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Gene therapy-based modulation of atrioventricular (AV) conduction by overexpression of a constitutively active inhibitory Gα(i) protein effectively reduced heart rates in atrial fibrillation (AF). However, catecholamine stimulation caused an excessive increase in ventricular rate. We hypothesized that modest genetic suppression of a stimulatory G protein in the AV node would allow persistent rate control in acute AF and would prevent undesired heart rate acceleration during β-adrenergic activation. Atrial fibrillation was induced in 12 pigs by atrial burst pacing via an implanted cardiac pacemaker. Study animals were then assigned to receive either Ad-siRNA-Gα(s) gene therapy to inactivate Gα(s) protein or Ad-β-gal as control. Gα(s) protein inactivation resulted in a 20 % heart rate reduction (P < 0.01). AH and HV intervals were prolonged by 37 ms (P < 0.001) and 28 ms (P < 0.001), respectively, demonstrating atrioventricular conduction delay. Impairment of left ventricular ejection fraction (LVEF) during AF was attenuated by Gα(s) suppression (LVEF 49 %) compared with controls (LVEF 34 %; P = 0.03). Isoproterenol application accelerated ventricular heart rate from 233 to 281 bpm (P < 0.001) in control animals but did not significantly affect pigs treated with Ad-siRNA-Gα(s) (192 vs. 216 bpm; P = 0.19). In conclusion, genetic inhibition of Gα(s) protein in the AV node reduced heart rate and prevented AF-associated reduction of cardiac function in a porcine model. Rate control by gene therapy may provide an alternative to current pharmacological treatment of AF.

Objective: Increased dispersion (DISP) of refractoriness (ERP) facilitates the induction of malignant ventricular arrhythmias. Accordingly, QT DISP on surface ECG, supposedly reflecting ERP DISP, has been proposed as a noninvasive marker for risk stratification. However, a comparative analysis of local ERPs and QT measurements is not available so far., Methods and Results: In 19 healthy dogs, standard 12 lead surface ECGs were recorded to measure QT and RR intervals. Based on these measurements, corrected QT intervals (QTc, Bazett formula) and DISP (maximum difference) of both QT and QTc intervals (QT-DISP and QTc-DISP, respectively) were calculated. Subsequently, 60 custom-made needle electrodes (12 mm long, 4 bipolar electrodes per needle, interelectrode distance 2.5 mm) were inserted into the left (LV) and right ventricle (RV). At each bipole of 14 randomly selected needle electrodes (8 LV, 6 RV) local ERPs were determined (extrastimulus technique, basic cycle length 1000 ms). Interventricular DISP of ERP (LV-RV-DISP) was defined as the difference between the longest and shortest ERP within both ventricles. Respective values were calculated for each ventricle (LV-DISP; RV-DISP). Scatter plots and correlation analysis did not reveal a significant correlation between QT, QTc, QT-DISP, QTc-DISP and any of the ERP measurements or calculations. Although not statistically significant, the closest correlation was found between QTc and mean ERP and between QTc-DISP and LV-RV-DISP., Conclusion: QT measurements on surface ECG are poorly correlated with local ERPs. If anything, QT- or QTc-DISP might provide a rough estimate of interventricular, that is, global DISP of ERP. Local or even intraventricular DISP of ERP is definitely not reflected by these QT measurements.

Background: Dogs with chronic AV block exposed to type-III antiarrhythmic agents develop polymorphic ventricular tachycardias (PVT). Controversy exists regarding PVT mechanism and underlying pathophysiology., Methods and Results: In dogs with acute (n = 10, AAVB) or chronic AV block (n = 14, CAVB, 62 +/- 5 days after AV-node ablation) 60 pins (12 mm long, 4 bipolar electrodes) were inserted into both ventricles. QT intervals and effective refractory periods (ERP) at 56 +/- 22 randomly selected sites (extrastimulus technique, 800 ms basic cycle length) were determined before and after Almokalant (0.34 micromol/kg). A multiplexer mapping system was used to reconstruct 3D activation patterns. The heart-to-body-weight index (HBWI) was obtained after the experiments. CAVB led to a significant increase in HBWI (11.3 +/- 1.5 vs. 9 +/- 1.2 g/kg BW, p < 0.001), and a significant increase in ERP (280 +/- 28 ms vs. 260 +/- 37 ms, p < 0.05) and QT interval (339 +/- 16 vs. 288 +/-12 ms, p < 0.05). Dispersion (DISP) of ERP was similar for AAVB and CAVB dogs. No AAVB dog, but 9 of 14 CAVB dogs developed PVTs in response to Almokalant. All PVTs originated from an endocardial focus. Consecutive beats continued to reveal centrifugal activation patterns in 8 of 10 episodes. In only 2 episodes was reentrant activation evident., Conclusion: Myocardial hypertrophy associated with CAVB predisposes the canine heart to drug induced PVTs. This seems to be primarily linked to prolonged repolarization. PVTs in this model are not only initiated, but also perpetuated by a centrifugal spread of activation.

Background: The prognostic role of asymptomatic nonsustained ventricular tachycardia (NSVT) and programmed ventricular stimulation (PVS) in patients with idiopathic dilated cardiomyopathy (IDC) remains controversial., Methods: The prognostic significance of ventricular arrhythmias, ejection fraction, NYHA class, atrial fibrillation and age for overall and sudden death mortality was prospectively studied in 157 patients with IDC (group 1) free of documented sustained ventricular arrhythmia and syncope. In 99 patients with asymptomatic NSVT (group 2), PVS with 2 - 3 extrastimuli was performed. Non-inducible patients were discharged without specific antiarrhythmic therapy, whereas those with inducible monomorphic ventricular tachycardia were implanted with an ICD., Results: In group 1, 48% of patients had NSVT. Overall and sudden death mortality were significantly higher in patients with NSVT (34.2 vs. 9.8%, p = 0.0001 and 15.8 vs. 3.7%, p = 0.0037; follow-up 22 +/- 14 months). Multivariate analysis revealed that NSVT independently predicts both overall and sudden death mortality (p = 0.0021 and.0221, respectively; adjusted for EF, NYHA class and age). In group 2, inducibility of sustained ventricular tachyarrhythmia was 7%, but sustained monomorphic VT occurred in 3% only. Two of 7 inducible patients experienced arrhythmic events during a follow-up of 25 +/- 21 months (positive predictive value 29%). Overall and sudden death mortality were 29% and 0% in the inducible group vs. 17 and 4% in the non-inducible group. Both overall and sudden death mortality were significantly lower in non-inducible patients from group 2 as compared to patients from group 1 with NSVT (p = 0.0043 and 0.0048), most likely due to a more common use of betablockers and a higher EF in the former group (p < 0.001, respectively)., Conclusions: In patients with IDC, NSVT independently predicts both overall and sudden death mortality. Due to a low inducibility rate and a poor positive predictive value, PVS seems inappropriate for further arrhythmia risk assessment. However, in spite of documented NSVT, the incidence of SCD in patients on optimized medical treatment including betablockers seems to be very low, questioning the need for specific arrhythmia risk stratification.

Objectives: Successful RF ablation of atrial fibrillation supposedly requires the creation of continuous linear lesions. This study aimed to determine the potential role of functional modifications of atrial myocardium in the vicinity of anatomic RF lesions., Methods: In 10 normal beagles (group A), a multiplexer mapping system and an epicardial multi-electrode were used to reconstruct atrial activation patterns during pacing at two cycle lengths before and after attempts to induce two linear right atrial lesions with a standard ablation catheter, respectively. An intercaval "drawback" was repeated 3 times over 5 min at a set temperature of 70 degrees C, followed by a transversal "point-by-point" ablation from the interatrial septum to the right-lateral tricuspid annulus at 70 degrees C/60 s each. Induction of atrial flutter was attempted before and after each ablation. In another 6 beagles (group B), a high-resolution multi-electrode was used to study epicardial functional effects resulting from single endocardial RF lesions on the free right atrial wall. Using three energy settings (60 degrees C/30 s, 60 degrees C/60 s, 70 degrees C/60 s), activation patterns were analyzed at two cycle lengths and local effective refractory periods were measured across the lesion., Results: The lesions induced in group A only marginally affected atrial activation patterns and total activation times. However, as shown in dogs with atrial flutter, regional slow conduction was enhanced and functional conduction blocks were facilitated at high atrial rates, resulting in a significant prolongation in the revolution time of respective reentrant circuits. Apart from inducing anatomic lesions, single endocardial RF lesions (group B) were shown to delay epicardial conduction in adjacent myocardium in an energy- and rate-dependent way. Furthermore, an energy-dependent prolongation of effective refractory periods by far exceeding the size of anatomic lesions was observed., Conclusions: Continuous linear atrial lesions are hard to achieve with conventional ablation techniques. However, RF lesions induce changes in conduction and refractoriness around the anatomic lesion, which are likely to contribute to the overall effect of respective therapeutic interventions.

Background: Structural complexities of the intact ventricular wall cause a very complex spread of activation. The effects of regional tissue damage and of antiarrhythmic drugs on directional differences in activation should help to further elucidate intramural conduction patterns., Methods and Results: In 10 healthy dogs and in 5 dogs with subacute anterior wall infarction, 6 parallel rows of 6 needle electrodes with 4 bipolar electrode pairs per needle were inserted into the left anterior ventricular wall. Using a computerized multiplexer-mapping system, the spread of activation in epi-, endo- and midmyocardial muscle layers and in the surviving epicardium, respectively, was reconstructed. Marked differences in conduction velocities relative to fiber orientation were evident in the surviving epicardium of infarcted hearts. Directional differences in conduction velocities, although less pronounced, were still preserved throughout the intact ventricular wall. Epicardial transverse conduction in intact hearts was significantly faster than transverse conduction in infarcted hearts (0.87 +/- 0.11 m/s vs 0.68 +/- 0.1 m/s). In normal hearts, propafenone (2 mg/kg) decreased conduction velocities primarily in longitudinal directions (-27 +/- 10%), but also moderately in transverse directions (-13 +/- 7 %) of all muscle layers, with no significant effect on straight (-4 +/- 8 %), but on oblique transmural conduction (-33 +/- 18 %). In infarcted hearts propafenone decreased conduction particularly in longitudinal direction (-23 +/- 14 %) without affecting conduction transverse to the fiber orientation (+3 +/- 6%)., Conclusions: Longitudinal intramural shortcircuits reduce directional differences in activation. Transmural infarction results in a loss of alternative intramural pathways, unmasking marked anisotropy in the surviving epicardium. Conduction delay in intramural pathways explains the effects of propafenone on transverse and oblique transmural conduction. Primarily longitudinal conduction delay results in reduced tissue anisotropy.

Objectives: Aim of the present study was to investigate site- and rate dependent effects of the IKs-blocking agent chromanol 293b on conduction and refractoriness in normal, infarcted, and transitional regions of in-situ canine hearts., Methods: In five dogs with subacute myocardial infarction, three-dimensional mapping was performed after insertion of 6 x 6 needle electrodes in the left ventricle. Before and after application of chromanol 293b (10 mg/kg), activation patterns and local refractory periods (ERPs) at pacing intervals of 300, 500 and 850 ms were obtained for the surviving epicardial muscle layer of the infarct zone (IZ) and for epi-, endo-, and midmyocardial muscle layers of both the normal zone (NZ) and the border zone (BZ) separating normal and infarcted areas., Results: At baseline, both the NZ and the BZ exhibited uniform ERPs throughout the ventricular wall. Epicardial ERPs were longer in the IZ than in the NZ, and intermediate in the BZ. Chromanol 293b did not affect total activation times. However, at fast heart rates regional areas of slow conduction occurred. Chromanol 293b ubiquitously prolonged local ERPs, most markedly in the IZ. A preferential effect on individual muscle layers of the NZ or BZ and, thus, drug-induced transmural dispersion of ERP could not be observed. Again ubiquitously, the effect on ERP was more pronounced at faster than at slower heart rates, that is, positive use-dependent. At a basic cycle length of 300 ms, chromanol 293b prolonged local ERPs in the IZ by 46 +/- 24 %, in the BZ by 34 +/- 26%, and in the NZ by 20 +/- 17% (p < or = 0.05)., Conclusions: At least in theory, the electrophysiologic properties of chromanol 293 b, that is, preferential prolongation of refractoriness in ischemic myocardium, more pronounced at faster than at slower heart rates, but homogeneously throughout the intact ventricular wall, appear to be favorable. Whether this translates into a clinical benefit, particularly in the treatment of ischemia-related ventricular tachyarrhythmias, remains to be determined.