Sterile Pericarditis Research Articles

Signal Transducer and Activator of Transcription 3/MicroRNA-21 Feedback Loop Contributes to Atrial Fibrillation by Promoting Atrial Fibrosis in a Rat Sterile Pericarditis Model.

Postoperative atrial fibrillation is a frequent complication in cardiac surgery. The aberrant activation of signal transducer and activator of transcription 3 (STAT3) contributes to the pathogenesis of atrial fibrillation. MicroRNA-21 (miR-21) promotes atrial fibrosis. Recent studies support the existence of reciprocal regulation between STAT3 and miR-21. Here, we test the hypothesis that these 2 molecules might form a feedback loop that contributes to postoperative atrial fibrillation by promoting atrial fibrosis. A sterile pericarditis model was created using atrial surfaces dusted with sterile talcum powder in rats. The inflammatory cytokines interleukin (IL)-1β, IL-6, transforming growth factor-β, and tumor necrosis factor-α, along with STAT3 and miR-21, were highly upregulated in sterile pericarditis rats. The inhibition of STAT3 by S3I-201 resulted in miR-21 downregulation, which ameliorated atrial fibrosis and decreased the expression of the fibrosis-related genes, α-smooth muscle actin, collagen-1, and collagen-3; reduced the inhomogeneity of atrial conduction; and attenuated atrial fibrillation vulnerability. Meanwhile, treatment with antagomir-21 decreased STAT3 phosphorylation, alleviated atrial remodeling, abrogated sterile pericarditis-induced inhomogeneous conduction, and prevented atrial fibrillation promotion. The culturing of cardiac fibroblasts with IL-6 resulted in progressively augmented STAT3 phosphorylation and miR-21 levels. S3I-201 blocked IL-6 induced the expression of miR-21 and fibrosis-related genes in addition to cardiac fibroblast proliferation. Transfected antagomir-21 decreased the IL-6-induced cardiac fibroblast activation and STAT3 phosphorylation. The overexpression of miR-21 in cardiac fibroblasts caused the upregulation of STAT3 phosphorylation, enhanced fibrosis-related genes, and increased cell numbers. Our results have uncovered a novel reciprocal loop between STAT3 and miR-21 that is activated after heart surgery and can contribute to atrial fibrillation.

Interleukin-17A contributes to the development of post-operative atrial fibrillation by regulating inflammation and fibrosis in rats with sterile pericarditis.

Post-operative atrial fibrillation (AF) remains a common cause of morbidity. Increasing evidence indicates that inflammation and atrial fibrosis contribute to the pathogenesis of this condition. Interleukin (IL)-17A, a potent pro-inflammatory cytokine, has been implicated in the development of a number of cardiovascular diseases. However, its role in post-operative AF remains unknown. In the present study, sterile pericarditis (SP) was induced in rats by the epicardial application of sterile talc. AF was induced by transesophageal burst pacing. Western blot analysis was applied to quantify the expression of IL-17A. Quantitative PCR was used to detect the mRNA expression of IL-17A, IL-6, IL-1β, transforming growth factor-β1 (TGF-β1), collagen type 1 (Col-1), collagen type 3 (Col-3) and α-smooth muscle actin (α-SMA). Gelatin zymography and reverse gelatin zymography were used to quantify the levels of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs). Histological analyses were performed to determine the extent of tissue inflammation and fibrosis. The rats with SP presented with a shorter refractoriness, a higher incidence and duration of AF, an enhanced susceptibility to developing AF, increased mRNA levels of AF-related pro-inflammatory cytokines (IL-6, IL-1β and TGF-β1), as well as marked atrial inflammation and fibrosis. The atrial IL-17A levels were elevated and correlated with the probability of developing AF. Treatment with anti-IL-17A monoclonal antibody decreased the levels of atrial IL-17A, prolonged refraction and markedly suppressed the development of AF. Simultaneously, inflammation and fibrosis were alleviated, which was further demonstrated by a decreased expression of AF-related pro-inflammatory cytokines, a down-regulation in fibrosis-related mRNA expression (Col-1, Col-3 and α-SMA) and by the decreased activity of MMP-2/9 and TIMPs. Thus, the findings of our study indicate that IL-17A may play a pathogenic role in post-operative AF by inducing inflammation and fibrosis in rats with SP.

Termination of Atrial Flutter and Fibrillation by K201's Metabolite M-II: Studies in the Canine Sterile Pericarditis Model.

K201, a 1,4-benzodiazepine derivative, acts on multiple cardiac ion channels and the ryanodine receptor. We tested whether administration of M-II, the main metabolite of K201, would terminate induced atrial flutter (AFL) or atrial fibrillation (AF) in the canine sterile pericarditis model. In 6 dogs, electrophysiologic studies were performed at baseline and after drug administration, measuring atrial effective refractory period (AERP), and conduction time from 3 sites during pacing at cycle lengths (400, 300, and 200 milliseconds) on postoperative days 1-4. In 12 induced episodes of sustained AF/AFL (2/10, respectively), M-II was administered intravenously to test efficacy. Five of the AFL episodes were studied in the open chest state during simultaneous multisite atrial mapping. M-II terminated 2/2 AF and 8/10 AFL episodes, prolonged AERP (P < 0.05), significantly increased atrial pacing capture thresholds but did not significantly change atrial conduction time. AFL CL prolongation was largely explained by prolonged conduction in an area of slow conduction in the reentrant circuit. AFL terminated with block in the area of slow conduction. M-II was very effective in terminating AFL/AF in the canine sterile pericarditis model. AFL terminated due to block in the area of slow conduction of the reentrant circuit.

Insights into new-onset atrial fibrillation following open heart surgery and implications for type II atrial flutter.

Postoperative atrial fibrillation (POAF), new-onset AF after open heart surgery (OHS), is thought to be related to pericarditis. Based on AF studies in the canine sterile pericarditis model, we hypothesized that POAF in patients after OHS may be associated with a rapid, regular rhythm in the left atrium (LA), suggestive of an LA driver maintaining AF. The aim of this study was to test the hypothesis that in patients with POAF, atrial electrograms (AEGs) recorded from at least one of the two carefully selected LA sites would manifest a rapid, regular rhythm with AEGs of short cycle length (CL) and constant morphology, but a selected right atrial (RA) site would manifest AEGs with irregular CLs and variable morphology. In 44 patients undergoing OHS, AEGs recorded from the epicardial surface of the RA, the LA portion of Bachmann's bundle, and the posterior LA during sustained AF were analysed for regularity of CL and morphology. Sustained AF occurred in 15 of 44 patients. Atrial electrograms were recorded in 11 of 15 patients; 8 of 11 had rapid, regular activation with constant morphology recorded from at least one LA site; no regular AEG sites were present in 3 of 11 patients. Atrial electrograms recorded during sustained POAF frequently demonstrated rapid, regular activation in at least one LA site, consistent with a driver maintaining AF.

GBR-12909: Potent Blocker of Peak and Late Nav1.5 Currents

GBR-12909 (vanoxerine) is a potent highly selective dopamine transporter antagonist. It was initially developed for treatment of Parkinson's disease and while safe in man, lacked efficacy. Although a potent hERG blocker, the drug exhibits multiple ion channel effects including frequency-dependence. The drug effectively terminated induced, sustained atrial fibrillation (AF) and atrial flutter in a canine model of sterile pericarditis. Subsequently the drug terminated AF in a Phase 2B ascending dose trial. Previous in vitro measurements used protocols that did not address the issue of the late Nav1.5 current which is important in understanding safety of a potent hERG blocker. Peak and late sodium currents were measured in HEK-293 cells stably expressing the human Nav1.5 channel. Peak currents were measured using a step-ramp protocol consisting of a 40 ms step to −15 mV (where the peak current was measured), a 180 ms step to +30 mV and a 200 ms ramp to the holding potential of −80 mV (1 Hz stimulating frequency). The effect of the drug was parameterized with a single binding isotherm having an IC50 of 29 ± 3 nM (95% CI: 22-37) and a Hill coefficient of 0.91 ± 0.10 (95% CI: 0.68-1.18) (seven cells, three concentrations). We also evaluated the effect of GBR-19209 on currents increased using the sea-anemone toxin ATX-II as a surrogate of the late sodium current. The calculated IC50 and Hill coefficients from five cells and five concentrations were 93 ± 9 nM (95% CI: 7-117) and 1.57 ± 0.24 (95% CI: 1.05-2.67), respectively. Thus, GBR-12909 block is at least sixty times more potent than ranolazine's (IC50 = 6 µM).The combination of potent peak and late sodium block may explain the antiarrhythmic and safe profile of the drug.

Role of inflammation in the initiation and maintenance of atrial fibrillation and the protective effect of atorvastatin in a goat model of aseptic pericarditis.

The present study was designed to determine the association between atrial fibrillation (AF) and inflammation in a goat sterile pericarditis model and to assess the effect of atorvastatin, a cholesterol-reducing drug, on AF. A total of 15 adult male goats were randomly divided into control, untreated pericarditis and atorvastatin-treated pericarditis groups. Pericarditis was induced via thoracotomy and atorvastatin was administered orally (60 mg/day) to the goats in the latter group for the duration of the study, commencing 1 week prior to surgery. The levels of high-sensitivity C-reactive protein (hs-CRP), interleukin(IL)-6 and tumor necrosis factor-α (TNF-α) were significantly elevated following surgery in the untreated pericarditis and atorvastatin groups compared with the control group (P<0.05). However, lower levels of hs-CRP, IL-6 and TNF-α were observed in the atorvastatin group compared with the untreated pericarditis group (P<0.05). Additionally, the animals in the atorvastatin-treated pericarditis group had a longer effective refractory period (ERP) and a higher rate adaptation of the ERP compared with those in the untreated pericarditis group (P<0.05). There was a significant negative correlation between the levels of ERP and hs-CRP in the untreated pericarditis group. The inducibility of AF in the left atrium and the duration of AF in the untreated pericarditis and atorvastatin-treated groups increased significantly following surgery (P<0.05). The pericarditis group, however, had a longer duration of AF compared with the atorvastatin group (P<0.05). Thus, inflammation may promote AF by shortening atrial ERP and by reducing the rate adaptation of ERP. These results suggested that atorvastatin can attenuate AF by inhibiting inflammation and may assist in preventing the occurrence and recurrence of AF following cardiac surgery.

Diagnostics and therapy of pericarditis and pericardial effusion

This article describes the diagnostics, differential diagnostics, multimodal imaging, medicinal and invasive diagnostic therapy of acute and chronic pericarditis, constrictive pericarditis, pericardial effusion and cardiac tamponade under etiological aspects and on the basis of the guidelines of the European Society of Cardiology (ESC). The starting point of the decision tree is the symptomatic patient with echocardiographic evidence of pericardial effusion. The principle feature of the diagnostics is the etiopathogenetic allocation of the pericardial disease which influences the clinical picture, course therapy and prognosis. Infectious pericarditis (e.g. viral, bacterial and tuberculous) is differentiated from sterile autoreactive pericarditis and from neoplastic pericardial effusion by the cytology of the effusion and immunohistological and molecular investigations of the pericardial and epicardial biopsies. Pericardioscopy plays an important role in the recognition of suspicious areas. In many cases intrapericardial administration of cisplatin for neoplastic pericardial effusion and instillation of triamcinolone for autoreactive pericarditis prevent recurrence just as a treatment of several months with colchicine.

Ranolazine terminates atrial flutter and fibrillation in a canine model.

Ranolazine has been shown to have antiarrhythmic properties. We tested the hypothesis that intravenous ranolazine would terminate induced atrial flutter (AFL) or atrial fibrillation (AF) in the canine sterile pericarditis model. In 6 dogs with sterile pericarditis, we performed electrophysiological measurements of the atrial effective refractory period (AERP) and conduction time (CT) while pacing from the right atrial appendage, Bachmann bundle, and the posteroinferior left atrium at cycle lengths (CLs) of 400, 300, and 200 ms before and after the administration of ranolazine. In 13 induced episodes of AFL (n = 9) and AF (n = 4), ranolazine was administered intravenously as a 3.2 mg/kg bolus, followed by a maintenance infusion of 0.17 mg/(kg·min). Six episodes (4 AFL and 2 AF) were induced in the open-chest state to perform simultaneous, multisite (486 electrodes), epicardial mapping of the arrhythmia and its termination. Ranolazine terminated 7 of 9 AFL and 3 of 4 AF episodes. Ranolazine significantly prolonged the AFL CL by a mean of 43 ms (P < .001) and the AF CL by a mean of 34 ms (P < .01). The AERP was prolonged (P < .05 overall), and the atrial capture threshold increased minimally (P < .01 for all). Ranolazine prolonged CTs (P < .01 overall). During open-chest, multisite mapping, block in the region of slow conduction in the reentrant circuit terminated AFL and interruption of the regular driver terminated AF. Ranolazine terminated AFL/AF in our canine sterile pericarditis model by interrupting the regular driver. Ranolazine was found to significantly prolong the AERP, CT, and tachycardia CLs.

Bachmann’s Bundle

Bachmann’s bundle (BB), also known as the interatrial bundle, is well recognized as a muscular bundle comprising of parallel aligned myocardial strands connecting the right and left atrial walls and is considered to be the main pathway of interatrial conduction.1 Disruption of the bundle’s structure causes interatrial conduction block (IAB),2 which is associated with development of various atrial tachyarrhythmias3,4 and with electromechanical dysfunction of the left atrium.5 Technological progress providing sophisticated mapping and imaging techniques in the past decade has increased our knowledge of specific anatomic structures and their role in development of both atrial brady- and tachyarrhythmias. This review outlines the current knowledge of the relation between anatomic and electrophysiological properties of BB and its possible role in initiation and perpetuation of atrial fibrillation (AF). In 1963, Thomas N. James described 3 pathways connecting the sinus node to the atrioventricular node (AVN), namely the anterior, medial, and posterior internodal pathways.6 Whether these conduction pathways were because of the presence of specialized conduction tissue or because of the anisotropic orientation of the muscle fibers remains controversial. Nevertheless, James described the anterior pathway as leaving the sinus node in anterior direction and giving off a secondary branch at the level of the superior vena cava to form BB.1 BB stretches subepicardially across the interatrial groove (septal raphe). It is at the interatrial groove that the BB can be identified as a discrete bundle (Figures 1 and 2) separated by fatty tissues from the infolded right atrial wall that is the limbus of the oval fossa. Notably, the bundle is not surrounded by a fibrous tissue sheath. Instead, the bundle is comprised of strands of atrial myocardium that are similarly aligned in parallel fashion. Its rightward and leftward extensions bifurcate to pass to either …

Sterile Pericarditis Leading To Cardiac Temponade from Intrapericardial Foreign Body 3 Months Following Gunshot Injury to Chest: Syndrome of Acute Intermittent Pericarditis

Patients with bullets in the pericardial sac without myocardial injuries are rare and most commonly are associated with significant trauma. The diagnosis of an intrapericardial foreign body can be difficult. Its removal is always indicated because it prevents pericarditis either sterile or infectious with potential for other significant complications. The syndrome of acute intermittent pericarditis from a foreign body within the pericardium is rarely seen except during time of war. Recently the authors treated a patient with a bullet in the pericardium three month following gunshot injury. During this period the patient developed sterile pericarditis and tamponade which necessitated emergency pericardiectomy and removal of the bullet. This experience and a brief review of the pertinent literature follows.

An Algorithm to Measure Beat‐to‐Beat Cycle Lengths for Assessment of Atrial Electrogram Rate and Regularity During Atrial Fibrillation

Experimental models have demonstrated that atrial fibrillation (AF) may be due to one or more rapid drivers (source) producing AF. These drivers may be characterized by rapid and regular cycle lengths (CLs), producing fibrillatory conduction to the rest of the atria. The ability to reliably identify such drivers would be invaluable. The purpose of this study was to develop and validate a CL variability detection (CLVD) analysis capable of accurately determining beat-to-beat CLs of atrial electrograms (AEGs) during AF, and then to compare this analysis with dominant frequency (DF) analysis. We analyzed 6 episodes of AF in 6 dogs (sterile pericarditis model) due either to a single, stable left atrial reentrant circuit, or unstable reentrant circuits causing fibrillatory conduction to the rest of the atria. During AF, AEGs were recorded simultaneously from 400 to 420 electrodes on both atria. CLs from over 20,000 AEGs were manually measured, and compared to CLs detected using both the CLVD and DF analyses. There was significant correlation between (1) CLs measured manually and the CLVD analysis (mean CL: correlation coefficient [CC]= 0.96, standard deviation [SD]: CC = 0.89); and (2) mean CL measured manually and the DF analysis (CC = 0.84). However, there was poor correlation between SD of CLs measured manually and the organization index (OI) by DF analysis (CC =-0.59). The CLVD analysis was validated as being accurate for detecting both rate and degree of regularity of AEGs during AF, and more accurate than DF analysis.

Colchicine for the Prevention of Postoperative Atrial Fibrillation

Colchicine for the Prevention of Postoperative Atrial Fibrillation

Fish Oil for Secondary Prevention of Atrial Fibrillation

Several epidemiological and large randomized, clinical trials carried out in the general population and in patients with cardiovascular disease have reported a significantly lower incidence of sudden cardiac death (presumably arrhythmic) with high dietary fish consumption or omega-3 polyunsaturated fatty acid (PUFA) supplements.1 This has prompted interest in exploring the antiarrhythmic potential of PUFAs in patients at particularly high risk of sudden arrhythmic death (ie, patients with internal cardioverter-defibrillators for secondary prevention), but the results were unexpectedly disappointing: the meta-analysis of the controlled studies failed to show any benefit from treatment with PUFAs.2 At about the same time, a proof-of-concept open-label study demonstrated a remarkable 65% reduction in the occurrence of atrial fibrillation (AF) after coronary artery bypass grafting surgery,3 and the search for antiarrhythmic activity of PUFAs in atrial tachyarrhythmias has begun. Article see p 1100 Various animal models of AF, including atrial pacing, simultaneous atrioventricular pacing, vagal stimulation, cardiac surgery and sterile pericarditis, and congestive heart failure induced by ventricular tachypacing or intracoronary infusion of doxorubicin, have been used to demonstrate the effects of PUFAs on electric and structural atrial remodeling.4 In these experiments, treatment with PUFAs prevented significant shortening of the atrial effective refractory period associated with AF, reduced inducibility of AF and duration of induced AF, and attenuated atrial fibrosis although a difference in response was noted in some models (eg, lack of effect in atrial tachypacing was reported).5 Results in the clinical arena have been less consistent. Although an early open-label and a larger observational study reported a reduction in the incidence of postoperative AF,3 3 subsequent trials with a more rigorous design (double-blind, placebo-controlled) did not reproduce these results.6 Similarly, in several epidemiological analyses, high dietary-fish consumption conferred no benefit on the prevention of AF in the …

N-3 polyunsaturated fatty acids prevents atrial fibrillation by inhibiting inflammation in a canine sterile pericarditis model

Objective It has been recently reported that atrial fibrillation (AF) is associated with inflammation and inflammatory cytokines, and n-3 polyunsaturated fatty acids (PUFAs) might be of anti-inflammatory effects. This study was to evaluate the anti-inflammatory effect of PUFAs on AF in a canine sterile pericarditis model. Methods 20 dogs were randomly assigned to two groups: control group (10 dogs) and PUFA treatment group (10 dogs), in which sterile pericarditis was created by open-chest operation. PUFAs were administered orally (2 g/day) 4 weeks before the operation till the end of the study. Before and 2 days after the operation, CRP, IL-6, TNF-α levels, the inducibility and maintenance of AF, the atrial effective refractory period (AERPs), and intra-atrial conduction time were determined. Results Before the operation, there were no significant differences in any of the parameters between the two groups. On the second postoperative day, the PUFA group had a lower CRP level (7.6 ± 0.5 vs. 11.7 ± 1.3 mg/dl, P < 0.0001), a lower IL-6 level (112.0 ± 37.3 vs. 142.0 ± 19.6 pg/ml, P < 0.01), a lower TNF-α level (83.3 ± 8.5 vs. 112.4 ± 8.2 pg/ml, P < 0.0001), a less AF inducibility (percentage of burst attempts leading to AF episodes: 11 ± 7.4 vs. 28 ± 10.3, P < 0.001) and maintenance [median AF duration: 1105 s (655.8–1406.5) vs. 2516.5 s (1187–3361), P < 0.05], a longer AERP (133.4 ± 4.1 vs. 129.8 ± 4.3 ms, P < 0.05), and a shorter intra-atrial conduction time (46.6 ± 4.4 vs. 51.9 ± 4.8 ms, P < 0.05) than the control group. Conclusions Dietary n-3 PUFA supplementation attenuates the inducibility and maintenance of AF in the sterile pericarditis model by reducing the production of proinflammatory cytokines.

Vanoxerine, a New Drug for Terminating Atrial Fibrillation and Flutter

Vanoxerine produces potent block of cardiac hERG, sodium, and L-type calcium channels. Block is strongly frequency dependent, is unassociated with transmural dispersion of repolarization, and occurs at concentrations safe in humans. Therefore, we proposed that vanoxerine might be antiarrhythmic. In these studies, we tested the hypothesis that vanoxerine would terminate induced atrial fibrillation (AF) and atrial flutter (AFL) in dogs with sterile pericarditis (SP). In 9 SP dogs, 11 episodes each of sustained (>10 minutes) AF and AFL were induced. Electrophysiological studies were performed before and after infusion of vanoxerine, which effectively terminated AF and AFL in 19 of 22 episodes. Simultaneous multisite mapping during 3 AF and 3 AFL episodes demonstrated that termination of each arrhythmia occurred with termination of the driver (a reentrant circuit) following an increase in tachycardia CL. Except for conduction in an area of slow conduction in the driver's reentrant circuit, vanoxerine did not significantly affect intraatrial or atrioventricular conduction time, QRS duration, or QT/QTc intervals. Ventricular refractoriness prolonged minimally during ventricular pacing at 400 and 333 ms (176 +/- 16 ms to 182 +/- 16 ms; 173 +/- 11 ms to 178 +/- 18 ms, respectively). Vanoxerine minimally increased (mean 0.7 mA) atrial stimulus threshold for capture. Vanoxerine effectively terminated induced, sustained AF and AFL in the canine SP model, and produced insignificant or minimal changes in refractoriness, conduction time, or stimulus threshold, consistent with little proarrhythmic risk.

Frequency Analysis of Atrial Electrograms Identifies Conduction Pathways from the Left to the Right Atrium During Atrial Fibrillation—Studies in Two Canine Models

Studies of atrial fibrillation (AF) have demonstrated that a stable rhythm of very short cycle length in the left atrium (LA) can cause fibrillatory conduction in the rest of the atria. We tested the hypothesis that fast Fourier transform (FFT) analysis of atrial electrograms (AEGs) during this AF will rapidly and reliably identify LA-to-right atrium (RA) conduction pathway(s) generated by the driver. During induced atrial tachyarrhythmias in the canine sterile pericarditis and rapid ventricular pacing-induced congestive heart failure models, 380-404 AEGs were recorded simultaneously from epicardial electrodes on both atria. FFT analysis of AEGs during AF demonstrated a dominant frequency peak in the LA (driver), and multiple frequency peaks in parts of the LA and the most of the RA. Conduction pathways from the LA driver to the RA varied from study-to-study. They were identified by the presence of multiple frequency peaks with one of the frequency peaks at the same frequency as the driver, and traveled (1) inferior to the inferior vena cava (IVC); (2) between the superior vena cava and the right superior pulmonary vein (RSPV); (3) between the RSPV and the right inferior pulmonary vein (RIPV); (4) between the RIPV and the IVC; and (5) via Bachmann's bundle. Conduction pathways identified by FFT analysis corresponded to the conduction pathways found in classical sequence of activation mapping. Computation time for FFT analysis for each AF episode took less than 5 minutes. FFT analysis allowed rapid and reliable detection of the LA-to-RA conduction pathways in AF generated by a stable and rapid LA driver.

The Gap Junction Modifier, GAP-134 [(2S,4R)-1-(2-Aminoacetyl)-4-benzamido-pyrrolidine-2-carboxylic Acid], Improves Conduction and Reduces Atrial Fibrillation/Flutter in the Canine Sterile Pericarditis Model

Gap junction uncoupling can alter conduction pathways and promote cardiac re-entry mechanisms that potentiate many supraventricular arrhythmias, such as atrial fibrillation (AF) and atrial flutter (AFL). Our objective was to determine whether GAP-134 [(2S,4R)-1-(2-aminoacetyl)-4-benzamido-pyrrolidine-2-carboxylic acid], a small dipeptide gap junction modifier, can improve conduction and ultimately prevent AF/AFL. In rat atrial strips subjected to metabolic stress, GAP-134 prevented significantly conduction velocity slowing at 10 nM compared with vehicle (p < 0.01). In the canine sterile pericarditis model, conduction time (CT; n = 5), atrial effective refractory period (AERP; n = 3), and AF/AFL duration/inducibility (n = 16) were measured 2 to 3 days postoperatively in conscious dogs. CT was significantly faster after GAP-134 infusion (average plasma concentration, 250 nM) at cycle lengths of 300 ms (66.2 +/- 1.0 versus 62.0 +/- 1.0 ms; p < 0.001) and 200 ms (64.4 +/- 0.9 versus 61.0 +/- 1.3 ms; p < 0.001). No significant changes in AERP were noted after GAP-134 infusion. The mean number of AF/AFL inductions per animal was significantly decreased after GAP-134 infusion (2.7 +/- 0.6 versus 1.6 +/- 0.8; p < 0.01), with total AF/AFL burden being decreased from 12,280 to 6063 s. Western blot experiments showed no change in connexin 43 expression. At concentrations exceeding those described in the AF/AFL experiments, GAP-134 had no effect on heart rate, blood pressure, or any electrocardiogram parameters. In conclusion, GAP-134 shows consistent efficacy on measures of conduction and AF/AFL inducibility in the canine sterile pericarditis model. These findings, along with its oral bioavailability, underscore its potential antiarrhythmic efficacy.

Abstract 646: Epicardial Ablation Of Ventricular Tachycardia - A Single Centre Experience

Background: Radiofrequency current ablation (RFA) of ventricular tachycardia (VT) focuses on endocardial (endo) substrates. However, if endo RFA fails, an epi approach is a potential treatment option. We report a single centre experience of epi VT ablation. Patients and Methods: Between 06/2005 and 02/2008 42 pts (14 female, mean age 49 ± 18 years) underwent electroanatomical endo and epi mapping and ablation for intractable VT, syncope or VT storm with multiple ICD discharges. Pts with normal heart (n=7), ischemic cardiomyopathy (ICM; n=8), NICM (n=11), ARVD (n=8), LV-aneurysm (n=7) or sarcoidosis (n=1) were studied. Mean LV ejection fraction was 45±12%. 20/42 had had at least 1 previous ablation attempt for VT (range 1– 4 ablations). Acute success was defined as non-inducibility of the previously inducible VT. Chronic success was defined as recurrence of any VT. Results: Acute procedural success rate was 79% (30/38). In 4 pts VTs were not inducible during EPS. In 28/42 pts endo mapping revealed no pathologic potentials. In 23/38 pts and 7/38 the succesful RFC ablation site was epi and endo, respectively. In 9/38 pts endo ablation failed and VT could only be ablated from epi. Further 7/38 pts needed both endo and epi ablation. In In 4/8 failed ablations epi RFC ablation was impossible due to failed access to target site (adhesions; n=2), close vicinity of a coronary artery (n=1) or the phrenic nerve (n=1). Procedure duration was 263±97 min. Unfortunately, 1 pt died due to perforation of RV and 1 pt had severe hepatic bleeding after epi puncture. One pt died in cardiogenic shock 1 d after the procedure. In 2 pts a sterile pericarditis occurred which resolved without any further intervention. After a median follow-up of 293 days (1–929 days) 53% of pts were alive and free from any VT. Conclusion: In pts with failed endo RFC ablation for VT due to different etiologies epi RFC ablation was acutely successful in 61% of pts with a moderate chronic success rate. However, major complications occured in approximately 5% of pts. Epi mapping should be considered if endo pathologic potentials are absent or if endo ablation failed.

Fixed intercaval block in the setting of atrial fibrillation promotes the development of atrial flutter

In the canine sterile pericarditis model, typically only atrial fibrillation (AF) is inducible on postoperative day 2. In this model, we tested the hypothesis that on postoperative day 2, placing a fixed line of block (LoB) between the vena cavae critically alters the atrial substrate, favoring the induction of sustained atrial flutter (AFL) instead of AF. In 6 sterile pericarditis dogs, sustained AF was induced by rapid atrial pacing. After terminating AF, a fixed LoB between the vena cavae was created (cryoablation), and AF reinduction was attempted. Simultaneous mapping from 400 to 420 electrodes on the right and left atrial epicardium and the interatrial atrial septum was performed during all studies. Before creation of the LoB, in all 6 dogs, rapid atrial pacing induced sustained AF because of a rapid (mean cycle length [CL] 110 +/- 10 ms), regular, left atrial reentrant driver, which caused fibrillatory conduction. After creation of the LoB, in 5 dogs, rapid atrial pacing now induced sustained AFL (mean CL 167 +/- 13 ms). In the 6th dog, AFL failed to develop because the left atrial driver that was induced before the LoB was still reproducibly induced despite the LoB. In this model of sustained AF, altering the substrate to create a fixed LoB between the vena cavae creates a substrate favoring the induction of AFL.

Interleukin-8 and atrial fibrillation

A large number of studies have now documented that atrial fibrillation (AF) is often associated with inflammation.1 Given that AF predisposes to stroke and thrombo-embolism and is associated with a hypercoagulable or prothrombotic state, the causal relationship among these ‘partners-in-crime’—that is, inflammation and thrombosis—is still a matter of intense debate. Besides its intellectual thrill, this quest may have very practical implication in pinpointing specific targets for the prevention of AF or stroke. The relationship between AF and inflammation is evident when studied locally in atrial tissue or at the level of ‘whole’ organism, using biomarkers in the systemic circulation. Examination of atrial biopsies from subjects with paroxysmal AF but without other cardiovascular disease documented myocarditis confined to atria in almost 2/3 of cases.1 Another example is AF in post-thoracotomy patients where inflammatory pericarditis is a significant contributor. Indeed, sterile pericarditis induced by talcum dust in dogs is associated with increased ability to sustain AF.2 This suggests that focal atrial inflammation per se can be the primary cause of AF in a part of AF subjects. Besides this local milieu, AF patients often demonstrate signs of low-grade systemic inflammation as evidenced by the elevation of inflammatory biomarkers in the systemic circulation, such as C-reactive protein … *Corresponding author. Tel: +420 236 055 190; fax: +420 261 362 985. E-mail address : vojtech.melenovsky{at}ikem.cz or vome{at}medicon.cz