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ABSTRACT: Atrial fibrosis is important for the pathogenesis of atrial fibrillation (AF) but the underlying signal transduction is incompletely understood. We therefore studied the role of microRNA-21 (miR-21) and its downstream target Sprouty 1 (Spry1) during atrial fibrillation. Left atria (LA) from patients with AF showed a 2.5-fold increased expression of miR-21 compared to matched LA of patients in sinus rhythm. Increased miR-21 expression correlated positively with atrial collagen content and was associated with a reduced protein expression of Spry1 and increased expression of connective tissue growth factor (CTGF), lysyl oxidase and Rac1-GTPase. Neonatal cardiac fibroblasts treated with angiotensin II (AngII) or CTGF showed an increased miR-21 and decreased Spry1 expression. Pretreatment with an inhibitor of Rac1 GTPase, NSC23766, reduced the AngII-induced upregulation of miR-21. A small molecule inhibitor of lysyl oxidase, BAPN, prevented the AngII as well as the CTGF-induced miR-21 expression. Transgenic mice with cardiac overexpression of Rac1, which develop spontaneous AF and atrial fibrosis with increasing age, showed upregulation of miR-21 expression associated with reduced Spry1 expression. miR-21 expression and signalling in vivo were prevented by long-term treatment of the mice with statins. Direct inhibition of miR-21 by antagomir-21 prevented fibrosis of the atrial myocardium post-myocardial infarction. Left atria of patients with atrial fibrillation are characterized by upregulation of miR-21 und reduced expression of Spry1. Activation of Rac1 by angiotensin II leads to a CTGF- and lysyl oxidase-mediated increase of miR-21 expression contributing to structural remodelling of the atrial myocardium.
Archiv für Kreislaufforschung 09/2012; 107(5):278. · 7.35 Impact Factor
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Clinical Research in Cardiology 05/2012; 101(10):851-2. · 2.95 Impact Factor
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Journal of the American College of Cardiology 01/2012; 59(1):71-3. · 14.16 Impact Factor
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ABSTRACT: The aim of the study is to characterize the signal transduction leading to interstitial fibrosis in the pathogenesis of atrial fibrillation (AF) and atrial remodeling. Samples of the left atrial appendage (LA) from patients with AF showed higher collagen content (73 ± 5 vs. 38 ± 2 μg/mg protein) and 2.5-fold increased collagen crosslinking compared to patients with sinus rhythm (SR). Affymetrix-assays, RT-PCR and western Blot analysis revealed that LA of AF patients are characterized by increased lysyl oxidase (LOX) mRNA (218 ± 42%) and protein (253 ± 11%) expression. This was associated with increased expression of connective tissue growth factor (CTGF), fibronectin and Rac1 activity compared to SR. In neonatal cardiac fibroblasts, the Rac1 specific small molecule inhibitor NSC23766 prevented angiotensin II (AngII) induced upregulation of LOX (214 ± 16%) expression. Inhibition of CTGF by siRNA transfections completely inhibited AngII induced LOX expression. The LOX specific small molecule inhibitor BAPN prevented AngII and CTGF induced fibronectin expression. Left atria of transgenic mice with cardiac overexpression of Rac1 (RacET) that develop AF at high age exhibited upregulation of CTGF as well as LOX (187 ± 7%) and fibronectin (627 ± 146%) expression. Atria of RacET showed increased collagen content (28 ± 2 μg/mg protein) and crosslinking (10 ± 0.7) compared to wildtypes (20 ± 0.4 μg/mg protein; 5 ± 0.9). Left atrial myocardium of patients with atrial fibrillation is characterized by increased lysyl oxidase and fibronectin expression as well as collagen cross-linking. In cardiac fibroblasts, Rac1 GTPase mediates upregulation of fibronectin via LOX and CTGF. Inhibition of this signaling pathway may therefore represent a target for the prevention of fibrotic atrial remodeling.
Journal of Molecular and Cellular Cardiology 01/2011; 50(4):678-85. · 5.17 Impact Factor
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Jan-Christian Reil,
Mathias Hohl,
Martin Oberhofer,
Andrey Kazakov,
Lars Kaestner,
Patrick Mueller, Oliver Adam,
Christoph Maack,
Peter Lipp,
Christian Mewis,
Maurits Allessie,
Ulrich Laufs,
Michael Böhm,
Hans-Ruprecht Neuberger
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ABSTRACT: The small GTPase Rac1 seems to play a role in the pathogenesis of atrial fibrillation (AF). The aim of the present study was to characterize the effects of Rac1 overexpression on atrial electrophysiology.
In mice with cardiac overexpression of constitutively active Rac1 (RacET), statin-treated RacET, and wild-type controls (age 6 months), conduction in the right and left atrium (RA and LA) was mapped epicardially. The atrial effective refractory period (AERP) was determined and inducibility of atrial arrhythmias was tested. Action potentials were recorded in isolated cells. Left ventricular function was measured by pressure-volume analysis. Five of 11 RacET hearts showed spontaneous or inducible atrial tachyarrhythmias vs. 0 of 9 controls (P < 0.05). In RacET, the P-wave duration was significantly longer (26.8 +/- 2.1 vs. 16.7 +/- 1.1 ms, P = 0.001) as was total atrial activation time (RA: 13.6 +/- 4.4 vs. 3.2 +/- 0.5 ms; LA: 7.1 +/- 1.2 vs. 2.2 +/- 0.3 ms, P < 0.01). Prolonged local conduction times occurred more often in RacET (RA: 24.4 +/- 3.8 vs. 2.7 +/- 2.1%; LA: 19.1 +/- 6.3 vs. 1.2 +/- 0.7%, P < 0.01). The AERP and action potential duration did not differ significantly between both groups. RacET demonstrated significant atrial fibrosis but only moderate systolic heart failure. RacET and statin-treated RacET were not significantly different regarding atrial electrophysiology.
The substrate for atrial arrhythmias in mice with Rac1 overexpression is characterized by conduction disturbances and atrial fibrosis. Electrical remodelling (i.e. a shortening of AERP) does not play a role. Statin treatment cannot prevent the structural and electrophysiological effects of pronounced Rac1 overexpression in this model.
Cardiovascular research 03/2010; 87(3):485-93. · 5.80 Impact Factor
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Oliver Adam,
Daniel Lavall,
Katharina Theobald,
Mathias Hohl,
Markus Grube,
Sabine Ameling,
Mark A Sussman,
Stephan Rosenkranz,
Heyo K Kroemer,
Hans-Joachim Schäfers,
Michael Böhm,
Ulrich Laufs
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ABSTRACT: We studied the signal transduction of atrial structural remodeling that contributes to the pathogenesis of atrial fibrillation (AF).
Fibrosis is a hallmark of arrhythmogenic structural remodeling, but the underlying molecular mechanisms are incompletely understood.
We performed transcriptional profiling of left atrial myocardium from patients with AF and sinus rhythm and applied cultured primary cardiac cells and transgenic mice with overexpression of constitutively active V12Rac1 (RacET) in which AF develops at old age to characterize mediators of the signal transduction of atrial remodeling.
Left atrial myocardium from patients with AF showed a marked up-regulation of connective tissue growth factor (CTGF) expression compared with sinus rhythm patients. This was associated with increased fibrosis, nicotinamide adenine dinucleotide phosphate oxidase, Rac1 and RhoA activity, up-regulation of N-cadherin and connexin 43 (Cx43) expression, and increased angiotensin II tissue concentration. In neonatal rat cardiomyocytes and fibroblasts, a specific small molecule inhibitor of Rac1 or simvastatin completely prevented the angiotensin II-induced up-regulation of CTGF, Cx43, and N-cadherin expression. Transfection with small-inhibiting CTGF ribonucleic acid blocked Cx43 and N-cadherin expression. RacET mice showed up-regulation of CTGF, Cx43, and N-cadherin protein expression. Inhibition of Rac1 by oral statin treatment prevented these effects, identifying Rac1 as a key regulator of CTGF in vivo.
The data identify CTGF as an important mediator of atrial structural remodeling during AF. Angiotensin II activates CTGF via activation of Rac1 and nicotinamide adenine dinucleotide phosphate oxidase, leading to up-regulation of Cx43, N-cadherin, and interstitial fibrosis and therefore contributing to the signal transduction of atrial structural remodeling.
Journal of the American College of Cardiology 02/2010; 55(5):469-80. · 14.16 Impact Factor
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ABSTRACT: Recruitment of circulating monocytes into the vasculature and release of reactive oxygen species (ROS) promote atherogenesis. Rac1-GTPase is an essential component of the superoxide-producing NADPH-oxidase complex. Estrogens inhibit production of vascular reactive oxygen species. Angiotensin II as well as overexpression of the constitutively active mutant RacL61 increased ROS production in monocytes. AngII-mediated ROS release was completely inhibited by overexpression of the dominant negative mutant RacN17 or treatment with 17beta-estradiol. 17beta-Estradiol reduced Rac1-expression concentration- and time-dependently and decreased basal, as well as AngII-induced Rac1 activity. The effects of 17beta-estradiol were receptor-mediated. In vivo, down-regulation of Rac1 by 17beta-estradiol was observed in human mononuclear cells of women with elevated 17beta-estradiol levels after controlled ovarian hyperstimulation. In summary, the data show that down-regulation of Rac1-GTPase contributes to the inhibition of angiotensin II-mediated superoxide release by 17beta-estradiol in monocytes.
Biochemical and Biophysical Research Communications 07/2009; 386(1):45-9. · 2.48 Impact Factor
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ABSTRACT: Atrial fibrillation (AF) and chronic heart failure (CHF) can be caused by each other, and therefore constitute a vicious circle. The prevalence of both conditions is about 1% in industrialized countries and increases with age. Although mortality is increased in heart failure, the additional prognostic relevance of AF in these patients is less clear. AF in patients with CHF can worsen heart failure symptoms, cause complications (eg, stroke), and is difficult to treat. Thus, prevention of AF entirely is an important goal. This review summarizes recent data concerning prognostic relevance, treatment, and means of primary and secondary prevention of AF in patients with CHF.
Current Heart Failure Reports 01/2009; 5(4):219-25.
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ABSTRACT: Dyspnoea is one of the typical symptoms of congestive heart failure. The cause of dyspnoea in this patient with chronic heart failure, 8 months after coronary artery bypass grafting, was a great surprise for the heart failure physician, showing that a more broad view of dyspnoea is warranted in this common symptom.
Case Reports 01/2009; 2009.
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ABSTRACT: This article summarizes the results of a number of clinical trials in the field of cardiovascular medicine which were presented during the Hotline and Clinical Trial Update Sessions at the annual meeting of the European Society of Cardiology, held in Munich, Germany, from 30th August to 3rd September 2008. The data were presented by leading experts in the field with relevant positions in the trials. It is important to note that unpublished reports should be considered as preliminary data, as the analysis may change in the final publications. The comprehensive summaries have been generated from the oral presentation and the webcasts of the European Society of Cardiology and should provide the readers with the most comprehensive information on diagnostic and therapeutic developments in cardiovascular medicine.
Clinical Research in Cardiology 11/2008; 97(12):851-64. · 2.95 Impact Factor
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Circulation 10/2008; 118(12):1285-93. · 14.74 Impact Factor
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ABSTRACT: HMG CoA reductase inhibitors (statins) have been shown to be effective lipid lowering agents and are beneficial in the primary and secondary prevention of coronary heart disease. However, the overall benefits observed with statins appear to be greater than what might be expected from changes in lipid levels alone and the positive effects have only partially been reproduced with other lipid lowering drugs, suggesting effects in addition to cholesterol lowering. In experimental models, many of the cholesterol-independent effects of statins are mediated by inhibition of isoprenoids, which serve as lipid attachments for intracellular signalling molecules such as small Rho guanosine triphosphate-binding proteins, whose membrane localization and function are dependent on isoprenylation. This review summarizes the effects of statins on endothelial function and oxidative stress.
Archive für Toxikologie 09/2008; 82(12):885-92. · 4.67 Impact Factor
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ABSTRACT: The risk of thromboembolic complications is increased in patients with advanced chronic heart failure and severe left ventricular dysfunction. Accepted indications for oral anticoagulation include patients with a history of thromboembolism, concomitant atrial fibrillation, or venous, arterial or cardiac thrombosis. In other subgroups, the benefit of chronic anticoagulation has not been proven and existing data from uncontrolled nonrandomized, mostly retrospective studies and prospective, randomized controlled studies are conflicting. This article summarizes the available data on the thromboembolic risk and the potential benefit of antithrombotic therapy and attempts to provide current orientation and recommendations for anticoagulant therapy in patients with chronic heart failure and severe left ventricular dysfunction.
Herz 03/2008; 33(1):20-4. · 0.92 Impact Factor
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ABSTRACT: Der Nutzen einer antithrombotischen Therapie mit oralen Antikoagulanzien wird bei Patienten mit chronischer Herzinsuffizienz
kontrovers diskutiert. Das Risiko für thromboembolische Komplikationen ist bei fortgeschrittener linksventrikulärer Funktionseinschränkung
erhöht. Die Ätiologie ist dabei multifaktoriell, insbesondere ein reduzierter Blutfluss, Gefäßwandveränderungen, Hyperkoagulabilität
und Vorhofflimmern sind von Bedeutung.
Bei Patienten mit begleitendem Vorhofflimmern besteht eine klare Indikation zur Antikoagulation. Bei Patienten mit abgelaufenen
Thromboembolien oder nachgewiesenen intrakardialen Thromben wird auch im Sinusrhythmus gleichfalls eine Antikoagulation durchgeführt,
obwohl in diesen Fällen der Nutzen weniger gut belegt ist. Hingegen konnte bei Patienten mit Herzinsuffizienz und Sinusrhythmus
ohne vorangegangene thromboembolische Komplikationen der Nutzen einer chronischen Antikoagulation nicht nachgewiesen werden.
Kontroverse Daten erschweren die Quantifizierung des Risikos. Jedoch erscheint die Inzidenz schwerwiegender Thromboembolien
überraschend gering.
Dieser Beitrag fasst die verfügbaren Daten zum Risiko thromboembolischer Komplikationen und zum Nutzen einer antithrombotischen
Therapie bei Patienten mit Herzinsuffizienz und schwerer linksventrikulärer Dysfunktion zusammen und versucht, individuelle
Indikationsstellungen zur Antikoagulation zu berücksichtigen.
The risk of thromboembolic complications is increased in patients with advanced chronic heart failure and severe left ventricular
dysfunction. Accepted indications for oral anticoagulation include patients with a history of thromboembolism, concomitant
atrial fibrillation, or venous, arterial or cardiac thrombosis. In other subgroups, the benefit of chronic anticoagulation
has not been proven and existing data from uncontrolled nonrandomized, mostly retrospective studies and prospective, randomized
controlled studies are conflicting.
This article summarizes the available data on the thromboembolic risk and the potential benefit of antithrombotic therapy
and attempts to provide current orientation and recommendations for anticoagulant therapy in patients with chronic heart failure
and severe left ventricular dysfunction.
Herz 12/2007; 33(1):20-24. · 0.92 Impact Factor
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ABSTRACT: Cusp prolapse may be an isolated cause of aortic regurgitation or may exist in conjunction with dilatation of the proximal aorta. Prolapse can be corrected by central plication, triangular resection, or pericardial patch implantation. We retrospectively analyzed our results with these techniques.
From October 1995 to December 2006, 604 patients (aged 3-86 years) underwent aortic valve repair. Cusp prolapse was found in 427 patients (246 tricuspid, 181 bicuspid). Prolapse was corrected by central plication (n = 275) or triangular resection (n = 80). A pericardial patch was implanted for pre-existing cusp defects or after excision of calcium (n = 72). One cusp was repaired in 198 patients; the remaining patients underwent repair of 2 (n = 189) or 3 cusps (n = 40). In 102 patients more than one technique was used, and the patients were allocated to the group of the assumedly more complex repair (central plication < triangular resection < pericardial patch plasty). Cumulative follow-up was 1238 patient-years (mean 35 +/- 27 months).
Hospital mortality was 2.6% (11/427). Actuarial freedom from aortic regurgitation of grade II or more at 5 years was 92% (central plication), 90% (triangular resection), and 90% (pericardial patch plasty). Thirteen patients were reoperated on, with prolapse as the most common reason for failure (n = 7); 6 underwent re-repair. Freedom from reoperation at 5 years was 95% (central plication), 94% (triangular resection), and 94% (pericardial patch plasty). Freedom from valve replacement at 5 years was 97% (central plication), 99% (triangular resection), and 98% (pericardial patch plasty).
In aortic valve repair, cusp prolapse can be treated reliably by central plication. In the presence of more complex disease, triangular resection or pericardial patch plasty may be used without compromising midterm durability.
The Journal of thoracic and cardiovascular surgery 12/2007; 134(6):1533-8; discussion 1538-9. · 3.41 Impact Factor
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ABSTRACT: This article provides information and commentaries on trials which were presented at the Hotline and Clinical Trial Update Sessions at the European Society of Cardiology Congress 2007 in Vienna. The key presentations were performed by leading experts in the field with relevant positions in the trials or registries. It is important to note that unpublished reports should be considered as preliminary data, as the analysis may change in the final publications. The comprehensive summaries have been generated from the oral presentation and the webcasts of the European Society of Cardiology and should provide the readers with the most comprehensive information of relevant publications.
Clinical Research in Cardiology 12/2007; 96(11):767-86. · 2.95 Impact Factor
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ABSTRACT: This article provides information and commentaries on trials which were presented at the Hotline and Clinical Trial Update
Sessions at the European Society of Cardiology Congress 2007 in Vienna. The key presentations were performed by leading experts
in the field with relevant positions in the trials or registries. It is important to note that unpublished reports should
be considered as preliminary data, as the analysis may change in the final publications. The comprehensive summaries have
been generated from the oral presentation and the webcasts of the European Society of Cardiology and should provide the readers
with the most comprehensive information of relevant publications.
Clinical Research in Cardiology 10/2007; 96(11):767-786. · 2.95 Impact Factor
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ABSTRACT: We aimed to study the role of Rac1 GTPase in atrial fibrillation (AF).
The signal transduction associated with AF is incompletely understood. We hypothesized that activation of Rac1 GTPase contributes to the pathogenesis of AF via activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and production of reactive oxygen species.
Old mice with cardiac-specific overexpression of constitutively active V12Rac1 (RacET) were compared with wild-type (WT) and WT undergoing transaortic constriction (TAC). In addition, samples of human left atrial appendages were analyzed in patients with sinus rhythm (SR) compared with patients with permanent AF matched for atrial diameter.
At age 16 months, 75% of RacET but no WT or TAC mice showed AF. Treatment of RacET with statins for 10 months did not alter weight or fibrosis of atria or ventricles but decreased cardiac Rac1 and NADPH oxidase activity and reduced the incidence of AF by 50%. The left atria of patients with AF showed increased fibrosis, up-regulation of NADPH oxidase activity, a 4-fold increase of Rac1 total protein and membrane expression as well as up-regulation of Rac1 activity.
Chronic cardiac overexpression of Rac1 represents a novel mouse model for AF. Rac1 GTPase contributes to the pathogenesis of AF and identifies a target for the prevention and treatment of AF.
Journal of the American College of Cardiology 08/2007; 50(4):359-67. · 14.16 Impact Factor
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New England Journal of Medicine 03/2007; 356(8):874-5. · 53.30 Impact Factor
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ABSTRACT: Lymphocyte homing to peripheral lymph nodes is governed by adhesion molecules, including lymphocyte function-associated antigen 1 (LFA-1). Statins are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and exert anti-inflammatory effects, e.g. inhibition of LFA-1. It is still not known whether statin compounds are capable of inhibiting lymphocyte homing in vivo. We used a cervical lymph node preparation to study the effects of simvastatin on lymphocyte adhesion to high endothelial venules (HEVs) by means of intravital fluorescence microscopy (IVM). IVM revealed that firm adhesion of lymphocytes to HEV endothelium critically depends on the adhesive function of LFA-1. The number of firmly adherent lymphocytes was reduced by 58% in LFA-1-deficient mice (P < 0.05 versus wild-type controls). As in mutant mice, acute treatment with simvastatin (i.p. injection at 2 hr prior to IVM) inhibited the firm adhesion of lymphocytes to HEV endothelium of wild-type animals by 63% (P < 0.05 versus vehicle-treated wild-type controls). In addition, acute treatment with the synthetic statin-derivate LFA878 also reduced firm lymphocyte adhesion in HEVs by 63% (P > 0.05 versus placebo-treated controls). Histological analysis after a 10-day treatment with simvastatin showed reduced cellularity of cervical lymph nodes, as indicated by a reduction of the relative area of haematoxylin-stained cell nuclei in cervical lymph node cross-sections from 94 +/- 0% in vehicle-treated controls to 77 +/- 3% in simvastatin-treated mice (P < 0.05). We conclude that statin compounds are capable of inhibiting lymphocyte homing to murine peripheral lymph nodes in vivo. This may have novel implications for the treatment of adaptive immune responses, e.g. transplant rejection.
Immunology 03/2007; 120(3):315-24. · 3.32 Impact Factor
