Continuous Rapid Atrial Pacing Research Articles

Abstract 12313: Uncovering Functional and Structural Remodeling Progression of Persistent Atrial Fibrillation Over Time in a Rapid Atrial Pacing Canine Model - New Mechanistic Insights in Persistent Atrial Fibrillation

Introduction: The specific underlying persistent AF mechanisms are complex, and their development and remodeling processes over time are still not well understood. Hypothesis: We hypothesized that continuous rapid atrial pacing (RAP) in dogs induces persistent AF by affecting electrogram measures, fibrosis and oxidative stress (OS). Methods: AF was induced in 15 dogs (25-35 kg, 1 year) by RAP (3-14 weeks RAP, 600 beats/min), and 7 control dogs were used. We performed high-resolution epicardial mapping in 15 dogs and 8 controls using a high-density epicardial mapping plaque (6 regions, 130 electrodes, electrode distance 2.5mm) ( Figure A ). We analyzed the electrogram measures cycle length (CL) and dominant frequency (DF) in the 6 atrial regions in the left (LA) and right atrium (RA). MRI native T1 mapping was performed using a 1.5T clinical scanner (Siemens Aera) in 7 persistent AF dogs and in 8 dogs at baseline in the posterior left atrium (PLA). We quantified in 6 atrial regions in both atria the oxidative stress (OS) levels as the ratio of oxidatively damaged nuclei against the total number in 8-OHdG staining in (N=36 samples in 6 animals) and the degree of dense fibro-fatty tissue in Masson’s trichrome stained tissue (N=24 in 4 animals) using Qupath in all 6 regions in both atria. Results: Rapid atrial pacing (RAP) weeks correlated with CL (R=0.6, P 0.05) in the PLA ( Figure B ). Native T1 signal intensity increased with RAP days (R=0.6, P 0.05) in the PLA (less than 142 pacing days) ( Figure C ). Highest degree of dense focal fibrosis/ fat was in the left atrial free wall (LAFW) (49+/-14%) and in the PLA (47+/-19%) ( Figure F ). OS levels, highest in the LAFW, lowest in the appendages increased with the degree fibrosis (R=0.6, P<0.05) and with decreasing cycle length (R=0.5, P<0.05) in all atrial regions ( Figure D,E,G,H,I ). Conclusions: Continuing persistent AF is associated with smaller CL, increasing fibrosis, and oxidative injury rapid atrial pacing time.

Canagliflozin Suppresses Atrial Remodeling in a Canine Atrial Fibrillation Model

BackgroundRecent clinical trials have demonstrated the possible pleiotropic effects of SGLT2 (sodium–glucose cotransporter 2) inhibitors in clinical cardiovascular diseases. Atrial electrical and structural remodeling is important as an atrial fibrillation (AF) substrate.Methods and ResultsThe present study assessed the effect of canagliflozin (CAN), an SGLT2 inhibitor, on atrial remodeling in a canine AF model. The study included 12 beagle dogs, with 10 receiving continuous rapid atrial pacing and 2 acting as the nonpacing group. The 10 dogs that received continuous rapid atrial pacing for 3 weeks were subdivided as follows: pacing control group (n=5) and pacing+CAN (3 mg/kg per day) group (n=5). The atrial effective refractory period, conduction velocity, and AF inducibility were evaluated weekly through atrial epicardial wires. After the protocol, atrial tissues were sampled for histological examination. The degree of reactive oxygen species expression was evaluated by dihydroethidium staining. The atrial effective refractory period reduction was smaller (P=0.06) and the degree of conduction velocity decrease was smaller in the pacing+CAN group compared with the pacing control group (P=0.009). The AF inducibility gradually increased in the pacing control group, but such an increase was suppressed in the pacing+CAN group (P=0.011). The pacing control group exhibited interstitial fibrosis and enhanced oxidative stress, which were suppressed in the pacing+CAN group.ConclusionsCAN and possibly other SGLT2 inhibitors might be useful for preventing AF and suppressing the promotion of atrial remodeling as an AF substrate.

Arterial hypertension drives arrhythmia progression via specific structural remodeling in a porcine model of atrial fibrillation

Arterial hypertension (HT) contributes to progression of atrial fibrillation (AF) via unknown mechanisms. We aimed to characterize electrical and structural changes accounting for increased AF stability in a large animal model of rapid atrial pacing (RAP)-induced AF combined with desoxycorticosterone acetate (DOCA)-induced HT. Eighteen pigs were instrumented with right atrial endocardial pacemaker leads and custom-made pacemakers to induce AF by continuous RAP (600 beats/min). DOCA pellets were subcutaneously implanted in a subgroup of 9 animals (AF+HT group); the other 9 animals served as controls (AF group). Final experiments included electrophysiology studies, endocardial electroanatomic mapping, and high-density mapping with epicardial multielectrode arrays. In addition, 3-dimensional computational modeling was performed. DOCA implantation led to secondary HT (median [interquartile range] aortic pressure 109.9 [100-137] mm Hg in AF+HT vs 82.2 [79-96] mm Hg in AF; P < .05), increased AF stability (55.6% vs 12.5% of animals with AF episodes lasting >1 hour; P < .05), concentric left ventricular hypertrophy, atrial dilatation (119 ± 31 cm2 in AF+HT vs 78 ± 23 cm2 in AF; P<.05), and fibrosis. Collagen accumulation in the AF+HT group was mainly found in non-intermyocyte areas (1.62 ± 0.38 cm3 in AF+HT vs 0.96 ± 0.3 cm3 in AF; P < .05). Left and right atrial effective refractory periods, action potential durations, endo- and epicardial conduction velocities, and measures of AF complexity were comparable between the 2 groups. A 3-dimensional computational model confirmed an increase in AF stability observed in the invivo experiments associated with increased atrial size. In this model of secondary HT, higher AF stability after 2 weeks of RAP is mainly driven by atrial dilatation.

Specificity of electrocardiographic criteria for the differential diagnosis of wide QRS complex tachycardia in patients with intraventricular conduction defect

In patients with organic intraventricular conduction defects (IVCDs), (1) QRS morphology during sinus rhythm frequently meets ventricular tachycardia (VT) morphological criteria and (2) there are further rate-related changes in QRS morphology. To search for the best morphological criteria in this context. We prospectively studied 69 patients, in sinus rhythm, with QRS duration ≥120 ms. Continuous rapid atrial pacing (RAP) trains were introduced at increasing rates in order to mimic supraventricular tachycardia. We analyzed the specificity of VT criteria during RAP. Finally, we used the criteria with a specificity of ≥0.9 in a "test sample" of 53 patients with preexisting IVCD and wide complex tachycardia to confirm their validity. Only 10 of the 20 analyzed criteria had a specificity of ≥0.9 during RAP at the highest rate. The specificity of these 10 criteria was confirmed in the test sample. The best accuracy to diagnose VT was obtained: for an isolated criterion: "R-wave peak time (RWPT) ≥50 ms at lead II" (specificity = 0.97; sensitivity = 0.67); for an algorithm: the combination of 2 criteria "RWPT ≥50 ms at lead II" and "absence of RS patterns in precordial leads" (specificity = 0.97; sensitivity = 0.88). In patients with IVCD, (1) specificity of most VT criteria is low during RAP, suggesting a limited applicability of many of these criteria in case they develop supraventricular tachycardia, and (2) the superior accuracy to diagnose VT was observed with "RWPT ≥50 ms at lead II" and for an algorithm with the combination of "RWPT ≥50 ms at lead II" and "absence of RS patterns in precordial leads."

Increased expression of extracellular matrix proteins in rapid atrial pacing-induced atrial fibrillation

Atrial fibrillation (AF) is characterized by structural remodeling of the extracellular matrix (ECM) in cardiac atrium. The purpose of this study was to gain further insight into atrial ECM remodeling at the molecular level and to test whether altered expression of ECM proteins was associated with the disease. Sustained AF was induced in nine adult pigs after 3-4 weeks of continuous rapid atrial pacing at a rate of 600 bpm. Histologic studies and immunohistochemical stain were performed to identify the potential pathologic substrate underlying abnormalities in atrial tissues with sustained AF. In the pathologic findings, the fraction of myocardial ECM (ECM%) was measured, with a significantly greater ECM% found in the AF group compared with the sham operated group (n = 6; i.e., pigs with normal sinus rhythm [SR]). A set of 9,182 genes was screened with cDNA microarray analysis. In AF animals, expression of 121 genes increased and 24 genes decreased by > or =1.75-fold compared with SR animals. Significant up-regulation of fibronectin-1 (4.9-fold), fibrillin-1 (3.1-fold), and fibromodulin (1.9-fold) in the fibrillating atria was confirmed by quantitative real-time reverse transcriptase-polymerase chain reaction. Western blot analysis revealed significantly increased atrial fibronectin-1, fibrillin-1, and fibromodulin in the AF group compared with the SR group (1.5-, 2.7-, and 2.1-fold, respectively). Immunohistochemical staining of AF tissue displayed increased accumulation of fibronectin-1 and fibrillin-1 in the atrial interstitial space. Increased expression of ECM proteins in fibrillating atria supports the hypothesis that ECM metabolism contributes to the development of AF.

Downregulation of angiotensin converting enzyme II is associated with pacing-induced sustained atrial fibrillation

Atrial fibrillation (AF), the most common cardiac arrhythmia, is frequently accompanied by atrial interstitial fibrosis. Angiotensin II (Ang II) dependent signaling pathways have been implicated in interstitial fibrosis during the development of AF. However, Ang II could be further degraded by angiotensin converting enzyme II (ACE2). We examined expression of ACE2 in the fibrillating atria of pigs and its involvement in fibrotic pathogenesis during AF. Nine adult pigs underwent continuous rapid atrial pacing to induce sustained AF and six pigs were sham controls (i.e., sinus rhythm; SR). In the histological examinations, extensive accumulation of extracellular matrix in the interstitial space of the atria, as evidenced by Masson’s trichrome stain, were found in fibrillating atria. The relative amount of collagen type I in the atria with AF was significantly increased as compared with that in the SR. Local ACE activity in the fibrillating atria was also markedly higher than that in the SR subjects. ACE2 gene and protein expression in the AF subjects were significantly decreased compared with those in the SR subjects, whereas expression of mitogen-activated/ERK kinase 1/2 (MEK1/2), extracellular signal-regulated protein kinase 2 (ERK2), and activated ERK2 were significantly greater in the AF subjects. We propose that decreasing ACE2 expression during AF may affect the Ang II-dependent signaling pathway. In addition, our results suggest that atrial fibrosis in AF may be induced by antagonistic regulation between ACE and ACE2 expression.

Expression and function changes of ryanodine receptors and inositol 1,4,5-triphosphate receptors of atrial myocytes during atrial fibrillation

To investigate the expression and function changes of inositol 1,4,5-triphosphate receptor (IP3R) and ryanodine receptor (RyR) in the atrial myocytes during atrial fibrillation. Ten adult mongrel dogs were randomly divided into 2 groups: 5 dogs underwent continuous rapid atrial pacing (500 beats/min) for twenty-four weeks to create persistent atrial fibrillation, and the other 5 size-matched dogs without pacemaker implantation were used as controls. Twenty-four weeks after the dogs' hearts were taken out and the canine atrial myocytes were isolated by enzymatic dissociation: fluorescent indicator Fluo-3/AM was added into the buffer to load the myocytes and then the Ca(2+) concentration was determined by confocal microscopy. BODIPY TR-X ryanodine was added into the buffer to stain the myocytes. Caffeine and ATP were added separately to stimulate the release of Ca(2+) from RyR. (1) The expression of RyR in the sarcoplasmic reticulum of the atrial myocytes of the control group was (2.70 +/- 0.23), significantly higher than that of the atrial fibrillation group (0.25 +/- 0.14, P < 0.05). RyR was expressed mostly around the nucleus and only expressed in a small amount in the nucleus in the atrial fibrillation group. However, it was not expressed in the nucleus of the control group. The expression of IP3R in the atrial fibrillation group was significantly higher than that of the control group (P < 0.05). (2) After caffeine stimulation, the concentration in the atrial myocytes of the control group was (1.74 +/- 0.16), significantly higher than that of the fibrillation group (1.26 +/- 0.06, P < 0.05). (3) After ATP stimulation the Ca(2+) concentration in the atrial myocytes of the control group was (1.23 +/- 0.23), not significantly increased in comparison with that before ATP stimulation; however, the Ca(2+) concentration in the atrial myocytes of the fibrillation group after ATP stimulation was (2.29 +/- 0.65), significantly increased in comparison with that before ATP stimulation (P < 0.05). (1) The expression of RyR is down-regulated, the function of RyR is decreased, and it is expressed in the nucleus during atrial fibrillation which shows that RyR is possibly translocated into the nucleus. (2) The expression of IP3R is up-regulated and the function of IP3R is increased during atrial fibrillation, which may be one of the major mechanisms of intracellular Ca(2+)-overload during atrial fibrillation.

Differences in organization between acute and chronic atrial fibrillation in dogs

OBJECTIVESThe purpose of this study was to determine differences in acute and chronic atrial fibrillation (AF) “organization” in canine models.BACKGROUNDElectrophysiologic changes occur during atrial remodeling, but little is known about how remodeling affects AF organization. We hypothesized that atrial remodeling induced by long-term rapid atrial rates heterogeneously decreases AF organization.METHODSIn seven dogs, acute AF was induced by atrial burst pacing, and in eight dogs chronic AF was created by six weeks of continuous rapid atrial pacing. Atrial fibrillation was epicardially mapped from the right atria (RA) and left atria (LA). Atrial cycle length (CL), spatial organization and activation maps were compared. Spatial organization was quantified by an objective signal processing measure between multiple electrograms.RESULTSIn acute AF, mean CL was slightly shorter in the LA (124 ± 16 ms) than it was in the RA (131 ± 14 ms) (p < 0.0001). In chronic AF, LA CL (96 ± 14 ms) averaged 24 ms shorter than RA CL (121 ± 18 ms) (p < 0.0001). Right atria and LA in acute AF had similar levels of organization. In chronic AF, the LA became ∼25% more disorganized (p < 0.0001) while the RA did not change. In acute AF, a single broad wave front originating from the posterior and medial atrium dominated LA activation. In chronic AF, LA activation was more complex, sustaining multiple reentrant wavelets in the free wall and lateral appendage.CONCLUSIONSAcute and chronic AF exhibit heterogeneous differences in CL, organization and activation patterns. The LA in chronic AF is faster and more disorganized than it is in acute AF. Differences in the models may be due to heterogeneous electrophysiologic remodeling and anatomic constraints. The design of future AF therapies may benefit by addressing the patient specific degree of atrial remodeling.

Evidence of heterogeneous remodeling in canine atrial fibrillation

Although electrophysiologic changes occur during atrial remodeling, little is known how remodeling affects atrial fibrillation (AF) organization. We hypothesized that, in animals with long-term rapid atrial rates and a rapid ventricular response, AF would be more disorganized than in animals with rapid atrial rates only. In 8 dogs, chronic AF was created by 6 weeks of continuous rapid atrial pacing. In this group, the ventricular response to AF was spontaneous and unaltered. Twenty-one epochs of AF were epicardially mapped from the right and left atria. In 6 dogs, chronic AF was also created with rapid atrial pacing, however, the AV node was ablated and the ventricles were VVI paced at 80 BPM. Only 1 epoch of AF per dog was mapped. Atrial cycle length (CL) and spatial organization were compared. In chronic AF with a spontaneous ventricular rate, left atrial CL (96±14 ms) averaged 24 ms shorter than right atrial CL (121±18 ms) ( P<0001). With VVI pacing, AFCL was longer than in the dogs with the spontaneous ventricular rate. However, the left atrial CL (109±30 ms) was still significantly shorter than the right atrial CL (145±43 ms) ( P<.001). Spatial organization values showed that during chronic AF with a spontaneous ventricular rate, the left atrium is more disorganized (2593±497) than the right atrium (2052±732) ( P<.0001). With VVI pacing, the left atrium (2202±597) is still more disorganized than the right (1620±936) ( P<.05). However, with VVI pacing, both atria appear less disorganized than dogs with VVI pacing. Atrial remodeling caused by heart failure that is superimposed on the remodeling due to rapid atrial rates causes the atria to be more disorganized than remodeling due to rapid atrial rates alone. However, in either case the left atrium is faster and more disorganized than the right atrium. Atrial fibrosis caused by the heart failure may increase the disorganization of AF activation

Chronic Rapid Atrial Pacing

Despite the clinical importance of atrial fibrillation (AF), the development of chronic nonvalvular AF models has been difficult. Animal models of sustained AF have been developed primarily in the short-term setting. Recently, models of chronic ventricular myopathy and fibrillation have been developed after several weeks of continuous rapid ventricular pacing. We hypothesized that chronic rapid atrial pacing would lead to atrial myopathy, yielding a reproducible model of sustained AF. Twenty-two halothane-anesthetized mongrel dogs underwent insertion of a transvenous lead at the right atrial appendage that was continuously paced at 400 beats per minute for 6 weeks. Two-dimensional echocardiography was performed in 11 dogs to assess the effects of rapid atrial pacing on atrial size. Atrial vulnerability was defined as the ability to induce sustained repetitive atrial responses during programmed electrical stimulation and was assessed by extrastimulus and burst-pacing techniques. Effective refractory period (ERP) was measured at two endocardial sites in the right atrium. Sustained AF was defined as AF > or = 15 minutes. In animals with sustained AF, 10 quadripolar epicardial electrodes were surgically attached to the right and left atria. The local atrial fibrillatory cycle length (AFCL) was measured in a 20-second window, and the mean AFCL was measured at each site. Marked biatrial enlargement was documented; after 6 weeks of continuous rapid atrial pacing, the left atrium was 7.8 +/- 1 cm2 at baseline versus 11.3 +/- 1 cm2 after pacing, and the right atrium was 4.3 +/- 0.7 cm2 at baseline versus 7.2 +/- 1.3 cm2 after pacing. An increase in atrial area of at least 40% was necessary to induce sustained AF and was strongly correlated with the inducibility of AF (r = .87). Electron microscopy of atrial tissue demonstrated structural changes that were characterized by an increase in mitochondrial size and number and by disruption of the sarcoplasmic reticulum. After 6 weeks of continuous rapid atrial pacing, sustained AF was induced in 18 dogs (82%) and nonsustained AF was induced in 2 dogs (9%). AF occurred spontaneously in 4 dogs (18%). Right atrial ERP, measured at cycle lengths of 400 and 300 milliseconds at baseline, was significantly shortened after pacing, from 150 +/- 8 to 127 +/- 10 milliseconds and from 147 +/- 11 to 123 +/- 12 milliseconds, respectively (P < .001). This finding was highly predictive of inducibility of AF (90%). Increased atrial area (40%) and ERP shortening were highly predictive for the induction of sustained AF (88%). Local epicardial ERP correlated well with local AFCL (R2 = .93). Mean AFCL was significantly shorter in the left atrium (81 +/- 8 milliseconds) compared with the right atrium 94 +/- 9 milliseconds (P < .05). An area in the posterior left atrium was consistently found to have a shorter AFCL (74 +/- 5 milliseconds). Cryoablation of this area was attempted in 11 dogs. In 9 dogs (82%; mean, 9.0 +/- 4.0; range, 5 to 14), AF was terminated and no longer induced after serial cryoablation. Sustained AF was readily inducible in most dogs (82%) after rapid atrial pacing. This model was consistently associated with biatrial myopathy and marked changes in atrial vulnerability. An area in the posterior left atrium was uniformly shown to have the shortest AFCL. The results of restoration of sinus rhythm and prevention of inducibility of AF after cryoablation of this area of the left atrium suggest that this area may be critical in the maintenance of AF in this model.

Continuous rapid atrial pacing to control recurrent or sustained supraventricular tachycardias following open heart surgery.

A technique is described to control recurrent or sustained supraventricular tachycardia associated with rapid ventricular rates following open heart surgery. The technique utilizes a pair of temporarily implanted atrial epicardial wire electrodes to pace the heart. In one group of patients with recurrent atrial flutter and 2:1 A-V conduction, continuous rapid atrial pacing at 450 beats/min produced and sustained atrial fibrillation. The ventricular response rate immediately slowed when compared to that during atrial flutter, and if further slowing was required, it was easily accomplished by the administration of digitalis. Another group of patients with different arrhythmias (recurrent paroxysmal atrial tachycardia, sustained ectopic atrial tachycardia, or sinus rhythm with premature atrial beats which precipitated runs of atrial fibrillation) was treated with continuous rapid atrial pacing to produce 2:1 A-V block. In all instances, the continuous rapid atrial pacing suppressed the supraventricular tachycardia and maintained the ventricular response rate in a therapeutically desirable range. It was demonstrated that the technique is safe, effective, and reliable.