimulation of human mesenchymal cells with BM plasma obtained from CHF patients increased the formation of osteoclasts, and this effect was blocked by the RANKL inhibition. Conclusions-CHF is associated with a profound and selective elevation of the bone resorption stimulating RANKL within the BM microenvironment. These data for the first time disclose a direct pathophysiological pathway linking CHF with catabolic bone remodeling associated with an increased osteoporotic fracture risk. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifiers: NCT 00289822, NCT 00284713, NCT 00326989, NCT 00962364. © 2012 American Heart Association, Inc.
Schmid E.,Institute of Pharmacology and Toxicology |
Neef S.,University of Regensburg |
Berlin C.,Institute of Pharmacology and Toxicology |
Tomasovic A.,Institute of Pharmacology and Toxicology |
And 31 more authors.
Nature Medicine | Year: 2015
In heart failure therapy, it is generally assumed that attempts to produce a long-term increase in cardiac contractile force are almost always accompanied by structural and functional damage. Here we show that modest overexpression of the Raf kinase inhibitor protein (RKIP), encoded by Pebp1 in mice, produces a well-tolerated, persistent increase in cardiac contractility that is mediated by the β 1 -adrenoceptor (β 1 AR). This result is unexpected, as β 1 AR activation, a major driver of cardiac contractility, usually has long-term adverse effects. RKIP overexpression achieves this tolerance via simultaneous activation of the β 2 AR subtype. Analogously, RKIP deficiency exaggerates pressure overload-induced cardiac failure. We find that RKIP expression is upregulated in mouse and human heart failure, indicative of an adaptive role for RKIP. Pebp1 gene transfer in a mouse model of heart failure has beneficial effects, suggesting a new therapeutic strategy for heart failure therapy. © 2015 Nature America, Inc.
PubMed | Institute of Pharmacology and Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Saarland University, University of Heidelberg and 4 more.
Type: Journal Article | Journal: Nature medicine | Year: 2015
In heart failure therapy, it is generally assumed that attempts to produce a long-term increase in cardiac contractile force are almost always accompanied by structural and functional damage. Here we show that modest overexpression of the Raf kinase inhibitor protein (RKIP), encoded by Pebp1 in mice, produces a well-tolerated, persistent increase in cardiac contractility that is mediated by the 1-adrenoceptor (1AR). This result is unexpected, as 1AR activation, a major driver of cardiac contractility, usually has long-term adverse effects. RKIP overexpression achieves this tolerance via simultaneous activation of the 2AR subtype. Analogously, RKIP deficiency exaggerates pressure overload-induced cardiac failure. We find that RKIP expression is upregulated in mouse and human heart failure, indicative of an adaptive role for RKIP. Pebp1 gene transfer in a mouse model of heart failure has beneficial effects, suggesting a new therapeutic strategy for heart failure therapy.
PubMed | Charité - Medical University of Berlin, Catalan Institution for Research and Advanced Studies, Katharinen Hospital, Comprehensive Heart Failure Center and Klinikum Straubing GmbH
Type: Journal Article | Journal: The American journal of cardiology | Year: 2016
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 Holter 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 Holter ECGs. Patients received an implantable loop recorder and were prospectively followed with telemedicine for a median of 1.2years (range 0.3 to 2.0years). 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 3seconds) and 7 bradycardia events; 5 episodes of intermittent atrial fibrillation (>3minutes) 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 Holter ECGs in patients with advanced stage Fabry cardiomyopathy, but they can be detected by telemonitoring withanimplantable loop recorder.
Gutjahr F.T.,University of Würzburg |
Gutjahr F.T.,Comprehensive Heart Failure Center |
Kampf T.,University of Würzburg |
Winter P.,University of Würzburg |
And 6 more authors.
Magnetic Resonance in Medicine | Year: 2015
Purpose A method for the quantification of perfusion in murine myocardium is demonstrated. The method allows for the reconstruction of perfusion maps on arbitrary time points in the heart cycle while addressing problems that arise due to the irregular heart beat of mice. Methods A flow-sensitive alternating inversion recovery arterial spin labeling method using an untriggered FLASH-read out with random sampling is used. Look-Locker conditions are strictly maintained. No dummy pulses or mechanism to reduce deviation from Look-Locker conditions are needed. Electrocardiogram and respiratory data are recorded for retrospective gating and triggering. A model-based technique is used to reconstruct missing k-space data to cope with the undersampling inherent in retrospectively gated methods. Acquisition and reconstruction were validated numerically and in phantom measurements before in vivo experimentation. Results Quantitative perfusion maps were acquired within a single slice measurement time of 11 min. Perfusion values are in good accordance to literature values. Myocardial infarction could be clearly visualized and results were confirmed with histological results. Conclusion The proposed method is capable of producing quantitative perfusion maps on arbitrary positions in the heart cycle within a short measurement time. The method is robust against irregular breathing patterns and heart rate changes and can be implemented on all scanners. Magn Reson Med 74:1705-1715, 2015. © 2014 Wiley Periodicals, Inc.
Faller H.,University of Würzburg |
Stork S.,University of Würzburg |
Stork S.,Comprehensive Heart Failure Center |
Gelbrich G.,University of Würzburg |
And 6 more authors.
Journal of Psychosomatic Research | Year: 2015
Objective: The prognostic potential of depressive symptoms independent of somatic features of heart failure severity has repeatedly been demonstrated. However, patient-reported functional status has rarely been accounted for in these studies. Thus, it has remained unclear to what extent the predictive power of depressive symptoms may mirror functional status. We therefore aimed to evaluate the prognostic value of depressive symptoms adjusting for patient-reported functional status in a large, well-characterized sample of patients with systolic heart failure. Methods: Eight hundred sixty-three patients, 67 ± 12. years old, 72% men, and 42% with New York Heart Association functional classes III/IV, who participated in the extended Interdisciplinary Network Heart Failure (INH) study were investigated. We assessed depressive symptoms using the Patient Health Questionnaire (PHQ-9) and patient-reported functional status with the Kansas City Cardiomyopathy Questionnaire (KCCQ). Data on survival was obtained after a follow-up of 18. months (100% complete). Results: Depressive symptoms predicted mortality risk (HR per PHQ-9 scale point = 1.07, 95% CI 1.04-1.09, p < .001), even after adjustment for heart failure severity and co-morbidities (HR = 1.04, 95% CI 1.01-1.07, p = .017). However, they were no longer significant predictors (HR = 1.01, 95% CI 0.98-1.05, p = 0.46) after additional adjustment for patient-reported functional status, which proved predictive of mortality risk (HR = 0.90, 95% CI 0.82-0.99, p = .025). Conclusion: Our results suggest that the association of depressive symptoms with functional status may at least partly explain the prognostic potential of depressive symptoms. © 2015 Elsevier Inc.
Stab D.,University of Würzburg |
Wech T.,University of Würzburg |
Breuer F.A.,Research Center Magnetic Resonance Bavaria |
Weng A.M.,University of Würzburg |
And 5 more authors.
Journal of Magnetic Resonance Imaging | Year: 2014
Purpose To evaluate and to compare Parallel Imaging and Compressed Sensing acquisition and reconstruction frameworks based on simultaneous multislice excitation for high resolution contrast-enhanced myocardial first-pass perfusion imaging with extended anatomic coverage. Materials and Methods The simultaneous multislice imaging technique MS-CAIPIRINHA facilitates imaging with significantly extended anatomic coverage. For additional resolution improvement, equidistant or random undersampling schemes, associated with corresponding reconstruction frameworks, namely Parallel Imaging and Compressed Sensing can be used. By means of simulations and in vivo measurements, the two approaches were compared in terms of reconstruction accuracy. Comprehensive quality metrics were used, identifying statistical and systematic reconstruction errors. Results The quality measures applied allow for an objective comparison of the frameworks. Both approaches provide good reconstruction accuracy. While low to moderate noise enhancement is observed for the Parallel Imaging approach, the Compressed Sensing framework is subject to systematic errors and reconstruction induced spatiotemporal blurring. Conclusion Both techniques allow for perfusion measurements with a resolution of 2.0 × 2.0 mm2 and coverage of six slices every heartbeat. Being not affected by systematic deviations, the Parallel Imaging approach is considered to be superior for clinical studies. Copyright © 2013 Wiley Periodicals, Inc.
Ramos G.,Martin Luther University of Halle Wittenberg |
Hofmann U.,Martin Luther University of Halle Wittenberg |
Hofmann U.,Comprehensive Heart Failure Center |
Frantz S.,Martin Luther University of Halle Wittenberg
Journal of Molecular and Cellular Cardiology | Year: 2016
Lymphocytes came recently into focus as modulators of non-infectious myocardial diseases. Several lines of experimental evidence now indicate that CD4+ T-cells can influence the healing and scarring processes that follow a myocardial infarction episode. Furthermore, such heart-directed T-cell activity has also been implicated in the pathogenesis cardiac remodeling that develops in response to chronic pressure-overload conditions. Mechanistically, different T-cell subsets can secrete several mediators and growth factors that influence the myocardial molecular milieu and directly interfere with the macrophages' and fibroblasts' activity. Therefore, the present review summarizes the current experimental evidence on the role of T-cells in myocardial scar formation after infarction and myocardial fibrosis as central mechanism of ventricular remodeling. © 2016 Elsevier Ltd.
Hu K.,University of Würzburg |
Hu K.,Comprehensive Heart Failure Center |
Liu D.,University of Würzburg |
Liu D.,Comprehensive Heart Failure Center |
And 13 more authors.
Circulation: Cardiovascular Imaging | Year: 2011
Background-For the clinical assessment of patients with dyspnea, the inversion of the early (E) and late (A) transmitral flow during Valsalva maneuver (VM) frequently helps to distinguish pseudonormal from normal filling pattern. However, in an important number of patients, VM fails to reveal the change from dominant early mitral flow velocity toward larger late velocity. Methods and Results-From December 2009 to October 2010, we selected consecutive patients with abnormal filling with (n=25) and without E/A inversion (n=25) during VM. Transmitral, tricuspid, and pulmonary Doppler traces were recorded and the degree of insufficiency was estimated. After evaluating all standard echocardiographic morphological, functional, and flow-related parameters, it became evident that the failure to unmask the pseudonormal filling pattern by VM was related to the degree of the tricuspid insufficiency (TI). TI was graded as mild in 24 of 25 patients in the group with E/A inversion during VM, whereas TI was graded as moderate to severe in 24 of the 25 patients with pseudonormal diastolic function without E/A inversion during VM. Conclusions-Our data suggest that TI is a major factor to prevent E/A inversion during a VM in patients with pseudonormal diastolic function. This probably is due to a decrease in TI resulting in an increase in forward flow rather than the expected decrease during the VM. Thus, whenever a pseudonormal diastolic filling pattern is suspected, the use of a VM is not an informative discriminator in the presence of moderate or severe TI. © 2011 American Heart Association, Inc.
PubMed | Comprehensive Heart Failure Center
Type: Journal Article | Journal: European journal of medical research | Year: 2016
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 bulls 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 bulls eye mapping is clinically feasible and the plot patterns could provide clues to the etiology of cardiomyopathies. The present review summarizes the longitudinal strain, bulls eye plot features in patients with various cardiomyopathies and concentric left ventricular hypertrophy and the bulls eye plot features might serve as one of the cardiac workup steps on evaluating patients with left ventricular hypertrophy.