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Karsten Knobloch

Publications and source records attributed to Karsten Knobloch.

27 records · Page 2Linked to original sources
PubMed2004

Atrial-selective antiarrhythmic actions of novel Ikur vs. Ikr, Iks, and IKAch class Ic drugs and beta blockers in pigs.

BACKGROUND: The Kv1.5 channel, underlying IKur, is supposed to be atrial selective in pigs and humans. We investigated the effects of different potassium channel blockers, i.e. the IKur blockers AVE 0118, S9947 and S20951, with amiodarone (AM), dofetilide (DO), azimilide (AZ), ibutilide (IB), the IKs blocker HMR 1556, atropine (ATR), flecainide (FL), propafenone (PR), d,l-sotalol (SO), atenolol (ATE), and esmolol (ES), on the left and right atrial and ventricular refractoriness and left atrial vulnerability (LAV) in vivo in pigs. MATERIAL/METHODS: In pentobarbital-anesthetized pigs (n=81), atrial and ventricular effective refractory periods (ERPs) were measured with the S1-S2-extrastimulus-method and QTc time from electrocardiograms. LAV was assessed after S2-extrastimulus to the left atrium. RESULTS: All IKur blockers prolonged left stronger than right atrial ERP and did not change QTc. All IKr blockers predominantly prolonged the right vs. left atria. AM prolonged both atria equally, and ATR the left only. Pure beta blockers acted predominantly on the left atrium, as did FL and PR, while d,l-sotalol acted predominantly on the right. AVE 0118, S9947, S20951, ibutilide, and d,l-sotalol significantly decreased LAV (-100%, -100%, -82%, -53%, -42%; p<0.05), in contrast to all other drugs. CONCLUSIONS: The IKur blockers exhibited stronger effects on the left atrium, which itself has shorter refractoriness, but strikingly with no effect on ventricular repolarization, while IKr blockers, IKs blockers, and d,l-sotalol exerted predominantly right atrial effects and known ventricular effects. IKur blockers inhibited atrial tachyarrhythmias stronger than all available drugs. Therefore, IKur blockers seem to be promising new atrial-selective antiarrhythmic drugs.

Adrenergic beta-Antagonists↗
PubMed2004

Replacement of the aortic root for acute prosthetic valve endocarditis: prosthetic composite versus aortic allograft root replacement.

OBJECTIVE: Aortic root replacement for prosthetic aortic valve endocarditis with accompanying destruction of the aortic root is a well-established surgical intervention. However, there is still no consensus whether prosthetic material or allogeneic material should be used. Here we report on our experience with prosthetic composite and aortic allograft root replacement in such patients during a 10-year interval. METHODS: From 1991 through 2001, 29 patients with prosthetic aortic valve endocarditis combined with aortic root destruction underwent reoperation at our institution. Sixteen patients received aortic root replacement with a cryopreserved aortic root allograft (group A) and 13 with a prosthetic composite graft (group B). The interval between the initial operation and reoperation was 29 months (range, 5-168 months) in group A and 55 months (range, 7-248 months) in group B. RESULTS: Hospital mortality was 18.5% (n = 5 patients, 3 in group A and 2 in group B). Median follow-up was 21 months (range, 1-48 months) for group A and 34 months (range, 1-152 months) for group B (P >.2). Survival at 1 and 5 years was 81% +/- 10% and 81% +/- 10% in group A and 85% +/- 10% and 85% +/- 10% in group B, respectively. No patient underwent reoperation for recurrent prosthetic aortic valve endocarditis. CONCLUSIONS: Our results indicate that excellent long-term results can be achieved regardless of the material used for aortic root replacement in patients with prosthetic aortic valve endocarditis.

Acute Disease↗
PubMed2003

Atrial effects of the novel K(+)-channel-blocker AVE0118 in anesthetized pigs.

OBJECTIVES: AVE0118 is a novel blocker of the K(+) channels K(v)1.5 and K(v)4.3 which are the molecular basis for the human cardiac ultrarapid delayed rectifier potassium current (I(Kur)) and the transient outward current (I(to)). The objective of this study was to investigate the effect of AVE0118 on atrial refractoriness (ERP), left atrial vulnerability (LAV) and on left atrial monophasic action potentials (MAP) in pentobarbital anesthetized pigs in comparison to the selective I(Kr) blocker dofetilide in order to assess the therapeutic potential of the novel K(+) channel blocker for atrial fibrillation. METHODS: Atrial ERP was determined with the S1-S2-stimulus method in the free walls of left and right atrium at 240, 300 and 400 ms basic cycle length (BCL). The inducibility of mostly nonsustained atrial tachyarrhythmias by the premature S2 extrastimulus, which is very high in the left pig atrium and referred to as LAV, was evaluated before and after drugs. Left atrial epicardial MAP was recorded to study the influence of the potassium channel blockers on the time course of repolarization. Left ventricular epicardial MAP, ERP and QT interval were measured to investigate a possible effect of AVE0118 on ventricular repolarization. RESULTS: ERPs determined at 240, 300 and 400 ms BCL were significantly shorter in the left vs. right atrium (99+/-3, 106+/-4 and 113+/-3 ms vs. 133+/-4 ms, 142+/-4 and 149+/-5, respectively; p<0.001; n=21). AVE0118 administered i.v. dose-dependently prolonged the atrial ERP independent from rate and inhibited LAV (100% at 0.5 and 1 mg/kg) while having no effect at all on the corrected QT (QTc) interval. At 1 mg/kg (n=5) AVE0118 prolonged left vs. right atrial ERP by 49.6+/-4.1 ms vs. 37.7+/-9.7 ms (means+/-SEM of changes at 240, 300, and 400 ms BCL), respectively, corresponding to a relative increase of 53.2+/-6.2% vs. 27.6+/-6.8% (p<0.05 for percent increase of left vs. right atrial ERP). In a separate group of pigs (n=5) AVE0118 had no effect on left ventricular ERP at 333, 400 and 500 ms BCL and no effect on MAP duration and QT at 600 ms BCL. After 1 mg/kg of AVE0118 the atrial MAP was significantly prolonged already at 10% repolarization (P<0.05; n=7) reaching the maximum at 40% repolarization. In contrast to AVE0118 the effect of dofetilide (10 microg/kg) on atrial MAP started to become significant only at 60% repolarization (n=6) with a maximum increase at 90%. Dofetilide, which prolonged the QTc interval by 16.9% (P<0.001), had a significantly stronger effect on right (34.7+/-5 ms) vs. left atrial ERP (23.5+/-7 ms) at 300 ms BCL, respectively, but did not significantly inhibit LAV (14%; n=6). CONCLUSION: The novel K(+) channel blocker AVE0118 prolonged atrial ERP and showed strong atrial antiarrhythmic efficacy with no apparent effect on ventricular repolarization in pigs in vivo.

Action Potentials↗
PubMed2003

Methylene blue: the drug of choice for catecholamine-refractory vasoplegia after cardiopulmonary bypass?

OBJECTIVES: Vasoplegia is a frequent complication after cardiopulmonary bypass that often requires the application of norepinephrine. In a number of cases, however, vasoplegia is refractory to norepinephrine. The guanylate cyclase inhibitor methylene blue could be an attractive treatment alternative in such cases. This study examines the results of methylene blue therapy for norepinephrine-refractory vasoplegia after cardiopulmonary bypass. METHODS: A total of 54 patients with norepinephrine-refractory vasoplegia after cardiopulmonary bypass were treated with methylene blue (2 mg/kg) administered intravenously through a period of 20 minutes. The effects on hemodynamics, norepinephrine dosage, and clinical outcome were evaluated. RESULTS: Three patients (5.6%) died during the hospital stay. A clinically relevant increase in systemic vascular resistance and a decrease in norepinephrine dosage were observed in 51 patients within 1 hour after methylene blue infusion. Four patients (7.4%) had no response to methylene blue. No adverse effects related to methylene blue were observed. CONCLUSIONS: A single dose of methylene blue seems to be a potent approach to norepinephrine-refractory vasoplegia after cardiopulmonary bypass for most patients, with no obvious side effects. Guanylate cyclase inhibitors could be a novel class of agents for the treatment of norepinephrine-refractory vasoplegia after cardiopulmonary bypass. A controlled clinical trial is now needed to evaluate the role of methylene blue in this situation.

Cardiopulmonary Bypass↗
PubMed2002

Electrophysiological and antiarrhythmic effects of the novel I(Kur) channel blockers, S9947 and S20951, on left vs. right pig atrium in vivo in comparison with the I(Kr) blockers dofetilide, azimilide, d,l-sotalol and ibutilide.

Inhibition of the cardiac Kv1.5 channel, the molecular base for the human cardiac ultrarapid delayed rectifier potassium current (I(Kur)), is considered a new promising atrial selective antiarrhythmic concept since this channel is presumed to contribute to atrial but not ventricular repolarization in the human heart. In a previous study in pigs we found clear baseline differences in refractoriness between left and right atrium with shorter effective refractory periods (ERPs) of the left atrium associated with a high left atrial vulnerability for tachyarrhythmias. In this newly established model we compared atrial and ventricular effects of two novel I(Kur) blockers, S9947 and S20951, with the I(Kr) blockers dofetilide, azimilide, ibutilide and d,l-sotalol. In pentobarbital anesthetized pigs (n=45) we determined ERPs in the free walls of both atria with the S1-S2-stimulus method at three basic cycle lengths (BCL 240/300/400 ms) and QTc-intervals. The incidence of atrial tachyarrhythmias triggered by the S2-extrastimulus of the left atrium was evaluated (referred to as left atrial vulnerability). In contrast to I(Kr) blockade, I(Kur) blockade had no effect on the QT-interval, but prolonged the atrial ERP. The I(Kur) blockers were significantly stronger on left atrial ERP, I(Kr) blockers on right atrial ERP (P<0.05 for all compounds tested). At 240 ms BCL the I(Kur) blocker S20951, 3 mg/kg, prolonged left vs. right atrial ERP by 28+/-5 ms vs. 12+/-3 ms and S9947, 3 mg/kg, by 45+/-7 ms vs. 19+/-6 ms. By contrast the effect of dofetilide, 10 microg/kg, was stronger on the right than left atrium (47+/-6 ms vs. 25+/-2 ms), a profile also found with azimilide (5 mg/kg, 43+/-3 ms vs. 17+/-3 ms), ibutilide (15 microg/kg, 70+/-10 ms vs. 29+/-4 ms) and d,l-sotalol (1.5 mg/kg, 57+/-6 ms vs. 36+/-4 ms). The I(Kur) blockers, S20951and S9947, significantly decreased left atrial vulnerability (-82% and -100%, respectively, P<0.01) in contrast to the selective I(Kr) blocker dofetilide (-14%; n.s.). In conclusion, I(Kur) and I(Kr) blockers showed substantial differences in their atrial and ventricular actions in pigs. I(Kr) blockers were stronger on right atrial ERP, I(Kur) blockers on left atrial ERP, suggesting interatrial differences in the expression of potassium channels. In contrast to selective I(Kr) blockade, I(Kur) blockade inhibited left atrial vulnerability and had no effect on the QT-interval. Thus, blockade of I(Kur) seems to be a promising atrial selective antiarrhythmic concept.

Animals↗