Direction-dependent conduction abnormalities in a canine model of atrial fibrillation due to chronic atrial dilatation

Chronic rapid atrial pacing (RAP) leads to changes that perpetuate atrial fibrillation (AF). Chronic atrial dilatation due to mitral regurgitation (MR) also increases AF inducibility, but it is not clear whether the underlying mechanism is similar. Therefore, we have investigated atrial electrophysiology in a canine MR model (mitral valve avulsion, 1 mo) using high-resolution optical mapping and compared it with control dogs and with the canine RAP model (6-8 wk of atrial pacing at 600 beats/min, atrioventricular block, and ventricular pacing at 100 beats/min). At followup, optical action potentials were recorded using a 16 x 16 photodiode array from 2 x 2-cm left atrial (LA) and right atrial (RA) areas in perfused preparations, with pacing electrodes around the field of view to study direction dependency of conduction. Action potential duration at 80% repolarization (APD(80)) was not different between control and MR but was reduced in RAP atria. Conduction velocities during normal pacing were not different between groups. However, the MR LA showed increased conduction heterogeneity during pacing at short cycle lengths and during premature extrastimuli, which frequently caused pronounced regional conduction slowing. Conduction in the MR LA during extrastimulation also displayed a marked dependence on propagation direction. These phenomena were not observed in the MR RA and in control and RAP atria. Thus both models form distinctly different AF substrates; in RAP dogs, the decrease in APD(80) may stabilize reentry. In MR dogs, regional LA conduction slowing and increased directional dependency, allowing unidirectional conduction block and preferential paths of conduction, may account for increased AF inducibility.     

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.     

Mechano-electric feedback and atrial fibrillation

Atrial fibrillation frequently occurs under conditions associated with atrial dilatation suggesting a role of mechano-electric feedback in atrial arrhythmogenesis. Although atrial arrhythmias may be due both to abnormal focal activity and reentrant mechanisms, the majority of sustained atrial arrhythmias have been ascribed to reentrant activity. Atrial stretch may contribute to focal arrhythmias by inducing afterdepolarizations and to reentrant arrhythmias by increasing the atrial surface, by shortening the refractory period and/or slowing the conduction velocity and by increasing their spatial dispersion. Experimental and clinical studies have demonstrated that changes in mechanical loading conditions may modulate the electrophysiological properties of the atria. These studies have, for the most part, involved the effects of acute stretch on atrial refractoriness. While studies in humans and intact animals yield divergent results due to the variety of loading conditions and neurohumoral influences, experimental studies in isolated preparations clearly show that atrial refractory period and action potential duration at early levels of repolarization shorten by acute atrial dilatation. Both experimental and human studies have shown that acute atrial stretch is arrhythmogenic and may induce triggered premature beats and atrial fibrillation.     

Rotigaptide (ZP123) reverts established atrial conduction velocity slowing

Rotigaptide (ZP123) increases gap junction intercellular communication (GJIC) and prevents stress-induced cardiac conduction velocity (CV) slowing. However, the effect of rotigaptide on established cardiac conduction slowing and the duration of effect on rotigaptide during washout is unknown. Metabolic stress (induced by superfusion with nonoxygenated glucose-free Tyrodes buffer) was associated with a 30% decrease in atrial CV in vehicle-treated rat atria. Rotigaptide treatment initiated after a period of 30 minutes of metabolic stress produced a rapid and significant increase in CV compared to vehicle-treated time controls. During washout of rotigaptide for 30 min (while subjected to metabolic stress), there was a minor decrease in atrial CV; however, this was not significantly different from atrial CV in a rotigaptide-treated time control group. Rotigaptide treatment rapidly normalizes established conduction slowing in atria subjected to metabolic stress. However, the cessation of effect was considerably slower than the onset of action.     

Rotigaptide (ZP123) Reverts Established Atrial Conduction Velocity Slowing

Rotigaptide (ZP123) increases gap junction intercellular communication (GJIC) and prevents stress-induced cardiac conduction velocity (CV) slowing. However, the effect of rotigaptide on established cardiac conduction slowing and the duration of effect on rotigaptide during washout is unknown. Metabolic stress (induced by superfusion with nonoxygenated glucose-free Tyrodes buffer) was associated with a 30% decrease in atrial CV in vehicle-treated rat atria. Rotigaptide treatment initiated after a period of 30 minutes of metabolic stress produced a rapid and significant increase in CV compared to vehicle-treated time controls. During washout of rotigaptide for 30 min (while subjected to metabolic stress), there was a minor decrease in atrial CV; however, this was not significantly different from atrial CV in a rotigaptide-treated time control group. Rotigaptide treatment rapidly normalizes established conduction slowing in atria subjected to metabolic stress. However, the cessation of effect was considerably slower than the onset of action.     

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.     

Electrophysiological effects of ethmozine in perfused rabbit hearts

His-bundle electrocardiography was used to evaluate the effects of ethmozine on cardiac conduction in isolated perfused rabbit hearts electrically driven at cycle lengths of 320 and 250 ms. There was no significant change in conduction until high concentrations of ethmozine were reached. His-Purkinje and atrioventricular (AV) nodal conduction were slowed significantly at 0.1 microgram/mL and atrial conduction at 1.0 microgram/mL. Conduction block occurred at 10.0 micrograms/mL in all the hearts treated. Effects of the drug (0.1 and 0.01 microgram/mL) on conduction of extrasystoles were also studied in hearts driven at a basic cycle length of 270 ms. No significant change was observed in atrial conduction of extrasystoles throughout the coupling intervals tested at both concentrations. Ethmozine (0.01 and 0.1 microgram/mL) caused slowing of His-Purkinje conduction of extrasystoles but the effect of the drug did not change as a function of the coupling interval. An interval-dependent increase in AV-nodal conduction time was observed, with the maximum slowing of conduction occurring at coupling intervals close to the effective refractory period of the AV node. AV-nodal functional refractory period was increased significantly by ethmozine (0.01 and 0.1 microgram/mL). The effective refractory period was significantly increased only at the higher concentration.     

Mechanisms of perpetuation of atrial fibrillation in chronically dilated atria

The progressive nature of atrial fibrillation (AF) has been demonstrated in numerous experimental as well as clinical investigations. 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 stability of AF continues to increase after electrical remodeling has been completed. Chronic atrial stretch induces activation of numerous signaling pathways leading to cellular hypertrophy, fibroblast proliferation and tissue fibrosis. The resulting electro-anatomical substrate is characterized by increased non-uniform anisotropy and local conduction heterogeneities facilitating reentry in the dilated atria. Atrial fibrosis may lead to disruption of the electrical side-to-side junctions between muscle bundles. This can result in electrical dissociation between neighboring muscle bundles, i.e. they become activated out-of-phase. Recent mapping studies in goats with persistent AF showed that electrical dissociation can not only occur between neighboring muscle bundles but also in the third dimension, i.e. between the epicardial layer and the endocardial bundle network. Such endo-epicardial dissociation will significantly increase the number of wavefronts which can simultaneously be present in the atrial wall. This article reviews data suggesting a role of endo-epicardial dissociation in dilated and fibrillating atria, for the self-perpetuating nature of AF as well as its possible implications for therapeutic interventions.     

Stretch-induced alterations of human Kir2.1 channel currents

The inward rectifier potassium channel, Kir2.1, contributes to the I(K1) current in cardiac myocytes and is closely associated with atrial fibrillation. Strong evidences have shown that atrial dilatation or stretch may result in atrial fibrillation. However, the role of Kir2.1 channels in the stretch-mediated atrial fibrillation is not clear. In this study, we constructed the recombinant plasmid of KCNJ2 that encodes the Kir2.1 channel and expressed it in CHO-K1 cells. We recorded I(K1) currents using the whole-cell patch clamping technique. Our data showed that I(K1) currents were significantly larger under stretch in the hypotonic solution than under non-stretch in the iso-osmotic solution, and the activation kinetics of the Kir2.1 channel were changed markedly by stretch as well. Thus, atrial stretch in human heart might result in excessive I(K1) currents, which is likely to increase the resting membrane potential and decrease the effective refractory period, to initiate and/or maintain atrial fibrillation.     

Experimental and computational studies of strain-conduction velocity relationships in cardiac tissue

Velocity of electrical conduction in cardiac tissue is a function of mechanical strain. Although strain-modulated velocity is a well established finding in experimental cardiology, its underlying mechanisms are not well understood. In this work, we summarized potential factors contributing to strain-velocity relationships and reviewed related experimental and computational studies. We presented results from our experimental studies on rabbit papillary muscle, which supported a biphasic relationship of strain and velocity under uni-axial straining conditions. In the low strain range, the strain-velocity relationship was positive. Conduction velocity peaked with 0.59 m/s at 100% strain corresponding to maximal force development. In the high strain range, the relationship was negative. Conduction was reversibly blocked at 118+/-1.8% strain. Reversible block occurred also in the presence of streptomycin. Furthermore, our studies revealed a moderate hysteresis of conduction velocity, which was reduced by streptomycin. We reconstructed several features of the strain-velocity relationship in a computational study with a myocyte strand. The modeling included strain-modulation of intracellular conductivity and stretch-activated cation non-selective ion channels. The computational study supported our hypotheses, that the positive strain-velocity relationship at low strain is caused by strain-modulation of intracellular conductivity and the negative relationship at high strain results from activity of stretch-activated channels. Conduction block was not reconstructed in our computational studies. We concluded this work by sketching a hypothesis for strain-modulation of conduction and conduction block in papillary muscle. We suggest that this hypothesis can also explain uni-axially measured strain-conduction velocity relationships in other types of cardiac tissue, but apparently necessitates adjustments to reconstruct pressure or volume related changes of velocity in atria and ventricles.     

Functional mathematical model of dual pathway AV nodal conduction

Dual atrioventricular (AV) nodal pathway physiology is described as two different wave fronts that propagate from the atria to the His bundle: one with a longer effective refractory period [fast pathway (FP)] and a second with a shorter effective refractory period [slow pathway (SP)]. By using His electrogram alternance, we have developed a mathematical model of AV conduction that incorporates dual AV nodal pathway physiology. Experiments were performed on five rabbit atrial-AV nodal preparations to develop and test the presented model. His electrogram alternances from the inferior margin of the His bundle were used to identify fast and slow wave front propagations. The ability to predict AV conduction time and the interaction between FP and SP wave fronts have been analyzed during regular and irregular atrial rhythms (e.g., atrial fibrillation). In addition, the role of dual AV nodal pathway wave fronts in the generation of Wenckebach periodicities has been illustrated. Finally, AV node ablative modifications have been evaluated. The model accurately reproduced interactions between FP and SP during regular and irregular atrial pacing protocols. In all experiments, specificity and sensitivity higher than 85% were obtained in the prediction of the pathway responsible for conduction. It has been shown that, during atrial fibrillation, the SP ablation significantly increased the mean HH interval (204 ± 39 vs. 274 ± 50 ms, P < 0.05), whereas FP ablation did not produce significant slowing of ventricular rate. The presented mathematical model can help in understanding some of the intriguing AV node mechanisms and should be considered as a step forward in the studies of AV nodal conduction.     

Experimental and computational studies of strain–conduction velocity relationships in cardiac tissue

Velocity of electrical conduction in cardiac tissue is a function of mechanical strain. Although strain-modulated velocity is a well established finding in experimental cardiology, its underlying mechanisms are not well understood. In this work, we summarized potential factors contributing to strain–velocity relationships and reviewed related experimental and computational studies. We presented results from our experimental studies on rabbit papillary muscle, which supported a biphasic relationship of strain and velocity under uni-axial straining conditions. In the low strain range, the strain–velocity relationship was positive. Conduction velocity peaked with 0.59 m/s at 100% strain corresponding to maximal force development. In the high strain range, the relationship was negative. Conduction was reversibly blocked at 118±1.8% strain. Reversible block occurred also in the presence of streptomycin. Furthermore, our studies revealed a moderate hysteresis of conduction velocity, which was reduced by streptomycin. We reconstructed several features of the strain–velocity relationship in a computational study with a myocyte strand. The modeling included strain-modulation of intracellular conductivity and stretch-activated cation non-selective ion channels. The computational study supported our hypotheses, that the positive strain–velocity relationship at low strain is caused by strain-modulation of intracellular conductivity and the negative relationship at high strain results from activity of stretch-activated channels. Conduction block was not reconstructed in our computational studies. We concluded this work by sketching a hypothesis for strain-modulation of conduction and conduction block in papillary muscle. We suggest that this hypothesis can also explain uni-axially measured strain–conduction velocity relationships in other types of cardiac tissue, but apparently necessitates adjustments to reconstruct pressure or volume related changes of velocity in atria and ventricles.     

The role of stretch-activated channels in atrial fibrillation and the impact of intracellular acidosis

The incidence of atrial fibrillation correlates with increasing atrial size. The electrical consequences of atrial stretch contribute to both the initiation and maintenance of atrial fibrillation. It is suggested that altered calcium handling and stretch-activated channel activity could explain the experimental findings of stretch-induced depolarisation, shortened refractoriness, slowed conduction and increased heterogeneity of refractoriness and conduction. Stretch-activated channel blocking agents protect against these pro-arrhythmic effects. Gadolinium, GsMTx-4 toxin and streptomycin prevent the stretch-related vulnerability to atrial fibrillation without altering the drop in refractory period associated with stretch. Changes the activity of two-pore K+ channels, which are sensitive to stretch and pH but not gadolinium, could underlie the drop in refractoriness. Intracellular acidosis induced with propionate amplified the change in refractoriness with stretch in the isolated rabbit heart model in keeping with the clinical observation of increased propensity to atrial fibrillation with acidosis. We propose that activation of non-specific cation stretch-activated channels provides the triggers for acute atrial fibrillation with high atrial pressure while activation of atrial two-pore K+ channels shortens atrial refractory period and increases heterogeneity of refractoriness, providing the substrate for atrial fibrillation to be sustained. Stretch-activated channel blockade represents an exciting target for future antiarrhythmic drugs.     

Optimal ventricular rate slowing during atrial fibrillation by feedback AV nodal-selective vagal stimulation

Although the beneficial effects of ventricular rate (VR) slowing during atrial fibrillation (AF) are axiomatic, the precise relationship between VR and hemodynamics has not been determined. We hypothesized that selective atrioventricular node (AVN) vagal stimulation (AVN-VS) by varying the nerve stimulation intensity could achieve precise graded slowing and permit evaluation of an optimal VR during AF. The aims of the present study were the following: 1) to develop a method for computerized vagally controlled VR slowing during AF, 2) to determine the hemodynamic changes at each level of VR slowing, and 3) to establish the optimal anterograde VR during AF. AVN-VS was delivered to the epicardial fat pad that projects parasympathetic nerve fibers to the AVN in 14 dogs. Four target average VR levels, corresponding to 75%, 100%, 125%, and 150% of the sinus cycle length (SCL), were achieved by computer feedback algorithm. VR slowing resulted in improved hemodynamics and polynomial fit analysis found an optimum for the cardiac output at VR slowing of 87% SCL. We conclude that this novel method can be used to maintain slow anterograde conduction with best hemodynamics during AF.     

4:2:1 conduction of an AF initiating trigger

A 44 year old male with idiopathic dilated cardiomyopathy was undergoing persistent atrial fibrillation (AF) ablation. Following antral ablation, AF terminated into a regular narrow complex rhythm. Earliest activation was mapped to a focus in the superior vena cava (SVC) which was conducted in a 2:1 ratio to the atria which in turn was conducted with 2:1 ratio to the ventricles, resulting in an unusual 4:2:1 conduction of the SVC tachycardia. 1:1 conduction of the SVC tachycardia to the atrium preceded initiation of AF. During AF, SVC tachycardia continued unperturbed. Sinus rhythm was restored following catheter ablation of the focus.     

A Three-Dimensional Human Atrial Model with Fiber Orientation. Electrograms and Arrhythmic Activation Patterns Relationship

The most common sustained cardiac arrhythmias in humans are atrial tachyarrhythmias, mainly atrial fibrillation. Areas of complex fractionated atrial electrograms and high dominant frequency have been proposed as critical regions for maintaining atrial fibrillation; however, there is a paucity of data on the relationship between the characteristics of electrograms and the propagation pattern underlying them. In this study, a realistic 3D computer model of the human atria has been developed to investigate this relationship. The model includes a realistic geometry with fiber orientation, anisotropic conductivity and electrophysiological heterogeneity. We simulated different tachyarrhythmic episodes applying both transient and continuous ectopic activity. Electrograms and their dominant frequency and organization index values were calculated over the entire atrial surface. Our simulations show electrograms with simple potentials, with little or no cycle length variations, narrow frequency peaks and high organization index values during stable and regular activity as the observed in atrial flutter, atrial tachycardia (except in areas of conduction block) and in areas closer to ectopic activity during focal atrial fibrillation. By contrast, cycle length variations and polymorphic electrograms with single, double and fragmented potentials were observed in areas of irregular and unstable activity during atrial fibrillation episodes. Our results also show: 1) electrograms with potentials without negative deflection related to spiral or curved wavefronts that pass over the recording point and move away, 2) potentials with a much greater proportion of positive deflection than negative in areas of wave collisions, 3) double potentials related with wave fragmentations or blocking lines and 4) fragmented electrograms associated with pivot points. Our model is the first human atrial model with realistic fiber orientation used to investigate the relationship between different atrial arrhythmic propagation patterns and the electrograms observed at more than 43000 points on the atrial surface.     

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.     

Myocardial gap junctions: targets for novel approaches in the prevention of life-threatening cardiac arrhythmias

Direct cell-to-cell communication in the heart is maintained via gap junction channels composed of proteins termed connexins. Connexin channels ensure molecular and electrical signals propagation and hence are crucial in myocardial synchronization and heart function. Disease-induced gap junctions remodeling and/or an impairment or even block of intercellular communication due to acute pathological conditions results in derangements of myocardial conduction and synchronization. This is critical in the development of both ventricular fibrillation, which is a major cause of sudden cardiac death and persistent atrial fibrillation, most common arrhythmia in clinical practice often resulting in stroke. Many studies suggest that alterations in topology (remodeling), expression, phosphorylation and particularly function of connexin channels due to age or disease are implicated in the development of these life-threatening arrhythmias. It seems therefore challenging to examine whether compounds that could prevent or attenuate gap junctions remodeling and connexin channels dysfunction can protect the heart against arrhythmias that cause sudden death in humans. This assumption is supported by very recent findings showing that an increase of gap junctional conductance by specific peptides can prevents atrial conduction slowing or re-entrant ventricular tachycardia in ischemic heart. Suppression of ischemia-induced dephosphorylation of connexin seems to be one of the mechanisms involved. Another approach for identifying novel treatments is based on the hypothesis that even non-antiarrhythmic drugs with antiarrhythmic ability can modulate gap junctional communication and hence attenuate arrhythmogenic substrates.