Structural atrial remodeling alters the substrate and spatiotemporal organization of atrial fibrillation: a comparison in canine models of structural and electrical atrial remodeling

Several animal models of atrial fibrillation (AF) have been developed that demonstrate either atrial structural remodeling or atrial electrical remodeling, but the characteristics and spatiotemporal organization of the AF between the models have not been compared. Thirty-nine dogs were divided into five groups: rapid atrial pacing (RAP), chronic mitral regurgitation (MR), congestive heart failure (CHF), methylcholine (Meth), and control. Right and left atria (RA and LA, respectively) were simultaneously mapped during episodes of AF in each animal using high-density (240 electrodes) epicardial arrays. Multiple 30-s AF epochs were recorded in each dog. Fast Fourier transform was calculated every 1 s over a sliding 2-s window, and dominant frequency (DF) was determined. Stable, discrete, high-frequency areas were seen in none of the RAP or control dogs, four of nine MR dogs, four of six CHF dogs, and seven of nine Meth dogs in either the RA or LA or both. Average DFs in the Meth model were significantly greater than in all other models in both LA and RA except LA DFs in the RAP model. The RAP model was the only one with a consistent LA-to-RA DF gradient (9.5 +/- 0.2 vs. 8.3 +/- 0.3 Hz, P < 0.00005). The Meth model had a higher spatial and temporal variance of DFs and lower measured organization levels compared with the other AF models, and it was the only model to show a linear relationship between the highest DF and dispersion (R(2) = 0.86). These data indicate that structural remodeling of atria (models known to have predominantly altered conduction) leads to an AF characterized by a stable high-frequency area, whereas electrical remodeling of atria (models known to have predominantly shortened refractoriness without significant conduction abnormalities) leads to an AF characterized by multiple high-frequency areas and multiple wavelets.     

Left atrial dilatation resulting from chronic mitral regurgitation decreases spatiotemporal organization of atrial fibrillation in left atrium

Atrial conduction properties have been shown to differ among animal atrial fibrillation (AF) models of rapid atrial pacing (RAP), chronic mitral regurgitation (MR), and control. We hypothesized that these conduction differences would continue with the onset of AF, which would affect AF spatiotemporal organization, resulting in model-specific characteristics of AF. With frequency domain analysis of electrograms acquired from high-density optical mapping, AF from the right (RA) and left (LA) atrium in animals with RAP and MR were compared with control animals. At follow-up, the hearts were excised and perfused, and optical action potentials were recorded from a 2 x 2-cm area each of the RA and LA free wall with a 16 x 16 photodiode array. AF was induced with extra stimuli, several 2.4-s AF episodes were recorded in each dog, and a fast Fourier transform was calculated. The dominant frequency (DF) was determined, and the organization (organization index, OI) was calculated as the ratio of the area under the dominant peak and its harmonics to the total area of the spectrum. All possible pairs of electrograms for each episode were cross-correlated. LA AF in the chronic MR model showed an increase in the highest DF, the number of DF domains, and in frequency gradient compared with AF in control or RAP models. In addition, there was a decrease in OI and in the correlation coefficients in the LA of the MR model. These results suggest that the AF substrate in the MR model may be different from that of control or RAP models.     

Metformin regulates adiponectin signalling in epicardial adipose tissue and reduces atrial fibrillation vulnerability

Epicardial adipose tissue (EAT) remodelling is closely related to the pathogenesis of atrial fibrillation (AF). We investigated whether metformin (MET) prevents AF‐dependent EAT remodelling and AF vulnerability in dogs. A canine AF model was developed by 6‐week rapid atrial pacing (RAP), and electrophysiological parameters were measured. Effective refractory periods (ERP) were decreased in the left and right atrial appendages as well as in the left atrium (LA) and right atrium (RA). MET attenuated the RAP‐induced increase in ERP dispersion, cumulative window of vulnerability, AF inducibility and AF duration. RAP increased reactive oxygen species (ROS) production and nuclear factor kappa‐B (NF‐κB) phosphorylation; up‐regulated interleukin‐6 (IL‐6), tumour necrosis factor‐α (TNF‐α) and transforming growth factor‐β1 (TGF‐β1) levels in LA and EAT; decreased peroxisome proliferator‐activated receptor gamma (PPARγ) and adiponectin (APN) expression in EAT and was accompanied by atrial fibrosis and adipose infiltration. MET reversed these alterations. In vitro, lipopolysaccharide (LPS) exposure increased IL‐6, TNF‐α and TGF‐β1 expression and decreased PPARγ/APN expression in 3T3‐L1 adipocytes, which were all reversed after MET administration. Indirect coculture of HL‐1 cells with LPS‐stimulated 3T3‐L1 conditioned medium (CM) significantly increased IL‐6, TNF‐α and TGF‐β1 expression and decreased SERCA2a and p‐PLN expression, while LPS + MET CM and APN treatment alleviated the inflammatory response and sarcoplasmic reticulum Ca²⁺ handling dysfunction. MET attenuated the RAP‐induced increase in AF vulnerability, remodelling of atria and EAT adipokines production profiles. APN may play a key role in the prevention of AF‐dependent EAT remodelling and AF vulnerability by MET.     

Differential impact of short periods of rapid atrial pacing on left and right atrial mechanical function

Current techniques to describe atrial function are limited by their load dependency and hence do not accurately reflect intrinsic mechanical properties. To assess the impact of atrial fibrillation on atrial function, combined pressure-volume relationships (PVR) measured by conductance catheters were used to evaluate the right (RA) and left (LA) atrium in 12 isoflurane-anesthetized pigs. Biatrial PVR were recorded over a wide range of volumes during transient caval occlusion at baseline sinus rhythm (SR), after onset of rapid atrial pacing (RAP), after 1 h of RAP, after conversion to SR, and after 1 h of recovery. Cardiac output decreased by 16% (P = 0.008) with onset of RAP. Mean LA and RA pressures increased by 21 and 40% (P < 0.001), respectively, and remained elevated during the entire recovery period. RA reservoir function increased from 51 to 58% and significantly dropped to 43% after resumption of SR (P = 0.017). Immediately after RAP, a right shift of LA end-systolic PVR-intercept for end-systolic volume required to generate an atrial end-systolic pressure of 10 mmHg (24.4 ± 4.9 to 28.1 ± 5.2 ml, P = 0.005) indicated impaired contractility compared with baseline. Active LA emptying fraction dropped from 17.6 ± 7.5 to 11.7 ± 3.7% (P < 0.001), LA stroke volume and ΔP/Δt(max)/P declined by 22% (P = 0.038 and 0.026, respectively), while there was only a trend to impaired RA systolic function. Stiffness quantified by the ratio of pressure to volume at end-diastole was increased immediately after RAP only in the RA (P = 0.020), but end-diastolic PVR shifted rightward in both atria (P = 0.011 LA, P = 0.045 RA). These data suggest that even short periods of RAP have a differential impact on RA and LA function, which was sustained for 1 h after conversion to SR.     

Nonreentrant focal activations in pulmonary veins in canine model of sustained atrial fibrillation

Repetitive rapid activities are present in the pulmonary veins (PVs) in dogs with pacing-induced sustained atrial fibrillation (AF). The mechanisms are unclear. We induced sustained (>48 h) AF by rapidly pacing the left atrium (LA) in six dogs. High-density computerized mapping was done in the PVs and atria. Results show repetitive focal activations in all dogs and in 12 of 18 mapped PVs. Activation originated from the middle of the PV and then propagated to the LA and distal PV with conduction blocks. The right atrium (RA) was usually activated by a single large wavefront. Mean AF cycle length in the PVs (left superior, 82 +/- 6 ms; left inferior, 83 +/- 6 ms; right inferior, 83 +/- 4 ms) and LA posterior wall (87 +/- 5 ms) were significantly (P < 0.05) shorter than those in the LA anterior wall (92 +/- 4 ms) and RA (107 +/- 5 ms). PVs in normal dogs did not have focal activations during induced AF. No reentrant wavefronts were demonstrated in the PVs. We conclude that nonreentrant focal activations are present in the PVs in a canine model of pacing-induced sustained AF.     

星状神经节电刺激建立交感神经介导的急性房颤犬模型

目的建立交感神经张力异常介导的急性房颤动物模型的方法学。方法将16只随意来源犬分为三组：对照组（n=4）,右侧星状神经节（aSG）组（n=6）和左侧星状神经节（LSG）组（n=6）,测定心房和肺静脉不同部位的房颤诱发率、房颤持续时间。结果RSG刺激显著增加右心房（RA）的房颤诱发率和持续时间（P〈0．05）,LSG刺激显著增加左心房（LA）、左上肺静脉（LSPV）、左下肺静脉（LIPV）的房颤诱发率和持续时间（P〈0．05）;与刺激时相比,RSG切除显著降低RA的房颤诱发率和持续时间（P〈0．05）;LSG切除显著降低LA、LSPV、LIPV的房颤诱发率和持续时间（P〈0．05）。结论星状神经节电刺激同时快速心房起搏6h可成功建立交感神经介导的急性房颤犬模型,星状神经节电刺激使心房和肺静脉部位的房颤诱发率显著升高,房颤持续时间显著延长,去星状神经节支配可减少房颤的发生和维持。     

Effects of sterile pericarditis on connexins 40 and 43 in the atria: correlation with abnormal conduction and atrial arrhythmias

The canine sterile pericarditis model is characterized by impaired conduction and atrial arrhythmia vulnerability. Electrical and structural remodeling processes caused by the inflammatory response likely promote these abnormalities. In the present study, we tested the hypothesis that altered distribution of atrial connexins is associated with markedly abnormal atrial conduction, thereby contributing to vulnerability to atrial flutter (AFL) and atrial fibrillation (AF) induction and maintenance. During rapid pacing and induced, sustained AFL or AF in five sterile pericarditis (SP) and five normal (NL) dogs, epicardial atrial electrograms were recorded simultaneously from both atria (380 electrodes) or from the right atrium (RA) and Bachmann's bundle (212 electrodes). Tissues from RA sites were subjected to immunostaining and immunoblotting to assess connexin (Cx) 40 and Cx43 distribution and expression. Transmural myocyte (alpha-actinin) and fibroblast (vimentin) volume were also assessed by immunostaining. RA pacing maps showed markedly abnormal conduction in SP, with uniform conduction in NL. Total RA activation time was significantly prolonged in SP vs. NL at 300-ms and 200-ms pacing-cycle lengths. Sustained arrhythmias were only inducible in SP [total: 4/5 (AFL: 3/5; AF: 1/5)]. In NL, Cx40, Cx43, alpha-actinin, and vimentin were homogeneously distributed transmurally. In SP, Cx40, Cx43, and alpha-actinin were absent epicardially, decreased midmyocardially, and normal endocardially. SP increased epicardial vimentin expression, suggesting fibroblast proliferation. Immunoblot analysis confirmed reduced expression of Cx40 and Cx43 in SP. The transmural gradient in the volume fraction of Cx40 and Cx43 in SP is associated with markedly abnormal atrial conduction and is likely an important factor in the vulnerability to induction and maintenance of AFL/AF in SP.     

Thoracic vein ablation terminates chronic atrial fibrillation in dogs

The thoracic vein hypothesis of chronic atrial fibrillation (AF) posits that rapid, repetitive activations from muscle sleeves within thoracic veins underlie the mechanism of sustained AF. If this is so, thoracic vein ablation should terminate sustained AF and prevent its reinduction. Six female mongrel dogs underwent chronic pulmonary vein (PV) pacing at 20 Hz to induce sustained (>48 h) AF. Bipolar electrodes were used to record from the atria and thoracic veins, including the vein of Marshall, four PVs, and the superior vena cava. Radio frequency (RF) application was applied around the PVs and superior vena cava and along the vein of Marshall until electrical activity was eliminated. Computerized mapping (1,792 electrodes, 1 mm resolution) was also performed. Sustained AF was induced in 30.6 +/- 6.5 days, and ablation was done 17.3 +/- 8.5 days afterward. Before ablation, the PVs had shorter activation cycle lengths than the atria, and rapid, repetitive activations were observed in the PVs. All dogs converted to sinus rhythm during (n = 4 dogs) or within 90 min of completion of RF ablation. Rapid atrial pacing afterward induced only nonsustained (<60 s) AF in all dogs. Average AF cycle lengths after reinduction were significantly (P = 0.01) longer (183 +/- 31.5 ms) than baseline (106 +/- 16.2 ms). There were no activation cycle length gradients after RF application. We conclude that thoracic vein ablation converts canine sustained AF into sinus rhythm and prevents the reinduction of sustained AF. These findings suggest that thoracic veins are important in the maintenance of AF in dogs.     

Effect of c‐Ski on atrial remodelling in a rapid atrial pacing canine model

Atrial fibrosis is an important factor in the initiation and maintenance of atrial fibrillation (AF); therefore, understanding the pathogenesis of atrial fibrosis may reveal promising therapeutic targets for AF. In this study, we successfully established a rapid atrial pacing canine model and found that the inducibility and duration of AF were significantly reduced by the overexpression of c‐Ski, suggesting that this approach may have therapeutic effects. c‐Ski was found to be down‐regulated in the atrial tissues of the rapid atrial pacing canine model. We artificially up‐regulated c‐Ski expression with a c‐Ski–overexpressing adenovirus. Haematoxylin and eosin, Masson's trichrome and picrosirius red staining showed that c‐Ski overexpression alleviated atrial fibrosis. Furthermore, we found that the expression levels of collagen III and α‐SMA were higher in the groups of dogs subjected to right‐atrial pacing, and this increase was attenuated by c‐Ski overexpression. In addition, c‐Ski overexpression decreased the phosphorylation of smad2, smad3 and p38 MAPK (p38α and p38β) as well as the expression of TGF‐β1 in atrial tissues, as shown by a comparison of the right‐atrial pacing + c‐Ski‐overexpression group to the control group with right‐atrial pacing only. These results suggest that c‐Ski overexpression improves atrial remodelling in a rapid atrial pacing canine model by suppressing TGF‐β1–Smad signalling and p38 MAPK activation.     

Echocardiographic [correction of Ehocardiographic] evaluation of regional left atrial function after rapid atrial pacing

Rapid regular atrial pacing (RAP) produces changes in atrial function similar to those caused by atrial fibrillation in animal models. Left atrial appendage (LAA) function represents regional atrial function. The aim of our study was to investigate the influence of RAP on left atrial regional function and to evaluate the reversibility of changes after termination of pacing in a canine model. Eight dogs were subjected to RAP (400 bpm) for 16 days. Transesophageal echocardiography was performed at baseline, immediately after RAP and 4 weeks after the termination of RAP. The LAA peak late emptying velocity (LAA-E) and filling wave (LAA-f) were measured. LAA-E velocities were significantly reduced and filling wave velocities (LAA-f) were significantly less negative after RAP compared with the baseline values. Four weeks after termination of pacing, the LAA-E and LAA-f velocities were normal. RAP results in impaired regional atrial systolic and diastolic function. The changes were completely reversible 4 weeks after termination of pacing. These results suggest that the LAA is mechanically stunned after RAP.     

Effects of procainamide on electrical activity in thoracic veins and atria in canine model of sustained atrial fibrillation

Focal discharges (FDs) are present in thoracic veins during atrial fibrillation (AF). We hypothesize that procainamide exerts its anti-AF action by suppressing FDs in the thoracic veins. We studied six mongrel dogs (22-27 kg) with sustained (>6 h) AF induced by 47 +/- 20 days of chronic rapid LA appendage (LAA) or pulmonary vein (PV) pacing. Procainamide was infused intravenously until AF was terminated or a cumulative dose of 20 mg/kg was reached. High-resolution mapping during AF showed FDs in the vein of Marshall, PVs, and the LAA. Procainamide significantly (P < 0.05) reduced the frequency of these FDs and suppressed the interactions of wave fronts between PVs and LA. The cumulative dose of PA needed to terminate AF correlated negatively (r =-0.9, P < 0.05) with the baseline effective refractory period (ERP) of PV and positively (r = 0.8, P < 0.05) with the baseline maximum dominant frequency (DF) of AF. In four of five dogs, AF converted to atrial tachycardia originating from the PVs before termination. Attempts to reinduce sustained AF were unsuccessful in these five dogs. AF was resistant to procainamide in the sixth dog. In conclusion, procainamide reduced the rate of FDs in the thoracic veins and the LA and suppressed the interaction between PVs and LA. Second, FDs in the PV are more resistant to procainamide's action than FDs in the atria. Third, inherent PV ERP is important in determining the antifibrillatory efficacy of procainamide.     

Increased vulnerability to inducible atrial fibrillation caused by partial cellular uncoupling with heptanol

We hypothesized that partial cellular uncoupling produced by low concentrations of heptanol increases the vulnerability to inducible atrial fibrillation (AF). The epicardial surface of 12 isolated-perfused canine left atria was optically mapped before and after 1-50 microM heptanol infusion. At baseline, no sustained (>30 s) AF could be induced in any of the 12 tissues. However, after 2 microM heptanol infusion, sustained AF was induced in 9 of 12 tissues (P < 0.001). Heptanol >5 microM caused loss of 1:1 capture during rapid pacing, causing no AF to be induced. AF was initiated by conduction block across the fiber leading to reentry, which broke up after one to two rotations into two to four independent wavelets that sustained the AF. Heptanol at 2 microM had no effect on the cellular action potential duration restitution or on the maximal velocity rate over time of the upstroke. The effects of heptanol were reversible. We conclude that partial cellular uncoupling by heptanol without changing atrial active membrane properties promotes wavebreak, reentry, and AF during rapid pacing.     

Loss of atrial contractility is primary cause of atrial dilatation during first days of atrial fibrillation

Atrial fibrillation (AF) induces a progressive dilatation of the atria which in turn might promote the arrhythmia. The mechanism of atrial dilatation during AF is not known. To test the hypothesis that loss of atrial contractile function is a primary cause of atrial dilatation during the first days of AF, eight goats were chronically instrumented with epicardial electrodes, a pressure transducer in the right atrium, and piezoelectric crystals to measure right atrial diameter. AF was induced with the use of repetitive burst pacing. Atrial contractility was assessed during sinus rhythm, atrial pacing (160-, 300-, and 400-ms cycle length), and electrically induced AF. The compliance of the fibrillating right atrium was measured during unloading the atria with diuretics and loading with 1 liter of saline. All measurements were repeated after 6, 12, and 24 h of AF and then once a day during the first 5 days of AF. Recovery of the observed changes after spontaneous cardioversion was also studied. After 5 days of AF, atrial contractility during sinus rhythm or slow atrial pacing was greatly reduced. During rapid pacing (160 ms) or AF, the amplitude of the atrial pressure waves had declined to 20% of control. The compliance of the fibrillating atria increased twofold, whereas the right atrial pressure was unchanged. As a result, the mean right atrial diameter increased by approximately 12%. All changes were reversible within 3 days of sinus rhythm. We conclude that atrial dilatation during the first days of AF is due to an increase in atrial compliance caused by loss of atrial contractility during AF. Atrial compliance and size are restored when atrial contractility recovers after cardioversion of AF.     

Mechanoelectric feedback leads to conduction slowing and block in acutely dilated atria: a modeling study of cardiac electromechanics

Atrial fibrillation, a common cardiac arrhythmia, is promoted by atrial dilatation. Acute atrial dilatation may play a role in atrial arrhythmogenesis through mechanoelectric feedback. In experimental studies, conduction slowing and block have been observed in acutely dilated atria. In the present study, the influence of the stretch-activated current (I(sac)) on impulse propagation is investigated by means of computer simulations. Homogeneous and inhomogeneous atrial tissues are modeled by cardiac fibers composed of segments that are electrically and mechanically coupled. Active force is related to free Ca(2+) concentration and sarcomere length. Simulations of homogeneous and inhomogeneous cardiac fibers have been performed to quantify the relation between conduction velocity and I(sac) under stretch. In our model, conduction slowing and block are related to the amount of stretch and are enhanced by contraction of early-activated segments. Conduction block can be unidirectional in an inhomogeneous fiber and is promoted by a shorter stimulation interval. Slowing of conduction is explained by inactivation of Na(+) channels and a lower maximum upstroke velocity due to a depolarized resting membrane potential. Conduction block at shorter stimulation intervals is explained by a longer effective refractory period under stretch. Our observations are in agreement with experimental results and explain the large differences in intra-atrial conduction, as well as the increased inducibility of atrial fibrillation in acutely dilated atria.     

Catheter-Based Renal Sympathetic Denervation Significantly Inhibits Atrial Fibrillation Induced by Electrical Stimulation of the Left Stellate Ganglion and Rapid Atrial Pacing

Background

Sympathetic activity involves the pathogenesis of atrial fibrillation (AF). Renal sympathetic denervation (RSD) decreases sympathetic renal afferent nerve activity, leading to decreased central sympathetic drive. The aim of this study was to identify the effects of RSD on AF inducibility induced by hyper-sympathetic activity in a canine model.

Methods

To establish a hyper-sympathetic tone canine model of AF, sixteen dogs were subjected to stimulation of left stellate ganglion (LSG) and rapid atrial pacing (RAP) for 3 hours. Then animals in the RSD group (n = 8) underwent radiofrequency ablation of the renal sympathetic nerve. The control group (n = 8) underwent the same procedure except for ablation. AF inducibility, effective refractory period (ERP), ERP dispersion, heart rate variability and plasma norepinephrine levels were measured at baseline, after stimulation and after ablation.

Results

LSG stimulation combined RAP significantly induced higher AF induction rate, shorter ERP, larger ERP dispersion at all sites examined and higher plasma norepinephrine levels (P<0.05 in all values), compared to baseline. The increased AF induction rate, shortened ERP, increased ERP dispersion and elevated plasma norepinephrine levels can be almost reversed by RSD, compared to the control group (P<0.05). LSG stimulation combined RAP markedly shortened RR-interval and standard deviation of all RR-intervals (SDNN), Low-frequency (LF), high-frequency (HF) and LF/HF ratio (P<0.05). These changes can be reversed by RSD, compared to the control group (P<0.05).

Conclusions

RSD significantly reduced AF inducibility and reversed the atrial electrophysiological changes induced by hyper-sympathetic activity.     

3D virtual human atria: A computational platform for studying clinical atrial fibrillation

Despite a vast amount of experimental and clinical data on the underlying ionic, cellular and tissue substrates, the mechanisms of common atrial arrhythmias (such as atrial fibrillation, AF) arising from the functional interactions at the whole atria level remain unclear. Computational modelling provides a quantitative framework for integrating such multi-scale data and understanding the arrhythmogenic behaviour that emerges from the collective spatio-temporal dynamics in all parts of the heart. In this study, we have developed a multi-scale hierarchy of biophysically detailed computational models for the human atria - the 3D virtual human atria. Primarily, diffusion tensor MRI reconstruction of the tissue geometry and fibre orientation in the human sinoatrial node (SAN) and surrounding atrial muscle was integrated into the 3D model of the whole atria dissected from the Visible Human dataset. The anatomical models were combined with the heterogeneous atrial action potential (AP) models, and used to simulate the AP conduction in the human atria under various conditions: SAN pacemaking and atrial activation in the normal rhythm, break-down of regular AP wave-fronts during rapid atrial pacing, and the genesis of multiple re-entrant wavelets characteristic of AF. Contributions of different properties of the tissue to mechanisms of the normal rhythm and arrhythmogenesis were investigated. Primarily, the simulations showed that tissue heterogeneity caused the break-down of the normal AP wave-fronts at rapid pacing rates, which initiated a pair of re-entrant spiral waves; and tissue anisotropy resulted in a further break-down of the spiral waves into multiple meandering wavelets characteristic of AF. The 3D virtual atria model itself was incorporated into the torso model to simulate the body surface ECG patterns in the normal and arrhythmic conditions. Therefore, a state-of-the-art computational platform has been developed, which can be used for studying multi-scale electrical phenomena during atrial conduction and AF arrhythmogenesis. Results of such simulations can be directly compared with electrophysiological and endocardial mapping data, as well as clinical ECG recordings. The virtual human atria can provide in-depth insights into 3D excitation propagation processes within atrial walls of a whole heart in vivo, which is beyond the current technical capabilities of experimental or clinical set-ups.     

The role of atrial dilatation in the domestication of atrial fibrillation

Numerous clinical investigations as well as recent experimental studies have demonstrated that atrial fibrillation (AF) is a progressive arrhythmia. With time paroxysmal AF becomes persistent and the success rate of cardioversion of persistent AF declines. Electrical remodeling (shortening of atrial refractoriness) develops within the first days of AF and contributes to the increase in stability of the arrhythmia. However, ‘domestication of AF’ must also depend on other mechanisms since the persistence of AF continues to increase after electrical remodeling has been completed. During the first days of AF in the goat, electrical and contractile remodeling (loss of atrial contractility) followed exactly the same time course suggesting that they are due to the same underlying mechanism. Contractile remodeling not only enhances the risk of atrial thrombus formation, it also enhances atrial dilatation by increasing the compliance of the fibrillating atrium. In goats with chronic AV-block atrial dilatation increased the duration of artificially induced AF-episodes but did not change atrial refractoriness or the AF cycle length. When AF was maintained a couple of days in these animals, a shortening of the atrial refractory period did occur. However, the AF cycle length did not decrease. Long lasting episodes of AF with a long AF cycle length and a wide excitable gap suggest that in this model AF is mainly promoted by conduction disturbances. Chronic atrial stretch induces activation of numerous signaling pathways leading to cellular hypertrophy, fibroblast proliferation and tissue fibrosis. The resulting electroanatomical substrate in dilated atria is characterized by increased non-uniform anisotropy and macroscopic slowing of conduction, promoting reentrant circuits in the atria. Prevention of electroanatomical remodeling by blockade of pathways activated by chronic atrial stretch therefore provides a promising strategy for future treatment of AF.     

Effects of pituitary adenylate cyclase-activating polypeptide on canine atrial electrophysiology

We hypothesized that pituitary adenylate cyclase-activating polypeptide (PACAP) activates intracardiac postganglionic parasympathetic nerves and has a different effect than cervical vagal stimulation. We measured effective refractory period (ERP) and conduction velocity at four atrial sites [high right atrium (HRA), low right atrium (LRA), high left atrium (HLA), and low left atrium (LLA)] and minimum atrial fibrillation (AF) cycle length at 12 atrial sites during cervical vagal stimulation and after PACAP in 26 autonomically decentralized, open-chest, anesthetized dogs. PACAP shortened ERP to a similar extent at all four sites (HRA, 58 +/- 2.0 ms; LRA, 60 +/- 6.3 ms; HLA, 68 +/- 11.5 ms; and LLA, 60 +/- 8.3 ms). Low- and high-intensity vagal stimulation shortened ERP at the HRA, but not in the other atrial sites (low-intensity stimulation: HRA, 64 +/- 4.0 ms; LRA, 126 +/- 5.1 ms; HLA, 110 +/- 9.5 ms; and LLA, 102 +/- 11.5 ms; high-intensity stimulation: HRA, 58 +/- 4.2 ms; and HLA, 101 +/- 4.0 ms). Conduction velocity was not altered by any intervention. Minimum AF cycle length after PACAP was similar in both atria but was shorter in the right atrium than in the left atrium during vagal stimulation. After atropine administration, no interventions changed ERP. These results suggest that PACAP shortens atrial refractoriness uniformly in both atria through activation of intrinsic cardiac nerves, not all of which are activated by cervical vagal stimulation.     

High-density mapping of pulmonary veins and left atrium during ibutilide administration in a canine model of sustained atrial fibrillation

Ibutilide can prolong refractory period and terminate reentry. Whether ibutilide has the same effects on pulmonary vein (PV) focal discharge (FD) is unclear. We induced sustained atrial fibrillation (AF) in seven dogs by rapid left atrial (LA) pacing for 74 +/- 46 days. Ibutilide was repeatedly infused until it terminated AF (0.02 +/- 0.01 mg/kg) or when a cumulative dose was reached (0.04 mg/kg). High-resolution computerized epicardial mapping was performed. We found intermittent FD at the PVs and reentry at the PV-LA junction during AF. Ibutilide increased the cycle length of consecutive reentry from 97 +/- 13 to 112 +/- 18 ms and increased FD from 96 +/- 7 to 113 +/- 9 ms. In four dogs with both FD and reentry at the PVs, the incidence of reentry decreased from 3.5 +/- 1.9/s at baseline to 2.2 +/- 1.8/s after ibutilide administration. However, the incidence of FD remained unchanged. The conducted wave fronts between PV and LA were significantly reduced by ibutilide (10.4 +/- 2.0/s vs. 8.0 +/- 1.6/s). The ibutilide dose needed to terminate AF correlated negatively with the baseline effective refractory period of PV and LA. We conclude that ibutilide reduces reentrant wave fronts but not PV FD in a canine model of pacing-induced sustained AF. These findings suggest that the PV FD during AF is due to nonreentrant mechanisms. High doses of ibutilide may completely terminate all reentrant activity, converting AF to PV tachycardia before the resumption of sinus rhythm.     

Electrical connections between left superior pulmonary vein, left atrium, and ligament of Marshall: implications for mechanisms of atrial fibrillation

The importance of the ligament of Marshall (LOM) to rapid activations within the left superior pulmonary vein (LSPV) during atrial fibrillation (AF) remains poorly understood. We aimed to characterize the importance of electrical coupling between the LSPV with the left atrium (LA) and the LOM in the generation of high-frequency activations within this PV. We performed high-density mapping of the LSPV-LA-LOM junction in eight dogs, using 1,344 electrodes with a 1-mm resolution before and after posterior ostial ablation to diminish PV-LA electrical connections. A LOM potential was recordable up to 6.5 mm (SD 2.2) into the LSPV in all dogs during sinus rhythm (SR) and LA pacing. Functional LOM-LSPV electrical connections bypassing the PV-LA junction were present in five of eight dogs. Direct LOM-LSPV connections contributed to 46.5% (SD 16.0) of LSPV activations during AF, resulting in a greater propensity to develop focal activations (P < 0.05) and a higher activation rate during AF of LSPVs with direct LOM connections compared with those without (P < 0.03). Posterior LSPV ostial ablation without damaging the anterior wall or LOM slowed residual LA-PV conduction (P < 0.001). This diminished PV-LA coupling prevented the reinduction of LSPV focal activations in all dogs. However, persistent LOM focal activations in two dogs continued to activate the LSPV rapidly [cycle length 151.8 ms (SD 4.8)] via direct LOM-LSPV connections. LOM-LSPV connection forms an accessory pathway that contributes to the electrical coupling between LSPV and LA during SR and AF. This pathway may contribute to rapid activations within the LSPV during AF.