L Seipel

University of Tuebingen, Tübingen, Baden-Wuerttemberg, Germany

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Publications (454)1141.75 Total impact

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    ABSTRACT: Vorhofflimmern führt zu Veränderungen der atrialen Elektrophysiologie, wodurch das Auftreten und der Erhalt der Arrhythmie begünstigt werden. Die zellulären und molekularen Mechanismen dieses Prozesses sind vielfältig, sie waren in den letzten Jahren Gegenstand intensiver Forschungsbemühungen die wesentlich zum besseren Verständnis der Pathophysiologie des Vorhofflimmerns beitrugen. Ziel der Arbeit ist die Darstellung des derzeitigen Wissensstands. Auf zellulärer Ebene kommt es bei Vorhofflimmern zu einer deutlichen Verkürzung und verminderten Frequenzadaptation der Aktionspotenzialdauer sowie zu einer veränderten Aktionspotenzialmorphologie. Vorhofflimmern führt zu einer Modulation der Genexpression des L-Typ Kalziumkanals (ICa,L) und von Kaliumkanälen (Ito, IK1, IKACh). Die molekularen Mechanismen der bei Vorhofflimmern beobachteten intraatrialen Leitungsverzögerungen sind weniger klar, ihr scheinen Veränderungen der Expression und Verteilung von Gap-junction Proteinen oder eine Verminderung des schnellen Natriumkanals (INa) zu Grunde zu liegen. Ein Auslöser für viele der gemachten Beobachtungen ist die Überladung der Myozyten mit Ca2+ mit einer Verminderung des systolischen Kalziumtransienten, ebenso lassen sich Veränderungen der die Kalziumhomöostase beeinflussenden Proteine bei Vorhofflimmern nachweisen. Im letzten Teil werden die klinische Bedeutung der gemachten Beobachtungen und daraus potentiell resultierende, neuartige Therapieansätze diskutiert. Atrial fibrillation is associated with changes in atrial electrophysiology that facilitate the initiation and persistence of the arrhythmia. The underlying cellular and molecular mechanisms are diverse; they have intensively been investigated over the past few years. The results, that have substantially improved the understanding of the pathophysiology of atrial fibrillation are reviewed. On the cellular level, atrial fibrillation leads to a strong shortening and an impaired rate adaptation of the action potential as well as changes in action potential morphology. Atrial fibrillation is associated with an altered gene expression of the L-type calcium channel (ICa,L) and of potassium channels (Ito, IK1, IKACh). The molecular mechanisms of intraatrial conduction slowing are less well understood; changes in the expression or distribution of gap junction proteins or a decrease of the fast sodium inward channel (INa) seem to be involved. A trigger for many of the observations is an overload of the myocyte cytoplasm with Ca2+ and a consecutive decrease of the systolic calcium gradient, furthermore changes in calcium-handling proteins are detectable in atrial fibrillation. In the last part, the clinical relevance and potential new therapeutic approaches are discussed. Schlüsselwörter Vorhofflimmern – Ionenkanäle – Aktionspotenziale – Connexine – KalziumhomöostaseKey words Atrial fibrillation –¶ion channels – action potentials – connexins – calcium homeostasis
    Zeitschrift für Kardiologie 04/2012; 89(9):795-802. · 0.97 Impact Factor
  • G. Breithardt, L. Seipel
    Der Kardiologe 01/2010; 4(6):500-501.
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    ABSTRACT: In late 1997, the German Cardiac Society set up a multicenter registry to evaluate the acute and mid-term course of all patients (pts.) treated with septal ablation for symptomatic hypertrophic obstructive cardiomyopathy (HOCM). An analysis of the acute results has already been published. We now report on the mid-term course (3-6 months) of 242 pts. registered through September 1999. Follow-up was 92% complete (n=222). During follow-up (mean: 4.9+/-2.3 months), an additional 3 pts. died (in-hospital mortality: 3 pts.). A satisfactory clinical effect was reported by 195 pts. (88%); 27 pts. (12%) remained in NYHA classes III and IV. Overall symptomatic improvement (NYHA class: from 2.8+/-0.7 to 1.7+/-0.7) paralleled the outflow gradient (LVOTG) reduction which was further accentuated as compared with the acute result (Doppler measurement at rest: from 57+/-31 to 25+/-25 mmHg to 20+/-21 mmHg; with provocation: from 107+/-53 to 49+/-40, to 44+/-40 mmHg, p<0.001, resp.). Left atrial (LA) diameter (from 46+/-8 to 44+/-7 mm) and septal thickness (from 20+/-5 to 15+/-5 mm; p<0.001, resp.) were also reduced. Comparing the methods for target vessel selection (i.e., with contrast echo monitoring vs pressurefluoroscopy guidance), at followup clinical improvement and hemodynamic measurements were comparable. Clinical success can be achieved by septal ablation, both with the echocontrast guided and gradient-fluoroscopy guided method, in 88% of highly symptomatic HOCM pts. At mid-term follow-up, symptoms, left atrial size and septal thickness are reduced, and outflow gradients are further improved as compared to the acute result.
    Zeitschrift für Kardiologie 09/2005; 94(8):516-23. · 0.97 Impact Factor
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    ABSTRACT: Comparative studies with invasive coronary angiography (ICA) indicated a good sensitivity and specificity in the noninvasive detection of coronary artery disease (CAD) using Multi-slice spiral computed tomography coronary angiography (MS-CTA). The aim was to investigate the usefulness of MS-CTA as first-line imaging technique in patients (pts) with known or suspected CAD and low to intermediate probability of a severe coronary lesion. We report on our initial clinical experience using MS-CTA without compelled ICA. One hundred thirty six patients with chest pain underwent MS-CTA on an outpatient basis (age 60+/-10, suspicion of CAD: n=95, suspicion of restenosis: n=24, after CABG: n=17). Based on the MS-CTA results, a recommendation concerning further diagnostics and therapy was given to each pt. A telephone interview was performed after 455+/-166 days to evaluate the further clinical course. Per pt, 8.2+/-2.7 coronary segments could be evaluated. Based on the MSCT results, the presence of flow-limiting stenoses was excluded in n=77 (57%) pts (group I). An additional ICA was recommended in n=59 (43%) pts (group II). An ICA had been performed in meantime in 27/136 (20%) pts, and could be avoided in the majority of pts. Nevertheless, 58/136 (42%) pts reported on improved clinical symptoms and 42/136 (31%) pts of improved quality of life. MS-CTA was found to be useful to evaluate the need and to reduce the total number of ICA in pts with unclear chest pain. It appears to be the first noninvasive modality, which might be used on a clinical routine basis in selected groups of pts.
    International Journal of Cardiology 08/2005; 102(3):469-75. · 5.51 Impact Factor
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    ABSTRACT: IntroductionIn late 1997, the German Cardiac Society set up a multicenter registry to evaluate the acute and mid-term course of all patients (pts.) treated with septal ablation for symptomatic hypertrophic obstructive cardiomyopathy (HOCM). An analysis of the acute results has already been published. We now report on the mid-term course (3–6 months) of 242 pts. registered through September 1999.ResultsFollow-up was 92% complete (n=222). During follow-up (mean: 4.92.3 months), an additional 3 pts. died (in-hospital mortality: 3 pts.). A satisfactory clinical effect was reported by 195 pts. (88%); 27 pts. (12%) remained in NYHA classes III and IV. Overall symptomatic improvement (NYHA class: from 2.80.7 to 1.70.7) paralleled the outflow gradient (LVOTG) reduction which was further accentuated as compared with the acute result (Doppler measurement at rest: from 5731 to 2525 mmHg to 2021 mmHg; with provocation: from 10753 to 4940, to 4440 mmHg, pConclusionClinical success can be achieved by septal ablation, both with the echocontrast guided and gradient-fluoroscopy guided method, in 88% of highly symptomatic HOCM pts. At mid-term follow-up, symptoms, left atrial size and septal thickness are reduced, and outflow gradients are further improved as compared to the acute result.EinleitungIm Herbst 1997 richtete die Deutsche Gesellschaft fr Kardiologie ein bundesweites Register ein, das den Hospital- und mittelfristigen Verlauf bei mittels perkutaner Septumablation behandelten Patienten (Pat.) mit hypertropher obstruktiver Kardiomyopathie (HOCM) erfassen sollte. Die Analyse des Hospitalverlaufs liegt inzwischen vor. Wir berichten jetzt ber den mittelfristigen Verlauf (3–6 Monate) der bis September 1999 eingeschlossenen Patienten.ErgebnisseRckmeldungen lagen fr 222 von 242 initial erfassten Pat. vor (92%). Im Follow-up-Zeitraum (4,92,3 Monate) verstarben 3 weitere Pat. (Hospitalmortalitt: 3 Pat. (1,2%)). ber einen zufriedenstellenden Effekt der Intervention berichteten 195 Pat. (88%). Die akut erreichte Senkung des LVOT-Gradienten (LVOTG) von 5731 auf 2525 mmHg in Ruhe und von 10753 auf 4940 mmHg unter Provokation war nach 3–6 Monaten weiter akzentuiert (auf 2021 mmHg in Ruhe bzw. 4440 mmHg unter Provokation, p smtlich SchlussfolgerungIm mittelfristigen Verlauf nach Kathetertherapie, sowohl kontrastechokardiographisch wie auch per Druckmessung/fluoroskopisch gesteuert, besttigen sich die positiven Akutergebnisse mit einem weiteren Absinken des LVOTG. LA-Last und Septumdicke nehmen ab, die krperliche Belastbarkeit nimmt weiter zu.
    Zeitschrift für Kardiologie 07/2005; 94(8):516-523. · 0.97 Impact Factor
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    ABSTRACT: ICDs provide protection against sudden cardiac death in patients with life-threatening arrhythmias. Nevertheless, efficacy of defibrillation remains an important issue to guarantee the future safety of patients who receive an ICD. There is a significant number of patients who need an additional subcutaneous lead to obtain a defibrillation safety margin of at least 10 J between the maximum output of the ICD and the energy needed for ventricular defibrillation. However, few data exists about the long-term performance of different types of subcutaneous leads. Therefore, the aim of this study was to analyze the long-term experience with three different types of subcutaneous leads. The study included 132 patients (109 men, 23 women; mean age 59.8 years [SD +/- 10.7 years]). All of them received a subcutaneous lead in addition to a single chamber or dual chamber ICD between October 1990 and April 2002. Two patients received a second subcutaneous lead after the first lead had been removed so that a total of 134 subcutaneous leads were evaluated. Inclusion criteria for the implantation of an additional subcutaneous lead were (1) unsuccessful ventricular defibrillation at implant without a subcutaneous lead, (2) insufficient safety margin (< 10 J) between the maximum output of the ICD and the energy needed for ventricular defibrillation, or (3) clinical evaluation of a new subcutaneous lead (Medtronic 13014). There were no significant differences between the three study groups with regard to age, sex, underlying cardiac disease, left ventricular ejection fraction, NYHA class assessment and clinical arrhythmia. The results of the DFT testing during follow-up (prehospital discharge test and 1 and 3 years) were compared to the baseline value obtained during the implantation procedure. All lead related complications were analyzed. Eighty-two single element subcutaneous array electrodes (SQ-A1), 31 subcutaneous three-finger electrodes (SQ-A3), and 21 subcutaneous patch electrodes (SQ-P) were implanted during the study period. The median follow-up was 1,499 days (25th percentile: 798 days, 75th percentile: 1,976 days) in the SQ-A1 group, 2,209 days (25th percentile: 1,242 days, 75th percentile: 2,710 days) in the SQ-A3 group, and 1,419 days (25th percentile: 787 days, 75th percentile: 2,838 days) in the SQ-P group. None of the three groups had a significant change of the DFT during follow-up compared to baseline. Major complications occurred in six (7.3%) patients in group SQ-A1 and in two (9.5%) patients in group SQ-P. There were no major complications in group SQ-A3. Kaplan-Meier curves analyzing freedom from subcutaneous lead related complications did not show a significant difference between the three study groups (P = 0.16). SQ-A1, SQ-A3, and SQ-P leads provide stable DFTs during long-term follow-up. Major complications are rare. However, a careful follow-up including chest radiographs at regular intervals is needed to detect potentially fatal complications like lead fractures.
    Pacing and Clinical Electrophysiology 11/2004; 27(10):1355-61. · 1.75 Impact Factor
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    ABSTRACT: In patients with persistent atrial fibrillation (AF), the efficacy and safety of two anti-arrhythmic drugs in preventing the recurrence of AF after successful direct current (DC) cardioversion was prospectively assessed in a multi-centre double-blind, placebo-controlled, randomised trial using daily trans-telephonic monitoring. 1182 patients with persistent AF were prospectively enrolled, 848 patients were successfully cardioverted and then randomised to either sotalol (383 patients), quinidine plus verapamil (377 patients) or placebo (88 patients). The primary outcome parameter was AF recurrence or death. All patients received an event recorder (Tele-ECG) and had to record and transmit via telephone at least one ECG per day during follow-up. The mean follow-up period was 266 days. A total of 191,103 Tele-ECGs were recorded and transmitted. The primary outcome parameter (AF recurrence of any kind or death) was observed in 572 patients (67%) in whom at least one episode of AF recurrence was documented during follow-up, in 348 patients (41%) AF recurrence was persistent. The recurrence rates after one year for any AF were 83% for placebo, 67% for sotalol and 65% for quinidine plus verapamil, the latter being statistically superior to placebo but not different from sotalol. The recurrence rates for the secondary outcome parameter persistent AF were 77%, 49% and 38%, respectively. Quinidine plus verapamil was significantly superior to placebo and to sotalol. About 95% of all AF recurrences were initially detected in the daily Tele-ECG, about 70% of all AF recurrences occurred completely asymptomatic. Adverse events on sotalol and quinidine plus verapamil were comparable with the exception that all torsade de pointes tachycardias occurred on sotalol. Anti-arrhythmic treatment after DC cardioversion of persistent AF significantly decreases the recurrence rates of persistent AF compared to placebo with superiority of quinidine plus verapamil compared to sotalol. Symptoms were not reliable as clinical surrogates to detect episodes of AF.
    European Heart Journal 09/2004; 25(16):1385-94. · 14.10 Impact Factor
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    ABSTRACT: Registry results of the new catheter-based method in the treatment for HOCM are missing so far. In 1997, the Transcoronary Ablation of Septal Hypertrophy Registry (TASH Registry) was established by the German Cardiac Society (GCS) as a multicenter, national registry of patients with HOCM undergoing the new catheter interventional therapy. This is the report of the in-hospital outcome of patients who underwent the procedure during the first two years of data collection in the registry. Information was based on three standard forms for each patient, with a total of 86 variables. Information was collected on an "intention to treat" basis. The TASH Registry includes the establishment of a data base in the data collecting center. Ten centers participated. Enrollment forms were received for 264 patients out of 279 patients registered up to January 2000. There was a history of medical treatment of 3.6+/-3.9 years. The vast majority of patients (91%) were treated in three centers. The Vasalva maneuver and the exercise Doppler echocardiography were used for noninvasive stress testing. Exercise Doppler echocardiography induced a significantly higher augmentation of the baseline gradient (70.1% vs 133.4%; p<0.01). The echo-contrast guided technique was used for the intervention in 50.8% and the pressure angiography guided technique in 49.2%. On the average 2.8+/-1.3 ml of alcohol were injected. Before the procedure, the gradient measured by catheterization was 60.4+/-38.6 mmHg at baseline and 142.7+/-46.2 mmHg following the extrasystolic beat. At the end of the session it was reduced significantly by 75% and 67%. The peak phosphocreatine kinase activity was 482.5+/-246.4 U/L. Major complications occurred in 15.6% including a mortality rate of 1.2% and a permanent pacemaker implantation rate because of total heart block in 9.6%. There was an early in-hospital improvement of dyspnoe corresponding to a significant decrease of NYHA functional class from 2.8+/-0.7 to 1.8+/-0.6 (p<0.001). Similar hemodynamic and clinical benefit was found in patients with and without resting gradient at baseline. This analysis for the first time gives a comprehensive overview of clinical characteristics, technique, procedural data, in-hospital outcome and complications in a large number of patients with HOCM who were treated by the new catheter-based method and prospectively enrolled in a registry. The results contribute considerably to critical evaluation and validation of the new technique. This analysis supports the catheter-based method to constitute a new therapeutic option for very symptomatic patients, to be effective both in patients with and without intraventricular pressure gradient at rest and to be an alternative to surgical treatment, as has been stated recently.
    Zeitschrift für Kardiologie 01/2004; 93(1):23-31. · 0.97 Impact Factor
  • Zeitschrift Fur Kardiologie - Z KARDIOL. 01/2004; 93(1):23-31.
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    ABSTRACT: Registerergebnisse einer Katheterbehandlung der HOCM stehen bisher nicht zur Verfügung. 1997 wurde durch die Deutsche Gesellschaft für Kardiologie das nationale, multizentrische TASH-Register (Transkoronare Ablation der Septum-Hypertrophie-Register) von HOCM-Patienten eingeführt, die mit der neuen katheterinterventionellen Methode behandelt wurden. Erstmals wird über die Akutergebnisse während des Aufenthaltes der Patienten im Krankenhaus berichtet, die in den ersten beiden Jahren nach Einführung des Registers erfasst wurden.Es wurde eine Datenbank etabliert. Die Rekrutierung erfolgte auf Intention to treat Basis und sah insgesamt 86 Variable auf drei Standard Formularen vor. Zehn Zentren nahmen teil. Schriftliche Formulardaten standen von 264 Patienten zur Verfügung aus einer Gesamtgruppe von 279 Patienten, die bis Januar 2000 gemeldet wurden. Die Patienten waren im Mittel 3,6±3,9 Jahre medikamentös behandelt worden. Die Mehrzahl der registrierten Patienten (91%) stammte aus drei Zentren. Als Stress-Methode wurden der Valsalva- Versuch oder die Belastungs- Doppler-Echokardiographie verwendet. Die Belastungs-Doppler- Echokardiographie führte zu einer signifikant stärkeren Zunahme des Druckgradienten (70,1% vs. 133,4%, pVor der Behandlung betrug der invasiv gemessene Gradient 60,4±38,6 mmHg in Ruhe und 142,7±46,2 mmHg postextrasystolisch. Bei Beendigung des Eingriffs war er um 75% bzw. 67% reduziert. Die maximale Aktivität der Phosphokreatin-Kinase im Serum betrug 482,5±264,4 U/L. Gravierende Komplikationen traten in 15,6% auf einschließlich einer Mortalität von 1,2% und einer Schrittmacher-Implantationsrate wegen totalen av-Blocks in 9,6%. Es kam zu einer frühzeitigen Besserung der Luftnot bei Belastung entsprechend einer Abnahme des NYHA-Stadiums von 2,8±0,7 auf 1,8±0,6 (pErstmals steht eine auf Registerbasis vorgenommene Datenanalyse von HOCM-Patienten zur Verfügung, die mittels der neuen Kathetermethode behandelt wurden. Sie ermöglicht einen umfassenden Überblick über klinische Daten, Technik, periinterventionelle Ergebnisse und Komplikationen bei einer großen Zahl von Patienten. Die Ergebnisse tragen wesentlich zur kritischen Beurteilung und Validierung der neuen Methode bei. Sie unterstützen bisherige Ergebnisse, nach denen die Katheterbehandlung der HOCM als Alternative zur herzchirurgischen Behandlung eine neue therapeutische Option bei sehr symptomatischen HOCM-Patienten darstellt. Sie erwies sich sowohl bei Patienten mit als auch bei Patienten ohne intraventrikulärem Druckgradienten in Ruhe als effektiv.
    Zeitschrift für Kardiologie 01/2004; 93(1). · 0.97 Impact Factor
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    ABSTRACT: DPI 201-106 delays sodium channel inactivation. Acute administration of DPI 201-106 prolonged the QT interval, provoked spontaneous torsades de pointes in one patient, and facilitated stimulation-induced polymorphic ventricular tachyarrhythmias in two patients. Similar to the observations in animal studies, delaying sodium channel inactivation is a new form of the acquired long QT syndrome, mimicking long QT syndrome type 3.
    Journal of Cardiovascular Pharmacology 08/2003; 42(1):113-7. · 2.38 Impact Factor
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    ABSTRACT: The chromanol HMR 1556 is a potent blocker of KvLQT1/minK potassium channels expressed in Xenopus oocytes. The compound is therefore a new class III antiarrhythmic drug with a distinct mechanism of action. However, the effect of HMR 1556 on atrial ion channels and the selectivity of block in the human heart has not been investigated. We tested the effects of HMR 1556 on repolarizing potassium currents in human and guinea pig atrial myocytes. Single atrial myocytes were isolated by enzymatic dissociation. Atrial potassium currents (I(Ks), I(Kr), in guinea pig, I(to), I(Kur), I(K1) in humans) were recorded at 36 degrees C in the whole cell mode of the patch clamp technique. HMR 1556 produced a concentration-dependent and reversible block of I(Ks) with a half maximal concentration (EC(50)) of 6.8 nmol/l. 10 micromol/l HMR 1556 almost completely inhibited I(Ks) (97.2+/-3.2%, n=6). Steady-state activation as well as kinetic properties of the current were not altered by HMR 1556. I(Kr) currents were not affected up to concentrations of 10 micromol/l. HMR 1556 did not inhibit other potassium currents in human atrium: I(to), I(Kur) and the classical inward rectifier potassium current I(K1) were not significantly affected up to concentrations that completely blocked I(Ks) (10 micromol/l). HMR 1556 is a highly-potent blocker of I(Ks) channels without exerting effects on other potassium currents involved in atrial repolarization. Given the potential advantages of I(Ks) vs. I(Kr) blockade, the drug's new mechanism of action warrants further investigation to clarify its role as an antiarrhythmic agent.
    Archiv für Experimentelle Pathologie und Pharmakologie 04/2003; 367(3):281-8. · 2.15 Impact Factor
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    ABSTRACT: The purpose of the study was to characterize the ionic and molecular mechanisms in the very early phases of electrical remodeling in a rabbit model of rapid atrial pacing (RAP). Long-term atrial fibrillation reduces L-type Ca(2+) (I(Ca,L)) and transient outward K(+) (I(to)) currents by transcriptional downregulation of the underlying ionic channels. However, electrical remodeling starts early after the onset of rapid atrial rates. The time course of ion current and channel modulation in these early phases of remodeling is currently unknown. Rapid (600 beats/min) right atrial pacing was performed in rabbits. Animals were divided into five groups with pacing durations between 0 and 96 h. Ionic currents were measured by patch clamp techniques; messenger ribonucleic acid (mRNA) and protein expression were measured by reverse transcription-polymerase chain reaction and Western blot, respectively. L-type calcium current started to be reduced (by 47%) after 12 h of RAP and continued to decline as pacing continued. Current changes were preceded or paralleled by decreased mRNA expression of the Ca(2+) channel beta subunits CaB2a, CaB2b, and CaB3, whereas significant reductions in the alpha(1) subunit mRNA and protein expression began 24 h after pacing onset. Transient outward potassium current densities were not altered within the first 12 h, but after 24 h, currents were reduced by 48%. Longer pacing periods did not further decrease I(to). Current changes were paralleled by reduced Kv4.3 mRNA expression. Kv4.2, Kv1.4, and the auxiliary subunit KChIP2 were not affected. L-type calcium current and I(to) are reduced in early phases of electrical remodeling. A major mechanism appears to be transcriptional downregulation of underlying ion channels, which partially preceded ion current changes.
    Journal of the American College of Cardiology 04/2003; 41(5):858-69. · 14.09 Impact Factor
  • Volker Kühlkamp, Ludger Seipel
    New England Journal of Medicine 04/2003; 348(13):1284-6; author reply 1284-6. · 51.66 Impact Factor
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    ABSTRACT: Statins exert pleiotropic effects on several other cellular functions besides lipid-lowering. Previously, it was found that cerivastatin is a very potent inhibitor of human arterial smooth muscle cell (haSMC) growth. However, because increased extracellular matrix (ECM) synthesis also accounts mainly for intimal plaque formation, the effects of cerivastatin on ECM expression was examined in this study. Furthermore, the influence of varying glucose and low-density lipoprotein (LDL) levels on cerivastatin-treated haSMCs was analyzed to mimic the conditions in patients with diabetes or hypercholesterolemia. The haSMCs were treated with 0.001-5.0 microM cerivastatin in the presence of 5.5-18.9 m glucose and 10-1000 microg/ml LDL. After 3 days, the messenger RNA (mRNA) expression of eight ECM proteins was analyzed and, after 7 days, mitotic and mitochondrial activities and thrombospondin (TSP)-1 protein expression were analyzed. TSP-1 and TSP-2 mRNA expression was inhibited highly significantly at cerivastatin doses >or=0.01 microM with maximums of 72% and 35%, respectively, at high glucose levels. The mRNA signals of the third glycoprotein fibronectin were not influenced. Furthermore, collagen-1 mRNA was inhibited highly significantly up to 71% and biglycan mRNA was similarly inhibited up to 45%. The mRNA expression of the matrix-stimulating transforming growth factor (TGF)-beta1 and matrix metalloproteinase (MMP)-2 was not altered significantly, whereas mRNA expression of the tissue inhibitor of metalloproteinase (TIMP)-2 was stimulated clearly up to 150%. Mevalonate, but not LDL replacement, reversed the effects. Immunofluorescence staining showed an unaltered TSP-1 pattern with cerivastatin doses up to 0.1 microM whereas higher doses impaired TSP-1 excretion. The effects of cerivastatin on haSMC growth and mRNA expression of the eight ECM components were not diminished by the increase in LDL and glucose levels. Since accelerated SMC growth and ECM formation contribute mainly to intimal thickening, cerivastatin may be protective against the development of atherosclerotic and restenotic lesions by its direct cellular effects. Increased LDL and glucose levels, as in diabetes, do not mitigate the beneficial effects of cerivastatin on cell growth and ECM formation in vitro.
    Journal of Cardiovascular Pharmacology 03/2003; 41(3):422-33. · 2.38 Impact Factor
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    ABSTRACT: In severe acute coronary syndromes (ACS) elevation of markers of inflammation and acute phase reaction (APR) like C-reactive protein (CRP) as well as a release of troponin have been reported. Using a high sensitivity troponin T (TnT) test we investigated whether an APR occurs in ACS only in the presence of ischemic myocardial damage. In 85 patients with ACS C-reactive protein (CRP), serum amyloid A (SAA), fibrinogen, thrombin antithrombin III complexes (TAT) and kallikrein were determined vs. high sensitive TnT (> or =0.02 ng/ml) initially and 2 d later vs. 45 patients with stable angina pectoris and 42 controls. In stable angina pectoris, markers of inflammation and coagulation were slightly elevated (p < 0.05). Initially in ACS elevations of CRP to 1.2 +/- 0.3 mg/dl, SAA to 4.8 +/- 2.6 mg/dl and fibrinogen to 448 +/- 21 mg/dl (all p < 0.01 vs. controls) were found followed by a significant APR (p < 0.01). In the subgroup of TnT positive ACS patients, an APR with increased CRP (4.1 +/- 1.3 mg/dl), SAA (20.4 +/- 8.3 mg/dl), and fibrinogen (641 +/- 45 mg/dl) was detectable (all p < 0.05 vs. TnT negative patients). In contrast, patients without TnT release showed APR markers comparable to patients with stable angina pectoris. Our findings demonstrate an association between myocardial injury in ACS and acute phase reaction as evidenced by several molecular markers. A highly sensitive TnT-test identified myocardial injury in about all patients with APR while a standard TnT cut-off (0.1 ng/ml) missed 32% of these patients. Thus, the APR in patients with ACS is strongly associated with at least minor ischemic myocardial damage and prior findings of an APR independent from myocardial injury are probably based on less sensitive troponin tests.
    Journal of Thrombosis and Thrombolysis 02/2003; 15(1):33-9. · 1.99 Impact Factor
  • Journal of The American College of Cardiology - J AMER COLL CARDIOL. 01/2003; 41(6):241-241.
  • Journal of The American College of Cardiology - J AMER COLL CARDIOL. 01/2003; 41(6):467-468.
  • Journal of the American College of Cardiology 01/2003; 41(5). · 14.09 Impact Factor
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    ABSTRACT: I(Ks), the slow component of the delayed rectifier potassium current, underlies a strong beta-adrenergic regulation in the heart. Catecholamines, like isoproterenol, induce a strong increase in I(Ks). Recent work has pointed to an opposing biological effect of beta(1)- and beta(3)-adrenoceptors in the heart. However the role of these subtypes in the regulation of cardiac ion channel function is unknown. We investigated the effects of beta(1)- and beta(3)-adrenoceptor modulation on I(Ks) in guinea-pig ventricular myocytes, using patch-clamp techniques. Superfusion with 100 nmol/l isoproterenol increased the step current amplitude by 81.3+/-8.0%. In contrast, after block of beta(1)- (1 micromol/l atenolol) and beta(2)-receptors (1 micromol/l ICI118,551), isoproterenol induced a reduction of the step current amplitude by 34.3+/-3.5%. The beta(3)-selective agonist BRL37344 significantly reduced the I(Ks) step current at +70 mV in a concentration-dependent manner (IC(50): 5.01 nmol/l). In the presence of bupranolol (beta(1)-, beta(2)- and beta(3)-adrenoceptor antagonist), the effect of BRL37344 was markedly attenuated, from 27.3+/-5.6% (100 nmol/l BRL37344 alone) to 4.0+/-1.3% (100 nmol/l BRL37344+1 micromol/l bupranolol). BRL37344 (100 micromol/) did not alter current amplitudes of KvLQT1/minK expressed in CHO cells or in Xenopus oocytes, excluding a direct effect of BRL37344 on the channel. 1 micromol/l BRL37344 mildly prolonged action potentials in guinea pig ventricle (APD(90):+7.8%) We have demonstrated a functional coupling between the beta(3)-adrenoceptor and ion channel function in the mammalian heart. Our findings point to a potential role for beta(3)-adrenoceptors in cardiac electrophysiology and pathophysiology.
    Cardiovascular Research 01/2003; 56(3):393-403. · 5.94 Impact Factor

Publication Stats

2k Citations
1,141.75 Total Impact Points

Institutions

  • 1987–2012
    • University of Tuebingen
      • • Institute for Physiology
      • • Faculty of Medicine
      Tübingen, Baden-Wuerttemberg, Germany
    • Universitätsklinikum Jena
      Jena, Thuringia, Germany
  • 1990–2001
    • Universitätsklinikum Tübingen
      • Department of Medicine
      Tübingen, Baden-Württemberg, Germany
  • 1975–1990
    • Heinrich-Heine-Universität Düsseldorf
      • Klinik für Allgemein-, Viszeral- und Kinderchirurgie
      Düsseldorf, North Rhine-Westphalia, Germany
  • 1989
    • University of Chicago
      Chicago, Illinois, United States
  • 1975–1985
    • Universitätsklinikum Düsseldorf
      Düsseldorf, North Rhine-Westphalia, Germany