Roman Laszlo

Inhibition of the renin-angiotensin system: effects on tachycardia-induced early electrical remodelling in rabbit atrium

Introduction. Tachycardia-induced atrial remodelling (as an equivalent to atrial fibrillation) can be influenced by the renin-angiotensin system. Effects of a seven-day enalapril pre-treatment (EPT, 0.16 mg/kg body weight subcutaneously every 24 h) on ionic currents underlying tachycardia-induced early electrical remodelling after 24 h rapid atrial pacing (RAP, 600 beats/min) in rabbit atrium were studied. Materials and methods. Animals were divided into four groups (n=4 each): control; paced only; enalapril only; and enalapril and paced, respectively. Using patch-clamp technique in whole-cell mode, current densities were measured in isolated atrial myocytes. Results. EPT nearly doubled L-type calcium current (ICa,L, −7.7±0.6 pA/pF [control] vs. f −12.3±1.2 pA/pF [enalapril only]). RAP reduced ICa,L to −3.6±0.7 pA/pF (paced only). Also after EPT, RAP led to a significant downregulation of ICa,L by 39% (−7.5±1.3 pA/pF [paced and enalapril]). RAP decreased transient outward potassium current (Ito, −45%, 51.5±3.9 pA/pF [control] vs. 28.5±4.5 pA/pF [paced only]). EPT did not alter Ito (44.2±8.1 pA/pF [enalapril only]). However, RAP did not affect Ito in enalapril-treated animals and averaged 50.4±9.8 pA/pF (paced and enalapril). Conclusions. In summary, EPT has several effects on ion channels in rabbit atrium: 1) EPT increases ICa,L current density, but cannot prevent its downregulation due to RAP; 2) EPT has no influence on Ito current density, but can prevent its downregulation due to RAP. Although changes of single ion channels must be interpreted in context of the complex atrial electrophysiology as a whole, our results provide a possible explanation of the in vivo observation that angiotensin-converting enzyme inhibition is mainly beneficial on the early electrical remodelling due to the atrial fibrillation-equivalent RAP.

Influence of dexamethasone on atrial ion currents and their early ionic tachycardia-induced electrical remodeling in rabbits.

Background: Certain evidence points to a role of inflammation in AF pathophysiology. Thus, antiinflammatory treatment of AF is discussed. Effects of a dexamethasone treatment (7 days) on atrial ion currents (ICa,L, Ito, Isus) and their tachycardia-induced remodeling were studied in a rabbit model. Methods: 6 groups of 4 animals each were built. Rapid atrial pacing (600 min) was performed for 24 and 120 hours with/ without dexamethasone treatment. Ion currents were measured using whole cell patch clamp method. Results: Rapid atrial pacing reduced (ICa,L, Ito was decreased after 24 hours but almost returned to control values after 120 hours. When dexamethasone-treated animals also underwent atrial tachypacing, pacing-induced reduction of ICa,L was still observed after 24 hours and was even augmented after 120 hours compared to untreated but tachypaced animals. Ito was not influenced by dexamethasone alone. In dexamethasone-treated animals, reduction of Ito was not observed after 24 hours but occurred after 120 hours of atrial tachypacing. Isus was neither influenced by rapid atrial pacing nor by dexamethasone. Biophysical properties of all currents were affected neither by rapid atrial pacing nor by dexamethasone. Conclusion: Dexamethasone influenced tachycardia-induced alterations of atrial Ito. Our experiments give evidence that - amongst other anti-inflammatory action – impact of dexamethasone on ion currents and their tachycardia-induced alterations might also play a role in treatment/prevention of AF with steroids.

Genetic Polymorphisms as Risk Stratification Tool in Primary Preventive ICD Therapy

More and more implantable cardioverter-defibrillators (ICDs) are implanted as primary prevention of sudden cardiac death (SCD). However, major problem in practice is to identify high-risk patients for SCD. Different methods for noninvasive risk stratification do not have a sufficient positive or negative predictive value. Since current approaches lead to implantation of ICDs in a large number of patients who will never suffer an arrhythmic event and simultaneously patients still die of SCD who currently did not seem eligible for primary preventive ICD implantation, there is a need for additional tools for risk stratification. Epidemiological studies point to a hereditary risk of SCD. Different susceptibility of each person concerning arrhythmogenic events might be explained by genetic polymorphisms. By obtaining an individual “pattern” of polymorphisms of genes encoding for proteins which are important in arrhythmogenesis in one patient, risk stratification in primary prevention of SCD might by improved.

Atrial reverse remodeling: Restitution of early tachycardia-induced alterations of atrial ion currents after termination of rapid atrial pacing in rabbits

BACKGROUND AND PURPOSE Studies report on the reversal of electrophysiological parameters altered by atrial tachycardia after cessation of the latter. However, there is no data concerning reversal of tachycardia-induced alterations of ion currents. Reverse remodeling of atrial ion currents (I(Ca,L), I(to), I(sus)) was studied in our rabbit model of tachycardia-induced electrical remodeling. METHODS Three groups each with four animals were built. Rapid atrial pacing (600/min) for 5 days was applied in all groups. Thereafter, different time intervals (5, 10, 20 days) were awaited before the patch clamp experiments. RESULTS Similar to I(to) remodeling in our model, within 20 days after cessation of atrial tachycardia, time course of I(to) reverse remodeling was also U-shaped. In contrast, there was no significant recovery of I(Ca,L) which was initially reduced by rapid atrial pacing. CONCLUSION Relevance of a missing recovery of I(Ca,L) is likely as this current is closely linked with intracellular calcium handling.

Efficacy of Cut-and-Sew Box Isolation of the Posterior Left Atrium for Treatment of Atrial Fibrillation-Long-term Follow-up after a Modified Maze Procedure

BACKGROUND Box isolation of the posterior left atrium is one surgical or catheter ablative approach for treating atrial fibrillation (AF). In such cases, incomplete transmurality or recovery of pulmonary vein conduction after the application of various ablative techniques is considered the main reason for the recurrence of postprocedural arrhythmia. The use of solely cut-and-sew box isolation does not have these disadvantages and therefore demonstrates maximum efficacy for this therapeutic approach. METHODS We treated 15 patients with both an indication for open heart surgery and AF (2 paroxysmal, 6 short persistent [<12 months], and 7 long persistent [>12 months] cases) with a solely cut-and-sew box lesion. These patients were then retrospectively followed up over the long term with respect to the end point of freedom of atrial tachyarrhythmias >30 seconds. RESULTS The median follow-up duration was 42 months (range, 32-84 months). Five (63%) of 8 patients with preoperative paroxysmal or short persistent AF had no arrhythmia recurrence, whereas arrhythmia recurrence was documented in all 7 patients with preoperative long persistent AF. CONCLUSIONS Despite reliable transmural isolation with cut-and-sew lesions, we observed long-term arrhythmia recurrence in patients who had preoperative paroxysmal or short persistent AF, suggesting that therapy approaches that are more complex than box isolation might be needed for selected patients to achieve long-term stable sinus rhythm, despite the initially paroxysmal or short persistent character of the arrhythmia. A high rate of recurrence in patients with severe structural heart disease and preoperative long persistent AF might indicate that, in general, isolation of the left posterior atrium alone is not an adequate therapeutic approach for these patients.